A Silanediol Inhibitor of the Metalloprotease Thermolysin: Synthesis and Comparison with a Phosphinic Acid Inhibitor

Article abstract of DOI:10.1021/jo049929i

A silanediol inhibitor of the metalloprotease thermolysin was prepared for comparison to a known phosphinic acid inhibitor, providing the first comparison of these second-row element based transition-state analogues. Inhibition of thermolysin by the silanediol (K_i = 41 nM) was comparable to that of the phosphinic acid (K_i = 10 nM) even though the silanediol is uncharged and thereby lacks the intrinsic Coulombic attraction of the phosphinate anion to the active-site zinc cation. This silanediol protease inhibitor is the least sterically encumbered example prepared to date and, therefore, the most prone toward polymerization. Hydrolysis of a difluorosilane intermediate to the silanediol leads cleanly to a monomeric product.

Full text of DOI:10.1021/jo049929i

A Sila n ed iol In h ibitor of th e Meta llop r otea se Th er m olysin :
Syn th esis a n d Com p a r ison w ith a P h osp h in ic Acid In h ibitor 1
J aeseung Kim† and Scott McN. Sieburth*,†,‡
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York
11794-3400, and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19010
scott.sieburth@temple.edu
Received J anuary 10, 2004
A silanediol inhibitor of the metalloprotease thermolysin was prepared for comparison to a known
phosphinic acid inhibitor, providing the first comparison of these second-row element based
transition-state analogues. Inhibition of thermolysin by the silanediol (Ki ) 41 nM) was comparable
to that of the phosphinic acid (Ki ) 10 nM) even though the silanediol is uncharged and thereby
lacks the intrinsic Coulombic attraction of the phosphinate anion to the active-site zinc cation.
This silanediol protease inhibitor is the least sterically encumbered example prepared to date and,
therefore, the most prone toward polymerization. Hydrolysis of a difluorosilane intermediate to
the silanediol leads cleanly to a monomeric product.
In tr od u ction
values of 1.4-3.1,9 and therefore carry a negative charge
except under strongly acidic conditions. The charge of the
anion provides a Coulombic attraction between the
inhibitor and the active-site zinc cation. Dialkylsilane-
diols are less acidic, with a pKa near 10-12,10-12 and are
neutral species at physiological pH, lacking a negative
charge and its attraction to the active site zinc. This
neutrality, however, would be expected to allow them to
directly penetrate cell membranes,13 a supposition born
out in HIV protease inhibitor testing.14 Comparison of
the two inhibitors phosphinamide 1b (Ki ) 9.1 nM) and
phosphinate 1c (Ki ) 9000 nM) has provided insight into
the importance of the hydrogen bond from the nitrogen
of the scissile amide group to the enzyme (as well as to
solvent) for active-site binding.9,15-19 Silanediol-based
inhibitor analogues of 1b and 1c (substitution of PO2H
by SiO2H2) are unlikely to be useful, however, because
of the hydrolytic instability of Si-N and Si-O bonds.
Based on the strength of the Si-C bond, phosphinic acid
Metalloproteases are one of the four major classes of
proteolytic enzymes,2 distinguished by the presence of a
zinc cation secured at the active site by three amino
acidssusually two histidines and a glutamatesthat
coordinates and activates the scissile amide carbonyl.3
Among this important class of proteolytic enzymes,4
thermolysin has the distinction of being the first metal-
loprotease to have its detailed structure revealed by X-ray
crystallography.5 Thermolysin is considered to be one of
the prototypical metalloproteases and to be structurally
similar to important pharmaceutical targets.6 Many
inhibitors of this enzyme have been developed.7,8
Inclusion of this benchmark metalloprotease in our
study of silanediol-based protease inhibitors presented
the opportunity to compare the silanediol inhibitors to
those utilizing phosphorus acids, two second-row ele-
ments. Several phosphorus-based enzyme inhibitors of
thermolysin are known in which the scissile amide of the
substrate has been replaced with a phosphinic acid (1a ),
a phosphinamide (1b), and a phosphinate ester (1c). All
of these phosphorus-based groups are acidic, with pKa
(9) Grobelny, D.; Goli, U. B.; Galardy, R. E. Biochemistry 1989, 28,
4948-4951.
(10) West, R.; Baney, R. H. J . Am. Chem. Soc. 1959, 81, 6145-6148.
(11) Kreshkov, A. P.; Andronov, V. F.; Drozdov, V. A. Russ. J . Phys.
Chem. 1972, 49, 1605-1606.
* To whom correspondence should be addressed. Tel: 215-204-7916.
† State University of New York at Stony Brook.
‡ Temple University.
(1) A preliminary report of these results: Kim, J .; Glekas, A.;
Sieburth, S. McN. Bioorg. Med. Chem. Lett. 2002, 12, 3625-3627.
(2) Leung, D.; Abbenante, G.; Fairlie, D. P. J . Med. Chem. 2000,
43, 305-341.
(12) Steward, O. W.; Fussard, D. R. J . Organomet. Chem. 1977, 120,
C28-C32.
(13) Phosphorus acid-based pharmaceuticals are generally admin-
istered as phosphorus esters that require in vivo hydrolysis for activity.
See: Chen, H.; Noble, F.; Roques, B. P.; Fournie-Zaluski, M.-C. J . Med.
Chem. 2001, 44, 3523-3530 and references therein.
(14) Chen, C.-A.; Sieburth, S. McN.; Glekas, A.; Hewitt, G. W.;
Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; J effrey,
S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161-1166.
(15) Bartlett, P. A.; Marlowe, C. K. Science (Washington, D.C.) 1987,
235, 569-571.
(3) Matthews, B. W. Acc. Chem. Res. 1988, 21, 333-340.
(4) Handbook of Proteolytic Enzymes; Barrett, A. J ., Rawlings, N.
D., Woessner, J ., Fred, J ., Eds.; Bath Press: Bath, England, 1998.
(5) Colman, P. M.; J ansonius, J . N.; Matthews, B. W. J . Mol. Biol.
1972, 70, 701-724.
(16) Tronrud, D. E.; Holden, H. M.; Matthews, B. W. Science
(Washington, D.C.) 1987, 235, 571-574.
