Diastereoselective palladium(O)-catalyzed azidation of 1- alkenylcyclopropyl esters: Asymmetric synthesis of (-)-(1R,2S)-norcoronamic acid

Article abstract of DOI:10.1016/S0957-4166(98)00107-4

Palladium(0)-catalyzed azidation of (1R,2S)-l-(1-alkenyl)2- methylcyclopropyl esters 10a,b proceeds with complete retention of configuration to provide, after reduction of the azide and oxidative cleavage of the allylic double bond, the (1R,2S)-norcoronam

Full text of DOI:10.1016/S0957-4166(98)00107-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1131–1135
Diastereoselective palladium(0)-catalyzed azidation of
1-alkenylcyclopropyl esters: asymmetric synthesis of
(−)-(1R,2S)-norcoronamic acid
Valérie Atlan,a Sandrine Racouchot,a Michael Rubin,a Claudia Bremer,a,b Jean Ollivier,a
Armin de Meijere∗, b and Jacques Salaün a,∗
aLaboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
bInstitut für Organische Chemie der Georg August Universität, D-37077 Göttingen, Germany
Received 6 March 1998; accepted 12 March 1998
Abstract
Palladium(0)-catalyzed azidation of (1R,2S)-1-(1-alkenyl)2-methylcyclopropyl esters 10a,b proceeds with com-
plete retention of configuration to provide, after reduction of the azide and oxidative cleavage of the allylic double
bond, the (1R,2S)-norcoronamic acid 22 (>99% e.e.). © 1998 Elsevier Science Ltd. All rights reserved.
Due to the physiological importance of 1-aminocyclopropanecarboxylic acids (2,3-methanoamino
acids) considerable effort has been, and currently still is, devoted towards their total synthesis,1 and
their incorporation into peptidic chains which provide conformationally constrained peptidomimetics
with enhanced biological activities.2 Moreover, incorporation of 2,3-methanoamino acids increases the
bioavailability of peptides by reducing their hydrolysis rate (proteolytic degradation).3 Substituted 1-
aminocyclopropanecarboxylic acids also provide enzyme inhibitors, biological probes for mechanistic
studies and allow the design of new drugs.1,2 The different methodologies recently reported for their
asymmetric synthesis were mainly based on the cyclopropanation of chiral alkenes or on the enantio-
selective cyclopropanation performed in the presence of chiral auxiliaries by means of the hazardous
diazomethane or Et2Zn/CH2I2 reagents.4 However, we have previously reported that the base-induced
diastereoselective cyclization of 2-(N-benzylideneamino)-4-chlorobutyronitriles (d.e. 60–78%)5 and the
palladium(0)-catalyzed substitution on (4S)-1-chloropent-2-ene-4-ol (readily available from ethyl (2S)
lac0tate) with the anion of N-(diphenylmethyleneamino)acetonitrile, followed by a diastereo-selective
SN cyclization under Mitsunobu conditions (DEAD, PMe3) (d.e. 88%),6 provided chiral non-racemic
(1S,2S)-2,3-methanoamino acids (ACCs) with 84–88% enantiomeric excesses.
∗
Corresponding authors. Fax: +33(1)69156278; e-mail: jasalaun@icmo.u-psud.fr. Fax: +49 551399475; e-mail: ameijer@uni-
goettingen.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00107-4

