General approach for the synthesis of ajmaline/sarpagine indole alkaloids: Enantiospecific total synthesis of (+)-ajmaline, alkaloid G, and norsuaveoline via the asymmetric Pictet-Spengler reaction

Article abstract of DOI:10.1021/ja990184l

A general approach (oxyanion-Cope strategy) for the synthesis of sarpagine/ajmaline indole alkaloids has been developed. (+)-Ajmaline 1 and alkaloid G 2 as well as norsuaveoline 3 have been synthesized from D-(+)-tryptophan in enantiospecific fashion via

Full text of DOI:10.1021/ja990184l

6998
J. Am. Chem. Soc. 1999, 121, 6998-7010
General Approach for the Synthesis of Ajmaline/Sarpagine Indole
Alkaloids: Enantiospecific Total Synthesis of (+)-Ajmaline, Alkaloid
G, and Norsuaveoline via the Asymmetric Pictet-Spengler Reaction
Jin Li, Tao Wang, Peng Yu, A. Peterson, R. Weber, D. Soerens, D. Grubisha,
D. Bennett, and J. M. Cook*
Contribution from the Department of Chemistry, UniVersity of WisconsinsMilwaukee,
Milwaukee, Wisconsin 53201
ReceiVed January 19, 1999
Abstract: A general approach (oxyanion-Cope strategy) for the synthesis of sarpagine/ajmaline indole alkaloids
has been developed. (+)-Ajmaline 1 and alkaloid G 2 as well as norsuaveoline 3 have been synthesized from
D-(+)-tryptophan in enantiospecific fashion via the asymmetric Pictet-Spengler reaction and a stereocontrolled
oxyanion-Cope rearrangement as key steps. The synthesis of these indole alkaloids employed a stereospecific
Pictet-Spengler/Dieckmann protocol to prepare the key intermediate, (-)-Nb-benzyl tetracyclic ketone (7a or
7b). This ketone was converted into R,â-unsaturated aldehyde (8a or 8b) and further transformed into (+)-
ajmaline 1 and alkaloid G 2 as well as norsuaveoline 3. It was also found that reduction of 29 can be done
stereospecifically to form the 2-epidiacetylajmaline derivative 30 which has the same configuration at C(2) as
that of quebrachidine and of the bisindole alstonisidine. The ring closure reaction (from 27 to 28) to form the
sarpagine skeleton was completed in 91% yield. It should now be possible to prepare the antipode of (+)-
ajmaline via this approach for biological screening.
(+)-Ajmaline 1 was isolated from the roots of Rauwolfia
successful treatment with return to normal sinus rhythm in 85%
or more of the subjects required two drugs, electrolyte replace-
ment therapy, and the administration of thiamine. The action
of ajmaline involves a dose-dependent reduction in the maxi-
mum rate of rise of the muscle action potential, without affecting
the resting potential.6,9 Studies still continue on (+)-ajmaline
in order to develop new treatments for a variety of cardiovas-
cular diseases.2-4 However, the antipode, (-)-ajmaline, has
never been isolated nor synthesized, the use of which might
provide a new adjunct to antiarrhythmic therapy. An important
review by Creasey has also detailed the ganglionic blocking
activity of other ajmaline-related alkaloids.6 The structure of
ajmaline 1 was originally suggested by Robinson13,14 and
proposed correctly by Woodward.15 The stereochemistry was
assigned16 on the basis of additional chemical and spectroscopic
observations in 1962. The structure was confirmed by X-ray
crystallography.17 Ajmaline 1 can be converted into another
natural product, isoajmaline, simply by heating 1 above its
melting point.13 Alkaloid G 2 recently isolated from plant cell
cultures of Rauwolfia serpentina Benth by Sto¨ckigt et al.18 after
feeding experiments with ajmaline is also structurally similar
to 4. Both of these bases are related by the presence of the
serpentina in 19311 and contains four heteroatoms, six rings,
as well as nine asymmetric centers. It is a clinically important
cardiovascular indole alkaloid2-7 with historical significance1,8
and is related to the sarpagine bases (see 2 vs 4).9,10 “The most
prominent action of ajmaline is an antiarrhythmic effect on the
heart” as was reviewed by Creasey, “that is less pronounced
than that of propranolol,7 but is superior in terms of the ratio of
the refractory phase over reduced conduction to that of procaine
amide and quinidine.” 6,11 In a study that involved 900 patients
with acute or subacute myocardial infarction, ajmaline was found
to be useful in the management of both ventricular and supra
ventricular arrhythmias.12 It should be noted, however, that
(1) Siddiqui, S.; Siddiqui, R. H. J. Indian Chem. Soc. 1931, 8, 667.
(2) Brugada, J.; Brugada, P. Am. J. Cardiol. 1996, 78(5A), 69.
(3) Slowinski, S.; Rajch, D.; Zabowka, M. Przegl. Lek. 1996, 53, 196.
(4) Chen, X.; Borggrefe, M.; Martinez, R. A.; Hief, C.; Haverkamp, W.;
Hindricks, G.; Breithardt, G. J. CardioVasc. Pharmacol 1994, 24, 664.
(5) Mozo, d. R. F.; Moreno, J.; Bodegas, A.; Melchor, J.; Fernandez, L.
L.; Aranguren, G. Eur. J. Obstet., Gynecol. Reprod. Biol. 1994, 56, 63.
(6) Creasey, W. A. The Monoterpenoid Indole Alkaloids. In Heterocyclic
Compounds, Indole Series; Saxton, J. E., Ed.; John Wiley and Sons: New
York, 1983; Vol. 25, p 783.
(7) Best, H. J.; Winkler, J.; Foerster, W. Acta Biol. Med. Ger. 1977, 36,
1193.
(8) Koskinen, A.; Lounasmaa, M. The Sarpagine-Ajmaline Group of
Indole Alkaloids. In Progress in the Chemistry of Organic Natural Products;
Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer-Verlag: New York,
1983; Vol. 43, p 267.
(9) Bi, Y.; Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline
Related Alkaloids. In Studies in Natural Products Chemistry, BioactiVe
Natural Products, Part A; Basha, F. Z., Rahman, A., Eds.; Elsevier
Science: Amsterdam, The Netherlands, 1993; Vol. 13, p 383.
(10) Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline Related
Sarpagine Alkaloids. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9, p 23.
(11) Benthe, H. F. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol.
1956, 229, 82.
(12) Graslin, V. S.; Romanov, A. I.; Bykov, I. I.; Palii, V. I. Kardiologiya
1977, 17, 5.
