A stereoselective synthesis of (+)-physoperuvine using a tandem aza-Claisen rearrangement and ring closing metathesis reaction

Article abstract of DOI:10.1039/b907341h

A stereoselective synthesis of (+)-physoperuvine, a tropane alkaloid from Physalis peruviana Linne has been developed using a one-pot tandem aza-Claisen rearrangement and ring closing metathesis reaction to form the key amino-substituted cycloheptene ring

Full text of DOI:10.1039/b907341h

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Volume 7 | Number 13 | 7 July 2009 | Pages 2657–2820
ISSN 1477-0520
COMMUNICATION
Ahmed M. Zaed et al.
A stereoselective synthesis of
(+)-physoperuvine using a tandem
aza-Claisen rearrangement and ring
closing metathesis reaction
1477-0520(2009)7:13;1-E

COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
A stereoselective synthesis of (+)-physoperuvine using a tandem aza-Claisen
rearrangement and ring closing metathesis reaction†
Ahmed M. Zaed, Michael D. Swift and Andrew Sutherland*
Received 14th April 2009, Accepted 6th May 2009
First published as an Advance Article on the web 13th May 2009
DOI: 10.1039/b907341h
A stereoselective synthesis of (+)-physoperuvine, a tropane
alkaloid from Physalis peruviana Linne has been developed
using a one-pot tandem aza-Claisen rearrangement and ring
closing metathesis reaction to form the key amino-substituted
cycloheptene ring.
one-pot tandem process for the highly efficient synthesis of an
N-(cycloheptenyl)-trichloroacetamide and the elaboration of
this carbocyclic amide to complete a novel total synthesis of
(+)-physoperuvine.
Results and discussion
Introduction
As outlined in Scheme 2, our strategy for synthesising 1
required the asymmetric synthesis of (S)-N-(cycloheptenyl)-
trichloroacetamide 4. It was proposed that this could be achieved
using an asymmetric one-pot tandem Overman rearrangement
and RCM reaction of allylic trichloroacetimidate 5, which in
turn could be easily prepared from commercially available ethyl
6-heptenoate 7 using standard procedures. After the one-pot
process, the final stage would then involve an allylic oxidation
of the cycloheptene ring leading to ketone 3. Hydrogenation and
deprotection of 3 would then give aminoketone 2, which would
cyclise to form (+)-physoperuvine 1.
(+)-Physoperuvine 1 is a tropane alkaloid found in the leaves
and roots of the Indian plant Physalis peruviana Linne.1
Based on chemical and spectroscopic studies, the structure of
(+)-physoperuvine was originally assigned as 3-methylaminocy-
cloheptanone.1 A re-investigation using primarily, X-ray crystal-
lography allowed determination of the absolute configuration and
showed that the structure is (S)-4-methylaminocycloheptanone 2,
which is in equilibrium with the bicyclic tautomer 1 (Scheme 1).2,3
Analysis of the equilibrium using both CD and NMR spec-
troscopy revealed that (+)-physoperuvine exists almost entirely
in the bicyclic form.2,4
Scheme 1
Elucidation of the bicyclic hemiaminal structure of 1 has
resulted in a number of stereoselective syntheses of (+)-
physoperuvine and its enantiomer.5 The groups of Ogasawara5a
and Majewski5b,c synthesised (+)-physoperuvine by desymmetri-
sation of meso-intermediates while Wightman and co-workers
synthesised (-)-physoperuvine by cycloaddition of cyclohepta-1,3-
diene with an a-chloronitroso derived carbohydrate.5d,e Recently,
we reported the highly efficient synthesis of 5-, 6-, 7- and 8-
membered carbocyclic amides from allylic trichloroacetimidates
using a one-pot tandem Overman rearrangement and ring-closing
metathesis (RCM) reaction.6 A stereoselective version of this
process was also achieved for the preparation of N-(cyclohexenyl)-
trichloroacetamides using chiral palladium(II)-catalysts.6 In this
paper, we report the first use of the asymmetric version of this
Scheme 2 Retrosynthesis of (+)-physoperuvine 1.
Synthesis of key allylic trichloroacetimidate 5 started from
commercially available ethyl 6-heptenoate 7 which was reduced
to 6-hepten-1-ol 8 in 94% yield using DIBAL-H (Scheme 3).
6-Hepten-1-ol 8 was then subjected to a one-pot Swern oxidation
and Horner–Wadsworth–Emmons reaction7 which gave (E)-a,b-
unsaturated ester 9 in 85% yield over the two steps. Allylic alcohol
6 was then formed by DIBAL-H reduction of 9 and this was con-
verted to allylic trichloroacetimidate 5 using trichloroacetonitrile
and catalytic amounts of DBU. With allylic trichloroacetimidate
5 in hand, this was then subjected to a one-pot Overman
rearrangement and RCM reaction using commercially available
WestChem, Department of Chemistry, The Joseph Black Building, University
of Glasgow, Glasgow, UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk;
Fax: +44 (0)141 330 4888; Tel: +44 (0)141 330 5936
† Electronic supplementary information (ESI) available: Experimen-
tal procedures and spectroscopic data for all compounds. See DOI:
10.1039/b907341h
2678 | Org. Biomol. Chem., 2009, 7, 2678–2680
This journal is
The Royal Society of Chemistry 2009
©

