Enantiospecific formal total synthesis of (+)-fawcettimine

Article abstract of DOI:10.1021/ol1009762

The diastereospecific attack of the silyl enol ether on the activated cyclopropyl diester 27 generated the hydrindanone 28 with complete stereocontrol. Thermal decarbomethoxylation of 28 gave the monoester 29, a key intermediate in Heathcocks synthesis, thereby completing a formal total synthesis of (+)-fawcettimine 1. The analogous cyclization of 33, the diastereomer of 27, afforded the diastereomeric diester 34, thereby demonstrating that the cyclization process is diastereospecific.

Full text of DOI:10.1021/ol1009762

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2962-2965
Enantiospecific Formal Total Synthesis
of (+)-Fawcettimine
Michael E. Jung* and Jonah J. Chang
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095
jung@chem.ucla.edu
Received April 28, 2010
ABSTRACT
The diastereospecific attack of the silyl enol ether on the activated cyclopropyl diester 27 generated the hydrindanone 28 with complete
stereocontrol. Thermal decarbomethoxylation of 28 gave the monoester 29, a key intermediate in Heathcock’s synthesis, thereby completing
a formal total synthesis of (+)-fawcettimine 1. The analogous cyclization of 33, the diastereomer of 27, afforded the diastereomeric diester 34,
thereby demonstrating that the cyclization process is diastereospecific.
(+)-Fawcettimine 1 is a tetracyclic alkaloid belonging to the
Lycopodium class of alkaloids and was isolated in 1959 by
Burnell (Figure 1).1 It exists predominantly as the carbino-
lamine, and the first total synthesis by Heathcock and co-
workers proved the stereochemistry at C4.2 Because of its
challenging tetracyclic structure and postulated role as a
biosynthetic precursor to additional members of the Lyco-
podium family, it has generated considerable synthetic
interest.3 We now report the enantiospecific formal total
Figure 1
synthesis of (+)-fawcettimine 1 intercepting the Heathcock
ester intermediate 29.
Recently we reported4 the acid-promoted stepwise
and enone 9 to access the hydrindanone core 11 by a tandem
Mukaiyama-Michael homo-Michael process via the inter-
mediate 10 (Scheme 2). Donor-acceptor (DA) cyclopro-
panes,5 including cyclopropane-1,1-diesters, are known to
undergo a wide array of reactions that include [3 + 2] and
[4 + 3] cycloadditions leading to a variety of heterocycles,
radical ring-openings, nucleophilic ring-openings, and metal-
mediated coupling reactions;6 however, an annulation of this
Mukaiyama-Michael addition of hindered silyloxy dienes
5 to hindered enones 4 to give the formal cycloadduct 7 via
the initial Mukaiyama-Michael adduct 6 (Scheme 1). For
(+)-fawcettimine, a similar double addition process was
conceived, this time with the cyclopropyl silyl enol ether 8
(1) Burnell, R. H. J. Chem. Soc. 1959, 3091–3093.
(2) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem.
1989, 54, 1548–1562.
(5) For reviews on donor-acceptor cyclopropanes, see: (a) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179. (b) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. (c) Reissig, H.-U.;
Zimmer, R. Chem. ReV. 2003, 103, 1151–1196. (d) Wong, H. N. C.; Hon,
M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989,
89, 165–198. (e) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66–72. (f)
Carson, C. A.; Kerr, M. A. Chem. Soc. ReV. 2009, 38, 3051–3060.
(3) (a) Nishio, K.; Fujiwara, T.; Tomita, K.; Ishii, H.; Inubushi, Y.;
Harayama, T. Tetrahedron Lett. 1969, 10, 861–864. (b) Linghu, X.;
Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 7671–
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10.1021/ol1009762  2010 American Chemical Society
Published on Web 06/01/2010

