Enantioselective total synthesis of (-)-strychnine using the catalytic asymmetric Michael reaction and tandem cyclization

Article abstract of DOI:10.1021/ja028457r

The enantioselective total synthesis of (-)-strychnine was accomplished through the use of the highly practical catalytic asymmetric Michael reaction (0.1 mol % of (R)-ALB, more than kilogram scale, without chromatography, 91% yield and >99% ee) as well as a tandem cyclization that simultaneously constructed B- and D-rings (>77% yield). Moreover, newly developed reaction conditions for thionium ion cyclization, NaBH₃CN reduction of the imine moiety in the presence of Lewis acid to prevent ring opening reaction, and chemoselective reduction of the thioether (desulfurization) in the presence of exocyclic olefin were pivotal to complete the synthesis. The described chemistry paves the way for the synthesis of more advanced Strychnos alkaloids. Copyright

Full text of DOI:10.1021/ja028457r

Published on Web 11/13/2002
Enantioselective Total Synthesis of (-)-Strychnine Using the Catalytic
Asymmetric Michael Reaction and Tandem Cyclization
Takashi Ohshima,† Youjun Xu,†,‡ Ryo Takita,† Satoshi Shimizu,† Dafang Zhong,‡ and
Masakatsu Shibasaki*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,
and Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical UniVersity,
Wenhua Road 103, Shenyang 110016, China
Received September 7, 2002
We report a new entry for the synthesis of (-)-strychnine (1)1
from easily accessible optically pure Michael adduct 5, which is
synthesized by the catalytic asymmetric Michael reaction on a
greater than kilogram scale.2c Another key step in this entry is a
novel tandem cyclization promoted by Zn for the simultaneous
construction of B- and D-rings (Figure 1).3
(-)-Strychnine is the flagship compound of the family of
Strychnos alkaloids and, considering its molecular weight, is one
of the most complex natural products.1 Nearly 40 years after
Woodward’s pioneering achievement,4a a number of groups have
reported the total synthesis4 and four of them have culminated in
enantioselective synthesis of the natural enantiomer.4c,e,g,i The major
Figure 1. Retrosynthetic analysis of (-)-strychnine.
stumbling blocks in the synthesis are the generation of the
Finally, protection of the primary alcohol with SEMCl and removal
of the TIPS group provided the key intermediate 4 in excellent
yield.
spirocenter at C7 and the assembling of the CDE core ring.1 In the
previous strategies, the C6-C7 bond was generated in the early
stage of synthesis; thus, in many cases, the CDE ring system was
We then focused on the construction of the BCDE-ring system.
assembled in the direction of C-ring to D-ring. Although an
Initially, we examined 1,4-addition of the secondary amine to the
intramolecular alkylation strategy was applied for the construction
enone after introduction of the amine moiety at C21 of 4; however,
of the C-ring in the synthesis of structurally simpler indole
it was found to be difficult due to the rapid retro reaction.11
alkaloids,2b,5 this strategy has not been utilized for the synthesis of
Numerous attempts finally led us to examine a tandem cyclization.6
1. In the present synthesis, to utilize 5 effectively in the synthesis,
After introduction of the amine moiety, crude 17 was simply treated
with Zn in MeOH-aqueous NH4Cl to provide 3 in 77% yield. This
tandem cyclization might proceed by the following sequence: (1)
reduction of nitro group to amine by Zn, (2) 1,4-addition of the
secondary amine, and (3) irreversible indole formation of the aniline
moiety with the resulting ketone. Remarkably, the present process
we assembled the CDE ring system from the D-ring to the C-ring
and constructed the C7 spirocenter in the last stage by intramolecular
alkylation.
