Total synthesis of the opioid agonistic indole alkaloid mitragynine and the first total syntheses of 9-methoxygeissoschizol and 9-methoxy-N b-methylgeissoschizol

Article abstract of DOI:10.1021/ol071220l

An enantiospecific method for the synthesis of 4-methoxytryptophan has been developed via a regiospecific Larock heteroannulation and employed for the first total syntheses of 9-methoxygeissoschizol and 9-methoxy-N _b-methylgeissoschizol, as well as the total synthesis of the opioid agonistic alkaloid mitragynine. The asymmetric Pictet-Spengler reaction and a Ni(COD)₂-mediated cyclization served as key steps.

Full text of DOI:10.1021/ol071220l

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3491-3494
Total Synthesis of the Opioid Agonistic
Indole Alkaloid Mitragynine and the First
Total Syntheses of
9-Methoxygeissoschizol and
9-Methoxy-Nb-methylgeissoschizol
Jun Ma, Wenyuan Yin, Hao Zhou, and James M. Cook*
Department of Chemistry and Biochemistry, UniVersity of Wisconsin-Milwaukee,
3210 N. Cramer Street, Milwaukee, Wisconsin 53211
capncook@uwm.edu
Received May 23, 2007
ABSTRACT
An enantiospecific method for the synthesis of 4-methoxytryptophan has been developed via a regiospecific Larock heteroannulation and
employed for the first total syntheses of 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeissoschizol, as well as the total synthesis of the
opioid agonistic alkaloid mitragynine. The asymmetric Pictet−Spengler reaction and a Ni(COD)2-mediated cyclization served as key steps.
Mitragynine (1) was isolated from Mitragyne speciosa Korth1
and has been employed as a substitute for opioids in the
treatment of pain in Thailand. The X-ray crystal structure
of the hydroiodide salt of mitragynine was determined in
1965.2 Although mitragynine was the major alkaloid from
the extract of Mitragyne speciosa, a more careful study
indicated that a more potent alkaloid, 7-hydroxymitragynine
(2), was present in the mature leaves of M. speciosa
(Thailand). This hydroxyl derivative could also be obtained
from the oxidation of mitragynine with iodobenzene di-
acetate.3 The interesting analgesic activity and relatively
complex structure of mitragynine prompted Takayama et al.
to carry out the first total synthesis of mitragynine4 and an
SAR study.5 Interestingly, the methoxyl functional group was
found essential for the analgesic acitivity.5d Mitragynine itself
was a full opioid agonist and primarily acted on µ- and
δ-opioid receptors, whereas the desmethyl mitragynine
exhibited high affinity for µ-opioid receptors; however, it
was only a partial agonist. Furthermore, the desmethoxy
analogue of mitragynine, corynantheidine, did not exhibit
any opioid agonistic activity at all, but it reversed the
morphine-inhibited twitch contraction. Therefore, corynan-
theidine is an opioid receptor antagonist.5d The alkaloid
9-methoxy-geissoschizol (3) was first isolated from the bark
(1) (a) Hooper, D. Pharm. J. 1907, 78, 453. (b) Field, E. J. Chem. Soc.
Trans. 1921, 119, 887. (c) Hendrickson, J. B. Chem. Ind. (London) 1961,
713. (d) Joshi, B. S.; Raymond, H.; Taylor, W. I. Chem. Ind. (London)
1963, 573.
(2) Zacharias, D. E.; Rosenstein, R. D.; Jeffrey, G. A. Acta Crystallogr.
1965, 18, 1039.
(3) (a) Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.;
Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S. Planta Med. 1994, 60, 580.
(b) Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.; Aimi, N.;
Ponglux, D.; Watanabe, K. Life Sci. 2004, 74, 2143.
(4) Takayama, H.; Maeda, M.; Ohbayashi, S.; Kitajima, M.; Sakai, S.-
I.; Aimi, N. Tetrahedron Lett. 1995, 36, 9337.
(5) (a) Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi,
N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto,
L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med. Chem. 2002, 45,
1949. (b) Takayama, H. Chem. Pharm. Bull. 2004, 52, 916. (c) Takayama,
H.; Kitajima, M.; Kogure, N. Curr. Org. Chem. 2005, 9, 1445. (d)
Matsumoto, K.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux, D.;
Watanabe, K.; Horie, S. Life Sci. 2006, 78, 2265.
10.1021/ol071220l CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/08/2007

