Asymmetric total synthesis of dendrobatid alkaloid 251F.

Full text of DOI:10.1021/ja027113y

Published on Web 08/03/2002
Asymmetric Total Synthesis of Dendrobatid Alkaloid 251F
Aaron Wrobleski, Kiran Sahasrabudhe,† and Jeffrey Aube´*
Department of Medicinal Chemistry, UniVersity of Kansas, Lawrence, Kansas 66045-2506
Received May 30, 2002
Scheme 1
In 1992, Daly, Spande, and co-workers reported the isolation of
a structurally unique tricyclic alkaloid, 251F, 1, from the skin
exudate of a Columbian dendrobatid poison frog, Minyobates
bombetes.1 As a class,2 the dendrobatid alkaloids possess numerous
kinds of biological activities; well-known examples include batra-
chotoxin3 (agonist of voltage-dependent sodium channels) and
epibatidine4 (potent analgesic). However, the pharmacological
profile of 251F remains unknown, not least because only 300 µg
of the natural product was isolated from its amphibious source.1
Matters of potential bioactivity aside, 251F constitutes an attractive
synthetic target due to several challenging structural features, which
include three fused rings and seven stereogenic centers (six of which
are contiguous). To date, one synthesis of alkaloid 251F, by Taber
and You, has been reported.5 Herein, we describe a new total
synthesis of 251F that features an intramolecular Schmidt reaction6
(a process that has only recently been applied to problems in
alkaloid synthesis7) as well as an unusually expedient route to a
key chiral [3.3.0]bicyclooctane intermediate (Scheme 1). This
strategy was particularly attractive because four of the seven
stereocenters of 251F would directly arise in an asymmetric Diels-
Alder reaction affording 4. It was further expected that two
additional centers would be susceptible to substrate control in
reactions of the bicyclic enone.
Scheme 2
Diels-Alder adduct 4 was prepared according to literature
methods (we obtained material of 93% ee on a 1-2 g scale).8 Our
early work on the conversion of 4 to enones related to 3 utilized
ozonolysis/aldol strategies.9 However, a second-generation route
featuring a tandem ring-opening/ring-closing metathesis (ROM/
RCM) reaction ultimately proved most efficient in providing
sufficient quantities of this key bicyclic intermediate.10 Thus,
conversion of acid 4 to the corresponding vinyl ketone (5) was
carried out via the Weinreb amide11 in 85% overall yield (Scheme
2). Treatment of 5 with Grubbs’s catalyst 6 in methylene chloride
saturated with ethylene afforded the bicyclic enone 3 in 93% yield.
The ethylene atmosphere permits the recycling of alternative
products (e.g., polymers or regioisomeric ring-opened products) into
the pathway leading to 3.
A 1,2-derivatization of the enone was necessary to prepare
intramolecular Schmidt precursor 2 (Scheme 3). Thus, treatment
of 3 with Me2CuLi followed by quenching with aldehyde 712
resulted in formation of enone 8. Cuprate addition occurred from
the exposed face of 3 and installed the methyl substituent with the
desired exo stereochemistry. Dehydration of the initial aldol adduct
occurred in situ and afforded the new enone as a single geometric
isomer. Extensive 2D NMR analysis (COSY, HMQC, HMBC,
NOESY) was used to assign E configuration to enone 8; this
presumably occurs to minimize steric interactions between the
exocyclic olefin substituent and the nearby methyl group on the
cyclopentyl ring. Treatment of compound 8 with Na/NH3 effected
both cleavage of the benzyl ether and reduction of the enone.
This resulted in an approximately 4:1 mixture of inseparable
diastereomers in 60% yield, in which the major isomer resulted
from placement of the four-carbon side chain in the desired endo
position. The side-chain stereochemistry could be explained on
either thermodynamic (trans to the adjacent methyl group) or kinetic
(exo protonation) grounds. The alcohol functionality could be
converted into its azide derivative 9, again isolated as a mixture of
diastereomers in 50% yield from 8, using an azide-modified
Mitsunobu reaction.13
Standard conditions for carrying out the intramolecular Schmidt
reaction, developed in these laboratories,6 were then inflicted on
9. However, treatment of 9 with either triflic acid (TfOH) or TiCl4
yielded no lactam products, with only degradation products
observed. To surmount this problem, 9 was converted to 2 via
ozonolysis/DMS workup and careful reduction with NaBH4. The
two diastereomeric alcohols were separable at this stage using
column chromatography. Satisfyingly, treatment of 2 with TfOH
resulted in an intramolecular Schmidt reaction forming lactam 10
as a single diastereomer in 79% yield. X-ray analysis of lactam 10
established the relative stereochemistry of the molecule. The total
synthesis of alkaloid 251F, 1, was then completed by LAH reduction
* To whom correspondence should be addressed. E-mail: jaube@ku.edu.