Scheme 4 Reagents and conditions: i. 2 M NaOH then Boc2O, 100%; ii.
NaH, MeI, THF, 84%; iii. 10% Pd/C, t-BuOOH, K2CO3, CH2Cl2, 45%;
iv. 10% Pd/C, H2, MeOH, 66%; v. TFA, CH2Cl2, 60%.
a,b-unsaturated ketone 3 in only 22% yield. A second attempt
at the allylic oxidation of 13 used a protocol reported by Yu
and Corey which involved a palladium mediated oxidation with
t-BuOOH as the oxidant under basic conditions.12b This gave a,b-
unsaturated ketone 3 in an improved yield of 45%. Hydrogenation
of 3 under standard conditions then gave the saturated ketone
in 66% yield and TFA deprotection of the amine completed
the eleven-step synthesis of (+)-physoperuvine 1. The optical
rotation and spectroscopic data of our synthetic material was in
complete agreement with those reported for the naturally derived
(+)-physoperuvine.2–5
Scheme 3 Reagents and conditions: i. DIBAL-H (2.2 eq.), Et2O, -78 ◦
C
to RT, 94%; ii. (COCl)2, Et3N, DMSO, CH2Cl2, -78 ◦C to RT, then triethyl
phosphonoacetate, LiCl, DBU, MeCN, 85%; iii. DIBAL-H (2.2 eq.),
Et2O, -78 ◦C to RT, 100%; iv. DBU, Cl3CCN, CH2Cl2; v. (S)-COP-Cl 11
(10 mol%), CH2Cl2, 45 ◦C; vi. Grubbs’ 1st generation catalyst (10 mol%),
D, 82% from 6.
(S)-COP-Cl8 11 to catalyse the rearrangement and Grubbs’ first
generation catalyst to effect the RCM reaction. This gave (S)-
N-(cycloheptenyl)-trichloroacetamide 4 in an excellent 82% yield
from allylic alcohol 6 and in 84% ee.9 The enantiomeric excess
of 4 was improved to >99% on recrystallisation from a mixture
of ethyl acetate and petroleum ether. It should be noted that the
facile synthesis of dienol substrates such as 6 in combination with
this one-pot tandem process allows the highly efficient and rapid
synthesis of allylic carbocyclic amides (e.g. 66% overall yield of 4
from 7).
Conclusions
In summary, we have developed a novel approach for the synthesis
of the tropane alkaloid, (+)-physoperuvine using for the first
time a highly efficient one-pot tandem Overman rearrangement
and RCM reaction for the asymmetric preparation of a N-
(cycloheptenyl)-trichloroacetamide.
The next stage of the synthesis of (+)-physoperuvine required
introduction of the N-methyl group and this was initially at-
tempted by methylating the amide of trichloroacetamide 4 using
the standard conditions of sodium hydride and iodomethane.10
However, treatment of 4 with sodium hydride led to hydrolysis
of the trichloroacetamide functional group and recovery of the
corresponding amine. This problem was easily overcome by the
one-pot conversion of 4 to Boc-analogue 12 in quantitative yield
(Scheme 4).11 Subsequent methylation then proceeded smoothly
to give 13 in 84% yield. The last key transformation in the
synthesis of (+)-physoperuvine involved the allylic oxidation of the
cycloheptene ring. While a number of general procedures do exist
for the mild and efficient allylic and benzylic oxidation of organic
compounds,12 relatively few have been utilized for the oxidation of
cycloheptenes.13 Initial attempts of allylic oxidation of 13 utilised a
manganese(III) acetate catalysed procedure with t-BuOOH as the
oxidant under an atmosphere of oxygen.12c Despite investigating
various conditions and increasing amounts of oxidant, this gave
Acknowledgements
The authors gratefully acknowledge financial support from the
Libyan People’s Bureau, London (studentship to A.M.Z.), EPSRC
(studentship to M.D.S.) and the University of Glasgow.
References
1 (a) A. B. Ray, M. Sahai and P. D. Sethi, Chem. Ind., 1976, 454; (b) M.
Sahai and A. B. Ray, J. Org. Chem., 1980, 45, 3265.
2 A. B. Ray, Y. Oshima, H. Hikino and C. Kabuto, Heterocycles, 1982,
19, 1233.
3 (a) A. R. Pinder, J. Org. Chem., 1982, 47, 3607; (b) A. T. McPhail and
A. R. Pinder, Tetrahedron, 1984, 40, 1661.
4 D. E. Justice and J. R. Malpass, J. Chem. Soc., Perkin Trans. 1, 1994,
2559.
5 (a) K. Hiroya and K. Ogasawara, J. Chem. Soc., Chem. Commun.,
1995, 2205; (b) M. Majewski and R. Lazny, Synlett, 1996, 785; (c) M.
Majewski, R. Lazny and A. Ulaczyk, Can. J. Chem., 1997, 75, 754;
(d) A. Hall, P. D. Bailey, D. C. Rees and R. H. Wightman, Chem.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2678–2680 | 2679
©

