.
Angewandte
Communications
this one-pot, heterogeneous reaction. After the one-pot
double Michael addition and the subsequent inversion of
the configuration at the C4-position, the ee value for com-
pound 5a was determined to be 87% by HPLC on a chiral
stationary phase (Chiralcel OJ-H column).[12]
The reductive aminocyclization and subsequent intra-
molecular amidation of 5a gave the tricyclic amide 6 in 81%
yield (Scheme 7). Amide 6 was then treated with lithium
chloride and water in dimethyl sulfoxide to give ketone 16 in
Figure 1. Absolute configuration of (À)-oxostenine.
confirmed by X-ray crystallography (Figure 1) with Cu-Ka
radiation.
The conversion of amide 19 into the thioamide 20: [a]D =
À87.08, c = 0.5, CH2Cl2; literature [a]D = À54.38, c = 0.4,
CH2Cl2[2c]) with Lawessonꢀs reagent and subsequent desul-
furization with Raney nickel[2a] gave (À)-stenine in 90% yield
in two steps (Scheme 7, [a]D = À30.38, c = 0.5, MeOH,
literature [a]D = À30.28, MeOH[1a]). The NMR spectra of
our synthetic sample were in complete agreement with the
reported spectra.[2]
In summary, we have developed a catalytic, enantioselec-
tive strategy for the synthesis of (À)-stenine. This route, which
features a highly stereocontrolled, one-pot cyclization to
establish the required stereogenic centers, gives (À)-stenine
in 14 steps from commercially available materials (11 steps
from known starting materials) in an overall yield of 5.9%.
This strategy is flexible and could be used for the synthesis of
stenine analogues, which are of interest in medicinal chemis-
try. The application of this method to the catalytic asymmetric
synthesis of (À)-tuberostemonine (2), which is a more
complex target, is currently under investigation.
Scheme 7. Enantioselective synthesis of (À)-stenine: a) 14, 58C; then
KOH/SiO2, THF, sonicated in a water bath at 358C, 80% yield;
b) acetic acid, H2O, 908C, then Zn powder. The crude product was
then heated to 908C in toluene, 81% yield; c) LiCl, H2O, DMSO,
1558C, 89% yield; d) [(CH3)3Si]2NLi, THF, À788C, ethyl bromoacetate,
78% yield; e) NaBH4, MeOH, 08C, 51% yield after recrystallization;
f) [(CH3)3Si]2NLi, THF, À788C, MeI, 65% yield; g) Lawesson’s reagent,
CH2Cl2; h) Raney Ni, EtOH, 258C, 90% yield over two steps.
Received: September 16, 2011
Revised: November 22, 2011
Published online: December 16, 2011
Keywords: asymmetric catalysis · cyclization · Michael addition ·
(À)-stenine · total synthesis
89% yield. By using the elegant procedure developed by
Zeng and Aubꢁ,[2i] the treatment of ketone 16 with ethyl
bromoacetate in the presence of lithium bis(trimethylsilyl)-
amide in THF gave ester 17 in 78% yield. After reduction of
17 with sodium borohydride in methanol, lactone 18 was
obtained in 62% yield. After recrystallization, the isomeric
purity of lactone 18 was greater than 98%, as determined by
HPLC analysis. Lactone 18 was treated with methyl iodide in
the presence of lithium bis(trimethylsilyl)amide in THF to
give oxostenine 19 as white, platelike crystals in 65% yield
([a]D = À136.38, c = 0.40, CH2Cl2, literature [a]D = À84.78, c =
0.37, CH2Cl2[2c]). The absolute configuration of 19 was
.
b) H. Haroda, H. Irie, N. Masaki, K. Osaki, S. Uyeo, J. Chem.
Soc. Chem. Commun. 1967, 460; c) R. A. Pilli, M. d. C. Ferreira
Alkaloids”: R. A. Pilli, G. B. Rosso, M. d. C. Ferreira de Oli-
veira in The Alkaloids: Chemistry and Biology, Vol. 62 (Eds.:
G. A. Cordell), Academic Press, New York, 2005, pp. 77 – 173,
and references therein.
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1024 –1027