group of an aldehyde or ketone without the risk of over-
alkylation.5 Accordingly, the introduction of fully substituted
carbons by means of enamine alkylation is much less well
precedented.3,6
Scheme 1.
Alternative Routes to Allylated Glyceraldehyde 2a
Butane-2,3-diacetal (BDA) protected diols have been
applied as chiral building blocks in several natural product
syntheses.7 Most recently, we have employed BDA-protected
diols as convenient chiral starting materials in the synthesis
of bicyclic acetals,8 and we disclosed a new protocol for
the removal of BDA protecting groups under mild condi-
tions.9 A particularly attractive feature of BDA building
blocks is that the diacetal moiety can preserve stereochemical
information during a reaction sequence. Such chiral memory
protocols have been successfully implemented in the stereo-
selective alkylation of BDA-protected glycolic acid,10 in the
desymmetrization of meso-tartrate11 and in the alkylation of
BDA-protected methyl glycerate.12 In addition, BDA-
protected glyceraldehyde has been introduced as a stable
alternative to glyceraldehyde acetonide.13
aRef 13.
Here we report the first use of enamines derived from
BDA-protected glyceraldehyde as substrates for aza-Claisen
rearrangements and C-alkylation reactions.14
For a future natural product synthesis program, reliable
access to allylated aldehyde 2 was required (Scheme 1). The
initial synthetic plan was based on the selective allylation
of the lithium enolate of ester 1, which allowed intermediate
2 to be prepared in eight steps from L-ascorbic acid with an
overall yield of 9.6%.12,15 To shorten this sequence, we
decided to investigate whether aldehyde 2 could be efficiently
accessed by an aza-Claisen rearrangement of enammonium
ion 4.
(5) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954,
76, 2029–2030. (b) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz,
J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207–222. (c) Whitesell, J. K.;
Whitesell, M. A. Synthesis 1983, 517–536.
(6) (a) Opitz, G.; Hellman, H.; Mildenberger, H.; Suhr, H. Justus Liebigs
Ann. Chem. 1961, 649, 36–47. (b) Stevens, R. V.; Christensen, C. G.;
Edmonson, W. L.; Kaplan, M.; Reid, E. B.; Wentland, M. P. J. Am. Chem.
Soc. 1971, 93, 6629–6637. (c) Martin, S. F. J. Org. Chem. 1976, 41, 3337–
3338. (d) Martin, S. F.; Chou, T-S.; Payne, C. W. J. Org. Chem. 1977, 42,
2520–2523. (e) Taylor, E. C.; LaMattina, J. L. Tetrahedron Lett. 1977, 18,
2077–2080.
Reaction of BDA-protected glyceraldehyde 313b with a
secondary amine would lead to an enamine in which the
original stereogenic center of glyceraldehyde has been
removed; however, the chiral information is retained in the
diacetal backbone. After N-allylation, we expected the aza-
Claisen rearrangement to proceed stereoselectively with the
allyl group approaching from an equatorial trajectory as had
been previously observed in the allylation of the related ester
enolate.12 The resulting iminium ion would be easily
hydrolyzed upon workup to form the desired aldehyde.
In the event, we found that treatment of aldehyde 3 with
piperidine afforded an enamine as a single isomer in
quantitative yield.16 Subsequent reaction with allyl bromide
in refluxing acetonitrile for 12 h led, after aqueous workup,
to a 4:1 diastereomeric mixture of the rearranged product
(Scheme 1). Surprisingly, analysis of the 1H NMR spectrum
revealed that the desired diastereomer 2 was the minor
component of this mixture. The crystal structure of the 2,4-
dinitrophenyl hydrazone of the major diastereomer confirmed
it to be epimeric aldehyde epi-2. Despite the modest isolated
yield of 40%, we decided to further explore this reaction
sequence, since starting from the enantiomeric aldehyde ent-
3, which is available in two steps from D-mannitol,13a would
(7) For reviews, see: (a) Ley, S. V.; Baeschlin, D. K.; Dixon, D. A.;
Foster, A. C.; Ince, S. J.; Priepke, H. W. M.; Reynolds, D. J. Chem. ReV.
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M. S. Bull. Chem. Soc. Jpn. 2007, 80, 1451–1472. (c) Ley, S. V.; Polara,
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C. D.; Scott, J. S.; Osborn, D. P.; Ley, S. V. Angew. Chem., Int. Ed. 2007,
46, 591–597. (e) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.;
Ley, S. V. Chem.-Eur. J. 2007, 13, 5515–5538. (f) Guo, H.; O’Doherty,
G. A. Angew. Chem., Int. Ed. 2007, 46, 5206–5208. (g) Marchart, S.; Mulzer,
J.; Enev, V. S. Org. Lett. 2007, 9, 813–816.
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Angew. Chem., Int. Ed. 2008, 47, 209–212. (b) Milroy, L.-G.; Zinzalla, G.;
Prencipe, G.; Michel, P.; Ley, S. V.; Gunaratnam, M.; Beltran, M.; Neidle,
S. Angew. Chem., Int. Ed. 2007, 46, 2493–2496.
(9) Tzschucke, C. C.; Pradidphol, N.; Die´guez-Va´zquez, A.; Kongkathip,
B.; Kongkathip, N.; Ley, S. V. Synlett 2008, 1293–1296.
(10) (a) Ley, S. V.; Dixon, D. J.; Guy, R. T.; Rodriguez, F.; Sheppard,
T. D. Org. Biomol. Chem. 2005, 3, 4095–4107. (b) Ley, S. V.; Dixon, D. J.;
Guy, R. T.; Palomero, M. A.; Polara, A.; Rodriguez, F.; Sheppard, T. D.
Org. Biomol. Chem. 2004, 2, 3618–3627. (c) Ley, S. V.; Diez, E.; Dixon,
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Chem. 2004, 2, 3608–3617. (d) Dixon, D. J.; Guarna, A.; Ley, S. V.; Polara,
A.; Rodriguez, F. Synthesis 2002, 1973–1978. (e) Dixon, D. J.; Ley, S. V.;
Rodriguez, F. Org. Lett. 2001, 3, 3753–3755. (f) Dixon, D. J.; Ley, S. V.;
Polara, A.; Sheppard, T. Org. Lett. 2001, 3, 3749–3752. (g) Diez, E.; Dixon,
D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001, 40, 2906–2909.
(11) Dixon, D. J.; Foster, A. C.; Ley, S. V.; Reynolds, D. J. J. Chem.
Soc., Perkin Trans. 1 1999, 1631–1634.
(12) Ley, S. V.; Michel, P.; Trapella, C. Org. Lett. 2003, 5, 4553–4555.
(13) (a) Ley, S. V.; Michel, P. Synthesis 2004, 147–150. (b) Michel,
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(15) Stepan A. F., Ph.D. thesis, University of Cambridge, 2006.
(16) The Z-geometry of the enamine double bond was established by
1H NMR spectroscopy through the observation of an nOe between the
exocyclic enamine proton and the methylene group of the dioxane ring.
This assignment was subsequently confirmed by the crystal structure of
the corresponding N-(2-methylallyl)enammonium bromide ent-4b (see
Supporting Information).
(14) A related imine, derived from BDA-glyceraldehyde 4, was recently
employed in the synthesis of ꢀ-lactams by [2 + 2] cycloaddition: Carrasco,
E.; Light, M. E.; Santos, M.; Plumet, J. Synlett 2007, 3180–3182.
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