Scheme 1. Retrosynthetic Analysis of Intermediate 5
date, 4-methoxytryptophan could be obtained in high optical
purity only by the use of immobilized penicillin G acylase,
in a kinetic resolution reported by Ley et al.13 However, the
Larock heteroannulation14 is a powerful method for the
synthesis of ring-A substituted indole derivatives and has
been employed for the regiospecific synthesis of both 11-
and 12-methoxy-substituted indole alkaloids.15 The strength
of the Larock process stems from the regioselectivity that
can be achieved when a bulky silyl-substituted internal alkyne
is employed as a substrate. This regioselectivity is due, in
large part, to steric interactions between the ortho aromatic
H atom and the substituent on the alkyne.14b,16 This steric
effect is even more demanding when the aromatic hydrogen
atom is replaced by a methoxyl group in the Larock
heteroannulation, as required in the synthesis of 4-methoxy
indole derivatives. Initial attempts of the Larock heteroan-
nulation with aniline 9a and the TES propargyl-substituted
Scho¨llkopf chiral auxiliary 10b,18 under conditions analogous
to those successfully employed to prepare 11- and 12-
methoxy indoles, gave only 40% of the desired indole 11a.
Gratifyingly, the Larock heteroannulation process between
Boc-protected 2-iodo-3-methoxyaniline17 9b and the TMS
alkyne 10a18 gave the Na-Boc-protected indole derivative 12
in 80% yield in 6 h. Moreover, when the Boc-protected
indole 12 was allowed to stir for 3 days, the desired
4-methoxy Na-H indole 11b could be obtained in 82% yield.
This was carried out on 50 g scale. When the TES-substituted
alkyne 10b and the Boc-protected aniline 9b were subjected
Figure 1. Examples of 9-methoxy indole alkaloids.
of Strychnos guianensis,6 which was found in the basin of
the middle and upper Rio Orinoco rivers and throughout the
Amazon basin. The crude extracts from the root and stem
bark displayed muscle relaxant activity.7 The related 9-meth-
oxy-Nb-methylgeissoschizol (4), a quaternary indole alkaloid,
was identified later.8 To our knowledge, no total syntheses
of 3 and 4 have appeared to date, in part due to the difficulty
in regiospecific formation of the 4-methoxyindole unit.
Herein is reported the first enantiospecific total syntheses
of 3 and 4, as well as the total synthesis of mitragynine.
It was envisioned that these Corynathe indole alkaloids
mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-
Nb-methylgeissoschizol (4) could be synthesized from the
same 9-methoxy-substituted tetracyclic intermediate 5 (see
Scheme 1). Analogous to the previous work of Yu,9 the C(3)
and C(15) cis configuration might be generated via Ni(0)10
mediated cyclization of the vinyl iodide with the double bond
of the R,â-unsaturated ester in intermediate 6. The C(3)
configuration could be set up stereospecifically by the
asymmetric Pictet-Spengler reaction11 of the secondary Nb-
alkyl amine 7 and the aldehyde 8.9,12 The Nb-alkyl group of
the secondary amine 7 would direct the diastereoselectivity
at C(3)11 and, presumably, could be obtained from monoal-
kylation of 4-methoxy-D-tryptophan 9.
A key obstacle in the preparation of 1, 3 and 4 stems from
the availability, or lack thereof, of 4-methoxytryptophan. To
(13) (a) Ley, S. V.; Priour, A. Eur. J. Org. Chem. 2002, 3995. (b) Ley,
S. V.; Priour, A.; Heusser, C. Org. Lett. 2002, 4, 711.
(14) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(15) (a) Liu, X.; Deschamps, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339.
(b) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Am. Chem. Soc. 2004, 126, 1358.
(c) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 1187. (d) Castle, S.
L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
(6) Mavar-Manga, H.; Quetin-Leclercq, J.; Labres, G.; Belem-Pinheiro,
M.-L.; Imbiriba Da Rocha, A. F. Phytochemistry 1996, 43, 11.
(7) West, R. Arch. Int. Pharmacodyn. Ther. 1937, 56, 81.
(8) Penelle, J.; Tits, M.; Christen, P.; Molgo, J.; Brandt, V.; Frederich,
M.; Angenot, L. Phytochemistry 2000, 53, 1057.
(9) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc. 2000, 122,
7827.
(10) (a) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307. (b) Fornicola, R. S.; Subburaj, K.; Montgomery, J.
Org. Lett. 2002, 4, 615.
(16) Dussault, D. D. Master’s Thesis, Massachusetts Institute of Technol-
ogy, 2003.
(11) (a) Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. (b) Cox, E. D.
Cook, J. M. Chem. ReV. 1995, 95, 1797.
(12) Massiot, G.; Mulamba, T. J. Chem. Soc., Chem. Commun. 1983,
1147.
(17) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
(18) (a) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem. 1981, 93,
793. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525.
3492
Org. Lett., Vol. 9, No. 18, 2007