(13) Anet, F. A. L.; Chakravarti, D.; Robinson, R.; Schlittler, E. J. Chem.
Soc. 1954, 1242.
(14) Robinson, R.; Hobson, J. D.; Anet, F. A. L.; Finch, F. C. Chem.
Ind. (London) 1955, 653.
(15) Woodward, R. B. Angew. Chem. 1956, 68, 13.
(16) Bartlett, M. F.; Sklar, R.; Taylor, W. I.; Schlittler, E.; Amai, R. L.
S.; Beak, P.; Bringi, N. V.; Wenkert, E. J. Am. Chem. Soc. 1962, 84, 622.
(17) Prewo, R.; Stezowski, J. J. Acta Crystallogr., Sect. B 1978, 34, 454.
The crystal structure of 1 was also carried out by R. B. Woodward and N.
C. Yang, personnel communication, N. C. Yang.
(18) Endreb, S.; Takayama, H.; Suda, S.; Kitajima, M.; Aimi, N.; Sakai,
S.-I.; Sto¨ckigt, J. Phytochemistry 1993, 32, 725.
10.1021/ja990184l CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 6999
Scheme 1
Figure 1.
quinuclidine ring and the C(5)-C(16) bond linkage. The
absolute configurations of the stereogenic centers at C(3), C(5),
and C(15) of members of both the sarpagine and ajmaline class
of indole alkaloids are identical. The alkaloid norsuaveoline 3
is related to 1 and 2, although ring E is fully aromatic (Figure
1).
Scheme 2
Three important reports on the synthesis of ajmaline have
appeared previously.19-22 The first was published by Masamune
et al. in 1967 and involved sixteen steps; this elegant approach
was unique and the chemistry employed was important for those
who later worked on the synthesis of ajmaline-related indole
alkaloids. However, this route was not enantiospecific, and the
yields were not reported in some cases. Two years later,
Mashimo and Sato converted tryptophan into an intermediate
employed by Masamune in the earlier synthesis of ajmaline in
order to provide a formal total synthesis of this alkaloid. Van
Tamelen in 1970 employed a new synthetic route in a biogenetic
approach to ajmaline and synthesized deoxyajmaline.21-23 Since
Hobson et al.24 had earlier converted deoxyajmaline into
ajmaline, a second total synthesis of ajmaline was completed.
This biogenetic route involved 17 steps and shed much light
on potential biogenetic pathways to 1. We wish to report here
a general approach to the synthesis of the ajmaline/sarpagine
family of indole alkaloids as well as the first enantiospecific
total synthesis of (+)-ajmaline, alkaloid G, and norsuaveoline.
As illustrated in Scheme 1, in a retrosynthetic sense both
ajmaline 1 and alkaloid G 2 might be available via a common
intermediate, the monoaldehyde 5. This aldehyde 5 could arise
from 1,5-dialdehyde 6 by a cyclization process which involves
the Nb-nitrogen function. The synthesis of 1,5-dialdehyde 6
could be approached either from the R,â-unsaturated aldehyde
8 or from the monoaldehyde 9. If both carbonyl-substituted
intermediates could be obtained in high yield from the (-)-
tetracyclic ketone 7, then the 1,5-dialdehyde 6 could serve as a
key intermediate in the synthesis of ajmaline 1 and alkaloid G
2 as well as norsuaveoline 3. Furthermore, since all of the
sarpagine/ajmaline alkaloids possess the same stereochemistry
at C(3), C(5), and C(15), the dialdehyde 6 might also serve as
a precursor for the sarpagine alkaloids.9,10 The initial goal,
therefore, was to develop a general synthetic route to 1,5-
dialdehyde 6 on a multiple gram scale from readily available
starting materials in an enantiospecific fashion.
As illustrated above the (-)-tetracyclic ketone (7a or 7b) was
synthesized25,26 via an improved route with these goals in mind,
while the racemic compound had been prepared on a kilogram
scale in the late 1970s in our laboratory.27
The synthesis of (()-5-methyl-9-oxo-12-benzyl-6,7,8,9,10,-
11-hexahydro-6,10-imino-5H-cycloocta[b]indole 7b (RdCH3)
was first reported by Yoneda28 and was significantly improved
by Soerens.29 The enantiospecific preparation of tetracyclic
ketone 7b in optically active form was originally developed by
Zhang26 and was recently improved to a two-pot process
(Scheme 2).30-32 The tryptophan methyl ester 10b was converted
into the Nb-benzyltryptophan derivative on stirring 10b with
benzaldehyde (1.1 equiv) in CH3OH at room temperature for 2
h, followed by reduction of the imine which resulted with
(25) Zhang, L. H. Ph.D. Thesis, University of Wisconsin-Milwaukee,
1990.
(19) Masamune, S.; Ang, S. K.; Egli, C.; Nakatsuka, N.; Sarkar, S. K.;
Yasunari, Y. J. Am. Chem. Soc. 1967, 89, 2506.
(20) Mashimo, K.; Sato, Y. Tetrahedron Lett. 1969, 901.
(21) Van Tamelen, E. E.; Oliver, L. K. J. Am. Chem. Soc. 1970, 92,
2136.
(22) Van Tamelen, E. E.; Oliver, L. K. Bioorg. Chem. 1976, 5, 309.
(23) Van Tamelen, E. E.; Shamma, M.; Burgstahler, A. W.; Wolinsky,
J.; Tamm, R.; Aldrich, P. E. J. Am. Chem. Soc. 1969, 91, 7315.
(24) Hobson, J. D.; McCluskey, J. G. J. Chem. Soc. 1967, 2015.
(26) Zhang, L. H.; Cook, J. M. Heterocycles 1988, 27, 2795.
(27) Soerens, D. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1978.
(28) Yoneda, N. Chem. Pharm. Bull. 1965, 13, 1231.
(29) Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.;
Yamanaka, E.; Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem. 1979,
44, 535.
(30) Li, J.; Cook, J. M. J. Org. Chem. 1998, 63, 4166.
(31) Yu, P.; Cook, J. M. J. Org. Chem. 1998, 63, 9160.
(32) Wang, T.; Yu, P.; Li, J.; Cook, J. M. Tetrahedron Lett. 1998, 8009.

7000 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
sodium borohydride (1.3 equiv) at -30 °C to -15 °C (3 h).