(17) Bash, P. A.; Singh, U. C.; Brown, F. K.; Langridge, R.; Kollman,
P. A. Science (Washington, D.C.) 1987, 235, 574-576.
(18) Morgan, B. P.; Scholtz, J . M.; Ballinger, M. D.; Zipkin, I. D.;
Bartlett, P. A. J . Am. Chem. Soc. 1991, 113, 297-307.
(19) Wolfenden, R.; Liang, Y.-L. Bioorg. Chem. 1991, 19, 152-156.
(6) Antonczak, S.; Monard, G.; Lopez, M. R.; Rivail, J . L. J . Mol.
Model. 2000, 6, 527-538.
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2403.
10.1021/jo049929i CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/24/2004
3008
J . Org. Chem. 2004, 69, 3008-3014

Silanediol Thermolysin Inhibitor
SCHEME 2. Syn th esis of Key In ter m ed ia tes
F IGURE 1. Phosphorus- and silicon-based thermolysin in-
hibitors.
SCHEME 1. Retr osyn th etic P la n
SCHEME 3. F ir st Syn th esis Ap p r oa ch
1a was an ideal target for comparison of phosphorus and
silicon, in the form of structure 2 (Figure 1). We describe
below the preparation of 2 and its evaluation as a
thermolysin inhibitor.
sium chloride, followed by stirring the resulting mixture
with aqueous 48% hydrofluoric acid, gave fluorosilane 7
in 65% distilled yield. Fluorosilanes have been convenient
intermediates in our prior silanediol protease inhibitor
syntheses23,24 and continue to play an important role here
(see below). Mono- and difluorosilanes are easily handled
intermediates that are stable to moisture, yet are very
reactive with organometallic reagents.
The iodide precursor of lithium reagent 6 was prepared
using the Evans chiral auxiliary derivative of isohexanoic
acid, 8. Alkylation of the titanium enolate of 8 with
benzyl chloromethyl ether gave 9 as a single diastereomer
in 86% yield. Reduction of 9 with lithium borohydride25
gave alcohol 10 (87%), which was converted to iodide 11
using iodine and triphenylphosphine (85%).26,27
Iodide 11 and fluorosilane 7 were coupled by initial
conversion of 11 to lithium reagent 6 using 2 equiv of
tert-butyllithium under the Bailey-Negishi conditions,28,29
Scheme 3. Addition of silane 7 led to the isolation of 12
in 74% yield. Transformation of the hindered chloro-
methyl group to an amine was performed by displace-
ment with azide and reduction of the product with lithum
Silanediols are well represented in the chemical lit-
erature20,21 but have been best known for their propensity
to undergo dehydration/condensation, forming siloxane
polymers (silicones). They can, however, be stable. The
stability of dialkylsilanediols is dependent in part on the
steric effect of the alkyl groups. We have found that
silanediol peptide mimics can be effective inhibitors of
metallo- and aspartic proteases, such as angiotensin-
converting enzyme (ACE)22,23 and the HIV protease.14 In
this earlier work, the inhibitors were prepared as diphe-
nylsilanes and hydrolyzed to silanediols with triflic acid.
Following this successful approach, the synthetic plan
for 2 anticipated diphenylsilane intermediate 3 as the
immediate precursor, Scheme 1. Treatment of 3 with
strong acid would hydrolyze the two phenyl-silicon
bonds and the tert-butyl ester. The central silane amino
acid 4 would be derived from commercially available
chloromethyltrichlorosilane 5 and the enantiomerically
pure lithium reagent 6.
Resu lts a n d Discu ssion
The two key components for assembly of silane 4 were
prepared as described in Scheme 2. Treatment of chlo-
romethyltrichlorosilane 5 with 2 equiv of phenylmagne-
(24) Glekas, A.; Sieburth, S. McN. Tetrahedron Lett. 2001, 42, 3799-
3801.
(25) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307-312.
(20) Lickiss, P. D. Adv. Inorg. Chem. 1995, 42, 147-262.
(21) Lickiss, P. D. In The Chemistry of Organic Silicon Compounds;
Rappoport, Z., Apeloig, Y., Eds.; J ohn Wiley & Sons: New York, 2001;
Vol. 3, pp 695-744.
(22) Sieburth, S. McN.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew.
Chem., Int. Ed. 1998, 37, 812-814.
(23) Mutahi, M. wa; Nittoli, T.; Guo, L.; Sieburth, S. McN. J . Am.
Chem. Soc. 2002, 124, 7363-7375.
(26) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866-2869.
(27) Corey, E. J .; Pyne, S. G.; Su, W. G. Tetrahedron Lett. 1983, 24,
4883-4886.
(28) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404-
5406.
(29) Negishi, E.-i.; Swanson, D. R.; Rousset, C. J . J . Org. Chem.
1990, 55, 5406-5409.
J . Org. Chem, Vol. 69, No. 9, 2004 3009

Kim and Sieburth
SCHEME 4. Syn th esis of th e Sila n ed iol In h ibitor
aluminum hydride (77%, two steps). The resulting amino
ether was cleaved to the amino alcohol with boron
tribromide and then directly coupled with benzyl chlo-
roformate yielding 13 (75%, two steps). Oxidation of the
alcohol to an acid was initiated with TPAP oxidation to
the aldehyde. Unfortunately, this aldehyde immediately
cyclized to 4-hydroxy-1,3-azasilinane 14 (as a single
diastereomer).30 Attempts to avoid the formation of 14
or to use it to meet subsequent synthetic goals were
frustrated, and so an alternative route was investigated.
To avoid the unwanted cyclization leading to 14, the
nitrogen was introduced as a phthalimide, Scheme 4.
