CA1340984E

CA1340984E - Peptidylaminodiols

Info

Publication number: CA1340984E
Application number: CA616530
Authority: CA
Inventors: Jay Richard Luly; Dale John Kempf; Jacob John Plattner
Original assignee: Abbott Laboratories
Current assignee: Abbott Laboratories
Priority date: 1986-01-16
Filing date: 1987-01-16
Publication date: 1992-09-08

Abstract

The present application discloses compounds of formula:
(see formula I) wherein R is lower alkyl, cycloalkylmethyl or benzyl;
R' is H, loweralkyl, vinyl or arylalkyl:
P2 and P3 are independently selected from H or an O-protecting group; and P1 is H or an N-protecting group;
or acid addition salts thereof.
The compounds. of the present invention are useful as intermediates for the preparation of renin inhibiting compounds.

Description

1340984 ' PEPTIDYLAMINODIOLS INTERMEDIATES
This is a divisional of copending application S.N. 527,514 filed January 16, 1987.
Technical Field ThE: present invention relates to synthetic intermediates employed in the preparation of compounds which inhibit re:ni.n.

Background A:rt Renin i_s a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself;
(b) a decrease in the blood volume in the body; or (c) a fall in the concentration of sodium in the distal tubules of the kidney.
When the renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. The renin acts on a circulating protein, angiotensinogen, to cleave out ~~ fragment called angiotensin I (AI). AI
x itself has only alight pharmacologic activity_but..after additional c:leavage by a second enzyme. angiotensin converting enzyme (ACE), forms the potent molecule angiotensin I:I (AII)~. The major pharmacological effects !s of All are vasoconstriction and stimulation of the adrenal cortex to release ~aldosterone; a hormone which causes sodium retention. All is cleaved by an aminopeptidaser to form angiotensin III (HIII), which, compared to A:II, is a less potent vasoconstrictor but a more potent ir~ducer of aldosterone release.
Inhibitors of renin have been sought as agents .for control o~~ hypertension and as diagnostic agents for identification, of cases of hypertension due to renin excess.
With these objectives in mind, the renin-angioten.sion system has been modulated or manipulated, is the past, with ACE inhibitors. However.
ACE acts on several substrates other than angiotensin I
(AI), most notably the kinins which cause such 20 desirable s:fde effects as pain, "leaky" capillaries, prostaglandin release and a variety of behavioral and aeurologic ef;Eects. Further, ACE inhibition leads to the accumulation of AI. Although AI has much less vasoconstrictor activity than AII, its presence may 25 negate some o;E the hypotensive effects of the blockade of All synthesis.
Inhibition of other targets in the renin-angiotensin system such as All with compounds such as saralasia can block All activity, but would leave 30 impaired andl perhaps enhance the :~ypertensive effects of HIII.
On the other hand, there are no known side effects which result when renin is inhibited from acting on its substrate. Considerable research efforts have 3;5 thus been carried out to develop useful inhibitors of renin. Past research efforts have been directed to 1 34Q gg 4 renin antibodies, pepstatin. phospholipids and substrate analogs such as tetrapeptides and octapeptides to tridecapeptid~as. These inhibitors either demonstrate poor activith in inhibiting renin production or poor 'S specificity for inhibiting renin only. However, Boger et al. have reported that statine-containing peptides possess potent and specific renin-inhibiting activity (Nature. Vol. 303, p. 81, 1983). In addition, Szelke and co-workers have described polypeptide analogs containing a non-peptide link (Nature, Vol. 299, p. 555, 1982) which also cause potent renin inhibition and show _ a high specificity for this enzyme.
Disclosure of the Invention In accordance with the present invention, there are provided compounds of formula:
OP, P,NH R' :'0 wherein R is loweralkyl, cycloalkylmethyl or benzyl;
R' is H, loweralkyl, vinyl or arylalkyl:
Pz and P3 are independently selected from H or ~5 an O-protecting group: and P~ is H or an N-protecting group; or acid addition salts thereof.
The compounds of the present invention are f0 useful intermediates in the preparation of renin inhibiting compounds of formula:

3a ~ 3 40 9e'~ _ s :LO
J
R3 H Ra A i W. N
:;0 U _ (I) R.1 O ~ RS

wherein A is hydrogen: loweralkyl; arylalkyl: OR10 or SRlQ wherein R10 is hydrogea, loweralkyl or amiaoalkyl: NR11R~2 wherein R11 and R12 are independently selected from hydrogen, loweralkyl, aminoalkyl, cy~anoalkyl and hydroxyalkyl;
Ri3 ~ B Ri3 ~ / B
or . O~ O

whereia H is NFi, alkylamino, S. O, CHZ or CHOH and R13 is lowErralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alksanyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, 5~ (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic;
W is C=O or CHOH;
U is~ CH2 or NR2, provided that when W is CHOH then U is CH2; .
' R1 :ls loweralkyl, cycloalkylmethyl, benzyl', 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, a , a-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R1 is phenoxy, thioyhenoxy or anilino, B is CH2 or CHOH or A
is hydrogen; R2 is hydrogen or loweralkyl; R3 is loweralkyl, loweralkenyl, [(alkoxylalkoxylloweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R4 is loweralkyl, cycloalkylmethyl or benzyl; R5 is vinyl, formyl, hydroxymethyl or hydrogen; R7 is hydrogen or loweralkyl; Ra andR9 are independently selected from OH and NH2; and R6 is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when RS and R7 .are both hydrogen and Re and R9 are OH, the carbon bearing RS is of a "R"
configuration and the carbon bearing R6 is of a "S"
configuration; or pharmaceutically acceptable salts or esters thereof.
3~) The c:hiral centers of the compounds of the invention may have either the "R" or "S" configuration but preferable have an "S" configuration except where noted. The terms "S" and"R" configuration are as .
defined by the IUPAC 1974 Recommendations for Secticn E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
x.

s . 1 3 40 9B 4 The term "N-protecting group" or "N-protected"
as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during syntheaic procedures or to prevent the attack of 'S exopeptidases on the final compounds or to increase the solubility oi: the final compounds and includes but is not limited to aryl, acetyl, pivaloyl, t-butylacetyl, t-butyloxycarbonyl(Hoc), benzyloxycarbonyl (Cbz)or benzoyl groups or an L- or D- aminoacyl residue, which may itself be N-pratected similarly.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 15 sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "loweralkenyl" as used herein refers to a loweralkyl radical which contains at least one 20 carbon-carbon'~double bond.
The term."arylalkyl" as used herein refers to an urisubstituted or substituted aromatic ring appended to an alkyl radical including but not limited to benzyl, 1- and 2-napht:hylmethyl, halobenzyl and alkoxybenzyl.
The i:erm "aminoalkyl" as used herein refers to -NH2 appended to a loweralkyl radical.
The germ "cyanoalkyl" as used herein ref ers to -CN appended t:o a loweralkyl radical.
The 'term "hydroxyalkyl" as used herein refers to -OH appends~d to a loweralkyl radical.
The germ "alkylamino" as used herein ref ers to a loweralkyl radical appended to an NH radical.
The germ "cycloalkyl" as used herein refers to an aliphatic ring having 4 to 7~carbon atoms.
The term "cycloalkylmethyl" as used herein refers to an. cycloalkyl group appended to a methyl ~ ~ 40 98 4 radical, including but not limited to cyclohexylmethyl.
The term "aryl" as used herein refers to a substituted or unsubstituted aromatic ring including but not limited to phenyl, naphthyl. halophenyl and alkoxyphenyl.
The terms "alkoxy" and "thioalkoxy" as used herein refer: to R1~0- and R14S-, respectively, wherein RI4 i;~ a Ioweralkyl group.
The term '''alkenyloxy" as used herein refers to . R1S~ wherein R15 is an unsaturated alkyl group. .
The term "hydroxyalkoxy" as used herein refers to -OH appendEad to an alkoxy radical.
The term "dihydroxyalkoxy" as used herein refers to an alkoxy radical which is disubstituted with ~,5 -OH radicals .
The i~erm "arylalkoxy" as used herein refers to an aryl appended to an alkoxy radical.
The term "arylalkoxyalkyl" as used herein refers to an aryalkoxy appended to a loweralkyl radical.
The term "(thioalkoxy)alkyl" as used herein refers to thioalkoxy appended to a loweralkyl radical.
The term "'dialkylamino" as used herein refers to -NR16R1~ wherein R16 and R1~ are independently selected from loweralkyl groups.
The term "[(alkoxy)alkoxy]alkyl" refers to an alkoxy group appended to an alkoxy group which is appended to a Ioweralkyl radical.
The term "(hydroxyalkyl)(alkyl)amino" as used herein refers to -NR18RI9 wherein R18 is hydroxyalkyl a.nd R1~ is Ioweralkyl.
The term "N-protected aminoalkyl" as used herein refers to NfLR20 is appended to a loweralkyl group, wherein. R20 s an N-protecting group.
The term "alkylaminoalkyl" as used herein .
refers to ~FiR21 appended to a loweralkyl radical, wherein R21 is a loweralkyl group.

_. , . 1 3 4th g8 4 The term "(N-protected)(alkyl)aminoalkyl" as used herein refers to NR20R21, which is appended to a loweralkyl radical, wherein R20 and R21 are as def fined above .
The term "dialkylaminoalkyl" as used herein refers to :DTR22R23 is appended to ' a Ioweralkyl radical wherein R22 and R23 are independently selected from loweralkyl.
The i:erm "(heterocyclic)alkyl" as used herein 1.0 . refers to a heterocyclic group appended, to a loweralkyl radical, including but not limited to imidazoylalkyl. . °
The i:erm "'0-protecting group" as used herein refers to .a substituent which protects hydroxyl groups and includes but is not limited to substituted methyl 15 ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and tehahydropyranyl; substituted ethyl ethers, for example, 2,2"2-trichloroethyl, t-butyl, benzyl and triphenylmethy:l; silyl ethers, for example.
trimethylsilyl, t-butyldimethyls~lyl and t-butyldipheny:lsilyl; cyclic acetals and ketals, for example, meth~~lene acetal, acetonide and benzylidene ~acetal; cyc:Lic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates.
The term ":heterocyclic ring" or "heterocyclic"
as used herein ref ers to any 5-, 6-, 9- or 10- membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; having various degrees of unsaturation; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized; wherein the nitrogen heteroatom may optionally .
be cruaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the 3!i heteroatom are preferred. Fully saturated heterocyclics X.

s 1 3 4Q 98 4 are also preferred. Preferred heterocyclics are:
pyrryl, Fyrrvlinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl~ oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiaxolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazoly:l, benzothiazolyl, benzoxazolyl, furyl, .10 thienyi and bE~nzothienyl.
Saturated heterocyclics-may be unsubstituted or monosubstitutE~d with hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl. Unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, :15 amino, alkylanaino, dialkylamino or loweralkyl.
The most preferred heterocyclics are as follows:
_! _! _ _! _ N ~ t I
N N N
s s OH
O OH
OH
\ \ N ~ HO
vN ~ / ' I / ' ~~X~ zO ' /~X~ 2);
/ -N /'N
wherein n is 7; or 2 and X is N, NH, O, S, provided that X is the point: of connection only when X is N, Y
Y
0 wherein Y is NH, N-loweralkyl, 0, S, or S02, or X

Z' ~ , Z=' O ~ ~ O ,.
wherein Z1 is N, 0, or S and not the point of connection arid Z2 is N when it is the point of connection anti NH, O or S when it is not the point of connection.
The terms "Ala", "His", "Leu", "Phe", "Tyr", "Cys", "Gly", "Lys", Sar" and "Pro" as used herein refer to alamine, histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine, sarcosine and proline, l~p respectively.
Most of the compounds of the invention may be made as shown in Scheme I. The amino diol intermediate 5 represents a transition-state mimic for the Leu-Val scissile bond of the renin substrate, angiotensinogen.
Incorporation of this amine into the angiotensinogen sequence in place of Leu-Val Ile-Protein provides potent inhibitors of human renin. For example, acylation of amine 5 with. an acyl-Phe-His-OH residue or other appropriately modified amino acid derivatives produces 2p small peptide analogues which are potent renin inhibitors.
.. ~~ '.

a~' IZ
N

~
IV

Q

O

C
.

V
m O

d i -(r C
m t LL o m m N

C
m C

' ~ ~r ~

s ~

a o >

a E

o , o m ~

_ C
m C O L

N t0 .- D N N N tll M ) ~ ~
C

X
/ a ac oc x a a Morn particularly, the process shown in Scheme I discloses an N-protected-aminoaldehyde 1 (P1 is an N-protecting group) which is treated with an glide to give the corresponding allylic amine 2. Oxidation gives diol 3 (PZ and P3 are, both hydrogen).
N-deprotection gives ~; and free-basing gives amine 5.
Either intermediate 4 or S can be converted to 7 by standard peptide coupling methods. The same sequence (3 - 7) can be carried out with hydroxy protecting :LO groups present (where P2 and/or P3 are 0-protecting groups), thEr final step then being 0-deprotection.
Alternatively, allylic amine 2 may be N-deprotected, peptide coupled using standard methods to give 6, and then oxidized to give the desired peptide diols _7.
:LS The protected aminodiol fragment may be alternatively prepared as shown in Scheme II. Aldehyde 9 (prepared, for example, by oxidation of alcohol 8) is converted ta~ its cyanohydrin 10. Addition of an organometallic reagent (such as a Grignard reagent) and >0 acidic workuF~ provides ketone 12. Reduction of ketone 12 then provides the desired protected- aminodiol 13.
a 13 1340gg4 The following Examples will serve to further illustrate preparation of the novel compounds of the invention.
- Example 1 2(S)-t-Hutyloxycarbonvlamino-1-cyclohexylbut 3 ene A 0°C solution of potassium hexamethyl-disilazide (22.9 mmol in 115 mL of 5:1, tetrahydrofuran (THF): dimethYl sulfoxide (DMSO) was added dropwise to triphenylmeth~rlphosphonium iodide (26.81 mmol). After :LO stirring at 0°C fox 1 hour, the solution was cooled to -78°C and a solution of Hoc-cyclohexylalaninal (4.90 g, 19.08 mmol, p;~epared by Swern oxidation (Mancuso, A.J.;
Huang " S.-L.; and Swern, D., J. OrQ. Chem. 19?8, _43, 2480) of Hoc-~:yclohexylalaninol~ in dry THF (95 mL) was added. After stirring at -?8°C for 1 hour, the mixture was allowed to warm to room temperature. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ether (2x300 mL). The combined organic phase was washed with 10% HC1 (200 mL), saturated 20 NaHS03 (2x2a~0 mL), H20 (2x200 mL), saturated NaHC03 (2x200 mL), and brine (200 mL), dried (MgSO~), filtered, and evaporated. The residue was purified by chromatography (40 m Si02; ether: hexane, 15:85) to giver the desired compound in 60% yield. Mass 25 spectrum: (M+.H)+ ~ 254.
Example 2 Hoc-Phe-Ala Amide of (2S)-Amino-1-cyclohexylbut-3-ene The resultant compound of Example 1 (310 mg, 1.22 mmol) w,as dissolved in 1 M anhydrous HC1 in anhydrous methanol 1;35 mL). After 22 hours, the solvent was evaporated to give 230 mg (99%) of the corresponding amine hydrochloride which was used without further purification.

