Total Synthesis of Incarvillateine
A R T I C L E S
Scheme 4 a
Scheme 5 a
a Reagents and conditions: (a) O3, CH2Cl2-MeOH, -78 °C, then Me2S,
96%; (b) NaBH4, EtOH, 0 °C, 71%; (c) TsNHBoc, DEAD, Ph3P, THF,
room temperature, 99%; (d) CF3CO2H, CH2Cl2, room temperature, 95%;
(e) K2CO3, CH3CN, reflux, 81%; (f) Pd(OAc)2, BBEDA, PMHS, benzene,
95 °C, 9%; (g) K2CO3, CH3CN, reflux, 80%; (h) PdCl2(CH3CN)2, Et3N,
HCO2H, CH3CN, room temperature, 72%.
a Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 97%; (b)
TBDMSCl, imidazole, 93%; (c) H2, PtO2, MeOH, 96%; (d) sodium
naphthalenide, DME, -50 °C, 78%; (e) 35% HCHO, NaBH3CN, AcOH,
CH3CN, 97%; (f) H2, PtO2, 5 atm, MeOH, 84%.
to the construction of the 1-pyrindine skeleton in the total
synthesis of streptazolin.14 Thus, the N-tosyl amide 19 was
propargylated using the tosylate of propargyl alcohol under basic
conditions to give the enyne compound 20. Upon treatment of
20 with 10 mol % of Pd(OAc)2 and N,N′-bis(benzylidene)-
ethylenediamine (BBEDA) in the presence of polymethylhy-
drosiloxane (PMHS), reductive cyclization proceeded to give
the expected cis-perhydro-2-pyrindine 21; however, the poor
yield (9%) rendered this transformation of little value (Scheme
4). Thus, we sought to develop an alternative palladium-
mediated cyclization methodology for the synthesis of 21. In
this regard, our attention next was focused on a reductive Heck-
type reaction which has been employed for palladium-catalyzed
conjugate addition of aryl iodides.15 To apply this method to
intramolecular vinylation, the N-tosyl amide 19 was con-
verted to the alkenyl iodide 23 by treatment with 2-iodo-2-
propenyl tosylate (22) and K2CO3. Upon treatment of 23 with
PdCl2(CH3CN)2 in the presence of triethylamine and formic acid,
a reductive cyclization proceeded with exclusive formation of
21 in 72% yield. The cis-stereochemistry of the ring fusion in
21 was confirmed by a NOESY interaction observed between
the two angular hydrogens.
Reduction of 21 with sodium borohydride provided the (6S)-
alcohol 24 as a single isomer in 97% yield (Scheme 5). The
stereochemistry of the hydroxyl group of 24 was confirmed by
NOE analysis. After protection of the secondary alcohol as its
TBDMS ether, compound 25 was subjected to catalytic hydro-
genation over PtO2 in MeOH, resulting in the â-methyl product
26 and its epimer 27 as a 3:1 diastereomeric mixture. The
observed 3:1 preference for the formation of 26 with the desired
stereochemistry at C4 can be understood as arising from
hydrogenation of 25 on the convex face of the cis-fused ring
system. When the hydrogenation was carried out (PtO2, 5 atm,
MeOH) using 29 with a methyl group on nitrogen instead of
the tosyl group as in 25, complete diastereoselectivity was
realized for the formation of 30 (84% yield) with the desired
4R configuration.
Deptrotection of the TBDMS group in 30 with Bu4NF
furnished (+)-6-epi-incarvilline (4) [[R]20 +18.1 (c 1.42,
D
(CHCl3)]. Inversion of configuration of the C6 hydroxyl stereo-
center was accomplished using Mitsunobu reaction with p-
nitrobenzoic acid16 followed by hydrolysis of the resulting
epimeric p-nitrobenzoate 31, leading to the synthesis of
(-)-incarvilline (3) as a white crystalline solid: mp 94.4-95.5
°C (lit.5 mp 93.4-93.8 °C); [R]20 -8.1 (c 0.18, CHCl3) [lit.5
D
[R]24D -8.0 (c 1.24, CHCl3)], exhibited 1H and 13C NMR data
identical to those reported5 for the natural product (Scheme 6).
On the other hand, 4 underwent Mitsunobu condensation
with (E)-ferulic acid (4-hydroxy-3-methoxycinnamic acid) (32)
with complete inversion of configuration at C6, furnishing
(+)-incarvine C (2) whose spectral properties (1H and 13C NMR)
were identical to those published4 for natural incarvine C
(Scheme 6). We were surprised to find, however, that the optical
rotation of the synthetic material [[R]20D +20.0 (c 0.46, CHCl3)]
was almost equal in magnitude but opposite in sign to that [[R]D
-20.8 (c 0.46, CHCl3)] published4 for the natural product. This
lack of congruence indicated that the synthetic dextrorotatory
incarvine C (2), which possesses the same absolute configuration
as natural incarvilline (3) at all stereogenic centers, is the
unnatural enantiomer, despite the fact that incarvine C is
considered to be biogenetically derived from incarvilline. We
therefore undertook a study to verify the absolute configuration
of natural incarvine C by HPLC analysis on a chiral phase
[Daisel Chiralcel OD 0.46 × 25 cm; eluent, hexane/EtOH/
Et2NH (38:2:1); flow rate, 0.5 mL/min; UV detection, 254 nm].
(14) (a) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 1996, 118,
1054-1059. (b) Yamada, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
1996, 48, 8787-8790.
(15) (a) Cacchi, S.; Arcadi, A. J. Org. Chem. 1983, 48, 4236-4240. (b) Schmidt,
B.; Hoffmann, H. M. R. Tetrahedron 1991, 47, 9357-9368.
(16) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
(b) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234-
236.
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J. AM. CHEM. SOC. VOL. 126, NO. 50, 2004 16555