Formal synthesis of (±)-peduncularine: Use of the [3 + 2] annulation of allylic silanes and chlorosulfonyl isocyanate

Article abstract of DOI:10.1021/ol9913744

(equation presented) The formal synthesis of the alkaloid (±)-peduncularine (1) was accomplished through the use of a [3 + 2] allylic silane annulation. The annulation of cyclohexadienyl silane 6 with chlorosulfonyl isocyanate followed by an in situ reduction provided bicyclic lactam 7. Conversion of this intermediate to 2 in three steps completed the formal synthesis of (±)-peduncularine.

Full text of DOI:10.1021/ol9913744

ORGANIC
LETTERS
2000
Vol. 2, No. 5
621-623
Formal Synthesis of (±)-Peduncularine:
Use of the [3 + 2] Annulation of Allylic
Silanes and Chlorosulfonyl Isocyanate
Claudia W. Roberson and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received December 20, 1999
ABSTRACT
The formal synthesis of the alkaloid (±)-peduncularine (1) was accomplished through the use of a [3 + 2] allylic silane annulation. The
annulation of cyclohexadienyl silane 6 with chlorosulfonyl isocyanate followed by an in situ reduction provided bicyclic lactam 7. Conversion
of this intermediate to 2 in three steps completed the formal synthesis of (±)-peduncularine.
The alkaloid peduncularine (1) (Scheme 1), which was first
isolated in 1971,1,2 is the principal alkaloid of the Tasmanian
shrub Aristotelia peduncularis.3 It represents an interesting
synthetic target due to its unusual 6-azabicyclo[3.2.1]octane
core.4 The natural product was synthesized once in an
asymmetric total synthesis by Hiemstra and Speckamp,5 and
a racemic formal synthesis was also recently reported by
Rigby.6 Both approaches rely on the stereocontrolled syn-
thesis of bicyclic lactam 2. We recognized that our previously
developed [3 + 2] annulation of allylic silanes and chloro-
sulfonyl isocyanate7 (CSI) could lead to a concise and
stereocontrolled synthesis of bicyclic lactams such as 2. We
proposed that the 6-azabicyclo[3.2.1]octane core could be
accessed through the annulation of a cyclohexadienyl silane
such as 4. The annulation product 3 would possess the
requisite handles for further elaboration to the formal
synthesis target 2. In this paper, we report the successful
application of the strategy shown in Scheme 1. Our synthesis
provides the alkaloid core in three synthetic steps and
compound 2 in six steps from commercially available
materials. This synthesis also represents the first use of the
[3 + 2] annulation of allylic silanes in a natural product
synthesis.
Scheme 1
(1) Bick, I. R. C.; Bremner, J. B.; Preston, N. W. J. Chem. Soc., Chem.
Commun. 1971, 1155-1156.
(2) Ros, H.-P.; Kyburz, R.; Preston, N. W.; Gallagher, R. T.; Bick, I. R.
C.; Hesse, M. HelV. Chim. Acta 1979, 62, 481-487.
(3) Bick, I. R. C.; Hai, M. A. In The Alkaloids; Brossi, A., Ed.;
Academic: New York, 1985; Vol. 24; pp 113-151.
(4) For lead references on other 6-azabicyclo[3.2.1]octane systems, see:
(a) Holmes, A. B.; Kee, A.; Ladduwahettey, T.; Smith, D. F. J. Chem. Soc.,
Chem. Commun. 1990, 1412-1414. (b) Triggle, D. J.; Kwon, Y. W.;
Abraham, P.; Pitner, J. B.; Mascarella, S. W.; Carroll, F. I. J. Med. Chem.
1991, 34, 3164-3171.
(5) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc.
1989, 111, 2588-2595.
(6) Rigby, J. H.; Meyer, J. H. Synlett 1999, S1, 860-862.
(7) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-
1435.
10.1021/ol9913744 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/10/2000