Acetic acid was then added to the reaction mixture to destroy
any remaining NaBH4, and the solvent was removed under
reduced pressure. Chloroform, methyl 4,4-dimethoxybutyrate
(1.1 equiv), and TFA (3 equiv) were then added directly to the
reaction vessel, and the solution was brought to reflux to provide
the trans diester 11b in high yield (overall yield >85%). The
trans isomer 11b underwent epimerization and a Dieckmann
cyclization to furnish the â-ketoester after which the solvent
was removed under reduced pressure. Acetic acid and hydro-
chloric acid were added carefully to the reaction vessel and, on
heating, ketone 7b was obtained in greater than 98% ee (overall
yield from 10 >74%). The ketone 7a was prepared via a similar
process. Importantly, five chemical transformations from tryp-
tophan methyl ester 10 to ketone 7 were accomplished in two
reaction vessels. The utility of this enantiospecific two-pot
sequence via the trans transfer of chirality in the asymmetric
Pictet-Spengler reaction is key since these reactions can be
run on a multihundred gram scale to provide the (-)-tetracyclic
ketone [7a or 7b (300 g scale)], which can now be considered
a readily available starting material for the synthesis of optically
pure macroline/sarpagine/ajmaline alkaloids. In addition, both
D-(+)-tryptophan and L-(-)-tryptophan are readily available
from commercial sources permitting entry into both antipodes
of the natural products for biological screening.
Figure 2.
Scheme 3
With sufficient quantities of the tetracyclic ketone (7a or 7b)
in hand, attention focused on methods to convert 7 into 1,5-
dialdehyde 6. Two synthetic approaches were envisaged, the
earlier of which centered on the functionalization of the
R-position of the carbonyl group in ketone 7 to furnish aldehyde
9 (or its equivalent) and then to convert 9 into 1,5-dialdehyde
6. The second route rested on the conversion of the ketone 7
via R,â-unsaturated aldehyde 8, which could be transformed to
1,5-dialdehyde 6 in subsequent steps. A series of intermolecular
processes was attempted in order to functionalize the C(15)
position of 7. These included direct alkylation reactions,33,34,35
enamine promoted processes,35 as well as metal promoted 1,4-
addition reactions,33-39 but with one notable exception,36,39 all
have failed (see Supporting Information for details).33,38,39 In
addition, attempts to treat R,â-unsaturated aldehyde 8b or 8c
under conditions to promote heterodiene Diels-Alder reac-
tions,27,40 titanium-promoted aldol processes,41 or cuprate-
mediated additions were likewise unsuccessful (see Supporting
Information for details). The inability to intermolecularly
functionalize the tetracyclic ketone 7b and the R,â-unsaturated
aldehyde 8b is believed to be due to steric constraints inherent
in this tetracyclic [3.3.1] system and electronic effects which
retard addition of reagents at C(15) from the bottom face of
the π system. The approach of a nucleophilic reagent at C(15)
of enone 8b from the less hindered bottom (R) face of the
molecule (equatorial position) is electronically disfavored; while
approach from the top (â) face (axial position) is severely
hindered by the 1,3-diaxial interactions with the cis fused
diaxial-indolomethylene bridge (Figure 2).
To overcome these steric and electronic constraints, we
envisaged execution of an intramolecular approach for the
functionalization of this tetracyclic [3.3.1] system at C(15). It
was felt that an intramolecular [3,3] sigmatropic rearrangement
could be employed to introduce the side chain at C(15) and
generate the basic carbon skeleton of the ajmaline/sarpagine
indole alkaloids. The thermal conditions of the pericyclic process
would leave the remainder of the molecule unharmed.
As shown in Scheme 3, the 1,5-dialdehyde 6 might be
prepared from the allylic alcohol 12 via an oxyanion-Cope
rearrangement. The anionic oxy-Cope rearrangement appeared
to present several advantages not the least of which rests on
generation of the olefinic bond in 13, a required latent aldehyde
moiety. Oxidative cleavage of the double bond of the alkenic
aldehyde 13 would provide the desired aldehyde 6 directly. More
importantly, the oxyanion-Cope rearrangement of allylic alcohol
12 should take place stereoselectively from the R face of the
double bond via a chair transition state to furnish the desired
configuration at C(15) required for the synthesis of all ajmaline/
macroline/sarpagine alkaloids.37
Addition of the primary Grignard reagent available from
trans-1-bromo-2-pentene 14a to the R,â-unsaturated aldehyde
8a (RdH) or 8b (RdCH3) provided the expected but undesired
alcohol 15 which resulted from allylic rearrangement of the
Grignard reagent.37 Although Benkeser et al42 reported that the
reversible Grignard addition process favored the normal addition
from the R position when the initially formed adducts were
heated at higher temperature in the cases of hindered carbonyl
substrates, the reaction of 8b (RdCH3) with trans-1-bromo-2-
pentene 14a in refluxing THF furnished none of the desired
alcohol 16a.37 Since barium reagents were reported by Yama-
moto43 to react with carbonyl compounds to yield regioselective
(33) Weber, R. W. Ph.D. Thesis, University of Wisconsin-Milwaukee,
1984.
(34) Cloudsale, I. S.; Kluge, A. F.; McClure, N. L. J. Org. Chem. 1982,
47, 919.
(35) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
(36) Fu, X.; Cook, J. M. J. Am. Chem. Soc. 1992, 114, 6910.
(37) Fu, X.; Cook, J. M. J. Org. Chem. 1993, 58, 661.
(38) Hollinshead, S. Ph.D. Thesis, University of York, 1987.
(39) Trudell, M. L.; Cook, J. M. J. Am. Chem. Soc. 1989, 111, 7504.
(40) Desimoni, G.; Tacconi, G. Chem. ReV. 1975, 75, 651.
(41) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223.
(42) Benkeser, R. A.; Siklosi, M. P.; Mozdzen, E. C. J. Am. Chem. Soc.
1978, 100, 2134.