† Current address: Celgene Corp.
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J. AM. CHEM. SOC. 2002, 124, 9974-9975
10.1021/ja027113y CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Supporting Information Available: Experimental procedures and
characterization data for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Spande, T. F.; Garraffo, H. M.; Yeh, H. J. C.; Pu, Q.-L.; Pannell, L. K.;
Daly, J. W. J. Nat. Prod. 1992, 55, 707-722.
(2) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1993; Vol. 43, pp 185-288.
(3) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, p 1.
(4) Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563.
(5) Taber, D. F.; You, K. K. J. Am. Chem. Soc. 1995, 117, 5757-5762.
(6) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995, 117,
10449-10459.
(7) (a) Aube´, J.; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141-
1147. (b) Iyengar, R.; Schildknegt, K.; Aube´, J. Org. Lett. 2000, 2, 1625-
1627. (c) Smith, B.; Wendt, J.; Aube´, J. Org. Lett. 2002, 4, 2577-2579.
(8) Preparation of 4: (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am.
Chem. Soc. 1988, 110, 1238-1256. For some recent examples of the use
of acid 4 in total synthesis, see: (b) Vandewalle, M.; Van der Eycken, J.;
Oppolzer, W.; Vullioud, C. Tetrahedron 1986, 42, 4035-4043. (c) Krotz,
A.; Helmchen, G. Tetrahedron: Asymmetry 1990, 1, 537-540. (d)
Shimizu, I.; Matsuda, N.; Noguchi, Y.; Zako, Y.; Nagasawa, K.
Tetrahedron Lett. 1990, 31, 4899-4902. (e) Krotz, A.; Helmchen, G.
Liebigs Ann. Chem. 1994, 601-609.
(9) (a) Sternbach, D. D.; Ensinger, C. L. J. Org. Chem. 1990, 55, 2725-
2736. (b) Sternbach, D. D.; Hughes, J. W.; Burdi, D. F.; Banks, B. A. J.
Am. Chem. Soc. 1985, 107, 2149-2153. Details of this route will be
described in the full account of this work.
of 10, which proceeded in 86-100% yield. Spectral data (1H, 13
C
NMR, IR, and HRMS) were consistent with literature values,1 and
synthetic 1 had [R] ) -11.1 (c ) 0.960), which is believed to
correspond to material of ca. 93% ee.14
(10) This reaction was inspired, if not literally preceded, by a reaction used in
Grubbs’s total synthesis of capnellene. (a) Stille, J. R.; Santarsiero, B.
D.; Grubbs, R. H. J. Org. Chem. 1990, 55, 843-862. For other examples
of this kind of “domino metathesis” process, see: (b) Stragies, R.; Blechert,
S. Synlett 1998, 169-170. (c) Arjona, O.; Csaky, A. G.; Medel, R.; Plumet,
J. J. Org. Chem. 2002, 67, 1380-1383. (d) Professor Andrew Phillips at
the University of Colorado has independently been exploring reactions
such as this conversion in a synthetic program directed toward cylindra-
mide and related natural products. Phillips, A., personal communication
and Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357-
5360.
Noteworthy features of this synthesis (13 steps, 5-8% overall
yield) include (1) the use of the very well-known Diels-Alder
adduct 4 in total synthesis, (2) the use of ROM/RCM to effect an
overall [2.2.1] f [3.3.0] ring system inversion (a process having
considerable synthetic potential in a general sense), and (3) the use
of an intramolecular Schmidt reaction to provide the ring system
of 251F. Finally, we have prepared ca. 100 mg of 251F and are
currently engaged in biological screening of this material and
selected derivatives.
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(12) Aldehyde 7 was prepared in 70% overall yield from (2S)-2-methyl-4-
penten-1-ol (Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.
1988, 110, 2506-2526) via the following route: (a) NaH, BnBr, DMF;
(b) cat. OsO4, NMNO, NaIO4, Et2O/H2O.
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM-49093). A. Wrobleski acknowl-
edges the receipt of an American Chemical Society graduate
fellowship, sponsored by Abbott Laboratories. The authors also
thank Dr. David Vander Velde for NMR assistance and Dr. Doug
Powell for crystallographic data.
(13) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(14) The specific rotation of 251F has not previously been reported (see refs
1 or 5). The enantiomeric purity and the absolute stereochemistry of the
synthetic material are presumed to reflect those of acid 4 ([R]D ) -140,
c ) 3.6, 95% EtOH): 93% ee (cf., ref 8a).
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