to the same conditions, the yield of indole decreased to 70%.
Presumably, the Boc-protected iodoaniline 9b increased the
reaction rate by accelerating the oxidative addtion of Pd(0)
to the aryl iodide. Furthermore, since the steric demands of
the methoxyl function are greater than the corresponding
aromatic H atom, the TMS substituted alkyne is bulky
enough to promote the regioselectivity while binding more
rapidly to the Pd catalyst than the corresponding TES-
substituted analogue. The hydrolysis of the Scho¨llkopf chiral
auxiliary was accompanied by concomitant loss of the indole-
2-silyl group of 11b. This smoothly took place in aqueous 2
N HCl in THF to provide 4-methoxy-D-tryptophan ethyl ester
(13) in a single step in 91% yield. The valine ethyl ester
could be removed by Kugelrohr distillation and reused. The
ethyl ester 13 was hydrolyzed in ethanolic NaOH solution
and then converted into the benzyl ester 14 by a literature
procedure in high yield, analogous to the process employed
in the synthesis of corynantheidine (Scheme 2).9,19
Scheme 3
corresponding carboxylic acid was converted into the tetra-
cyclic ester 5 via the Barton-Crich decarboxylation pro-
cess.9,23 Although one hates to remove a carboxylic acid
function during total synthesis, this function originated from
glycine employed in the Scho¨llkopf chiral auxiliary. The ester
5 was reduced with LAH to give 9-methoxygeissoschizol
(3) in 90% yield. 9-Methoxy-Nb-methylgeissoschizol (4) was
then synthesized via the Nb methylation of 3 with methyl
iodide followed by exchange of the iodide to the chloride
using AgCl (Scheme 4). To the best of our knowledge, this
Scheme 2
Scheme 4
The monoalkylation of benzyl ester 14 with the allylic
bromide20 afforded the secondary amine 7 in 85% yield when
21
Cs2CO3 was used as the base in a mixture of DMF and
THF (Scheme 3). The desired stereocenter at C-3 was
achieved via the asymmetric Pictet-Spengler reaction11
between the secondary amine 7 and the aldehyde12 8 to
furnish the tetrahydro-â-carboline 15. This diester 15 was
converted into the desired R,â-unsaturated ester 6 in 64%
overall yield via a series of standard transformations includ-
ing removal of 1 equiv of thiophenol from 15, followed by
an oxidation with m-CPBA and a sulfoxide elimination
sequence (Scheme 3).9,12
The R,â-unsaturated ester 6 was then subjected to the Ni-
(COD)2-mediated cyclization9,10 to provide the desired
Corynanthe skeleton 16 in 75% yield. Removal of the benzyl
group of the benzyl ester 16 was achieved when 16 was
treated with PdCl2 in the presence of Et3SiH,9,22 and the
is the first total synthesis of 9-methoxygeissoschizol (3) and
9-methoxy-Nb-methylgeissoschizol (4). The 13C NMR data
of synthetic (+)-4 agree in all respects with those reported
for the natural product.6,8
To prepare 1, reduction of the olefin bond in 5 was
required. The reduction of this double bond turned out to be
difficult. Many attempts with PtO2 or Pd/C reduction with
H2 were unsuccessful. However, when Crabtree’s catalyst24
(19) Wilchek, M.; Patchornik, A. J. Org. Chem. 1963, 28, 1874.
(20) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47,
404.
(21) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org.
Lett. 1999, 1, 1893.
(22) Birkofer, L. B. E.; Ritter, A. Chem. Ber. 1961, 94, 821.
(23) (a) Barton, D. H. R.; Crich, D.; Potier, P. Tetrahedron Lett. 1985,
41, 5943. (b) Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79.
(c) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1443.
Org. Lett., Vol. 9, No. 18, 2007
3493

mitragynine kindly supplied by Professor Takayama (Chiba
University), and the 1H NMR data were in excellent
agreement with the data kindly supplied by Professor
Takayama.
Scheme 5
In summary, the 4-methoxy-D-tryptophan ethyl ester 13
was prepared via Larock heteroannulation, and the Boc-
substituted aniline 9b provided much better yields of indole
than the iodoaniline 9a itself. This process could be employed
for the synthesis of 4-methoxy-D-tryptophan on large scale,
and 4-methoxy-L-tryptophan could also be synthesized in a
similar manner by employing D-valine.25 The first total
syntheses of 9-methoxygeissoschizol (3) and 9-methoxy-Nb-
methylgeissoschizol (4), as well as the total synthesis of
mitragynine (1), was achieved from 4-methoxy-D-tryptophan.
The asymmetric Pictet-Spengler reaction and Ni(COD)2-
mediated cyclization served as key steps to set up the
stereochemistry at C(3) and C(15) in these indole alkaloids.
was employed, the desired ester 17 was obtained in 70%
yield. With the tetracycle 17 in hand, it was then treated
with (Boc)2O in the presence of a catalytic amount of DMAP
to provide the Boc derivative 18 in 91% yield. The ester 18
was then subjected to formylation, and the Boc group was
removed in EtOAc that had been saturated with HCl gas.
This was followed by acetal formation and t-BuOK mediated
elimination of MeOH to provide mitragynine 1, analogous
to the final steps reported by Takayama et al.4 The synthetic
mitragynine 3 was identical on TLC to the sample of
Acknowledgment. The authors thank Professor Hiromitsu
Takayama (Chiba University) for kindly providing an
authentic sample of mitragynine, as well as copies of proton
NMR and carbon NMR data of mitragynine. Financial
support from the Research Growth Initiative of the University
of Wisconsin-Milwaukee and the NIMH are gratefully
acknowledged.
OL071220L
(24) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331.
(25) Ma, J. Ph.D. Thesis, University of Wisconsin-Milwaukee, 2006.
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