Treatment of chloromethyl 12 with potassium phthal-
imide gave 15 in 72% yield. Excess boron tribromide then
removed the benzyl ether (74%). Oxidation of the alcohol
to aldehyde 16 proceeded without incident (95%), and
Pinnick oxidation31 to the acid 17 occurred in high yield
(90%). Coupling of acid 17 with the tert-butyl ester of
l-leucine using EDC/HOBt led to 18 (89%). Intermediate
18 was formed as a single diastereomer, confirming that
the stereochemical integrity of the chiral center in 11 had
not been compromised. Removal of the phthalimide group
with hydrazine gave the corresponding amine 19 in high
yield. Treatment of this amine with benzyl chloroformate
gave silane 20a (91%).
of 20a , and use of our standard hydrolysis conditions led
to product mixtures missing the benzyl ester group
(NMR). Despite a series of experiments to remove the
phenyl groups under strongly acidic conditions, we were
unable to produce the desired silanediol 2. Nevertheless,
the phenyl groups could be hydrolyzed using mercuric
ion as the electrophile. Because these conditions were
mild enough to preserve the tert-butyl ester, this group
was removed first using standard trifluoroacetic acid
conditions, to give acid 21 (74%). Exposure of diphenyl-
silane 21 to an excess of mercuric acetate in methylene
chloride at 0 °C led rapidly to cleavage of both silicon-
phenyl bonds. While this provided the desired 2 in
acceptable overall yield, separation of this product from
all of the mercury salts and organomercury products
proved to be difficult. The amalgamated problems of Cbz
group preservation with the undesirable use of mercury
reagents led us to modify our synthetic target. Some
motivation for avoiding the use of mercury reagents in
this last stage of the synthesis was to ensure confidence
in the subsequent thermolysin inhibition data.33 We
therefore changed our synthetic target to 23, substituting
the isosteric 3-phenyl propionamide group for the benzyl
carbamate group.
Inspection of the crystal structures of phosphinic acid
1a and related inhibitors bound to thermolysin indicated
that the alcohol oxygen of the Cbz group was not involved
in hydrogen bonding to the enzyme. Anticipating that
replacing the benzyloxy group of 2 with a phenethyl
group would lend stability under the acidic conditions of
silanediol deprotection, but would have little consequence
to the enzyme inhibition, we coupled amine 19 with
3-phenyl propionyl chloride to give 20b (84%).
Carbamate-protected amines have been dealkylated
using triflic acid with preservation of the carbamate
group.32 This precedent, however, did not translate to a
stable Cbz group during triflic acid mediated hydrolysis
(30) For similar observations of spontaneous cyclizations in related
all-carbon systems, see: Thoen, J . C.; Morales-Ramos, A. I.; Lipton,
M. A. Org. Lett. 2002, 4, 4455-4458. Yu, C.; Hu, L. Tetrahedron Lett.
2001, 42, 5167-5170.
(31) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(32) Earle, M. J .; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.
Synlett 1990, 621-623.
(33) Matthews, B. W.; Weaver, L. H.; Kester, W. R. J . Biol. Chem.
1974, 249, 8030-8044.
3010 J . Org. Chem., Vol. 69, No. 9, 2004

Silanediol Thermolysin Inhibitor
Consistent with these expectations, treatment of 20b
with triflic acid resulted in the rapid loss of the tert-butyl
ester and the two phenyl groups from silicon, without
alteration of the rest of the molecule. This hydrolysis
reaction is believed to involve the participation of the
amide groups flanking the silane, and neutralization of
the triflic acid with ammonium hydroxide was used to
ensure that any cyclized intermediates were hydrolyzed.23
The resulting silanediol 23 was clearly not homogeneous,
however, as determined by inspection of the proton NMR
spectrum. This was not entirely unexpected, as silanediol
23 had the least steric hindrance of any protease inhibitor
we had prepared and therefore the most potentially prone
to siloxane formation.
Steric hindrance is a key element of silanediol stabil-
ity.21,34,35 Diethylsilanediol polymerizes at one-tenth of the
rate of dimethylsilanediol, and di-tert-butylsilanediol
cannot be polymerized. Therefore, the rather limited
steric hindrance of the aminomethyl component of 23 was
of some concern. Moreover, silanediol polymerization is
promoted by both acid and base catalysts36,37sboth
employed in the hydrolysis of 20b. The two silanols of
23 are also diastereotopic, and therefore, any siloxane
formation between two molecules of 23 will transform
both silicon atoms to stereogenic centers, leading to
diastereomeric mixtures.
F IGURE 2. Inhibitors of ACE and the HIV protease.
including the carbonyls and the four diastereotopic
methyl groups (see the Supporting Information).
Inhibition of thermolysin by 23 was determined using
the commercially available enzyme and a commercially
available profluorescent substrate described by Feder et
al.39 Dixon plot of the data gave a Ki ) 41 nM, a value
intriguingly similar to the Ki reported for the phosphinate
analogue 1a (10 nM). This suggests that the silanediol
binds to the enzyme in a manner similar to the phos-
phorus inhibitors 1. Little is known about the propensity
of silanols for interaction with zinc ions (for a review of
silanol-metal interactions, see ref 21; see also ref 23).
The crystal structure of 1b bound to thermolysin shows
a single oxygen of the phosphinamide group within
contact distance of the active site zinc.3 A very similar
conformation of the silanediol 23 complex with thermo-
lysin has now been determined and will be reported
elsewhere.
Silanediol 23 is the third example of an effective
protease inhibitor built around a central silanediol
transition state analogue and the second example of
metalloprotease inhibition by such a structure. Silanediol
24a , Figure 2, was prepared as an analogue of ketone
25. Silanediol 24a , a mixture of diastereomers, was found
to inhibit angiotensin-converting enzyme (ACE, a met-
alloprotease) with an IC50 value of 14 nM, comparing
favorably with the 1 nM IC50 of 25.23 Replacement of one
of the hydroxyls of the silanediol group of 24a with a
methyl group, to give methylsilanol 24b, eliminated the
inhibition of ACE (IC50 > 3000 nM), consistent with the
silanediol providing a critical interaction with the en-
zyme.
The silanediol product resulting from treatment of 20b
with triflic acid followed by ammonium hydroxide was
clearly a mixture. In an attempt to modify the acid-
catalyzed hydrolysis yet retain its simplicity and general-
ity, we followed the ammonium hydroxide treatment with
addition of aqueous hydrofluoric acid. Strong acid and
hydrofluoric acid are both commonly used for peptide
deprotection. Aqueous HF will react with a broad set of
silicon-heteroatom bonds, replacing the heteroatoms
with fluoride. This mild procedure was reported by
Eaborn in 1952 as a general method to prepare fluorosi-
lanes from chlorosilanes, silyl ethers, and silanols.38 The
resulting fluorosilanes are stable to moisture (under
neutral and acidic conditions) yet are very reactive
toward nucleophiles. For the deprotection of 20b, the
addition of hydrofluoric acid led to the formation of a
single isomeric and crystalline 22 that precipitated from
the reaction mixture and was purified by filtration (67%).
