59
I. B. Seiple et al.
Letter
Synlett
O
HO
N
K2OsO4 (1.2 mol%)
NaIO4, 2,6-lutidine
TBDPSCl
imidazole
O
H3C
CH3
OTBDPS
H3C
CH3
OTBDPS
1a
99% ee
96%
93%
5
7
(1 mol%)
H
H3C
H3C
CH3
Et2Zn
76% after distillation
O
OH
2
TBSCl
imidazole
K2OsO4 (1 mol%)
NaIO4, 2,6-lutidine
O
H3C
CH3
H3C
CH3
90% over 2 steps
OTBS
OTBS
1b
8
Scheme 3 Synthesis of (R)-3-silyloxypentan-2-ones 1a and 1b
thesis of macrolide antibiotics. We believe this chemistry
may be useful for other applications that require large
quantities of various ethers of enantioenriched 3-hydroxy-
pentan-2-one.
(7) For a report of a five-step synthesis of (+)-2 of 65% ee, see:
Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van
Sterkenburg, M. Tetrahedron: Asymmetry 2000, 11, 4227.
(8) For a report of a two-step synthesis of (+)-2, see: Geurts, K.;
Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 15572.
(9) For a report of a three-step synthesis of (+)-2 of 76% ee, see:
Jones, S.; Valette, D. Org. Lett. 2009, 11, 5358.
(10) Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1978,
601.
(11) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am.
Chem. Soc. 1979, 101, 1455.
(12) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(13) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(14) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(15) Qiu, J.; Guo, C.; Zhang, X. M. J. Org. Chem. 1997, 62, 2665.
(16) Nugent, W. A. Chem. Commun. 1999, 1369.
Acknowledgment
We most gratefully acknowledge funding from Alastair and Celine
Mactaggart, from a private family foundation, and from the Blavatnik
Biomedical Accelerator Program at Harvard University. We thank Zi-
yang Zhang for helpful advice and editorial assistance. I.B.S. acknowl-
edges the National Institutes of Health for a postdoctoral fellowship
(GM099233). D.T.H. is indebted to the Deutsche Forschungsgemein-
schaft (DFG) for a postdoctoral fellowship (HO 5326/1-1).
(17) Morinaka, B. I.; Pawlik, J. R.; Molinski, T. F. J. Org. Chem. 2010,
75, 2453.
(18) Nugent, W. A. Org. Lett. 2002, 4, 2133.
Supporting Information
(19) (R)-2-Methylpent-1-en-3-ol (2)
Supporting information for this article is available online at
A solution of Et2Zn in hexanes (800 mL, 1.0 M, 800 mmol, 1.94
equiv) was added via cannula to an ice-cooled, stirring suspen-
sion of (1R,2S)-1-cyclohexyl-2-morpholino-2-phenylethanol
(5) (1.24 g, 4.28 mmol, 0.01 equiv) in n-hexane (288 mL) in a 3 L
round-bottom flask. White vapor formed in the receiving flask
during the transfer. The resulting solution was allowed to stir
for 30 min at 0 °C, then methacrolein (34 mL, 412 mmol, 1.0
equiv, freshly distilled) was added dropwise over 90 min using a
syringe pump, producing a pale yellow, homogeneous solution.
After 3 h, HCl (850 mL, 3 M) was added slowly (Caution: exo-
therm). A white precipitate was visible during the addition, but
this redissolved toward the end of the addition (pH 1). The
biphasic mixture was transferred to a separating funnel and the
layers were separated. The aq layer was further extracted with
Et2O (2 × 500 mL), the organic layers were combined, and the
resulting solution was washed with brine (500 mL). The washed
solution was dried over Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure (~40 Torr) at ≤10 °C. The
resulting clear oil was transferred to a 250 mL round-bottom
flask, and the transfer was quantitated with Et2O (2 × 15 mL).
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(1) Racemic 1b has been synthesized by a seven-step sequence
from propionaldehyde, see: Amarante, G. W.; Cavallaro, M.;
Coelho, F. J. Braz. Chem. Soc. 2011, 22, 1568.
(2) (R)-3-Benzyloxypentan-2-one has been prepared by resolution
of (±)-2, see: Overman, L. E.; Lin, N. H. J. Org. Chem. 1985, 50,
3669.
(3) A synthesis of (R)-2-methylpent-1-en-3-ol tert-butyldimethyl-
silyl ether has been reported, see: Cossy, J.; Bauer, D.; Bellosta,
V. Synlett 2002, 715.
(4) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.;
Fu, G. C. Chem. Commun. 2000, 1009.
(5) Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(6) Discordia, R. P.; Dittmer, D. C. J. Org. Chem. 1990, 55, 1414.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 57–60