Our synthesis of 1 began with the highly practical catalytic
asymmetric Michael reaction.2 Only 0.1 mol % of (R)-AlLibis-
(binaphthoxide) (ALB) under almost neat conditions completed the
made it possible to skip more than eight steps in the synthesis.6
Michael reaction of 6 with 7 in 24 h to afford more than a kilogram
Our next goal was to construct the C-ring. We examined the
intramolecular electrophilic attack of a thionium ion to generate
of the enantiomerically pure (>99% ee) product 5 in 91% yield
without chromatographic separation.2c We then focused on the
the C7 spirocenter.6 The reported procedure using DMTSF,2b,5a
transformation of 5 to the key intermediate 4 (Scheme 1). First,
unfortunately, provided unsatisfactory results (<20% yield) due to
generation of aldehyde, formation of an unknown dimer, and over-
reaction of 18 with DMTSF. The descried condition (Scheme 1)
successfully suppressed such side reactions and highly improved
the yield (86%).6 Reductions of imines in similar indole alkaloids
the (E)-selective introduction of the hydroxylydene subunit was
achieved by anti-selective reduction of â-keto ester 9 by NaBH3-
CN with TiCl4 at -55 °C and following syn-elimination (Overman’s
method; 72%, E:Z ) 15.7:1).4c,6 DIBAL reduction of 10, followed
by silylation of the primary alcohol and conversion of the ketal to
ketone afforded, after silica gel chromatography, pure (E)-11.
Regioselective enol silyl ether formation was facilitated by the
action of lithium 2,2,6,6-tetramethylpiperidide (C7:C16 ) >6:1).
under neutral conditions often result in the cleavage of C3-C7
bond and acidic conditions solved this problem.4b,c,e,5 On the other
hand, reduction of 18 under acidic conditions proceeded by
elimination of the “SEMO” moiety to give C16-C17 exocyclic
olefin. After testing numerous neutral or acidic conditions, we
determined that treatment of 5 equiv of TiCl4 at -78 °C before the
addition of NaBH3CN effectively prevented the ring opening
reaction and as a result 2 was obtained in 68% yield.
The stage was now set for the completion of the synthesis. The
Following the Saegusa-Ito reaction using Pd2(dba)3‚CHCl3 (5 mol
%) provided 13 in 90% yield.6,7 Next, mild aldol reaction8 of enol
silyl ether (R:â ) ca. 3:1) followed by treatment with DBU afforded
the thermodynamically more stable 14R.9 Subsequent iodination
with DMAP and the Stille coupling produced 16 efficiently.10
last major hurdle involved chemoselective reduction of the thioether
(desulfurization)12 in the presence of exocyclic olefin. The Raney
Ni (W-2) reduction was the first choice for this purpose. Even
* To whom correspondence should be addressed. E-mail: mshibasa@
mol.f.u-tokyo.ac.jp.
† The University of Tokyo.
‡ Shenyang Pharmaceutical University.
9
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J. AM. CHEM. SOC. 2002, 124, 14546-14547
10.1021/ja028457r CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
a Key: (a) (R)-ALB (0.1 mol %), KO-t-Bu (0.09 mol %), MS 4A, THF (49 M), 91%, >99% ee; (b) 2-ethyl-2-methyl-1,3-dioxolane, catalytic TsOH; (c)
LiCl, H2O, DMSO, 140 °C, 97% in two steps; (d) LDA, N-methoxy-2-(4-methoxybenzyloxy)-N-methylacetamide, THF, -78 °C, 72% (conversion 82%);
(e) NaBH3CN, TiCl4, THF-CH2Cl2, -55 °C; (f) DCC, CuCl, benzene, reflux, 70% in two steps; (g) DIBAL, CH2Cl2, -78 °C; (h) TIPSOTf, Et3N, CH2Cl2,
-78 °C, 98% in two steps; (i) catalytic CSA, acetone, 62% (conversion 90%); (j) lithium 2,2,6,6-tetramethylpiperidide, TMSCl, THF, -78 °C; (k)
Pd2(dba)3‚CHCl3 (5 mol %), diallyl carbonate, MeCN, 90% in two steps; (l) LDA, TMSCl, THF, -78 °C; (m) aq. HCHO, Yb(OTf)3 (20 mol %), THF; (n)
DBU, CH2Cl2, 57% in three steps from the mixture of regioisomers 13 (conversion 80%) (o) I2, DMAP, CH2Cl2, 89%; (p) 1-iodo-2-trimethylstannylbenzene,
Pd2(dba)3‚CHCl3 (5 mol %), Ph3As (20 mol %), CuI (10 mol %), DMF, quantitative; (q) SEMCl, i-Pr2NEt, CH2Cl2, quantitative; (r) 3HF‚Et3N, THF,
quantitative; (s) Tf2O, i-Pr2NEt, then 2,2-bis(ethylthio)ethylamine, CH2Cl2, -78 °C; (t) Zn, MeOH-aqueous NH4Cl, 77% in two steps; (u) DMTSF (5
equiv), MS 4A, CH2Cl2 (0.005 M), 86%; (v) NaBH3CN, TiCl4, THF-CH2Cl2, -78 °C, 68%; (w) 1.0 N HCl in MeOH, 55 °C; (x) Ac2O, pyridine; (y)
NaOMe, MeOH; (z) TIPSCl, imidazole, DMF-CH2Cl2, 4 °C, 51% in four steps; (aa) NiCl2, NaBH4, EtOH/MeOH (4:1), 61% isolated yield after 3 times
process; (bb) SO3‚Py, Et3N, DMSO; (cc) 3HF‚Et3N, THF 83% in two steps; (dd) NaOMe, MeOH, 40 °C; (ee) malonic acid, NaOAc, Ac2O, AcOH, 110 °C,
42% in two steps.
