Silanediol inhibitors of angiotensin-converting enzyme. Synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analogues

Article abstract of DOI:10.1021/jo048121v

Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from

Full text of DOI:10.1021/jo048121v

VOLUME 70, NUMBER 15
JULY 22, 2005
© Copyright 2005 by the American Chemical Society
Silanediol Inhibitors of Angiotensin-Converting Enzyme.
Synthesis and Evaluation of Four Diastereomers of Phe[Si]Ala
Dipeptide Analogues1
Jaeseung Kim,†,‡ Gregory Hewitt,† Patrick Carroll,§ and Scott McN. Sieburth*,†,‡
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794,
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19010, and Department of
Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
scott.sieburth@temple.edu
Received October 23, 2004
Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of
angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist
et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl
3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second
stereogenic center. The diastereomeric identities were established by X-ray crystallography of an
intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC50 ) 3.8-207 nM) closely
paralleled that of the corresponding diastereomeric ketones (IC50 ) 1.0-46 nM). The fourth
diastereomer, corresponding to the least inhibitory ketone (IC50 ) 3200 nM), exhibited an unexpected
level of inhibition in the silanediol (IC50 ) 72 nM), suggesting an alternative mode of binding to
the enzyme.
Inhibition of angiotensin-converting enzyme (ACE) is
a classic medicinal chemistry approach to the treatment
of hypertension, with 10 inhibitors currently sold in the
U.S.2 Captopril, 1ad Figure 1, was the first protease
inhibitor to achieve commercial success. Despite the long-
standing importance of this enzyme, its crystal structure
has only recently been reported.3
ACE is a metalloprotease4 and inhibitors incorporate
a functional group (X, Figure 1) that interacts with the
active site zinc ion: thiol a, carboxylates b and c (R )
H), and the phosphinic acid of 4 (R ) H). Among the
commercially successful inhibitors, most are based on the
alanine-derived fragment 1, with one of three substitu-
ents a-c, and proline or a proline surrogate (d-j).2
Our interest in exploring the use of a silanediol group
as a central, zinc chelating component of a protease
inhibitor6-10 was motivated by both the similarity and
the dissimilarity of carbon and silicon chemistry. Silicon
* Address correspondence to this author at the Department of
Chemistry, Temple University. Phone: 215-204-7916.
† State University of New York at Stony Brook.
‡ Temple University.
§ University of Pennsylvania.
(1) Initial report: Kim, J.; Sieburth, S. McN. Bioorg. Med. Chem.
Lett. 2004, 14, 2853-2856.
(3) Natesh, R.; Schwager, S. L. U.; Sturrock, E. D.; Acharya, K. R.
Nature (London) 2003, 421, 551-554.
(4) Lipscomb, W. N.; Stra¨ter, N. Chem. Rev. 1996, 96, 2375-2433.
(2) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000,
43, 305-341.
10.1021/jo048121v CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/16/2005
J. Org. Chem. 2005, 70, 5781-5789
5781

Kim et al.
FIGURE 1. Components of commercial ACE inhibitors.5
FIGURE 2. Almquist’s ketone inhibitor 5, silanediol ana-
is the element most closely related to carbon, but it forms
double bonds only under duress. This property allows
silanediols to act as tetrahedrally stable mimics of a
hydrated carbonyl, although as a second row element the
silane would be marginally larger. Silanediols may have
advantages over other hydrated carbonyl isosteres be-
cause they are neutral at physiological pH. Phosphinic
acids 4 and carboxylates b and c have pKa values below
5 and can require delivery as ester prodrugs.
We targeted ACE as our initial foray into metallopro-
tease inhibition with silanediols because of the maturity
of this enzyme’s structure-activity mapping, its ready
availability, and its importance as a pharmaceutical
target. A critical issue, however, was the choice of an
inhibitor structure with which one could formulate a first-
generation silanediol-based inhibitor, a structure with a
degree of steric hindrance surrounding the zinc-binding
element.
Silanediols are best known as unstable precursors of
siloxane polymers.11 The stability of silanediols is intrin-
sically linked to the steric shielding provided by the two
organic groups that flank the silanediol.12 Introduction
of a silanediol group into one of the commercial ACE
inhibitors, Figure 1, at a position that would interact with
the active site zinc ion, would replace the thiol or the
carboxylate groups in partial structures a-c, or the
phosphorus in 4. Unfortunately, none of the resulting
structures would have provided a silanediol environment
commensurate with unequivocally suppressing oligomer
formation. In contrast, Almquist’s ketone 5,13-15 Figure
2, has a more substantial peptide-like structure, with
what appeared to be an ideal level of substitution on
either side of the ketone. The ketone is presumably bound
logues 6-9, and the first silanediol inhibitor structures 10 and
11.
to the enzyme as the ketone hydrate.16,17 At the outset
of this project, the literature contained approximately 100
characterized silanediols.18 None, however, contained
stereogenic centers or functional groups. The effect of the
latter on the silanediols was, therefore, unknown.
In our first exercise in silanediol-based protease inhibi-
tor synthesis, the initial structures to be prepared
included silanediol 10 and methylsilanol 11.7 Silanediol
10 was the structure most analogous to ketone 5, but
carried an isobutyl group where 5 has a benzyl group.
In addition, the two stereogenic carbons flanking the
silanediol were not controlled, yielding a mixture of four
diastereomers. Nevertheless, this diastereomeric mixture
was found to inhibit ACE with an IC50 value of 14 nM.
Considering that only one of the four diastereomers
would be expected to provide most of the inhibition, this
was considered a highly successful outcome. In compari-
son, replacement of the central silanediol, anticipated to
be important for interaction with the enzyme active site,
with a methylsilanol group, 11, gave little enzyme
inhibition (IC50 > 3000 nM). These results were consis-
tent with the silanediol group interacting with the
enzyme as a transition state analogue inhibitor of ACE,
and provided impetus for additional investigation.
The publications of Almquist et al. included ACE
inhibition data for 5, and for the three individual dia-
stereomers derived by systematically changing the ster-
eochemistry of the methyl and benzyl substituents.15 We
therefore set out to prepare the exact silanediol analogue
6 and each of the analogous diastereomers 7-9 for
comparison with their respective ketones.
(5) Captopril (1ad), perindopril (1bg), enalapril (1cd), ramipril (1cf),
trandolapril (1ch), quinapril (1ci), moexipril (1cj), lisinopril (2cd),
benzapril (3c), fosinopril (4e).
(13) Almquist, R. G.; Chao, W.-R.; Ellis, M. E.; Johnson, H. L. J.
Med. Chem. 1980, 23, 1392-1398.
(6) Sieburth, S. McN.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew.
Chem., Int. Ed. 1998, 37, 812-814.
(14) Meyer, R. F.; Nicolaides, E. D.; Tinney, F. J.; Lunney, E. A.;
Holmes, A.; Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Kaplan, H.
R.; Almquist, R. G. J. Med. Chem. 1981, 24, 964-969.
(15) Almquist, R. G.; Crase, J.; Jennings-White, C.; Meyer, R. F.;
Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Kaplan, H. R. J. Med.
Chem. 1982, 25, 1292-1299.
(7) Mutahi, M. W.; Nittoli, T.; Guo, L.; Sieburth, S. McN. J. Am.
Chem. Soc. 2002, 124, 7363-7375.
(8) Kim, J.; Glekas, A.; Sieburth, S. McN. Bioorg. Med. Chem. Lett.
2002, 12, 3625-3627.
(9) Kim, J.; Sieburth, S. McN. J. Org. Chem. 2004, 69, 3008-3014.
(10) Kim, J.; Sieburth, S. McN. Bioorg. Med. Chem. Lett. 2004, 14,
2853-2856.
(16) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985,
24, 1813-1817.
(17) Brady, K.; Abeles, R. H. Biochemistry 1990, 29, 7608-7617.
(18) A current search of the Beilstein-Crossfire database indicates
that the number is now closer to 140.
(11) West, R. In Encyclopedia of Inorganic Chemistry; King, R. B.,
Ed.; Wiley: New York, 1994; Vol. 6, pp 3389-3404.
(12) Lickiss, P. D. Adv. Inorg. Chem. 1995, 42, 147-262.
5782 J. Org. Chem., Vol. 70, No. 15, 2005

Silanediol ACE Inhibitors
SCHEME 1. Retrosynthesis of 6-9
Nucleophile 16 was prepared in four steps, beginning
with (S)-17, following the method of White et al.20
O-Benzylation of the alcohol using benzyl trichlorometh-
ylimidate (83%), followed by reduction of the ester by
lithium aluminum hydride (87%) and conversion of the
resulting alcohol to the iodide using iodine and triphen-
ylphosphine (85%), gave 21. This iodide was converted
to the corresponding lithium reagent 16 using 2 equiv of
tert-butyllithium.21,22 Addition of this anion to fluorosilane
20 gave the silane 22 in 65% yield. Hydrolysis of the
dithiane using mercuric chloride in aqueous acetonitrile
gave the yellow, sensitive silyl ketone 13 (73%),23-25
which was immediately reduced to a 1:1 mixture of
diastereomeric alcohols 23 in quantitative yield.
