General approach to the total synthesis of 9-methoxy-substituted indole alkaloids: Synthesis of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeissoschizol

Article abstract of DOI:10.1021/jo801839t

(Chemical Equation Presented) Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-N_b-methylgeissoschizol (4) are described. Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a multigram scale was developed via a Mori-Ban-Hegedus indole synthesis. The ethyl ester of D-4-methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12 serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-protected aniline 10b was crucial to the success of this heteroannulation. The α,β-unsaturated ester 6 was synthesized via the Pictet-Spengler reaction as the pivotal step. This was followed by a Ni(COD)₂-mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-N _b-methylgeissoschizol (4) as well as the opioid agonistic indole alkaloid mitragynine (1).

Full text of DOI:10.1021/jo801839t

General Approach to the Total Synthesis of 9-Methoxy-Substituted
Indole Alkaloids: Synthesis of Mitragynine, as well as
9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol
Jun Ma, Wenyuan Yin, Hao Zhou, Xuebin Liao, and James M. Cook*
Department of Chemistry and Biochemistry, UniVersity of WisconsinsMilwaukee, 3210 North Cramer,
Milwaukee, Wisconsin 53211
capncook@uwm.edu
ReceiVed August 17, 2008
Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids
mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-Nb-methylgeissoschizol (4) are described.
Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a
multigram scale was developed via a Mori-Ban-Hegedus indole synthesis. The ethyl ester of D-4-
methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12
serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized
by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-
protected aniline 10b was crucial to the success of this heteroannulation. The R,ꢀ-unsaturated ester 6
was synthesized via the Pictet-Spengler reaction as the pivotal step. This was followed by a Ni(COD)2-
mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to
provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total
synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-Nb-methylgeissoschizol (4) as well as the opioid
agonistic indole alkaloid mitragynine (1).
Introduction
structure of mitragynine hydroiodide salt was completed by
Zacharias.5 The first formal study of the pharmacology of
mitragynine (1) indicated that it was a central nervous system
(CNS) stimulant.6,7 Subsequent in vivo and in vitro studies
indicated mitragynine primarily acted on µ-opioid receptors.8,9
Although mitragynine was the major alkaloid in the extract of
Mitragyne speciosa, it was not as active as the extract of
Kratom is the common name of Mitragyne speciosa Korth,
a plant native to Thailand, which has often been used as an
opium substitute administrated by smoking, chewing, or drinking
a broth form of the kratom leaves. The alkaloid content of the
leaves of Mitragyne speciosa is about 0.5%, about half of which
is comprised of mitragynine (1). Although the structure deter-
mination of 1 has a rich history,1-4 the actual structure of 1
was unambiguously confirmed in 1964 when the X-ray crystal
(5) Zacharias, D. E.; Rosenstein, R. D.; Jeffrey, G. A. Acta Crystallogr. 1965,
18, 1039.
(6) Grewal, K. S. J. Pharmacol. 1932, 46, 251.
(1) Hooper, D. Pharm. J. 1907, 78, 453.
(2) Field, E. J. Chem. Soc., Trans. 1921, 119, 887.
(3) Hendrickson, J. B. Chem. Ind. (London) 1961, 713.
(4) Joshi, B. S.; Raymond, H.; Taylor, W. I. Chem. Ind. (London) 1963,
573.
(7) Jansen, K. L.; Prast, C. J. J. Ethnopharmacol. 1988, 23, 115.
(8) Matsumoto, K.; Mizowaki, M.; Suchitra, T.; Murakami, Y.; Takayama,
H.; Sakai, S.-i.; Aimi, N.; Watanabe, H. Eur. J. Pharmacol. 1996, 317, 75.
(9) Matsumoto, K.; Mizowaki, M.; Suchitra, T.; Takayama, H.; Sakai, S.-i.;
Aimi, N.; Watanabe, H. Life Sci. 1996, 59, 1149.
264 J. Org. Chem. 2009, 74, 264–273
10.1021/jo801839t CCC: $40.75 2009 American Chemical Society
Published on Web 12/02/2008

Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids
SCHEME 1. Retrosynthetic Analysis
FIGURE 1. Structures of some 9-methoxy-substituted indole alkaloids.
extracts from the root and stem bark displayed muscle-relaxant
activity.17 The related 9-methoxy-Nb-methylgeissoschizol (4) as
well as other quaternary indole alkaloids have also been
identified.18 These geissoschizol bases are biogenetically related
to the Corynanthe alkaloids, which enables the design of a
general approach to the synthesis of these 9-methoxy-substituted
indole alkaloids. To date, many total syntheses of corynanthei-
dine have been published.19 However, few syntheses of mi-
tragynine (1) have been reported.20,21 Presumably, the difficulty
in acquiring 4-methoxyindole starting materials has retarded
other efforts in this area.
Mitragyne speciosa. This interesting behavior prompted a careful
study and led to the discovery of another component, 7-hy-
droxymitragynine (2).10,11 This alkaloid 2 could also be readily
obtained by the oxidation of mitragynine with phenyliodine
bis(trifluoroacetate) (PIFA).12 This hydroxyl-substituted alkaloid
was 46- and 17-fold higher in activity than mitragynine and
morphine, respectively, on twitch contraction induced by
electrical stimulation in the guinea pig ileum.13,14 In vitro
receptor binding studies revealed that 7-hydroxymitragynine (2)
bound preferentially to µ-opioid receptors, although it also
interacted with δ and κ receptors, albeit less potently.
Interestingly, the demethoxy analogue of mitragynine, corynan-
theidine, did not exhibit opioid agonistic activity but reversed
the morphine-inhibited twitch contraction. Therefore, corynan-
theidine is an opioid receptor antagonist.14,15 When the methoxy
group at C-9 was replaced with an ethoxy moiety or isopropoxy
group, no opioid analgesic activity was observed. The 9-acetoxy
analogue exhibited much less activity than mitragynine. In
addition, the Nb-oxide derivative of mitragynine was not active.
These results indicated the 9-methoxy group was a very
important functional group for ligand binding to opioid recep-
tors. It also demonstrated that the lone pair of electrons on the
Nb nitrogen atom was indispensable in regard to opioid agonistic
activity.14,15 In summary, the mitragynine class of compounds
are structurally different from morphine, and some of these
indole alkaloids still exhibited high opioid agonistic activity
primarily via µ-receptors similar to morphine. This renders these
novel lead compounds for the design of new antinociceptive
agents and tools with which to study opioid receptors.
In this report, the details of the development of the recent
syntheses of these 9-methoxy-substituted indole alkaloids are
described. From a retrosynthetic perspective, it was felt the
common 9-methoxy-substituted tetracyclic intermediate 5 could
be transformed into the Corynathe indole alkaloids mitragynine
(1), 9-methoxygeissoschizol (3), and 9-methoxy-Nb-methylgeis-
soschizol (4) in simple fashion (Scheme 1). The cis configuration
at C-3 and C-15 could presumably be installed via a Ni(0)-
mediated cyclization22 of the vinyl iodide with the double bond
of the R,ꢀ-unsaturated ester 6, analogous to the previous work
of Yu.19f An asymmetric Pictet-Spengler reaction23 of the
secondary Nb-alkylamine 7 and the aldehyde 819f,24 would be
employed to stereospecifically install the correct chirality at C-3.
The Nb-allyl group of the secondary amine 7 would be required
to direct the diastereoselectivity at C-3,11 and presumably, this
(17) West, R. Arch. Int. Pharmacodyn. Ther. 1937, 56, 81.
(18) Penelle, J.; Tits, M.; Christen, P.; Molgo, J.; Brandt, V.; Frederich, M.;
Angenot, L. Phytochemistry 2000, 53, 1057.
