Highly Diastereoselective Nitrone Cycloaddition onto a Chiral Ketene Equivalent: Asymmetric Synthesis of Cispentacin

Article abstract of DOI:10.1021/ol025665f

matrix presented A highly diastereoselective intramolecular nitrone cycloaddition onto a chiral ketene equivalent, obtained by Horner-Wadsworth-Emmons olefination of either enantiomer of bis-sulfinyl phosphonate 6, is described. Cycloaddition gave 5,5-disubstituted isoxazolidine 10 in good yield as a single diastereomer. Catalytic hydrogenolysis of 10 furnished either enantiomer of optically pure cis-2-aminocyclopentane-1-carboxylic acid.

Full text of DOI:10.1021/ol025665f

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1227-1229
Highly Diastereoselective Nitrone
Cycloaddition onto a Chiral Ketene
Equivalent: Asymmetric Synthesis of
Cispentacin
Varinder K. Aggarwal,* Stephen J. Roseblade, Juliet K. Barrell, and
Rikki Alexander
Department of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol, and
Celltech R+D Ltd, 216 Bath Road, Slough SL1 4EN, U.K.
V.aggarwal@bris.ac.uk
Received February 5, 2002
ABSTRACT
A highly diastereoselective intramolecular nitrone cycloaddition onto a chiral ketene equivalent, obtained by Horner−Wadsworth−Emmons
olefination of either enantiomer of bis-sulfinyl phosphonate 6, is described. Cycloaddition gave 5,5-disubstituted isoxazolidine 10 in good
yield as a single diastereomer. Catalytic hydrogenolysis of 10 furnished either enantiomer of optically pure cis-2-aminocyclopentane-1-carboxylic
acid.
Although there are numerous chiral auxiliaries and chiral
catalysts for Diels-Alder reactions,1 there are only a limited
number of effective chiral controllers for [3 + 2] cyclo-
addition reactions.2 The auxiliaries for these cycloaddition
processes are invariably based on chiral acrylate derivatives.3
We have investigated reagents for the more difficult to access
chiral ketene equivalents and have discovered that the ketene
dithioacetal 1 is highly effective. This auxiliary shows high
reactivity and excellent diastereoselectivity in not only a
range of Diels-Alder cycloadditions but also in nitrone
cycloadditions as well.4 As 1 can be easily made in racemic
and enantiomerically pure form in four high yielding steps
and the bis-sulfinyl moiety can be converted into a carbonyl
group, its merits as one of the most effective chiral ketene
equivalents available have been demonstrated.
In this paper we report on the further application of
sulfoxide-based ketene thioacetals as dipolarophiles in an
intramolecular nitrone cycloaddition and its application to a
short synthesis of the antifungal antibiotic cispentacin.
Cispentacin, (1R,2S)-2-aminocyclopentane-1-carboxylic acid,
was isolated from Bacillus cereus5a,b and Streptomyces
(1) For recent reviews, see: (a) Evans, D. A.; Johnson, J. S. Compre-
hensiVe Asymmetric Catalysis III; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999; p 1177 (b) Kagan, H. B.; Riant, O. Chem.
ReV. 1992, 92, 1007 (c) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984,
96, 876.
(2) (a) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem.
Soc. 1998, 120, 12355. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV.
1998, 98, 863.
(3) Enantioselective cycloaddition reactions of activated nitrones onto
ketene acetals have been carried out: (a) Seerden, J. P. G.; Boeren, M. M.
M.; Scheeren, H. W. Tetrahedron 1997, 53, 11843. (b) Seerden, J. P. G.;
Scholte op Reimer, A. W. A.; Scheeren, H. W. Tetrahedron Lett. 1994, 35,
4419.
(4) (a) Aggarwal, V. K.; Drabowicz, J.; Grainger, R. S.; Gu¨ltekin, Z.;
Lightowler, M.; Spargo, P. L. J. Org. Chem. 1995, 60, 4962. (b) Aggarwal,
V. K.; Gu¨ltekin, Z.; Grainger, R. S.; Adams, H.; Spargo, P. L. J. Chem.
Soc., Perkin Trans. 1 1998, 2771. (c) Aggarwal, V. K.; Grainger, R. S.;
Adams, H.; Spargo, P. L. J. Org. Chem. 1998, 63, 3481.
