Total synthesis of (-)-strychnine

Article abstract of DOI:10.1002/1521-3773(20020603)41:11<1934::AID-ANIE1934>3.0.CO;2-F

The power of palladium catalysts is shown in a total synthesis of (-)-strychnine (A). The construction of all the rings of this challenging molecule relied on Pd⁰- or Pd^II-catalyzed reactions. The final step in this efficient synthes

Full text of DOI:10.1002/1521-3773(20020603)41:11<1934::AID-ANIE1934>3.0.CO;2-F

COMMUNICATIONS
[1] a) S. K. Haram, B. M. Quinn, A. J. Bard, J. Am. Chem. Soc. 2001, 123,
8860; b) T. Trindade, P. O×Brein, N. L. Pickett, Chem. Mater. 2001, 13,
3843; c) C. Feldmann, H. O. Jungk, Angew. Chem. 2001, 113, 37 2;
Angew. Chem. Int. Ed. 2001, 40, 359; d) H. Yu, P. C. Gibbons, K. F.
Kelton, W. E. Bubro, J. Am. Chem. Soc. 2001, 123, 9198.
[2] a) M. P. Pileni, J. Phys. Chem. B 2001, 105, 3358; b) C. B. Murray, C. R.
Kagan, M. G. Bawendi, Science 1995, 270, 1335; c) S. He, J. Yao, P.
Jiang, D. Shi, H. Zhang, S. Xie, S. Pang, H. Gao, Langmuir 2001, 17,
1571; d) J. Lergand, A. T. Ngo, C. Petit, M. P. Pileni, Adv. Mater. 2001,
13, 58; e) M. A. Firestone, D. E. Williams, S. Seifert, R. Csencsits,
Nano Lett. 2001, 1, 129; f) K. Soulantica, A. Maisonnat, M. C. Fromen,
M. J. Casanove, P. Lecante, B. Chaudret, Angew. Chem. 2001, 113, 462;
Angew. Chem. Int. Ed. 2001, 40, 448.
[3] a) T. Yonezawa, S. Onoue, N. Kimizuka, Adv. Mater. 2001, 13, 140;
b) B. A. Korgel, S. Fullam, S. Connolly, D. Fitzmaurice, J. Phys. Chem.
B 1998, 102, 8379; c) R. Maoz, E. Frydman, S. R. Cohen, J. Sagiv, Adv.
Mater. 2000, 12, 424; d) Z. Y. Pan, X. J. Liu, S. Y. Zhang, G. J. Shen,
L. G. Zhang, Z. H. Lu, J. Z. Liu, J. Phys. Chem. B 1997, 101, 97 03; e) T.
Vossmeyer, E. DeIonno, J. R. Heath, Angew. Chem. 1997, 109, 1123;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1080.
[4] a) P. C. Ohara, J. R. Heath, W. M. Gelbart, Angew. Chem. 1997, 109,
1119; Angew. Chem. Int. Ed. Engl. 1996, 36, 1078; b) X. M. Liu, H. M.
Jaeger, C. M. Sorensen, K. J. Klabunde, J. Phys. Chem. B 2001, 105,
3353; c) Z. L. Wang, Z. Dai, S. Sun, Adv. Mater. 2000, 12, 1944.
[5] R. P. Andres, J. D. Bielefeld, J. I. Henderson, D. B. Janes, V. R.
Kolagunta, C. P. Kubiak, W. J. Mahoney, R. G. Osifchin, Science
1996, 273, 1690.
Total Synthesis of (À)-Strychnine
Masato Nakanishi and Miwako Mori*
(À)-Strychnine (A),[1] the most famous of the Strychnos
alkaloids, has seven rings and six stereogenic centers in the
molecule and is one of the most complex natural products of
its size. Although Woodward et al.
N
succeeded in the total synthesis of
C
D
(À)-strychnine in 1954,[2] there were
H
H
A
B
E
no reports of its total synthesis for
40 years. In 1992, Magnus et al. re-
ported the total synthesis of strych-
nine,[3] and then Overman and co-
workers succeeded in the first asym-
N
F
H
H
O
G
O
A
metric total synthesis of (À)- and (‡)-strychnine in 1993.[4]
Since then, several groups have reported the total synthesis of
(À)- or (Æ)-strychnine.[5, 6] Very recently, Vollhardt and co-
workers completed the total synthesis of (Æ)-strychnine by
using an ingenious cobalt-catalyzed [2‡2‡2] cycloaddition as
a key step.[7]
We recently reported a novel method for synthesizing
indole derivative 4 by means of palladium-catalyzed cycliza-
tion of 2-bromoaniline 3. The aniline derivative 3 was
obtained from cyclohexenol 1 and aniline 2 by using
[6] I. Willner, F. Patolsky, J. Wasserman, Angew. Chem. 2001, 113, 1913;
Angew. Chem. Int. Ed. 2001, 40, 1861.
