A concise synthesis of turneforcidine via a metalloiminium ion cyclization terminated by the 2-(methylthio)-3-(trimethylsilyl)-1-propenyl moiety.

Article abstract of DOI:10.1021/ol010122b

A concise synthetic route to racemic turneforcidine (1) is described that relies on the stereocontrolled cyclization of the 2-(methylthio)-3-(trimethylsilyl)-1-propenyl bearing imine 5 in the presence of TiCl(4). Reaction: see text.

Full text of DOI:10.1021/ol010122b

ORGANIC
LETTERS
2001
Vol. 3, No. 19
2961-2963
A Concise Synthesis of Turneforcidine
via a Metalloiminium Ion Cyclization
Terminated by the
2-(Methylthio)-3-(trimethylsilyl)-1-propenyl
Moiety
Duk Keun An, David Duncan, Tom Livinghouse,* and Paul Reid
Department of Chemistry and Biochemistry, Montana State UniVersity, Bozeman,
Montana 59717
liVinghouse@chemistry.montana.edu
Received June 4, 2001
ABSTRACT
A concise synthetic route to racemic turneforcidine (1) is described that relies on the stereocontrolled cyclization of the 2-(methylthio)-3-
(trimethylsilyl)-1-propenyl bearing imine 5 in the presence of TiCl4.
The pyrrolizidine alkaloids constitute a large and structurally
diverse class of azabicyclo[3.3.0]-based natural products that
possess a noteworthy range of biological activities.1 Although
the structural and stereochemical complexity of these alka-
loids is comparatively modest by contemporary standards,
these compounds remain popular targets for total synthesis
and the demonstration of new synthetic methodology.2 We
recently reported that imines tethered to the 2-(methylthio)-
3-(trimethylsilyl)-1-propenyl terminator could be induced to
undergo highly stereoselective cyclizations,3a in close analogy
with our previous results involving 2-propylidine-1,3-bis-
(silane) terminated heteroannulations.3b,4 In this Letter, we
show the efficacy of this protocol in a stereocontrolled total
synthesis of the pyrrolizidine alkaloid turneforcidine (1).
Turneforcidine was envisaged to arise from the bicyclic
pyrrolizidone 7 by global reduction. Pyrrolizidone 7, in turn,
was anticipated to be available by oxidation of 6, which
should derive from the TiCl4-mediated bicyclization of imine
(3) (a) Duncan, D.; Livinghouse, T. J. Org. Chem. 2001, 66, 5237. (b)
The intermolecular addition of 2-(methylthio)-3-(trimethylsilyl)-1-propene
to simple imines has previously been described: Narasaka, K.; Shibata,
T.; Hayashi, Y. Bull. Soc. Chem. Jpn. 1992, 65, 1392.
(4) (a) Kercher, T.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118, 4200.
(b) For cyclizations involving the intramolecular coupling of C-acylnitrilium
ions with 2- propylidene-1,3-bis(silane)s, see: Kercher, T.; Livinghouse,
T. J. Org. Chem. 1997, 62, 805.
(5) (a) It should be noted that the stereochemical outcome of cyclizations
involving aldimines is, in the cases studied thus far, generally opposite that
observed for ketimines, with aldimines leading to trans-2, 3-disubstituted
pyrrolidines.3a,4 (b) As part of a related study, we have found that
2-propylidene-1,3-bis(silane) containing imines bearing a comparatively
more coordinating R-benzyloxy moiety are prone to undergo competitive
protodesilylation in the presence of TiCl4.
(1) (a) Culvenor, C. C. J.; Bull, L.; Dick, A. T. The Pyrrolizidine
Alkaloids; North-Holland Publishing Co.: Amsterdam, 1968. (b) Mattocks,
A. R. Chemistry and Toxicology of the Pyrrolizidine Alkaloids; Academic
Press: San Diego, 1986.
(2) (a) For a particularly intriguing and general synthetic strategy to the
pyrrolizidine alkaloids, see: Denmark, S. E.; Thorarensen, A. J. Am. Chem.
Soc. 1997, 119, 125; J. Org. Chem. 1994, 59, 5672 and references therein.
(b) Simple allylsilanes have been used as terminators in cyclizations
involving acyliminium ions to provide the pyrrolizidine nucleus: Hiemstra,
H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1985,
50, 4014. (c) For the use of allylstannanes as terminators in a related context,
see: Keck, G. E.; Cressman, E. N. K.; Enholm, E. J. J. Org. Chem. 1989,
54, 4345.
10.1021/ol010122b CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