(5) (a) Konishi, M.; Nishio, M.; Saitoh, T.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749. (b) Oki, T.; Hirano, M.; Tomatsu,
K.; Numata, K.; Kamei, H. J. Antibiot. 1989, 42, 1756. (c) Iwamoto, T.;
Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.; Okuhara. M.; Kohsaka, M.;
Imanaka, H. J. Antibiot. 1990, 43, 1. (d) Kawabata, K.; Inamoto, Y.; Sakane,
K. J. Antibiot. 1990, 43, 513.
10.1021/ol025665f CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/12/2002

setonii5c,d and was found to exhibit potent in vivo activity
against several Candida species in mice.5 As a result of its
biological activity and the inactivity of the unnatural (1S,2R)
enantiomer,5d several asymmetric syntheses have been re-
ported.6
We have previously studied intermolecular nitrone cyclo-
additions with 1 and found that the 4,4-disubstituted isoxa-
zolidine 2 was formed exclusively in high yield and with
>18:1 diastereoselectivity (Scheme 1). None of the 5,5-
enantioselectivity.12 Attempts to carry out a Horner-Wads-
worth-Emmons olefination with glutaraldehyde (as a 25%
aqueous solution) under a variety of conditions only led to
low yields of the mono- and bis-olefinated products. To avoid
the possibility of bis-olefination we decided to employ the
terminally differentiated aldehyde 7, which was readily
available by ozonolysis of cyclopentene using the Schreiber
procedure.13 In the event the Horner-Wadsworth-Emmons
reaction occurred smoothly with this aldehyde on small scale,
but on scale-up, the bond isomerized out of conjugation with
the sulfoxides to give 8.13c The problem was solved using a
slight deficiency of base (Scheme 2).
Scheme 1. Diastereoselective Inter- and Intramolecular
Nitrone Cycloadditions onto C2-Symmetric Ketene Dithioacetals
Scheme 2. Asymmetric Synthesis of ent-Cispentacina
disubstituted regioisomer was observed, which was unusual
as nitrone cycloadditions with 1,1-disubstituted olefins
bearing electron-withdrawing groups normally furnish 5,5-
disubstituted isoxazolidines.7
We reasoned that a 5,5-disubstituted isoxazolidine could
be accessed by linking the two components with a suitable
tether. A three-carbon tether (3)8 should result in diastereo-
selective formation of the cis-fused 5,5-disubstituted isoxa-
zolidine 4.9 Following hydrogenolysis of the N-O and
N-Bn bonds, the thioacetal moiety should collapse and
directly furnish cispentacin 5 (Scheme 1).
Our synthesis began with dithiane, which was converted
into the 2-phosphonate10 and oxidized to the bis-sulfoxide
68a using the Modena protocol11 in good yield and very high
a (i) (a) NCS, benzene, rt, 24 h, (b) P(OEt)3, 60 °C, 4 h, 78%
yield. (ii) PhC(CH3)2OOH (4 equiv), Ti(OiPr)4 (0.5 equiv), (-)-
DET (2 equiv), DCM, 43% yield, >98% ee. (iii) aldehyde (1.5
equiv), LiOH‚H2O (0.99 equiv), THF, 80 °C, 4 h, 80% yield. (iv)
PdCl2(CH3CN)2 (1 mol %), acetone, 60 °C, 1 h then BnNH2OH‚Cl
(1.3 equiv) and NaHCO3 (3 equiv), 60 °C, 4 h, 70% yield. (v) Pd/C
(10 mol %), AcOH, H2 (100 psi), 48 h, 65% yield. (vi) Pd(OH)2/C
(10 mol %), NEt3 (10 mol %), EtOH, 40 °C, H2 (1 atm), 4 h, 85%
yield.