This acetone-soluble product had two resonances in the
19F NMR spectrum, consistent with the presence of two
nonequivalent fluorine atoms.
Suspension of 22 in water and addition of sodium
hydroxide led to a rapid conversion of the fluorine signals
in the 19F NMR to a single absorption at -120 ppm,
consistent with the generation of sodium fluoride. The
resulting solution of silanediol 23 was monomeric and
stable in aqueous solution. The 13C NMR spectrum
clearly showed all the 21 carbons of the structure,
The C2 symmetric silanediol 26a was prepared as an
inhibitor of the C2 symmetric HIV protease and as an
analogue of carbinol inhibitor 26b. The HIV protease is
an aspartic protease, with two aspartic acid residues at
the active site that catalyze the scissile amide bond
hydrolysis through charge and hydrogen bonding inter-
(34) Osterholtz, F. D.; Pohl, E. R. J . Adhes. Sci. Technol. 1992, 6,
127-149.
(35) Armitage, D. A. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: New York,
1982; Vol. 2, pp 1-203.
(36) Dejak, B.; Lasocki, Z.; Mogilnicki, W. Bull. Acad. Polon. Sci.,
Se´r. Sci. Chim. 1969, 17, 7-12.
(37) Dejak, B.; Lasocki, Z.; Mogilnicki, W. Bull. Acad. Polon. Sci.,
Se´r. Sci. Chim. 1969, 17, 571-574.
(39) Feder, J .; Brougham, L. R.; Wildi, B. S. Biochemistry 1974, 13,
1186-1189.
(38) Eaborn, C. J . Chem. Soc. 1952, 2846-2849.
J . Org. Chem, Vol. 69, No. 9, 2004 3011

Kim and Sieburth
0.26, CH2Cl2); Rf 0.33 (1:5 ethyl acetate/hexanes); IR (KBr)
actions. Silanediol 26a and carbinol 26b were found to
inhibit the enzyme with IC50 values of 2.7 and 0.38 nM,
respectively.14 Silanediol 26a was also found to be effec-
tive for protection of cells from HIV infection by the virus,
demonstrating that this neutral structure could ef-
fectively cross cell membranes. The first silanediol inhibi-
tors of a serine protease have recently been reported.40
3029, 1762, 1693, 1394, 1362, 1214, 1109 cm-1 1H NMR
;
(CDCl3) δ 7.33-7.17(m, 10H), 4.71 (m, 1H), 4.54 (d, J ) 3.9
Hz, 2H), 4.39 (m, 1H), 4.14 (m, 2H), 3.70 (m, 2H), 3.24 (dd, J
) 3.3, 13.5 Hz, 1H), 2.64 (dd, J ) 9.3, 13.5 Hz, 1H), 1.64 (m,
2H), 1.34 (m, 1H), 0.92 (d, J ) 3.9 Hz, 3H), 0.90 (d, J ) 2.7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.5, 153.1, 138.1,
135.4, 129.4, 128.8, 128.3, 127.6, 127.5, 127.2, 73.0, 71.9, 65.7,
55.3, 41.4, 37.9, 37.6, 26.1, 22.7; exact mass (EI) MH+ calcd
for C24H30NO4 396.2175, found 396.2162.
Con clu sion s
(R)-2-Ben zyloxym eth yl-4-m eth yl-p en ta n -1-ol 10. To a
0 °C solution of 9 (13.0 g, 34.6 mmol) in diethyl ether (110
mL) under a nitrogen atmosphere was added LiBH4 (20.0 mL
of a 2 M solution in THF, 40.0 mmol), and the resulting
mixture was stirred for 2.5 h. A 1 N NaOH solution was then
added slowly until both layers were clear (60 mL). The aqueous
phase was extracted with ether (3 × 50 mL), and the combined
organics were washed with saturated NaCl (50 mL) and dried
over Na2SO4. The solution was then concentrated in vacuo,
diluted with hexanes, and filtered. The filtrate was concen-
trated and purified by flash chromatography (1:20-1:10 ethyl
The finding that silanediol 23 inhibits thermolysin
(Ki ) 41 nM) at concentrations similar to those for
phosphinic acid 1a (Ki ) 10 nM) suggests that the
uncharged silanediol group can provide an interaction
with the positively charged active site zinc ion of ther-
molysin that is comparable to that of the phosphinic acid
anion. This may seem surprising when considering the
charge carried by the phosphinic acid anion and its
expected attraction to the active site zinc. Binding of the
phosphinic acid anion to the enzyme, however, would be
expected to require substantially more solvent reorgani-
zation than would the neutral silanediol. Efforts to more
completely define the utility of silanediols as central
components of protease inhibitors, and related studies
are continuing.
acetate/hexanes) to afford 10 as a clear oil (5.42 g, 87%): [R]20
D
+15.4 (c 1.17, CH2Cl2); Rf 0.24 (1:5 ethyl acetate/hexanes); IR
(neat) 3414.8, 2954.8, 1454.2, 1098.4, 697.2 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.51 (d, J ) 2.7 Hz, 2H), 3.69
(dd, J ) 3.6, 10.8 Hz, 1H), 3.59 (m, 2H), 3.44 (dd, J ) 7.8, 9
Hz, 1H), 2.94 (s, 1H), 1.94 (m, 1H), 1.60 (septet, J ) 6.3 Hz,
1H), 1.12 (m, 2H), 0.89 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 137.9, 128.3, 127.5, 127.4, 73.9, 73.2, 65.9, 38.2, 37.1,
25.2, 22.6; exact mass (EI) MH+ calcd for C14H23O2 223.2698,
found 223.2696.
