C O M M U N I C A T I O N S
Table 2. Reactions with Different Nucleophilic Moietiesa
alkylation of siloxy enol carbonates. The excellent selectivity toward
aldehyde was achieved by using chiral ligand L, which is in stark
contrast to dppe, which favors ketone formation. The reaction
proceeds under very mild conditions and generates an R-tetrasub-
stituted stereogenic center with excellent yield and enantiomeric
excess. Further investigation of the mechanism, reaction scope, and
its application in organic synthesis is ongoing.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Grant GM13598, for their generous support of our programs. J.X.
has been supported by Abbott Laboratories Fellowships. Mass
spectra were provided by the Mass Spectrometry Regional Center
of the University of CaliforniasSan Francisco supported by the
NIH Division of Research Resources. We thank Chirotech (now
Dow) for their generous gifts of ligands, and Johnson Matthey for
gifts of palladium salts.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
a All reactions were performed on a 0.2 mmol scale at 0.1 M in dioxane
at 23 °C using 2.5 mol % of Pd2(dba)3CHCl3 and 5.5 mol % of ligand L;
the yields were isolated yields, and ee values were determined by chiral
HPLC.
References
Table 3. Reactions with Different Electrophilic Moieties
(1) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Syntheses; Wiley-VCH: Weinheim, Germany, 1997.
entry
substrate
time
yield
dr
ee of major ee of minor ee of 15
(2) (a) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley & Sons: New York, 1995. (b) Ruano, J. L. G.;
Barros, D.; Maestro, M. C.; Alcudia, A.; Ferna´ndez, I. Tetrahedron:
Asymmetry 1998, 9, 3445. (c) Tamura, Y.; Kondo, H.; Annoura, H.;
Takeuchi, R.; Fujioka, H. Tetrahedron Lett. 1986, 27, 81. (d) Guanti, G.;
Narisano, E.; Pero, F.; Banfi, L.; Scolastico, C. J. Chem. Soc., Perkin
Trans. 1 1984, 189. (e) Guanti, G.; Narisano, E. Tetrahedron Lett. 1983,
24, 817. (f) Mukaiyama, T. Tetrahedron 1981, 37, 4111.
1
2
3
4
5
13a (n ) 1)
12b (n ) 2)
1 h quant. 2.5:1
2 h quant. 11:1
13b (n ) 2) 16 h quant. 11:1
92%
>99%
>99%
>99%
>99%
87%
43%
84%
12c (n ) 3) 16 h quant. 50:1
13c (n ) 3) 16 h 30%
99%
50:1
(3) (a) Hughes, D. L. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, p
1273. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (c) Hof, R. R.; Kellogg, R. M. J. Chem. Soc., Perkin
Trans. 1 1996, 2051. (d) Ooi, T.; Fukumoto, K.; Maruoka, K. Angew.
Chem., Int. Ed. 2006, 45, 3839. (e) Brunel, J. M.; Holmes, I. P. Angew.
Chem., Int. Ed. 2004, 43, 2752.
Scheme 1. Formal Synthesis of (S)-Oxybutynina
(4) Enantioseletive aldol reactions of R-oxyaldehydes catalyzed by organo-
catalysts have been reported. See: Northrup, A. B.; Mangion, I. K.;
Hettche, F.; MacMillian, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152.
(5) (a) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180. (b) Trost,
B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (c) Similar results were
reported independently by Stoltz et al. using t-Bu-PHOX ligands. See:
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(6) See Supporting Information for the examples of the synthesis of siloxy
enol carbonates.
(7) (a) Thompson, I. M.; Lauvetz, R. Urology 1976, 8, 452-454. For the
synthesis of (S)-oxybutynin see: (b) Tokuda, O.; Kano, T.; Gao, W. G.;
Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103. (c) Gupta, P.;
Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 4231. (d)
Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2002, 43, 8647. (e) Grover, P. T.; Bhongle, N. N.; Wald, S. A.;
Senanayake, C. H. J. Org. Chem. 2000, 65, 6283. (f) Senanayake, C. H.;
Fang K.; Crover, P.; Bakale, R. P.; Vandenbossche, C. R.; Wald, S. A.
Tetrahedron Lett. 1999, 40, 819.
(8) The absolute configuration of 1a was determined by reduction of CHO
to CH2OH followed by removal of TBDMS and comparison of the optical
rotation of the product 1,2-diol ([R]D24 ) -45.2 (c 1.2, CHCl3)) with the
reported data for (2R)-1,2-dihydroxy-2-phenylpent-4-ene ([R]D20 ) +43.4
(c 1.2, CHCl3)). Agami, C.; Couty, F.; Lequesne, C. Tetrahedron 1995,
51, 4043.
(9) Waetzig, S. R.; Rayabarapu, D. K.; Weaver, J. D.; Tunge, J. A. Angew.
Chem., Int. Ed. 2006, 45, 4977.
(10) The absolute configuration of 8 was determined by removal of TBDMS
and comparison of the optical rotation of the product ([R]D24 ) -91.3 (c
1.05, benzene)) with the reported data for (S)-3-hydroxy-3-phenylhex-5-
en-2-one ([R]D26 ) +124.7 (c 0.635, benzene)). Soai, K.; Ishizaki, M. J.
Org. Chem. 1986, 51, 3290.
a Reagents and conditions: (a) NaH, CO2, THF, then PhCOCH2Br, DMF,
23 °C, 42%; (b) NaHMDS, TBSCl, THF, -78 to 23 °C, 83%; (c) 2.5 mol
% of Pd2(dba)3CHCl3, 5.5 mol % of L, 1,4-dioxane, 23 °C, 99% (dr 11:1);
(d) H2, cat. Pd/C, EtOH, 23 °C, 96%, 84% ee; (e) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH, H2O, 23 °C, 95% (recrystallization from
hexane/DCM, >99% ee).
the R-enantiomer.10 The reaction also works for the synthesis of a
cyclic R-tertiary siloxy ketone 10 with a moderate ee in favor of
the R-enantiomer (entry 14).11
Variation of the allyl moiety to cycloalkenyl as in 12 led to 14
quantitatively (eq 3). The regioisomer 13b reacted slower than 12b
but still in quantitative yield, whereas the reaction of 13c proceeded
only in 30% conversion. The diastereomeric ratio (dr) of 14 in-
creased from 2.5:1 to over 50:1 with increasing cycloalkenyl ring
size. Removal of one of the stereogenic centers by hydrogenation
of the CdC double bond gave compounds 15a-c (n ) 1-3). The
ee of 15 reflected the dr of 14. 15b was converted into the key
intermediate 17 for the synthesis of (S)-oxybutynin in 95%
yield, wherein one recrystallization increased the ee to over 99%
(Scheme 1).
(11) The absolute configuration of 10 was determined by removal of TBDMS
and comparison of the optical rotation of the product ([R]D23 ) -73.4 (c
2.6, CHCl3)) with the reported data for (S)-2-allyl-2-hydroxycyclohexanone
([R]D ) +136.6 (c 2, CHCl3)). Compain, P.; Gore´, J.; Vate`le, J. M.
Tetrahedron 1996, 52, 6647.
In summary, we report the first catalytic asymmetric synthesis
of R-tertiary hydroxyaldehydes by palladium-catalyzed allylic
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