(6) (a) Konosu, T.; Oida, S. Chem. Pharm. Bull. 1993, 41, 1012. (b)
Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1411. (c) Theil, F.; Ballschuh, S. Tetrahedron: Asymmetry
1996, 7, 3565.
(7) (a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396. (b) Tufariello, J.
J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley &
Sons: New York, 1984; Vol. 2, pp 83-168.
(8) Although dithiolane 1 had been employed in intermolecular nitrone
cycloadditions, we chose to work on the dithiane derivative 3 as the synthesis
of such substituted alkenes had already been successfully achieved and
employed in epoxidation: (a) Aggarwal. V. K.; Barrell, J. K.; Worrall, J.
M.; Alexander, R. J. Org. Chem. 1998, 63, 7128. In related Diels-Alder
cycloadditions, dithiolane 1 was found to be more reactive and more
selective than the dithiane analogue of 1: (b) Aggarwal, V. K.; Gu¨ltekin,
Z.; Grainger, R. S.; Adams, H.; Spargo, P. L. J. Chem. Soc., Perkin Trans.
1 1998, 2771. The dithiolane analogue of 3 would have been investigated
had low diastereoselectivity been observed in the current nitrone cycload-
dition with the dithiane derivative 3.
(9) (a) LeBel, N. A.; Whang, J. L. J. Am. Chem. Soc. 1964, 20, 3759.
(b) LeBel, N. A.; Banucci, E. G. J. Org. Chem., 1971, 2440. (c) Baldwin,
S. W.; Wilson, J. D.; Aube´, J. J. Org. Chem. 1985, 50, 4432.
(10) Mlotkowska, B.; Gross, H.; Costisella, B.; Mikolajczyk, M.;
Grzejszczak, S.; Zatorski, A. J. Prakt. Chem. 1977, 319, 17.
(11) Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325-326.
Attempts to hydrolyze the methoxy acetal 9 under protic
conditions were unsuccessful, but use of 1 mol % (bisaceto-
nitrile)palladium(II) chloride in acetone furnished the cor-
responding aldehyde in excellent yield.14 The above reaction
mixture was used directly in the formation of the nitrone
and subsequent [3 + 2] cycloaddition to give 10. Further-
(12) Oxidation of 2-carboethoxy-1,3-dithiane and other 2-substituted 1,3-
dithianes with (+)-DET gave the (R)-sulfoxide as noted in: (a) Aggarwal,
V. K.; Evans, G. R.; Moya, E.; Dowden, J. J. Org. Chem. 1992, 57, 6390.
(b) Aggarwal, V. K.; Esquivel-Zamora, B. N.; Evans, G. R.; Jones, E. J.
Org. Chem. 1998, 63, 7306. (c) Page, P. C. B.; Wilkes, R. D.; Namwinda,
E. S.; Witty, M. J. Tetrahedron 1996, 52, 2125. (d) Samuel, O.; Ronan, B.;
Kagan, H. B. J. Organomet. Chem. 1989, 370, 43.
(13) (a) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867. (b) Claus, R. E.; Schreiber, S. L. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, pp 168-171. (c) Initially the 1,3-dioxolane
monoacetal was used. For its synthesis, see: Grigorieva, N. Y.; Yudina,
O. N.; Moiseenkoz, A. M. Synthesis 1989, 8, 591.
(14) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705.
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Org. Lett., Vol. 4, No. 7, 2002

ides, which all show the same conformation.17 The face
selectivity of the nitrone is opposite to what we had expected
on the basis of the diastereoselective epoxidations of related
ketene dithioacetals.8a In epoxidation the nucleophilic per-
oxide attacks the top face of the ketene thioacetal to give 15
(Scheme 4), whereas in the intramolecular nitrone cyclo-
Scheme 3. Competing Transition States in the Cycloaddition
Scheme 4. Diastereoselective Nucleophilic Epoxidation
addition the nitrone attacks the lower face, as shown in 13
(Scheme 3). In this case the facial selectivity is controlled
by the destabilizing steric and electrostatic interactions
between the negatively charged oxygen atom of the (Z)-
nitrone and the axial sulfinyl oxygen, as depicted in the
disfavored TS 14 (Scheme 3).18,19
By using (+)-DET in the Modena oxidation, an asym-
metric synthesis of the natural product has been achieved
more, this sequence of reactions occurred in high yield (70%)
and with complete diastereoselectivity.
using identical chemistry ([R]22 -9, c ) 1.1 in H2O).
