Communications
J . Org. Chem., Vol. 62, No. 3, 1997 441
Sch em e 2
in excellent yield. Isomerization of 10 to allylic alcohol
11 was best accomplished by the method of Sharpless.13
Oxidation of 11 with tetra-n-propylammonium perruth-
enate-N-methylmorpholine N-oxide (TPAP-NMO)14
yielded enone 12, which was iodinated to deliver R-iodo
enone 13.15 Introduction of the remaining aminopropyl
fragment was then achieved in 88% yield by Suzuki
coupling16 of 13 with borane 14, which was generated in
situ by hydroboration of N-BOC-allylamine with 1 equiv
of 9-BBN-H.17,18
To close the final ring, 15 was treated with TFA to
remove the BOC protecting group, and the resulting
amine salt was exposed to aqueous NaOH. After 5 min,
a single cis-fused tetracycle 16 was produced. However,
if base treatment was allowed to proceed for several days,
or if tetracycle 16 was re-exposed to aqueous base, a 4:1
mixture of tetracyclic imine 18 and trans-fused tetracycle
19 was formed (eq 2).19 Treatment of crude 16 with
NMO.14 The resulting enone 20 was iodinated and cross-
coupled with borane 14 to afford enone 22. When 22 was
deprotected with TFA and the crude product exposed to
NaOH in MeOH for 24 h at rt, imine 23 was produced
as virtually the sole product. Without purification, this
intermediate was reduced stereoselectively with NaBH4
from the convex â-face to provide 24 in essentially
quantitative yield from 21. Finally, reduction of 24 with
LiAlH4 provided syn-syn aloperine isomer 4, whose 1H
NMR spectrum was also not consistent with that of
aloperine.7
Shortly after initiating the synthesis of 4, we obtained
a sample of natural aloperine 2, which was converted to
the crystalline dihydrochloride monohydrate salt, mp 280
°C dec. Single-crystal X-ray analysis of this material
demonstrated that natural aloperine was the anti-syn
isomer and established that the absolute configuration
was 6R,7R,9R,11S as depicted in 2.24-26
In summary, this study demonstrates that iodide can
be employed to control the outcome of N-acyliminium
ion-alkene cyclizations. Using this approach, racemic
aloperine stereoisomers 3 and 4 were prepared in ste-
reocontrolled fashion in 12-13 steps and 13-27% overall
yield from ene amide 8. An enantioselective synthesis
of aloperine and preliminary pharmacological character-
ization of 3 and 4 will be described in due course.
LiAlH4 furnished a diamino alcohol (J 16,17 ) 10.8 Hz),
which was selectively protected on nitrogen by reaction
with 2,2,2-trichloroethyl chloroformate (Troc-Cl)20 to
provide 17 in 70% overall yield from 15. Finally, syn
dehydration of the equatorial alcohol with POCl3 and
pyridine at 100 °C, followed by cleavage of the Troc
functionality with 10% Cd-Pb,21 afforded 3. The 1H
NMR spectrum of this syn-anti isomer was not consistent
with the published spectrum of aloperine.7,22
Tricyclic enone 12 also proved to be a useful intermedi-
ate for preparing the syn-syn aloperine isomer 4 (Scheme
2).22 Our approach to constructing the piperidine ring
drew upon the observation that imine 18 was the
thermodynamic product of base-promoted cyclization of
the primary amine derivative of 15 (eq 2). To exploit this
thermodynamic preference in the synthesis of 4, isomeric
enone 20 was required. This intermediate was accessed
by nucleophilic epoxidation of enone 12, followed by
Wharton rearrangement of the derived â-epoxide23 and
oxidation of the resulting crude allyl alcohol with TPAP-
Ack n ow led gm en t. This research was supported by
grants from the NIH (HL-25854) and through graduate
fellowships to A.D.B. from Pfizer Research and the
Department of Education. We particularly thank Pro-
fessors Chongchu Zhou and Zhang Qi-Ming for provid-
ing samples of natural aloperine, Dr. J . Ziller for the
single-crystal X-ray analysis of 2‚2HCl‚H2O, and Dr.
Matthew Abelman for initially drawing our attention
to aloperine.
(13) Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1973, 95, 2697.
(14) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(15) J ohnson, C. R.; Adams, J . P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33,
917.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(17) Kabala, G. W.; Li, N.-S.; Pace, R. D. Synth. Commun. 1995,
25, 2135.
(18) To our knowledge, this transformation is the first example of
coupling an R-iodo enone with a nitrogen-containing borane partner.
For related precedents, see: (a) J ohnson, C. R.; Braun, M. P. J . Am.
Chem. Soc. 1993, 115, 11014. (b) Narukawa, Y.; Nishi, K.; Onoue, H.
Tetrahedron Lett. 1996, 37, 2589.
(19) The stereochemistry of tetracycles 16 and 19 was determined
by 1H-1H COSY experiments. Copies of these spectra are provided in
the Supporting Information. The constitution of imine 18 was estab-
lished by 1H and 13C NMR analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for new compounds reported
in Schemes 1 and 2, copies of 1H-1H COSY spectra for 16 and
19, and copies of 1H (500 MHz) and 13C (125 MHz) spectra for
2 (31 pages).
(20) Windholz, T. B.; J ohnston, D. B. R. Tetrahedron Lett. 1967,
2555.
(21) Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 5681.
J O9621231
(22) The terms syn-anti and syn-syn refer to the orientation of the
angular methine hydrogens H6 and H11, respectively, with respect to
the methano bridge.
(23) (a) Di Grandi, M. J .; Coburn, C. A.; Isaacs, R. C. A.; Danishef-
sky, S. J . J . Org. Chem. 1993, 58, 7728. (b) Maas, D. D.; Blagg, M.;
Wiemer, D. F. J . Org. Chem. 1984, 49, 853. (c) Wharton, P. S.; Bohlen,
D. H. J . Org. Chem. 1961, 26, 3615.
(24) Absolute configuration was assigned by refinement of the Flack
parameter.25
(25) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(26) The authors have deposited atomic coordinates for 2 with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.