Exp er im en ta l Section
(Ch lor om eth yl)flu or od ip h en ylsila n e (7).41 To a 0 °C
solution of chloromethyltrichlorosilane 5 (4.60 mL, 35.1 mmol)
in ether (40 mL) was added phenylmagnesium chloride (36.0
mL of a 2 M solution in THF, 72.0 mmol) over 1 h. The
resulting solution was then refluxed for 24 h. After being cooled
to rt, the solvent was removed using a rotary evaporator and
the residue was taken up in a mixture of ethanol (50 mL) and
48% aqueous HF (4.20 mL). After the mixture was stirred for
48 h, water (10 mL) and CH2Cl2 (30 mL) were added. The
aqueous phase was extracted with CH2Cl2 (3 × 30 mL), and
the combined organics were washed successively with water
(50 mL) and saturated NaCl (50 mL) and then dried over Na2-
SO4. Concentration and distillation (145-146 °C, 3 mm Hg)
gave 7 as a clear oil (5.74 g, 65%): IR (neat) 3091, 1591, 1429,
1126, 884, 737, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.93-
7.60 (m, 10Η), 3.49 (d, J ) 3.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 134.5, 131.3, 130.2 (d, J C-F ) 64 Hz), 128.2, 26.2 (d,
J C-F ) 76 Hz); 19F NMR (376 MHz, CDCl3) δ -170.2; MS m/e
(rel intensity) 273 (MNa, 12),201 (35), 179 (21), 165 (18), 155
(21).
(S)-2-Ben zyloxym et h yl-1-iod o-4-m et h ylp en t a n e (11).
To a solution of alcohol 10 (4.80 g, 21.6 mmol) in a mixture of
diethyl ether (40 mL) and CH3CN (20 mL) were added
triphenylphosphine (6.30 g, 24.0 mmol) and imidazole (1.63
g, 23.9 mmol), and the solution was cooled to 0 °C. A solution
of iodine (6.04 g, 23.8 mmol) in ether (20 mL) was added slowly
and then stirred for 3 h at 0 °C. After dilution with ether (50
mL), the solution was successively washed with saturated
Na2S2O3 (30 mL), saturated CuSO4 (30 mL), and saturated
NaCl (50 mL) and then dried over anhydrous Na2SO4. Con-
centration and flash chromatography (2:98-1:10 ethyl acetate/
hexanes) gave 11 as a clear oil (6.08 g, 85%): [R]20 -43.8 (c
D
0.32, CH2Cl2); Rf 0.63 (1:20 ethyl acetate/hexanes); IR (neat)
2954.8, 1452.3, 1102.3, 697.2 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.4-7.2 (m, 5H), 4.55 (s, 2H), 3.6-3.3 (m, 4H), 1.58 (m, 2H),
1.20 (m, 2H), 0.89 (t, J ) 6.6 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 128.2, 127.5, 127.1, 73.2, 40.5, 37.0, 24.8, 22.9, 22.3,
+
13.8; exact mass (EI) MNH4 calcd for C14H25NOI 350.0981,
found 350.0991.
(S)-(2-Ben zyloxym eth yl-4-m eth ylp en tyl)ch lor om eth yl-
d ip h en ylsila n e (12). To a -78 °C solution of 11 (4.04 g, 12.2
mmol) in ether (120 mL) was added tert-butyllithium (18.0 mL
of a 1.5 M solution in pentane, 27.0 mmol). The solution was
stirred for 1 h at 78 °C and a further 1 h at rt. The solution
was cooled to 0 °C, and 7 (2.90 g, 11.6 mmol) was added. After
1 h, the solution was warmed to rt and stirred for 40 h.
Saturated NH4Cl (45 mL) was added, the aqueous phase was
extracted with ether (3 × 30 mL), and the combined organics
were washed successively with water (10 mL) and saturated
NaCl (10 mL) and then dried over Na2SO4. Concentration and
flash chromatography (1:200-1:100 ethyl acetate/hexane)
afforded 12 as a colorless oil (3.93 g, 74%): [R]20D -16.2 (c 0.52,
CHCl3); Rf 0.19 (1:39 ethyl acetate/hexane); IR (neat), 3069.5,
2953.8, 1427.2, 1111.9, 734.8, 697.2 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.6-7.2 (m, 15H), 4.28 (d, J ) 3.9 Hz, 2H), 3.32 (s,
2H), 3.26 (m, 2H), 2.0 (m, 1H), 1.6-1.8 (m, 5H), 0.78 (d, J )
2.7 Hz, 3H), 0.76 (d, J ) 2.7 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.7, 135.1, 135.0, 134.1, 129.7, 128.2, 127.9, 127.8,
127.5, 127.3, 75.2, 72.7, 44.5, 32.3, 28.7, 25.2, 22.7, 22.6, 14.6;
exact mass (FAB) M - H+ calcd for C27H32ClOSi 435.1911,
found 435.1913.
(R)-4-Ben zyl-3-[(S)-2-b en zyloxym et h yl-4-m et h ylva le-
r oyl]oxa zolid in -2-on e (9).41 To a 0 °C solution of (R)-4-
benzyl-3-(4-methylvaleroyl)oxazolidin-2-one 8 (10.70 g, 38.86
mmol) in methylene chloride (100 mL) under a nitrogen
atmosphere was added a 1.0 M TiCl4 solution (40.0 mL of a
1.0 M solution in methylene chloride, 40.0 mmol) followed by
diisopropylethylamine (7.0 mL, 40 mmol). The solution was
stirred for 1 h. Benzyloxymethyl chloride (13.3 g, 84.8 mmol)
was added, and the mixture was stirred for 7 h at 0 °C.
Aqueous saturated ammonium chloride (75 mL) was added,
and after being stirred for 15 min the aqueous phase was
extracted with methylene chloride (3 × 40 mL). The combined
organics were washed with 50 mL of saturated NaCl solution
and dried over Na2SO4. Concentration and flash chromatog-
raphy (gradient of 1:20 to 1:10 ethyl acetate/hexanes) afforded
9 (13.20 g, 86%) as a colorless solid: mp 54 °C; [R]20 -38.5 (c
D
(40) Showell, G. A. Silicon Diols - Effective Inhibitors of Human
Leukocyte Elastase, Presented at 2nd European Organosilicon Days,
Munich, Germany, 11-12 Sep 2003, A7.
(41) Kim, J .; Glekas, A.; Sieburth, S. McN. Bioorg. Med. Chem. Lett.
2002, 12, 3625-3627.
3012 J . Org. Chem., Vol. 69, No. 9, 2004

Silanediol Thermolysin Inhibitor
2-([(2(S)-Ben zyloxym et h yl-4-m et h ylp en t yl)d ip h en yl-
sila n yl]m eth yl)isoin d ole-1,3-d ion e (15). To a solution of 12
(2.67 g, 6.11 mmol) in anhydrous dimethylformamide (15 mL)
at rt was added potassium phthalamide (2.11 g, 11.6 mmol),
and the solution was then heated to 90-100 °C overnight.