Scheme 1
Scheme 3
type has not been previously reported to our knowledge. Only
two references have cited the attack of silyl enol ethers on
cyclopropane-1,1-diesters, but in both cases the reactions
were intermolecular.7 Therefore, we decided to test the
viability of this idea using a model system.
of the system, the ketone 15 was subjected to standard Wittig
methenylation conditions to give the 1,1-disubstituted olefin 17
in 73% yield. Treatment of 17 with a catalytic amount (20 mol
%) of Sc(OTf)3 gave the desired hydrindanone product 18 in
71% yield as a single regioisomer. To our knowledge, this is
the first example of an intramolecular attack of a silyl enol ether
on a cyclopropane-1,1-diester resulting in a new carbon-carbon
bond to give an annulated product.
Scheme 2
Encouraged by the results in the model system, we decided
to demonstrate the utility of this method in a formal total
synthesis of (+)-fawcettimine. Since only one regioisomer
was obtained, we could safely rule out any “SN2′-like” or
“SN1′-like” reaction mechanisms. Previous work9 done in
this area on intermolecular cyclopropane-1,1-diester ring
openings allowed us to postulate that the key ring-opening
reaction occurred via a stereospecific SN2-like mechanism
as shown in Figure 2. Thus, Lewis acid complexation of one
(or both) of the two esters of A would be followed by attack
of the silyl enol ether on the activated allylic cyclopropyl-
1,1-diester B without any loss of stereocontrol to give
stereospecifically C. To test this hypothesis, we decided to
synthesize one diastereomer of the substrate and see if there
were any loss of stereochemistry in the cyclized product.
After a simple molecular model analysis, it was determined
that the previously unreported (S)-methyl ketone 23 was
Thus, the known methyl ketone 128 was converted to the
kinetic (and thermodynamic) TBS silyl enol ether 13 by
treatment with TBSOTf and Hu¨nig’s base (Scheme 3).
Triflimide-mediated Mukaiyama-Michael addition4 of 13
to 2-methylcyclohexenone 14 gave the ketone 15 as a mixture
of diastereomers. Warming the reaction mixture did not
afford the cyclopropane ring-opened product but instead gave
the silyl enol ether hydrolysis product 16. Various fluoride
reagents and Lewis acids were screened, but none of the
conditions gave the annulated product and, in most cases,
gave only the product of hydrolysis. To increase the reactivity
(6) For selected examples see: (a) Jackson, S. K.; Karadeolian, A.;
Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196–4201. (b)
Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242–8244. (c) Young,
I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023–3026. (d) Pohlhaus,
P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014–16015. (e)
Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de Meijere,
A. J. Org. Chem. 2007, 72, 7504–7510. (f) Pohlhaus, P. D.; Sanders, S. D.;
Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642–
8650. (g) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B.
Org. Lett. 2008, 10, 689–692. (h) Ivanova, O. A.; Budynina, E. M.; Grishin,
Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed. 2008,
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2009, 74, 7684–7689.
Figure 2
(8) Le Menn, J.-C.; Tallec, A.; Sarrazin, J. Can. J. Chem. 1991, 69,
761–767.
Org. Lett., Vol. 12, No. 13, 2010
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annulation had proceeded with complete stereocontrol in this
system. To finish the formal total synthesis of 1, subjection
of 28 to modified Krapcho decarboxylation conditions12 gave,
in 73% yield, the ester 29, which was identical in all respects
to the ester previously reported by Heathcock,2 indicating
that our molecular modeling prediction was correct.
Scheme 4
Scheme 6
required to intercept Heathcock’s intermediate 29 for the
formal synthesis of fawcettimine 1. Thus, the known bicyclic
lactam 19 was treated sequentially with sodium hexameth-
yldisilazide, methyl chloroformate, and phenylselenenyl
bromide, followed by an oxidative workup to give the R,ꢀ-
unsaturated amide 20 in 77% yield (Scheme 4). Subjecting