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V. Atlan et al. / Tetrahedron: Asymmetry 9 (1998) 1131–1135
We now report that the palladium(0)-catalyzed azidation of non-racemic 1-(1-alkenyl)cyclopropyl
esters can diastereoselectively lead to precursors of (1R,2S)-ACCs. While the palladium(0)-catalyzed
amination with, for example, dibenzylamine of 1-ethenylcyclopropyl tosylate 1a, which is readily
available from cyclopropanone hemiacetal,7 led exclusively to N,N-dibenzylcyclopropylideneethylamine
3a in 85% yield, the palladium(0)-catalyzed azidation of 1a,b, on the other hand, with sodium azide in the
presence of 15-crown-5 ether (10%) was reported to provide in 80% yield, the 1-(1-alkenyl)cyclopropyl
azides 4a,b, exclusively, suitable precursors of 2,3-methanoalanine 5.8 This regioselectivity was shown
to result from the non-symmetric charge distribution in the π-1,1-dimethyleneallylpalladium complex 2a
which led to substitution either at the primary allylic end by soft nucleophiles (e. g. stabilized carbanions)
or on the cyclopropyl ring by hard nucleophiles (hydride donors, organometallics, etc., and also by
azide).7
Commercially available methyl (2S) 3-hydroxy-2-methylproponiate 6a (>99% e.e.)9 was reacted
with mesyl chloride in the presence of NEt3 to produce the mesylate (2S)-6b (91%) which was then
treated with lithium bromide in NMP to give the bromide (2S)-6c (82%); alternatively, reaction of
20
D
(2S)-6a with carbon tetrabromide/PPh3 in CH2Cl2 led directly to the bromide (2S)-6c, [α] =−18 (c
1, CHCl3), in 73% yield. Cyclization of (2S)-6c by treatment with sodium in diethyl ether in the presence
of chlorotrimethylsilane (Et2O at reflux) gave a 1:1 diastereomeric mixture of 1-ethoxy-2-methyl-1-
trimethylsiloxycyclopropanes (2S)-7, which on acid-catalyzed methanolysis (MeOH, ClSiMe) led to
the hemiacetals (2S)-8 in 85% overall yield from (2S)-6c.10 Upon treatment with two equivalents of
vinylmagnesium chloride of the 1:1 mixture of (2S)-8, followed by the addition of two equivalents of tosyl
chloride in THF, the (1R,2S) 2-methyl-1-tosyloxycyclopropane 10a was obtained directly in 67% overall
yield, as a single diastereomer, as revealed by its 1H and 13C NMR spectra. Likewise, successive addition
of one equivalent of ethylmagnesium bromide and of one equivalent of lithium phenylacetylide to (2S)-
8 gave in 76% yield a 91:9 diastereomeric mixture of 2-methyl-1-(phenylethynyl)cyclopropanols (11),
which on lithium aluminum hydride reduction led in 96% yield to the 2-methyl-1-styrylcyclopropanols
9b. While tosylation of 9b failed, mesylation was achieved under classical conditions (MeSO2Cl, NEt3,
Et2O) to produce a 90:10 diastereomeric mixture of the expected mesylates 10b in 96% yield.

