Efficient, enantioselective assembly of silanediol protease inhibitors

Article abstract of DOI:10.1021/ol2002978

A five-step assembly of silicon-protected dipeptide mimics from commercially available reagents is described. This methodology makes silanediol protease inhibitors readily available for the first time. The sequence features asymmetric hydrosilylation, a novel reduction of a silyl ether to a silyllithium reagent, and addition of this dianion to a sulfinimine, to produce the complete inhibitor skeleton with full control of stereochemistry. Oxidation of the primary alcohol to an acid completes the synthesis.

Full text of DOI:10.1021/ol2002978

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1787–1789
Efficient, Enantioselective Assembly of
Silanediol Protease Inhibitors
Yingjian Bo, Swapnil Singh, Hoan Quoc Duong, Cui Cao, and Scott McN. Sieburth*
Department of Chemistry, Temple University, 1901 North 13th Street, Philadelphia,
Pennsylvania 19122, United States
scott.sieburth@temple.edu
Received January 30, 2011
ABSTRACT
A five-step assembly of silicon-protected dipeptide mimics from commercially available reagents is described. This methodology makes
silanediol protease inhibitors readily available for the first time. The sequence features asymmetric hydrosilylation, a novel reduction of a silyl
ether to a silyllithium reagent, and addition of this dianion to a sulfinimine, to produce the complete inhibitor skeleton with full control of
stereochemistry. Oxidation of the primary alcohol to an acid completes the synthesis.
Inhibition of proteolytic enzymes remains a fundamental
approach to the design of new pharmaceuticals, with recent
examples including the treatment of cancer and antiretro-
virus diseases (HIV) as well as treatment for Alzheimer’s
and hepatitis C.1 Most protease inhibitors utilize now-
standard functionality to mimic the transition state or to
intercept the catalytic functional groups: hydroxamic,
carboxylic and phosphinic acids (for metalloproteases),
hydroxyls (for aspartic acids), and activated carbonyls
(for serine proteases).2 Fundamentally different functional
groups that can act as transition-state analogs have the
potential to give enhanced enzyme binding and phar-
macokinetic properties, as well as intellectual property
novelty.3
Dialkylsilanediol dipeptide analogs (e.g., 1, Scheme 1)
are tetrahedral functional groups that can mimic hydrated
carbonyls.4 When silanediols are embedded in a peptide-
like structure such as 1, they are recognized by protease
enzymes and, as hydrolytically stable entities, act as
inhibitors. Tripeptide analog 1, for example, is a 4 nM
inhibitor of the metalloprotease angiotensin-converting
enzyme, an important therapeutic target for hypertension.5
A silanediol has also been shown to be a 3 nM inhibitor of
Scheme 1. Protease Inhibitor 1, Originally Prepared via 2 from
3-5
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r
10.1021/ol2002978
2011 American Chemical Society
Published on Web 03/07/2011