The 6-azabicyclo[3.2.1]octane core can be accessed ste-
reoselectively in three steps with the use of our [3 + 2]
annulation.7 Alkylation of 1,4-cyclohexadiene with dimeth-
ylbenzhydrylsilyl chloride 5, prepared in one step from
diphenylmethane and dichlorodimethylsilane,8 provided the
requisite bisallylic silane 6 (Scheme 2) as the sole product.
C-1 of the allylic cation (route a) yields the desired
N-chlorosulfonyl bicyclic lactam 11, which is subsequently
reduced to 7 by Na2SO3. Ring closure at C-3 (route b) yields
the bicyclic lactam 12, which is reduced to compound 8.
The ratio of 11 to 12, approximately 5:1, could not be altered
by solvent or temperature changes. For comparison, the ratio
of the dimethylphenylsilyl analogues of 11 and 12 was 10:
1. The dimethylphenylsilyl group, however, proved to be
unsuitable in subsequent steps (vide infra). We believe that
the lower selectivity observed for the dimethylbenzhydrylsilyl
compounds is due to the developing steric interactions
between the silyl group and the three-carbon bridge. Further
investigations will be needed to determine conclusively the
cause of the observed selectivities.
Scheme 2
The completion of the formal synthesis required installa-
tion of the isopropyl group and oxidation of the carbon-
silicon bond. A reductive N-alkylation15 with 2,2-dimethoxy-
propane was performed on the mixture of lactams 7 and 8,
from which 13 could be isolated in 62% yield (Scheme 4).
Scheme 4
The dimethylbenzhydrylsilyl group is currently being de-
veloped in our laboratories for general use in the [3 + 2]
annulation of allylic silanes.8 The thermally unstable cyclo-
hexadienyl silane 6, once prepared, was then submitted to
the annulation conditions. Initial attempts using the procedure
previously developed for acyclic allylic silanes7 (CSI, PhCH3;
Red-Al) gave unsatisfying results due to a competing
Hosomi-Sakurai pathway9,10 and to the sensitivity of the
bicyclic lactam to Red-Al. The optimized conditions for 6
required that the annulation took place at -40 °C in CH2Cl2
for 24 h. Additionally, the milder reduction conditions of
11
25% Na2SO3 were used to yield lactams 7 and 8 in a 82:
18 ratio, each as single diastereomers. These modified
conditions suppress the Hosomi-Sakurai reaction and pro-
vided the annulation products in 76% overall yield.
The appearance of both annulation products 7 and 8 can
be understood by consideration of the annulation mechanism.
Electrophilic attack of 6 by chlorosulfonyl isocyanate,
antiperiplanar to the silyl group,12 yields zwitterionic inter-
mediate 9 (Scheme 3).13 A 1,2-silyl migration14 occurs to
provide the more stable allylic cation 10. Ring closure at
Displacement of the benzhydryl group of 13 with TBAF (1
M in THF)16 followed by Tamao oxidation17-19 provided
alcohol 14. Optimized Tamao oxidation conditions required
heating to 65 °C in DMF for 17 h. Attempts to oxidize the
dimethylphenylsilyl analogue of 13 failed due to both the
acid19 and base20 sensitivity of the allylic amide. Use of the
dimethylbenzhydrylsilyl group allowed us to obtain 14 in
good yield under milder reaction conditions. Swern oxidation
(8) Peng, Z.-H.; Woerpel, K. A. University of California, Irvine,
unpublished results.
(9) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295-1298.
(10) Fleming, I.; Dunogue´s, J.; Smithers, R. Org. React. 1989, 37, 57-
574.
Scheme 3
(11) Durst, T.; O’Sullivan, M. J. J. Org. Chem. 1970, 35, 2043-2044.
(12) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 650-663.
(13) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183-190.
(14) Jarvie, A. W. P.; Holt, A.; Thompson, J. J. Chem. Soc. B 1969,
852-855.
(15) Dube´, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295-2298.
(16) Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998,
63, 5517-5522.
(17) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694-1696.
(18) Jones, G.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(19) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1-64.
(20) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-
6046.
622
Org. Lett., Vol. 2, No. 5, 2000

of 14 furnished 2, completing the formal synthesis of (()-
peduncularine. The spectroscopic data of 2 were identical
to those reported in the literature.5
Acknowledgment. This research was supported by a
CAREER Award from the National Science Foundation
(CHE-9701622). K.A.W. thanks the American Cancer So-
ciety, AstraZeneca, Glaxo-Wellcome, the Camille and Henry
Dreyfus Foundation, Merck, and the Research Corporation
for awards to support research. We thank Dr. John Greaves
and Dr. John Mudd for mass spectrometric data.
A concise formal synthesis of peduncularine (1) has been
developed using the [3 + 2] allylic silane annulation
previously reported from our laboratories.7 The synthesis of
2 has been accomplished in six steps from commercially
available materials. All synthetic steps of this sequence
proceeded in good yield, and the stereogenic centers formed
from the annulation were established with high stereoselec-
tivity. The use of a readily oxidized silyl group allowed for
the installation of the required ketone of 2. The formal
synthesis of this natural product demonstrates the synthetic
utility of the [3 + 2] annulation of allylic silanes with
chlorosulfonyl isocyanate.
Supporting Information Available: Full experimental
and analytical data for all new compounds and compound
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL9913744
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