(19) (a) Weisbach, J. A.; Kirkpatrick, J. L.; Williams, K. R.; Anderson, E. L.;
Yim, N. C.; Douglas, B. Tetrahedron Lett. 1965, 6, 3457. (b) Autrey, R. L.;
William, S. P. J. Am. Chem. Soc. 1968, 90, 4917. (c) Van Tamelen, E. E.; Hester,
J. B., Jr. J. Am. Chem. Soc. 1969, 91, 7342. (d) Beard, R. L.; Meyers, A. I. J.
Org. Chem. 1991, 56, 2091. (e) Lounasmaa, M.; Jokela, R.; Laine, C.; Hanhinen,
P. Tetrahedron Lett. 1995, 36, 8687. (f) Yu, S.; Berner, O. M.; Cook, J. M.
J. Am. Chem. Soc. 2000, 122, 7827.
(20) Takayama, H.; Maeda, M.; Ohbayashi, S.; Kitajima, M.; Sakai, S.-i.;
Aimi, N. Tetrahedron Lett. 1995, 36, 9337.
(21) (a) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491. (b)
Ma, J. PhD Thesis, University of WisconsinsMilwaukee, Milwaukee, WI, 2006.
The alkaloid 9-methoxygeissoschizol (3) (see Figure 1) was
first isolated from the bark of Strychnos guianensis.16 The crude
(10) Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.;
Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S.-i. Planta Med. 1994, 60, 580.
(11) Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.; Aimi, N.;
Ponglux, D.; Watanabe, K. Life Sci. 2004, 74, 2143.
(12) Ishikawa, H.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 5637.
(13) Takayama, H. Chem. Pharm. Bull. 2004, 52, 916.
(14) 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.
(15) Matsumoto, K.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux, D.;
Watanabe, K.; Horie, S. Life Sci. 2006, 78, 2265.
(16) Mavar-Manga, H.; Quetin-Leclercq, J.; Llabres, G.; Belem-Pinheiro, M.-
L.; Imbiriba Da Rocha, A. F. Phytochemistry 1996, 43, 1125.
(22) (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.
(23) (a) Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. (b) Cox, E. D.; Cook,
J. M. Chem. ReV. 1995, 95, 1797.
(24) Massiot, G.; Mulamba, T. J. Chem. Soc., Chem. Commun. 1983, 20,
1147.
J. Org. Chem. Vol. 74, No. 1, 2009 265

Ma et al.
SCHEME 2. Initial Synthesis of Bromide 13
SCHEME 3. Possible Pathway for Synthesis of Bromide 13
SCHEME 4. Improved Synthesis of Bromide 13 and Its
Application in 4-Methoxytryptophan Synthesis
amine 7 could be obtained from monoalkylation of 4-methoxy-
D-tryptophan 9.
Results and Discussion
A key obstacle in the preparation of 1, 3, and 4 stems from
the general lack of availability of 4-methoxytryptophans.
Extensive efforts by Ley et al.25 led to a synthesis of 4-meth-
oxytryptophan (9) in high optical purity by the process of
enzymatic kinetic resolution employing immobilized penicillin
Gacylase.TheinitialstrategyherewastousetheMori-Ban-Hegedus
indole synthesis to synthesize 4-methoxy-3-methylindole (11),
which could undergo regioselective bromination and coupling
with the anion of the Scho¨llkopf chiral auxiliary26 to provide
4-methoxyindole derivative 18 (Scheme 4). This process had
previously been successfully employed to synthesize 5-meth-
oxytryptophan27 in a regiospecific fashion. The protection of
the indole Na-H function with an electron-withdrawing group
such as a Boc moiety to decrease the electron density of the
2,3-indole double bond was essential to decrease the nucleo-
philicity at the C-2 position. Thus, the readily available aryl
iodide 10b28 was subjected to the conditions of allylic alkylation
followed by the Mori-Ban-Hegedus indole synthesis, to give
a 1:1 mixture of 3-methylindoline 12 and 3-methylindole 11;
the latter compound was presumably formed from the isomer-
ization of the 3-methylindoline 12 under the reaction conditions
(Scheme 2). The 3-methylindoline 12 was found to isomerize
rapidly to the thermodynamically more stable 3-methylindole
11 during chromatography on silica gel.21b Alternatively, the
crude mixture of 11 and 12 could be stirred under acidic
conditions to provide the 4-methoxy-3-methylindole 11 in 90%
overall yield from aryl iodide 10b. Unfortunately, the radical-
mediated bromination of the methyl indole 11 gave both the
desired 3-bromomethyl indole 13, as well as the dibromide 14.
Although the successful radical bromination of the electron-
rich 5-methoxy-3-methylindole had been reported,27 the dif-
ficulty in achieving the regioselective bromination of the
4-methoxy-3-methylindole was not unexpected. Presumably, the
methoxy substituent at the C-4 position not only enhanced the
nucleophilicity at the C-2 position but also increased the steric
hindrance at C-3 due to its proximity to the benzylic methyl
group.
Numerous attempts to optimize the reaction conditions failed
to avoid electrophilic aromatic substitution at C-2 of the indole
11. It was later decided the 3-methyleneindoline 12 might
actually serve as a better substrate for the radical bromination
since the electrophilic attack at the C-2 position in 12 would
not occur. Moreover, the allylic radical intermediate generated
from the 3-methyleneindoline 12 should aromatize rapidly to
the lower energy indolic radical 15 (Scheme 3), which could
undergo the radical bromination to give the desired 3-bromom-
ethylindole 13. Alternatively, the electrophilic addition of the
NBS to the 3-methyleneindoline 12 to provide the cationic
intermediate might occur and this could be followed by loss of
a H+ to regenerate the indole ring and provide the bromide 13.
Presumably, this ionic process was slow compared with the
radical process.
(25) (a) Ley, S. V.; Priour, A. Eur. J. Org. Chem. 2002, 23, 3995. (b) Ley,
S. V.; Priour, A.; Heusser, C. Org. Lett. 2002, 4, 711. (c) Siu, J. B.; Baxendale,
I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160.
(26) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem. 1981, 93, 793.
(27) (a) Zhang, P.; Cook, J. M. Synth. Commun. 1995, 25, 3883. (b) Zhao,
S.; Liao, X.; Cook, J. M. Org. Lett. 2002, 4, 687. (c) Zhao, S.; Liao, X.; Wang,
T.; Flippen-Anderson, J.; Cook, J. M. J. Org. Chem. 2003, 68, 6279. (d) Sarma,
S. P. V. V.; Cook, J. M. Org. Lett. 2006, 8, 1017.
(28) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
266 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids
SCHEME 5. Larock Heteroannulation
To minimize the isomerization of the 3-methyleneindoline
12 to the 3-methylindole 11 in the Mori-Ban-Hegedus indole
synthesis, it was necessary to switch the base from potassium
carbonate to silver carbonate. This silver salt is known to
minimize the isomerization of the double bond effected by the
HPdX species in the Heck coupling, and it has been previously
employed as the base in the Mori-Ban-Hegedus indole
synthesis.29 Gratifyingly, when silver carbonate was employed
in the Heck reaction, the process was much faster, and the
reaction could be carried out at room temperature (Scheme 4).
The desired 3-methyleneindoline 12 was obtained, accompanied
by a small amount of the 3-methylindole 11. The subsequent
NBS-mediated radical reaction of 12 then gave bromide
selectively, and the reaction conversion was increased from 80%
to 90%. The dibromide byproduct 14 was observed only in trace
amounts by NMR analysis of the crude material. The process
could also be scaled up to the 50 g level without loss of
selectivity or yield, although the workup was more tedious and
extra care was required to avoid isomerization. It had been
reported by Ley25a that the instability of a similar intermediate
16 led to the failure of its coupling with the anion of the
Scho¨llkopf chiral auxiliary 17. Indeed, the reaction mixture of
13 was initially yellow in CCl4 or cyclohexane solution, but on
removal of solvent the reaction mixture rapidly decomposed to
a black solid which is no longer soluble in CCl4 or cyclohexane.