Alcohols 23 proved to be difficult to separate and the
next four stages of the syntheses were conveniently
carried out on the diastereomeric mixture. Displacement
of the alcohol with phthalimide using Mitsunobu condi-
tions (63%), followed by removal of the phthalimide group
using hydrazine, gave a primary amine that was con-
densed with benzoyl chloride to furnish amide 24 (91%
for two steps). Removal of the benzyl protecting group
with boron tribromide then gave a mixture of 25 and 26
(90%). With an alcohol and a secondary amide adjacent
to the two stereogenic centers, these diastereomers could
be readily separated over silica gel. For the two diaster-
eomers, one of the stereogenic centers was established
by its source in 17, but the relatively remote R-aminosi-
lane stereocenter of the (S,S) and (S,R) isomers was more
difficult to define and was eventually resolved by X-ray
crystallography (see below).
Results and Discussion
To prepare the individual stereoisomers 6-9, we
adopted the retrosynthetic plan shown in Scheme 1.
Using our previously successful approach, acidic hydroly-
sis of a diphenylsilane to reveal the silanediol in the last
stage of the synthesis,6-8,19 the direct precursor of 6
became diphenylsilane 12. R-Aminosilane 12 would be
prepared from the ketone 13. Indiscriminant reduction
the carbonyl of 13 would yield two diastereomers, and
ultimately both 6 and 7. The ketone 13 would be prepared
via three-component coupling of nucleophiles 14 and 16
with diphenyldifluorosilane 15. The enantiomerically
pure lithium reagent 16 would be derived from the
commercially available (S)-17. In a similar fashion,
silanediols 8 and 9 would be prepared from the com-
mercially available (R) isomer 18.
Completion of the silanediol synthesis was conducted
using the individual stereoisomers 25 and 26. Alcohol 26
was oxidized to the acid in two stages, using Ley’s
Assembly of the silanediols is shown in Scheme 2,
which begins with dithiane 19. Metalation of 19 followed
by transfer of the anion to a slight excess of difluo-
rodiphenylsilane at -78 °C gave the fluorosilane 20 in
83% yield, ready for introduction of the nucleophile 16.
perruthinate method to give the aldehyde,26
immediately
followed by Pinnick oxidation27 to the acid using buffered
SCHEME 2. Synthesis of Silanediols 6-9
J. Org. Chem, Vol. 70, No. 15, 2005 5783

Kim et al.
SCHEME 3. Hydrolysis of the Diphenylsilanes to
Silanediols
FIGURE 3. Crystal structure of alcohol 26.
relative stereochemistry shown in the crystal structure
defined the absolute configurations of 25 and 26, and
therefore 6 and 7. With the origin of 8 and 9 from (R)-
18, the chromatographic properties of ent-25 and ent-26
fully clarified the identity of the stereoisomers of their
progeny 8 and 9, setting the stage for evaluation of their
ability to inhibit ACE.
sodium chlorite (77% for the two steps). The acid was
then coupled with the tert-butyl ester of L-proline using
diethyl cyanophosphonate to give diamide 27 (80%).28 The
ultimate step in the preparation of the silanediol was
acidic hydrolysis of the diphenylsilane 27 with simulta-
neous removal of the tert-butyl ester, to give the silanediol
6, performed using triflic acid. The two remaining dia-
stereomeric silanediols 8 and 9 were prepared from the
(R) hydroxy ester 18, with a set of reactions identical with
those used with 17.
It is notable that the L-proline adducts of the stereo-
isomers derived from (S)-alcohol 17 exhibited well-
resolved signals in the NMR spectra. In contrast, the (R)-
alcohol 18-derived adducts with L-proline gave the ap-
pearance of a mixture in their NMR spectra. These were
conformation/rotamer-based subspecies of the pure sub-
stances, shown by heating the samples to 105 °C in
DMSO-d6, which collapsed the multiplicity of NMR
absorbances into a single set of peaks.
Hydrolysis of the diphenylsilanes merits discussion.
The protolytic cleavage of aryl groups from silicon is a
long-established transformation, involving ipso protona-
tion of the aromatic ring followed by cleavage of the
silicon-carbon bond, a bond cleavage that requires
simultaneous attack of a nucleophile on silicon, Scheme
3.30 In the case of the diphenylsilane 27 and its stereo-
isomers, two amides are poised for intramolecular attack
to yield a postulated spirocyclic intermediate 29. Addition
of ammonium hydroxide allows the silyl ethers, which
are strained,31 to hydrolyze to the silanediol. In some
cases, the silanediol 6 can be isolated directly following
the ammonium hydroxide treatment; however, acidic and
basic conditions promote polymerization of dialkylsi-
lanediols.32 To counteract any oligomer formation, we
have incorporated the addition of 48% HF to the hydroly-
sis procedure, which converts any silicon-heteroatom
bond to a silicon-fluorine bond, yielding the monomeric
difluorosilane 30.33,34 This procedure has proven to be
particularly valuable for silanediols less sterically pro-
tected than 6-9,9 and when used with the compounds
described here lead to very clean, monomeric difluorides
and silanediols. As in prior examples, treatment of the
difluorosilane 30 with sodium hydroxide led to a rapid
hydrolysis to the silanediol.
The hydroxyamide stereoisomer 26 provided crystals
and a crystal structure, Figure 3, revealing the relative
stereochemistry of the two stereogenic centers.29 The
crystal structure of 26 shows the alcohol forming an
eight-membered ring hydrogen bond to the secondary
amide. The derivation of 26 from (S)-17 coupled with the
(19) Chen, C.-A.; Sieburth, S. McN.; Glekas, A.; Hewitt, G. W.;
Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffrey,
S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161-1166.
(20) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292-5300.
(21) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404-
5406.
(22) Negishi, E.-i.; Swanson, D. R.; Rousset, C. J. J. Org. Chem.
1990, 55, 5406-5409.
Evaluation of the silanediols 6-9 was conducted using
(23) Brook, A. G.; Duff, J. M.; Jones, P. F.; Davis, N. R. J. Am. Chem.
Soc. 1967, 89, 431-434.
Holmquist’s modification35 of the enzyme assay described
(24) Corey, E. J.; Seebach, D.; Freedman, R. J. Am. Chem. Soc. 1967,
89, 434-436.
(25) Page, P. C. B.; McKenzie, M. J. Sci. Synth. 2002, 4, 513-567.
(26) Ley, S. Y.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(30) Eaborn, E. J. Organomet. Chem. 1975, 100, 43-57.
(31) Corriu, R. J. P.; Gue´rin, C.; Guirand, G. J. Chem. Soc., Chem.
Commun. 1979, 8-9.
(27) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(32) Osterholtz, F. D.; Pohl, E. R. J. Adhes. Sci. Technol. 1992, 6,
127-149.
(28) Takuma, S.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982,
30, 3147-3153.
(33) Marans, N. S.; Sommer, L. H.; Whitmore, F. C. J. Am. Chem.
Soc. 1951, 73, 5127-5130.
(29) Compound 26 crystallizes from acetonitrile in the monoclinic
space group P21 with a ) 13.8822(8) Å, b ) 8.4270(6) Å, c ) 24.2031-
(14) Å, b ) 92.353(5)°, V ) 2829.0(3) Å3, Z ) 4, and dcalc ) 1.126 g/cm3.
Final least-squares refinement using 9016 unique reflections with I
> 3σ(I) gave R (Rw) ) 0.1060 (0.1933).
(34) Eaborn, C. J. Chem. Soc. 1952, 2846-2849.
(35) Holmquist, B.; Bu¨nning, P.; Riordan, J. F. Anal. Biochem. 1979,
95, 540-548.
5784 J. Org. Chem., Vol. 70, No. 15, 2005

Silanediol ACE Inhibitors
(0:1-2:98 ethyl acetate/hexanes) to produce ent-21 (5.47 g,
85%) as a clear oil.
(S)-21: [R]20 14.5 (c 1.41, CHCl3); IR (neat) 3029, 2868,
D
1453, 1361, 1199, 1100, 736, 697 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 7.39-7.26 (m, 5H), 4.53 (s, 2H), 3.43-3.28 (m, 4H),
1.85-1.75 (m, 1H), l.00 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.3, 128.3, 127.6, 74.1, 73.1, 35.1, 17.6, 13.9.
(R)-ent-21: [R]20 -10.0 (c 5.4 CH2Cl2); Rf 0.42 (1:19 ethyl
D
acetate/hexanes); IR (neat) 3029.0, 2960.6, 1453.3, 1361.7,
1
1101.3, 697.2 cm-1; H NMR (300 MHz, CDCl3) δ 7.37-7.33
(m, 5H), 4.53 (s, 2H), 3.42-3.29 (m, 4H), 1.85-1.75 (m, 1H),
l.00 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.3,
128.3, 127.6, 74.0, 73.1, 35.1, 17.6, 13.9; exact mass (FAB) MH+
calcd for C11H16IO 291.0246, found 291.0240.