1~ 134pg84 To :~ stirred -13°C solution of Boc-Phe-Ala (408 mg, 1.21 mmol) in dry THF (8 mL) containing N-methylmorpholine (122 mg, 1.21 mmol) was added isobutyl chloroformate (165 mg, 1.21 mmol) dropwise.
After 3 minutes, a -i3°C solution of the above amine hydrochloride (230 mg, 1.21 mmol) in 1:1, THF:dimethyl formamide (D~I~') (4 mL) containing N-methylmorpholine (122 mg) was added dropwise. The mixture was warmed to room temperature for 2 hours. Evaporation provided a residue which was partitioned between ethyl acetate (30 mL) and 0.1 M H3F0! (10 mL). The organic phase was washed with brine (10 mL), saturated NafiC03 (10 mL), and brine (10 mL). Drying, filtering, evaporating, and chromatographing (55 g Si02; 95:5. CH2C12:CH3~H) LS gave the desi:ced compound (462 mg, 81~).
Example 3 -Ala Amide of 3(S)-Amino-4-cvclohexvi-;t0 To a stirred solution of the resultant compound of Example 2 (100 mg, 0.212 mmol) in THF (5 mL) were added OsO~ solution (0.065 mL of a 2.5 W/V~ solution in t-butanol) and N-methylmorpholiae N-oxide (57 mg, 0.424 mmol) sequentially. After 4.5 hours, brine (10 ;s mL) was added, and the mixture was extracted with ether (4x8 mL). Tree combined organic phase was washed with 10~ Na2S03 (3 x 6 mL), 0.1 M H3P0~ (5 mL), and brine (5 mL). Drying, filtering, and evaporating provided the desired product (97 mg, 91~). Mass spectrum: M+ » 505.
F.x amp 1 a 4 Sit-Butyloxycarbonylamino-4-cvclohexvl-an To a stirred solution of 2(S)-t-butyloxy-carbonylamino-1-cyclohexylbut-3-ene (1.00 g, 3.95 mmol) 15 ~34pgg4 , in THF (20 mL) were added Os04 solution (1.2 mL of a 2.5 W/V~ solution in t-butanol) and N-methylmorpholine N-oxide (1.07 g, 7.90 mmol). After 24 hours, the mixture was partitioned between ether (50 caL) and brine (25 mL). The layers were separated, and the organic phase was e:~ctracted with ether (3 ° x 25 mL) . The combined organic phase was washed with 10~ Na2S03 (4x10 mL), 1.0 M H3P04 (2x8 mL), and brine (15 mL).
Drying and e'raporating provided the desired product as 7.0 an oil (1.14 g, 100 0 . 'H NMR shows a 1:1 mixture of diastereomers (NH 4.~3 and 4.56 ppm).
Example 5 Hoc-Phe-His Amides of 3(S)-Amino-4-cyclohexyl-15 2 R,S -yydroxy-1-t-butyldimethylsilyloxybutane The resultant compound of Example 4 (1.10 g, 3.82 mmol) ways treated with anhydrous 1M HCl/CH30H (80 mL) for 16 hours at which time evaporation and drying provided the corresponding amine hydrochloride (0.85 g, 1000.
To a suspension of the above hydrochloride salt (344 mg, 1.54 Col) and imidazole (105 mg) in dichloromethane (15 mL) were added triethylamine (156 mg) and t-butyldimethylsilyl chloride (232 mg). The 25 solvent was evaporated after 31 hours, and the residue was then re-dissolved in anhydrous dimethylformamide (DMF, 15 mL). Hoc--Phe-His (619 mg) and 1-hydroxybenzo-triazole (HOHT~, 312 mg) were then added. After cooling the stirred solution to -23°C, 1,3-dicyclohexyl-30 carbodiimide (DCC, 318 mg) was added. The mixture was warmed to ro«m temperature 3 hours later. After 13 hours the solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate (40 mL), filtered, washed with saturated NaHC03 (2x10 mL) and 35 brine (10 mL), and dried (Na2S0~). Filtration and evaporation provided a residue which was chromatographed 1 3 4p g$ 4 , on silica <lel eluting with dichloromethane/methanol mixtures to give 441 mg (42~) of the desired product.
Mass spectrum: (M+H)+ = 686.
Anal. calcd. for C36H59N506Si:
C. 63.0: H, 8.7; N, 10.2. Found: C.r62.8; H, 9.0; N, 9.9.
Example 6 ides of 3(S)-Amine-4-w~loha~t-To a. stirred solution of the resultant product of Example 5 (200 mg, 0.291 mmol) in anhydrous THF (5 mL) at 0°C was added tetrabutylammonium fluoride (0.58 mL of a 1 M solution in THF). The solution was warmed to room temperature for 4 hours and then evaporated.
The residue was dissolved in chloroform and washed with water (3X) and brine (iX). Drying and evaporating provided a giun which was treated with hot ethyl acetate (8 mL). Cooking and filtration provided 25 mg of the desired material. Mass spectrum: (M+H)+ = 572.
Anal. Calcd for C30H45N5O6 1/2H20: C, 62.1; H, 8.0; N. 12.1. Found: C. 62.4; H,.8.2; N, 12Ø
Example 7 4S -2,8-Dimethyl-4-((toluenesulfonylZamino7 5-nonanone To a stirred -78°C solution of toluenesulfonyl (Ts)-Leu (15 g, 53 mmol) in dry THF (240 mL) was added butyl lithium (57.8 mL of a 0.91 M_ solution in hexane) followed 15 minutes later by isopentyl magnesium bromide (185 mL of a 0.8 M solution in THF). The mixture was heated at reflux for 3 days, then cooled and poured into 0°C 1 M HC1 (;500 mL;) . The layers were separated and the aqueous phase was extracted with ether (3x150 mL). The combined org,3nic layers were washed with saturated NaHC03 (2x150 mL) and brine (150 mL). Drying and 17 .1 34p 9g 4 .' evaporating provided a residue which was chromatographed on silica c~el to give 7.43. g (41%) of the desired product. Mass spectrum: (M+H)+ - 340.
Anal. calcd, for C18H29N03S: C, 63.7; H, 8.6; N, 4.1. Found: C, 64.0; H, 8.6; N, 4.1.
Example 8 4S)-2,.8-Dimethyl-5-hydroxy-4-((toluenesulfonyl ammo]-5-vinvlnonane To a stirred 0°C solution of the resultant compound .of Example 7 (79 mg, 0.23 mmol) in dry THF
(8 mL) was added vinyl magnesium bromide (1.5 mL of a 1.0 M solution in THF) dropwise. The mixture was. warmed (room temperature, 10 hours), quenched (8 mL H20 +
1,5 2 mL brine), acidified with 0.1 M H3P04 (pH=7), and extracted with ether (3 x 4 mL). The combined ether phase was washed (4 mL brine), dried (Na2S04), filtered, and evaporated to give 81 mg (95%) of the desired product as a 4:1 mixture of diastereomers.
Example 9 Boc-Phe-Ala Amide of (4S)-Amino-2,8-dimethyl 5-hvdroxv-5-vinvlnnnanA
To a solution of the resultant compound of Ex~Ple 8 (400 mg, 1.09 mmol) in liquid ammonia (80 mL) was added sodium ( 150 mg, 6 . 5 mmol ) . After 6 hours the ammonia was allowed to slowly evaporate under a stream of nitrogen. Benzene (50 mL) and 1:1, ethanol: water (20 mL) were added with stirring. The layers were separated, and the aqueous phase was extracted with ether. The combined organic phase was dried (Na2S04), filtered, and evaporated to give 85 mg (37%) of the desired product.
Foll~~wing the procedure of Example 2, but replacing the amine hydrochloride and N-methylmorpholine with the abovE~ resultant product, gave the desired major is ~ 1 3 40 9g 4 diastereomer in 35% yield after chromatography. FAH
mass spectrum: (M+R)+ - 570.
Anal. calcd. for C30H49N305: % C, 67.8;
H, 9.3; N, 7.5~. Found: C, 67.7; H, 9.6; N, 7.3.
Example 10 .
Boc-Phew-Ala Amide of (3S)-Amino-2-hydroxy-2 isopentyl-5-methylhexanal Following the procedure of Example 3 with the resultant compound of Example 9 except replacing N-methylmorpholine N-oxide with aqueous NaI04 gave the desired compound.
Example 11 Hoc-Phe_-Ala Amide of 3-Amino-1,2-dihydroxy 2-iso entyl-5-methylhexane Treatment of the resultant compound of Example 10 w:~th one equivalent of NaBH4 in methanol provided the <iesired compound after aqueous work-up.
Example 12 Boc-Ph_e-Ala Amide of 3-Amino-1,2-dihydroxy-2-isopentyl-5-methylhexane ScaIE~ up of the procedure of Example 8 led to the isolation of the minor diastereomer pure after ZS chromatograph;i. Treatment as in Examples 9, 10, and 11 provided the desired isomer of the resultant product of Example 11.
Example 13 2(S)-1~-Butyloxycarbonylamino-1-cyclohexyl-6-methvlhe~t-3-ene To a stirred -78°C solution of Boc-cyelohexy:lalanine methyl ester (40 g, 140 mmol) in anhydrous toluene (250 mL) was added diisobutylaluminum hydride (130 M%. 1.5 M solution in toluene, 121.4 mL) at a rate to keep the internal temperature below -60°C.
After stirring for an additional 20 minutes at -78°C, the aldehyde solution is used immediately as described below.
To <i potassium hydride (35%'dispersion in oil, 32.09 g) suspension in a 0°C mixture of anhydrous THF/DMSO (1(100 mL/200 mL) under dry N2 was added 1,1,1,3,3,3-h.examethyldisilazane (209 M%, 49.07 g) dropwise. After stirring at 0°C for 1 hour, the resulting so7.ution was added via cannula to a 0°C flask containing :isopentyltriphenylphosphonium bromide (209 M%, 125.66 g). .The mixture was stirred vigorously for 1 hour at which time it was cooled to -78°C. The -78°C
aldehyde solution prepared above was then added via cannula. After stirring at -78°C for 15 minutes, the mixture was allowed to slowly warm to room temperature and then heated to 40°C for 12 hours. The mixture was then cooled to~ room temperature and quenched with methanol (7.65 mL:) followed by aqueous Rochelle salts (100 mL sat.urated solution and 500 mL H20). The mixture was i:hen extracted with ethyl acetate (2x). The combined extracts were washed with water and brine.
Drying (MgS04) and evaporating provided crude alkene which was cr~romatographed on silica gel (ether/hexane) to give 16.5 g (38%) of the desired compound as an 85:15 mixture of cis:trans isomers. Mp=53-55°C. Mass spectrum: M~~ =309.
Anal,. calcd, for C1gH35N02: C, 73.7; H, 11.4; N, 4.5. Found: C, 73.8; H, 11.4; N, 4.5.
. Example 14 2 S)-t-~Butyloxycarbonylamino-1-cyclohexyl-3,4-dihvdroxy~-6-methylheptane: The 3(R)4(S); 3(S)4(S
To a solution of the resultant compound of Example 13 (8.50, 27.5 mmol) in dry THF (150 mL) were r added Os04 (2..8 mL of a 2.5~ solution in t-butanol and N-methylmorphol.ine N-oxide (9.28 g, 68.7 mmol). After 4 days the mixture was partitioned between ether (200 mL) and brine (100 mL). The aqueous layer was back-'S extracted witri ether (2x100 mL), aid the combined organic phase was washed with 10~ Na2S03. 0.1 M
H3P04, and brine. Drying (MgS04) and evaporating provided a re:>idue (10.81 g) which was chromatographed on -silica gel t:o elute a 60~ yield of the 4 diols in the :LO following order.
3 R ~~ Mass spectrum: (M+H)+ _ 344.
Anal. calcd. for Ci9H37N04: C' 66.4; H, 10.9; N, 4.1. Found: (:, 66.4: H. 10.8; N, 3.9.
3 S ~~ Mass spectrum: (M+H)+ = 344. Anal.
calcd. for Ci9H37N04: C, 66.4; H, 10.9; N, S.l.
Found: C' 66.4,; H, l:l.i: N, 4Ø
3 R ~~ Mass spectrum: (M+H)+ = 344.
3 S ~~ Mass spectrum: (M+H)+ = 344. Anal.
calcd. for Ci9H37N04: C, 66.4: H, 10.9; N, 4.1.
20 Found: C' 66.0,; H, 10.7; N, 4Ø
Example 15 Boc-Phe-His Amide of 2(S)-Amino-i-cyclohexYl-The :I(R),4(S) diastereomer of Example 14 was ' deprotected with HC1/methanol, and the resulting product was coupled to Boc-Phe-His using 1-hydroxybenzo-triazole and 1,3-dicyclohexylcarbodiimide according to the procedure of Example 5. The desired product was obtained in 40~-60~ yield. Mass spectrum: (M+H)+ = 628.
Anal. cal.cd. for C34H53N506 H20~ C, 63.2: H, 8.6: ;N, 10.8. Found: C, 63.2: H, 8.4; N, 10.5.

Example 16 ide of 2(S)-Amino-1-cvclohexvl-Following the procedure of Example 15, but replacing the 3(R).~(S) diastereomer with the 3(S).4(S) diastereomer gave the desired compound. Mass spectrum:
(M+H)+ = 628.
Anal.. calcd. for C3~H53N506 1/2H20:
C. 64.1; H, 8.6: N. 11Ø Found: C. 64.0; H. 8.6: N, 10.6.
Exam Ip a 17 -Ph~e-His Amideof 2(S)-Amino-1-cvclohexvl-~sm .~wr-amyaroxy-6-mecnylneptane n Following the procedure of Example 15, but replacing thin 3(R).4(S) diastereomer with the 3(R),4(R) diastereomer gave the desired compound. Mass spectrum:
(M+H)+ = 628.
Anal. calcd. for C34H53N5C6 H2W C.
63.2; H. 8.6; N. 10.8. Found: C. 63.1: H, 8.5: N. 10.7.
Example i8 -Ph~a-His Amide of 2(S)-Amino-1-cvclohexvl-Following the procedure of Example 15, but replacing they 3(R),~1(S) diastereomer with the 3(S),4(R) diastereomer gave the desired compound. Mass spectrum:
(M+H)+= 628.
Anal. calcd. for C34H53N5C6 3/4H20:
C. 63.7; H. 8.6; N. 10.9. Found: C. 63.8: H. 8.8: N.
10.7.