Moreover, the coupling of this crude material in THF with the
anion of the Scho¨llkopf chiral auxiliary 17 provided bislactim
18, albeit in very low yields. Consequently, after removal of
the excess NBS and N-succinimide by filtration, most of the
cyclohexane was removed while a small portion of cyclohexane
remained to avoid decomposition. This cyclohexane solution
of the bromide 13 was directly used to couple with the anion
of the Scho¨llkopf chiral auxiliary 17 in THF to furnish the
desired bislactim 18 in 52% overall yield for the four steps.
With the bislactim 18 in hand, the thermal deprotection of the
Boc moiety in 18 was attempted in refluxing xylene; unfortu-
nately, this gave the desired product in only 80% yield,
accompanied by a minor product, which was believed to be the
epimerized product at the chiral auxiliary. Other alternative
methods for removal of the Boc group under various conditions,
including TMSOTf/lutidine, silica gel-mediated30 deprotection
of the Boc moiety (under reduced pressure), and KOtBu/Et2O,31
were attempted, but the epimerization was observed in all cases.
To circumvent this problem, the Scho¨llkopf chiral auxiliary was
removed under acidic conditions (90%), and this was followed
by the acid-mediated cleavage of the indole Na-Boc group by
stirring in a saturated solution of anhydrous HCl in chloroform
(80%).
the Larock heteroannulation.32 Since its development in 1991,
the Larock heteroannulation had been used extensively in the
synthesis of indoles. The strength of the Larock process stems
from the facile construction the indole ring from halide-
substituted aniline and alkyne. Good regioselectivity in most
cases can be achieved when a bulky silyl-substituted internal
alkyne was employed as a substrate. The steric interactions
between the ortho aromatic H atom and the substituent on the
alkyne (see intermediates 23 and 24 in Scheme 5) are the key
factors controlling the regioselectivity.32b,33 In the case of
4-methoxyindole derivatives, this steric effect was even more
demanding because the aromatic hydrogen atom was now
replaced by a methoxyl group in the Larock heteroannulation.
Analogous to the successful synthesis of 6- and 7-methoxy
indoles,34 the Larock heteroannulation of aniline 10a28 and the
TES propargyl-substituted Scho¨llkopf chiral auxiliary 21b34 was
attempted. Unfortunately, this provided only 40% of the desired
bislactim 22a. It was observed that the reaction rate of the
Larock heteroannulation in the 4-methoxyindole series was
slower than the corresponding 6- and 7-methoxy analogues. It
was felt that the 4-methoxyl group in the aromatic ring
substantially decreased the reaction rate of the oxidative addition
step both for electronic and steric reasons. An electron-
withdrawing group such as a Boc group on the aniline nitrogen
atom might speed up the oxidative addition step in the catalytic
cycle. Gratifyingly, the Boc-protected 2-iodo-3-methoxyaniline
10b and the TMS alkyne 21a34 underwent the Larock heteroan-
nulation at a much faster rate to afford the Na-Boc-protected
indole derivative 22c in 80% yield in 6 h. Moreover, the removal
The initial development of the synthesis of the optically active
4-methoxytryptophan ethyl ester (20) had involved a Mori-
Ban-Hegedus indole synthesis and the regioselective bromi-
nation of the 3-methylene indole 12. However, a tedious workup
process and skillful experimental techniques were required in
this process to obtain good yields. This prompted a study of
(29) Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J. Chem. Soc.,
Perkin Trans. 1 1993, 1941.
(30) Apelqvist, T.; Wensbo, D. Tetrahedron Lett. 1996, 37, 1471.
(31) (a) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am. Chem.
Soc. 1976, 98, 1275. (b) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977,
42, 918.
(33) Dussault, D. D. MS Thesis, Massachusetts Institute of Technology,
Cambridge, MA, 2003.
(32) (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. (c)
Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611. (d) Gathergood, N.;
Scammells, P. J. Org. Lett. 2003, 5, 921. (e) Larock, R. C. J. Organomet. Chem.
1999, 576, 111.
(34) (a) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525. (b) Liu, X.; Cook, J. M. Org. Lett. 2002, 4,
3339. (c) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249. (d) Yu, J.;
Wearing, X.; Cook, J. M. J. Am. Chem. Soc. 2004, 126, 1358. (e) Lewis, S. E.
Tetrahedron 2006, 62, 8655.
J. Org. Chem. Vol. 74, No. 1, 2009 267

Ma et al.
SCHEME 6. Establishment of Stereochemistry at C-3
When DMF was used as the only solvent, dialkylation was
observed. When THF was used as the only solvent the reaction
was very slow. It had been established that a bulky group on
the Nb-nitrogen atom was required to achieve 100% trans
diastereoselectivity in the asymmetric Pictet-Spengler reac-
tion.36 The Pictet-Spengler reaction of the aldehyde 824 and
the secondary amine 7 was then attempted in TFA/CH2Cl2.19f
Unfortunately, decomposition of 4-methoxyindole 7 was ob-
served under these conditions. A switch to weaker acids such
as trichloroacetic acid or chloroacetic acid resulted in decom-
position as well. Finally, acetic acid was employed to initially
provide a mixture of cis and trans isomers in a 1:3 ratio. When
this solution was allowed to stir for 5 days, the epimerization
of the cis isomer to provide the desired trans-tetrahydro-ꢀ-
carboline 29 went to completion, and an overall yield of 90%
was obtained. Alternatively, the cis and trans mixture could be
stirred in dilute TFA/CH2Cl2 solution for 30 min, although this
should be monitored by TLC carefully to avoid the decomposi-
tion of the 4-methoxyindole system.
With the trans-tetrahydro-ꢀ-carboline 29 in hand, the desired
R,ꢀ-unsaturated ester 6 was readily prepared in good yield
(Scheme 7).19f,24 The removal of 1 equiv of thiophenol from
29 was achieved in the presence of thiophenol and a catalytic
amount of NaH to furnish the monosulfide 30 in 92% yield.
Selective oxidation of the second phenyl sulfide moiety in the
presence of the Nb nitrogen atom was accomplished with
m-CPBA at -78 °C to give the sulfoxide. This material was
heated to reflux in toluene in the presence of sodium carbonate
to afford the R,ꢀ-unsaturated ester 6 in 72% yield over the three
steps. The R,ꢀ-unsaturated ester 6 was then subjected to the
Ni(COD)2-mediated cyclization, analogous to the work reported
by Yu19f and Takayama22a to afford the Corynanthe skeleton
in 31 in 75% yield. The hydrogenolysis of the benzyl ester 31
of the Boc moiety was achieved after the reaction mixture
continued to stir for 3 days to afford the desired 4-methoxy
Na-H indole 22b in 82% yield. This was carried out on a 50 g
scale. A switch from the TMS- to the TES-substituted alkyne
21b resulted in a lower yield (70%) of indole 22a. Presumably,
the oxidative addition of Pd(0) to the Boc-protected iodoaniline
10b was more facile than in the free aniline 10a. Furthermore,
the TMS-substituted alkyne was bulky enough to achieve the
regioselectivity while binding more rapidly to the Pd catalyst
than the corresponding TES substituted analogue. Overall,
excellent regioselectivity and reaction rate in the Larock
heteroannulation was a delicate balance between electronic and
steric effects.