(4) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
deactivated Raney Ni in acetone, however, promoted considerable
H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749; Woodward, R.
migration of exocyclic olefin (C19-C20) to endocyclic olefin
B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.
(C20-C21).12 Eventually, Ni boride14 emerged as a promising
Tetrahedron 1963, 19, 247. (b) Magnus, P.; Giles, M.; Bonnert, R.; Kim,
C. S.; McQuire, L.; Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114,
candidate. Although a conventional protocol caused over-reduction
4403; Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.;
instead of migration, by changing the solvent (EtOH:MeOH ) 4:1)
and addition order, 20 was obtained in 91% yield based on
consumed starting material with high selectivity (>10:1).6 Consecu-
tive SO3‚Py oxidation of the primary alcohol and deprotection of
the TIPS group afforded (+)-diaboline (21)15 through epimerization
of the C16 stereocenter. Finally, removal of the acetyl group
provided the crude Wieland-Gumlich aldehyde, which was con-
verted to (-)-strychnine (1)6 by the established method.4
In conclusion, an enantioselective total synthesis of (-)-
strychnine was accomplished through the use of the highly practical
catalytic asymmetric Michael reaction as well as a tandem cycliza-
tion that simultaneously constructed B- and D-rings. Moreover,
newly developed reaction conditions for thionium ion cyclization,
reduction of the imine moiety, and desulfurization were pivotal to
complete the synthesis. The described chemistry paves the way for
the synthesis of more advanced Strychnos alkaloids for chemical
biology studies.
Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993,
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(6) See Supporting Information for details.
(7) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J. Tetrahedron
1986, 42, 2971 and references therein.
(8) (a) Kobayashi, S. Chem. Lett. 1991, 2087. (b) Kobayashi, S.; Hachiya, I.
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(9) Both diastereomers were expected to be applicable to the synthesis because
the C16 stereocenter can be epimerized during the last stage. Unexpected
aromatization, however, proceeded in the next iodination step when 14â
was used.
Acknowledgment. This work was supported by RFTF and
Encouragement of Young Scientists (A) of Japan Society for the
Promotion of Science.
(10) (2-Nitrophenyl)ketone moiety was selected as a latent form of the indoline
based on the previous results, see ref 4g.
(11) Easy retro-1,4-additions of 8-aryl-2-azabicyclo[3.3.1]nonan-7-ones were
reported, see: Bonjoch, J.; Quirante, J.; Sole´, D.; Castells, J.; Galceran,
M.; Bosch, J. Tetrahedron 1991, 47, 4417.
(12) For a general review, see: Caube`re, P.; Coutrot, P. In ComprehensiVe
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1991; Chapter 4.3, Vol. 8, p 835.
Supporting Information Available: Experimental details for the
preparation of all new compounds and complete characterization with
copies of their 1H, 13C, and DEPT NMR spectra (PDF). This material
is available free of charge via Internet at http://pubs.acs.org.
(13) The transformation of strychnine to neostrychnine by normal Raney Ni
in EtOH was reported, see: Beddoes, R. L.; Gorman, A. A.; Prescott, A.
L. Acta Crystallogr. 1994, C50, 447 and references therein.
(14) Boar, R. B.; Hawkins, D. W.; McGhie, J. M. J. Chem. Soc., Perkin Trans.
1 1973, 654.
(15) (a) Nicoletti, M.; Goulart, M. O. F.; De Lima, R.; Goulart, A. E.; Delle
Monache, F.; Marini, B. G. B. J. Nat. Prod. 1984, 47, 953. (b) Wenkert,
E. Cheung, H. T. A.; Gottlieb, H. E. J. Org. Chem. 1978, 43, 1099 and
references therein.
References
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