Enantioselective total synthesis of (-)- Stenine

Article abstract of DOI:10.1002/anie.201106587

In control: (-)-Stenine has been synthesized in 14 steps from commercially available compounds with an overall yield of 5.9 % by using a method that is based on double Michael addition. In the key step, the stereogenic centers that are required for (-)-stenine are generated in a highly stereocontrolled, asymmetric, one-pot cyclization to give a densely substituted cyclohexane core. Copyright

Full text of DOI:10.1002/anie.201106587

.
Angewandte
Communications
DOI: 10.1002/anie.201106587
Total Synthesis
Enantioselective Total Synthesis of (À)-Stenine**
Jingbo Chen, Jingchao Chen, Yan Xie, and Hongbin Zhang*
The roots of Stemonaceae plants are used in traditional
Chinese medicines for the treatment of various respiratory
ailments. The structure of (À)-stenine (1; Scheme 1), an
Scheme 1. (À)-stenine and (À)-tuberostemonine.
alkaloid that is isolated from the roots of Stemona species, is
unique among Stemona alkaloids; it has a pyrrolo[1,2-
a]azepine nucleus and a highly substituted perhydroindole
ring system.[1] The polycyclic system and the seven contiguous
stereogenic centers in (À)-stenine as well as (À)-tuberoste-
monine (2) present a challenge for asymmetric organic
synthesis. Previous efforts to synthesize (À)-stenine have
resulted in a number of elegant total syntheses.[2] However,
only two asymmetric syntheses have been reported; these
involve 25[2c] and 30 synthetic steps.[2d] Most of the synthetic
strategies rely on a Diels–Alder reaction as the key step in
assembling the core cyclohexane ring.[3] Herein, we report an
alternative, efficient approach for the enantioselective syn-
thesis of (À)-stenine.
Scheme 2. Retrosynthetic analysis of (À)-stenine.
tive Michael addition of nitroolefin 3 to b-ketoester 4.
Although asymmetric Michael additions of nitroolefins have
been intensively studied in recent years,[4] the development of
a practical method for the proposed carbocyclization, which is
initiated by a Michael addition and builds up five consecutive
stereogenic centers in the newly formed cyclohexane ring,
remains a challenge. Furthermore, few nitroalkene-based
strategies have been developed for the synthesis of polycyclic
natural products.[5]
Nitroolefin 3 was prepared in two steps in 81% yield by
the oxidative cleavage of commercially available diethoxy-
butene,[6] and then a Henry reaction (Scheme 3) and subse-
quent dehydration with trifluoroacetic anhydride (TFAA) in
With the aim of developing efficient and flexible synthetic
strategies for bioactive natural products and their analogues,
we studied the synthesis of (À)-stenine and (À)-tuberoste-
monine. Our retrosynthetic analysis is outlined in Scheme 2.
We anticipated that the densely substituted cyclohexane core
could be assembled by using a sequential double Michael
addition, and that the key azepinoindole intermediate 6 could
be obtained by reductive amination and subsequent amida-
tion. The key issue in this new approach is the enantioselec-
[*] Dr. J.-B. Chen, J.-C. Chen, Y. Xie, Prof. Dr. H.-B. Zhang
Key Laboratory of Medicinal Chemistry for Natural Resources
(Yunnan University), Ministry of Education
Scheme 3. Synthesis of 3: a) O3, CH2Cl2, À788C, then Me2S;
b) MeNO2, EtOH, NaOH. The crude product was then treated with
Et3N and TFAA in THF, 81% yield over two steps.
School of Chemical Science and Technology
Yunnan University, Kunming, 650091 (P. R. China)
E-mail: zhanghb@ynu.edu.cn
[**] This work was supported by grants (20925205, 20562013, and
20832005) from the National Natural Science Foundation of China
and a grant (973 program: 2009CB522304) from the National Basic
Research Program of China. Dr. Xiaonian Li from the Kunming
Institute of Botany is gratefully acknowledged for the X-ray
crystallographic analysis of compound 19.
the presence of triethylamine. Although relatively unstable,
pure 3 can be kept at À808C for several months.
b-Ketoester 4 was synthesized from commercially avail-
able Meldrumꢀs acid. Treatment of Meldrumꢀs acid with
butyryl chloride gave ketal 8, and the reaction of 8 with
diethyl chlorophosphite in the presence of a base furnished
the dioxenone phosphonate 9 in 80% yield in two steps
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106587.
1024
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1024 –1027