[2-(Phenylmethyl)-1,3-dithian-2-yl]fluorodiphenylsi-
lane (20). To a 0 °C solution of 2-benzyl-1,3-dithiane (19) (9.86
g, 46.9 mmol) in THF (200 mL) was added n-butyllithium (2.5
M in hexane, 20.0 mL, 50 mmol). The resulting solution was
stirred for 1.25 h at 0 °C, cooled to -78 °C, and then
transferred by cannula to a -78 °C solution of diphenyldi-
fluorosilane (12.46 g, 56.56 mmol) in THF (100 mL) over 10
min. After 1 h at -78 °C, the solution was allowed to gradually
warm to room temperature over 5 h and then stirred overnight.
After addition of water (200 mL), the aqueous phase was
extracted with CH2Cl2 (3 × 200 mL). The combined organics
were then washed with brine and dried over Na2SO4. The
solution was concentrated and purified by flash chromatog-
raphy (5:95 ethyl acetate/hexanes) to give 20 as a colorless
solid (16.06 g, 83%). Mp 83-84 °C; Rf 0.42 (5:95 ethyl acetate/
hexanes); IR (neat) 3112, 2924, 1442, 1289, 1121, 862, 694
FIGURE 4. Comparative IC50 data for silanediols 6-9 and
ketones 5 and 31-33.15 P indicates proline.
by Cushman and Cheung,35,36 employing commercially
available enzyme and fluorescent substrate,37 and the
results are shown in Figure 4. Gratifyingly, the potency
of the most effective silanediol inhibitor 6 was nearly as
effective as the corresponding ketone 5, less inhibitory
by a factor of 4. Similarly, silanediols 7 and 8 were
slightly less potent inhibitors than the ketone diastere-
omers 31 and 32, by a factor of 2.3 and 4.5, respectively,
confirming the greater sensitivity of the methyl stereo-
chemistry relative to the benzyl group. Surprisingly,
inverting both stereogenic centers relative to the most
potent inhibitors led to a silanediol (9) that was more
potent of an inhibitor of ACE than simply changing the
methyl stereochemistry (8). This is in stark contrast to
the effect of these stereogenic centers with the ketone
33 where the effect is synergistic; inverting both stereo-
genic centers relative to 5 results in a structure with very
low inhibitory activity. This result may indicate that the
silanediol 9, with its slightly altered bond lengths and
bond angles relative to the carbonyl hydrate, can interact
with the enzyme in a different manner. Additional
studies are in progress.
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.94-7.27 (m, 15H), 3.34
(s, 2H), 2.73-2.67 (m, 2H), 2.52-2.45 (m, 2H), 1.80-1.76 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 136.0, 135.4, 131.48, 131.39,
130.7, 127.8, 127.5, 126.9, 44.2, 38.0 (d due to F, J ) 56.0 Hz),
25.6, 23.2; 19F NMR (376 MHz, CDCl3) δ -168.5; exact mass
(FAB) (M - H)+ calcd 409.0916, found 409.0911.
[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl][2-(phen-
ylmethyl)-1,3-dithian-2-yl]diphenylsilane (ent-22). To a
solution of [[(2R)-3-iodo-2-methylpropoxy]methyl]benzene (ent-
21) (7.47 g, 25.8 mmol) in pentane (150 mL) and ether (105
mL) at -78 °C was added tert-butyllithium (1.38 M, 44.0 mL,
60.7 mmol) slowly over 2 min. After being stirred for 30 min
at -78 °C, the solution was warmed to room temperature over
20 min, then recooled to -78 °C. this solution was transferred
by cannula over 5 min to a -78 °C solution of (2-benzyl[l,3]-
dithian-2-yl)fluorodiphenylsilane (20) (10.9 g, 26.6 mmol) in
ether (105 mL). After 3 h at -78 °C the solution was allowed
to slowly warm to room temperature over 6 h and kept at room
temperature overnight. After addition of water (200 mL) and
extraction of the aqueous phase with CH2Cl2 (3 × 250 mL),
the combined organics were washed with brine, dried over Na2-
SO4, concentrated, and purified by flash chromatography (1:1
methylene chloride/hexanes) to give ent-22 as a clear viscous
Experimental Section
[[(2R)-3-Iodo-2-methylpropoxy]methyl]benzene (ent-
21).38 To a 0 °C solution of (2S)-2-methyl-3-(phenylmethoxy)-
1-propanol20 (3.99 g, 22.17 mmol), triphenylphosphine (6.30
g, 24.0 mmol), and imidazole (1.63 g, 23.9 mmol) in ether (40
mL) and CH3CN (25 mL) under nitrogen was added a solution
of iodine (6.05 g, 23.8 mmol) in ether (35 mL). The reaction
was kept at 0 °C for 3.5 h. The solution was transferred to a
separatory funnel with ether (50 mL). The solution was
washed successively with saturated Na2S2O3 (60 mL), satu-
rated Cu2SO4 (30 mL), water (40 mL), and brine (40 mL). The
organic portions were dried over MgSO4, filtered, and concen-
trated. Cold hexanes was added to precipitate triphenylphos-
phine oxide, which was removed by vacuum filtration. The
filtrate was concentrated and purified by flash chromatography
oil (9.31 g, 65%): Rf 0.28 (5:95 ethyl acetate/hexanes); [R]20
D
18.7 (c 0.87 CHCl3); IR (neat) 3054, 2966, 1422, 1265, 911, 745,
1
650 cm-1; H NMR (400 MHz, CDCl3) δ 8.06-7.41 (m, 20 H),
4.53 (s, 2H), 3.60 (s, 2H), 3.34-3.29 (m, 2H), 2.65-2.58 (m,
2H), 2.52-2.47 (m, 2H), 2.29-2.16 (m, 1H), 2.02-1.94 (m, 2H),
1.77 (dd, J ) 4.2, 15.2 Hz, 1H), 1.34 (dd, J ) 8.0, 15.2 Hz,
1H), 0.92 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz CDCl3) δ
138.9, 138.4, 136.9, 133.2, 132.7, 131.5, 129.6, 128.2, 127.7,
127.4, 127.3, 126.7, 77.7, 72.6, 47.0, 37.6, 29.5, 25.2, 23.4, 20.3,
14.8; exact mass (FAB) MNa calcd for C34H38ONaS2Si 577.2031,
found 577.2052.
(S)-22: [R]20 -16.6 (c 0.82, CHCl3); IR (neat) 3003, 2900,
D
1
1467, 1427, 1101, 752, 704 cm-1; H NMR (300 MHz, CDCI3)
δ 7.84-7.17 (m, 20 H), 4.31 (s, 2H), 3.38 (s, 2H), 3.15-3.01
(m, 2H), 2.45-2.35 (m, 2H), 2.31-2.24 (m, 2H), 2.00-1.90 (m,
1H), 1.83-1.71 (m, 2H), 1.56 (dd, J ) 4.9, 5.8 Hz, 1H), 1.12
(dd, J ) 8.0, 7.4 Hz, 1H), 0.70 (d, J ) 6.6 Hz, 3H); 13C NMR
(63 MHz CDCl3) δ 138.9, 138.4, 136.9, 133.2, 132.7, 131.5,
129.6, 128.2, 127.7, 127.4, 127.3, 126.7, 77.7, 72.6, 47.0, 37.6,
(36) Cushman, D. W.; Cheung, H. S. Biochem. Pharmacol. 1971, 20,
1637-1648.
(37) Angiotensin-converting enzyme from rabbit lung (Sigma) and
N-[3-(2-furyl)acryloyl]-Phe-Gly-Gly as substrate.
(38) Keck, G. E.; Palani, A.; McHardy, S. F. J. Org. Chem. 1994,
59, 3113-3122.
J. Org. Chem, Vol. 70, No. 15, 2005 5785

Kim et al.
