internal standard (Table 3).23 Finally, treatment of cis-cyclopropyl-
aldol (Z)-4h with LHMDS at 0 uC also resulted in a clean
retro-aldol reaction affording cis-cyclopropane carboxaldehyde
(1S,2R)-5h in 61% yield,24 with no epimerisation to its more stable
(1R,2R)-epimer having occurred under the basic conditions used to
facilitate the retro-aldol reaction.25
9 These conditions have been employed previously for asymmetric syn-
aldol reactions using imidazolidin-2-one derived glycine enolates, see:
S. Caddick, N. J. Parr and M. C. Pritchard, Tetrahedron Lett., 2000, 41,
5963.
10 We have used these conditions previously for the synthesis of racemic
syn-aldols derived from an achiral N-acyl-oxazolidin-2-one, see: F. J.
P. Feuillet, D. E. J. E. Robinson and S. D. Bull, Chem. Commun., 2003,
2184.
In summary, a novel three-step aldol–cyclopropanation–retro-
aldol sequence for the direct asymmetric synthesis of enantiopure
cyclopropane carboxaldehydes under non-oxidative/non-reductive
conditions has been developed. This protocol demonstrates the
potential of a novel synthetic strategy that employs a chiral
auxiliary to reversibly generate a temporary stereocentre that is
then employed as a stereodirecting group to control facial
selectivity for a substrate-directable reaction. We anticipate that
this new strategy will prove applicable to the combination of other
types of chiral auxiliary and substrate-directable reaction, thus
enabling its potential for asymmetric synthesis to be realised in a
wide range of different reaction scenarios.
11 For a previous example of a syn-aldol reaction between an N-acyl-
oxazolidin-2-one and an alkyn-2-al, see: T. Bach and S. Heuser, Angew.
Chem. Int. Ed., 2001, 40, 3184.
12 For a previous report of this type of (Z)-syn-aldol, see: J. C. Anderson,
B. P. McDermott and E. J. Griffin, Tetrahedron, 2000, 56, 8747.
13 For a review on stereoselective cyclopropanation reactions, see: H. Lebel,
J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev., 2003, 103,
977.
14 A. B. Charette and H. Lebel, J. Org. Chem., 1995, 60, 2966.
15 For a discussion on the mechanism of directed cyclopropanation
reactions of allylic alcohols, see: M. Nakamura, A. Hirai and
E. Nakamura, J. Am. Chem. Soc., 2003, 125, 2341.
16 The relative syn-configuration of the N-acyl fragment of o-nitrobenzyl-
cyclopropyl-aldol 4d was confirmed by X-ray crystallographic analysis,
whilst the absolute configuration follows from the known
(4S)-configuration of the oxazolidin-2-one fragment. Crystal data for
The authors would like to thank the EPSRC (MC, FJPF) and
the Royal Society (SDB) for funding, and the mass spectroscopic
facility at Swansea, University of Wales for their assistance.
4d: C25H28N2O6, M 5 452.49, orthorhombic, a 5 7.6700(1),
3
˚
˚
b 5 14.8370(3), c 5 20.5190(3) A, V 5 2335.06(7) A , T 5 150(2) K,
space group P212121, Z 5 4, m(Mo-Ka) 5 0.092 mm21, 43530 measured
reflections, 5310 unique (Rint 5 0.1280) which were used in
these calculations. GOF on F2 5 1.028, R1 5 0.0382, wR2 5 0.0792
[I . 2s(I)], R1 5 0.0568, wR2 5 0.0862 (for all data). CCDC 257652. See
in CIF or other electronic format.
Matt Cheeseman, Fred J. P. Feuillet, Andrew L. Johnson and
Steven D. Bull*
Department of Chemistry, University of Bath, Bath, UK BA2 7AY.
E-mail: s.d.bull@bath.ac.uk; Fax: (+44)-(0)1225-386231;
Tel: (+44)-(0)1225-383551
17 For a previous example where a retro-aldol reaction has been used to
remove a chiral auxiliary fragment, see: R. L. Funk and G. Yang,
Tetrahedron Lett., 1999, 40, 1073.
