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.
(12) Burk, M. J.; De, K. P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge,
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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