Dichloroketene-chiral olefin-based approach to pyrrolizidines: Highly stereocontrolled synthesis of (+)-amphorogynine A

Article abstract of DOI:10.1021/ol034369f

(Matrix presented) A highly stereoselective route to (+)-amphorogynine A, a novel pyrrolizidine recently isolated from the New Caledonian plant Amphorogynine spicata, has been realized. The key step in the approach is a diastereoselective [2 + 2] dichloro

Full text of DOI:10.1021/ol034369f

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1741-1744
Dichloroketene−Chiral Olefin-Based
Approach to Pyrrolizidines: Highly
Stereocontrolled Synthesis of
(+)-Amphorogynine A
Caroline Roche, Philippe Delair,* and Andrew E. Greene*
UniVersite´ Joseph Fourier de Grenoble, Chimie Recherche (LEDSS),
38041 Grenoble Cedex, France
philippe.delair@ujf-grenoble.fr; andrew.greene@ujf-grenoble.fr
Received March 2, 2003
ABSTRACT
A highly stereoselective route to (+)-amphorogynine A, a novel pyrrolizidine recently isolated from the New Caledonian plant Amphorogynine
spicata, has been realized. The key step in the approach is a diastereoselective [2 + 2] dichloroketene−chiral enol ether cycloaddition (dr g
93:7) to access a dichlorocyclobutanone intermediate, which is converted into the alkaloid natural product via a pyrrolidinone derivative.
The pyrrolizidines are numerous and widespread in nature.
To date, more than 370 of these alkaloids, which appear to
function as protective agents for plants, have been isolated
from over 560 species, for the most part belonging to the
botanical families Asteraceae, Boraginaceae, Fabaceae, and
Orchidaceae.1
of this total synthesis serves to demonstrate that dichlo-
roketene-chiral enol ether cycloaddition,3 previously used
to prepare indolizidines,4 can also be effective for the
preparation of pyrrolizidines.
Our nonchiral-pool approach to this natural product is
outlined retrosynthetically in Scheme 1. On the basis of
In 1998, a research group at ICSN in France reported2
the isolation and structural and stereochemical elucidation
of four new pyrrolizidines from the New Caledonian plant
Amphorogynine spicata (Santalaceae). These alkaloids (1a-
d, Figure 1) represent a previously unknown class of
pyrrolizidines, characterized by substitution at C-1 and C-6.
In this paper, we disclose the first synthesis of a member
of this new group, that of amphorogynine A (1a). The success
(1) For reviews on pyrrolizidines, see: Liddell, J. R. Nat. Prod. Rep.
2002, 19, 773-781. Hartmann, T.; Witte, L. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier Science, Ltd.:
Oxford, 1995; Vol. 9, Chapter 4. Naturally Occurring Pyrrolizidine
Alkaloids; Rizk, A.-F. M., Ed.; CRC Press: Boston, 1991. Pyrrolizidine
Alkaloids; World Health Organization: Geneva, 1988.
Figure 1. Novel pyrrolizidines from Amphorogynine spicata.
(2) Huong, D. T. T.; Martin, M.-T.; Litaudon, M.; Se´venet, T.; Pa¨ıs,
M. J. Nat. Prod. 1998, 61, 1444-1446.
10.1021/ol034369f CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/24/2003

