Enantioselective approach to the hetisine alkaloids. Synthesis of the 3-methyl-1-aza-tricyclo[5.2.1.03,8]decane core via intramolecular dipolar cycloaddition

Article abstract of DOI:10.1021/ol051184v

(Chemical Equation Presented) An efficient, enantioselective approach to the hetisine class of the C₂₀-diterpenoid alkaloids is described. The strategy involves an intramolecular oxidopyridinium dipolar cycloaddition as the key transformation,

Full text of DOI:10.1021/ol051184v

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3323-3325
Enantioselective Approach to the
Hetisine Alkaloids. Synthesis of the
3-Methyl-1-aza-tricyclo[5.2.1.03,8]decane
Core via Intramolecular Dipolar
Cycloaddition
Kevin M. Peese and David Y. Gin*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
gin@scs.uiuc.edu
Received May 19, 2005 (Revised Manuscript Received May 26, 2005)
ABSTRACT
An efficient, enantioselective approach to the hetisine class of the C20-diterpenoid alkaloids is described. The strategy involves an intramolecular
oxidopyridinium dipolar cycloaddition as the key transformation, in which simultaneous formation of the C5
−C6 and C10−C20 bonds in the
3-methyl-1-aza-tricyclo[5.2.1.03,8]decane core of the hetisine alkaloids is effected.
The C20-diterpenoid alkaloids isolated from the Aconitum,
Delphinium, Consolida, and Spiraea species comprise a
diverse family of compounds among which the atisane class
of alkaloids (1, Figure 1) is a principal constituent.1 This
of alkaloids is among the most structurally complex subgroup
of this family and is exemplified by kobusine (2),2 incor-
porating additional C14-C20 and N-C6 linkages relative
to the atisane skeleton.3 Kobusine was among the earliest
reported hetisine alkaloids, and it, together with several of
its C15-O-acyl derivatives, has recently been shown to
exhibit potent vasodilating activity in vivo.4
Although the structure of the hetisine alkaloids have been
known for more than 40 years, synthetic investigations into
these natural products have been rather sparse due to the
formidable challenges in constructing the 3-methyl-1-aza-
tricyclo[5.2.1.03,8]decane substructure (3, Scheme 1) embed-
(2) Suginome, H.; Shimanouti, F. Justus Liebigs Ann. Chem. 1940, 545,
220-228.
(3) (a) Okamoto, T.; Natsume, M.; Zenda, H.; Kamata, S. Chem. Pharm.
Bull. 1962, 10, 883-886. (b) Pelletier, S. W.; Wright, L. H.; Newton, M.
G.; Wright, H. J. Chem. Soc., Chem. Commun. 1970, 98-99. (c) Sakai, S.;
Yamamoto, I.; Yamaguchi, K.; Takayama, H.; Ito, M.; Okamoto, T. Chem.
Pharm. Bull. 1982, 30, 4579-4584. (d) Ulubelen, A.; Desai, H. K.;
Srivastava, S. K.; Hart, B. P.; Park, J.; Joshi, B. S.; Pelletier, S. W.; Mericli
A. H.; Mericli, F.; Ilarslan, R. J. Nat. Prod. 1996, 59, 360-366.
(4) (a) Wada, K.; Ishizuki, S.; Mori, T.; Bando, H.; Murayama, M.;
Kawahara, N. Biol. Pharm. Bull. 1997, 20, 978-982. (b) Wada, K.; Ishizuki,
S.; Mori, T.; Fujihira, E.; Kawahara, N. Biol. Pharm. Bull. 1998, 21, 140-
146. (c) Wada, K.; Ishizuki, S.; Mori, T.; Fujihira, E.; Kawahara, N. Biol.
Pharm. Bull. 2000, 23, 607-615.
Figure 1. Atisane and hetisine alkaloids.
class of compounds is in turn composed of several structural
subclasses of alkaloids, exhibiting varied degrees of structural
complexity and pharmacological activity. The hetisine class
(1) Wang, F.-P.; Liang, X.-T. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 2002; Vol. 59, pp 1-280.
10.1021/ol051184v CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/29/2005