V. Atlan et al. / Tetrahedron: Asymmetry 9 (1998) 1131–1135
1133
Treatment of the cyclopropanone hemiacetal with one equivalent of Grignard reagent (i.e. methyl-,
ethyl- or vinylmagnesium halides) has been shown to produce a magnesium salt which, contrary to the
hemiacetal itself, is able to react with organolithium reagents as well as with a second Grignard reagent,
to produce 1-alkyl(alkenyl)cyclopropanols in high yields.11 The diastereoselectivity observed here for
the nucleophilic substitutions (2S)-8-→(1R,2S)-9a,b strongly suggests that the intermediate magnesium
1-ethoxycyclopropanolate 12 behaves more as the cyclopropanone 120, which is probably stabilized by
ligation with MgXOEt. In any event, this reaction provides 2-methyl-1-alkenylcyclopropanols like 9a,b,
diastereoselectively; non-racemic 1-alkenylcyclopropanols such as 9a,b have also been prepared from
the dimethyl (2S)-2-methylsuccinate, via sodium-induced acyloin cyclization followed by a diastereose-
lective C4-→C3 ring contraction, with total preservation of the chirality of the stereocenter.12
Palladium(0)-catalyzed reaction (Pd(dba)2, 2PPh3) of the tosylate (1R,2S)-10a and of the 90:10
diastereomeric mixture of mesylates 10b with sodium azide in the presence of 10% 15-crown-5 ether,
gave either the single azide (1R,2S)-14a (R=H) or a 96:4 diastereomeric mixture of azides (1R,2S)-14b
and (1S,2S)-15b (R=C6H5), respectively, in 81–85% yields. COSY and NOESY experiments on the two-
dimensional NMR spectra of the azide 14a have confirmed the assigned configuration.
Alternatively, reaction of the hemiacetal 8 with ethoxycarbonylmethylenetriphenylphosphorane in
benzene in the presence of a catalytic amount of benzoic acid, gave in 58% yield a 2:1 diastereomeric
mixture of ethyl 2-(2-methylcyclopropylidene)ethyl acetate 1613 which was reduced to the allylic alcohol
17 with DIBAH (CH2Cl2, −78°C) and then esterified with acetic anhydride in the presence of DMAP and
NEt3 to give the allylic acetate 18 in 67% overall yield.8,14 Subsequent palladium(0)-catalyzed azidation
of 18, through the intermediate complex 13a, provided in 85% yield the same azide 14a as a single
diastereomer.14
Reduction of the azides 14a,b with 1,3-propanedithiol in MeOH containing NEt3,15 gave the cor-
responding primary amines 20a,b in 56 and 97% yield, respectively. The lower isolated yield of
20a most probably was due to its volatility, therefore the total synthesis of the non-racemic (1R,2S)-
norcoronamic acid 22 was performed with the 2-methyl-1-styrylcyclopropylamine 20b, initially as a
1
96:4 diastereomeric mixture, as revealed by the H NMR spectrum of the crude reduction product,
20
D
but in fact obtained as a single diastereomer after flash chromatography, [α] =+94 (c 1.15, CHCl3).

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V. Atlan et al. / Tetrahedron: Asymmetry 9 (1998) 1131–1135
Subsequent treatment of 20b with di-t-butyldicarbonate in water, containing KOH and t-BuOH, provided
21b in quantitative yield. Finally, oxidative degradation of the styryl group in 21b by ruthenium tetroxide
(RuCl3/NaIO4),16 N-deprotection by treatment with HCl and ion-exchange chromatography (Dowex
50WX 18) led to the (1R,2S)-norcoronamic acid 22,17 the enantiomeric purity (>99%) of which was
determined by deuterium NMR in a cholesteric lyotropic liquid crystal of the deuterated methyl ester of
the N-(diphenylmethylene)amino acid 22, following a recently reported accurate method.18
It is known that the palladium(0)-catalyzed azidation of allyl esters occurs with overall retention of
configuration,19 however, the substitution of the palladium moiety in the chiral complexes 13a,b with the
required inversion of configuration should lead as previously reported to (cyclopropylideneethyl)amine
derivatives (soft nucleophile behaviour),7 while substitution of complexes 13a,b with retention of con-
figuration should lead to azides of type (1S,2S)-15b as major products (hard nucleophile behaviour).7,12
Therefore the exclusive formation of azides (1R,2S)-14a,b must result via primarily formed (cyclopropy-
lideneethyl) azides and subsequent palladium(0)-induced isomerization19 which is stereocontrolled by
the palladium moiety coordinated to the double bond.
Acknowledgements
This work was financially supported by the CNRS and the Université de Paris-Sud (XI), by the
Deutsche Forschungs-gemeinschaft (SFB 416) as well as by the Fonds der Chemischen Industrie. A.d.M.
is grateful to the French MENRT for the Alexander von Humboldt–Gay Lussac prize which allowed him
to stay in Orsay; M.R. is indebted to the International Association for the Promotion of Cooperation with
Scientists from the Independant States of the Former Soviet Union (INTAS) for a fellowship and C.B. to
the Student Mobility Programme (ERASMUS) for a grant. Finally, we are very grateful to Cecile Canlet
and Jacques Courtieu who recorded the 2H NMR spectra of 22 derivatives in a cholesteric lyotropic liquid
crystal.
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