Synthesis of the nonproteinogenic amino acid (2s,3s,4s)-3-hydroxy-4- methylproline, a constituent of echinocandins

Article abstract of DOI:10.1016/S0957-4166(98)00112-8

An enantioselective synthesis of the unusual 3,4-disubstituted proline 2, a constituent of antifungal echinocandins, has been achieved through 1,3- dipolar cycloaddition of N-methylnitrone to the α,β-unsaturated lactam 4 derived from (S)-pyroglutaminol.

Full text of DOI:10.1016/S0957-4166(98)00112-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1333–1336
Synthesis of the nonproteinogenic amino acid (2S,3S,4S)-
3-hydroxy-4-methylproline, a constituent of echinocandins
Nicole Langlois ∗
Institut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France
Received 5 February 1998; accepted 13 March 1998
Abstract
An enantioselective synthesis of the unusual 3,4-disubstituted proline 2, a constituent of antifungal echinocan-
dins, has been achieved through 1,3-dipolar cycloaddition of N-methylnitrone to the α,β-unsaturated lactam 4
derived from (S)-pyroglutaminol. © 1998 Elsevier Science Ltd. All rights reserved.
(2S,3S,4S)-3-Hydroxy-4-methylproline 2 is a common component of antimicrobial echinocandins B,
C and D, 1,1 and several related natural cyclopeptides such as pneumocandins Ao–A4, sporiofungin A,
mulundocandin and deoxymulundocandin.2 An enantioselective synthesis of this unusual amino acid 2
could be useful for the preparation of structural analogs of these lipopeptides which are inhibitors of
1,3-β-D-glucan synthase and exhibit interesting specific fungicidal activities, specially against Candida
albicans and Pneumocystis carinii.3
Two syntheses of 24–6 and a synthesis of 2 methyl ester7 have already been described, all of them
involving aminocyclizations of suitably functionalized acyclic precursors. As part of a project towards
the synthesis of several substituted proline derivatives,8–11 it was planned to prepare 2 using inexpensive
(S)-pyroglutaminol 3 as the starting material (Scheme 1).
In a simple and direct strategy, it was anticipated that both hydroxyl groups and the additional carbon
of the methyl group in 2 could be introduced in the same step, through a 1,3-dipolar cycloaddition of a
nitrone to α,β-unsaturated derivative 4,12 as shown in Scheme 2. In this way, an appropriate precursor of
2, as the trisubstituted pyrrolidin-2-one 8, could be accessible through hydrogenolysis of the cycloadduct
5 with cleavage of the isoxazolidine N–O bond, subsequent elimination of N-methylamine followed by
hydrogenation of a 3-exomethylene intermediate.
The cycloaddition of N-methylnitrone to the unsaturated pyrrolidinone 4 was achieved with 70% yield
by heating in toluene. This improved yield (compared to our preliminary work12) was reached when
the N-methylnitrone was prepared with a large excess of paraformaldehyde with regard to the N-methyl
hydroxylamine and prolonged reaction time. The enantiopurity of the deprotected primary alcohol 6 was
∗
Fax: (0)1 69077247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
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PII: S0957-4166(98)00112-8

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N. Langlois / Tetrahedron: Asymmetry 9 (1998) 1333–1336
Scheme 1.
Scheme 2.
deteremined through its Mosher’s ester obtained with (−)-MTPA-Cl, and compared to the diastereomeric
esters prepared from racemic (ꢀ)-6 and the same acid chloride. Thus, the stereogenic C-5 center of (S)-
pyroglutaminol 3 was preserved under the cycloaddition conditions, unlike the partial racemization of
4, recently observed during aminonucleophilic conjugate addition.13 The cycloadduct 5 was hydrolyzed
over Pearlman’s catalyst (H2, 1 atm, r.t.) with concomitant elimination of methylamine to directly afford
the compound 8 in 72% yield, as a mixture of two inseparable diastereomers A and B. The ratio A:B
was evaluated as 2:3 by 1H NMR. The relative configurations were tentatively assigned in the acetates 9
prepared under the same conditions (73%, 9A:9B=2:3) from the acetoxy derivative 7, since it does not
possess the additional stereogenic center. A cis relationship between the substituents at C-3 and C-4 in
9A was supported by the strong NOE between H-3 and H-4, while in 9B an NOE was observed between
1
CH3-3 and H-4, and between H-4 and H-6. The H and 13C chemical shifts of the methyl groups and
adjacent H-C-3 are rather different in 8A and 8B [CDCl3, 13C δ ppm: 8A: 8.19 (CH3), 42.90 (C-3);
8B: 15.29 (CH3), 46.76 (C-3)]. They are respectively very close to those of 9A and 9B, and therefore
informative [9A: 8.19 (CH3), 42.73 (C-3); 9B: 13.85 (CH3), 46.80 (C-3)]. The diastereomer 9A could be
obtained as a major compound (A:B=2:1) by a deprotonation–protonation sequence of the initial mixture
9. The formation of another diastereomer through a retro-aldol reaction with cleavage of the C-3–C-4
bond was not observed.
For the next steps, a suitable protection of the hydroxyl group at C-4 was required to allow a further
selective deprotection of the primary alcohol before oxidation to the carboxylic acid. Attempts to silylate
9 under the usual conditions (t-BuMe2SiCl, Im, DMF)14 gave rise to only a moderate yield (47%) of
the silylated derivative 10. As the sensitivity towards elimination reactions of β-carbonylated hydroxy
derivatives has also to be taken into account, the lactams 8 were reduced before protection of the
secondary hydroxyl group. The straightforward sequence depicted in Scheme 3 was applied to the
mixture 8 without separation of the intermediates leading to 12 and 13.

N. Langlois / Tetrahedron: Asymmetry 9 (1998) 1333–1336
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Scheme 3.
Accordingly, the α-hydroxycarbamates 11 obtained in 98% yield by DIBAL-H reduction of 8 (in
hexane, 3 equiv., −78°C) was directly benzoylated (PhCOCl, Et3N–CH2Cl2). Subsequent reduction with
NaBH3CN in acetic acid15 and removal of EVE protection were achieved in one pot, giving rise to 12 and
13. The diastereomeric alcohols 12 and 13 were separated by chromatography on silica gel, with 32% and
36% yield respectively for the two steps. They were oxidized under Sharpless conditions (NaIO4–RuCl3,
H2O, CCl4–CH3CN–H2O)16 into the carboxylic acids 14 (88%) and 15 (75%) which were quantitatively
deprotected to 2 and 16 as hydrochloride salts, by heating in 6 N HCl. The amino acid 2 showed identical
spectroscopic data to those reported.1
This synthesis demonstrated that the unsaturated pyrrolidin-2-one 4 is a good precursor of (2S,3S,4S)-
3-hydroxy-4-methylproline 2, which was synthesized in seven steps and 14% yield, despite the lack of
selectivity in the C-3 stereocenter formation. The improvement of this diastereoselectivity is currently
under investigation.
Acknowledgements
We thank M.-T. Martin and J.-F. Gallard (ICSN, Gif-sur-Yvette) for NMR spectra.
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