Notes and references
18 For a previous report on the decomposition of lithium enolates of
N-acyl-oxazolidin-2-ones, see: S. D. Bull, S. G. Davies, S. Jones and
H. J. Sanganee, J. Chem. Soc., Perkin Trans. 1, 1999, 387.
19 (S,S)-5a gave an [a]2D4 of +392 (c 1.44, CHCl3) which compares with the
negative specific rotation reported previously for (R,R)-5a of [a]2D4 2324
(c 0.33, CHCl3), see: P. T. Kaye and W. E. Molema, Chem. Commun.,
1998, 2479.
20 (S,S)-5b gave an [a]2D4 of +45 (c 1.22, CHCl3) which compares with the
previously reported value of +41.4 (c 1.45, CHCl3) for this enantiomer,
see: J. R. Al Dulayymi, M. S. Baird and K. Jones, Tetrahedron, 2004, 60,
341.
21 P. Mangeney, A. Alexakis and J. F. Normant, Tetrahedron Lett., 1988,
29, 2677.
22 For examples where cyclopropane carboxaldehydes 5f and 5g have been
used as building blocks for natural product synthesis, see:
W. A. Donaldson, Tetrahedron, 2001, 57, 8589 and references contained
therein.
23 S. W. Gerritz and A. M. Sefler, J. Comb. Chem., 2000, 2, 39.
24 cis-(1S,2R)-1-Formyl-2-pentyl-cyclopropane 5h gave an [a]2D4 of 210.1
(c 1.05, CHCl3) compared with the previously reported value for
the structurally related cis-(1S,2R)-1-formyl-2-hexyl-cyclopropane of
[a]2D4 218.6 (c 1.4, CHCl3). See: G. D. Coxon, J. R. Al-Dulayymi,
M. S. Baird, S. Knobl, E. Roberts and D. E. Minnikin, Tetrahedron:
Asymmetry, 2003, 14, 1211.
25 For a study on the kinetics of epimerisation of cis-1,2-dimethyl esters of
cyclopropanes to their more thermodynamically stable trans-isomers,
see: D. S. Seigler and J. J. Bloomfield, J. Org. Chem., 1973, 38, 1375.
1 S. Jones, J. Chem. Soc., Perkin Trans. 1, 2002, 1.
2 A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93, 1307.
3 For an example of a directed carbonyl reduction strategy using an
oxazolidin-2-one chiral auxiliary, see: D. A. Evans and M. DiMare,
J. Am. Chem. Soc., 1986, 108, 2476.
4 For an alternative approach where the chiral auxiliary fragment was
retained as a protecting group throughout subsequent synthetic
transformations, see: D. A. Evans, A. S. Kim, R. Metternich and
V. J. Novack, J. Am. Chem. Soc., 1998, 120, 5921.
5 For other approaches to enantiopure cyclopropane carboxaldehydes,
see: (a) M. Dubs, H. Dieks, W. Gu¨nther, M. Ko¨tteritzsch, W. Poppitz
and B. Scho¨necker, Tetrahedron Lett., 2002, 43, 2499; (b) S. Hu and
J. S. Dordick, J. Org. Chem., 2002, 67, 314; (c) I. Arai, A. Mori and
H. Yamamoto, J. Am. Chem. Soc., 1985, 107, 8254 and references
contained therein.
6 For a discussion of the benefits of using 5,5-dimethyl-oxazolidin-2-one
(SuperQuat) chiral auxiliaries for asymmetric synthesis, see: S. D. Bull,
S. G. Davies, M.-S. Key, R. L. Nicholson and E. D. Savory, Chem.
Commun., 2000, 1721.
7 For a previous example where the lithium alkoxide of a b-hydroxy-
N-acyl-oxazolidin-2-one underwent an unwanted retro-ketol reaction,
see: J. Bartroli, E. Turmo, J. Belloc and J. Forn, J. Org. Chem., 1995, 60,
3000.
8 For a recent example where reaction of the boron enolate of an N-acyl-
oxazolidin-2-one with an a,b-unsaturated aldehyde gave a syn-aldol in
high de, see: C. D. Vanderwal, D. A. Vosburg, S. Weiler and
E. J. Sorensen, J. Am. Chem. Soc., 2003, 125, 5393.
2374 | Chem. Commun., 2005, 2372–2374
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