29.5, 25.2, 23.4, 20.3, 14.8; exact mass (FAB) [M - H]+ calcd
a solution of the mixture of two diastereomers of 1-[(3-
benzyloxy-2(R)-methylpropyl)diphenylsilanyl]-2-phenyletha-
nol (ent-23) (0.568 g, 1.22 mmol), phthalimide (0.248 g, 1.68
mmol), and triphenylphosphine (0.48 g, 1.83 mmol) in THF
(12.0 mL) at 0 °C was added diethyl azodicarboxylate (DEAD,
0.36 mL, 2.28 mmol) over 2 min. The flask was removed from
the cooling bath, and the resulting yellow solution was stirred
at room temperature for 24 h. The resulting mixture was
concentrated and purified by flash chromatography (2:98-1:9
ethyl acetate/hexanes) to provide an inseparable mixture of
the two diastereomers of 2-[1-[(3-benzyloxy-2(R)-methylpro-
pyl)diphenylsilanyl]-2-phenylethyl]isoindole-1,3-dione as a vis-
cous oil (0.458 g, 63%): Rf 0.32 (15:85 ethyl acetate/hexanes);
IR (neat) 3027.1, 2855.4, 1773.4, 1705.9, 1454.2, 1385.8,
1102.3, 735.8, 699.2 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.80-
7.15 (m, 24H), 4.83 (t, J ) 13.2 Hz, 1H), 4.42 (s, 2H), 3.50-
3.40 (m, 1H), 3.31-3.17 (m, 3H), 2.08-2.00 (m, 1H), 1.77 (dd,
J ) 4.8, 9.6 Hz, 1H), 1.34 (dd, J ) 4.8, 15.2 Hz, 1H), 0.90 (d,
J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.1 (br),
139.2, 138.6, 135.7, 135.4, 134.1, 133.9, 133.3, 133.2, 131.6,
129.6, 128.5, 128.2, 127.8, 127.6, 127.4, 127.2, 126.2, 77.4, 72.4,
41.6, 35.0, 29.5, 20.2, 16.0; exact mass (FAB) MNa, calcd for
C39H37NO3NaSi 618.2440, found 618.2432.
for C34H37OS2Si 553.2055, found 553.2051.
[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl][2-phenyl-
1-oxoethyl]diphenylsilane. To a solution of [(2R)-2-methyl-
3-(phenylmethoxy)-1-propyl][2-(phenylmethyl)-1,3-dithian-2-
yl]diphenylsilane (ent-22) (1.71 g, 3.08 mmol) in CH3CN (66
mL) was added HgCl2 (4.27 g, 15.7 mmol) and water (8.5 mL).
The resulting milky white suspension was stirred at room
temperature for 1.25 h. The suspension was concentrated
under reduced pressure, diluted with water (200 mL), and
extracted thrice with 200-mL portions of hexanes. The com-
bined organic extracts were washed with brine, dried over
MgSO4, and filtered through a 1 in. pad of Celite. The filtrate
was concentrated under reduced pressure and purified by flash
chromatography (1:9 ethyl acetate/hexanes) to give [(2R)-2-
methyl-3-(phenylmethoxy)-1-propyl][2-phenyl-1-oxoethyl]diphen-
ylsilane as a clear yellow oil (1.05 g, 73%): Rf 0.47 (1:9 ethyl
acetate/hexanes); [R]20D 11.0 (c 1.65 CHCl3); IR (neat) 3028.1,
1
2869.7, 1649.0, 1453.3, 1428.2, 1110.0, 734.8, 698.2 cm-1; H
NMR (300 MHz, CDCl3) δ 7.60-6.84 (m, 20H), 4.29 (s. 2H),
3.84 (s, 2H), 3.17 (d, J ) 6.3 Hz, 2H), 2.03-1.92 (m, 1H), 1.49
(dd, J ) 6.0, 15.3 Hz, lH), 1.13 (dd, J ) 8.1, 15.3 Hz, 1H), 0.83
(d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 240.2, 138.4,
135.5, 135.4, 132.8, 132.2, 132.1, 130.0, 129.8, 128.2, 128.0,
127.4, 127.3, 126.4, 77.2, 72.5, 55.6, 29.6, 20.3, 16.5; MS m/e
(rel intensity) 487 (MNa, 3), 137 (26), 155 (11), 177 (100), 199
(38), 259 (26), 375 (30), 439 (24)
(S): IR (neat) 3021, 1724, 1408, 1112, 721, 698 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.62-6.96 (m, 24H), 4.61 (t, J )
13.2 Hz, 1H), 4.24 (s, 2H), 3.31-3.20 (m, 1H), 3.11-2.98 (m,
3H), 1.87-1.82 (m, 1H), 1.56 (dd, J ) 4.8, 8.0 Hz, 1H), 1.14
(dd, J ) 8.8, 15.2 Hz, 1H), 0.70 (d, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.8 (br), 139.2, 138.6, 135.6, 135.5,
135.4, 134.0, 133.3, 133.2, 131.5, 129.6, 128.4, 128.1, 127.7,
127.3, 127.2, 126.2, 77.4, 72.5, 41.9, 35.1, 29.5, 20.3, 16.1; exact
mass (FAB) MNa+, calcd for C39H37NO3SiNa 618.2440, found
618.2427.
(S): [R]20D -11.5 (c 0.82 CHCl3); IR (neat) 33069, 2822, 1648,
1421, 1111, 735, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.60-
6.84 (m, 20H), 4.31 (m. 2H), 3.84 (s, 2H), 3.17 (dd, J ) 1.5, 6.5
Hz, 2H), 2.03-1.92 (m, 1H), 1.49 (dd, J ) 5.9, 14.9 Hz, lH),
1.13 (dd, J ) 7.9, 15.1 Hz, 1H), 0.83 (d, J ) 6.6 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 240.5, 138.6, 135.6, 132.9, 132.3,
132.2, 130.0, 129.9, 128.3, 128.1, 127.5, 127.4, 126.5, 77.3, 72.6,
55.7, 29.6, 20.3, 16.5; exact mass (FAB) (MNa+) calcd for
C31H32O2SiNa 487.2069, found 487.2048.
[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl][1-(ben-
zoylamino)-2-phenylethyl]diphenylsilane (ent-24). To a
solution of 1-{[(3-benzyloxy-2(R)-methylpropyl)diphenylsila-
nyl]-2-phenylethyl}isoindole-1,3-dione (135 mg, 0.227 mmol)
in absolute ethanol (3.5 mL) was added hydrazine (0.10 mL,
3.1 mmol), and the mixture was heated to reflux for 6 h, during
which a white precipitate was observed. The mixture was
cooled and filtered through a plug of glass wool, concentrated,
resuspended in ether, and filtered through a short pad of silica
gel. The filtrate was concentrated, diluted with ether (3.0 mL)
and saturated NaHCO3 (1.0 mL), and cooled to 0 °C. Benzoyl
chloride (0.03 mL, 36.3 mg, 0.258 mmol) was added and after
1.5 h the solution was washed with saturated NH4Cl solution.
The aqueous portion was extracted with ether (3 × 10 mL),
and the combined organic extracts were washed with saturated
NaCl (15 mL), dried over Na2SO4, concentrated, and purified
by flash column chromatography (2:98-1:4 ethyl acetate/
hexanes) to yield a mixture of diastereomers of ent-24 (117
mg, 91%): Rf 0.27 (15:85 ethyl acetate/hexanes); IR (neat)
3027.1, 2906.6, 1658.7, 1650.0, 1643.3, 1601.8, 1515.0, 1486.1,
1313.5, 1105.2, 1076.2, 733.9, 698.2 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.51-7.02 (m, 25H), 5.89 (d, J ) 10.4 Hz, 1H), 4.77-
4.71 (m, 1H), 4.24 (d, J ) 4.4 Hz, 2H), 3.06-2.92 (m, 3H), 2.50
(t, J ) 14.0 Hz, 1H), 1.84-1.76 (m, 1H), 1.38 (dd, J ) 4.8, 8.0
Hz, 1H), 0.97-0.90 (m, 1H), 0.70 (d, J ) 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.9, 139.1, 138.4, 135.5, 135.4, 135.3,
133.7, 133.3, 132.9, 130.8, 129.8, 128.8, 128.32, 128.22, 128.09,
127.6, 127.4, 127.3, 126.4, 126.1, 77.6, 72.8, 38.9, 37.7, 29.6,
20.4, 16.2; exact mass (FAB) (MH+) calcd for C38H40NO2Si
570.2828, found 570.2809.
[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl][2-phenyl-
1-hydroxyethyl]diphenylsilane (ent-23). To a 0 °C solution
of LiAlH4 (0.206 g, 5.4 mmol) in ether (40 mL) was added
dropwise a solution of 1-[(3-benzyloxy-2(R)-methylpropyl)-
diphenylsilanyl]-2-phenylethanone (0.51 g, 1.1 mmol) in ether
(10 mL) over 10 min. The reaction mixture was maintained
at 0 °C for 1 h and then warmed to room temperature over 2
h. The reaction was quenched with water (1 mL), 1 M NaOH
(1 mL), and water (2 mL). MgSO4 was added and the solution
was filtered and concentrated to afford a clear oil that was
purified by flash chromatography (2:98-1:4 ethyl acetate/
hexanes) to give a mixture of the two diastereomers 1-[(3-
benzyloxy-2(R)-methylpropyl)diphenylsilanyl]-2-phenyletha-
nol (ent-23) as a clear colorless oil (0.51 g, quantitative): Rf
0.36 (1:9 ethyl acetate/hexanes); IR (neat) 3549.8, 3027.1,
1
2855.4, 1453.3, 1427.2, 1109.0, 1076.2, 733.9, 699.2 cm-1; H
NMR (400 MHz, CDCl3) δ 7.81-7.27 (m, 20H), 4.49 (s, 1H),
4.43 (d, J ) 6.4 Hz, 1H), 4.26-4.24 (m, 1H), 3.36-3.31 (m,
2H), 3.04-2.99 (m, lH), 2.85-2.78 (m, 1H), 2.22-2.16 (m, 1H),
1.99 (br s, 1H), 1.66 (dd, J ) 5.6, 14.8 Hz, 1H), 1.25 (dd, J )
8.0, 14.8 Hz, 1H), 1.01 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 139.8, 138.4, 135.5, 134.3, 134.1, 129.4, 129.0, 128.4,
128.2, 127.8, 127.5, 127.4, 126.2, 77.6, 72.7, 65.2, 39.8, 29.6,
20.6, 15.6; exact mass (FAB) (MNa+) calcd for C31H34O2SiNa,
489.2226, found 489.2235.