The hydrolysis of the Scho¨llkopf chiral auxiliary and con-
comitant loss of the indole-2-silyl group of 22b smoothly took
place in aqueous 2 N HCl in THF to provide 4-methoxy-D-
tryptophan ethyl ester (20) in a single step in 91% yield (Scheme
6). The enantiomer, 4-methoxy-L-tryptophan ethyl ester, was
also synthesized (from D-valine) by the same route. With both
enantiomers in hand, the optical purity of the 4-methoxytryp-
tophan ethyl ester 20 could be determined by chiral HPLC [an
(S,S)-WHELK-01 chiral column was employed]. However, the
separation of the enantiomers 20 was not acceptable. Conse-
quently, the Nb nitrogen atom of 20 was protected by heating
with Boc anhydride (THF) to afford the Nb-Boc-protected
derivative 26. The enantiomer of 26 was also prepared, and both
were successfully separated on the HPLC when the (S,S)-
WHELK-01 chiral column was employed. The optical purity
of indole 20 was found to be >95% ee. The desired ethyl ester
20 was hydrolyzed in ethanolic NaOH solution and then
converted into the benzyl ester 27 in 84% yield.19f Cesium
carbonate35 was then employed as the base, and the monoalky-
lation of primary amine 27 with allylic bromide 28 was
successfully executed when THF/DMF (1:1) was used as a
mixed solvent system to give secondary amine 7 in 85% yield.
37
was mediated by Et3SiH in the presence of PdCl2 to afford
the corresponding carboxylic acid. (The catalytic debenzylation
had been attempted with Pd/C/H2, and the simultaneous reduc-
tion of the double bond had been observed.) The acid was then
activated via the mixed anhydride and converted into the
selenoester, which underwent the Martin modification of a
Barton-Crich decarboxylation38 to give the tetracyclic system
5 in 59% yield. The reduction of the ester 5 with lithium
aluminum hydride in THF at rt furnished the synthetic 9-meth-
oxygeissoschizol (3) in 90% yield. Methylation of 3 with methyl
iodide was followed by the exchange of the iodide anion to
chloride anion employing AgCl to provide the 9-methoxy-Nb-
methylgeissoschizol (4). The 13C NMR spectral data of 9-meth-
oxygeissoschizol (3) and 9-methoxy-Nb-methylgeissoschizol (4)
are in excellent agreement with the literature (see the Supporting
Information for details).16,18
Efforts then turned to the synthesis of mitragynine from the
common intermediate, R,ꢀ-unsaturated ester 6, analogous to the
work reported by Yu.19f The vinyl iodide 6 was subjected to
the Pd(OAc)2-catalyzed intramolecular Heck coupling in DMF
at 80 °C for 18 h to afford diene 32 in 92% yield (Scheme 8).
The reduction of the conjugated diene system was achieved with
(36) Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.; Deng,
L.; Bennett, D. W.; Cook, J. M.; Watson, W. H.; Krawiec, M. J. Org. Chem.
1997, 62, 44.
(37) Birkofer, L.B. E.; Ritter, A. Chem. Ber. 1961, 94, 821.
(38) (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.
(35) Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org. Lett.
1999, 1, 1893.
268 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids
SCHEME 7. Synthesis of 9-Methoxygessisoschizol (3) and 9-Methoxy-Nb-methylgeissoschizol (4)
SCHEME 8. Initial Synthesis of Tetracycle 35
NaBH4 in the presence of NiCl2 ·6H2O39 to provide the desired
cis system 33a in 55% yield, accompanied by the partially
reduced ꢀ,γ-unsaturated ester 33b, as a byproduct (40% yield).
In this process, NaBH4 was added in portions at 0 °C into a
mixture of the R,ꢀ-unsaturated ester 32 in MeOH and solid
NiCl2 ·6H2O. This step was exothermic, and the reaction was
carried out at 0 °C to avoid the hydrolysis of the methyl ester
moiety. The removal of the benzyl function of ester 33a was
again achieved with PdCl2 in the presence of Et3SiH37 to afford
the acid 34, which then underwent the Barton-Crich decar-
boxylation to provide cis intermediate 35 in 50% yield. The
acid 34 was activated by isobutyl chloroformate to provide the
mixed anhydride as the intermediate in the presence of NMM.
This process was followed by the addition of the 2-mercapto-
pyridine N-oxide and Et3N to provide the Barton ester. This
intermediate was then subjected to irradiation with a Q-beam
in the presence of t-BuSH until the disappearance of the
intermediate (TLC), to furnish the key intermediate 35 for
mitragynine. Unfortunately, this decarboxylation process gave
inconsistent yields. Attempts to use the radical mediated
decarboxylation of the selenoester analogous to the synthesis
of 5 furnished very low yields of 35. This prompted development
of an alternative route for the synthesis of this key tetracycle
35.
Due to the inconsistent yields, as mentioned, during the
decarboxylation of the acid 34, efforts were then directed toward
the synthesis of the tetracyclic intermediate 35 from the
stereoselective reduction of olefin 5, which had been employed
in the synthesis of 9-methoxygeissoschizol (3). Reduction of
the double bond in olefin 5 turned out to be problematic. The
reduction of 5 with Pd/C/H2 or PtO2/H2 was very slow at both
1 atm pressure and at 50 psi, returning mostly starting material.
Some isomerization of the double bond in 5 was also observed.
This isomerization took place, presumably, because of the slow
rate of the reduction. Finally, the reduction of olefin 5 to 35
was effected in 70% yield using Crabtree’s catalyst40a (Scheme
9), which has been widely employed in the reduction of tri-
and tetrasubstituted alkenes.40 With tetracycle 35 in hand, the
indole Na nitrogen atom in 35 was protected with a Boc group
to facilitate the formylation to provide the enol 37 accompanied
by its aldehydic tautomer. This enol/aldehyde mixture was then
treated with HCl (g) in EtOAc to remove the Boc group, and
(39) Jacobi, P. A.; Craig, T. A.; Walker, D. G.; Arrick, B. A.; Frechette,
R. F. J. Am. Chem. Soc. 1984, 106, 5585.
(40) (a) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331. (b) Cui, X.; Burgess,
K. Chem. ReV. 2005, 105, 3272.
J. Org. Chem. Vol. 74, No. 1, 2009 269

Ma et al.
SCHEME 9. Synthesis of Mitragynine (1)
mL, 0.188 mol) was injected via a syringe, and the mixture was
warmed to rt and stirred for 5 h, after which aq NH4Cl solution
(10 mL) was carefully added dropwise to destroy the excess NaH
at 0 °C. The mixture which resulted was poured into EtOAc (2.2
L) and H2O (300 mL), and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with H2O and
dried (Na2SO4). The solvent was removed to afford the crude
allylation product, which was used directly in the next step. To the
crude allylation product (58.0 g, 0.149 mol) were added palla-
dium(II) acetate (836 mg, 3.73 mmol), silver carbonate (49.34 g,
0.180 mol, 90% purity), triphenylphosphine (1.955 g, 7.454 mmol),
and DMF (320 mL, anhydrous). The reaction mixture was degassed
under vacuum and stirred at rt under a slow stream of argon for
8 h. The reaction mixture was poured into EtOAc (1 L) and filtered
through a pad of Celite to remove the Pd black and inorganic salts.
The solution which resulted was diluted with additional EtOAc (1
L) and was then washed with water and brine and dried (Na2SO4).