Angewandte
Chemie
than 5%) of the Michael addition product 12 were obtained.
However, the reaction with the Evans catalyst (14), which is
derived from (1R,2R)-(À)-1,2-diaminocyclohexane,[10] gave
12 in 96% yield under solvent-free conditions. Although the
first Michael addition was achieved, catalysts 13 and 14 did
not catalyze the second Michael addition. The enantioselec-
tivity for the first Michael addition was not determined at this
stage because our efforts were focused on the promotion of
the second Michael addition, which is the pivotal step in the
synthesis.
A number of base and solvent combinations, such as
K2CO3 in methanol, KOH in ethanol, NaH in THF, or
Triton B in methanol, were tested for the desired trans-
formation of 12 into 5a. Unfortunately, these conditions
yielded a complex mixture of products. After some exper-
imentation, a heterogeneous process for the second Michael
addition was developed; the cyclization was achieved in the
presence of potassium hydroxide that was supported on silica
gel (KOH/SiO2, see the Supporting Information) in anhy-
drous THF with ultrasound. KOH/SiO2 mediated the second
Michael addition with high diastereoselectivity. The keto
form of cyclohexanone derivative 15, which contains five
continuous stereogenic centers, was isolated as a single
diastereomer in high yield (Scheme 6).[11] When the reaction
time was extended under application of ultrasound, the key
intermediate 5a was obtained in 80% yield together with b-
ketoester 15 in 11% yield. Compound 5a was in the enol form
and had the correct relative configuration for the synthesis of
(À)-stenine. The inversion of the configuration of the nitro
group at the C4-position was also concomitantly achieved in
Scheme 4. Synthesis of 4: a) Pyridine, CH2Cl2, butyryl chloride, 93%
yield; b) [(CH3)3Si]2NLi, THF, À788C, diethyl chlorophosphite; then
30% H2O2, 86% yield; c) LDA, THF, À788C, Hexamethylphosphor-
amide (HMPA), then 10, 85% yield; d) MeOH, NaH, THF, 80% yield.
(Scheme 4).[7] Aldehyde 10 was prepared by the oxidative
cleavage of cyclopentene in methanol[8] and a Horner–Wads-
worth–Emmons reaction with 10 and 9 gave olefin 11 as a
mixture of geometrical isomers (E/Z ratio = 4:1) in 85% yield
(Scheme 4). Treatment of 11 with methanol in the presence of
sodium hydride afforded the desired E olefin 4 in 80% yield.
Compound 4 is an unsaturated b-ketoester with the ethyl
group that is required for the synthesis of (À)-stenine.
The double Michael addition is the key stage in the
synthesis. The challenge is to secure the required configu-
ration with a high enantioselectivity and diasteroselectivity.
To gain some insight into the stereoselectivity of the Michael
addition (Scheme 2), two catalysts were tested (13 and 14,
Scheme 5). Although the bifunctional thiourea catalyst 13 has
been used for similar asymmetric conjugate additions,[5h,9] it
was not effective with substrate 4. Only trace amounts (less
Scheme 5. Investigation of the asymmetric Michael addition. Inset:
prediction of the absolute configuration of 12 from the first Michael
addition of 3 and 4 based on Evans’ model. Bn=benzyl.
Scheme 6. Michael addition promoted by potassium hydroxide sup-
ported on silica gel.
Angew. Chem. Int. Ed. 2012, 51, 1024 –1027
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1025

.
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
.
[1] a) S. Uyeo, H. Irie, H. Haroda, Chem. Pharm. Bull. 1967, 15, 768;
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
de Oliveira, Nat. Prod. Rep. 2000, 17, 117; d) “The Stemona
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.
1026 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1024 –1027