(S)-23: IR (neat) 3412, 3022, 2901, 1420, 1113, 721, 701
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.67-7.14 (m, 20H), 4.38
(s, 1H), 4.33 (d, J ) 2.7 Hz, 1H), 4.18-4.10 (m, 1H), 3.22 (t, J
) 6.3 Hz, 2H), 2.94-2.85 (m, lH), 2.74-2.63 (m, 1H), 2.09-
2.01 (m, 1H), 1.78 (dd, J ) 4.2, 23.5 Hz, 1H), 1.49-1.39 (m,
IH), 1.17-0.99 (m, 1H), 0.87 (dd, J ) 2.6, 6.6 Hz, 3H); 13C NMR
(63 MHz, CDCl3) δ 139.8, 138.47, 135.57, 134.45, 134.21, 129.5,
129.1, 128.52, 128.50, 127.90, 127.58, 127.42, 126.30, 77.7,
72.8, 65.3, 39.9, 29.7, 20.6, 15.8.
(S)-24: IR (neat) 3428, 3312, 3104, 2881, 1688, 1541, 1485,
1112, 721, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52-7.04
(m, 25H), 5.93 (d, J ) 10.0 Hz, 1H), 4.80-4.73 (m, 1H), 4.25
(d, J ) 4.4 Hz, 2H), 3.11-2.95 (m, 3H), 2.52 (t, J ) 11.2 Hz,
1H), 1.87-1.79 (m, 1H), 1.42 (dd, J ) 4.8, 9.6 Hz, 1H), 1.00-
0.92 (m, 1H), 0.72 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.9, 139.1, 138.4, 135.5, 135.4, 135.3, 133.6, 133.3,
132.8, 130.8, 129.8, 128.8, 128.3, 128.2, 128.1, 127.6, 127.4,
2-[[1-[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl]diphen-
ylsilyl]-2-phenylmethyl]-1H-isoindole-1,3(2H)-dione. To
5786 J. Org. Chem., Vol. 70, No. 15, 2005

Silanediol ACE Inhibitors
127.3, 126.4, 126.1, 77.6, 72.8, 38.9, 37.6, 29.6, 20.4, 16.2; exact
mass (FAB) (MH+) calcd for C38H40NO2Si 570.2828, found
570.2854.
4.83 (m, 1H), 3.36-3.22 (m, 2H), 3.15 (dd, J ) 4.4, 14.5 Hz,
1H), 2.64 (dd, J ) 10.9, 14.5 Hz, 1H), 1.79-1.66 (m, 1H), 1.60
(s, 1H), 1.37 (dd, J ) 5.6, 15.1 Hz, 1H), 1.06 (dd, J ) 8.0, 15.0
Hz, 1H), 0.75 (d, J ) 6.7 Hz, 3H); 13C NMR (63 MHz, CDC13)
δ 167.0, 128.5, 128.3, 139.2, 135.5, 135.3, 135.2, 133.8, 133.1,
130.99, 129.95, 128.2, 126.5, 126.3, 70.1, 39.0, 37.7, 32.1, 19.9,
16.2. 129.92, 128.9; exact mass (FAB) (MH+) calcd for C31H34-
NO2Si 480.2359, found 480.2376.
(2R)-3-[[(1R)-1-(Benzoylamino)-2-phenylethyl]diphen-
ylsilyl]-2-methylpropanoic Acid. To a solution of N-[1-(R)-
[(3-hydroxy-2(R)-methylpropyl)diphenylsilanyl]-2-phenylethyl]-
benzamide ((R,R)-ent-25) (88 mg, 0.183 mmol) in CH2Cl2 (1.0
mL) at room temperature were added consecutively N-meth-
ylmorpholine N-oxide (27 mg, 0.23 mmol), powdered 4 Å
molecular sieves (300 mg), and TPAP (3.8 mg, 0.011 mmol).
The solution was stirred for 2.5 h, then filtered through a pad
of silica with 1:9 ethyl acetate/CH2Cl2. Concentration of the
filtrate produced the crude aldehyde as a clear colorless oil.
[(2R)-2-Methyl-3-(phenylmethoxy)-1-propyl][1-amino-
2-phenylethyl]diphenylsilane. A sample of the intermediate
amine was also characterized: IR (neat) 3359, 3083, 2908,
1
1494, 1427, 1109, 732, 700 cm-1; H NMR (400 MHz, CDCl3)
δ 7.56-7.02 (m, 20H), 4.26 (s, 2H), 3.13-3.05 (m, 2H), 2.99-
2.93 (m, 2H), 2.21 (t, J ) 12.8 Hz, 1H), 1.91-1.86 (m, 1H),
1.40 (t, J ) 5.2 Hz, 1H), 0.96 (dd, J ) 5.2, 8.8 Hz, 1H), 0.87
(br s, 2H), 0.77 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 140.4, 138.6, 135.6, 134.1, 134.0, 129.4, 128.9, 128.3, 127.8,
127.3, 126.0, 77.7, 72.6, 41.3, 40.3, 29.6, 20.4, 15.7; exact mass
(FAB) MNa+ calcd for C31H36NOSiNa 466.2566, found 466.2561.
[(2R)-2-Methyl-3-hydroxy-1-propyl][(1S)-1-(benzoylami-
no)-2-phenylethyl]diphenylsilane and [(2R)-2-Methyl-3-
hydroxy-1-propyl][(1R)-1-(benzoylamino)-2-phenylethyl]-
diphenylsilane (ent-25 + ent-26). To a -78 °C solution of
N-[1-[(3-benzyloxy-2(R)-methylpropyl)diphenylsilanyl]-2-phen-
ylethyl]benzamide (ent-24) (460 mg, 0.807 mmol) in CH2Cl2
(8.2 mL) was slowly added BBr3 (2.42 mL, 1.0 M in CH2C12)
and the resulting solution was stirred and allowed to warm
to room temperature over 5 h. The solution was recooled to
-78 °C and methanol (4 mL) was carefully added. The mixture
was warmed to room temperature over 20 min and concen-
trated, and the resulting oil was then taken up in CH2Cl2 (20
mL) and transferred to a separatory funnel, and water was
added until the yellow color had faded (10 mL). The aqueous
phase was extracted with CH2Cl2 (2 × 20 mL), and the
combined organics were washed with brine (20 mL), dried over
Na2SO4, filtered, concentrated, and purified by flash column
chromatography (2:98-1:4 ethyl acetate/hexanes) to yield
(S,R)-ent-26 (higher Rf, 191.5 mg, 49.5%) and (R,R)-ent-25
(lower Rf, 153.3 mg, 40%).
To the aldehyde in t-BuOH (4.0 mL) and water (1.0 mL)
was added NaH2PO4 (42.0 mg, 0.35 mmol) and 2-methyl-2-
butene (1.0 mL), followed by addition of NaClO2 (25.9 mg, 0.28
mmol). The resulting solution was stirred at room temperature
for 4 h and then diluted with saturated NH4Cl (12 mL) and
CH2Cl2 (10 mL) and the aqueous phase was extracted with
CH2Cl2 (3 × 10 mL). The combined organic phases were
washed with saturated NaCl (15 mL), dried over Na2SO4,
concentrated, and purified by flash column chromatography
(2:98 methanol/methylene chloride) to afford 3-[(1(R)-benzoyl-
amino-2-phenylethyl)diphenylsilanyl]-2(R)-methylpropionic acid
as a white foam (69 mg, 77%).
(R,R): [R]20 -7.8 (c 1.0, CH2Cl2); Rf 0.44 (1:15 methanol/
D
methylene chloride); IR (CHCl3) 3684.8, 3619.2, 3021.3, 1705.9,
1
1652.9, 1516.9, 1428.2, 1217.9, 1110.9, 928.7, 771.5 cm-1; H
NMR (400 MHz, CDCl3) δ 7.63-7.13 (m, 20 H), 5.92 (d, J )
10 Hz, 1H), 4.85 (dt, J ) 4.0, 10.8 Hz, 1H), 3.15 (dd, J ) 4.0,
14.4 Hz, 1H), 2.60 (dd, J ) 10.8, 14.4 Hz, 1H), 2.53-2.48 (m,
1H), 1.71 (dd, J ) 7.2, 14.8 Hz, 1H), 1.31 (dd, J ) 6.8, 15.2
Hz, 1H), 1.07 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDC13)
δ 182.2, 167.1, 138.9, 135.5, 135.3, 134.9, 132.7, 132.0, 131.0,
130.0, 128.8, 128.4, 128.2, 126.5, 126.3, 38.8, 37.3, 35.0, 20.5,
16.3; exact mass (FAB) MNa+ calcd for C31H31NO3NaSi
516.1971, found 516.1965.