Scheme 1
Scheme 2
ded within the diterpene-derived carbon scaffold. To this end,
a few creative racemic approaches to the construction of
bridged aza-bicyclo substructures of the hetisine alkaloids
have been reported.5 Model structures of the aza-tricyclo core
have also been accessed via late-stage stepwise formation
of the C-N bonds on a suitably derivatized polycyclic carbon
skeleton,6 with the latter efforts culminating in a recent
synthesis of (()-nominine in a 40-step sequence.7 However,
the notable paucity of efficient asymmetric strategies to the
aza-tricyclo core 3, characteristic of all hetisine alkaloids,
led us to consider the preparation of this substructure via
simultaneous formation of the C5-C6 and C10-C20 bonds
with the intramolecular combination of an appropriate aza-
dipole and dipolarophile (3 f 4).
Initial investigations into the feasibility of the strategy
involved the use of an oxidopyridinium betaine as a relatively
stable endocyclic aza-dipole8 tethered to a 2-enenitrile
dipolarophile in a dipole-HOMO-controlled cycloaddition
(Scheme 2). Preparation of the cycloaddition precursor
commenced with 1,4-addition of cyanide to 3-methylcyclo-
hex-2-enone (5) with Et2AlCN. The putative aluminum
enolate was then activated in situ with cesium fluoride and
subsequently trapped with Tf2O to give the vinyl triflate 6
in 69% yield. Reduction of the nitrile in 6 to the correspond-
ing aldehyde with DIBAL-H (82%) followed by immediate
reductive amination with furfurylamine provided furanyl-
amine 7 (99%). Palladium-catalyzed cyanation9 of the enol
triflate in 7 proceeded in 75% yield and was followed by
Br2-mediated oxidative rearrangement of the furan moiety10
to afford oxidopyridinium ylide 9 in 65% yield. Heating the
oxidopyridinium in a variety of solvents to effect dipolar
cycloaddition on the C5-C10 dipolarophile (10) was,
however, unsuccessful as direct intramolecular conjugate
addition of the oxidopyridinium nucleophile to C5 (11)
followed by re-aromatization was the dominant reaction
manifold, affording the racemic tricyclic oxidopyridinium
betaine 12 (73%).
While the formation of 12 in and of itself constitutes a
novel approach to the preparation of highly substituted
indolizinium heterocycles,11 the suppression of direct 1,4-
addition is critical to the construction of the hetisine aza-
tricyclic core. This led to the consideration of a new
cycloaddition substrate in which a removable electron-
deficient auxiliary (Z) is introduced at C5 rather than at C10
of the dipolarophile to favor the cycloaddition manifold (13,
Scheme 3). The undesired direct conjugate addition pathway
(5) (a) van der Baan, J. L.; Bickelhaupt, F. Recl. TraV. Chim. Pays-Bas
1975, 94, 109-112. (b) Kwak, Y.; Winkler, J. D. J. Am. Chem. Soc. 2001,
123, 7429-7430. (c) Williams, C. M.; Mander, L. N. Org. Lett. 2003, 5,
3499-3502.
(6) (a) Shibanuma, Y.; Okamoto, T. Chem. Pharm. Bull. 1985, 33, 3187-
3194. (b) Muratake, H.; Natsume, M. Tetrahedron Lett. 2002, 43, 2913-
2917.
Scheme 3
(7) Muratake, H.; Natsume, M. Angew. Chem., Int. Ed. 2004, 43, 4646-
4649.
(8) (a) Katritzky, A. R.; Takeuchi, Y. J. Am. Chem. Soc. 1970, 92, 4134-
4136. (b) Dennis, N.; Katritzky, A. R.; Takeuchi, Y. Angew. Chem., Int.
Ed. Eng. 1976, 15, 1-9. (c) Joshi, R. A.; Ravindranathan, T. Ind. J. Chem.
B 1984, 23, 300-302. (d) Katritzky, A. R.; Dennis, N. Chem. ReV. 1989,
89, 827-861. (e) Jung, M. E.; Longmei, Z.; Tangsheng, P.; Huiyan, Z.;
Yan, L.; Jingyu, S. J. Org. Chem. 1992, 57, 3528-3530. (f) Pham, V. C.;
Charlton, J. L. J. Org. Chem. 1995, 60, 8051-8055. (g) SÄliwa, W.
Heterocycles 1996, 43, 2005-2029. (h) Rumbo, A.; Mourin˜o, A.; Castedo,
L.; Mascaren˜as, J. L. J. Org. Chem. 1996, 61, 6114-6120. (i) Smith, M.
P.; Johnson, K. M.; Zhang, M.; Flippen-Anderson, J. L.; Kozikowski, A.
P. J. Am. Chem. Soc. 1998, 120, 9072-9073.
with this substrate would involve nucleophilic addition into
the C10 position (i.e., 14 f 15). This process is likely to
experience enhanced nonbonding interactions with the neces-
sary positioning of both the C1 and C2 methylene groups
directly over the oxidopyridinium ring in the formation of
the unwanted bridged aza-bicyclo[3.3.1]nonane oxidopyri-
dinium 15.
(9) Yamamura, K.; Murahashi, S. Tetrahedron Lett. 1977, 18, 4429-
4430.
(10) (a) Mu¨ller, C.; Diehl, V.; Lichtenthaler, F. W. Tetrahedron 1998,
54, 10703-10712. (b) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.;
Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105-114.
(11) Shono, T.; Matsumura, Y.; Tsubata, K.; Inoue, K.; Nishida, R. Chem.
Lett. 1983, 21-24.
3324
Org. Lett., Vol. 7, No. 15, 2005