[7] a) D. Xu, Y. Xu, D. Chen, G. Guo, L. Gui, Y. Tang, Adv. Mater. 2000,
12, 520; b) Z. L. Wang, Adv. Mater. 2000, 12, 1295; c) A. M. Morales,
C. M. Lieber, Science 1998, 279, 208; d) J. H. Song, B. Messer, Y. Wu,
H. Kind, P. Yang, J. Am. Chem. Soc. 2001, 123, 9714; e) Z. Zhang, D.
Gekhtman, M. S. Dresselhaus, J. Y. Ying, Chem. Mater. 1999, 11, 1659;
f) C. C. Chen, C. Y. Chao, Z. H. Lang, Chem. Mater. 2000, 12, 1519;
g) N. R. Hana, L. Gearheart, C. J. Murphy, J. Phys. Chem. B 2001, 105,
4065.
palladium-catalyzed
asymmetric
allylic
substitution
(Scheme 1).[8] (À)-Dehydrotubifolin and (À)-tubifolin were
synthesized from tetracyclic ketone 5, which was formed from
10 (Scheme 3; cf. 4).
NHTs
[8] a) L. Vayssieres, N. Beermann, S. E. Lindquist, A. Hagfeldt, Chem.
Mater. 2001, 13, 233; b) Z. Zhang, G. Ramanath, P. M. Ajavan, D.
Goldberg, Y. Bando, Adv. Mater. 2001, 13, 197; c) X. Peng, L. Manna,
W. Yang, J. Wickham, E. Scher, A. Kadavanich, A. P. Alivisatos,
Nature 2000, 404, 59; d) A. Hatzor, P. S. Weiss, Science 2001, 291, 1019;
e) Z. L. Wang, R. P. Gao, J. L. Gole, J. D. Stout, Adv. Mater. 2000, 12,
1938; f) M. Li, H. Schnablegger, S. Mann, Nature 1999, 402, 393;
g) J. K. N. Mbindyo, B. D. Reiss, B. R. Martin, C. D. Keating, M. J.
Natan, T. E. Mallouk, Adv. Mater. 2001, 13, 249.
Br
OTBDMS
OTBDMS
OTBDMS
R1
Ts
2
N
Pd0
*
*
*
Pd0
(S)-binapo
N
Br
80%, 84% ee
H
Ts
3
4
1
1a:
1b:
1c:
R = OCO2Me
R1 =
OCO2
NBoc
[9] a) H. Masuda, T. Yanagishita, K. Yasui, K. Nishio, I. Yagi, T. N. Rao,
A. Fujishima, Adv. Mater. 2001, 13, 247; b) D. Routkevitch, T. Bigioni,
M. Moskovits, J. M. Xu, J. Phys. Chem. 1996, 100, 14037.
R1 = OPO(OEt)
2
O
N
[10] H. Cao, Z. Xu, H. Sang, D. Sheng, C. Tie, Adv. Mater. 2001, 13, 121.
[11] M. H. Huang, S. Mao, H. Feick, H. Yan, Y. Wu, H. Kind, E. Weber, R.
Russo, P. Yang, Science 2001, 292, 1897.
H
Ts
5
[12] a) L. T. Canham, Appl. Phys. Lett. 1990, 57, 1046; b) L. Vayssieres, N.
Beermann, S. E. Lindquist, A. Hagfeldt, Chem. Mater. 2001, 13, 233;
c) Z. Zhang, G. Ramanath, P. M. Ajavan, D. Goldberg, Y. Bando, Adv.
Mater. 2001, 13, 197; d) J. K. N. Mbindyo, B. D. Reiss, B. R. Martin,
C. D. Keating, M. J. Natan, T. E. Mallouk, Adv. Mater. 2001, 13, 249.
[13] X. Zhong, W. Xiao, Q. Yuan, R. Lou, S. Xu, Q. Xu, Y. Tian, S. Liu, Y.
Lu, W. Wang, S. Liu, Z. Ji, A Series of Inorganic Chemistry Books (No.
6), 1st ed., Kexue Press, Beijing, 1995.
[14] X. Jiang, Y. Xie, J. Lu, W. He, L. Zhu, Y. Qian, J. Mater. Chem. 2000,
10, 2193.
[15] C. H. Liang, G. W. Meng, G. Z. Wang, L. D. Zhang, Chem. Mater.
2001, 13, 2150.