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7001
Scheme 4
Scheme 5
R-addition of the carbanion, this approach was examined with
the unsaturated aldehyde 8. Employment of a modified proce-
dure of the original report in a fashion43 similar to a Barbier-
Grignard44 process provided the desired allylic alcohol (see 12
and 16, respectively) in high yield in both the Na-H and Na-
methyl series.45 With the desired allylic alcohols represented
by 12 in hand, we examined both the trans and the cis alcohols
under the conditions of an oxyanion-Cope rearrangement. When
allylic alcohol trans-12a (or 16a, RdCH3) was heated individu-
ally with KH at 100 °C in dioxane for 14 h, two major
diastereomers 17a and 17b were obtained in high yield
accompanied by a trace of another diastereomer (Scheme 4).32
In the Na-methyl series 16a, these are represented by diaster-
eomers 18a and 18b. Both of the diastereomers 17a (RdH)
and 17b (RdH) as well as isomers 18a (RdCH3) and 18b (Rd
CH3), respectively, contained the correct chirality at C(15), and
more importantly, after treatment with DBU or NaOMe, the
aldehydes 17b (RdH) or 18b (RdCH3) could be converted into
the desired isomers 17a (RdH) or 18a (RdCH3) in almost
quantitative yield, respectively. Both aldehydes 17a (RdH) and
18a (RdCH3) contained the correct chirality at C(3), C(5),
C(15), C(16), and C(20) required for the synthesis of sarpagine/
macroline indole alkaloids. In addition, the reaction can be
carried out in a one-pot process first by execution of the
oxyanion-Cope rearrangement, followed by addition of MeOH
with stirring at room temperature.
Scheme 6
The very high stereoselectivity in the oxyanion-Cope rear-
rangement (>30:1) in the above system bodes well for the future
synthesis of macroline/sarpagine indole alkaloids. The ortho
ester Claisen rearrangement in a related Nb-benzyl system
occurred with a diastereofacial selectivity of 13:1 from the top
face of the double bond principally via boat transition states,46
while recent results47,48 indicated that the Claisen rearrangement
in this Nb-benzyl system occurred from the bottom face via a
chair transition state with a stereoselectivity of about 3(R):1(â)
to greater than 6:1 in the 11-methoxyindole series of Hamaker.48
The diastereoselectivity for the anionic oxy-Cope rearrangement
in the analogous Nb-benzyl system (trans-12a or 16a) provided
high R facial selectivity, presumably via a chair transition state
(Scheme 5). As shown in Scheme 5, the energy of the transition
state designated T1 is lower than that of transition state T2 and
the former was favored in the oxyanion-Cope rearrangement.
Execution of the oxyanion-Cope rearrangement of the cis
olefinic isomer cis-16b under analogous conditions provided 4
diastereomers, and the diastereoselectivity at C(15) and C(20)
was much lower (Scheme 6). This can be understood by
examination of the possible transition states for the cis olefinic
isomers (T3-T5) depicted in Scheme 6. It is clear that the
transition states T3-T5 would be higher in energy than T1
observed in the case of the trans olefinic alcohols [trans-12a
(RdH) or trans-16a (RdCH3), (Scheme 5)]. Consequently it is
(43) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc. 1991,
113, 8955.
(44) Blomberg, C.; Hartog, F. A. Synthesis 1977, 18.
(45) The reaction was executed by adding the mixture of the carbonyl
compound 8 with the bromide 14 to the preformed barium metal; otherwise,
only starting material 8 was recovered.
(46) Zhang, L. H.; Trudell, M. L.; Hollinshead, S. P.; Cook, J. M. J.
Am. Chem. Soc. 1989, 111, 8263.
(47) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J. M. J. Am. Chem.
Soc. 1994, 116, 9027.
(48) Hamaker, L. K. Ph.D. Thesis, University of Wisconsin-Milwaukee,
1995.

7002 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
Scheme 7
Scheme 8
provide the same C(15) functionalized tetracyclic systems 23a,b
and 23c,d in a ratio of 3:2 (see Scheme 8). The key diastere-
omers could also be obtained by executing the Barbier-
Grignard process at 25 °C (only 1,2-addition) followed by the
anionic oxy-Cope rearrangement. The desired aldehydes 23a,b,
which contained the correct stereochemistry at C(16) for the
synthesis of ajmaline/raumacline indole alkaloids, were obtained
(from 8b) with 64% stereoselectivity.37
not suprising that cis-16b gave 4 diastereomers in a combined
yield of 83% (see Scheme 6).
Although the results depicted in Schemes 4-6 are important
in regard to the study of sigmatropic rearrangements in
azabicyclo[3.3.1]nonane systems (ortho ester Claisen rearrange-
ment vs Claisen rearrangement vs oxyanion-Cope rearrange-
ment),37,47,48 the sequence outlined in Scheme 4 also provided
the first effective solution to the stereochemical problem at
C(15), C(16), and C(20) in the sarpagine series of indole
alkaloids.9,10,49 Since the rearrangement from trans-12a (RdH)
or 16a (RdCH3) to provide 17a (RdH) or 18a (RdCH3),
respectively, generated the desired chirality at C(15), C(16), and
C(20) with extremely high diastereoselectivity (>30:1) in a one-
pot process, the aldehydes 17a (RdH) or 18a (RdCH3) can
now be prepared on multigram scale and employed for the total
synthesis of many macroline/sarpagine indole alkaloids. In fact,
this process was employed recently in the total synthesis of
talcarpine and talpinine.31,32
As mentioned previously, the ajmaline/raumacline alkaloids
contain the same stereochemistry as the macroline/sarpagine
series at C(3), C(5), and C(15) but are antipodal at C(16).
Although the oxyanion-Cope rearrangement (Scheme 4) pro-
vided the desired system for the macroline/sarpagine indole
alkaloids with high diastereoselectivity, this rearrangement
yielded only 20% of the correct stereochemistry at the critical
aldehydic position at C(16) for the synthesis of the ajmaline/
raumacline indole alkaloids. The aldehydic group in this
sarpagine system was contained in the more stable R (R)
configuration (antipodal to the natural configuration of ajmaline)
at C(16) in the reported work.18,19,22 To synthesize (+)-ajmaline
and alkaloid G, one must overcome the stereochemical problem
at C(16) and epimerization of the aldehydic group at C(16) (S)
to the more stable R stereochemistry must be retarded.
When (-)-8b was stirred with trans 3-bromo-4-heptene 21
at 0 °C under the conditions of a Barbier-Grignard process,36
the products of 1,2-addition (allylic alcohol 22, isolated as a
mixture of diastereomers) and 1,4-addition (diastereomers 23a,b
and 23c,d) were obtained in a combined yield of 90% in a ratio
of 51(22):49(23).36 This was the first reported case of 1,4-
addition to this aldehyde 8b and remains the only example to
date to our knowledge (see Scheme 7).29,33,36,37,50-52 The ratio
of desired to undesired isomers from the 1,4-addition was 3:1
(see 23a,b vs 23c,d). The allylic alcohol 22 was easily separated
from the mixture by flash chromatography, and it underwent
the anionic oxy-Cope rearrangement at 150 °C in 88% yield to
The conversion of 8b into aldehydes 23a,b, although not
stereospecific, constitutes the first effective solution to the long
standing problem of the stereochemistry at C(16) in the ajmaline
series. In earlier work19,20,22 epimerization of the aldehydic group
at C(16) to the unnatural (R) configuration complicated the
process, the ratio of desired to undesired diastereomers was
reported as 7:43 and 3:7 from different laboratories.19,20,22 In
contrast, the presence of the ethyl group in 23a,b (compared to
18a) was found to be critical to retard epimerization of the
aldehydic moiety at C(16) to the unnatural (R) configuration.