(S,R)-ent-26: [R]20 80 (c 0.1, CH2Cl2); Rf 0.29 (4:6 ether/
D
hexanes); IR (neat) 3310.6, 3036.6, 2922.0, 1633.6, 1539.1,
1427.2, 1326.0, 1109.0, 698.2 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.67-7.13 (m, 20H), 5.91 (d, J ) 10.0 Hz, 1H), 4.94 (dt, J )
4.4, 12.0 Hz, 1H), 3.49 (dd, J ) 4.8, 10.4 Hz, lH), 3.23-3.17
(m, 2H), 2.57 (dd, J ) 12.0, 14.8 Hz, 1H), 2.47 (br s, 1H), 1.86-
1.82 (m, 1H), 1.51 (dd, J ) 5.2, 14.8 Hz, 1H), 0.91 (dd, J )
8.0, 15.2 Hz, 1H), 0.67 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz,
CDC13) δ 167.4, 139.0, 135.5, 135.4, 134.7, 133.3, 133.1, 131.1,
130.0, 129.9, 128.6, 128.4, 128.3, 128.2, 128.1, 126.5, 126.3,
69.8, 38.9, 37.2, 31.7, 19.9, 15.5; exact mass (FAB) (MH+) calcd
for C31H34NO2Si 480.2359, found 480.2353.
(S,R): [R]20 8.3 (c 0.7, CH2Cl2); Rf 0.44 (1:15 methanol/
D
methylene chloride); IR (CHCl3) 3684.8, 3625.9, 3024.2, 1705.0,
1
1652.7, 1519.8, 1428.2, 1219.0, 1045.4, 928.7, 772.4 cm-1; H
NMR (400 MHz, CDCl3) δ 7.63-7.07 (m, 20 H), 6.08 (d, J )
10.4 Hz, 1H), 4.93 (dt, J ) 3.6, 11.2 Hz, 1H), 3.10 (dd, J ) 4.0,
14.8 Hz, 1H), 2.58 (dd, J ) 12.0, 14.4 Hz, 1H), 2.52-2.47 (m,
1H), 1.73 (dd, J ) 8.0, 15.2 Hz, 1H), 1.18 (dd, J ) 6.0, 14.4
Hz, 1H), 1.00 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDC13)
δ 178.8, 167.0, 139.0, 135.0, 134.5, 132.8, 132.4, 130.6, 129.6,
129.5, 128.5, 127.9, 127.80, 127.77, 127.69, 126.4, 125.8, 39.1,
36.5, 34.6, 19.8, 15.7; exact mass (FAB) MH+ calcd for C31H32-
NO3Si 494.2151, found 494.2174.
(R,R)-ent-25: [R]20D -90 (c 0.2, CH2Cl2); Rf 0.24 (4:6 ether/
hexanes); IR (neat) 3317.4, 3067.6, 2923.9, 1644.2, 1517.9,
1316.3, 1109.0, 698.2 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67-
7.09 (m, 20H), 5.89 (d, J ) 10.0 Hz, 1H), 4.83 (dt, J ) 4.4,
10.8 Hz, 1H), 3.31 (dd, J ) 6.0, 10.8 Hz, 1H), 3.25 (dd, J )
6.4, 10.4 Hz, 1H), 3.15 (dd, J ) 4.4, 14.8 Hz, 1H), 2.64 (dd, J
) 10.8, 14.4 Hz, 1H), 1.78 (br s, 1H), 1.76-1.70 (m, 1H), 1.37
(dd, J ) 5.6, 14.8 Hz, 1H), 1.06 (dd, J ) 8.0, 15.2 Hz, 1H),
0.75 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 167.0,
139.1, 135.5, 135.3, 135.1, 133.8, 133.0, 131.0, 129.9, 128.8,
128.4, 128.2, 126.5, 126.2, 70.0, 39.0, 37.6, 32.0, 19.8, 16.1;
exact mass (FAB) (MH+) calcd for C31H34NO2Si 480.2359,
found 480.2371.
(R,S): mp 70-72 °C; [R]20 -48.6 (c 0.7, CHCl3); Rf 0.44
D
(1:15 methanol/methylene chloride); IR (neat) 3345, 3080,
1
2912, 1721, 1647, 1535, 1431, 1120, 743 cm-1; H NMR (400
MHz, CDCl3) δ 7.63-7.13 (m, 20 H), 5.90 (d, J ) 10.0 Hz, 1H),
4.87 (dt, J ) 4.0, 11.6 Hz, 1H), 3.15 (dd, J ) 4.0, 14.8 Hz, 1H),
2.66-2.56 (m, 2H), 1.71 (dd, J ) 5.6, 15.2 Hz, 1H), 1.25 (dd, J
) 7.2, 16.0 Hz, 1H), 0.94 (d, J ) 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 180.6, 167.6, 138.8, 135.5, 135.4, 134.5, 132.2,
132.0, 131.3, 130.2, 128.7, 128.5, 128.3, 126.6, 126.4, 39.0, 37.2,
34.9, 19.6, 16.5; exact mass (FAB) (MH+) calcd for C31H32NO3-
Si 494.215, found 494.214.
(R,S)-26: [R]20 -45 (c 0.24, CHCl3); IR (neat) 3300, 3086,
D
1
2902, 1634, 1520, 1421, 1105, 699 cm-1; H NMR (250 MHz,
CDCl3) δ 7.67-7.11 (m, 20H), 5.85 (d, J ) 10.0 Hz, 1H), 4.94
(m, 1H), 3.49 (dd, J ) 4.9, 10.6 Hz, lH), 3.23-3.17 (m, 2H),
2.57 (dd, J ) 11.8, 14.8 Hz, 1H), 2.07 (s, 1H), 1.91-1.78 (m,
IH), 1.51 (dd, J ) 5.4, 15.0 Hz, 1H), 0.91 (dd, J ) 7.7, 15.0 Hz,
1H), 0.67 (d, J ) 6.7 Hz, 3H); 13C NMR (63 MHz, CDC13) δ
128.5, 167.5, 139.1, 135.6, 135.5, 134.7, 133.3, 133.2, 131.2,
130.04, 129.98, 128.6, 128.3, 128.2, 126.6, 126.3, 69.9, 38.9,
37.3, 31.8, 19.9, 15.6.
(S,S): mp 78-80 °C; [R]20 50.3 (c 0.4, CHCl3); Rf 0.44 (1:
D
15 methanol/methylene chloride); IR (neat) 3310, 3062, 2912,
1710, 1528, 1421, 1115, 701 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.63-7.13 (m, 20 H), 5.84 (d, J ) 10.0 Hz, 1H), 4.83 (dt, J )
4.4, 11.2 Hz, 1H), 3.17 (dd, J ) 4.0, 14.4 Hz, 1H), 2.60 (dd, J
) 11.2, 14.4 Hz, 1H), 2.56-2.46 (m, 1H), 1.73 (dd, J ) 7.6,
(S,S)-25: [R]20 72.5 (c 0.4, CHCl3); IR (neat) 3389, 3301,
D
1
3084, 2901, 1640, 1512, 1419, 1097, 688 cm-1; H NMR (250
MHz, CDCl3) δ 7.67-7.09 (m, 20H), 5.86 (d, J ) 9.9 Hz, 1H),
J. Org. Chem, Vol. 70, No. 15, 2005 5787

Kim et al.
15.2 Hz, 1H), 1.32 (dd, J ) 6.8, 15.2 Hz, 1H), 1.06 (d, J ) 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 182.0, 167.1, 138.9,
135.5, 135.4, 135.0, 132.7, 132.0, 131.0, 130.1, 128.9, 128.4,
128.2, 126.5, 126.3, 38.8, 37.4, 35.0, 20.5, 16.3; exact mass
(FAB) (MNa+) calcd for C31H31NO3SiNa 516.1971, found
516.1976.
(2S)-1-[3-[[(1S)-1-(Benzoylamino)-2-phenylethyl]diflu-
orosilyl]-2-methyl-1-oxopropyl]-l-proline (30). To a 0 °C
solution of (S,S)-27 (70 mg, 0.108 mmol) in CH2Cl2 (5.0 mL)
was added trifluoromethane sulfonic acid (0.60 mL, 2.8 mmol).
