Purification was simplified by treating the reaction mixture
with HF‚pyridine6 to provide analytically pure R-hydroxy
acid 3 exclusively after extraction. This procedure obviated
the need for chromatography.
Scheme 1. Proposed Mechanism
Silylene transfer to R-keto esters enabled a stereoselective
synthesis of R-hydroxy acids possessing two contiguous
stereocenters (Table 2). In all cases, the R-hydroxy acids
Table 2. Silylene Transfer to a Range of Substrates
entry
R1
R2
product
yield (%)a
silane 9 through a chairlike transition state provides sila-
lactone 10, which was hydrolyzed to give R-hydroxy acid
7.4,8-11
1
2
3
4
5
6
7
8
9
Me
Et
i-Pr
t-Bu
Ph
Ph
Ph
Ph
Et
Ph
Ph
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
70
84
54
47
71
62
72b
71
75
Me
n-Bu
CH2OTBDMS
(CH2)2OBn
Except where noted, one diastereomer was observed by 1H NMR
spectroscopy. b A minor isomer (2%) was observed by 1H NMR spectros-
copy.
a
Figure 1. Intermediate silyl ether.
The silylene-mediated synthesis of R-hydroxy acids can
be employed to prepare enantiomerically enriched products.9
R-Keto ester 13, which was synthesized from commercially
available ethyl lactate,12 was treated under silylene transfer
conditions to provide R-hydroxy acid 14 in 77% yield as a
single enantiomer (Scheme 2).13 The relative and absolute
stereochemistry of acid 14 was proven by X-ray crystal-
lography of its phenethylamine salt.12 Remote stereocenters
were also observed to influence the configuration of the
R-hydroxy acid product. Although the stereocenter of R-keto
ester 15 would lie outside the chairlike transition state of
the Ireland-Claisen rearrangement, it was able to direct the
stereochemical course of the reaction.14-16
were formed with g97% diastereoselectivity (as determined
by 1H NMR spectroscopy), and the relative stereochemistry
of each product was assigned by analogy (vida infra).
Silylene transfer was general for a range of substrates,
although higher yields were obtained with less sterically
demanding substrates. In addition, protected allylic and
homoallylic alcohols were tolerated (Table 2, entries 8 and
9).
The proposed mechanism for the synthesis of R-hydroxy
acids is outlined in Scheme 1. Generation of the silver
silylenoid species4 followed by attack of the ketone carbonyl
oxygen leads to silacarbonyl ylide 8, which can then undergo
a 6π-electrocyclization to give silyl ketene acetal 9. Although
this intermediate has not been observed, its viability was
demonstrated by the conversion of ethyl pyruvate to a similar
silyl ketene acetal under identical silylene transfer conditions
(Figure 1).7 Subsequent Ireland-Claisen rearrangement of
(8) Ando, W.; Hagiwara, K.; Sekiguchi, A. Organometallics 1987, 6,
2270-2271.
(9) Calad, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 2046-
2047.
(10) Hiersemann, M.; Nubbemeyer, U. The Claisen Rearrangement:
Methods and Applications; Wiley-VCH: Weinheim, 2007.
(11) For Claisen rearrangements of R-keto ester derivatives, see: Wood,
J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich,
H.-J. J. Am. Chem. Soc. 1999, 121, 1748-1749.
(3) (a) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron Lett. 1981, 22,
4221-4224. (b) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313-1324. (c) Chang, J.-W.; Jang, D.-P.; Uang, B.-J.; Liao, F.-L.;
Wang, S.-L. Org. Lett. 1999, 1, 2061-2063. (d) Picoul, W.; Urchegui, R.;
Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40, 4797-4800. (e)
D´ıez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001, 40, 2906-
2909. (f) Hutchison, J. M.; Lindsay, H. A.; Dormi, S. S.; Jones, G. D.;
Vicic, D. A.; McIntosh, M. C. Org. Lett. 2006, 8, 3663-3665.
(4) Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9993-
10002.
(12) Details are provided as Supporting Information.
(13) Chelation-controlled Ireland-Claisen rearrangements proceed with
moderate to high diastereoselectivity: (a) ref 3c. (b) Bartlett, P. A.; Tanzella,
D. J.; Barstow, J. F. J. Org. Chem. 1982, 47, 3941-3945. (c) Hatakeyama,
S.; Sugawara, M.; Kawamura, M.; Takano, S. J. Chem. Soc., Chem.
Commun. 1992, 1229-1231.
(14) The product was predominantly one diastereomer, but 20% of other
compounds can be observed by 1H NMR spectroscopy. These materials
are likely to be isomers because the compound exhibits satisfactory
elementary analysis.
(5) Cleary, P. A.; Woerpel, K. A. Org. Lett. 2005, 7, 5531-5533.
(6) Trost, B. M.; Caldwell, C. G. Tetrahedron Lett. 1981, 22, 4999-
5002.
(15) The relative stereochemistry of the product was assigned based upon
analogies to similar systems: Nubbemeyer, U. Synthesis 2003, 961-1008.
(7) Heinicke, J.; Gehrhus, B. J. Organomet. Chem. 1992, 423, 13-21.
4652
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