Scheme 1. Palladium-catalyzed asymmetric allylic substitution. Ts ˆ to-
luene-4-sulfonyl, TBDMS ˆ tert-butyldimethylsilyl, binapo ˆ (S)-2,2'-bis-
(diphenylphosphanoxy)-1,1'-binapthyl, Boc ˆ tert-butoxycarbonyl.
These results prompted us to synthesize (À)-strychnine, as
tetracyclic ketone 5 is considered to be a very important
intermediate in the syntheses of Strychnos indole alkaloids.
Our retrosynthetic analysis of (À)-strychnine is shown in
Scheme 2. The method for the construction of the G ring is
[16] M. C. Brelle, J. Z. Zhang, L. Nguyen, R. K. Mehra, J. Phys. Chem. A
1999, 103, 10194.
[*] Prof. M. Mori, M. Nakanishi
Graduate School of Pharmaceutical Sciences, Hokkaido University
Sapporo 060-0812 (Japan)
Fax : (‡81)11-706-4982
E-mail: mori@pharm.hokudai.ac.jp
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
1934
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4111-1934 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 11

COMMUNICATIONS
NBoc
N
NBoc
NR
H
b)
a)
c)
A
5
N
N
N
N
56%
46%
H
64%
H
Br
H
G
HO
Ts
O
O
O
13
Isostrychnine
6
14
N
NBoc
d)
e)
5
NR
R
NR
I
N
N
O
48%
53%
O
O
N
H
N
O
OTBDMS
H
H
15
17
R
7
8
N
N
Scheme 2. Retrosynthetic analysis of (À)-strychnine (A).
f)
N
44%
N
H
important for the synthesis of (À)-strychnine from 5. Two
pathways should be considered: 1) introduction of an alkyl
group at the a position of the carbonyl group to give 7
O
HO
O
OTBDMS
(+)-Isostrychnine
g)
18
À
followed by C N bond formation to construct the G ring;
2) introduction of an acyl group at the nitrogen atom to form 8
followed by construction of the G ring.
I
Br
A
OTBDMS
The synthesis of 5 is summarized in Scheme 3. Indoline 10
(84% ee) was recrystallized from EtOH to give the enantio-
merically pure form (99% ee, 73% recovery, [a]2D0 ˆ À46.7
(c 2.16, CHCl3)),[9] The optically pure tetracyclic ketone 5
could then be prepared from 10.
16
Scheme 4. Synthesis of (À)-strychnine. a) 1. PhNTf2, KN(TMS)2, 2.
Pd(OAc)2, PPh3, HCO2H, iPr2NEt; b) 1. NaC10H8, 2. (Z)-3-bromoacryloyl
chloride, K2CO3; c) Pd(OAc)2 (10 mol%), PPh3 (20 mol%), iPr2NEt,
DMSO, 808C, 1.5 h; d) 1. NaOiPr, 2. CF3CO2H, 3. 16, Li2CO3, DMF,
408C; e) Pd(OAc)2, Bu4NCl, K2CO3, DMF, 708C, 0.5 h; f) 1. LiAlH4, 2.
HCl; g) KOH, EtOH. TMS ˆ trimethylsilyl, Tf ˆ trifluoromethanesulfonyl,
DMF ˆ N,N-dimethylformamide.
OTBDMS
CN
CN
Ts
Br
N
a)
b)
N
Br
86%
87%
that pentacyclic compound 15 was obtained in 46% yield after
the usual work-up procedure. Isomerization of the double
bond of 15 by treatment with NaOiPr in 2-propanol followed
by removal of the Boc group and then alkylation with 16
afforded compound 17, which is an intermediate in the
synthesis of (Æ)-strychnine by Vollhardt and co-workers. By
following their procedure, 17 was converted into pentacyclic
compound 18 by treatment with Pd(OAc)2, Bu4NCl, and
K2CO3 (Scheme 4).
N
Ts
H
H
3
Ts
10
9
99% ee (from EtOH)
NBoc
NHBoc
c)
d)
87%
e)
5
N
N
74%
70%
H
H
Ts
Ts
11
12
Treatment of 18 with LiAlH4 followed by cleavage of the
silyl group gave (‡)-isostrychnine, whose spectral data and
[a]2D0 value (‡23.7( c 0.59, EtOH)) agreed with those of (‡)-
isostrychnine reported by Woodward and co-workers.[2] (‡)-
Isostrychnine was converted into our final target (À)-strych-
nine (A) by treatment with KOH in EtOH according to a
known method.[10]
Scheme 3. Synthesis of 5. a) 1) HCl; 2) PBr3; 3) NaCN; b) Pd(OAc)2
(2 mol%), PPhMe2, Ag2CO3, DMSO, 908C, 17h; c) 1) LiAlH 4 2)
;
(Boc)2O; d) Pd(OAc)2, benzoquinone, MnO2, AcOH, 508C; e) 1) 9-BBN,
then H2O2, NaOH; 2) DMSO, (COCl)2, then NEt3. DMSO ˆ dimethyl
sulfoxide,
nonane.