The solvent was removed under reduced pressure. This residue
contained a trace amount of DMF which was subsequently removed
under vacuum at rt (heat should not be used to avoid isomer-
ization) overnight to provide the desired 3-methyleneindoline 12
as a yellow solid: IR (film) 2974, 2929, 1712, 1635, 1597, 1469,
1382, 1348, 1269, 1150, 1096, 903, 860, 791, 753, 695, 609 cm-1
;
1H NMR (300 MHz, C6D6) δ 1.40 (9H, s), 3.25 (3H, s), 4.30 (2H,
b), 4.97 (1H, t, J ) 0.7 Hz), 6.06 (1H, t, J ) 2.4 Hz), 6.12 (1H, d,
J ) 8.3 Hz), 7.02 (1H, t, J ) 8.2 Hz), 8.14 (1H, b); EIMS (m/e,
relative intensity) 261 (M+, 72), 205 (100), 188 (21), 160 (80),
146 (34). This material was used directly in the next step.
tert-Butyl 3-(Bromomethyl)-4-methoxy-1H-indole-1-carboxy-
late (13). To a three-neck round-bottom flask (5 L) equipped with
an overhead stirrer was added cyclohexane (2.5 L, not distilled),
and it was heated to reflux. The N-Boc 4-methoxy-3-methylenein-
doline 12 was added in one portion, and this was followed by
addition of N-bromosuccinimide (25.2 g, 0.142 mol) as well as
AIBN (750 mg, 4.567 mmol). After being heated at reflux for 30
min, the slurry was cooled in an ice bath and then filtered through
a pad of Celite to remove the succinimide. The filtrate was dried
(Na2SO4), and most of the solvent was removed to provide the
3-bromomethyl 4-methoxyindole 13 as a yellow solution (around
100 mL in volume). Caution: the product will rapidly decompose
if all the solvent is removed. This yellow solution was diluted
with anhydrous THF (180 mL), cooled to -78 °C, and used directly
in the next step: 1H NMR (300 MHz, CDCl3) δ 1.70 (9H, s), 3.99
(3H, s), 4.86 (2H, s), 6.65 (1H, d, J ) 8.0 Hz), 7.21 (1H, t, J ) 8.1
Hz), 7.52 (1H, s), 7.76 (1H, d, J ) 8.2 Hz). This material was
employed immediately in the next step.
this was followed by treatment with anhydrous methanolic
hydrogen chloride solution in the presence of trimethyl ortho-
formate to afford the corresponding acetal intermediate. Analo-
gous to the route of Takayama et al.,20 the acetal was dissolved
in DMF and treated with t-BuOK to furnish mitragynine (1).
Conclusion
An efficient synthesis of optically active D- or L-4-methox-
ytryptophan ethyl ester (20) has been developed. Both the
4-methoxy-3-methylindole (11) and the isomeric indoline
derivative 12 could be obtained via the Mori-Ban-Hegedus
indole synthesis. The regioselective radical bromination of
indoline 12 gave better yields of the bromide 13 than the indole
11. The bromide 13 was successfully converted into 4-methoxy
tryptophan ethyl ester (20) after coupling with the anion of the
Scho¨llkopf chiral auxiliary 17, followed by hydrolysis of the
chiral auxiliary. Alternatively, the Larock heteroannulation was
successfully employed to synthesize tryptophan derivative 20
in a more efficient way. Importantly, the Boc protection of the
aniline was crucial to the success of this heteroannulation. The
synthetic 4-methoxytryptophan ethyl ester (20) was transformed
into the tetracycle 5. The stereocenter at C-3 was installed by
the Pictect-Spengler reaction, and the cis configuration at C-3
and C-5 was achieved by the Ni(COD)2-mediated cyclization.
The total syntheses of mitragynine (1), 9-methoxygeissoschizol
(3), and 9-methoxy-Nb-methylgeissoschizol (4) were accom-
plished from the common intermediate 5.
tert-Butyl 3-(((2R,5S)-3,6-Diethoxy-5-isopropyl-2,5-dihydro-
pyrazin-2-yl)methyl)-4-methoxy-1H-indole-1-carboxylate (18).
To a solution of (3S)-3,6-dihydro-6-isopropyl-2,5-diethoxypyrazine
(17) (37.93 g, 0.179 mol) in anhydrous THF (500 mL) under argon
at -78 °C was added dropwise n-BuLi (2.5 M in hexane, 89.6
mL, 0.224 mol). This solution was stirred for 30 min at -78 °C,
and the solution of 3-bromomethyl 4-methoxyindole 13 from the
previous step was added slowly over a period of 15 min via a
cannula at -78 °C. The mixture was stirred at -78 °C for 6 h,
slowly warmed to rt, and then quenched with a saturated aqueous
NaHCO3 solution (80 mL). The mixture was poured into EtOAc
(1.5 L) and water (200 mL). The aqueous layer was extracted with
EtOAc. The organic layer was combined and washed with water
and brine and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue was purified by flash chroma-
tography (100% hexane gradient to 5% EtOAc in hexane) to afford
the desired indole 18 as a yellow oil: IR (film) 3206, 2974, 2871,
Experimental Section
1
2838, 1731, 1692, 1603, 1567, 1494, 1465, 1434, 1368 cm-1; H
tert-Butyl 4-Methoxy-3-methyleneindoline-1-carboxylate (12).
Carbamate 10b (54.7 g, 0.157 mol) in DMF (1 L) was cooled with
an ice bath and stirred at 0 °C for 10 min. To this cold solution
was added NaH (60% dispersion in mineral oil, 6.91 g, 0.172 mol),
and the mixture was stirred at 0 °C for 30 min. Allyl bromide (16.2
NMR (300 MHz, CDCl3) δ 0.72 (3H, d, J ) 6.8 Hz), 1.05 (3H, d,
J ) 6.8 Hz), 1.17-1.34 (6H, m), 1.66 (9H, s), 2.20-2.37 (1H, m),
3.01 (1H, dd, J ) 8.2, 14.3 Hz), 3.59 (1H, dd, J ) 4.2, 14.1 Hz),
3.82 (1H, t, J ) 3.3 Hz), 3.92 (3H, s), 4.00-4.12 (4H, m),
4.24-4.33 (1H, m), 6.64 (1H, d, J ) 8.1 Hz), 7.19 (1H, t, J ) 8.4
270 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids
Hz), 7.30 (1H, s), 7.77 (1H, d, J ) 8.4 Hz); 13C NMR (75.5 MHz,
CDCl3) δ 14.2 (2 carbons), 16.6, 19.0, 28.1 (3 carbons), 31.4, 31.6,
55.0, 56.4, 60.3, 60.4 (2 carbons), 82.9, 103.0, 108.1, 117.4, 120.3,
122.8, 124.6, 136. 8, 149.6, 154.4, 163.0, 163.4. Anal. Calcd for
C26H37N3O5: C, 66.22; H, 7.91, N, 8.91. Found: C, 66.04; H, 8.01;
N, 9.18.
5 (TLC). Aqueous 10% NaOH solution (0.5 mL) was added, and the
mixture stirred for 10 min. Some white precipitate formed during this
time, and the mixture was poured into EtOAc (20 mL) and H2O (5
mL). The mixture which resulted was then filtered through a pad of
Celite, and the aqueous layer was extracted with EtOAc. The organic
layers were combined, washed with brine, and dried (Na2SO4). The
solvent was removed under reduced pressure, and the residue was
purified on a short wash column (5% methanol in ethyl acetate) to
provide the 9-methoxygeissoschizol (3) (10 mg) as a light yellow foam
in 90% yield: IR (film) 3253, 2932, 1668, 1511, 1436, 1355 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.42-1.58 (2H, m), 1.64 (3H, dd, J )
1.2, 7.0 Hz), 2.10-2.40 (2H, m), 2.90 (2H, s), 2.91-3.12 (2H, m),
3.13-3.27 (2H, m), 3.47-3.70 (3H, m), 3.90 (3H, s), 4.23 (1H, t, J
) 5.3 Hz), 5.52 (1H, q, J ) 6.8 Hz), 6.48 (1H, d, J ) 7.5 Hz), 6.97
(1H, t, J ) 8.0 Hz), 7.03 (1H, t, J ) 7.9 Hz), 8.03 (1H, s), 8.56 (1H,
s); 13C NMR (75.5 MHz, CDCl3) δ 12.8, 20.0, 31.4, 32.4, 35.7, 51.2,
51.3, 53.5, 55.1, 61.5, 99.6, 104.5, 106.9, 117.3, 121.3, 122.0, 131.8,
136.0, 137.3, 154.2; EIMS (m/e, relative intensity) 326 (M+, 77.0),
325 (82.1), 309 (10.0), 279 (22.5), 199 (63.8), 55 (100). The signals
in the 13C NMR spectrum were in excellent agreement with the
literature values (see the Supporting Information).3
9-Methoxy-Nb-methylgeissoschizol (4). The 9-methoxygeissos-
chizol (3) (3.1 mg), MeI (0.05 mL), and freshly distilled MeOH (2
mL) were stirred at rt for 24 h until disappearance of the starting
material (TLC). The solvent and excess MeI was removed under
reduced pressure, and the residue was dissolved in freshly distilled
MeOH (2 mL). This was followed by addition of AgCl (6 mg).