Support for the importance of the ethyl group derives from the
experiments mentioned previously (Scheme 4). As described
above, when the anionic oxy-Cope rearrangement was carried
out with the 2-pentenyl derivative 14 rather than the heptenyl
analogue 21, the diastereoselectivity at C(15) was dramatically
improved; however, the ease of epimerization at C(16) to the
unnatural diastereomer was increased {ajmaline requires the S
configuration at this center [C(16)]}. This observation was also
supported by computational results.53 As shown in Figure 3,
the enol forms of the aldehydic products are initially produced
in the oxyanion-Cope rearrangement. Protonation can occur from
the top face or the bottom face of the enol form at C(16), and
the â-face of the enol appears more hindered to protonation in
the R ) ethyl (23a) case, as compared to the pentenyl case
(18a). Protonation then occurred more readily from the R-face
of the enol in the R ) ethyl (23a) case to generate the desired
(S) configuration at C(16) for ajmaline. The presence of an ethyl
moiety in 23a,b (from 21) in the anionic oxy-Cope approach
retarded isomerization at C(16) to the unnatural isomer. When
aldehydes 23a,b were stirred with base (NaOMe), it took 2 days
to epimerize the aldehydic group to the unnatural isomer (the
aldehyde with an R configuration). In contrast, in the pentenyl
case, when 17b (RdH) or 18b was stirred under the same
alkaline conditions, the epimerization was complete in a few
hours, an epimerization process which had hindered earlier work
toward (+)-1.19,20,22,54
The two diastereomers (23a and 23b) were separated by flash
chromatography. Because the absolute configurations of 23a,b
at C(3), C(5), C(15), and C(16) were identical to those of 1
and 2, both diastereomers could be employed in the synthesis
(49) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(50) Bailey, P. D.; Hollinshead, S. P.; Mclay, N. R. Tetrahedron Lett.
1987, 28, 5177.
(51) Bailey, P. D.; McLay, N. R. Tetrahedron Lett. 1991, 32, 3895.
(52) Bailey, P. D.; Hollinshead, S. P.; McLay, N. R.; Morgan, K.; Palmer,
S. J.; Prince, S. N.; Reynolds, C. D.; Wood, S. D. J. Chem. Soc., Perkin
Trans. 1 1993, 431.
(53) The program used for calculation was MacroModel 6.0. MMFF94S
force field and MCarlo methods were employed to conduct the conforma-
tional search.
(54) Mashimo, K.; Sato, Y. Tetrahedron 1970, 26, 803.

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7003
Figure 3.
Scheme 9
Scheme 10
It was therefore decided to first cyclize the lower (D) ring and
then to form the upper (E) ring to provide the ajmaline skeleton.
To differentiate between the aldehydic function at C(17) and
the latent aldehyde at C(21), we protected the aldehyde
functional groups of 23a,b as the ethylene acetals 26a,b in
excellent yield, as illustrated in Scheme 10. Oxidative cleavage
of the olefinic bond was executed via the osmium tetraoxide/
sodium periodate sequence to provide aldehyde 27 in excellent
yield.23,57
For the maximum conversion of acetals 26a and 26b into
the aldehydes represented by 27a and 27b, the osmylation
process was interrupted before the appearance of byproducts,
which resulted from the bisosmylation of both the olefinic bond
and the indole double bond. Under controlled conditions (∼90%
conversion of 26a and 26b), the osmates which resulted were
reductively hydrolyzed with aqueous NaHSO3 solution to
provide the corresponding diols, respectively. This was followed
by sodium periodate cleavage of the diol functions to furnish
the desired aldehydes 27a (S) and 27b (R) in greater than 90%
overall yield.
of (+)-1 and 2. The initial synthetic plan toward ajmaline 1 is
shown in Scheme 9. It was planned to connect C(17) to C(7) to
form the E ring or a suitable derivative and then to cleave the
double bond in 24 to provide the aldehyde at C(21). An
advantage of this approach rested on potential ozonolytic
cleavage of the olefinic bond of 24 to generate an aldehyde at
C(21) rather than use of the more expensive OsO4.55
Unfortunately, after many attempts under different reaction
conditions, the aldehyde 23a was recovered unchanged or
underwent decomposition.56 Careful examination of a model of
23a revealed that it resembled a tripod: the indole ring, the
Nb-benzyl ring, and the side chain all pointed in different
directions. Examination of the energy differences53 between 23a
and 24 (RdOAc) indicated that cyclization of the upper ring
(E ring) would need to overcome a large energy barrier, which
was simply not possible under these circumstances (see ref 55
for details).
The desired aldehyde 27a [C(20S)] contained all of the
required chirality for the preparation of ajmaline 1 and alkaloid
G 2. For this reason, the epimeric aldehyde 27b was treated
with base and converted into an equilibrium mixture of 27a
and 27b (1:1), which again was subjected to flash chromatog-
raphy (silica gel, EtOAc/hexane ) 2:8). In this manner, the
conversion of 27b into the required 27a could be increased to
greater than 80%. This approach could also be employed to
provide 27b [C(20R)] for a synthesis of isoajmaline by reversal
of the process, if desired.
(55) Li, J. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1999.
Ozonolysis of the olefinic bond in 23a was attempted many times and was
unsuccessful due to the activity of the indole 2,3-double bond toward ozone.
The olefinic bond could be selectively osmylated in the presence of the
indole moiety; however if this was attempted without protection of the C(16)
aldehyde, a hemiacetal resulted which prevented periodate cleavage.
(56) Some of the reaction conditions attempted are summarized below:
(1) HOAc/(Ac)2O/HCl(g), (2) CF3SO3Si(CH3)3/CH2Cl2, (3) Me3SiCl/CH2-
Cl2, (4) Me3SiI/CH2Cl2, (5) Me3SiCl/CH2Cl2/HCl (5%), and (6) Me3SiCl/
AlCl3/CH2Cl2 (or THF).
The (-)-(S)-aldehyde 27a was converted into the sarpagine
system present in 28 in 91% yield by catalytic debenzylation
(57) Schro¨der, M. Chem. ReV. 1980, 80, 187.