After the mixture was cooled to rt, ethyl acetate (15 mL), water
(15 mL), and a pH 7 buffer solution (15 mL) were added. The
aqueous portion was extracted with ethyl acetate (2 × 10 mL),
and the combined organics were washed with water (10 mL)
and saturated NaCl (10 mL) and then dried over Na2SO4.
Concentration and flash chromatography (12:88 ethyl acetate/
hexanes) gave 15 (2.45 g, 73%) as yellow oil: Rf 0.66 (1:5 ethyl
acetate/hexanes); [R]20D -3.8 (c 1.68, CHCl3); IR (neat) 3048.3,
washed with saturated NaCl (15 mL), dried over Na2SO4,
concentrated, and purified by flash chromatography (1:19
methanol/methylene chloride) to give 17 as a foam (570 mg,
90%): mp 49-50 °C; [R]20 -2.46 (c 3.66 CH2Cl2); Rf 0.50
D
(MeOH/CH2Cl2 1:15); IR (neat) 3457.2, 3070.5, 1776.3, 1760.9,
1
789.8, 678.0 cm-1; H NMR (300 MHz, CDCl3) δ 7.6-7.2 (m,
14H), 3.71 (s, 2H), 2.54 (m, 1H), 1.7-1.1 (m, 5H), 0.72 (d, J )
6.6 Hz, 3H), 0.67 (d, J ) 6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 182.8, 168.1, 135.1, 135.0, 133.4, 132.9, 132.0, 129.7,
127.7, 122.6, 44.2, 38.8, 26.3, 25.9, 22.8, 21.6, 16.4; exact mass
(FAB) MNa+ calcd for C28H29NO4SiNa 494.1764, found 494.1768.
2(S)-(2(S)-([(1,3-Dioxo-1,3-d ih yd r o-isoin d ol-2-ylm e-
th yl)-d ip h en yl-sila n yl]-m eth yl)-4-m eth yl-p en ta n oyla m i-
n o)-4-m eth yl-p en ta n oic a cid ter t-bu tyl ester (18). To a 0
°C solution of acid 17 (1.40 g, 3.0 mmol) in dry methylene
chloride (30 mL) were added 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (633 mg, 3.30 mmol) and
HOBt (447 mg, 3.31 mmol) and the mixture allowed to stir
for 1 h. Diisopropylethylamine (0.65 mL, 3.71 mmol) and
L-leucine tert-butyl ester hydrochloride (0.675 g, 3.0 mmol)
were added, and the solution was stirred and warmed to rt
over 24 h. The solution was diluted with methylene chloride
(10 mL), washed with saturated NH4Cl (2 × 5 mL), saturated
NaHCO3 (5 mL), water (5 mL), and saturated NaCl (5 mL),
and then dried over Na2SO4. Concentration and flash chro-
matography (1:4 ethyl acetate/hexanes) gave 18 (1.70 g, 89%)
as an oil: [R]20D -41.6 (c 1.85 CH2Cl2); Rf 0.21 (EtOAc/hexanes
1:5); IR (neat) 3385.8, 2955.7, 1730.1, 1708.8, 1675.1, 1385.8,
1154.3, 718.4 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.6-7.2 (m,
14H), 5.84 (d, J ) 8.0 Hz, 1H), 4.29 (q, J ) 6.8 Hz, 1H), 3.75
(d, J ) 6.8 Hz, 2H), 2.42 (m, 1H), 1.6-1.0 (m, 8H), 1.40 (s,
9H), 0.86 (d, J ) 6.4 Hz, 3H): 0.84 (d, J ) 6.4 Hz, 3H): 0.70
(d, J ) 6.4 Hz, 3H), 0.68 (d, J ) 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 175.8, 172.1, 168.2, 135.0, 133.8, 133.4, 133.3,
132.0, 129.8, 127.9, 127.8, 122.7, 81.4, 51.2, 44.4, 41.7, 40.3.
27.9, 26.4, 25.8, 24.8, 22.9, 22.5, 22.3, 21.9, 16.5; exact mass
(EI), MH+ calcd for C38H49N2O5Si 641.3411, found 641.3480.
2(S)-(2(S)-[(Am in om et h yld ip h en ylsila n yl)m et h yl]-4-
m eth ylp en ta n oyla m in o)-4-m eth ylp en ta n oic Acid ter t-
Bu tyl Ester (19). To a solution of 18 (1.15 g, 1.80 mmol) in
ethanol (18 mL) was added hydrazine (0.34 mL, 10.6 mmol).
The solution was heated to reflux for 2 h and then cooled to
rt. The solution was filtered through a pad of Celite, washing
with ether. Concentration and flash chromatography (1:1 ethyl
acetate/hexanes) gave 19 as an oil (845 mg, 91%): [R]20D -32.1
(c 4.76 CH2Cl2); Rf 0.30 (100% ethyl acetate); IR (neat) 3297.1,
3068.6, 2931.6, 2956.7, 1731.0, 1659.6, 1367.4, 1153.4, 729.0
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 10H), 6.43 (d,
J ) 7.5 Hz, 1H), 4.21 (q, J ) 6.9 Hz, 1H), 2.65 (s, 2H), 2.28
(m, 1H), 1.6-1.0 (m, 10H), 1.30 (s, 9H), 0.78 (d, J ) 4.2 Hz,
3H): 0.76 (d, J ) 4.5 Hz, 3H), 0.63 (t, J ) 4.5 Hz, 6H); 13C
NMR (63 MHz, CDCl3) δ 176.1, 172.2, 134.9, 134.8, 134.4,
134.3, 129.7, 128.1, 128.0, 81.3, 51.3, 45.3, 41.6, 39.8, 28.1, 28.0,
25.8, 24.9, 22.9, 22.5, 22.2, 15.6; exact mass (FAB) MH+ calcd
for C30H47N2O3Si 511.3379, found 511.3379.