roenol ether 2b (79%), which on treatment with 2.1 equiv
of butyllithium and then excess allyl iodide produced the
unstable ynol ether 3a (Scheme 2). Without purification, this
Scheme 1. Retrosynthesis of Amphorogynine A (1a)
Scheme 2a
previous studies, it was expected that pyrrolidine or pyrro-
lidinone III could be induced to cyclize to provide a bicyclo-
[3.3.0]azaoctane, which on functional group transformations
might be converted into amphorogynine A (1a). Intermediate
III would result from regioselective Beckmann ring expan-
sion, dechlorination, and double-bond functionalization of
cyclobutanone II, which might be secured diastereoselec-
tively by facially selective [2 + 2] dichloroketene-chiral
enol ether cycloaddition.
The (S)-enantiomer of 1-(2,4,6-triisopropylphenyl)ethanol,5
a previously used and highly effective chiral auxiliary, was
chosen as the starting material on the basis of precedent4,6
and conformational analysis,7 which clearly indicated the
CR-re face of the envisaged (Z)-enol ether to be the more
accessible (Figure 2).
a Reagents: (a) KH, THF; Cl2CdCHCl (79%). (b) C4H9Li, THF;
allyl iodide, HMPA. (c) Pd/BaSO4, H2, C5H5N, 1-hexene. (d)
Cl3CCOCl, Zn-Cu, (C2H5)2O. (e) NH2OSO2C6H2(CH3)3, CH2Cl2;
Al2O3, CH3OH. (f) Zn-Cu, NH4Cl, CH3OH (42% from 2b, 84%
yield per step).
material was carefully hydrogenated with palladium on
barium sulfate in the presence of 1-hexene in pyridine8,9 to
afford enol ether 3b together with small amounts of sub-
sequently removed over-reduced material and trans isomer.
Dichloroketene, generated in situ,10 entered smoothly into
cycloaddition with this enol ether with high facial selectivity
1
(93:7, H NMR) and total regioselectivity for the electron-
rich double bond to yield R,R-dichlorocyclobutanone 4.
Electronic effects (chlorine substituents) and Baeyer strain
present in 4 produced a rapid, highly regioselective ring
expansion reaction under Tamura’s Beckmann conditions11
to generate 5a, which on dechlorination12 afforded lactam
5b in 42% overall yield from 2b (84% yield per step).
Osmium tetroxide-catalyzed dihydroxylation of the double
bond in 5b, followed by highly selective monotosylation of
(5) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M.; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710.
(6) B. M. de Azevedo, M.; Greene, A. E. J. Org. Chem. 1995, 60, 4940-
4942. Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene, A. E. J. Chem.
Soc., Perkin Trans. 1 1997, 1911-1912. Nebois, P.; Greene, A. E. J. Org.
Chem. 1996, 61, 5210-5211. Kanazawa, A.; Gillet, S.; Delair, P.; Greene,
A. E. J. Org. Chem. 1998, 63, 4660-4663. Delair, P.; Brot, E.; Kanazawa,
A.; Greene, A. E. J. Org. Chem. 1999, 64, 1383-1386.
Figure 2. Lowest-energy conformation of enol ether 3b.7
(7) Molecular modeling was performed on a SGI02 workstation running
Insight II Discover 2000 (ACCELRYS, San Diego). The structure was
energy minimized with the force field cvff.frc. and the minimization
algorithm VA09A. The molecular dynamics study was performed at 1000
K in a vacuum (dielectric constant fixed at 1; 400 000 steps of 1 fs) and
consisted of generation of 500 structures. For 3b, the conformation is lowest
in energy by 1.5 kcal/mol. (The next lowest in energy would also be
expected to undergo cycloaddition largely on the CR-re face.)
(8) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74, 13-
22.
This enantiopure alcohol (2a) in the presence of potassium
hydride and trichloroethylene was converted8 into dichlo-
(3) Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525-
5528.
(4) Pourashraf, M.; Delair, P.; Rasmussen, M.; Greene, A. E. J. Org.
Chem. 2000, 65, 6966-6972. Rasmussen, M.; Delair, P.; Greene, A. E. J.
Org. Chem. 2001, 66, 5438-5443.
1742
Org. Lett., Vol. 5, No. 10, 2003