7004 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
Scheme 11
Scheme 13
Scheme 12
the transfer of hydrogen (or hydride ion) to 29, presumably
through reduction of the related iminium ion.55 Hydrolysis of
31 with aqueous K2CO3 in methanol furnished (+)-ajmaline 1
in 93% yield. This base was spectrometrically identical (IR, 1H
NMR, 13C NMR, MS, co-TLC), including the optical rotation,
to that of an authentic sample of ajmaline.1,13
Hydrolysis of the acetal 28 in the presence of p-TSA‚H2O in
acetone provided the aldehyde 32 in 89% yield (Scheme 13).
The aldehyde 32 was converted into a derivative of alkaloid G
33 by treatment with DDQ in aqueous THF at room temperature
in 94% yield.18,58 This alcohol 33 was then hydrolyzed in 5%
K2CO3-MeOH to provide alkaloid G 2 in 92% yield. The proton
and C-13 NMR spectra of 2 were identical to those reported
for the natural product by Sto¨ckigt and Sakai.18
Although reduction of 29 gave only 36% of diacetylajmaline
31, this still constitutes the highest conversion of alcohol 29 to
(+)-159 reported to date. As mentioned, the R-face of 29 is much
less hindered than the â-face; consequently, 2-epidiacetylajma-
line 30 can be formed with 100% stereoselectivity under certain
conditions (see Table 1, Supporting Information). This latter
reduction process provides a potential route to alkaloids with
the 2-epi configuration including quebrachidine and vincamajine
as well as the bisindole alkaloid alstonisidine.6, 8-10
Although the oxyanion-Cope rearrangement employed in the
synthesis of the ajmaline-related alkaloids was not stereospecific,
the similar process (see above) in the trans pentenyl system
occurred with greater than 30:1 diastereoselectivity in the Na-H
case. This provides a highly stereoselective route to the
suaveoline alkaloids illustrated below for norsuaveoline (Scheme
14).
The aldehydic moiety in 17a was protected by heating with
ethylene glycol in 95% yield. The protection step was necessary
since cleavage of the olefinic bond in 17a by OsO4/NaIO4 was
complicated by the presence of the C(16) aldehydic moiety in
the molecule (formation of a hemiacetal, see ref 55). The olefinic
bond in 34 was then cleaved by OsO4/NaIO4 to provide the
acetal aldehyde 35 in 85% yield. It was originally thought that
reaction of 35 directly with hydroxylamine hydrochloride might
provide the pyridine ring system. However many attempts in
this effort were not successful. Consequently, the acetal aldehyde
35 was hydrolyzed by heating in p-TSA/acetone for 2 days and
then the residue that resulted was heated with hydroxylamine
hydrochloride in ethanol to furnish Nb-benzyl norsuaveoline 36
in 88% yield in a one-pot process. The Nb-benzyl group of 36
was removed by catalytic hydrogenation (Pd/C/H2) to provide
norsuaveoline 360 in 92% yield. The total synthesis of norsua-
followed by addition of acetic anhydride in a one-pot process
(two chemical transformations, Scheme 11). This acetal 28 was
then treated with acetic acid and concentrated aqueous HCl for
3 h (hydrolysis of the acetal group to provide the aldehyde
moiety), after which this mixture was stirred with acetic
anhydride/HCl(g) to effect smooth cyclization to furnish the
2-hydroxyajmaline derivative 29 as a single diastereomer in 85%
yield. The structure of this carbinolamine was determined by
NMR spectroscopy and verified by single-crystal X-ray analysis
of a derivative 29 (21-OCbz).30 The hydroxyl group in 29 was
clearly in the R configuration. This demonstrated effectively
the hindered nature of the â face of the caged structure of 29.
Although conversion of the R-hydroxyl group in 29 to a â
hydrogen atom would provide the correct stereochemistry of
ajmaline, this was expected to be difficult due to the hindered
(caged) nature of the â-face. After many attempts (see Table in
Supporting Information) under many reaction conditions,55
2-epiajmaline (R-hydrogen) could be formed with 100% dias-
tereoselectivity (Et3SiH, TFA) in 91% yield, as expected.55 The
only reaction conditions which provided the correct stereo-
chemistry at the C(2) position of ajmaline were found to be
H2/platinum oxide in dry CH2Cl2 in the presence of BF3 etherate
or the analogous reaction in the presence of BCl3.55 The former
process afforded 2-epidiacetylajmaline 30 and diacetylajmaline
31 in a ratio of 3:2 in 89% yield as illustrated in Scheme 12.
Reaction conditions such as (C2H5CHCH3)3B/PtO2, H2; NaBH4/
DME; SOCl2, Bu3SnH; Pt/H2/TFA, CH2Cl2; PtO2/H2/TFA/CH2-
Cl2; Me3SiI/PtO2/H2/CH2Cl2; and many others55 gave only
2-epiajmaline diacetate 30, or products of overreduction (see
Supporting Information for details). Reduction of alcohol 29 in
the presence of BF3 etherate or BCl3 was felt to proceed in the
correct fashion by complexation of the Lewis acid to the Nb-
nitrogen atom, which retarded reduction19,21-23 from the R-face
of 29 (or the related iminium ion). However, this process was
not successful in the presence of (C2H5CHCH3)3B, a Lewis acid
chosen for the same purpose. The reduction of 29 in the presence
of BCl3 while successful was not as clean as the process in the
presence of BF3 etherate, presumably because HCl was gener-
ated in the former case. Mechanistically, it is felt that com-
plexation of the Nb-nitrogen function with BF3 etherate pre-
vented the interaction of a palladium hydride-related species
with 29 from the R-face, which would have been involved in
(58) Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M. J. Org. Chem.
1989, 54, 2170.
(59) Bartlett, M. F.; Lambert, B. F.; Werblood, H. M.; Taylor, W. I. J.
Am. Chem. Soc. 1963, 85, 475-477.
(60) Nasser, A. M. A. G.; Court, W. E. J. Ethnopharmacol. 1984, 11,
99.

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7005
reagents. Alkaloids were visualized with Dragendorf’s reagent or a
saturated solution of ceric ammonium sulfate in 50% sulfuric acid, or
an aqueous solution of 2,4-dinitrophenylhydrazine in 30% sulfuric acid.