Boc ˆ tert-butoxycarbonyl,
9-BBN ˆ 9-borabicyclo[3.3.1]-
In summary, palladium catalysis played an important role in
our total synthesis of (À)-strychnine: 1) rings A, B, and E
were constructed by using by palladium-catalyzed asymmetric
allylic substitution of a cyclohexenol derivative followed by
palladium-catalyzed cyclization; 2) ring C was formed by
means of a palladium-catalyzed allylic oxidation; 3) the
synthesis of ring G and then ring F required Pd(OAc)2. The
extensive use of Pd0 or PdII highlights the importance of
palladium catalysts in modern synthetic organic chemistry.
At first we chose the reaction pathway in which an acyl
group is introduced at the a position of the carbonyl group in
5. However, several attempts were unsuccessful as a result of
the steric hindrance of the large Ts protecting group on the
nitrogen atom. Instead, we tried to introduce an acyl group at
À
the nitrogen atom to form a C C bond by a Heck-type
reaction. Conversion of 5 into 13 was carried out by a known
method (Scheme 4). Detosylation followed by treatment with
(Z)-3-bromoacryloyl chloride gave 14, which was treated with
Pd(OAc)2 (10 mol%) and PPh3 (20 mol%) in the presence of
iPr2NEt in DMSO at 808C for 1.5 h. We were pleased to find
Received: February 11, 2002 [Z18687]
Angew. Chem. Int. Ed. 2002, 41, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4111-1935 $ 20.00+.50/0
1935

COMMUNICATIONS
[1] Isolation: a) P. J. Pelletier, J. B. Caventou, Ann. Chim. Phys. 1818, 8,
323; structural elucidation: b) L. H. Briggs, H. T. Openshaw, R.
Robinson, J. Chem. Soc. 1946, 903; c) R. B. Woodward, W. J. Brehm,
J. Am. Chem. Soc. 1948, 70, 2107.
Kuehne, F. Xu, J. Org. Chem. 1993, 58, 7490; c) V. H. Rawal, S. Iwasa,
J. Org. Chem. 1994, 59, 2685; for enantioselective syntheses, see:
¬
d) M. E. Kuehne, F. Xu, J. Org. Chem. 1998, 63, 9427; e) D. Sole, J.
¬
Bonjoch, S. GarcÌa-Rubio, E. Peidro, J. Bosch, Angew. Chem. 1999,
[2] a) R. B. Woodward, M. P. Cave, W. D. Ollis, A. Hunger, H. U.
Daeniker, K. J. Schenker, J. Am. Chem. Soc. 1954, 76, 4749; b) R. B.
Woodward, M. P. Cave, W. D. Ollis, A. Hunger, H. U. Daeniker, K. J.
Schenker, Tetrahedron 1963, 19, 247.
[3] P. Magnus, M. Giles, R. Bonnet, C. S. Kim, L. McQuire, A. Merritt, A.
Vicker, J. Am. Chem. Soc. 1993, 115, 8116.
[4] a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc.
1993, 115, 9293; b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am.
Chem. Soc. 1995, 117, 5776.
111, 408; Angew. Chem. Int. Ed. 1999, 38, 395.
[7] a) M. J. Eichberg, R. L. Dorta, K. Lamottke, K. P. C. Vollhardt, Org.
Lett. 2000, 2, 2479; b) M. J. Eichberg, R. L. Dorta, D. B. Grotjahn, K.
Lamottke, M. Schmidt, K. P. C. Vollhardt, J. Am. Chem. Soc. 2001,
123, 9324.
[8] M. Mori, M. Nakanishi, D. Kajishima, Y. Sato, Org. Lett. 2001, 3,
1913.
[9] The enantiomeric purity of 4a was determined by HPLC analysis
(DAICEL CHIRALPAK AD, hexane/2-propanol 95:5).
[10] V. Prelog, J. Battegay, W. I. Taylor, Helv. Chim. Acta 1948, 31,
2244.
[5] For a review of the total syntheses of strychnine, see: J. Bonjoch, D.
¬
Sole, Chem. Rev. 2000, 100, 3455.
[6] Racemic syntheses: a) G. Stork, reported at the Ischia Advanced
School of Organic Chemistry, Ischia Porto, Italy, 1992; b) M. E.
1936
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4111-1936 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 11