D
We had hoped to be able to reductively cleave the N-O
and N-Bn bonds together to furnish cispentacin. However,
this was not possible, and so we had to resort to a two-step
protocol. Thus hydrogenation of 10 with Pd/C gave the
N-benzyl amino acid 11. This was followed by debenzylation
using Pearlman’s catalyst, but initially this step was not
straightforward. Under standard reaction conditions, a mix-
ture of 2-amino-cyclopentane-1-carboxylic acid and its
N-ethyl derivative was obtained in a 1:1 ratio. The N-ethyl
derivative presumably originates from palladium-catalyzed
oxidation of ethanol to acetaldehyde followed by reductive
amination. However, using 5 mol % triethylamine deben-
zylation was faster, and none of the N-ethyl byproduct was
observed.15 Enantiomerically pure ent-cispentacin 12 was
obtained after a single recrystallization from water/acetone
and was spectroscopically identical to literature data.5d,6c The
absolute stereochemistry of the product was ascertained as
In conclusion, a highly diastereoselective, intramolecular
nitrone cycloaddition onto a chiral ketene equivalent has been
used as the key step in an asymmetric synthesis of both
enantiomers of cis-2-amino-cyclopentane-1-carboxylic acid.
A1,3 strain and repulsive electronic interactions between the
electronegative oxygen atoms of the nitrone moiety and axial
sulfinyl group are minimized in the preferred transition state.
Acknowledgment. We thank the EPSRC and Celltech
R+D Ltd for CASE Awards to S.J.R. and J.K.B.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025665F
(16) For a review on allylic 1,3-strain as a controlling factor in
stereoselective transformations, see: Hoffmann, R. W. Chem. ReV. 1989,
89, 1841-1860.
being (1S,2R) from the sign of the optical rotation ([R]22
D
+9, c ) 1.1 in H2O) and this provided evidence for the
relative stereochemistry of the cycloadduct 10.
(17) Barrell, J. K. Ph.D. Thesis, University of Sheffield, 1999.
(18) Acyclic (E)-nitrones have been postulated as intermediates in
cycloadditions at elevated temperatures: (a) Ishikawa, T.; Saito, S.; Kudo,
T.; Shigemori, K. J. Am Chem. Soc. 2000, 122, 7633. (b) LeBel, N. A.;
Banucci, E. G. J. Org. Chem. 1971, 36, 2440. (c) Rispens, M. T.; Keller,
E.; de Lange, B.; Zijlstra, R. W. J.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 607. (Z)-nitrones formed at lower temperatures have been isolated
and characterised using NOE NMR spectroscopy: (d) DeShong, P.; Leginus,
J. M. J. Am. Chem. Soc. 1983, 105, 1686. (e) Saito, S.; Ishikawa, T.;
Kishimoto, N.; Kohara, T.; Moriwake, T. Synlett 1993, 282.
Two factors control the diastereoselectivity of the cyclo-
addition process: the conformation and face selectivity of
the olefin. The preferred conformation of the olefin is 13,
as 13a suffers from severe A1,3 strain.16 Indeed we have a
number of X-ray structures of ketene thioacetal bis-sulfox-
(15) For another example of the acceleration of a palladium-catalysed
hydrogenolysis using triethylamine as an additive, see: Effenberger, F.;
Jager, J. Chem. Eur. J. 1997, 3, 1370.
(19) For a review on the use of the sulfinyl group in asymmetric synthesis,
see: (a) Carreno, M. Chem. ReV. 1995, 95, 1717-1760. (b) Garcia Ruano,
J. L. Top. Curr. Chem. 1999, 204 (Organosulfur Chemistry I), 1-126.
Org. Lett., Vol. 4, No. 7, 2002
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