Chromatography refers to flash chromatography using 230-400 mesh
60 A silica gel, grade 60 (EM reagent). Methanol was dried by
distillation over magnesium metal/I2. Tetrahydrofuran (Baker reagent),
benzene (EM reagent), and toluene (EM reagent) were dried by
distillation from sodium-benzophenone ketyl. Methylene chloride was
dried over MgSO4 and then was distilled from P2O5. Diisopropylamine
and pyridine were dried by distillation over KOH. The preparation of
7a (Na-H), 8a, and 17a (Na-H) on large-scale (two-pot processes) has
been reported elsewhere.62,63
Scheme 14
One-Pot Process for Converting D-(-)-Na-Methyl Tryptophan
Methyl Ester (10b) into trans-(1S,3R)-(-)-2-Benzyl-3-methoxycar-
bonyl-1-methoxycarbonylethyl-9-methyl-1,2,3,4-tetrahydro-9H-py-
rido[3,4-b]indole (11b). Benzaldehyde (100.0 g, 0.94 mol) was added
to a solution of D-(-)-Na-methyl tryptophan methyl ester (10b) (200.0
g, 0.87 mol) in dry methanol (1300 mL). The solution which resulted
was stirred for 2 h at room temperature. The mixture was then cooled
to -30 °C, and sodium borohydride (16.6 g, 0.42 mol) was added
portionwise over a period of 1 h (the internal temperature was kept
below -10 °C). The reaction was monitored by TLC (silica gel) with
EtOAc/hexane (1:1) as the eluent (Rf ) 0.59 for the product, and Rf )
0.44 for the imine), and the process was found to be complete after
the addition of sodium borohydride. The solution which resulted was
allowed to stir for an additional 0.5 h followed by addition of acetic
acid (40 mL) at -10 °C. The solvent was removed under reduced
pressure. Chloroform (1500 mL) was added to dissolve the residue,
and methyl 4,4-dimethoxybutyrate (162 g, 1 mol) was then added in
one portion. The reaction solution was held at reflux for 12 h. The
solvent was removed under reduced pressure to provide a mixture of
trans- and cis-diesters which were separated by flash chromatography
(silica gel, EtOAc/hexane ) 15:85) to provide the trans isomer 11b
(307.6 g, 85%) and the cis diastereomer (30.6 g, 8.4%) in pure form.
The cis isomer was converted into the trans diastereomer 11b by simply
stirring in TFA/CH2Cl2 or heating the reaction mixture in CHCl3 for a
longer period of time.
veoline 3 depicted in Scheme 14 was completed in 10 reaction
vessels with an overall yield of 28%.
In summary, a general approach (oxyanion-Cope strategy)
to the synthesis of a number of indole alkaloids via the
asymmetric Pictet-Spengler reaction was developed. Ajmaline
1 and alkaloid G 2 as well as norsuaveoline 3 have been
successfully prepared via this approach. The oxyanion-Cope
rearrangement of trans-12a (RdH) or 16a (RdCH3) to generate
17a (RdH) or 18a (RdCH3), respectively, provides facile entry
into the substructure of a number of sarpagine alkaloids9,10 with
extremely high diastereoselectivity (RdH, >30:1). The synthesis
of norsuaveoline 3 was accomplished via this strategy. Ajmaline
has been employed as a class I antiarrhythmic agent in Europe
for many years but is known to exhibit serious side effects.2-5
It is of medicinal interest to determine if the unnatural antipode,
(-)-ajmaline, behaves in the same fashion as (+)-ajmaline but
with fewer side effects or whether (-)-ajmaline antagonizes the
activity of (+)-ajmaline at ion channels in the heart. The steps
described above provide a route (from L-tryptophan) to prepare
the (-)-enantiomer of ajmaline via the trans transfer of chirality
in the asymmetric Pictet-Spengler reaction. The two-pot process
for the improved preparation of azabicyclo[3.3.1]nonane 7a or
7b (300 g scale) also streamlined this enantiospecific route to
1, 2, and 3. The strategy and chemistry employed in this
approach will be useful for the synthesis of other alkaloids in
the ajmaline/sarpagine/macroline series.
trans 11b. mp 119-120 °C; [R]2D2 ) -54.6 (c)0.95, CHCl3); lit.61
[R]2D8 ) -54.8 (c ) 1.42, CHCl3); IR (KBr) 1735 cm-1; 1H NMR (250
MHz, CDCl3) δ 1.85-2.00 (2H, m), 2.38 (1H, dt, J ) 17.5, 5.6 Hz),
2.61 (1H, ddd, J ) 17.5, 9.6, 5.6 Hz), 3.05 (1H, dd, J ) 15.8, 5.5 Hz),
3.12 (1H, dd, J ) 15.8, 11.0 Hz), 3.39-3.81 (2H, ABq, J ) 13.1 Hz),
3.50 (3H, s), 3.65 (3H, s), 3.51 (1H, dd, J ) 15.7, 5.2 Hz), 3.84 (3H,
s), 4.10 (1H, dd, J ) 11.0, 5.5 Hz), 7.12-7.40 (8H, m), 7.60 (1H, d,
J ) 8 Hz); 13C NMR (CDCl3) δ 20.25, 27.90, 29.60, 29.71, 51.26,
52.00, 52.79, 53.32, 56.12, 106.29, 108.90, 118.12, 119.11, 121.32,
126.52, 126.96, 128.14, 129.29, 135.67, 137.46, 139.25, 173.34, 173.87;
CIMS (m/e, relative intensity) 421 (M + 1, 100%).
Anal. calcd for C25H28N2O4: C, 71.40; H, 6.71; N, 6.67. Found: C,
71.61; H, 6.64; N, 6.57.
cis Isomer. mp 115-116 °C; [R]2D8 ) +20.2 (c)1.46, CHCl3); lit.37
[R]2D2 ) +20 (c ) 0.96, CHCl3); IR (KBr) 1740 cm-1; H NMR (250
1
MHz, CDCl3) δ 1.50 (1H, m), 1.95 (1H, m), 2.51 (1H, dt, J ) 18.0,
6.0 Hz), 2.81 (1H, ddd, J ) 18.0, 9.8, 6.0 Hz), 3.05 (1H, dd, J ) 18.6,
6.3 Hz), 3.37 (1H, dd, J ) 18.6, 2.1 Hz), 3.56 (3H, s), 3.65 (3H, s),
3.69 (3H, s), 3.75 (1H, d, J ) 9.5 Hz), 3.89 (2H, s), 3.92 (1H, dd, J )
6.3, 2.1 Hz), 7.10-7.48 (8H, m), 7.58 (1H, d, J ) 9.4 Hz); 13C NMR
(62.87 MHz, CDCl3) δ 17.95, 29.10, 29.66, 29.66, 51.30, 51.83, 54.09,
57.44, 61.16, 104.70, 108.79, 118.25, 118.93, 121.28, 126.58, 127.31,
128.36, 129.07, 134.65, 137.49, 138.93, 174.07, 174.25; CIMS (m/e,
relative intensity) 421 (M + 1, 100%).