Commun., 1998, 2251; (e) A. Hall, P. D. Bailey, D. C. Rees, G. M.
Rosair and R. H. Wightman, J. Chem. Soc., Perkin Trans. 1, 2000, 329.
6 M. D. Swift and A. Sutherland, Org. Lett., 2007, 9, 5239.
7 (a) R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50,
2198; (b) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masumune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2183.
8 (a) L. E. Overman, C. E. Owen, M. M. Pavan and C. J. Richards, Org.
Lett., 2003, 5, 1809; (b) C. E. Anderson and L. E. Overman, J. Am.
Chem. Soc., 2003, 125, 12412; (c) C. E. Anderson, L. E. Overman
and M. P. Watson, Org. Synth., 2005, 82, 134; (d) M. P. Watson,
L. E. Overman and R. G. Bergman, J. Am. Chem. Soc., 2007, 129,
5031.
10 R. Bischoff, N. McDonald and A. Sutherland, Tetrahedron Lett., 2005,
46, 7147.
11 A. G. Jamieson and A. Sutherland, Org. Lett., 2007, 9, 1609.
12 For example, see: (a) T. Nagai, K. Ogawa, M. Morita, M. Koyama,
A. Ando, T. Miki and I. Kumadaki, Chem. Pharm. Bull., 1989, 37,
1751; (b) J.-Q. Yu and E. J. Corey, Org. Lett., 2002, 4, 2727; (c) T. K. M.
Shing, Y.-Y. Yeung and P. L. Su, Org. Lett., 2006, 8, 3149; (d) G. Pandey,
K. N. Tiwari and V. G. Puranik, Org. Lett., 2008, 10, 3611; (e) E. C.
McLaughlin, H. Choi, K. Wang, G. Chiou and M. P. Doyle, J. Org.
Chem., 2009, 74, 730; (f) R. Martin, A. W. Schmidt, G. Theumer, T.
Krause, E. V. Entchev, T. V. Kurzchalia and H.-J. Kno¨lker, Org. Biomol.
Chem., 2009, 7, 909.
13 (a) N. Chidambaram and S. Chandrasekaran, J. Org. Chem., 1987, 52,
5048; (b) J.-Q. Yu and E. J. Corey, J. Am. Chem. Soc., 2003, 125, 3232;
(c) J.-Q. Yu, H.-C. Wu and E. J. Corey, Org. Lett., 2005, 7, 1415.
9 The enantiomeric excess of compound 4 was determined by chiral
HPLC. See, supplementary information for full details.
2680 | Org. Biomol. Chem., 2009, 7, 2678–2680
This journal is
The Royal Society of Chemistry 2009
©