2952.8, 1714.6, 1697.3, 1110.9, 1070.4 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.6-7.1 (m, 19 H), 4.15 (s, 2H), 3.70 (s,2H),
3.26 (dd, J ) 4.8, 9.0 Hz, 1H), 3.15 (dd, J ) 4.8, 9.0 Hz, 1H),
1.99 (sept, J ) 6.6 Hz, 1H), 1.6-0.8 (m, 5H), 0.73 (t, J ) 7.2
Hz, 6H); 13C NMR (63 MHz, CDCl3) δ 168.3, 138.7, 135.1,
135.0, 134.6, 134.5, 133.3, 132.2, 129.4, 128.2, 127.7, 127.6,
127.5, 127.3, 122.6, 75.1, 72.6, 44.6, 32.6, 26.8, 25.2, 22.8, 22.7,
+
16.4; exact mass (FAB) MNa
570.2440, found 570.2451.
calcd for C35H37NO3NaSi
2-([(2(S )-H yd r oxym e t h yl-4-m e t h ylp e n t yl)d ip h e n yl-
sila n yl]m eth yl)isoin d ole-1,3-d ion e. To a solution of 15 (1.39
g, 2.54 mmol) in methylene chloride (20 mL) at -78 °C was
added BBr3 (7.60 mL of a 1 M solution in methylene chloride,
75.2 mmol). After 2 h, methanol (10 mL) was added slowly
over 5 min, and then the solution was warmed to rt over 1 h.
The solvent was removed by rotary evaporation, and the
residue was taken up in methylene chloride (20 mL), washed
with water (10 mL) and saturated NaCl (10 mL), and dried
over Na2SO4. Concentration and flash chromatography using
(3:7 ethyl acetate/hexanes) gave the title compound as a yellow
oil (853.4 mg, 74%): Rf 0.59 (2:3 ethyl acetate/hexanes); [R]20
D
-36.1 (c 4.4, CHCl3); IR (neat) 3549.8, 1760.0, 1705.0, 770.5,
1
737.7, 718.4 cm-1; H NMR (300 MHz, CDCl3) δ 7.5-7.1 (m,
14H), 3.80 (AB quartet, J ) 15.3, 15.3 Hz, 2H), 3.51 (dd, J )
3.9,10.8 Hz, 1H), 3.33 (dd, J ) 6.3,10.8 Hz, 1H), 2.12 (br s,
1H), 1.79 (sept, J ) 6.6 Hz,1H), 1.56-0.93 (m, 5H), 0.67 (d, J
) 6.6 Hz, 6H); 13C NMR (63 MHz, CDCl3) δ 168.4, 135.0, 134.9,
134.2, 134.0, 133.5, 132.0, 129.6, 129.5, 127.9, 127.8, 122.7,
67.5, 44.0, 34.6, 26.8, 25.1, 22.8, 22.6, 15.9; exact mass (FAB)
MNa+ calcd for C28H31NO3SiNa 480.1971, found 480.1988.
2(S)-([(1,3-Dioxo-1,3-d ih yd r oisoin d ol-2-ylm et h yl)d i-
p h en ylsila n yl]m eth yl)-4-m eth ylp en ta n a l (16). To a solu-
tion of 2-([(2(S)-hydroxymethyl-4-methylpentyl)diphenyl-
silanyl]methyl)isoindole-1,3-dione (1.784 g, 3.90 mmol) in dry
methylene chloride (8 mL) were added N-methylmorpholine
N-oxide (612 mg, 5.07 mmol), tetrapropylammonium perru-
thenate (59.6 mg, 0.17 mmol), and finely ground 4 Å molecular
sieves (2.0 g). The solution was stirred for 2 h at rt and filtered
through a pad of silica, eluting the silica with methylene
chloride (150 mL). Concentration gave the crude aldehyde 16
(1.60 g, 95%): Rf 0.58 (1:4 ethyl acetate/hexanes); IR (neat)
1
1715, 1709.8, 1678.0, 720.4, 702.0 cm-1; H NMR (300 MHz,
CDCl3) δ 9.39 (d, J ) 3.0 Hz, 1H), 7.7-7.2 (m, 14H), 3.7 (s,
2H), 2.5 (m, 1H), 1.7-1.1 (m, 5H), 0.69 (d, J ) 6.3 Hz, 3H),
0.65 (d, J ) 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.4,
168.1, 135.0, 134.9, 133.4, 133.1, 132.9, 131.8, 129.8, 129.7,
127.8, 127.7, 122.6, 45.6, 41.0, 26.4, 25.5, 22.6, 22.0, 12.7; exact
mass (FAB) MNa+ calcd for C28H29NO3SiNa 478.1814, found
478.1937.
2(S)-([(1,3-Dioxo-1,3-d ih yd r oisoin d ol-2-ylm et h yl)d i-
p h en ylsila n yl]m eth yl)-4-m eth ylp en ta n oic Acid (17). To
a solution of 16 (609 mg, 1.34 mmol) in tert-butyl alcohol (16
mL) and water (4.0 mL) were added 2-methyl-2-butene (5 mL,
9.438 mmol) and sodium dihydrogenphosphate (50 mg, 0.41
mmol). After the mixture was stirred for 20 min at rt, NaClO2
(401 mg, 4.4 mmol) was added and stirring continued for 2 h.