Angewandte
Chemie
[2] a) C.-Y. Chen, D. Hart, J. Org. Chem. 1990, 55, 6236; b) C.-Y.
Chen, D. Hart, J. Org. Chem. 1993, 58, 3840; c) P. Wipf, Y. Kim,
D. M. Goldstein, J. Am. Chem. Soc. 1995, 117, 11106; d) Y.
Morimoto, M. Iwahashi, K. Nishida, Y. Hayashi, H. Shirahama,
Angew. Chem. 1996, 108, 968; Angew. Chem. Int. Ed. Engl. 1996,
35, 904; e) Y. Morimoto, M. Iwahashi, T. Kinoshita, K. Nishida,
Chem. Eur. J. 2001, 7, 4107; f) J. D. Ginn, A. Padwa, Org. Lett.
2002, 4, 1515; g) A. Padwa, J. D. Ginn, J. Org. Chem. 2005, 70,
5197; h) J. E. Golden, J. Aubꢁ, Angew. Chem. 2002, 114, 4492;
Angew. Chem. Int. Ed. 2002, 41, 4316; i) Y. Zeng, J. Aubꢁ, J. Am.
Chem. Soc. 2005, 127, 15712; j) K. J. Frankowski, J. E. Golden, Y.
Zeng, Y. Lei, J. Aubꢁ, J. Am. Chem. Soc. 2008, 130, 6018.
[3] To date, only one successful total synthesis of (À)-stenine and
the related compound (À)-tuberostemonine has been completed
by Wipf et al., who utilized a different approach for the
construction of the core cyclohexane ring system. See Ref. [2c]
and a) P. Wipf, S. R. Spencer, H. Takahashi, J. Am. Chem. Soc.
2002, 124, 14848; b) P. Wipf, S. R. Spencer, J. Am. Chem. Soc.
2005, 127, 225.
M. Yamashita, N. Fukuyama, K. Yamada, O. Muraoka, K.
Tomioka, Org. Lett. 2003, 5, 1123; d) Y. Hoashi, T. Yabuta, Y.
Takemoto, Tetrahedron Lett. 2004, 45, 9185; e) S. Gao, Y. Q. Tu,
Z. Song, A. Wang, X. Fan, Y. Jiang, J. Org. Chem. 2005, 70, 6523;
f) L. Dong, Y.-J. Xu, L.-F. Cun, X. Cui, A.-Q. Mi, Y.-Z. Jiang, L.-
Z. Gong, Org. Lett. 2005, 7, 4285; g) L. Dong, Y.-J. Xu, W.-C.
Yuan, X. Cui, L.-F. Cun, L.-Z. Gong, Eur. J. Org. Chem. 2006,
4093; h) Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe, Y. Takemoto,
Tetrahedron 2006, 62, 365; i) S. E. Denmark, R. Y. Baiazitov, J.
Org. Chem. 2006, 71, 593; j) M. Tang, C.-A. Fan, F.-M. Zhang, Y.-
Q. Tu, Tetrahedron 2009, 65, 5716.
[6] a) L. El Blidi, M. Ahbala, J. Bolte, M. Lemaire, Tetrahedron:
Asymmetry 2006, 17, 2684; b) B. M. Trost, J. Dumas, M. Villa, J.
Am. Chem. Soc. 1992, 114, 9836.
[7] a) R. K. Boeckman, Jr., P. Shao, S. T. Wrobleski, D. J. Boehmler,
G. R. Heintzelman, A. J. Barbosa, J. Am. Chem. Soc. 2006, 128,
10572; b) R. K. Boeckman, Jr., T. M. Kamenecka, S. G. Nelson,
J. R. Pruitt, T. E. Barta, Tetrahedron Lett. 1991, 32, 2581.
[8] J. D. Frein, T. Rovis, Tetrahedron 2006, 62, 4573.
[4] For recent reviews on the organocatalytic Michael addition to
electron-deficient conjugated olefins, which includes nitroole-
fins, see: a) D. Almas¸i, D. A. Alonso, C. Najera, Tetrahedron:
Asymmetry 2007, 18, 299; b) S. B. Tsogoeva, Eur. J. Org. Chem.
2007, 1701; c) K. S. Sulzer-Mossꢁ, A. Alexakis, Chem. Commun.
2007, 3123; d) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007,
2065; e) D. Enders, C. Grondal, M. R. M. Hꢂttl, Angew. Chem.
2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570; f) C.
Palomo, M. Oiarbide, R. Lꢃpez, Chem. Soc. Rev. 2009, 38, 632.
[5] a) G. Lakshmaiah, T. Kawabata, M. Shang, K. Fuji, J. Org.
Chem. 1999, 64, 1699; b) O. Andrey, A. Vidonne, A. Alexakis,
Tetrahedron Lett. 2003, 44, 7901; c) T. Yasuhara, K. Nishimura,
[9] T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119.
[10] a) D. A. Evans, D. Seidel, J. Am. Chem. Soc. 2005, 127, 9958;
b) D. A. Evans, S. Mito, D. Seidel, J. Am. Chem. Soc. 2007, 129,
11583.
[11] The relative stereochemistry of b-ketoester 15 was established
by a NOE NMR experiment and also by the characteristic
coupling constant (J = 12.6 Hz) between the H3 atom and the
H2 atom (C2-H: 4.51 ppm, d, J = 12.6 Hz).
[12] After the first Michael addition, the resulting mixture was
diluted with anhydrous THF and treated with KOH/SiO2 under
sonication at 25–358C for 48 h (see the Supporting Information).
Angew. Chem. Int. Ed. 2012, 51, 1024 –1027
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1027