Example 19 ~ 3 4 ~ 9 8 4 A. 4(S)-t-Butyloxycarbonylamino-5-cvclohexvl-ene To a stirred -78°C solution of Hoc-cyclohexylalanine methyl ester (10.2 g, 35.8 mmol) in dry toluene (60 mL) was added diisobutylaluminurn hydride (34 mL of a 1.5 M solution in toluene). After 30 minutes, vinyl magnesium bromide (108 mL of 1 M_ solution in THF) was added. After stirring for 15 hours ' 10 at 0 °C, thE~ mixture was careful ly quenched ~ with methanol, treated with Rochelle salts (22 mL of saturated aqueous solution in 140 mL H20), and filtered. After extracting the solids 5 times with ethyl acetate, the extracts and filtrate were combined and the organic phase was washed with brine, dried, filtered, and evaporated to an oil (10.2 g).
Chromatograph:Y on silica gel eluting with hexane/ethyl acetate mixtures provided 6.1 g (60%) of the desired product.
Anal. calcd. for C16H29N03 1/4H20: C, 66.8; H, 10.3; N, 4.9. Found: C, 66.9; H, 10.2; N, 4.7.
H. _4;S)-Cyclohexylmethyl-5(R,S)-vinyl-2 oxazolidinone The resultant product of Example 19A (2.80 g, 9.88 mmol) in dry dimethylformamide (DMF) (50 mL) was added to a starred suspension of NaH (593 mg of a 60%
dispersion in oil, 14.8 mmol, hexane washed) in dry DMF
(50 mL). After 3 :hours, the mixture was quenched (750 mL water + 100 mL brine) and extracted with ether (5x100 ~). ~e combined organic phase was washed with brine (3x50 mL), d:ried I;MgSO4), filtered, and evaporated to an oil 2.23 c~. The NMR spectrum of the crude product revealed an 82:18 mixture of 5 S:5 R diastereomers.
Silica gel chromatography gave 80% recovery of pure diastereomers. 5 S:
Anal. calcd. for C12H19N02: C~ 68.9; H.
9.1; N, 6.7. Found: 68. l; N, 9.2; N, 6.5. Mass spectrum: (M+1)+ ~~ 210. 5 R: Mas s spectrum: (M+1)+
= 210.
C. 5 R -Carboxy-!(S)-cyclohexylmethyl-2-oxazolidinone To a solution of the compound from Example 19H
( 1 g, ! . 78 m~nol ) di ssolved in 16 mL of benzene and 3 mL
of acetic acid was added a solution of 3.01 g of potassium pernnanganate in 16 mL of water. The resultant two-phase mixture was vigorously stirred and treated by portionwise addition with 153 mg of tetrabutylammonium bromide. After stirring for 2 hours at room temperature, the ,mixture was quenched with aqueous sodium bisulfj.te, acidified to pFi=3, and extracted with ethyl acetate.. Drying and evaporating gave the desired product as an oil in 59~ yield.
D. !(S)-Cvclohexylmethvl-5(R)-(3-(3-l~droxmentyl) -2-oxazolidinone To a solution of the compound from Example 19C
dissolved in tetrahydrofuran and cooled to -78°C was added 3.5 equivalents of ethyl magnesium bromide. After stirring at -i~8°C for 1.5 hours and at room temperature for 1 hour, the reaction mixture was quenched with water r and extracted with ether. The dried ethereal extract was evaporated to afford a 73~ yield of product.
E. 2(S)-Amino-1-c~rclohexyl-3(R)-3,4-dihydroxy-!-ethylhexane A solution of the compound from Example 19D
(1.69 mmol) and barium hydroxide octahydrate (3.38 mmol) in dioxane (60 mL) and water (40 mL) was heated at reflex under N2 for 21 hours. The solid barium carbonate was filtered and the filtrate was partially ~'~4~984 evaporated. The residue was diluted with water and the resulting solution was extracted with ether. The organic extr:pct was washed with brine solution, dried over MgS04, and evaporated to give the desired product in 76~ yield. s .
F. Boc-P:he-His Amide of 2(S)-Amino-1-cvclohexvi-The resultant product of Example 19E was coupled to 8oc-Phe-His using 1-hydroxybenzotriazole and 1,3-dicyclohe:ECylcarbodiimide according to the procedure of Example 5 vto give the desired product in 55~ yield.
Example 20 ( ~ Boc-His Amide of 2(S)-Amino-1-cyclohexyl-3~R~,4(S)-dihydroxy-6-methylheptane The procedure of Example 15 was followed except Boc-Phe-His was replaced with Hoc-His. Mass spectrum:
(M)+ = 480.
Ana l, calcd. for C25H44N405 3/4H20:
C. 60.8; H, 9.1; N, 11.3. Found: C, 60.9; H, 9.2: N, 11Ø
Example 21 TBA-CHA-His Amide of 2(S)-Amino-1-cyclohexyl-»w ~te»;~..a~,.,..._~__~~~,..,t,._~___ The resultant compound of Example 20 was deprotected w9lth HC1/methanol, and the resulting product was coupled to t-butylacetyl-cyclohexylalanine (THA-CHA) using the DCC/HOHT method of Example 5. HRMS
calcd. for C35H61N505' (M+H) 632.4751. Found:
632.4759.

. 1340984 z~s Example 22 Ami arDOrlY1-cocx~)Tvr-His Amirla of ~re1_ Using the procedure of Example 21, but replacing TB~~-CHA with ethoxycarbonyl-f~OCH3)Tyr-His gave the desired compound. Mass spectrum: (M+H)+ ~ 630.
Example 23 a-His Amide of 2(S)-Amino-1-Using the procedure of Example 21, but replacing T~3A-CHA with acetyl-N-methylPhe gave the desired compound. Mass spectrum: M+ ~ 583.
Example 24 Ac-P1--His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 21, but replacing THA-CHA with 0-acetyl-L-3-phenyllactic acid (Ac-P1-OH) gave the desired compound. HRMS calcd. for C31H46N406' (M+H) 571.349s. Found: s71.3489.
Example 2s 1-His Amide of2~S)-Amino-1-cvclohexvl-3(R).4(S)-_ __ __~ _____ ' The resultant compound of Example 24 (37.4 mg, 0.06s mmol) in MeOH at 0°C was treated with R2C03 (9.1 mg, 0.065 mmol) for 30 minutes at 0°C. Evaporation provided a residue which was partitioned between ethyl acetate and water. The organic phase was washed (brine). dried (MgS04), and evaporated to give the desired compound (32 mg, 93~). Mass spectrum: (M+H)+
= 529.
Anal. calcd. for C31H46N406 1~2H20:
C. 64.8; H, 8.4; N, 10.4. Found: C. 64.6: H, 8.3: N, 10.1.

Example 26 Boc-1-N;31-His Amide of 2(S)-Amino-1-cyclohexyl ~R ,4S8)-dihydroxv-6-methvl-heotane Using the procedure' of Example 21, but replacing TB~~-CHA with Boc-1-naphthylalanine (Boc-1-Nal).
provided the desired compound. Mass spectrum: (M+H)+
= 678.
Example 27 Dba-Ftis Amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane Using the procedure of Example 21, but replacing TBA-CHA 'with 2,2-dibenzylacetic acid (Dba-OH) gave the desired compound. HRMS calcd. for C36H50N4C4' (~K+H) 603.3910. Found: 603.3899.
Example 28 Pp-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane Usin~~ the procedure of Example 21, but replacing TBp,-CHA with 3-phenyl-propionic acid (Pp-OH) gave the desired compound. Mass spectrum: (M+H)+ -513.
Anal, calcd. for C29H44N404 1/2 H20:
C, 66. 8: H, F3. 7. , N, 10 .7. Found: C, 66. 6; H, 8. 8; N, 10.5.
Example 29 Ethoxycarbonyl-Phe-His Amide of 2(S)-Amino-1 cyclohexYl-3(R),4(S)-dihydroxy-6-ethylhe tane Using the procedure of Example 21, but replacing TB~4-CHA with ethoxycarbonyl-Phe gave the desired produca. Mass spectrum: (M+H)+ - 600.
Anal. calcd. for C32H49N5~6 1/2H20:
X

. 1340984 C, 63.1; H, 8.3s N, 11.5. Found: C, 62.8; H, 8.3: N, 11.4 Example 30 ide of 2(S)-Amino-lrcvclohexvl-Using tha procedure of Example 21, but replacing TBa~-CHA with acetyl(Ac)-Phe gave the desired product. Mass spectrum: (M+H)+ = 570.
Anal. calcd. for C31H47N5~5 1/2H20:
C, 64.3: H, 8.2; N, 12.1. Found: C, 64.2: H, 8.3: N, 12Ø
Example 31 c Boc-Leu-His Amide of 2(S)-Amino-1-cvclohexyl-31;R),4(S)-dihvdroxv-6-methvlhe~tane Using the procedure of Example 21, but replacing T13A-CHA with Boc-Leu gave the desired product. Mass spectrum: (M+H)+ = 594.
Anal. calcd. for C31H55N5~6 1/2H20:
C, 61.8; H, 9.4; L~, 11.6. Found: C, 61.8; H, 9.3; N, 11.6.
Example 32 -His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 21, but replacing ~THA-CHA with t-butyl-aminocarbonyl-Phe (Tbac-Phe) gave the desired product. Exact mass calcd for C34H55N6~5' 627.4233. Found: 627.4226.
Example 33 Boc-PhE~~-Ala Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of 2, but replacing the resultant compound of Example 1 with the 3(R),4(S) diastereomer of Example 14 gave the desired compound.
Mass spectrum: (M-H)+ = 560.
Anal. ca:lcd. for C3IHSiN3~6' C~ 66.3:
H, 9.1; N, 7.5. Found: C, 66.0; H, 9.2: N, 7.3.
Example 34 Boc-Phe~-Phe Amide of2(S)-Amino-1-cvclohexvl-Usin<~ the procedure of Example 33, but replacing Boc~-Phe-A:la with Boc-Phe-Phe, gave the desired product. Masr spectrum: (M+H)+ = 638.
Ana l, calcd. for C37H55N306: C, 69.7;
H. 8.7; N, 6.1i. Found C, 69.4: H, 8.8; N, 6.5 Example 35 Boc-Phe--PAla Amide of 2(S)-Amino-1-cvclohexvl-an Using the procedure of Example 33, but replacing Boc:-Phe-Ala with Boc-Phe-(3-pyrazoyl)alanine (Boc-Phe-PAla)~, gave the desired compound. Mass spectrum: (M+FI)+ = 628.
Anal. calcd, for C34H53N5~b 1/2H20:
C. 64.1; H, 13.5; N, 11Ø Found: C, 64.1: H. 8.3: N, 11.2.
Example 36 Ethoxy~~arbon~l-Phe-Leu Amide of 2 1-CVCIChe~xvl-3(R) .4(S)-AShv~rn~rts-~-n Using' the procedure of Example 33, but replacing Soc-~Phe-Ala with Boc-Phe-Leu, gave the desired compound. Mass spectrum: (M+H)+ ~ 576.
. Anal. calcd. for C32H53N3~6' C~ 66.7;
H. 9.3: N, 7.3. Found: C, 66.4; H, 9.5; N, 7.2.

Example 37 ino-1-cvclohexvl-Using the procedure of Example 33, but replacing Boc:-Phe-Ala with Boc-Phe-(SCH3)Cys, gave the desired compound. bass spectrum: (M+H)+ = 608.
Anal. calcd. for C32H53N306S' C, 62.8;
H, 8.8; N, 6.'9. Found: C, 62.8; H, 8.9; N, 6.6.
~~ple 38 s-(N Me,Nr~Bn)-His Amide of 2(S)-Amino-1-Usin~~ the procedure of Example 20, but replacing eoc~-His with (N tosyl, N methyl, N imidazole benzyl)-His (Ts-(N Me,NIMBn)-His) (DuVigneau, V.;
Behrens, O.R. J. 8iol. Chem. 1937, 117, 27), gave the desired compound. Mass spectrum: (M+H)+ = 639.
Example 39 . Ethoxycarbonyl-Phe-MeNis Amide of 2(S)-Amino-1-To a stirred -78°C solution of the resultant compound of Example 38 (100 mg, 0.156 mmol) in liquid NH3 (5 mL) auzd dry tetrahydrofuran (5 mL) was added sodium until a dark green/brown color persisted for 5 minutes. Sol'.id, powdered NHlC1 was then added, and the mixture was evaporated. The residue was suspended in water and extracted several times with chloroform.
The combined extracts were dried (Na2S0!), filtered.
and evaporated to give the Mefiis amide of 2(S)-amino-1-cyclohexyl-a(R),!(S)-dihydroxy-6-methylheptane. The material was coupled to ethoxycarbonyl-Phe using to DCC/H08T method described in Example 5 ~to give the desired produces. Mass spectrum: (M+H)+ = 61l.

Example 40 _-t-Hutyloxycarbonylamino-1-cvclohexvl-Usir.~g the procedure of Example 13, but 5 replacing isopentyltriphenylphosphonium bromide with ' isohexyltripr~enylpr~osphonium bromide, gave the desired product.
Example 41 10 2 S -~t-Hutyl~carbonylamino-1-cvclohexvl-Using the procedure of Example 14, but replacing they resultant compound of Example 13 with the resultant compound of Example 40, gave the desired 15 compound.
Example 42 Hoc-His Amide of 2(S)-Amino-1-cvclohexyl-3(R).4(S)-dihydroxy-7-methyloctane 20 Using the procedure of Example 20, but replacing the 3(R),4(S) diastereomer of Example i4 with the resultant: compound of Example 41, gave the desired product. Mass spectrum: (M+H)+ = 495.
Anal. calcd. for C26H46N405 1/2H20:
a 25 C. 62.0: H, 9.4; N. 11.1. Found: C, 62.2; H, 9.4: N.
10.9.
Example 43 TBA-Phe~-His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 15, but replacing th~a resultant compound of Example 14 and Boc-Phe-His ~~ith the resultant compound of Example 42 and t-butyla<:etyl('.~HA)-Phe gave the desired compound.
Mass spectrum: (M+H)+ = 640.