the in situ-generated dibutylstannoxane derivative,13 produced
in good yield hydroxy tosylate 6b (55:45 mixture of hydroxy
epimers), which cyclized on reduction with borane-dimethyl
sulfide to give pyrrolizidine 7 together with its C-6 epimer
(Scheme 3). The latter could be converted to the former
t-Butyldiphenylsilylation of 7, followed by inductor cleav-
age with trifluoroacetic acid, provided the monoprotected
diol 8a (74%), which was oxidized under Swern conditions
to afford in good yield the unstable ketone 8b. The enol
triflate, derived with LiHMDS and the Comins triflimide
(N-(5-chloro-2-pyridyl)triflimide, CPT),15 was subjected to
palladium-catalyzed carbomethoxylation to generate the
conjugated ester 9a in 65% yield. In view of the folded
geometry and the endo-face-encumbering silyl group in 9a
(Figure 3),7 hydrogenation was expected to take place
Scheme 3a
Figure 3. Lowest-energy conformation of ester 9a.7
predominantly on the exo face of the molecule; in fact, the
saturated ester 9b was the unique product of the reaction
(93% yield).
a Reagents: (a) OsO4, (CH3)3NO, (CH3)3COH/H2O (74%). (b)
(C4H9)2SnO, CH3OH; TsCl, (C2H5)3N (87%). (c) BH3‚S(CH3)2,
THF. (d) (ClCO)2, (CH3)2SO, CH2Cl2; (C2H5)3N; NaBH4, C2H5OH
(50% from 6b). (e) TBDPSCl, imidazole, DMAP, DMF; TFA,
CH2Cl2 (74%). (f) (ClCO)2, (CH3)2SO, CH2Cl2; (C2H5)3N. (g)
LiHMDS, THF; CPT (68% from 8a); Pd(OCOCH3)2, (C6H5)3P,
(C2H5)3N, CO, CH3OH-DMF (65%). (h) 10% Pd/C, H2, CH3OH
(93%). (i) TBAF, THF (82%); O-TBDMS hydroferulic acid, DIC,
DMAP, CH2Cl2 (70%); TBAF, THF (77%).
The concluding steps of the synthesis proved to be
uneventful. Desilylation at C-6 in 9b was readily ac-
complished in 82% yield with tetrabutylammonium fluoride
in THF to give the free alcohol, which was esterified with
t-butyldimethylsilyl-protected hydroferulic acid (70%).16
Desilylation of the phenolic protecting group then produced
in 77% yield enantiopure (+)-amphorogynine A, which
provided high-field 1H and 13C NMR and IR spectra
superimposable with those of an authentic sample of the
natural product.17,18
through oxidation-reduction (50% combined yield). The
identity of 7 (HCl salt), purified by crystallization from
dichloromethane-pentane, was fully confirmed by X-ray
diffraction analysis.14
In summary, a highly stereocontrolled approach to a new
class of pyrrolizidines, based on diastereofacially selective
[2 + 2] cycloaddition of dichloroketene with a chiral enol
ether, has been demonstrated by the synthesis of (+)-
(9) Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969-973.
(10) Hassner, A.; Krepski, L. R. J. Org. Chem. 1978, 43, 3173-3179.
Brady, W. T.; Lloyd, R. M. J. Org. Chem. 1979, 44, 2560-2564.
For reviews on dichloroketene, see: Hyatt, J. A.; Raynolds, P. W. Org.
React. 1994, 45, 159-646. Tidwell, T. T. Ketenes; Wiley: New York,
1995.
(14) Analysis was accomplished on microcrystals at the European
Synchrotron Radiation Facility. This study will be published separately.
(15) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
(11) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1-17.
(12) Johnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J. Org. Chem.
1985, 50, 114-117.
(13) For a similar transformation, see: Ley, S. V.; Brown, D. S.; Clase,
J. A.; Fairbanks, A. J.; Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.;
Wadsworth, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2259-2276. See
also: Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.;
Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V.
V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578-3585.
(16) See: Solladie´, G.; Gressot-Kempf, L. Tetrahedron: Asymmetry
1996, 7, 2371-2379. Hydroferulic acid is available from Lancaster
Synthesis, Bischheim, Strasbourg, France.
(17) Mp 103-104 °C (n-C7H16-CH3OH); [R]20 +42 (c 0.9, CHCl3).
D
Lit.2 mp 108 °C; lit.2 [R]20D +53 (c 1, CHCl3). Our authentic sample: mp
102-103 °C; [R]20 +44 (c 0.6, CHCl3).
D
(18) Note added in revision: A chiral-pool approach to amphorogynine
A has just appeared. See: Yoda, H.; Egawa, T.; Takabe, K. Tetrahedron
Lett. 2003, 44, 1643-1646.
Org. Lett., Vol. 5, No. 10, 2003
1743

amphorogynine A. The approach is currently being applied
in our laboratory to access other pyrrolizidine natural
products.
their technical support. Financial support from the CNRS
(UMR 5616) is gratefully acknowledged.
Supporting Information Available: Characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Professor P. Dumy for his
interest in our work, Drs. T. Se´venet and M. Pa¨ıs for a sample
of natural (+)-amphorogynine A, and Drs. M.-L. Dheu-
Andries, D. Flot, and C. Philouze and Ms. B. Escude´ for
OL034369F
1744
Org. Lett., Vol. 5, No. 10, 2003