The mixture was covered with aluminum foil and allowed to stir
at rt for 2 d. The mixture was filtered through Celite, and the solvent
was removed under reduced pressure to afford 9-methoxy-Nb-
methylgeissoschizol 4 (2.8 mg) in 78% yield: 1H NMR (300 MHz,
CD3OD) δ 1.32-1.44 (1H, m), 1.46-1.61 (1H, m), 1.75 (1H, dd,
J ) 1.3, 7.0 Hz), 2.14-2.33 (1H, m), 2.47-2.64 (1H, m), 3.09
(3H, s), 3.10-3.20 (2H, m), 3.42 (2H, t, J ) 6.2 Hz), 3.62 (1H, d,
J ) 12.6 Hz), 3.65-3.78 (2H, m), 3.81 (3H, s), 4.26 (1H, d, J )
12.8 Hz), 4.50-4.60 (1H, m), 5.90 (1H, q, J ) 7.0 Hz), 6.44 (1H,
d, J ) 7.7 Hz), 6.88 (1H, d, J ) 8.0 Hz), 6.99 (1H, t, J ) 7.9 Hz);
13C NMR (75.5 MHz, CD3OD) δ 12.6, 18.8, 29.8, 30.8, 35.3, 48.3,
54.1, 58.5, 59.6, 62.5, 64.4, 99.2, 103.9, 104.3, 116.4, 123.3, 126.3,
128.8, 131.8, 138.4, 154.3. The signals in the 13C NMR spectra of
4 are in good agreement with the literature values (see the
Supporting Information).3
3-(((2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)-
methyl)-4-methoxy-2-trimethyl-silyl)-1H-indole (22b). To car-
bamate 10b (51.20 g, 0.176 mol) were added the internal alkyne
21a (56.80 g, 0.159 mol), palladium acetate (650 mg, 2.90 mmol),
potassium carbonate (50.42 g, 0.365 mol), lithium chloride (6.365
g, 0.150 mol), and DMF (300 mL). The mixture was degassed under
vacuum (argon) and then heated at 100 °C under a slow stream of
argon for 72 h. The mixture was cooled to rt, and EtOAc (400
mL) was added and then filtered through Celite to remove the Pd
black and inorganic salts. The solution which resulted was diluted
with additional EtOAc (1.2 L), and it was then washed with water
and brine and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue was purified on silica gel (gradient
elution from hexane to 10% EtOAc in hexane) to give the
4-methoxyindole 22b as a yellow oil (53.43 g, 82%): IR (film) 3426,
2956, 1688, 1582, 1505, 1365 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.39 (9H, s), 0.73 (3H, d, J ) 6.8 Hz), 1.11 (3H, d, J ) 6.8 Hz),
1.17 (3H, t, J ) 7.1 Hz), 1.24 (3H, t, J ) 7.1 Hz), 2.35 (1H, m),
3.00 (1H, dd, J ) 10.2, 13.4 Hz), 3.54 (1H, dd, J ) 4.7, 13.4 Hz),
3.87 (3H, s), 3.94 (3H, m), 4.08 (1H, m), 4.21 (1H, m), 4.43 (1H,
m), 6.42 (1H, d, J ) 7.6 Hz), 6.96 (1H, d, J ) 8.0 Hz), 7.06 (1H,
t, J ) 7.8 Hz), 7.89 (1H, s); 13C NMR (75.5 MHz, CDCl3) δ 0.4,
14.2, 16.5, 19.2, 28.2, 30.9, 32.8, 54.6, 58.6, 60.0, 60.1, 60.3, 98.7,
104.0, 119.3, 122.7, 122.8, 129.5, 140.0, 154.6, 162.6, 164.8; EIMS
(m/e, relative intensity) 443 (M+, 19), 232 (100), 212 (27), 169
(27); HRMS m/z C24H38N3O3Si (M + H)+ calcd 444.2682, found
444.2686.
(2R,6R,12bS,E)-Benzyl 3-Ethylidene-8-methoxy-2-(2-meth-
oxy-2-oxoethyl)-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quino-
lizine-6-carboxylate (31). To a solution of R,ꢀ-unsaturated ester
6 (1.8 g, 2.93 mmol) in freshly distilled CH3CN (80 mL) was added
Et3N (1.9 mL), and this was followed by addition of Ni[COD]2
(1.51 g, air sensitive, weighed under argon) at rt. The reaction
mixture gradually turned red, and the starting material was
completely consumed after 40 min (TLC). To the above solution
was added Et3SiH (2.0 mL), and the mixture was stirred for 30
min. The reaction mixture was then poured into a saturated aqueous
solution of Na2CO3 (30 mL) and EtOAc (150 mL). The mixture
was filtered through a pad of Celite, and the aqueous layer was
extracted with EtOAc. The combined organic layers were washed
with brine and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue was subjected to flash column
chromatography (gradient elution from hexane to 30% EtOAc in
hexane) to afford the tetracycle 31 (1.07 g) in 75% yield: IR (film)
(2Z,3E,6R,12bS)-Benzyl 3-Ethylidene-8-methoxy-2-(2-meth-
oxy-2-oxoethylidene)-1,2,3,4,6,7,12,12 b-octahydroindolo[2,3-
a]quinolizine-6-carboxylate (32). To the solution of R,ꢀ-unsatur-
ated ester 6 (860 mg, 1.40 mmol) in DMF (10 mL) were added
Pd(OAc)2 (30 mg, 0.133 mmol), PPh3 (75 mg, 0.286 mmol), and
Et3N (0.5 mL). The mixture was degassed (under vacuum and then
argon) and then heated to 80 °C for 24 h. The mixture was diluted
with EtOAc (20 mL) and then filtered through a pad of Celite to
remove the inorganic salts. The filtrate was poured into EtOAc (150
mL) and H2O (20 mL), and the aq layer was extracted with EtOAc.
The organic layers were combined, washed with H2O and brine,
and dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue was purified on a short wash column
(gradient elution from hexane to 25% EtOAc in hexane) to give
the Heck coupling product 32 (626 mg) in 92% yield: IR (film)
1
3380, 2948, 2834, 1730, 1571, 1508, 1435, 1352 cm-1; H NMR
(300 MHz, CDCl3) δ 1.65 (3H, d, J ) 6.9 Hz), 1.98-2.05 (1H,
m), 2.16-2.22 (1H, m), 2.25-2.36 (2H, m), 3.13- 3.19 (1H, m),
3.22 (1H, d, J ) 12.2 Hz), 3.37-3.42 (1H, m), 3.48 (1 H, s),
3.50-3.56 (1H, m), 3.67 (3H, s), 3.85-3.90 (1 H, m), 3.87 (3 H,
s), 4.54 (1H, t, J ) 5.6 Hz), 5.07 (1H, d, J ) 12.4 Hz), 5.16 (1H,
d, J ) 12.4 Hz), 5.43 (1H, q, J ) 6.9 Hz), 6.47 (1H, d, J ) 7.5
Hz), 6.93 (1H, d, J ) 7.7 Hz), 7.02 (1H, t, J ) 7.8 Hz), 7.24-7.29
(5 H, m), 8.23 (1 H, s); 13C NMR (75.5 MHz, CDCl3) δ 12.6, 21.0,
31.4, 32.3, 37.9, 48.9, 51.6, 54.8, 55.1, 61.0, 66.1, 99.6, 104.2,
105.0, 117.4, 120.8, 122.3, 127.8 (2 carbons), 128.3 (2 carbons),
128.5, 131.9, 135.5, 135.9, 137.3, 154.2, 172.3, 173.7; EIMS (m/
e, relative intensity) 488 (M+, 54.0), 397 (19.5), 353 (100), 279
(19.2), 199 (12.0); HRMS m/z C29H32N2O5 (M + H)+ calcd
489.2389, found 489.2368.