the aspartic acid HIV-protease, an activity thattranslatesto
cell-protection assays.6
Scheme 2. Asymmetric Hydrosilylation of 2-Alkyl Diphenylsilyl
Ethersa
An impediment to utilization of these silanediol structures,
however, has been the methodology for their assembly. In
our original preparation of 1, Scheme 1, diphenylsilane 2
was the direct precursor of the silanediol; the R-amino
silane portion of 2 was prepared utilizing a dithiane
nucleophile 3 and six synthetic steps, while Roche ester
5 was transformed to the β-silyl acid of 2 in seven steps. In
this synthesis, the stereochemistry of the methyl substitu-
tion was purchased and the benzyl group stereochemistry
relied on separation of diastereomers. While effective,
this approach comprised 13 steps and was technically
challenging.7
We report here a short, general, asymmetric preparation
of silanediol precursor 2: one that employs intramolecular
asymmetric hydrosilylation to set the β-silyl acid stereo-
chemistry, a novel reduction of a silyl ether to a silyl anion,
and addition of the resulting dianion to a sulfinimine. The
resulting product requires only alcohol oxidation to give
the fully functionalized dipeptide mimic.
a Compound 7a was correlated with a known compound; 7d was
assigned using the Mosher ester method; 7b and 7c were assigned by
analogy. See Supporting Information.
with lithium aluminum hydride. Following the Skrydstrup
protocol,14 silane 8 was converted to the corresponding
lithium reagent and then coupled with sulfinimine 12to give
sulfinamide 9 as a single stereoisomer. Mild acidic depro-
tection of both the amine and the alcohol, followed by
Schotten-Baumann derivatization of the amine, gave
amide-alcohol 10. Oxidation of the alcohol with TEMPO
gave 11 in 72% yield.15
Asymmetric intramolecular hydrosilylation of 2-alkyl
allyl silyl ethers in the simple system 6a was described by
Bosnich, who found 25% ee was possible using BINAP-
rhodium complexes.8,9 We have reexamined this transfor-
mation, surveying a series of commercially available phos-
phine ligands.10 (S,S)-Diethylferrotane11 as a rhodium
ligand (2 mol %) was found to fully convert 2 g of the
methylallyl ether of diphenylsilane 6a into (4S)-2-diphe-
nylsilafuran 7a with good enantiomeric excess within 1 h
(Scheme 2).12 Additional examples b-d indicate a useful
breadth of utility for this ligand in these asymmetric
hydrosilylations, which all proceed quantitatively.
Conversion of silafuran 7a to a protease inhibitor was
conveniently effected (Scheme 3) by treatment with 48%
HF, protection of the alcohol as the MOM ether,13 and
transformation of the fluoride to the hydride 8 by reduction
Scheme 3. Conversion of the Silafuran to an Advanced Inter-
mediate
(6) Chen, C.-A.; Sieburth, S. McN.; Glekas, A.; Hewitt, G. W.;
Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffry,
S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161–1166.
(7) Kim, J.; Hewitt, G.; Carroll, P.; Sieburth, S. McN. J. Org. Chem.
2005, 70, 5781–5789.
(8) Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem.
Soc. 1992, 114, 2121–2128. Bergens, S. H.; Noheda, P.; Whelan, J.;
Bosnich, B. J. Am. Chem. Soc. 1992, 114, 2128–2135.
(9) Han, J. W.; Hayashi, T. Asymmetric Hydrosilylation of Carbon-
Carbon Double Bonds and Related Reactions. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, NY, 2010; pp 771-798.
(10) See: Hartwig, J. Organotransition Metal Chemistry; University
Science: Sausalito, CA, 2010, pp 603-611. Walsh, P. J.; Kozlowski,
M. C. Fundamentals of Asymmetric Catalysis; University Science Books:
Sausalito, CA, 2008; pp 114-164.
(11) Berens, U.; Burk, M. J.; Gerlach, A.; Hems, W. Angew. Chem.,
Int. Ed. 2000, 39, 1981–1984.
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G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern,
T. A.; Ramsden, J. A.; Wade, R. A. J. Org. Chem. 2003, 68, 5731–5734.
(13) Gras, J. L.; Chang, Y. Y. K. W.; Guerin, A. Synthesis 1985,
74–75.
(14) Ricci, M.; Blakskjr, P.; Skrydstrup, T. J. Am. Chem. Soc. 2000,
122, 12413–12421. Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.;
Skrydstrup, T. J. Org. Chem. 2007, 72, 10035–10044. Nielsen, L.;
Skrydstrup, T. J. Am. Chem. Soc. 2008, 130, 13145–13151. Hernandez,
D.; Lindsay, K. B.; Nielsen, L.; Mittag, T.; Bjerglund, K.; Friis, S.;
Mose, R.; Skrydstrup, T. J. Org. Chem. 2010, 75, 3283–3293. Hernandez,
D.; Mose, R.; Skrydstrup, T. Org. Lett. 2011, 13, 732–735.
This seven-step sequence, Scheme 3, cut the number of
steps required for preparation of 11 by nearly half while
simultaneously controlling the stereochemistry. Neverthe-
less, the inclusion of protection-deprotection protocols
suggested that further improvements were possible.
To explore a more direct conversion of 7a, this substrate
was subjected to standard lithiation conditions by stirring
with lithium metal. To our delight, formation of the typical
brown-green color of silyllithium reagents was observed.
After 7 h, the addition of chlorotrimethylsilane led to the
formation of 14, indicating that dianion 13 had been
produced (Scheme 4).
Repeating the lithiation step and addition to sulfinimine
17 gave alcohol 15 (0.2 g, 76%, Scheme 5). Exchange of the
sulfinamide for a Boc group and oxidation of the alcohol
with ruthenium chloride gave 16 in 43% yield (three steps).
Acid 16 is ideally configured for use in silanediol inhibitor
(15) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974–6977.
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Org. Lett., Vol. 13, No. 7, 2011