Anal. calcd. for C36H57N505 3/4H20:
C, 66.2 H, 9.0: N, 10.7. Found: C, 66.1: H, 9.1; N, 10.6.
Example 44 2 S =t-Hutyloxycarbonvlamino-i-c~r~~nho~1_ Usin~~ the procedure of Example 13, but replacing ifoopentyltriphenylphosphonium bromide with isobutyltriphenylphosphonium bromide, gave the desired product. Mass spectrum: M+ = 295.
Anal, calcd. for C18H33N02 1/4H20: C, 72.0; H, 11.3;; N, 4.7. Found: 71.7; H, 11.1: N, 4.5.
Example 45 2 S -t:-Butyloxycarbonvlamino-1-cvelot~p~~-Using the procedure of Example 14, but replacing the resultant compound of Example 13 with the resultant compound of Example 44, gave the desired compound.
Example 46 -Phe--His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 15, but replacing the resultant product of Example 14 with the resultant product of Example 45, gave the desired product. Mass spectrum: (M+H)+ = 614.
Example 47 Ethoxyc2~rbonyl-Phe-Leu Amide of 2(S)-Amino-1-Following the procedures used to make the resultant connpound of Example 36, but replacing isopentyltriph~enylphosphonium bromide with propyl-. 32 triphenylpho;sphonium bromide, gave the desired product.
Mass spectrwn: M* ~ 547.
Anal. calcd. for C30H49N3~6 1/4H20:
C, 6s.2; H, li.0; N,, 7.6. Found: C. 65.0; H, 8.9: N. 7.3.
Example 48 -pne-heu Amide of 2(S)-Amino-1-Following the procedures used to make the resultant compound of Example 36, but replacing isopentyltriphenylphosphonium bromide with pheneth-yltriphenylphosphonium bromide, gave the desired product.
Example 49 Boc-Phe-His Amide of 2(S)-Amino-1-cyclohexyl 3~R~ , 4 ( S ) -d ihydroxypent ane Following the procedures used to make the resultant compound of Example 15, but replacing isopentyltriF~henylphosphonium bromide with ethyltri phenylphosphonium bromide, gave the desired product.
Mass -spectrwt~: (M+H) ~ 600.
Anal.. calcd. for C3~H49N506 1/4H20:
C, 63.6; H, 8.3; N, 11.6. Found: C. 63.6; H, 8.3; N.
ll.s.
( ~ Example so 2 S -~t-Butsrloxycarbonvlamino-1-cvclohexvl-To F~ stirred -78°C solution of Boc-cyclohexyl-alanine meth;~l ~est.er (3s.0 g, 123 mmol) in anhydrous toluene (200 mL) was added diisobutylaluminum hydride ( 140 M~, 1 . s M solution in toluene, 117 mL) at a rate to keep the internal temperature below -60°C. After stirring for an additional 20 minutes at -78°C, allyl magnesium ch7loride (184 mL of a 2.0 M solution in THF) 35 was added. The mixture was allowed to stand at 0°C for 16 hours and was then quenched with methanol. The mixture was diluted with ether and then washed sequentially with .citric acid (aq) and brine. Drying (MgS04) and evaporating provided ans oil which was purified by silica gel chromatography to give the desired compound in 40~ yield.
Example 51 2(S)-t-Butyloxycarbonvlamino-1-cyclohexyl-3(R),4(S)-dihydroxyhex-5-ene An allylic oxidation using stoichiometric Se02 and t-butyl hydroperoxide (Umbriet, M.A. and Sharpless, R.13. J. Am. Chem. Soc. 1977, 99, 5526) was performed on the resultant product of Example 50 to give the desired product after silica gel chromatography.
Example 52 arDOnY~-Phe-Leu Ami de ef 2l S 1-nm; r, r,-~ -Following the procedure of Example 15, but replacing the resultant product of Example 14 and Boc-Phe-His with the resultant product of Example 51 and ethoxycarbonyl-Phe-Leu, gave the desired product. Anal.
calcd. for C'30H4~.N306: C, 66.03: H, 8.68: N.

7.70. Found: C, b6.10; H, 8.83: N, 7.43.
Example 53 ~N-suty~l, 4-OCH3)-Phenylalanine To a, stirred 0°C suspension of (4-OCH3)-phenylalanine (1.00 g, 5.12 mmol) and butyraldehyde (0.406 g, 110 M~) in methanol (10 mL) was added sodium cyanoborohydride (241 mg, 75M$). The mixture was warmed to room temperature fo;r 23 h and filtered. The solid was washed with methanol and suction dried to give 1.07 g (83%) of the desired p~:oduct. Mass spectrum: M+ = 251. Anal.

' 1 3 40 98 4 Calcd for ~=14H21N03.1/3H20: C. 65.3: H, 8.5: N, 5.4 Found: C, 65.1: H, 8.3: N, 5.6.
Example 54 N-Hutv:l~ 4-OCH3)Phe-His Amide of 2(S)-Amino-1-Using the procedure of Example 21, but replacing THA-CHA
with the resultant product of Example 53 gave the desired coml>ound. Mass spectrum: (M+H)+ ~ 614.
Anal. Calcd for C34H55N505'1/2 H20: C. 65.6:
H, 9.1; N, 11.2.. Found: C. 65.3: H, 9.0; N, 11.3.
Example 55 H- 4~-OCH3ZPhe-Leu Amide of 2(S)-Amino-1-......i..v........~ ~~,.w .~.,. ~.~ . _ . __ Using the procedure of Example 33, but replacing Boc-Phe-Ala ~~ith Cbz-(3-I,4- OCH3)Phe-Leu provided the protected iodinated product. Deprotection and de-iodination was achieved by hydrogenating 0.59 g in methanol (150 mL) with Na0Ac.3H20 (0.40 g), 2.5~
Rh/HaS04 (1.5 g), 20~ Pd/C (0.29 g) at 4 atmospheres H2 for 2.5, h. Filtration and evaporation provided a residue which was partitioned between ethyl acetate and sat. aq. NaHfC03. The organic layer was washed with dilute Na2S~;03 and brine, dried, filtered, and evaporated to give a solid. Recrystallization from CN2C12/hexane provided 260 mg (65~) of the desired compound. HRMS: M+ Calcd for ~3pH52N305' 534.3907. Measured.. 534.3925.
Ex ~p 1 a 5 6 X1.4-methoxy)-Phe-Leu Amide of 2(S)-Amino-1-The resultant product of Example 55 (130 mg, 0.243 mmol) was hydrogenated (1 atmosphere H2) with l0~ Pd/C
(39 mg) in methanol/formalin (12 mL/5 mL) for 8 h.

. 1340984 Filtering an~~ evaporating (high vacuum) provided a Oesidue which was chromatographed on silica gel to give 43 mg (32~) of the desired compound. HRMS: (M+H)+
calculated for C32H56N305' 562.4220.
5 Measured: 56:! : 4230.
Example 57 H-Phe-Leu Amide of 2(S)-Amino-1-cvclohexvl-10 Following the procedure of Example 55, but replacing Cbz-(3-I,4-OCHf3)Phe-~Leu with Cbz-Phe-Leu and omitting Na0Ac.3H20 and 2.5'~ Rh/BaS04 in the reduction step, provided the desired compound. Mass spectrum: (M+H)+
504. Anal. Calcd for C29H49N304: C, 69.1; H, 15 9.8; N, 8.3. Found: C, 69.0; H, 10.1; N, 8.3.
Example 58 -cj-C.Yanoetnyl))Phe-Leu Amide of 2(S)-Amino-1-20 A suspension of the resultant compound of Example 57 (297 mg, 0.~~90 mmol) in acrylonitrile (2 mL) was refluxed for 3 days. Evaporation provided a residue which was dlissolv~ed in ethyl acetate, filtered, evaporated and chromatographed on silica (dichloro-25 methane/methanol, 97.5/2.5) to give 162 mg (49~) of the r desired compound. Mass spectrum: (M+H)+ = 557.
Anal. Calcd for C~32N52N404: C, 69.0; H, 9.4; N, 10.1. Found: C, 68.6; H, 9.5: N, 9.9.
Example 59 3-Aminopropy~l))Phe-Leu Amide of 2(S)-Amino-1-The resultant compound of Example 58 (75 mg, 0.135 mmol) was hydrogenated (4 atmospheres H2) over Raney Nickel (85 mg) in anhydrous methanol/ammonia (20 mL/5 mL) for 3 h. Filtration and evaporation provided the desired 1 3 40 9g 4 ' product (68 mg). Mass spectrum: (M+H)+ = 561.
Example 60 N,N-Dimethvl,)Gly-Phe-His Amide of 2(S)-Am Using the procedure of Example 56, but replacing the resultant product of Example 55 with the resultant product of E:Kample 64, gave the desired product. Mass spectrum: (M+H)+ = 613.
~ Example 61 Cbz-D-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexvl-. Using the procedure of Example 21, but replacing THA-CHA
with Cbz-B-AT.a-Phe gave the desired compound. Mass spectrum: (1K+H)+ = 733. Analysis calculated for C40H56N6~7' C~ 65.5: H, 7.7; N, 11.5. Found:
C: 65.2; H, 7.7; N. 11.2.
Example 62 H-B-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(F
4(S)-dihyd(roxv-6-methylheptane Diacetic Acid Salt.
The resultant compound of Example 61 (1.00 g, 1.36 mmol) in acetic acid (14 mL) was hydrogenated at 1 atmosphere with 10~ Pd/C (0.50 g) for 3 h. Filtration, extraction of the catalyst with acetic acid, and evaporation of the combined acetic acid solutions gave a residue which was dissolved in water (25 mL) and lyopholized to provide 891 mg (91~) of the desired product. Mass spectrum:
(M+H)+ = 599 (free base). Analysis Calculated for C36H58N6~9~1/2H20: C, 59.4; H, 8.1; N, 11.5.
Found: C, 59.3.. H. 8.0; N, 11.2.

134p9~4 Example 63 -Sar-1?he-His Amide of 2(S)-Amino-i-ev~l~hp~i_ ~.i - ~ Y \r ~~ ~~rV .
Using the procedure of Example 21, but replacing TeA-CHA
with Cbz-Sa='-Phe gave the desired ' compound. Mass spectrum: (r~+H)+ ~ 733. Anal. Calcd for C, 64.8; H, 7.7; N, 11.3. Found: 6s.0; H, 7.6; N, 11.3.
Example 64 H-Sar-Phe-His Amide of 2(S)-Amino-1-cvclohexyl-3(R),4(S)-dihydroxy-6-methylheptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the resultant cornpound of Example 61 with the resultant compound of ;Example 63 gave the desired product. Mass spectrum: (~!~+H)+ ~~ s99 (free base) . Anal. calcd for C36H58N6~9'H2~~' C~ 58.7: H, 8.2; N, 11.4.
Found:
s8.s; H, 8.1; N, 11.4.
Example 6s z-GABA-Phe-His Amide of 2('S)-Amino-1-cyclohexyl-4(S)-dihydroxy-6-methvlhe~tane.
Using the procedure of Example 21, but relacing THA-CHA
with Cbz-GABA-Phe (GAHA is 4-aminobutyric acid) gave the desired compound.
Example 66 -Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(R),4 dihydroxy-6-methyl-heptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the resultant compound of Example 61 with the resultant compound of Example 6s gave the desired product.

38 ~34pge4 Example 67 -Isoni ectOyl-Fhe-His Amide of 2(S)-Amino-1--3(R),4(S)-d hydroxy-6-methylheptane.
Using the procedure of Example 21, but replacing TBA-CHA
with Cbz-Isonipectoyl-Phe gave the desired compound.
Mass spectrum: (M+H)+ = 773. Analysis calculated for C43H60N607.H~t0: C. 65.3; H, 7.9: N, 10.6.
Found: 65.4;. H. 7.,6; H, 10.5.
Example 68 H-IsonipectoylPhe-His Amide of'2(S)-Amino-1-cyclohexyl-3(R),4(S)-d~~hydroxy-6- methylheptane Diacetic Acid Salt.
Using the procedure of Example 62, but replacing the . resultant compound of Example 61 with the resultant compund of F;xample 67 gave the desired product. Mass spectrum: (ri+H)+ = 639 (free base).
Example 69 Cbz-D-Ala-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3~R).
4 S -dihydroxy-6-methylheptane.
Using the 'prc>cedure~ of Example 21, but replacing THA-CHA
with Cbz-D-p~la-Phe gave the desired compound. Mass spectrum: ~(M+H)+ = 733. Analysis calculated. for C40H56N6~7~1.5H20: C. 63.2; H, 7.8; N. 11Ø
Found: C. 63.0: H, 7.4; N. 11Ø
Example 70 H-D-Ala-Phs~-His Amide of 2(S)-Amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-~6-methylhe tape Diacetic Acid Salt.
Using the p~:ocedure of Example 62, but replacing the resultant compound. of Example 61 with the resultant compound of Example b9 gave the desired product. Mass spectrum: (xf+H)+ = 599 (free base).