this very activated alkene 20 to standard Corey-Chaykovsky
conditions gave the cyclopropane 21 as a single diastereomer.
Hydrolysis of 21 in acidic methanol gave the methyl ketone
22 which was identical in all respects to the known (R)
enantiomer, except for optical rotation.10 Finally, treatment
of 22 with TBSOTf and Hu¨nig’s base gave the desired kinetic
TBS silyl enol ether 23.
Scheme 5
Even though the Lewis acid-promoted intramolecular ring-
opening cyclization of 27 to give 28 had proceeded with
complete stereocontrol, we could not guarantee that this result
was not due to a “matched” diastereoselective process or to
kinetic control rather than a truly diastereospecific process.
Therefore, to prove that the observed stereospecificity of the
cyclization was not attributed to the intrinsic diastereose-
lectivity of the substrate, we decided to prepare the epimeric
cyclopropane 31 to synthesize the C4 epimer (fawcettimine
numbering) 34. Thus, the known (R) methyl ketone 3013 was
synthesized according to the procedure of Meyers and then
treated with TBSOTf and Hu¨nig’s base to give the corre-
sponding kinetic (R) silyl enol ether 31 (Scheme 7).
Triflimide-mediated Mukaiyama-Michael addition of the
silyl enol ether 31 to the enone 25 afforded the ketone 32.
Wittig methenylation gave in 70% yield (brsm) the olefin
33, which on treatment with Sc(OTf)3 afforded 34 as a single
diastereomer. Comparison of the spectroscopic data clearly
indicated that 34 was not identical to the previously prepared
malonate 28 and thus the ring opening was completely
diastereospecific. Although we have not carried this com-
pound forward, it is possible that compound 34 could still
be a viable intermediate toward the synthesis of (+)-
fawcettimine 1 based on the previous Heathcock synthesis.2
In summary, we have shown that the process of a stepwise
Mukaiyama-Michael addition of the silyl enol ether of an
The enone 25 required for the (+)-fawcettimine synthesis
was obtained by Michael addition of the known sulfoxide
24 to acrylonitrile followed by thermal sulfoxide elimination
in 51% yield11 (Scheme 5). The enone 25 and the silyl enol
ether 23 were then treated with triflimide to give the
corresponding ketone 26 as a single diastereomer (Scheme
6). Wittig methenylation of 26, though sluggish, afforded
the desired olefin 27 in 75% yield (based on recovered
starting material). To our delight, treatment of 27 with
Sc(OTf)3 afforded cleanly the cyclopropane ring-opened
product 28 in 77% yield as a single diastereomer. Thus this
(9) (a) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson,
J. S. J. Am. Chem. Soc. 2008, 130, 8642–8650. (b) Sapeta, K.; Kerr, M. A.
J. Org. Chem. 2007, 72, 8597–8599.
(10) Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57, 3814–3819.
(11) (a) Caine, D.; Proctor, K.; Cassell, R. A. J. Org. Chem. 1984, 49,
2647–2648. (b) Mutti, S.; Daubi, C.; Decalogne, K. F.; Fournier, R.; Rossi,
P. Tetrahedron Lett. 1996, 37, 3125–3128. (c) Kozak, J. A.; Dake, G. R.
Angew. Chem., Int. Ed. 2008, 47, 4221–4223.
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Org. Lett., Vol. 12, No. 13, 2010

hydrindanones in good yield and with complete diastereo-
control. Furthermore, we have shown that this process
proceeds via an “SN2-like” mechanism (Figure 2) and is
therefore completely diastereospecific with full retention of
the stereochemistry of the cyclopropyl center. Lastly, we have
completed a formal total synthesis of (+)-fawcettimine 1.
Scheme 7
Acknowledgment. This work was supported by the
National Science Foundation (CHE 0614591).
Supporting Information Available: Experimental pro-
cedures and proton and carbon NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL1009762
(12) (a) Krapcho, P. A. Synthesis 1982, 893–914. (b) Curran, D. P.;
Zhang, Q. AdV. Synth. Catal. 2003, 345, 329–332.
(13) Meyers, A. I.; Romine, J. L.; Fleming, S. A. J. Am. Chem. Soc.
1988, 110, 7245–7247.
acetylcyclopropane-1,1-dicarboxylate, Wittig olefination, and
final Lewis-acid-promoted cyclopropane opening affords
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