reaction was reported by Gilman in 1953.17 These appear
to be the only examples of this transformation.
Scheme 4. Lithiation of Silyl Ether 7a
The addition of dianion 13 to the sulfinimine follows the
seminal contributions of Nielsen and Skrydstrup.14 The
use of this silyl-alkoxy dianion, however, has a potential
complication arising from the competition of two different
basic and nucleophilic groups. The alcohol, in particular,
appears to be far less sterically encumbered. Nevertheless,
even with the difficult substrate 12 the silane addition
product 18 is isolated in good yield.
We have found the use of the sulfinimines developed
by Davis18 (p-toluene, e.g. 17) and by Ellman19 (tert-butyl,
e.g., 12) to be essentially interchangable, with only slight
differences in diastereoselectivity. In some cases slight dif-
ferences in stability or crystallinity may be advantageous.
An additional streamlining of this sequence could, in
principle, be achieved by oxidizing the alcohol of 15 to an
acid without oxidizing the easily removed sulfinamide to a
more robust sulfonamide. This remains under study.
This scalable, short sequence for building silicon-based
protease inhibitors makes these structures routinely avail-
able for the first time, with complete control of stereo-
chemistry. Investigations into the use of silyl ethers as
silyllithium reagent precursors and asymmetric intramole-
cular hydrosilylation will be reported elsewhere.
Scheme 5. Four-Step Assembly of 16 from 7a
Acknowledgment. We thank Franklin Davis (Temple
University) and Troels Skrydstrup (Aarhus University)
for helpful discussions. This work was supported by the
National Institutes of Health (R01GM076471).
investigations. The addition of dianion 13 to other sulfini-
mines gave 18 (0.37 g, 56%) and 19 (0.10 g, 71%).
Supporting Information Available. Detailed experimen-
tals, characterization data, and proton NMR spectra for
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
The reduction of diphenylsilyl ether 7a to a diphenylsilyl
lithium reagent has little precedent. Silyl anions are typi-
cally preparedfrom silanescarryingatleast one phenyland
a chloride, a fluoride, a hydride, or another silane.16
Benkeser reported the reduction of methoxytriphenylsi-
lane with a sodium-potassium alloy in 1952, and a similar
(17) Benkeser, R. A.; Landesman, H.; Foster, D. J. J. Am. Chem. Soc.
1952, 74, 648–650. Gilman, H.; Wu, T. C. J. Org. Chem. 1953, 18,
753–764.
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(16) Lickiss, P. D.; Smith, C. M. Coord. Chem. Rev. 1995, 145, 75–
124. Belzner, J.; Dehnert, U. The Chemistry of Organic Silicon Com-
pounds; Rappoport, Z., Apeloig, Y., Eds.; Wiley: New York, 1998; Vol. 2,
pp 780-825.Singer, R. D. Sci. Synth. 2002, 4, 237–246.
8030.
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