1340984 ' Example 71 3-Henzylo carbonylamino-3-methylbutanoic Acid.
A solution of 2,2-dimethyl-3-carbomethyoxypropionic acid (LeMaul, Hull. Soc. Chim. Fr., 828 (1965). 20 g, 0.125 mol], diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine~ was heated in toluene (150 mL) at 100°C
for 2 h. Afl:er cooling to 5°C, the toluene solution was washed successively with 0.5M HC1, aqueous NaHC03 and brine. Evaporation of the dried solution gave a residue which was chromatographed on silica gel eluting with 60/!0 hexane-- ether. There was obtained 13 g of methyl 3-isocyanato-3-methylbutanoate as a mobile liquid. A
solution of this material in toluene (20 mL) was treated with benzyl alcohol (13 mL) and the resulting mixture heated at re:Elux for !0 h. Evaporation of the toluene left a residue which was dissolved in methanol (125 mL) and then treated with a solution of NaOH (6.6 g, 0.165 mol) in 22 mL of water. After 5 h, the reaction mixture was partially evaporated, washed with ether and 2p acidified with 6N HCl. Extraction with methylene chloride and evaF~oration gave 21 g of the desired product. NI~9t (300 MHz, CDC13): 1.42 (s, 6H), 2.78 (s, 2H), 5.08 (s. 2H).
Exam lp a 72 i 25 (:bz= t ( 13 , f3-d i-Me ) -t3-A1 a ] -Phe-OCHa .
A 4.0 g sample of 3-benzyloxycarbonylamino-3-methyl-butanoic acid was .coupled to phenylalanine methyl ester hydrochloride (3.13 g) using the mixed anhydride 30 procedure described in Example 2. Purification of the crude product by flash chromatography eluting with 65/35 ether-hexane gave an 86~ yield of product. NMR (300 MHz, CDC13): 1.32 (s. 3H), 1.34 (s, 3H), 2.46 (d, 1H), 2.63 (d, 1H), 2.98 (dd, iH), 3.09 (dd, iH), 3.70 (s, 35 3H), 1.86 (dd, 1H), 4.97 (d, 1H), 5.2 (d, 1H), 5.3 (s, ~ 3 ~4 9e 4 1H), 6.13 (d, 1H).
Example 73 Cbz-[(B,B-di-Me)-B-Ala)-Phe-0H
To a 0°C solution of Cbz-[(B,B-di Me)-B-Ala]-Phe-OMe 5 (1.5 g, 3.63 mmol) in dioxane (15 mL) was added a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 ~r~L) . After stirring for 1 h at 0-5°C, the reaction mixture was diluted with cold water and - extracted 2)~ with ether. The aqueous portion was 10 acidified with 6N HC1 and extracted with ether. The organic extr:~ct was washed with brine and evaporated to give an 87~ hield of product as a viscous liquid.
Exam le 74 Cbz-[ (B,B-c!i-Me)--B-Ala -Phe-His Amide of 2(S)-Amino-1_-15 cyclohe~cyl3(R),4(S)- dihydroxy-6-methvlheotane.
Using the procedure of Example 21, but replacing TeA-CHA
with Cbz-[(B,B-di.-Me)-B-Ala]-Phe gave the desired compound. Mass spectrum: (M+H)+ = 761. Anal. Calcd for C42H60~46C7 ~ i,/4H20: C, 65. 5; H, 8. 0; N, 20 10.9. Found: C, E~5.6; H, 7.9; N, 11Ø
Example 75 H-[(B,B-di-Me)-t3-Ala]-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-:3 R ,4(S)-dihydroxy-6-methylhe tare Diaceti Acid Salt.
Using the procedure of Example 62, but replacing the resultant compound of Example 61 with the resultant compound of Example 74 gave the desired product. Mass spectrum: (~d+H)+ = 627 (free base). Anal. Calcd for C38H62N6~9~H20: C, 59.7; H. 8.4; N. 11Ø
Found: C, 59.5: H, 8.4; N, 11.3.

41 ~ 3 40 9e ~
Example 7s -Pro-Phe-His Amide of 2(8)-Amino-1-cyclohexvl Using the procedure of Example 21, but replacing THA-CHA
with Cbz-Pro-Phe gave the desired r compound. Mass spectrum: (M+N)+ = 759. Analysis calculated for C42H58N607~1/2H20: C. 65.7, H, 7.7; N, 10.9.
Found: 65.7, H, 7.7; N, 10.9.
to Example 77 Pro-Phe-l3is Amide of 2(S)-Amino-1-cyclohexyl-4(S)-dih~~droxv--6-mprl,vtl,ort~"o n,.e.;" r,.;,a ~., Using the procedure of Example 62, but replacing the resultant compound of Example 61 with the resultant compound of E;xample~ 76 gave the diacetic acid salt as a tacky solid. A portion of the di-salt was partioned betwen satd. NaHC0,3 and dichloromethane. The aqueous layer was further extracted with dichloromethane and the combined organic layers were dried, filtered and evaporated to give the desired product. Mass spectrum:
(M+H)+ = s2!i (free base). Analysis calculated for C36N56N607~2H~;0: C, 60.0: H, 8.4; N, 11.6.
Found: C. 59.51; H, 7.9; N, 11.5.
Example 78 3-Benzyloxy~carbonylamino-2,2-dimethyl ropionic Acid.
3-Carbomethox~~-3-methylbutanoic acid (Bull. Soc. C.him.
Fr., 828 (1965), 7.85 g, 0.049 mold was reacted with diphenylphosphorylazide and triethylamine as described in Example 71. After heating the toluene solution for 1.5 h, benzyl alcohol (8 g) was added directly to the reaction mixture and heating at reflex was continued for 20 h. Work-u.p and purification as in Example 71 gave methyl 3-benzyloxycarbonylamino-2,2-dimethylpropionate.
NMR (300 MHz. CDC1,~): 1.2 (s, 6H), 3.3 (d, 2H), 3.68 (s, 3H), 5.1. (s, 2H), 5.22 (m, 1H). A sample of the methyl ester (6.21 g, 0.023 mol) was saponified with 3.1 g (0.78 mol) of NaOH in 100 cnJ ethanol/10 mL H20 at room temperature fc~r ~8 h. Work-up as in Example 71 gave the desired product as a liquid.' NMR (300 MHz, CDC13): 1.2;3 (s. 6H), 3.32 (d, 2H), 5.10 (s, 2H), 5.27 (m, iH).
Example 79 ~i>z-( ( a , a -di-Me)-t3-Ala]-Phe-OCH3 .
To a solution of 3-benzyloxycarbonylamino-2,2-dimethyl-propionic acid (i.:i g, 5.97 mmol) in methylene chloride (13 mL) was added oxalyl chloride (0.757 g, 5.97 mmol) and dimethylformami.de (30 ul) . After stirring for 1 h at room tempE~rature, the reaction mixture was cooled to 0°C and treated successively with phenylalanine methyl ester hydrochloride (1.29 g, 5.97 mmol) and N-methyl-morpholine (1,.81 g, 17.9 mmol). Stirring for 1 h at 0-5°C was followed by distribution between CH2C12 and 0.5 N HC1. The organic phase was washed with aqueous NaH<:03 and brine and dried over MgSO~.
Evaporation of they solvent gave a residue which was purified by chromatography. There was obtained a yield of product as a liquid. NMR (300 MHz, CDC13):
l.il (s, 3H), 1.12 (s, 3H), 3.05 (dd. 1H), 3.18 (dd, iH). 3.23 (d, 1H), 3.24 (d, iH), 3.75 (s, 3H), 4.82 (dd, 1H), 5.08 (s, 2H), 5.37 (broad t, 1H), 6.0~ (d, 1H).
Example 80 C~ Z~( ( a , a -d i -Me ) -t3-A 1 a ] -Phe-OH .
The hydrolysis of the methyl ester was carried out by the procedur~a described in Example 71 to give the desired product in 90~ yield as a viscous liquid.

Example 81 Cbz-[ a. _a-di-Me _--!3-Ala]-Phe-His Amide of 2(S)-Amino-1-..' .
Using the procedure of Example 21. but replacing TBA-CHA
with Cbz-[ a. , a--di-Me)-B-Ala]-Phe gave the desired compound. Mass spectrum: (M+H)+ = 761.
Example 82 [ ( a, o-Di--Me -B-Ala]-Phe-His Amide of 2(S)-Amino-1-cyclohexy:l-3 R ,4(S)-dihydroxy-6-methylhe tape Bis acetic acid salt.
Using the compound from Example 81 and the procedure of Example 62 gage the desired product in 71~ yield. Mass spectrum: (M~~H)+ = 627.
Example 83 Cbz-Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(R), 4 S -dihydroxy-6-methylheptane Using the pro~~edure of Example 21 but replacing TBA-CHA
with Cbz-Phe gave the desired compound. Mass spectrum:
(M+H)+ = 661.
Example 84 Amide of 2(S)-Amino-1-cvclohexvl--v-.i ..r~rrvwl v .v.~.v..yasacY~.oaac.
A solution of the product from Example 83 (180 mg, 0.273 mmol) in methanol 1;50 mL) was hydrogenolyzed in a Parr Apparatus witlh 90 mg of 20~ Pd/C and 4 atmospheres of hydrogen. A:Eter the hydrogen uptake ceased, the catalyst was ~~iltered and the filtrate evaporated to the desired produ<a (90 mg, 63;t). Mass spectrum: (M+H)+ _ 527.

~3'~~g84 ~xample 85 a -Amino:~sobutyryl-Phe-His Amide of 2(S)-Amino-1_ cyclohexyl-3(it),4(S)-dihydroxy-6-methylhe tape.
A mixture of a -aminoisobutyric acid N-carboxy anhydride (10.9 mg, 0.1)85 mmol) and the product' from Example 84 (44.6 mg, 0.085 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 16 h. The dimethyl-formamide was. evaporated in vacuo and the residue was ' distributed between chloroform and water. The organic phase was dried arid evaporated to a residue which was chromatograph~ad ~on silica gel eluting with methanol-chlo:roform mixtures. There was obtained 35 mg (68~) of the desired product. Mass spectrum: (M+H)+
= 612.
Example 86 1-sulfonyl)-Phe-His Amide of 2fs)-Amine-i-.., Using the procedure of Example 21, but replacing THA-CHA
with (pyrid:ln-3-y:l-sulfonyl)-Ph~e . gave the desired product.
Example 87 (Pyrazin-2-5~1-carbonyl)-Phe-His Amide of 2(S)-Amino-1 cyclohexyl-3(R),4(S)-dihydroxy-6-methylhe tane.
Using the procedure of Example 21, but replacing THA-CHA
with (pyrazin-2-yl-carbonyl)-Phe gave the desired product. Mass spectrum: (M+H)+ = 634. Anal. Calcd for C34H4~rf~05. 1~~4H20: C, 64 . 0; H, 7. 5: N.
30 15.4. Found: C. 6:l.9; H, 7.6; N. 15.2.
Example 88 dazol-4~- 1-acetyl)-Phe-Leu Amide of 2(S)-Amino-1-yclohexYl-3(R.),4(S)-dihydroxy-6-methylheptane.
35 Using the coupling conditions of Example 21 with 1 3 4 0 9 8 .,~ . .
4-imidazoleacetic acid and the resultant product of Example 57 provided the desired product. Mass spectrum: (M+H)+ = 612. Analysis calculated for C34H53N505'1/2H20: C. 65.9; H. 8.9: N. 11.3.
5 Found: C. 65.9; H, 8.9; N, 11.3 Exampie 89 rroi-z-y~1-carbonyl)-Phe-HisAmide of 2(S)-Amino-1-10 Using the procedure of Example 21, but replacing THA-CHA
with (pyrrol-2-yl~-carbonyl)-Phe gave the desired product. Mas;a spectrum: (M+H)+ = 621.
Example 90 15 Allyloxycarbonyl-Phe-Leu Amide of 2(S)-Amino-1-cyclohexyl -3~1t ,~ S -dihydroxy-6-methvlhectaine.
Using the procedure of Example 33. but replacing Hoc-Phe-Ala with al.lyloxy carbonyl-Phe-Leu provided the desired product. Mass spectrum: (M+H)+ = 588. Anal.
20 Calcd for ~33H53N306' C~ 67.4; H, 9.1; N, 7.2.
Found: C. 67,6; H, 9.0; N, 7.1.
Example 91 1_oxycarbonyl-Phe-Leu Amide of 2(S)-Amino-1-25 ..s ~..,.r"~....~ .
;' To a stirred 0°C solution of the resultant compound of Example 90 (1..25 g, 2.13 mmol) in dry tetrahydrofuran (THF, 50 mL) was added 9-borabicyclol3.3.1~- nonane (9-BBN, 25.5 rtiL of a 0.5M solution in THF). The mixture 30 was warmed to room temperature for 12 h and then cooled to 0°C. Water (15 inL) and 3M NaOH (4.5 mL) were added followed 2 .min later by 30~C H202 (5 mL). The mixture was p<~rtitianed between brine (20 mL) and ethyl acetate (100 nnL). The organic phase was washed (brine).
35 dried (Na2S04), filtered, and evaporated to a thick oil. Recryst:allization twice (dichloromethane/ether) provided 670 mg (52~) of the desired compound. Mass spectrum: I;M+H)+ ~ 605. Analysis calculated for CC33H55N307: C, 65.4: H, 9.2; N. 6.9. Found:
C, 65.4; H, 9.1: N, 6.8.
Example 92 the Resultant Comvound of Example 9 To a stirred 0°C suspension of the resultant compound of Example 91 (60 mg, 0.099 mol), Cbz-Gly-OH (20.7 mg, 0,099 mmol), and 4-dimethylaminopyridine (60 mg, 0.495 mmol) in dichloromethane (10 mL) was added ethyldi-methylaminopropyl carbodiimide hydrochloride (38 mg, 0.198 mmol). The mixture was warmed at room temperature for 15 h a:nd than diluted with dichloromethane and washed sequ~?ntial:ly with 1M H3P04, satd NaHC033 and brine. Drying (Na2S04), filtering, and evaporating provided 57 mg (72t) of the desired compound. Mass spectrum: (M+H)+ = 797.
Example 93 H-Gly-Ester of t:he Resultant Compound of Exam le 91 , at 3-Hydroxypropyloxy Group).
The resultant compound of Example 92 (13 mg, 0.016 mmol) was hydrogenated (1 atmosphere H2) with 10~ Pd/C (4 mg) in methanol for 3 h. Filtration, evaporation and chromatography on silica (dichloromethane/methanol, 95/5- 90/10) provided 4 mg (37~) of the desired product. fiRMS: (M+H)+ calcd for C35HS8N408:
663.4333. Found: 663.4355.
Example 94 Lysine Ester of the Resultant Compound of Example 91 (at 3-Hycir~iopyloxy Group) Diacetic Acid Salt.
Following the procedure of Example 92 but replacing Cbz-Gly-OH w~~th a,e-di- Cbz-Lys-OH provide the desired ~3409g4 protected pE~ptide. Hydrogenation according to the procedure of Example 93, but replacing methanol with acetic acid provide the desired compound.
Example 95 Hemisuccinate Ester of the Resultan~
Using the procedure of Example 92, but replacing Cbz-Gly with benzyl succinate provided the protected product.
Deprotection was achieved by following the procedure of Example 103 to give the desired product.
Example 96 er of the Resultant Com and of ;at 3-Hvdroxvpropvloxv GIOUD).
Using the procedure of Example 92, but replacing Cbz-Gly with dibenzylphosphate provided the protected product.
Deprotection was achieved by following the procedure of Example 103 to give the desired product.
Example 97 2(R,S),3-DihS~droxypro yloxycarbonYl~Phe-Leu Amide of 2(S
-Amino-1-cYClohexvl-3(R),s(S)-dihvdroxv-6-methvlheDtane.
Following the procedure of Example 14, but replacing the resultant compound of Example 13 with the resultant f. 25 compound of l~cample 90, and heating the mixture at SO°C
for 2~ h, gave the desired product. Mass spectrum:
(M+H)+ = 622. Anal. Calcd for C33H55N3~8 .1/2H20: C. 62.8: H, 8.9; N, 6.7. Found: C, 63.0;
H, 8.6: N. 6.7.
Example 98 Using the procedure of Example 92, but replacing the 134pg8,~