After 1 h the solution was diluted with CH2Cl2 (10.0 mL),
followed by 14.8 N NH4OH (0.30 mL). The solution was stirred
for 35 min at 0 °C and 48% HF solution (0.20 mL) was added,
to give a pH of 2-3. Stirring was continued for 10 min. After
addition of CH2Cl2 (20 mL), the solution was washed with
water (10 mL) and saturated NaCl (10 mL), dried over Na2-
SO4, filtered, and concentrated to give (S,S)-30 (47 mg, 92%)
as a light yellow solid: Rf 0.75 on RP-TLC (C18, 1:1 ethanol/
water); mp 90-91 °C dec; IR (KBr) 3419, 2961, 1734, 1605,
1559, 1456, 1333, 1190, 707 cm-1; 1H NMR (400 MHz, acetone-
d6) δ 9.10 (br s, 1H), 7.99-7.20 (m, 10H), 4.15 (dd, J ) 2.8,
8.0 Hz, 1H), 3.56-3.47 (m, 2H), 3.24-3.15 (m, 2H), 2.93-2.73
(m, 2H), 1.86-1.81 (m, 2H), 1.60-1.56 (m, 2H), 1.22-1.18 (m,
1H), 1.13 (d, J ) 6.8 Hz, 3H), 1.04-1.01 (m, 1H); 13C NMR
(100 MHz, acetone-d6) δ 178.1, 173.0, 170.3, 141.3, 134.2, 130.0,
129.7, 129.2, 128.8, 127.0, 59.7, 47.5, 44.6 (dd, J ) 20.9, 30.3
Hz, due to F), 37.0, 34.6, 28.7, 25.2, 23.0 (dd, J ) 19.2, 24.9
Hz, due to F), 20.7; 19F NMR (376 MHz, acetone-d6) δ 0.00
(CFCl3), -122.7, -123.8; exact mass (FAB) M - F+ calcd for
C24H28N2O4FSi 455.1802, found 455.1812.
(R,S): Rf 0.72 on RP-TLC (C18, 1:1 ethanol/water); mp 150-
151 °C dec; IR (KBr) 3451, 2968, 1726, 1628, 1606, 1442, 1096,
702 cm-1; 1H NMR (400 MHz, 1% D2O in acetone-d6) δ 7.91-
7.17 (m, 10H), 4.21 (dd, J ) 4.0, 8.4 Hz, 1H), 3.60-3.56 (m,
2H), 3.20-3.06 (m, 2H), 2.96-2.88 (m, 2H), 1.90-1.77 (m, 4H),
1.10 (d, J ) 6.8 Hz, 3H), 0.86-0.82 (m, 2H); 13C NMR (100
MHz, acetone-d6) δ 178.5, 173.0, 170.7, 141.3, 134.2, 130.0,
129.8, 129.7, 129.3, 128.9, 127.1, 59.9, 47.6, 44.3 (t, J ) 25.2
Hz, due to F), 36.9, 34.6, 28.7, 25.3, 22.7 (t, J ) 20.0 Hz, due
to F), 20.9; 19F NMR (376 MHz, acetone-d6) δ 0.00 (CFCl3),
-127.7, -131.5; exact mass (FAB) M - F+ calcd for C24H28N2O4-
FSi 455.1802, found 455.1794.
(S,R): Rf 0.72 on RP-TLC (C18, 1:1 ethanol/water); mp 161-
162 °C dec; IR (KBr) 3312, 2973, 1733, 1718, 1617, 1456, 1326,
1092, 709 cm-1; 1H NMR (400 MHz, acetonitrile-d3) δ 8.13 (br
s, 1H), 7.92-7.23 (m, 10H), 4.42 (d, J ) 8. Hz, 1H), 3.63 (dt,
J ) 3.2, 10.4 Hz, 1H), 3.47 (dd, J ) 9.6, 16.4 Hz, 1H), 3.18
(dd, J ) 3.2, 17.0 Hz, 1H), 3.09-3.06 (m, 1H), 2.94-2.89 (m,
1H), 2.80 (dd, J ) 10.4, 13.6 Hz, 1H), 2.17-2.14 (m, 2H), 1.90-
1.70 (m, 2H), 1.32-1.17 (m, 1H), 1.12 (d, J ) 6.4 Hz, 3H),
0.93-0.90 (m, 1H); 13C NMR (100 MHz, acetonitrile-d3) δ
180.7, 172.8, 170.9, 141.1, 134.4, 130.3, 129.8, 129.5, 129.4,
128.9, 127.3, 61.0, 48.3, 44.1 (t, J ) 25.3 Hz, due to F) 36.7,
34.9, 28.2, 25.3, 22.7 (t, J ) 20.7 Hz, due to F), 20.3; 19F NMR
(376 MHz, acetonitrile-d3) δ 0.00 (CFCl3), -127.7, -131.5.
(R,R): Rf 0.75 on RP-TLC (C18, 1:1 ethanol/water); mp 92-
94 °C dec; IR (KBr) 3421, 2968, 1735, 1604, 1562, 1449, 1158,
707 cm-1; 1H NMR (400 MHz, acetonitrile-d3) δ 8.10 (brs, 1H),
7.80-7.21 (m, 10H), 4.42 (dd, J ) 2.8, 8.0 Hz, 1H), 3.47 (m,
2H), 3.18 (dd, J ) 3.6, 14.0 Hz, 1H), 3.12-3.08 (m, 1H), 2.85-
2.82 (m, 1H), 2.77 (dd, J ) 10.0, 13.6 Hz, 1H), 2.17-2.11 (m,
1H), 2.01-1.96 (m, 1H), 1.88-1.68 (m, 2H), 1.30-1.15 (m, 1H),
1.12 (d, J ) 6.4 Hz, 3H), 0.99-0.93 (m, 1H); 13C NMR (100
MHz, acetonitrile-d3) δ 180.6, 172.8, 170.8, 141.1, 134.4, 130.2,
129.9, 129.5, 128.9, 127.4, 61.0, 48.4, 44.2 (t, J ) 25.6 Hz, due
to F), 36.8, 34.8, 28.3, 25.3, 22.6 (t, J ) 21.1 Hz, due to F),
20.1; 19F NMR (376 MHz, acetonitrile-d3) δ -128.2, -129.4.
(2S)-1-[3-[[(1R)-1-(Benzoylamino)-2-phenylethyl]diphen-
ylsilyl]-2-methyl-1-oxopropyl]-l-proline 1,1-Dimethyleth-
yl Ester (27). To a 0 °C solution of 3-[(1-(R)-benzoylamino-2-
phenylethyl)diphenylsilanyl]-2(S)-methylpropionic acid (50.4
mg, 0.102 mmol) and l-proline tert-butyl ester (25.3 mg, 0.148
mmol) in DMF (2 mL) was added diethyl cyanophosphonate
(19 µL, 0.12 mmol) followed by triethylamine (32 L, 0.23
mmol). The reaction was maintained at 0 °C for 3 h, and
warmed to room temperature overnight. The mixture was
diluted with ethyl acetate (10 mL) and water (5 mL), the
organic phase was washed with 5-mL portions of 5% HCl,
saturated NaHCO3, water, and saturated NaCl, dried over Na2-
SO4, concentrated, and purified by flash column chromatog-
raphy (30:70, ethyl acetate/hexanes) to give 27 (RS) as a
colorless foam (53.1 mg, 80%): mp 65-66 °C; Rf 0.47 (1:2 ethyl
acetate/hexanes); [R]20D -61.8 (c 0.22, CHCl3); IR (KBr) 3321,
2929, 1724, 1637, 1617, 1511, 1278, 1165, 707 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.82-7.00 (m, 21H, including NH), 4.69-
4.63 (m, 1H), 3.55 (dd, J ) 3.6, 8.4 Hz, 1H), 3.05-3.02 (m,
1H), 2.99 (dd, J ) 4.4, 14.0 Hz, 1H), 2.77 (dd, J ) 9.2, 14.0
Hz, 1H), 2.42-2.37 (m, 1H), 2.30-2.25 (m, 1H), 1.63-1.51 (m,
5H), 1.35 (s, 9H), 1.23-1.19 (m, 1H), 1.12 (d, J ) 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 175.7, 170.9, 167.3, 139.5, 135.5,
135.3, 135.2, 134.2, 130.8, 129.6, 129.3, 128.3, 127.9, 127.7,
127.3, 126.0, 80.9, 58.9, 45.8, 39.5, 37.5, 34.8, 28.6, 27.9, 24.1,
21.5, 13.8; exact mass (FAB) MH+ calcd for C40H47N2O4Si
647.336, found 647.331.
