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Stereoselective Cycloadditionof Monosubstituted Keteneto a Methyl Glyoxylate- andThreonine-Derived Imine:Synthesis of Optically Pure β-Lactamic α-Amino Ester withHigh FunctionalitySerge Mignani a b , Dominique Mouysset b , IsabelleLe Roy a b & Lucien Stella ba Rhône-Poulenc Rorer, Centre de Recherche , 13Quai Jules Guesde, BP 14, 94403, Vitry sur Seine,Cedex, Franceb Université d'Aix-Marseille III, Laboratoire de ChimieMoléculaire Organique UMR 6517 , 13397, Marseille,Cedex 20, FrancePublished online: 04 Dec 2007.

To cite this article: Serge Mignani , Dominique Mouysset , Isabelle Le Roy & LucienStella (2000) Stereoselective Cycloaddition of Monosubstituted Ketene to a MethylGlyoxylate- and Threonine-Derived Imine: Synthesis of Optically Pure β-Lactamic α-Amino Ester with High Functionality, Synthetic Communications: An InternationalJournal for Rapid Communication of Synthetic Organic Chemistry, 30:20, 3685-3691,DOI: 10.1080/00397910008086995

To link to this article: http://dx.doi.org/10.1080/00397910008086995

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SYNTHETIC COMMUNICATIONS, 30(20), 3685-3691 (2000)

STEREOSELECTIVE CYCLOADDITION OF MONOSUBSTITUTED KETENE TO A METHYL

GLYOXYLATE- AND THREONINE-DERIVED IMINE: SYNTHESIS OF OPTICALLY PURE P-LACTAMIC a-AMINO ESTER WITH HIGH FUNCTIONALITY.

b b* Serge Mignani,a Dominique Mouysset, Isabelle Le and Lucien Stella

a Rhhe-Poulenc Rorer, Centre de Recherche, 13 Quai Jules Guesde, BP 14, 94403 Vitry sur Seine Cedex, France

Universitk d’ Aix-Marseille IU, Laboratoire de Chimie Mol6culaire Organique UMR 6517, 13397 Marseille Cedex 20, France

b

Abstract: The reaction of chloroacetyl chloride and triethylamine with a chiral imine derived from the combination of methyl glyoxylate and protected L- threonine gave two optically active a-amino acid derivatives with a cis-substituted p-lactam skeleton in a 72:28 ratio. The major product is obtained in 59% yield by simple crystallisation.

P-Lactams are precursors of biologically and clinically important antibiotics

including penicillins, cephalosporins, monobactams, and carbapenems. ’ The

asymmetric synthesis of p-lactam ring systems is a worthwhile objective, and the

Staudinger reaction (imine + ketene) is the most extensively developed method.’

The use of glyoxylate imines in the Staudinger reaction generally provides a-

amino acid derivatives with a p-lactam skeleton with almost complete cis-

~tereoselectivity,~ but the asymmetric induction is low when imines are derived

from chiral 1-aryl-ethylamine~.~ In general, the level of asymmetric induction

* To whom correspondence should be addressed

3685

Copyright Q 2000 by Marcel Dekker, Inc. www.dekker.com

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3686 MIGNANI ET AL.

achieved with imines derived from achiral aldehydes and chiral amines is lower

than that observed when starting either from a chiral ketene or a chiral aldehyde.'

However, threonine-derived imines have been shown to give cis-b-lactams in the

Staudinger reaction with a diastereoselectivity increasing as a function of the size

of the protective group of the threonine hydroxyl group.6 As part of our program

directed toward the synthesis of biologically interesting peptidomimetics, we are

currently developing routes to prepare conformationally constrained a-amino acids

from glyoxylate imines. In connection with these studies, we prepared an imine

from chiral threonine and methyl glyoxylate. We anticipated that such a compound

would react, through the Staudinger reaction with simple monosubstituted

ketenes, to provide optically active a-amino acids with a cis-substituted p-lactam

skeleton bearing high functionality. The functional groups of threonine provide a

variety of handles with which chemical manipulation can be performed?

As illustrated in the scheme 1, acid-catalysed esterification of L-threonine 1

using thionyl chloride in methanol gave L-threonine methyl ester hydrochloride 2

quantitatively. Silylation of 2 under standard conditions * (tert-butyldimethylsilyl

chloride, imidazole, N,N-dimethylformamide, room temperature, overnight)

afforded 0-silyl ether 3 in 90% yield. Even more eficiently, the protected L-

threonine 3 was obtained upon treatment of 2 with terf-butyldimethylsilyl triflate

and 2,6-lutidine9 at O'C, for 10 min (95% yield). Formation of chiral imine 4 was

accomplished by treatment of a mixture of 3 and methyl glyoxylate with 3A

molecular sieve beads in methylene chloride. Subsequent reaction of 4 with

chloroacetyl chloride in the presence of triethylamine was optimised by varying the

solvent, the temperature and the reaction time.

In methylene chloride, the efficiency of the reaction increased from 39% at

-8OoC, to 69% at -3O"C, and to 74% yield at room temperature. The

diastereoselectivity remained constant (70:30) whatever the temperature. The best

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OPTICALLY PURE P-LACTAMIC a-AMINO ESTER 3687

HzN ,.,\COzH a CIH, H z r e b ~

HO'CH3 HO CH3

1 2 3

/ % H3C C02Me TBDM!