resultant compound of Example 91 with the resultant compound of Example 97, provided a mixture of the desired mono- and diesters. Separation was achieved by silica gel chromatography.
Exa~le 99 ~of Example c Acid Salt.
Using the p:rocedu:re of Example 93, but replacing the resultant compound of Example 92 with the resultant monoester of Example 98 and replacing methanol with acetic acid, gave t:he desired product.
r EXample 100 H-Gly-Diest er of the Resultant Compound of Example 97 (at the 2,3-Dihydroxypropyl Group) Diacetic Acid Salt.
Using the procedure of Example 93, but replacing the resultant compound of Example 92 with the resultant diester of Example 98 and replacing methanol with acetic acid, provided the desired compound.
' Example 101 Ethoxycarbonvl-~(OBn)Thr-His Amide of 2(S)-Amino-1-Using the procedure of Example 21, but replacing THA-CHA
i_ with ethoxyc:arbonl~-threonine benzyl ether - [ (OBn)Thr~
gave the desired compound. Mass spectrum: (M+H)+ _ 616. Anal. Calcd for C32H~9N507: C, 62.4; H, 8.0; N, 11.x. Found: 62.3: H, 8.0; N, 11.3. , Example 102 BenzyloxYace~tvl-Phe-His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 21, but replacing TBA-CHA
with benzyloxyacetyl-Phe gave the desired compound.
Mass spectrunn: (M+H)+ = 676. Analysis calculated for C38H53N506'1/'~HZO: C. 67.1: H. 7.9: N. 10.3.
Found: 67.0: H, 7.9: N, 10.2.
Example 103 Hydroxvacetyl-Phe-_His Amide of 2(S)-Amino-1-cyclohexyl ~~~(S -dihydroxv-6-methvlheutane.
The resultant compound of Example 102 (250 mg, 0.370 mmol) in acetic acid (3.7 mL) was hydrogenated at 1 atmosphere H,t with 10~ Pd/C (125 mg) for 23 h.
Filtration, extraction of the catalyst with acetic acid, _ 10 and evaporation of the combined acetic acid solutions gave a residue which was partitioned between ethyl acetate and satd. aq. NaHC03. Exhaustive extraction of the aqueous phase with ethyl acetate, combination of all organic layers, and evaporation provided crude product which was recrystallized (ethylacetate/methanol/
methylcyclohe~;ane) to give 157 mg (72~) of the desired product. Mass spectrum: (M+H)+ = 586. Anal. Calcd for C3H4~N506.H20: C. 61.7; H. 8.2; N, 11.6.
Found: C. 62.1; H, 8.1; N. 11.4.
Example 104 1-Q-Ala.-Phe-His Amide of 2(S)-Amino-1-cvclohexvl-Using the procedure of Example 21, but replacing THA-CHA
with Acetyl-D-Ala-Phe provided the entire compound.
Example los i-Bu-P1-His.i~nide of 2(S)-Amino-1-cyclohexyl-3(R),4~-_..,_____ . ___~__,~ _ Using the procedure of Example 21, but replacing TBA-CHA
with 0-isobutltl-L-3--phenyllactic acid (i-Bu-P1-OH) gave the desired compound.

so Example 106 Isobutyryl-Homo-Phe methyl ester To a suspension of (t)- a -amino-!-phenylbutyric acid (Homo-Phe) methyl ester hydrochloride (0.83 g, 3.61 mmol) in met.hylene chloride cooled in an ice bath was added successively isobutyric anhydride (0.57 g, 3.61 mol) and N-mEathylmorpholine (0.79 mL, 7.22 mmol). After stirring for 30 min at 0-s°C, the reaction mixture was distributed between methylene chloride and O.sN HC1.
The organic layer was washed with aqueous NaHC03 and brine solution and. then dried over MgSOl. Evaporation of the solvent gave a solid residue which was triturated with hexane to provide 700 mg of product, mp 72-73°.
Example 107 Isobutyryl-Homo-Phe The hydrolys9~s of the methyl ester was carried out by the procedure described in Example 73 to give the desired product in 90~ yield.
Example 108 Isobutyryl-Homo-Phe-His Amide of 2(S)-Amino-1-cyclohexyl ~R),!(S)-dihydroxy-6-methvlheotane.
Using the procedure of Example 21, but replacing TBA-CHA
with isobuty~ryl-homo- Phe gave the desired compound.
Mass spectrum: (M+H)+ = 612.
Example 109 -IC(4-rtorpholinyl)carbonylJoxv]-3-phenvlprooioni acia methyl ester.
To L-phenylla~ctic acid methyl ester (-3.2 g) was added 150 mL of 12..5 phosgene in toluene and 25 drops of dimethylformamide. After stirring for 16 h at room temperature, the solvent was evaporated and the residue sl chased several times with benzene. The resulting product was dissolved in methylene chloride (50 mL), cooled to 0°C: and treated by dropwise addition with 3.86 g (0.0!! mol.) of morpholine. The reaFtion mixture was stirred for 2 h at 0-5°C and then distributed between O.sN HC1 and methylene chloride. The organic phase was washed with aqueous NaHC03 and brine and evaporated to a residue. 1?lash chromatography on silica gel eluting with 2/1 ether-hexane gave a 65~ yield of product. NMR
(300 MHz): 3.08 (dd, 1H), 3.20 (dd, 1H), 3.8 (s. 3H), 5.19 (dd, 1H).
Example iio 2(S)-f(!-Moroholinyl)carbonyl]oxy-3- henylpropionic acid.
Using the hy<irolys:is procedure of Example 73, the title compound was obtained in 90~ yield.
Example 111 2(S)-[(!-Morpholinyl)carbonyl]oxy-3- henylpro ionyl-His Amide of 2(S -Amino-1-cyclohexyl-3SR~ ~!(S)-dihydroxy-6 Using the procedure of Example 21, put replacing THA-CHA
with the product from Example 110, gave the desired product in b0~ yield. Mass spectrum: (M+H)+ = 6l2.
Example 112 2(S)-(C(!-Cbz-1-Pi~erazinvl)carbonvlloxvl-3 Using the F>rocedure of Example 109, but replacing morpholine with Cbz- piperazine, gave the desired product in 63~ yield.
Example 113 2(S)-(i~(!-Cbz-1-Piperazinyl)carbonyl]oxy])-3-phenylpropionic acid.
Using the hydrolysis procedure of Example 73 gave the s2 desired prod~sct in 93~ yield.
Example 114 10 Example lis 2(S)-(((i-F~i~eraxinyl)carbonyl~oxyJ-3-phenyl ro ionyl Phe-His A~mde of 2(S)-Amines-i-cv~lehp~t-~ru~~rc~_ Using the ~~rocedure of Example 62 gave the title compound in 8~s~ yield. M.p. 1s8°-160°C.
Example 116 4-M~~rpholinyl)carbonyl~-Phe methyl ester.
A suspension of L-phenylalanine methyl ester 20 hydrochloride (6 g) in toluene (12s mL) was heated to 100°C while ;phosgene gas was bubbled into the reaction mixture. After approximately 1-1/2-2 h, the mixture became homoc~eneoua. The passage of phosgene was continued for an additional is min, keeping the temp-25 erature at 90-100°C. The toluene was then evaporated and the residue chased several times with benzene. A
6.s g (0.03:167 mol) sample of a-isocyanato-L-phenyl-alanine methyl ester was dissolved in 50 mL of methylene chloride and cooled to 0°C. Morpholine (2.76 mL, 30 0.03167 mol) dissolved in 5 mL of methylene chloride was added dropwise. After 10 min at 0-5°C, the reaction mixture was distributed between O.SN HC1 and methylene chloride. Ttie organic layer was washed with aqueous NaHC03 and dried over MgS04. Evaporation of the 35 solvent gave 7 g of product after trituration with Using the procedure of Example 21, but replacing TBA-CHA
with the resultant compound from Example 113, gave the title compound. Mass spectrum: (M+H)+ = 77s.

hexane, mp 90-91~.
Example 117 [(4-Morpholinyl)carbonyl]~~Phe.
Using the procedure of Example 73 gave the title compound in 89~ yield.
ldnyl)caxbonyl -Phe-HisAmide of 2(S)-Amino-1-..1 _ .. ,.....,. .
Using the procedure of Example 21, but replacing THA-CHA
with [(4-mor;pholin.yl)carbonyl]-Phe, gave the desired compound. Mass spectrum: (M+H)+ = 6d1.
Example 119 (Dimethylamino)carbonyl]-Phe-His Amide of 2(S)-Amino-1 cyclohexyl3(R~,~(S)-dihydroxy-6-methylhe tape.
Using the procedures of Examples 116, 73, and 21, this compound was ~?repared. Mass spectrum: (M+H)+= 599.
Example 120 Using the procedures of Examples 116, 73, and 21, the title compound was synthesized. Anal. calcd for C32H52N6C6'1-'L/2 H20: C, 60.4: H, 8.~5: N, 12.82. Found.. C, 60.36: H, 8.11; N, 12.77.
Example 121 [(1-Cbz-4-P~ lperazinyl)carbonyl]-Phe methyl ester.
Using the procedure of Example 116, but replacing morpholine with 1-Cbz-piperazine, gave the desired product, mp 1114-115" .

1 3 40 9~ 4 s~
Example 122 ~(1-Cbz--4-Piperazinyl)carbonyl]-Phe Using the procedure of Example ~3 gave the desired product in 89~ yield.
Example 123 [(1-Cbz-4-P~erazinyl)carbonyl]-Phe-His Amide of 2(S)-Amino-1-cyc:lohexyl-3(R),~(S)-dihydroxy-6-methylhevtane.
Using the procedure of Example 21, but replacing TBA-CHA
with [(1-CY~z-4-piperazinyl)carbonyl]-Phe, gave the desired compound.
Example 124 [(1-Piperazin 1 carbonyl]-Phe-His Amide of 2(S)-Amino-1 cyclohexy7.-3 R -4(S)-dihydroxy-6-methvlh_eptane His=
Acetic Acid Salt.
IS
Using the procedure of Example 62 gave the desired compound in 90~ yield. Mass spectrum: (M+H)+ ~ 640 (free base).
Example 125 ~(~-Morpholinyl)carbonyl]-(4-OCH~)Phe methyl ester.
Using the procedure of Example 116 but replacing H-Phe-OCH3.HC1 with L-tyrosine methyl ester methyl ether.HC1 gave the title compound.
Example i26 [(4-M~orpholinyl)carbonyl]-(4-OCH3 Phe-OH.
Using the procedure of Example 73 gave the title compound in 9;2~ yie:ld.

ss Example 127 ((!-Morpholinyl)carbonyl]-(!-OCH3)Phe-His Amide of 2(S) -Amino-1-cyclohexyl-3(R),!(S)-dihydroxy-6 methylheptane Using the procedure of Example 21, but replacing THA-CHA
with I(!-morpholinyl)carbonyl]-(!-OCH )Phe gave the desired compound. Mass spectrum: (M+H)~ = 671.
. Example 128 !- 2-Ox:o~i~er~azinyl)carbonyl )-Phe methyl ester .
Using the F>rocedure of Example 116, but replacing morpholine with 2-oxopiperazine (Transition Met. Chem., 11, 27 (1986)] gave the desired compound in 80~ yield.
Example 129 - 2-Oxopiperazinyl)carboayl]-Phe.
Using the procedure of Example 73 gave the desired compound.
Exam le 130 (!-(2-Oxopi.perazinyl)carbonyl -Phe-His Amide of 2(S)-Amino-1-cvc7,ohex~l-3(R),!(S)-dihydroxv-6-methvlheptane.
Using the procedure of Example 21, but replacing THA-CHA
with (!-(2- oxopiperazinyl)carbonyl]-Phe, gave the desired produ~~t in 60~ yield.
Example 131 1-(!-Oxopiperidinyl)carbonyl~-Phe methyl ester.
Using the procedure of Example 116, but replacing morpholine ~rith 4-oxopiperidine gave the desired compound.

ss EX8mple 132 ~1.-(4-Oxopiperidinyl)carbonyl]-Phe.
Using the procedure of Example 73 gave the desired compund in 91~ yield.
Example 133 -.a~~mrnri~r~orir~inm .rarnnnv. .-vno-r~ic omino r~r vm-Using the procedure of Example 21, but replacing THA-CHA .
with (1-(4--oxopiperidinyl)carbonyl]-Phe, gave the desired product.
Example 134 (1-(4-~droxypiperidinyl~)carbonyl]-Phe methyl ester.
Using the procedure of Example 116, but replacing morpholine with 4--hydroxypiperidine, gave the desired compound.
Example 135 4-Hyd_roxypiperidinyl)carbonyl]-Phe.
Using the procedure of Example 73, gave the desired product in 82~ yield.
Example 136 il-(4-Hydrox5rpi~erxdiny])carbonyl]-Phe-His Amide of 2(S)-Amino-1-cyc7lohexyl-3(R L 4(S -dihydroxy-6-methylheptane.
Using the procedure of Example 21, but replacing THA-CHA
with (1-(4-hydroxypiperidiny])carbonyl]-Phe, gave the desired compound in. 56~C yield.
Example 137 1-(3-Hydroxy_piperidinyl)carbonyl]-Phe-His Amide of 2(S)-Amino-1-cvc:lohexvl-3(R),~(S)-dihydroxy-6-methylheptane.
Using the procedures described in Examples i16, 73 and 21, the titl~a compound was synthesized.
Example 138 3-C:arbomethoxy-3-pheno ro iortiic acid.
A solution of 2-phenoxybutyrolactone [Dareman, C., Hull.
Soc . Chim. F:c . . 29~! ( 1971 ) . 4 . 96 g. 0 . 028 mol ] was added to methanol (125 mL) containing 0.054 mol of sodium methoxide. After stirring for 3.5 hours at room temperature, the mixture was quenched, with 5 mL of acetic acid" and then distributed between ether and brine solution. The organic layer was washed with brine and evaporat~ad to a residue (methyl-4-hydroxy-2-phenoxy-butyrate). A solution of this material in acetone (300 mL) was tre~ited with Jones solution until the orange color persisted. The acetone was partially evaporated and the residue wa,s distributed between ether and brine solution. Evaporation of the dried ether layer gave the desired product as a waxy solid. NMR (300 NMR, CDC13): 3.02 (d, 2H), 3.78 (s. 3H), 5.11 (t. iH).
Example 139 -((~-Morpholinvl)carbonvl)-Using the mixed anhydride procedure described in Example 2, morpholir,~e was coupled to 3-carbomethoxy-3-phenoxy-propionic acid to give the desired product in 86~ yield.
mp 83-84°C. Ana:L. Calcd for C15H19NC5' C~ 61.2:
H, 6.53; N, ~f.78. Found: C. 61.17; H, 6.50: N, 4.61.
Example 140 3-((4-Morpholin~rl)carbonyl]-2-phenoxypropionic acid.
Using the procedure of Example 73 gave the desired product in 5!~~ yie:Ld, mp 150-151°C.