(S,S): 36 mg, 73%; mp 150-151 °C; [R]20 19.3 (c 0.27,
D
CHCl3); Rf 0.45 (1:2 ethyl acetate/hexanes); IR (KBr) 3304,
2921, 1732, 1644, 1631, 1545, 1420, 1153, 701 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.59-7.12 (m, 20H), 6.56 (d, J ) 10.0 Hz,
1H), 4.75 (dt, J ) 4.0, 11.2 Hz, 1H), 4.20 (dd, J ) 4.0, 8.4 Hz,
1H), 3.37-3.32 (m, 1H), 3.19 (dd, J ) 4.0, 14.0 Hz, 1H), 2.97-
2.91 (m, 1H), 2.70-2.64 (m, 1H), 2.52 (dd, J ) 11.2, 14.0 Hz,
1H), 2.02-1.72 (m, 5H), 1.43 (s, 9H), 1.29-1.24 (m, 1H), 1.20
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 171.4,
166.8, 139.4, 135.6, 135.3, 135.2, 133.9, 133.1, 130.8, 129.7,
128.9, 128.3, 128.0, 127.97, 127.92, 126.7, 126.0, 80.9, 59.5,
46.4, 38.9, 37.6, 34.0, 28.9, 28.0, 24.5, 21.7, 16.2; exact mass
(El) MH+ calcd for C40H47N2O4Si 647.3305, found 647.3319.
(R,R): Rf 0.42 (1:2 ethyl acetate/hexanes); IR (KBr) 3423,
1
2975, 1736, 1638, 1527, 1426, 1151, 701 cm-1; H NMR (400
MHz, CDCl3) δ 7.74-7.13 (m, 20H), 5.96 (d, J ) 9.6 Hz, 1H),
4.78-4.72 (m, 1H), 3.00 (dd, J ) 4.0, 14.4 Hz, 1H), 3.61 (dd, J
) 3.8, 8.0 Hz, 1H), 3.13-3.06 (m, 8H), 2.85-2.71 (m, 3H),
2.60-2.32 (m, 5H), 2.08-2.01 (m, 1H), 1.81-1.38 (m, 12H),
1.35 (s, 9H), 1.34 (s, 9H), 1.09 (d, J ) 6.8 Hz, 3H), 1.04 (d, J
) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCI3) δ 176.8, 171.5,
166.9, 139.6, 135.6, 135.3, 133.9, 133.3, 132.7, 130.8, 129.9,
129.6, 129.0, 128.4, 128.2, 128.1, 127.9, 126.7, 126.1, 81.7, 59.7,
46.6, 39.4, 37.4, 33.9, 31.2, 27.9, 24.6, 22.2, 17.7; exact mass
(FAB) MNa, calcd for C40H46N2O4NaSi 669.3125, found
669.3143.
(S,R): Rf 0.42 (1:2 ethyl acetate/hexanes); IR (KBr) 3450,
2976, 1737, 1641, 1626, 1425, 1151, 1108, 701 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.74-7.13 (m, 40H), 6.00 (d, J ) 10.0 Hz,
1H), 4.78-4.72 (m, 2H), 4.23 (dd, J ) 3.6, 8.4 Hz, 1H), 3.61
(dd, J ) 3.8, 8.0 Hz, 1H), 3.13-3.06 (m, 8H), 2.85-2.71 (m,
3H), 2.60-2.32 (m, 5H), 2.08-2.01 (m, 1H), 1.81-1.38 (m,
12H), 1.35 (s, 9H), 1.34 (s, 9H), 1.09 (d, J ) 6.8 Hz, 3H), 1.04
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCI3) δ 176.7, 171.3,
167.3, 139.4, 135.7, 135.5, 135.3, 134.9, 133.5, 130.8, 129.9,
129.7, 129.2, 128.9, 128.3, 128.2, 128.1, 127.2, 126.6, 126.1,
81.7, 59.5, 46.5, 39.2, 37.5, 34.6, 29.7, 27.9, 24.6, 22.2, 16.0;
exact mass (FAB) MNa, calcd for C40H46N2O4NaSi 669.3125,
found 669.3142.
(2R)-1-[3-[[(1S)-1-(Benzoylamino)-2-phenylethyl]dihy-
droxysilyl]-2-methyl-1-oxopropyl]-l-proline Sodium Salt
(6). To a 0 °C solution of 1-[3-[(1-(R)-benzoylamino-2-phenyl-
ethyl)difluorosilanyl]-2-(S)-methylpropionyl]pyrrolidine-3-(S)-
carboxylic acid (3 mg, 6.3 µmol) in 1:99 CD3CN/D2O (0.4 mL)
was added a 0.2 M NaOH solution in D2O (0.1 mL) at room
temperature. The reaction was monitored by 19F NMR and
after 20 min, the reaction was judged to be complete and
1
quantitative by H, 13C, and 19F.
6: 1H NMR (400 MHz, 1% CD3CN in D2O) δ 7.47-7.10 (m,
10H), 4.02 (dd, J ) 4.4, 8.8 Hz, 1H), 3.66 (dd, J ) 3.2, 12.8
5788 J. Org. Chem., Vol. 70, No. 15, 2005

Silanediol ACE Inhibitors
Hz, 1H), 3.43-3.29 (m, 2H), 3.07 (dd, J ) 3.2, 14.0 Hz, 1H),
2.72-2.66 (m, 2H), 1.97-1.92 (m, 1H), 1.76-1.65 (m, 2H),
1.60-1.54 (m, 1H), 1.08 (d, J ) 6.8 Hz, 3H), 0.78 (dd, J ) 3.2,
14.8 Hz, 1H), 0.58 (dd, J ) 10.8, 14.8 Hz, 1H); 13C NMR (100
MHz, 1% CD3CN in D2O) δ 179.8, 179.0, 169.4, 140.8, 134.0,
131.4, 129.0, 128.4, 128.0, 126.5, 125.7, 62.4, 48.3, 44.8, 36.6,
33.5, 30.4, 25.0, 20.2, 18.9.
(100 MHz, 1% CD3CN in D2O) δ 180.9, 180.0, 170.6, 141.9,
135.3, 132.4, 129.9, 129.5, 129.1, 127.6, 126.9, 63.4, 47.9, 46.0,
36.5, 34.1, 32.1, 25.1, 20.7, 19.9.
9: 1H NMR (400 MHz, D2O) δ 7.50-7.10 (m, 10H), 4.28 (dd,
J ) 2.4, 8.4 Hz, 1H), 3.61 (dd, J ) 2.8, 12.8 Hz, 1H), 3.34-
3.28 (m, 2H), 2.97 (dd, J ) 2.8, 14.0 Hz, 1H), 2.70-2.67 (m,
1H), 2.63 (t, J ) 7.6 Hz, 1H), 2.05-1.84 (m, 2H), 1.63-1.56
(m, 2H), 0.94 (d, J ) 6.8 Hz, 3H), 0.83 (dd, J ) 4.0, 15.2 Hz,
1H), 0.68 (dd, J ) 5.2, 15.2 Hz, 1H); 13C NMR (100 MHz, 1%
CD3CN in D2O) δ 180.9, 179.9, 170.9, 141.7, 135.2, 132.5, 130.0,
129.5, 129.2, 127.7, 126.9, 63.4, 48.4, 45.4, 36.5, 33.9, 32.2, 25.0,
20.7, 19.8.
7: 1H NMR (400 MHz, 1% CD3CN in D2O) δ 7.49-7.11 (m,
10H), 4.08 (dd, J ) 4.4, 8.8 Hz, 1H), 3.62 (dd, J ) 3.2, 12.8
Hz, 1H), 3.53-3.32 (m, 2H), 3.05 (dd, J ) 3.2, 14.0 Hz, 1H),
2.86-2.79 (m, 1H), 2.68 (t, J ) 12.8 Hz, 1H), 2.04-2.00 (m,
1H), 1.82-1.62 (m, 3H), 1.06 (d, J ) 6.8 Hz, 3H), 0.76 (dd, J
) 4.4, 15.2 Hz, 1H), 0.60 (dd, J ) 10.0, 14.8 Hz, 1H); 13C NMR
(100 MHz, 1% CD3CN in D2O) δ 182.1, 181.1, 171.8, 142.9,
136.1, 133.6, 131.0, 130.6, 130.2, 128.7, 127.9, 63.8, 49.6, 46.6,
37.5, 34.7, 31.5, 26.1, 21.3, 20.5.
Acknowledgment. This work was supported, in
part, by the Petroleum Research Fund, administered by
the American Chemical Society, and by the NIH.
8: 1H NMR (400 MHz, 1% CD3CN in D2O) δ 7.50-7.10 (m,
10H), 4.12 (dd, J ) 4.4, 8.8 Hz, 1H), 3.58 (dd, J ) 3.2, 12.8
Hz, 1H), 3.51-3.31 (m, 2H), 3.01 (dd, J ) 3.2, 14.0 Hz, 1H),
2.87-2.86 (m, 1H), 2.70 (t, J ) 12.8 Hz, 1H), 2.14-2.08 (m,
1H), 1.89-1.69 (m, 3H), 1.03 (d, J ) 6.0 Hz, 3H), 0.76 (dd, J
) 4.4, 15.2 Hz, 1H), 0.60 (dd, J ) 10.0, 14.8 Hz, 1H); 13C NMR
Supporting Information Available: NMR spectra of all
new structures. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO048121V
J. Org. Chem, Vol. 70, No. 15, 2005 5789