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´
Scheme 4 Reagents and conditions: (i) 10% Pd/C, ammonium formate,
t-BuOH, 48%; (ii) 6M HCl, D, 100%.
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12 For recent examples, see: (a) J. Marin, C. Didierjean, A. Aubry,
J.-R. Casimir, J.-P. Briand and G. Guichard, J. Org. Chem., 2004,
69, 130; (b) F. M. Cordero, P. Fantini and A. Brandi, Synlett, 2006,
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¨
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17 D. E. Rudisill and J. P. Whitten, Synthesis, 1994, 851.
18 A direct 6-endo-trig cyclisation of trityl protected enones 7 and 10
as well as the corresponding free amino and Boc-protected
compounds under acid, Lewis acid or base-mediated conditions
was initially attempted. However, these reactions either returned
starting material or generated a complex mixture of products.
19 See supporting information for NOE experiments for compounds
23, 24, 25 and 26w.
To demonstrate that compounds such as 23–26 could be
used to access the parent 6-substituted-4-hydroxy-L-pipecolic
acids, methyl analogue 25 was deprotected in two steps
(Scheme 4). Initially, the benzyl group was removed by
transfer hydrogenation to give the corresponding amine in
48% yield. Acid mediated hydrolysis of the methyl ester
gave the hydrochloride salt of (2S,4S,6R)-4-hydroxy-6-
methylpiperidine-2-carboxylic acid (27) in quantitative yield.
Recrystallisation of compound 27 allowed X-ray structure
determination (Scheme 4).22 The structure provides further
confirmation of the relative configuration of the stereogenic
centres generated during both the tandem reductive
amination/6-endo-trig cyclisation process and reduction of
the ketone.
In summary, a new tandem reductive amination/6-endo-trig
cyclisation process has been developed for the stereoselective
synthesis of 2,6-trans-6-substituted-4-oxo-L-pipecolic acid
derivatives. The substrates for this process, a-amino acids
bearing an enone side chain were easily accessed using a
Horner–Wadsworth–Emmons reaction resulting in the
preparation of a wide range of 4-oxo-L-pipecolic acids with
various 6-alkyl and 6-aryl substituents. These highly function-
alised compounds have significant potential for the synthesis
of a number of biologically and medicinally important targets
as demonstrated by their facile reduction to the corresponding
(2S,4S,6R)-6-substituted-4-hydroxypipecolic acid derivatives.
Work is currently underway to investigate the use of this
general strategy for the preparation of pipecolic acid derived
natural products.
The authors are grateful to the EPSRC (studentship to
L.S.F.), the University of Glasgow and Pfizer Ltd for financial
support.
Notes and references
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20 Due to a reversal of priority at C-6, the absolute configuration of
26 is (2S,4S,6S).
21 F. Johnson, Chem. Rev., 1968, 68, 375.
´
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22 X-Ray data for 27: C7H16O4ClN, MW = 213.66, orthorhomic,
space group P212121, Z = 4, T = 100 K, a = 8.2209(2), b =
8.9923(3), c = 13.8130(4) A, V = 1021.12(5) A3, Flack parameter =
´
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0.10(5), final R indices, R1 = 0.0283 for 2188 reflections
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I 4 2s(I), R1 = 0.0352, wR2 = 0.0639 for all data, reflections
collected/unique 8583/2148. Supplementary crystallographic data
have been deposited at the Cambridge Crystallographic Data
Centre, CCDC 817525w.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6569–6571 6571