1
3372, 2947, 2835, 1722, 1710, 1440, 1355, 1257 cm-1; H NMR
(300 MHz, CDCl3) δ 1.76 (3H, d, J ) 6.9 Hz), 2.38 (1H, t, J )
11.8 Hz), 3.39-3.45 (2H, m), 3.54 (1H, d, J ) 16.2 Hz), 3.75-3.80
(1H, m), 3.77 (3H, s), 3.86-3.92 (1H, m), 3.87 (3H, s), 4.14 (1H,
dd, J ) 2.6, 13.8 Hz), 4.48 (1H, d, J ) 9.8 Hz), 5.07 (2H, ABq,
J ) 12.6 Hz), 5.59 (1H, q, J ) 7.0 Hz), 5.78 (1H, d, J ) 1.4 Hz),
6.47 (1H, d, J ) 7.7 Hz), 6.92 (1H, d, J ) 7.9 Hz), 7.04 (1H, t, J
) 7.8 Hz), 7.18-7.32 (5H, m), 7.98 (1H, s); 13C NMR (75.5 MHz,
CDCl3) δ 14.5, 26.4, 35.4, 51.1, 53.8, 55.1, 60.3, 60.8, 65.8, 99.6,
104.3, 105.3, 116.9, 117.0, 122.2, 123.5, 127.6 (2 carbons), 127.9,
128.5 (2 carbons), 131.5, 135.8, 136.0, 137.5, 154.2, 154.3, 167.2,
172.3; HRMS m/z C29H31N2O5 (M + H)+ calcd 487.2233, found
9-Methoxygeissoschizol (3). The tetracyclic ester 5 (12 mg, 0.034
mmol) was dissolved in THF (2 mL), and the solution was cooled to
0 °C. Then LiAlH4 (3 mg, 0.079 mmol) was added, and the mixture
was stirred at 0 °C for 1 h until the disappearance of the starting ester
J. Org. Chem. Vol. 74, No. 1, 2009 271

Ma et al.
487.2237. Anal. Calcd for C29H30N2O5: C, 71.59; H, 6.21; N, 5.76.
Found: C, 71.38; H, 6.03; N, 5.52.
dried (Na2SO4), and the solvent was removed under reduced
pressure. The residue was subjected to flash chromatography
(gradient elution from hexane to 80% EtOAc in hexane) to yield
the tetracyclic ester 35 (9 mg) in 50% yield.
(2R,3S,6R,12bS)-Benzyl 3-Ethyl-8-methoxy-2-(2-methoxy-2-
oxoethyl)-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine-
6-carboxylate (33a). To a solution of the unsaturated ester 32 (326
mg, 0.67 mmol) in CH3OH (10 mL) was added NiCl2 ·6H2O (24
mg, 0.10 mmol) at 0 °C. After the solution was stirred at 0 °C for
15 min, NaBH4 (195 mg, 5.10 mmol) was added, and the mixture
was stirred at 0 °C for 2 h. The reaction mixture was quenched by
addition of water (0.5 mL) at 0 °C. The mixture was filtered through
a pad of Celite and poured into EtOAc (100 mL) and H2O (10
mL). The aqueous layer was extracted with EtOAc, the combined
organic layers were washed with brine and dried (Na2SO4), and
the solvent was removed under reduced pressure. The residue was
purified on a flash column (gradient elution from hexane to 20%
EtOAc in hexane) to provide the saturated ester 33a (180 mg) as
the first fraction in 55% yield: IR (film) 3388, 2955, 1734, 1718,
Method B: To a solution of trisubstituted olefin 5 (24 mg, 0.067
mmol) was added (1,5-cyclooctadiene) (pyridine)(tricycle-hexy-
lphosphine)iridium(I) hexafluorophosphate (Crabtree’s catalyst, 8
mg, 0.010 mmol) and CH2Cl2 (3 mL). The solution was degassed
and filled with H2. A balloon filled with H2 was connected to the
round-bottom flask via a needle. This solution was stirred at rt for
24 h, after which the balloon was removed and the solvent was
removed under reduced pressure. The residue was purified on a
flash column (gradient elution from hexane to 80% EtOAc in
hexane) to provide the desired saturated ester 35 (17 mg) in 70%
yield: IR (film) 3386, 2924, 2799, 2751, 1730, 1569, 1507, 1436,
1
1353 cm-1; H NMR (300 MHz, CDCl3) δ 0.91 (3H, t, J ) 7.3
1
1558, 1510, 1434, 1354 cm-1; H NMR (300 MHz, CDCl3) δ
Hz), 1.20-1.30 (1H, m), 1.40-1.74 (3H, m), 1.89 (1H, td, J )
2.7, 12.8 Hz), 2.19-2.43 (4H, m), 2.56 (1H, dt, J ) 4.4, 11.5 Hz),
2.85-3.33 (5H, m), 3.72 (3H, s), 3.87 (3H, s), 6.45 (1H, d, J )
7.7 Hz), 6.88 (1H, d, J ) 8.0 Hz), 6.99 (1H, t, J ) 7.9 Hz), 7.76
(1H, s); 13C NMR (75.5 MHz, CDCl3) δ 12.4, 18.2, 23.6, 31.6,
36.5, 37.9, 39.8, 51.5, 53.3, 55.2, 59.5, 60.0, 99.6, 104.2, 107.8,
117.4, 121.8, 132.5, 133.0, 137.2, 154.4; EIMS (m/e, relative
intensity) 356 (M+, 90.0), 325 (13.2), 299 (23.5), 283 (21.6), 255
(23.2), 220 (100), 199 (17.0), 156 (61.2).
0.83-0.94 (1H, m), 0.85 (3H, t, J ) 7.1 Hz), 1.13-1.25 (1H, m),
1.38-1.55 (2H, m), 1.85 (1H, d, J ) 14.6 Hz), 2.28-2.41 (3H,
m), 2.94 (1H, d, J ) 13.9 Hz), 3.13 (1H, d, J ) 11.3 Hz), 3.25-3.60
(2H, m), 3.73 (3H, s), 3.66-3.79 (1H, m), 3.89 (3H, s), 4.24 (1H,
d, J ) 12.2 Hz), 5.08 (2H, s), 6.48 (1H, d, J ) 7.7 Hz), 6.90 (1H,
d, J ) 8.1 Hz), 7.01 (1H, t, J ) 7.9 Hz), 7.13-7.32 (5H, m), 7.80
(1H, s); 13C NMR (75.5 MHz, CDCl3) δ 12.5, 17.3, 26.8, 33.5,
36.9, 38.2, 39.9, 51.5, 53.6, 54.9, 55.1, 61.8, 65.6, 99.6, 104.1,
105.3, 117.2, 122.1, 127.3 (2 carbons), 127.6, 128.3 (2 carbons),
133.0, 136.1, 137.4, 154.3, 172.9, 173.4; EIMS (m/e, relative
intensity) 490 (M+, 28), 399 (29), 355 (100), 281 (12), 199 (32),
91 (55); HRMS m/z C29H35N2O5 (M + H)+ calcd 491.2546, found
491.2535.