To evaluate this hypothesis, preparation of the new
cycloaddition precursor 22 proceeded in a sequence that is
also readily amenable to asymmetric induction (Scheme 4).
to install the π system of the dipolarophile. Reduction of
the ethyl ester within 18 to the alcohol with DIBAL-H (99%)
followed by oxidation with IBX afforded the aldehyde 19
in 95% yield. Oxidation of the vinyl sulfide with mCPBA
(94%) allowed for the introduction of the dipolarophile-
activating group at C5 in the form of an aryl sulfone.
Reductive amination of aldehyde 20 with furfurylamine
afforded the furanylamine 21 (91%), which underwent facile
oxidative rearrangement with bromine in aqueous acetic acid
to produce oxidopyridinium betaine 22 in 77% yield. Heating
of 22 in toluene (0.05 M) at reflux produced the cycloadduct
23 in 70% yield with no evidence of products arising from
simple conjugate addition (i.e., 15). Initial structure deter-
mination of the cycloadduct 23 came from a battery of NMR
data (1H, COSY, HMQC) including an observed nOe
between the C4 methyl group and the C6 angular proton,
data consistent with a regioselective dipole-HOMO-con-
trolled cycloaddition. Structure verification of the cycload-
duct ultimately came from single-crystal X-ray analysis.
Conjugate reduction of 23 and subsequent triflation of the
Scheme 4
13
transient enolate with PhNTf2 yielded the corresponding
vinyl triflate (70%), which was reduced to the alkene 24 with
formic acid and PdCl2(PPh3)2 (84%).14 Finally, desulfuriza-
tion of the C5 sulfone to form 25 proceeded in 82% yield,
demonstrating that this dipolarophile-activating auxiliary can
be removed without rearrangement or â-elimination in the
newly constructed aza-tricylcic skeleton.
In summary, the first asymmetric synthesis of the 3-meth-
yl-1-aza-tricyclo[5.2.1.03,8]decane core of the hetisine alka-
loids is reported. The strategy involves an intramolecular
oxidopyridinium dipolar cycloaddition as the key transforma-
tion in which simultaneous formation of the C5-C6 and
C10-C20 bonds is effected. The facile preparation of (+)-
25 clearly demonstrates feasibility of this approach and holds
promise for the efficient asymmetric synthesis of the hetisine
class of alkaloids.
Acknowledgment. This research was supported by the
NIH (GM67659). A Pharmacia (Pfizer) predoctoral fellow-
ship to K.M.P. is acknowledged.
Supporting Information Available: Experimental details
and analytical data for synthetic intermediates (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Asymmetric R-methylation of 2-oxo-cyclohexanecarboxylic
acid ethyl ester (16) via its corresponding (S)-t-butylvaline
enamine derivative12 provided the R,R-disubstituted cyclo-
hexanone 17 in 53% (98:2 er). Dehydrative condensation of
17 with thiophenol produced vinyl sulfide 18 in 93% yield
OL051184V
(12) (a) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J. Am. Chem.
Soc. 1984, 106, 2718-2719. (b) Ando, K.; Takemasa, Y.; Tomioka, K.;
Koga, K. Tetrahedron 1993, 49, 1579-1588.
(13) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335-337.
(14) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821-
4824.
Org. Lett., Vol. 7, No. 15, 2005
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