A. G. Brewster et al. / Tetrahedron Letters 43 (2002) 3919–3922
3921
Subjection of
L
-proline to the action of diketene (100
Synthesis Programme are gratefully acknowledged.
Thanks are also due to Dr. C. M. Raynor (UMIST) for
carrying out the HPLC analyses.
mol%) and triethylamine (catalytic amount) in
dichloromethane (reflux, 12 h) and esterification of the
product (PriOH, HCl, reflux, 4 h) gave compound 1c17
(75% yield after chromatography), [h]D −88 (c 0.8,
CH2Cl2). Under the usual basic conditions [KCN (150
mol%), MeOH], the proline 1c was converted into its
transesterification product which slowly cyclised to
give, after acidification, mainly the acylation product 4c
(earlier, the acylation product 4a predominated in the
corresponding reaction of the methyl ester counterpart
of 1a11). However, when heated under reflux for 24 h
with isopropyl alcohol and potassium cyanide (300
mol%), cyclisation occurred to give mainly a 55:19:26
mixture of compounds 2c, 3c and 4c (Scheme 1). After
chromatography, a 75:25 mixture of the aldols 2c and
3c, [h]D −37 (c 0.38, CH2Cl2), with e.e.s of 87%21 was
isolated in 35% yield.
References
1. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2708–2748.
2. Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227.
3. Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517–3599.
4. Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121,
10727–10737.
5. Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645–732.
6. Andrews, M. D.; Brewster, A. G.; Chuhan, J.; Ibett, A.
J.; Moloney, M. G.; Prout, K.; Watkin, D. Synthesis
1997, 305–308.
The alcohols 2c/3c were transformed into the bicyclic
alkene 9c22 (51% yield after chromatography), [h]D
+124 (c 0.52, CH2Cl2), by an acetylation–elimination
sequence (Scheme 4). Again, the reasonably high posi-
tive specific rotation of the alkene 9c provided support
for the absolute stereochemical assignment. Once more,
it is inferred that the CꢀC bond formations involved in
the 1c2c/3c conversion, which display selectivities of
ꢀ94:6, occur with predominant retention of
configuration.
7. Andrews, M. D.; Brewster, A. G.; Crapnell, K. M.; Ibett,
A. J.; Jones, T.; Moloney, M. G.; Prout, K.; Watkin, D.
J. Chem. Soc., Perkin Trans. 1 1998, 223–235.
8. Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl.
1981, 20, 971.
9. Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K.
J. Am. Chem. Soc. 1994, 116, 10809–10810.
10. Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373–376.
11. Brewster, A. G.; Frampton, C. S.; Jayatissa, J.; Mitchell,
M. B.; Stoodley, R. J.; Vohra, S. Chem. Commun. 1998,
299–300.
Clearly, the enolate intermediates involved in the 1b
2b/3b and 1c2c/3c conversions are imprinted with
stereochemical memories of the reactants. We attribute
the imprints to the axially chiral nature of the enolates,
e.g. 5b and 5c (Scheme 2). The greater loss in stereo-
12. Beagley, B.; Betts, M. J.; Pritchard, R. G.; Schofield, A.;
Stoodley, R. J.; Vohra, S. J. Chem. Soc., Perkin Trans. 1
1993, 1761–1770.
13. Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R.
J.; Vohra, S. J. Chem. Soc., Perkin Trans. 1 1999, 1067–
1072.
chemical integrity noted in the L-proline-derived aldols
2c and 3c may be ascribed to the harsher conditions
needed to effect the cyclisations; presumably, this is a
reflection of the reduced acidity of the 2-proton of the
precursor 1c (caused by the S/OCH2 replacement).
14. It was postulated earlier (Ref. 12) that the rotameric form
of the amide with the CꢁO bond anti to the N(1)ꢀC(2)
bond (required for the subsequent cyclisation reaction)
had a greater acidifying effect on the 2-proton than that
of the corresponding syn form; also, racemisation of the
enolate intermediate was considered to be associated with
a high energy barrier.
15. Elliott, D. F. J. Chem. Soc. 1949, 589–594.
16. Beulshausen, T.; Groth, U.; Scho¨llkopf, U. Liebigs Ann.
Chem. 1992, 523–526.
The aforecited results are of note in the following
respects. The finding that stereoretentive aldol cyclisa-
tions can be conducted on oxaproline and proline scaf-
folds significantly extends the scope of stereoinductions
attributable to axially chiral enolate intermediates.
Compounds 2b/3b and 2c/3c are interesting examples of
enantioenriched a-C-substituted a-amino units embed-
ded in heterocyclic frameworks.
17. Like the methyl ester relative of compound 1a (see Ref.
12), this compound existed (in CDCl3 at ꢀ25°C) as a
mixture of keto and enol tautomers, each as a mixture of
rotamers.
During the course of the work, memory of chirality
18. Data for compound 9b: wmax (film)/cm−1 inter alia 1725
(ester and pyrrolinone CꢁO) and 1635 (CꢁC); lH (400
MHz; CDCl3) 1.30 and 1.31 (each 3H, d, J 6.5 Hz,
Me2CH), 2.12 (3H, d, J 1.5 Hz, 7-Me), 3.67 and 4.37
(each 1H, d, J 8.5 Hz, 1-H2), 4.54 and 5.24 (each 1H, d,
J 5.5 Hz, 3-H2), 5.14 (1H, sept, J 6.5 Hz, CHMe2) and
5.84 (1H, apparent d, separation 1 Hz, 6-H); lC (100
MHz; CDCl3) 14.6 (CH3), 20.4 and 21.3 [(CH3)2CH],
69.4 (1-CH2), 70.1 (OCH), 77.6 (3-CH2), 123.5 (6-C),
161.5 (7-C), 167.9 (ester CO) and 177.9 (5-CO) [pre-
sumably, the 7a-C signal was masked by either the 3-CH2
signal or one of the CDCl3 signals (in the case of 9a, the
7a-C signal appeared at l 83.3)]; m/z (FAB) 226 (MH+,
effects involving a-amino acid derivatives have been
observed
in
photocylisations,23,24
oxidative
decarboxylations25 and enolate alkylations.26,27 With
other substrates, they have been noted in electron-
transfer28 and radical reactions.29
Acknowledgements
Research grants from the EPSRC (GR/L52246, GR/
L3439 and GR/M16054/01) and the Link Asymmetric