4 5 6

SCHEME 1 Reagents and Conditions: a) SOCl,, CH,OH, reflux, 18h, 100%. b) TBDMSOTf, lutidine, CH,Cl,, 0°C. 10 min, 95%. c) Methyl glyoxylate, 3A-ms, CH,Cl,, RT, lh , 100%. d) Monochloroacetyl chloride, TEA, toluene, RT, lh, 82%.

4

FIG. 1 : X-ray Crystal Structure of Azetidinone 5

result was obtained when using toluene as a solvent: the reaction of chloroketene

with 4 at room temperature provided a 72:28 mixture of diastereoisomeric 0- lactams 5 and 6 in 82 % yield. Separation of 5 and 6 by column chromatography

was easy (silica gel, CH,Cl,). Furthermore, from the crude mixture of

diastereoisomers, the optically pure enantiomer 5 was obtained in 59% yield by

simple crystallisation from pentane. The structure of compound 5 was

unambiguously determined by a single X-ray crystallography (Figure 1). It is

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3688 MIGNANI ET AL.

noteworthy that, fortunately, no migration of carbon-nitrogen double bond of

imine 4 was detected under the Staudinger conditions.

In order to introduce an amino function at C-3, we have also performed

some preliminary experiments introducing a phthaloyl group on the ketene

(scheme 2). In methylene chloride at room temperature, a lower stereoselectivity

(60/40) was obtained when phthaloylglycyl chloride 7 was used as the ketene

precursor.

co-CI 0

4 7 TEA, CH2C12, RT (70%) H3C C02Me

2 cis diastereoisomers (60/40)

SCHEME 2

Optically active monocyclic p-lactams bearing functions at both the

nitrogen atom and C-4 could be versatile precursors of many classes of fused-ring

p-lactams.

Experimental procedure for the preparation of 1 -[ 1-(S) - methoxycarbonyl)-2(R)-O-[(terl-butyl-dimethylsilyl)oxy]propyl]-

3(R)-chloro-4(S)-methoxycarbonyl-azetidin-2-one (5). To a solution of

4 (79 mg, 0.25 mmol) in toluene (4 mL) at rt was added triethylamine (121 pL,

0.87 mmol) followed by chloroacetyl chloride (60 pL 0.75 mmol) over a period of

5 min under Ar. The mixture was stirred for lh. The mixture was then washed

with 5% citric acid solution (2 x 5 mL), saturated NaHCO, solution (5 mL), H,O

(10 mL), brine (10 mL), dried (Na,SO,), filtered and concentrated (244 mg,

82%). GC and NMR 'H indicated the formation of two diastereomers in a ratio of

72:28. From the crude mixture in pentane, the pure major diastereomer 5 (150

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OPTICALLY PURE p-LACTAMIC a-AMINO ESTER 3689

mg, 59%) was crystallised: mp 99-100OC; +80,9 ( c 0.66, CH,Cl,); IR

(KBr) 3432,2957,2932, 2859, 1793, 1765, 1735, 1306, 1204, 1062,929, 838,

779 cm"; 'H NMR (CDCl,, 200 MHz) 6 0.30 (s, 3H), 0.32 (s, 3H), 0.81 (s,

9H), 1.44 (d, J = 10.4 Hz, 3H), 3.75 (s, 3H), 3.78 (s, 3H), 4.44 (m, lH), 4.55

(m, lH), 4.93 (d, J = 6.1 Hz, lH), 5.17 (d, J =6.1 Hz, 1H); "C NMR (CDCI,,

50 MHz) 6 -5.5, -4.5 , 17.80, 20.26, 25.46, 52.2, 52.7, 57.68, 61.12, 68.82,

166.66, 167.58, 169.26 ; MS (El, re1 int) m/z 41 (13.0), 59 (34.3), 73 (loo), 75

(27.4), 89 (96.8), 103 ( l IS) , 113 (15.3), 159 (32.1), 188 (10.8), 336 (83.6),

337 (16.8), 338 (31.3). Anal. Calcd for C16H28C1NO6Si : C, 48.78; H, 7.16;

N, 3.56; C1, 9.00. Found: C, 48.82; H, 7.13; N, 3.61; C1, 9.11. Colourless,

almost cubic, crystals of 5 are monoclinic, the space group is P2, with Q = 9.795

A, b = 8.334 A, c = 13.381 A, p = 98.20°, V = 1081 A', Z = 2, and Dxcokd =

1.210 g.cm", T = 293K, p = 0.255 mm.'. The final residue was R = 0.054, w R

= 0.068, S = 2.48 for 1421 reflections used with I > 3.000(1).

Acknowledgements. The authors thank Professors Claudio Palomo and Reiner

Sustmann for valuable discussions. This work was part of the Bio Avenir

program supported by Rhdne-Poulenc with the participation of the Ministkre de la

Recherche and the Minis3re de I'Industrie. We gratefully acknowledge Mrs

Patricia Perfetti for her contribution in this work.

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3690 MIGNANI ET AL.

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