Mitragynine 1. Diisopropylamine (0.053 mL, 0.37 mmol) and
THF (3 mL) were added to a round-bottom flask (10 mL), and the
solution which resulted was cooled to -78 °C and stirred for 10
min. This was followed by addition of n-BuLi (0.1 mL, 0.248 mmol,
2.5 M in hexane). The solution was stirred at -78 °C for 30 min,
and the tetracyclic ester 36 (30 mg, 0.062 mmol) in anhydrous THF
(2.5 mL) was added to this solution. The mixture was stirred at
-78 °C for 2 h and then warmed to 0 °C and stirred for 30 min.
The reaction mixture was quenched with an aqueous solution of
NaHCO3 (1 mL), and the mixture was poured into EtOAc (20 mL)
and H2O (5 mL). The aq layer was extracted with EtOAc, and the
organic layers were combined, washed (brine), and dried (Na2SO4).
The solvent was removed under reduced pressure to provide the
enol 37 together with its aldehyde tautomers (22.1 mg). Part of
this mixture (6 mg, 0.0165 mmol) was dissolved in a saturated
solution of hydrogen chloride (g) in EtOAc and stirred at rt for
8 h. The solvent was then removed under reduced pressure, and
the residue was dissolved in anhydrous methanol. To this mixture
were added methanolic HCl (1 drop) and trimethyl orthoformate
(0.1 mL), and the solution which resulted was stirred at rt for 5 h.
It was then heated to reflux for 12 h. The solvent was removed
under reduced pressure, and the residue was dissolved in DMF (2
mL). To this solution was added t-BuOK (3 mg), and the mixture
was stirred at rt for 8 h. The mixture was poured into EtOAc (20
mL) and aq NaHCO3 (5 mL).The aq layer was extracted with
EtOAc. The organic layers were combined, washed with H2O and
brine, and dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue was purified on a short wash column
(alumina, gradient elution from hexane to 40% EtOAc in hexane)
(6R,12bS)-Benzyl 3-Ethyl-8-methoxy-2-(2-methoxy-2-oxoet-
hyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-6-carbox-
ylate (33b). The tetrasubstituted olefin 33b was obtained as the
second fraction (30% EtOAc in hexane) in 40% yield (131 mg):
1H NMR (300 MHz, CDCl3) δ 1.01 (3H, t, J ) 7.6 Hz), 1.94-2.19
(2H, m), 2.24 (1H, d, J ) 13.9 Hz), 2.48 (1H, d, J ) 15.9 Hz),
2.98 (1H, d, J ) 15.0 Hz), 3.20 (1H, d, J ) 15.0 Hz), 3.27 (1H, d,
J ) 15.7 Hz), 3.50 (2H, m), 3.67 (3H, s), 3.73 (1H, m), 3.86 (3H,
s), 3.95 (1H, d, J ) 6.6 Hz), 4.50 (1H, d, J ) 10.3 Hz), 5.05 (2H,
s), 6.46 (1H, d, J ) 7.9 Hz), 6.89 (1H, d, J ) 8.2 Hz), 7.02 (1H,
t, J ) 8.1 Hz), 7.10-7.23 (5H, m), 7.83 (1H, s); 13C NMR (75.5
MHz, CDCl3) δ 12.9, 24.0, 26.8, 36.6, 37.6, 50.4, 51.8, 54.1, 55.1,
59.8, 65.6, 99.6, 104.2, 105.0, 117.1, 120.6, 122.1, 127.4 (2
carbons), 127.8, 128.3 (2 carbons), 132.6, 135.0, 135.5, 137.6,
154.3, 172.0, 172.6; EIMS (m/e, relative intensity) 488 (M+, 26),
397 (21), 353 (73), 199 (100), 155 (22), 91 (84); HRMS m/z
C29H33N2O5 (M + H)+ calcd 489.2390, found 489.2411.
Methyl 2-((2R,3S,12bS)-3-Ethyl-8-methoxy-1,2,3,4,6,7,12,12b-
octahydroindolo[2,3-a]quinolizin-2-yl)acetate (35). Method A: A
mixture of benzyl ester 33a (26 mg, 0.053 mmol) and PdCl2 (3
mg, 0.0168 mmol) in a solution of Et3SiH (0.5 mL) and freshly
distilled toluene (5 mL) was stirred at rt for 5 h until the
disappearance of the starting benzyl ester 33a by TLC. The mixture
was filtered through a pad of Celite, and the solvent was removed
under reduced pressure. The residue was purified on a short wash
column to give the acid (20 mg) in 93% yield. To this acid were
added freshly distilled CH2Cl2 (3 mL), isobutyl chloroformate (20
uL), and NMM (18 uL). The reaction mixture was stirred at rt for
1 h, at which time it was observed that the carboxylic acid was
completely consumed (TLC). The reaction vessel was covered with
aluminum foil, and to the above solution were added 2-mercapto-
pyridine N-oxide (14 mg) and Et3N (30 uL). The mixture was stirred
at rt for 2 h until the disappearance of the mixed anhydride. To the
above solution was added t-BuSH (0.2 mL), and the aluminum foil
was removed. The solution was then irradiated with a Q-beam light
for 2 h. The solution was poured into a mixture of EtOAc (30 mL)
and dilute aq NH4OH (5 mL). The aq layer was extracted with
EtOAc. The combined organic layers were washed with brine and
1
to give mitragynine 1 (1.0 mg): H NMR (300 MHz, CDCl3) δ
0.87 (3H, t, J ) 7.5 Hz), 1.58-1.70 (2H, m), 1.72-1.85 (2H, m),
2.40-2.60 (4H, m), 2.92 (1H, dd, J ) 5.5, 10.8 Hz), 2.96-3.08
(3H, m), 3.16 (1H, d, J ) 11.6 Hz), 3.70 (3H, s), 3.73 (3H, s),
3.88 (3H, s), 6.46 (1H, d, J ) 7.8 Hz), 6.90 (1H, d, J ) 8.0 Hz),
7.00 (1H, t, J ) 7.9 Hz), 7.43 (1H, s), 7.67 (1H, s); 13C NMR
(75.5 MHz, CDCl3) δ 12.9, 19.1, 23.9, 30.0, 39.9, 40.7, 51.3, 53.8,
55.3, 57.8, 61.3, 99.8, 104.2, 107.9, 111.3, 121.8, 133.7, 137.2,
154.5, 160.5; EIMS (m/e, relative intensity) 398 (M+, 100), 383
(43.5), 269 (14.3), 214 (74.5). The synthetic mitragynine was
identical on TLC to mitragynine kindly supplied by Professor
1
Takayama at Chiba University, and the H NMR and 13C NMR
272 J. Org. Chem. Vol. 74, No. 1, 2009

Total Synthesis of 9-Methoxy-Substituted Indole Alkaloids
are in good agreement with the data kindly supplied by Professor
Takayama.
paper is dedicated to Professor Kaoru Fuji for his seminal
contributions to organic chemistry.
Supporting Information Available: 1H NMR and 13C NMR
spectra for the intermediates and final products and chiral HPLC
chromatograms of the Nb-Boc-4-methoxytryptophan ethyl ester
(26). This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We thank Professor Hiromitsu Takayama
at Chiba University for providing an authentic sample of
1
mitragynine for TLC comparison, as well as a copy of the H
NMR and 13C NMR of mitragynine. We also thank Professor
John Montgomery at the University of Michigan for helpful
discussions on the Ni(COD)2-mediated cyclization. This work
was supported (in part) by NIMH and the Research Growth
Initiative of the University of WisconsinsMilwaukee. This
JO801839T
J. Org. Chem. Vol. 74, No. 1, 2009 273