Saturated NH4Cl (12 mL) and methylene chloride (10 mL)
were added, and the aqueous phase was extracted with
methylene chloride (3 × 10 mL). The combined organics were
2(S)-[2(S)-((Dip h en yl-[(3-p h en ylp r op ion yla m in o)m e-
th yl]sila n yl)m eth yl)-4-m eth ylp en ta n oyla m in o]-4-m eth -
ylp en ta n oic Acid ter t-Bu tyl Ester (20b). To a 0 °C solution
of 19 (707 mg, 1.52 mmol) in ether (21 mL) with saturated
NaHCO3 (6.0 mL) was added 3-phenylpropionyl chloride (0.25
mL, 1.65 mmol). After 1.5 h, saturated NH4Cl was added, and
the aqueous phase was extracted with ether (3 × 10 mL). The
combined organics were washed with saturated NaCl (15 mL)
and dried over Na2SO4. Concentration and flash chromatog-
raphy (2:98-1:4 ethyl acetate/hexanes) gave 20b as a colorless
oil (0.821 g, 84%): [R]20 -33.0 (c 4.5, CH2Cl2); Rf 0.46 (1:2
D
ethyl acetate/hexanes); IR (neat) 3282.6, 3027.1, 2955.7,
1
1735.8, 1644.2, 1538.1, 1367.5, 1153.4, 699.2 cm-1; H NMR
(300 MHz, CDCl3) δ 7.5-7.2 (m, 15H), 6.74 (br s, 1H), 6.05 (d,
J ) 8.1 Hz, 1H), 4.33 (q, J ) 6.3 Hz, 1H), 3.58 (dd, J ) 6.3,
15.6 Hz, 1H), 3.23 (dd, J ) 4.5, 15.6 Hz, 1H), 2.98 (t, J ) 10.5
Hz, 2H), 2.56-2.51 (m, 3H), 1.7-1.3 (m, 8H), 1.50 (s, 9H), 0.95
J . Org. Chem, Vol. 69, No. 9, 2004 3013

Kim and Sieburth
(t, 6H), 0.90 (d, J ) 6.3 Hz, 3H), 0.86 (d, J ) 6.3 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 176.5,172.4, 171.9, 141.1, 134.8,
134.7, 134.2, 133.6, 129.9, 129.8, 128.4, 128.3, 128.2, 128.1,
126.0, 81.7, 51.5, 45.8, 41.6, 40.4, 38.4, 31.9, 28.0, 26.1, 25.6,
24.9, 22.6, 22.4, 15.0; 29Si NMR (99 MHz, CDCl3) δ -10.2; exact
mass (FAB) MH+ calcd for C39H55N2O4Si 643.3931, found
643.3944.
by the disappearance of the two fluorine signals of 22 and the
appearance of a single fluoride signal: 1H NMR (400 MHz,
D2O) δ 7.26-7.11 (m, 5H), 4.06 (dd, J ) 6.4, 9.2 Hz, 1H), 2.79
(t, J ) 7.2 Hz, 2H), 2.48-2.35 (m, 5H), 1.50-1.29 (m, 5H),
1.17-1.10 (m, 1H), 0.91-0.82 (m, 9H), 0.69 (d, J ) 6.4 Hz,
3H), 0.61 (t, J ) 6.0 Hz, 2H); 13C NMR (100 MHz, 1% CD3CN
in D2O) δ 181.0, 180.6, 176.3, 141.6, 129.6, 129.3, 127.3, 54.5,
44.7, 41.8, 40.5, 38.4, 32.4, 30.0, 26.6, 25.4, 23.6, 23.3, 22.1,
21.7, 19.9;
En zym e Assa y. Thermolysin was obtained from a com-
mercial supplier and used without purification. Stock solutions
of Tris (50 mM), NaBr (2.5 M), and CaCl2 (10 mM), pH 7.0
were prepared and stored at 4 °C. A stock solution of FAGLA
(N-[3-(2-furyl)acryloyl]glycyl-L-leucinamide) was prepared in
DMF, diluting with buffer to a final concentration of 0.1 M
Tris, 0.1 M NaBr, and 2.5 mM CaCl2, pH 7.0 (final concentra-
tion of DMF, 2.5%).
The enzyme and inhibitor 22 were incubated for 15 min at
25 °C in a temperature-regulated cuvette, and then the FAGLA
solution was added to give a substrate concentration of either
0.8 or 1.5 mM. Initial velocities were determined for e10%
reaction and were performed in triplicate for each inhibitor
concentration, interspersing controls without inhibitor after
every two runs with inhibitor.
2(S)-[2(S)-((Diflu or o[(3-p h en ylp r op ion yla m in o)m eth -
yl]sila n yl)m et h yl)-4-m et h ylp en t a n oyla m in o]-4-m et h yl-
p en ta n oic Acid (22). To a 0 °C solution of 20b (109 mg, 0.17
mmol) in methylene chloride (6.0 mL) was added trifluo-
romethanesulfonic acid (0.25 mL, 2.8 mmol). The mixture was
stirred for 35 min at 0 °C, and then ammonium hydroxide (0.30
mL of a 14.8 N solution) was added. The solution was stirred
for an additional 35 min at 0 °C, and hydrofluoric acid (0.20
mL of a 48% solution) was then added. The solution was stirred
for 10 min. The colorless precipitate was collected to give 22
(53.7 mg, 67%): mp 106-108 °C; [R]20D -16.2 (c 0.21, acetone);
IR (neat) 3378, 3310, 1720, 1623, 1600, 1541, 1208, 871 cm-1
;
1H NMR (300 MHz, acetone-d6) δ 8.62 (bs, 1H), 7.29-7.25 (m,
5H), 5.61 (s, 1H), 4.50 (q, J ) 3.3 Hz, 1H), 2.98 (t, J ) 7.5 Hz,
2H), 2.68 (m, 3H), 2.34 (d, J ) 3.0 Hz, 2H), 1.81 (m, 1H), 1.67-
1.60 (m, 4H), 1.26 (m, 1H), 1.06 (m, 2H), 0.93-0.90 (m, 9H),
0.84 (d, J ) 6.3 Hz, 3H); 13C NMR (63 MHz, acetone-d6) δ
178.2,177.1, 174.1, 141.1,129.2, 129.1, 127.0, 51.4, 45.6, 41.5,
41.4, 40.8, 35.1, 31.8, 26.5, 25.4, 23.4, 22.8, 21.9; 19F NMR (235
MHz, Acetone-d6) δ -119 (d, J ) 20 Hz), -124 (d, J ) 20 Hz);
exact mass (FAB) MNa+ calcd for C23H36N2O4F2NaSi 493.2310,
found 493.2303.
Ack n ow led gm en t. Support from the NIH is grate-
fully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Proton and carbon
NMR spectra for all new compounds, the Dixon plot, and
experimental details for the preparation of 13, 14, 20a , 21,
and 2. This material is available free of charge via the Internet
at http://pubs.acs.org.
2-(S)-[2-(S)-((Dih yd r oxy[(3-p h en ylp r op ion yla m in o)-
m e t h yl]sila n yl)m e t h yl)-4-m e t h ylp e n t a n oyla m in o]-4-
m eth ylp en ta n oa te Sod iu m Sa lt (23). To a solution of 22
(30 mg, 63.7 µmol) in D2O (0.5 mL) at rt was added NaOH (10
mg, 0.25 mmol) in D2O (0.1 mL). The reaction was monitored
by 19F NMR. After 20 min, the reaction was complete as judged
J O049929I
3014 J . Org. Chem., Vol. 69, No. 9, 2004