Scheme 1
5, in close analogy with the bicyclization of imine 8 to
by sequential silylation [(t-Bu(Ph)2SiCl, imidazole, DMF]
and ozonolysis [(a) O3, (b) Me2S] of the readily available
3-hydroxyester 2.6 Condensation of 3 with amine 43 (4 Å
molecular sieves, CH2Cl2) furnished the precyclization imine
5 in quantitive yield, which was immediately subjected to
TiCl4-mediated cyclization without further purification. In
contrast to expectations based on our previous studies,3,4
pyrrolizidone 9 reported previously by us.3,5 Simplification
of imine 5 reveals the immediate precursors 3 and 4 (Scheme
1).
Synthesis of Turneforcidine. We commenced the present
synthesis of turneforcidine (1) with the preparation of the
4-oxoester 3, which was easily prepared in 84% overall yield
Scheme 2
2962
Org. Lett., Vol. 3, No. 19, 2001

Scheme 3
H2O, 23 °C, 12 h] then provided the desired acid 12 in 88%
exposure of 5 to 1.0 equiv of TiCl4 (CH2Cl2, -78 f -20
°C) gave rise to a highly stereoselective monocyclization to
afford pyrrolidine 11 in 60% yield. Presumably, pyrrolidine
11 is less predisposed to undergo spontaneous lactamization
since it does not benefit from Thorp-Ingold conformational
acceleration, which is operative in the bicyclization of the
pyrrolidine corresponding to pyrrolizidone 9. The stereo-
chemical outcome observed for the conversion of 5 to 11
can be rationalized by preferred si-attack of the nucleophilic
terminator on the conformationally biased metalloiminium
acceptor 10 (Scheme 2).5a Subsequent lactamization of 11
was readily accomplished by simple treatment with Me3Al
to provide the desired pyrrolizidone 6 in 99% purified yield.
The direct oxidative degradation of the vinyl sulfide moiety
present in 7 to the corresponding carboxylic acid, under a
wide variety of reaction conditions, proved ineffective, with
the observed formation of multiple products. Accordingly,
7 was first converted to the corresponding sulfone (OXONE,
MeOH-H2O, 23 °C, 5 h)7 in 92% isolated yield. Subsequent
oxidative degradation [RuCl3 (cat.), NaIO4, CCl4-CH3CN-
purified yield. Global reduction of 12, with concomitant
hydride-mediated O-desilylation, (LiAlH4, THF, reflux, 12
h) ultimately delivered racemic turneforcidine (1) in 65%
yield after chromatographic purification (Scheme 3).8
In conclusion, this study has demonstrated that a metal-
loiminium ion cyclization terminated by a 2-(methylthio)-
3-(trimethylsilyl)-1-propenyl moiety serves as an effective
means for the synthesis of a pyrrolidine that contains the
essential stereochemical triad present in turneforcidine (1).
In addition, an efficient method for the oxidative degradation
of vinyl sulfide substituents that result from this method of
cyclization has been developed. The utilization of this
annulation strategy for the stereodefined synthesis of other
bioactive substances and alternative methods for the synthetic
modification of the postcyclization vinyl sulfide are under
current investigation.
Acknowledgment. Generous financial support for this
research by a grant from the National Institutes of Health is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and listings of spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(6) Ethyl 3-oxo-4-pentanoate (Nazarov’s reagent). Zibuck, R.; Streiber,
J. Org. Synth. 1993, 71, 236.
(7) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(8) The spectroscopic characteristics of the synthetic turneforcidine
prepared in this manner were identical to those reported in the literature.9
(9) Knight, D. W.; Share, A. C.; Gallagher, P. T. J. Chem. Soc., Perkin
Trans. 1 1997, 2089.
OL010122B
Org. Lett., Vol. 3, No. 19, 2001
2963