' ~ . 1 3 40 9g 4 Example 141 Using the procedure of Example 21, but replacing TBA-CHA
with the re~:ultant product of Example 140, gave the desired product as a mixture of R and S diastereomers.
Chromatograph;Y on silica (dichloromethane/methanol, 95/5) provided the less polar diastereomer (isomer A) and the more polar diastereomer (isomer H). Isomer A:
Mass spectrum: (M+H)+ = 642. Analysis calculated for C34HSiN507.1/2H20: C, 62.7; H, 8.0; N, 10.7.
Found: C. 62.7; H, 8.1; N, 10.3. Isomer B: Mass spectrum: (M+H)+ = 642. Analysis calculated for C34H51N5C7'H2~3' C~ 61.9; H, 8.1; 10.6.
Found: C, 62.2; H, 7.8; N, 10.4.
Example 142 2~R,,S - 4-Morpholinylcarbonylmethyl) 3~phenylpropionic Acid.
Ethyl a-carboxymeth;ylcinnamate was prepared as reported (Cohen, S.G. and Milovanovic, A. Biochemistry, 1968, 3495) and hydrogenated according to the procedure of Example 93. The resulting dihydrocinnamate was coupled to morpholine using the procedure of Example 21. Ester hydrolysis according to the procedure of Example 73 provided the desired compound. Mass spectrum: (M+H)+
= 278. Anal. Calcd for Ci5H13N04.1/8H20: C, 64.4: H, 6.9; N, 5Ø Found: C. 64.4; N, 6.8: N, 4.9.
Example 143 2(R,S)-(4-Mor~holinylcarbonylmethyl)-3-phenylpropionyl-His Amide of 2 S -Amino-1-cyclohexyl-3(R),4(S)-dihvdroxv-Using the procedure of Example 21, but replacing TBA-CNA
with 2(Ft,S)-(4-morpholinylcarbonylmethyl)-3-phenyl-propionic acid provided the desired product as a mixture of R and S diastereomers. Chromatography on silica (dichloro- mEathane/methanol 95/5 - 90/10) provided the less polar diastereomer (isomer A) and the more polar diastereomer (isomer B). Isomer A: Mass spectrum:
(M+H)+ ~ 640.' Anal. Calcd for C35H53N5~6 .1/2H20: C, 64.8: H, 8.4: N, 10.8. Found: C. 65.1:
H, 8.4, N. 10.3. Isomer H: Mass spectrum: (M+H)+
640. Ana:l.Calcd for C35H53NSW 1/2H20: C, 64.8; H, 8.4; N, 10.8. Found: C, 65.0; H, 8.3; N, 10.6.
Example 144 N- Benzyloxyacetyl)morpholine.
Using the mixed anhydride procedure described in Example 2, morpholinEa was coupled to benzyloxyacetic acid to give the desi~:ed product in 90~ yield.
Exam le 145 Methyl 2-benzyl-3=-benzyloxy-3- (4-mor holinyl)carbonyl propionate.
A -78°C solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethyla>ilyl)amide (17 mL of a 0.5M solution).
After stirrin<1 for 10 min at -78°C, a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in TNF (5 mL) was added dropwi:;e. Stirring at -78°C for 30 min was followed by warming to 0°C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgS04. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield.
Example 146 -Benzyl~-3-hydroxy-3_-[(4-morpholinyl)carbonylJ-~ro~ionic acid.
Using the procedure of Example 84, the benzyl ether so protecting group was removed by catalytic hydrogenolysia to give methyl 2-benzyl-3-hydroxy-3-I(!- morpholinyl) carbonyl]propionate. The methyl ester function was hydrolyzed using the procedure in Examgle 73 to give the title compound.
Example 1!7 2-Hen Example 1!8 2-Hydroxy-~3- !--morpholinyl]carbonyl]propionic acid acetonide.
A mixture of dl-malic acid (5 g), 2,2-dimethoxypropane (100 mL) and catalytic p-TsOH was heated at 100°C for 5 h~ After cooling and evaporation the residual solid was recrystallize~d from carbon tetrachloride to give the corresponding acet.onide lactone. This material was coupled to morpholine using the mixed anhydride procedure of 'Example 2 to give the title compound.
Example 1!9 Methyl 2-hydro -3-((!-morpholinyl)carbonyl]propionate.
A solution of 2-hydroxy-3-(!-(morpholinyl)-carbonyl]
propionic acid acet;onide (5 g) in methyl alcohol (75 mL) was treated with 1 mL of concentrated sulphuric acid and the mixture was stirred for 2! h at room temperature.
Partial evaporation of the solvent gave a residue which was distributed between either and brine solution. The ether layer was dried over MgSO! and evaporated to give the desired product.
Using the procedure of Example 21, but replacing THA-CHA
with 2-benzyl-3-hydroxy-3-((!-morpholinyl)carbonyl]
propionic ac id, gave the desired product in 51~ yield.

~ X40984 Example 150 Methyl 2-anilino-3-[(4-mor holinyl)carbonyl]propionate.
The trifluoromethanesulfonate of methyl 2-hydroxy-3-[4-morpholiny:l)carbonyl] propionate wasp prepared by the method of Shi~osaki [J. Org. Chem. , 46, 3230 ( 1981) ] . A
solution of this compound (7 mmol) in methylene chloride (25 mL) was added dropwise within S minutes at room temperature to a stirred solution of aniline (14 mmol) in methylene chloride (25 mL), and stirring continued for 30 min at room temperature. The reaction mixture was filterd, the solution was washed with water, dried over Na2S04, concentrated and the residue purified by chromatogr2~phy. Yield of product = 80;.
Example 1s1 ino-3-[(4-morpholinyl)carbonyl]propionyl-His J
!(S)-Amino-1-cvclohexvl-3(R).4(S)-dihvdroxv-6-Using the product from Example 150 and the methods of Examples 73 ar,~d 21 gave the title compound.
Example 152 Ethyl 5-p,cetamido-2(R,S)-benzyl-4-oxopentanoate.
Ethyl a-carbo:Kymethylcinnamate was prepared as reported (Cohere, S.G. and Milovanovic, A. Biochemistry, 1968, 3495) and hy~drogen.ated according to the procedure of Example 93. The resulting acid was converted to the desired acetarnidomethyl ketone using the methodology of Pfaltz et al." (Tetrahedron Lett. 1984, 25, 2977: acid to acid chloride t:o cyanoketone followed by 2n/acetic acid/acetic anhydride treatment).

134pgg4 Example 153 amido-2(R.S)-benzyl-4-oxo entanoyl-His Ami )Amino-1-cyclohexyl-3 ( R) , 4 ( S )-dihydroxv-i The resultant product of Example 152 was hydrolyzed according to the procedure of Example 73 provided the corresponding acid which was coupled in place of TBA-CHA
according to the procedure of Example 21. The desired product was obtained as an (R,S) mixture which was separated by <;hromatography.
Example 154 -[(4-Morpholin 1 carbonyl]-2-thiophenoxypr methyl ester.
Using the procedure of Example 139, but replacing 3-carbomethox)r-3-phenoxypropionic acid with 3-carbo-methoxy-3-thiophenoxypropionic acid, gave the desired product.
Ex amp 1 a 15 5 -((4-Morpholinyl)carbonyl]-2-(R, S)-thioohenox~rvrooionvl-6-methylheptane.
Using the procedures of Examples 73 and 21, the title compound was ~>repared in ~9~ overall yield.
f Example 156 -t-Buty7loxycarbonylamino-1-cyclohexyl-3-hydroxy-6-methylheptan-4-one.
To a solution of resultant compound of Example 13 (8.50, 27,5 mmol) in. dry TNF (150 mL) were added OsO~ (2.8 mL
of a 2.5~ so:lution in t-butanol and N-methylmorpholine N-oxide (9.28 g, 68.7 mmol). After 4d the mixture was partitioned b~atween either (200 mL) and brine (100 mL).
The aqueous :layer was back-extracted with either (2 x 100mL), and the combined organic phase was washed with 134pg84 .

10~ Na2S03, 0.1 M H3P04, and brine. Drying (MgS04) and evaporating prow;ded a residue (10.81 g) which was chromatographed on silica gel to remove the four diastereomeric diols from 0.70f g (7;) of the desired product. Mass spectrum: (M + H) = 342.
Example 157 Hoc~Phe-His Amide of 2(S)-t-Butyloxycarbonylamino-1 c clohexyl-3-hydroxy-6-methylheptan-4-one.
The resultant product of Example 156 (220 mg, 0:645 mmol) was treated with 4 M HCi/dioxane for 6 hours.
Evaporation ~3nd drying under high vacuum provided the corresponding amine hydrochloride which was dissolved in dry dimethyl!'ormamade (DMF, 1.0 mL), treated with Boc-Phe-His (260 mg), N-methylmorpholine (0.142 mL), and 1-hydroxybenzotriazole hydrate (261 mg), cooled to -23°C, and then treated with 1-ethyl-3-(dimethyl-aminopropyl) carbodiimide Hydrochloride (124 mg).
Evaporation after :16 h provided a thick oil which was partitioned t~betwee~n ethylacetate (60 mL) and saturated NaHC03 (30 mL). The organic phase was washed with brine, dried (MgS04), and evaporated to give a residue which was c:hromatographed on silica gel (dichloro-methane/methanol) t:o give 161 mg (40~) of the desired product. Mass spectrum: (M + H)+ = 626. Anal.
calcd. for C34H51N506' ~ C. 65.3: H, 8.3: N.
11.2. Found: ~ C, 65.6: H. 8.3: N. 11.2.
Example 158 Hoc-Phe-His Amide (at N-2) of 1-Cyclohexyl-2(S),4-(R,SZ-diamino-3-hydroxy-6-methylheptane.
Treatment of the resultant compound of Example 157 with hydroxylamine followed by reduction of the oxime over platinum oxide gave the desired product.

6!
Example 159 1-Phe-Leu Amide oft-Cyclohexvl-2(S). 3(R
The resultant compound of Example 3'6 was acetylated using acetic anhydride and the corresponding 3-hydroxy-!-acetox~ compound was isolated by silica gel chromatograph;Y. Oxidation to the 3 -one using Jones reagent, dea~cetylization using sodium methoxide in methanol, and reductive amination as in Example 158 gave the desired product.
Example 160 -Phe-His Amide of 2(S)-Amino-1-phenvl-3(R
Using the pr~~cedure of Example 13, but replacing Boc-cyclohexylalanine methyl ester with Boc-Phe-OCH3 and then followin~~ the ;procedures of Examples 1! and 29 gave the desired product.
Example 161 lic Carbonate of 2(S)-t-Hutvloxvcarbonvlamino- -The 3(R),!(S)~diastereomer of Example 1! was heated with N,N'-carbonyl~iiimid~azole in benzene to give the desired compound in 8~5~ yield.
Example 162 D-Ser-Phe-His amide of 2(S)-Amino-1-cyclohexyl-_3(R),!(S) dihydraxy-6-methylheptane.
Following the procedure of Example 15, but replacing the resultant product of Example 14 with the resultant product of Example 161 and replacing Boc-Phe-His with Cbz-D-Ser-Phe--His gave the desired N,0-diprotected material. N--deprotection following the procedure of Ex~ple 62 followed, by 0-deprotection with 0.5M NaOH in ~34~984 ss s0~ aq:dioxane, gave the desired compound.
Example 163 S(+)-2-mercapto-3-phenylpropionic acid was prepared as described (Acton, N and Komoriya, A. Organic Preparation and ProcedurE!s Int. 1982, 14, 381-392.) and acylated with isobutyric anhydride. Replacing TBA-CHA with this acid and using the procedure of Example 21, gave the titled compound.
Example 164 -t(2-Aminoethvl)merca~tol-3-~henv~rooionvl-Phe-Hi ~"°lu~ vL ~w~!-~muv-a-c:ycivriexyt-J\~J.~~~~-ainyarvxy-o-methvlhe~tane.
2(S)-((2-Aminoethyl)mercapto]-3-phenylpropionic acid was made using literature methodology (Acton, N. and Komoriya, A. Or anic Preparations and Procedures Int.
1982, 14, 381-392.) Replacing THA-CHA with this acid and using thE! procedure of Example 21, gave the titled compound.
Example 16s (2S,3R,sP:)-2-(t-HutYloxycarbonylamino)-3-hydroxY-7-methyl-1-ahp en~rl.octane-s-carboxylic Acid Lithium Salt A solution of 27.1 mg (0.075 mmol) of (3R,sR,1'S)-5-((t-butyloxyc~arbonylamino)-2-phenylethyl]-3-isobutyldi-hydrofuran-2-(3H)-o:ne (D. J. Kempf, J. Orc. Chem. 1986.
51, 3921) in 1 mL of dioxane was treated with 18s ul (0.092 mmol) of LiOH (O.s.M in H20) and stirred at ambient temperature for 8 h. Removal of the solvent in vacuo gave the desired compound as a white solid.

134pg84 Example 166 (2S,.3R,5R)-3-(t-Butyldimethylsilyloxy) 2-(t-butyloxycarbonylamino)-7-methyl-I- henyloctane 5-carboxylic Acid t-Butyldimethvlsilvl Ester A solution of they resultant compound of Example 165 (0.075 mmol), 42 mg (0.28 mmol) of t-butyldimethylsilyl chloride and 31 mg (0.45 mmol) of imidazole in 0.8 mL of dimethylformamide was allowed to stand at ambient temperature f~~r 2 days. Removal of the solvent in vacuo gave the crude desired compound.
Example 167 2S,3R,5R)-3-(t-Butyldimethylsilyloxy)-~t-butyloxycarbonylamino)-7-methyl-1-phenWloctar.~e-5-carboxylic Acid Lithium Salt A solution o:E the crude resultant compound of Example 166 (0.075 mmol) in 2 mL of dioxane was treated with 0.6 mL (0.3 aanol) of LiOH (0.5 M in H20) and allowed to stir at ambient temperature for 2 days. After removal of t:he solvent, purification by flash column chromato ra h;~ usin 3% methanol/chloroform g p g gave 18.3 mg (49%) of the desired compound (Rf 0.10, 2%
methanol/chloroform).
Example 168 (2S,3R,5R,8S,9R,lOS)-7-Aza-3-(t-butyldimethylsilyloxy)-2-(t-butyloxycarbonyl amino)-8-(cyclohexylmethyl)-9, I0-dihydroxy-5-isobutyl I2-methyl-1-phenvltridecane Using the coupling procedure of Example 21 but replacing Boc-Phe-His-OFi with the resultant compound of Example 167 g<ive the desired compound in 62% yield after purification by MhLC using 6:1 hexane/ethyl acetat a (Rf 0.50, 2:1 hexane/ethyl acetate).

Example 169 _ 2S 3R,SR,8S,9R,lOS)-7-Aza-2-(t-butvloxvcarbonvlamino)-8-(cvclohexvlmethvl)--iz-metnvi-i-onenvl-3,9,io-trinvar A solution of 16.5 mg (0.023 mmol) of the resultant compound of Example 168 in 1 mL of tetrahydrofuran was treated with 70 mL (0.07 mmol) of tetra-n-butylanmmonium fluoride (1 M in tetrahydrofuran) and allowed to stir at ambient temperature for 16 h. After concentration in vacuo. separation by MPLC using 2:1 hexane/ethyl acetate gave 10.5 mg (76~) of the desired compound as a white crystalline solid. Mass spectrum: (M + H)+ = 605.
Example 170 Cbz-6-aminohexanoyl-(4-methoxy)phenylalanine Benzyl Ester Using the procedure of Example 72 but replacing 3-benzyloxycarbonylamino-3-methylbutanoic acid with 6-(Cbz-amino)-n-caproic acid and replacing phenylalanine methyl ester with (4-methoxy)phenylalanine benzyl ester gave, after ;purification by flash column chromatography using 9:1 chloroform/ethyl acetate, a 38~ yield of the desired compound.
Example 171 ( 25 Cbz-6-~aminohexanoyl-(4-methoxy)phenylalanine A solution o1~ 2.66 g (5 mmol) of the resultant compound of Example 1 ~~0 in X60 mL of tetrahydrofuran was cooled to 0°C, treated with 0.63 g (15 mmol) of LiOH in 30 mL of H20 and allowed to stir for 2 h. After concentration of the solvent, 'the mixture was partitioned between H20 and ether, acidified, extracted with ethyl acetate, dried over MgS04 and concentrated to give 1.55 g (70~) of the desired compound.

Example 172 Cbz-6-aminohexanoyl-(4-methoxy)Phe-His AmidE: o.f (2S,3R.~S)-2-Amino-1-cyclohexyl 3,4-d hydroxy-6-methvlheptane.
Using the procedure of Example 21 but replacing TeA-CHA
with the resultant compound of Example 171 gave, after recrystallization from ethyl acetate, a 79i yield of the desired compound. '.Mass spectrum: (M + H)+ = 805.
Example 173 6-Aminohexanov7 A mixture of 0.97 g (1.2 mmol) of the resultant compound of Example 172 and 0.20 g of 20~ palladium on carbon in 150 mL of 95'1 aqueous acetic acid was shaken in a Parr Apparatus vender four atmospheres of H2. After filtration to remove catalyst, the solution was concen-trated in v~acuo, diluted with 75 mL of H20, and concentrated by lyophilization to give 0.86 g (91~) of the desired compound as a white solid. Mass spectrum:
(M+H)+ = 671.
Example 17~
Using the procedures of Examples 116. 117 and 118 but replacing L-Phe-C~CH3 'HC1 with D-Phe-OCH3 'HCl, gave the title compound. Mass spectrum: (M + H)+ _ 6 X11 .
Example 175 Ethyl H. dro en ( a . a -dimethylbenzyl )malonate .
Diethyl ( a , a -dimethylbenzyl)malonate was prepared by the congugate addition of phenyl magnesium bromide to - _ 1340984 diethyl isopropylidenemalonate as described by C. Holmberg [Liebiqs Ann. Chem., 748 (1981)]. A
solution of this diester (42.1 g, 0.15 mole) in ethanol (100 mL) wa:; treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mole) in 100 mL of ethanol. After heating at 90°C for 1 h and at 50°C for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water' and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5°C, acidified to pH 3, with 6N HC1 and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate. Evaporation of the solvent gave 27.3 g (84%) of liquid product. NMR (CDC13): 1.05 (3H, t), 1.6 (6H, s), 3.78 (1H, s), 3.96 (2H, m), 7.2-7.4 (5H, m).
Example 176 Ethyl 2(R,S)-[[(4-morpholinyl)carbonyl]amino]-3,3-dimethyl-3-phenylpropionate.
To a solution of ethyl hydrogen ( « , « -dimethylbenzyl) malonate (4 g, 0.016 mole) in toluene was added triethylamine (2.23 mL, 0.016 mole) and diphenyl-phosphoryl azide (4.4 g, 0.016 mole). The reaction mixture was heated at 100°C for 2.5 h, cooled to 5°C, and treated with 1.4 mL (0.016 mole) of morpholine.
After stirring overnight at room temperature, the toluene solution was washed successively with 1N HCI and aqueous sodium bicarbonate solution. The dried organic solution was evaporated to a residue which was purified by column chromatography on silica gel. There was obtained 3.7 g (69%) of product after trituration with hexane, mp 93-94°C.
Anal. ca:lcd. for C18H26N204: C, 64.65;
H, 7.84: N, 8.38.
Found: C. 64.72; H, 7.95; N, 8.33.

134pg84 Example 177 2(R,.S)-[[(4-Morpholinyl)carbonyl]amino]
3,:3-dimethvl-3- henyl ropionic Acid.
A solution of the product form Example 176 (2 g, 5 5.99 mmole) in dioxane (10 mL) was treated with 0.26 g (6.5 mmol) of sodium hydroxide in 5 mL of water. After stirring for 16 h at 35°C, the reaction was worked up as described in Example 175 to give a 93% yield of product.
10 Example 178 2 R,:~)-[[(4-Morpholinyl)carbonyl]amino]-3,3-dimethvl-3-phenylpropionyl-His Amide of 2(S)-Annino-1-cvclohexvl-3(R),4(S)-dihvdroxv-6-methylheptane.
The product from Example 20 was deprotected with HC1/
15 methanol and coupled to the product from Example 177 using the procedures described in Example 5 but modified as follows. IaOBT was not used in the coupling and the reaction time was 20 h. There was obtained an 80% yield of the desired product. Mass spectrum: (M + H)+ -20 669.
Example 179 H-Isonipecotyl-(4-OCH3)Phe-His Amide of 2 S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy 6-methyl:heptane Diacetic Acid Salt.

Using the pro~:edure of Examples 67 and 68, but replacing Cbz-isonipecot:yl-Phe with Cbz-isonipecotyl-(4-OCH3) Phe gave the desired product. Mass spectrum: (M + H)+
669 (free b~~se) .
30 Example 180 H-[ 8,13-~di-Me)-?-Ala]-(4-OCH )Phe-His Amide of 2(S)-Amino-1-cyclohexyl-3(R~,4(S)-dihydroxy 6-methylheptane Diacetic Acid Salt.
Using the procedures of Examples 74 and 75, but . 134984 replacing Cbz-[(ti,t3-di-Me)-B-Ala)-Phe with Cbz-[(D,a-di--Me)-Q-~Ala~-(OCH3)Phe gave the desired product. iM + H)+ = 657 (free base).
Example 181 2 S --t-Butyloxycarbonylamino-1-cyclohexyl-3(R)-hydroxy-6-methylheptan-4-one To ;d stirred -63°C solution of oxalyl chloride (784 mg, 6.18 mmol) in dry dichloromethane (15 mL) was added dry dimethylsulfoxide (708 mg, 9.06 mmol) dropwise over 5 minutes. After another 5 minutes, Boc-cyclo-hexylalanino7. (l.OSg, 4.12 mmol) in dichloromethane (5 mL) was addsad dropwise over 5 minutes, and 5 minutes later, triet;hylamine (1.67 g, 16.48 mmol) was added similarly. 'ZnI2 (300 mg, 0.94 mmol) was added over 5 minutes. After stirring for 2 minutes, trimethylsilyl cyanide (1.438, 1,.42 mmol) was added and the mixture was warmed to room temperature for 1 hour. The mixture was then cooled to 0°C and isobutylmagnesium chloride (22.0 mL of a 2 M soln. in ether) was added. After warming to room temperature for 4 hours, the mixture was poured into 1 I~ H3P04 (40 mL)/ice (SO mL) and extracted w9lth ethyl acetate. The combined organic phase was washed sequentially with 1 M H3P04, water, satd. NaHC:03, and brine. Drying (MgS04), filtering, and evaporating provided 1.75 g of, an oil which was dissolved in THF (75 mL) and treated with 1 M
H3P04 (25 m1~) for 18 hours at 5°C. The solution was partitioned between ethyl acetate/brine, a.nd the resulting organic phase was washed sequentially with brine, satd. NaHC03, and brine. Drying (MgS04), filtering, and evaporating provided the desired product (1.39 g, 994;) which was used directly in the next step.

. X340984 Example 182 -Butyloxycarbonvlamino-1-cvclohexvl-To a stirred solution of 2(S)-t-Hutyloxy-carbonylamino-1-cyclohexyl-3(R)-hydroxy-6-methylheptan-4-one (200 mg, 0.586 mmol) in THF (10 mL) was added NaHH4 (22 mg,, 0.588 mmol). After 2 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate! and brine. The organic~phase was washed (brine), driE~d (MgS04), filtered and evaporated. The residue was recrystallized from methylcyclohexane to give 76 mg (38~) of the desired product. M.p.
130-131°C. The mother liquor was chromatographed (silica gel, ~ether/Izexane) to afford 43 mg (21~) more.
Example 183 3R,5R,8S.,9R,lOS)-7-Aza-2-(t-Hutyloxycarbonylamino)--8- c clohexylmethyl)-12-methyl-5-(4- entenyl)_--1~-phenyl-3,9,10-trihvdroxvtridecane Using the procedures of Examples 165-169, but re lacin (3R,5R,1'S)-5-E(t-but to p g y xycarbonylamino)--2-phenylethy:l~-3-isobutyldihydrofuran-2-(3H)-one with (3R,5R,1'S)-5~-[(t-butyloxycarbonylamino)-2-phenylethyl~-3-(4-pentenyl)d:ihydrofuran-2-(3H)-one (D. J. Rempf, J.
Orq. Chew. 1986, 5:1, 3921) gave the desired compound in 52~ yield ~~fter purification by MPLC using 2:1 hexane/ethyl ~icetate. Mass spectrum: (M+H)+ = 617.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulf ate.
butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanep~:opionate, dodecylsulfate, ethanesulfonate, glucoheptanoai:e, glycerophosphate, hemisulfate, ~~~~984 heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate.
lactate, maleate, methanesulfonate, nicotinate.
2-naphthalene;~ulfonate, oxalate, pactwate, pectinate.
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate.
and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, 'and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl., and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples o:f acids which may be employed to form pharmaceutica~.ly acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, malefic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium.
calcium or magnesium or with organic bases.
Z'he <:ompounds of formula I can also be used in the form of esters. Examples of such esters include a hhdroxy:l-substituted compound which has bean acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used. These esters serve as pro-drugs of the compounds of formula I and serve to increase the solubility of these substances in the gastrointestinal tract. The preparation of the pro-drug esters is carried out . 1340984 reacting a .hydroxyl-substituted compound of formula I
with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester. s The compounds of formula I
possess an excellent degree of activity and specificity in treating resin-.associated hypertension in a host. The ability of the compounds to inhibit human renal resin can be demonstrated in vitro by reacting a aelected compound at varied concentrations ' with human renal resin, free from acid proteolytic activity, a.nd with resin substrate (human angio-tensinogen) at 37°C and pH 6Ø At the end of the incubation, the amount of angiotensin I formed is measured by :radioiunmunoassay and the molar concentration required to cause 50~ inhibition, expressed as the IC50, is calculated. When tested in accordance with the foregoin~~ procedure, the compounds of formula I
demonstrated IC50"s in the range of 10-5 to 10-10 M as seen in Table I.

Table I
Example Example Number IC50_,~ Number IC50- (nM) 3 4000 63 0.45 15 1.5 67 0.8 17 35 69 ' 0.81 18 95 70 2.5 21 2 74 0.7 22 1.5 75 0.4 23 10 76 0 . 5 10 24 2 77 0.98 25 20 81 0.6 26 1.5 82 0.6 27 7 83 0.6 29 0.6 85 0.4 30 4 . T5 87 0 .~55 31 1 88 0.6 33 5 90 0.!

34 1.5 91 0.3 35 1 92 0.5 36 0.4 93 0.55 37 0.5 97 0.3 20 !3 5 102 0.6 !6 1.5 103 1 47 1 108 0.55 49 2 111 0.5 54 0.95 114 1.3 56 5.5 118 0.5 25 57 7 =i 124 0 . 65 sg 7 127 0.75 61 0.55 141 5.5 62 2 143 0.3 169 6.0 178 2 173 0 . Si 179 1 174 12 180 0.8 1 3 4p gg 4 The c;ompounds of formula I also be used with one or more antihypertensive agents selected from the group consisting of diuretics, and/or t3-adrenergic blocking agena:s, central nervous syste~g -acting agents, adrenergic neuron blocking agents, vasodilators.
angiotensin I converting enzyme inhibitors, and other antihypertensive agents.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg. Dosage unit compositions may contain such aunounts of submultiples thereof to make up the dai ly dose .
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will :be understood, however, that the specific dose level for any particular patient will ;zp depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health., sex, diet, time of administration, route of administration, rate of excretion, drug combination.
and the severity of the particular disease undergoing ( ;~5 therapy.
The compounds of formula I may be administered ~~rally, parenterally, by inhalation spray.
rectally, or topic: ally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. 7:n addition, sterile, fixed oils are conventionall;Y employed as a solvent or suspending medium. For this, purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be F~repared by mixing the drug with a suitable nonirritating exci,pient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g.,~lubricating agents such as magnesium stearate. In the case of capsules, ta~~lets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluent:s commonly used in the art, such as water.

Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and . 1340984 sweetening, flavoring, and perfuming agents.
The foregoing is merely illustrative and is not intended to limit the invention to the disclosed', compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

1. A compound of the formula:
wherein R' is loweralkyl, vinyl or arylalkyl; P2 and P3 are independently selected from hydrogen and an O-protecting group: and P1 is hydrogen or an N-protecting group; or an acid addition salt thereof.

2. The compound of Claim 1 wherein R' is -CH2CH(CH3)2.

3. A compound of the formula:
wherein P1 is hydrogen or an N-protecting group and P2 and P3 are independently selected from hydrogen and an O-protecting group: or an acid addition salt thereof.

4. 2(S)-t-butyloxycarbonylamino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane.

5. 2(S)-amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane, or acid addition salts thereof.