Experimental Section
Microanalysis was performed on an F and M Scientific Corp. Model
185 carbon, hydrogen, and nitrogen analyzer. Melting points were taken
on a Thomas-Hoover melting point apparatus and are reported
uncorrected. Proton and carbon NMR spectra were recorded on a Bruker
250 MHz, 300 MHz NMR spectrometer or a GE 500 MHz NMR
spectrometer. Infrared spectra were recorded on a Mattson Polaris IR-
10400 spectrometer or a Nicolet MX-1 FT-IR spectrometer. Mass
spectral data (EI/CI) were obtained on a Hewlett-Packard 5985B GC-
mass spectrometer or a VG Autospec (Manchester, England) mass
spectrometer. Optical rotations were measured on a JASCO DIP-370
polarimeter.
Anal. calcd for C25H28N2O4: C, 71.40; H, 6.71; N, 6.67. Found: C,
71.37; H, 6.54; N, 6.77.
One-Pot Process for Converting trans-(1S,3R)-(-)-2-Benzyl-3-
methoxycarbonyl-1-methoxycarbonylethyl-9-methyl-1,2,3,4-tetrahy-
dro-9H-pyrido[3,4-b]indole 11b into (6S,10S)-(-)-5-Methyl-9-oxo-
12-benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-cycloocta[b]in-
dole (-)-7b. The trans diester 11b (208.0 g, 0.5 mol) was dissolved in
All chemicals were purchased from Aldrich Chemical Co. unless
otherwise noted. The analytical TLC plates used were E. Merck
Brinkmann UV active silica gel (Kieselgel 60 F254) on plastic. The
TLC plates were visualized under UV light or developed with spray
(61) 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.

7006 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
dry toluene (400 mL) and added to a mixture of sodium hydride (60.8
g of 60% NaH) and dry toluene (2600 mL) under an atmosphere of
argon. Dry methanol (52 mL) was added carefully (a large amount of
H2 was evolved at this point). The mixture was stirred at room
temperature for 0.5 h and then heated to reflux for an additional 4 h.
The reaction was quenched with glacial acetic acid (50 mL), and the
solvent was removed under reduced pressure. At this point the reaction
vessel also contained mineral oil, which was decanted. Additional
glacial acetic acid (700 mL), hydrochloric acid (1000 mL, concentrated),
and water (260 mL) were added to the reaction solution, and the mixture
which resulted was heated at reflux for 8 h. After removal of the solvent
under reduced pressure, the residue was brought to pH 9 by the addition
of aq NaOH (3 N). The mixture which resulted was extracted with
CH2Cl2 (4 × 2000 mL), and the combined organic extracts were washed
with saturated aq NH4Cl (1000 mL) and brine (2 × 1000 mL) and
dried with K2CO3. The organic solution was then filtered through a
short column of alumina. Removal of the solvent under reduced pressure
afforded an oil which was chromatographed on silica gel with EtOAc/
hexane (3:7) to provide the tetracyclic ketone (-)-7b (144 g, 88%).
118.40, 119.72, 121.91, 127.33, 127.49, 128.49, 128.81, 133.28, 136.06,
138.65, 143.66, 147.81, 192.56; CIMS (m/e, relative intensity) 329 (M
+ 1, 100%).
Anal. calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C,
79.92; H, 6.12; N, 8.45.
(6S,10S)-(-)-5-Methyl-9-formyl-12-benzyl-6,7,10,11-tetrahydro-
6,10-imino-5H-cycloocta[b]indole 8b was prepared following the
procedure reported in ref 37.
(6S, 10S)-5-Methyl-9-(1′-hydroxy-hex-3′-enyl)-12-benzyl-6,7,10,-
11-tetrahydro-6,10-imino-5H-cycloocta[b]indole cis-16b. To a 100
mL flask which contained lithium metal (81.0 mg, 11.7 mmol) in dry
THF (30 mL) was added biphenyl (1.8 g, 11.7 mmol). The mixture
was stirred for 16 h until the lithium was consumed. Freshly dried BaI2
(2.20 g, 5.6 mmol) was added and the reaction mixture stirred for 1 h
and then cooled to -78 °C. A solution of the R,â-unsaturated aldehyde
8b (1.03 g, 3.0 mmol) and cis 1-bromo-2-pentene 14b (745 mg, 5. 0
mmol) in THF (10 mL) was added via a double-ended needle over 30
min. The mixture was stirred at -78 °C for an additional 2 h and then
quenched with 10% NH4OH (3 mL). The solvent was removed under
reduced pressure. The residue which resulted was dissolved in a mixture
of CH2Cl2 and H2O (1:1, 150 mL) and the aqueous layer was extracted
with CH2Cl2 (20 mL × 3). The combined organic layers were washed
with brine (30 mL), dried (K2CO3), and concentrated. The residue which
resulted was first passed through a short column of alumina (elution
with hexane) to remove biphenyl. The crude product was then
chromatographed on silica gel (ethyl acetate/hexane ) 3:7) to obtain
the 1,2-addition product (cis-16b) as a mixture of two diastereomers:
major isomer, 0.77 g, (62.3%); and minor isomer, 0.28 g, (22.8%)
(combined yield 85.1%).
7b. mp 142-144 °C; [R]D22 ) -203.4 (c ) 0.51, CHCl3); lit.37 [R]2D8
) -200.5 (c ) 0.62, CHCl3); IR (KBr) 1710 cm-1; 1H NMR (250 MHz,
CDCl3) δ 1.95-2.20 (2H, m), 2.45 (2H, m), 2.69 (1H, d, J ) 16.2
Hz), 3.24 (1H, dd, J ) 16.2, 6.3 Hz), 3.61 (3H, s), 3.71 (2H, s), 3.76
(1H, d, J ) 6.3 Hz), 4.05 (1H, t, J ) 4.0 Hz), 7.15 (1H, t, J ) 8.1 Hz),
7.25 (1H, t, J ) 8.2 Hz), 7.30-7.38 (6H, m), 7.52 (1H, d, 8.2 Hz);
CIMS (m/e, relative intensity) 331 (M + 1, 100%).
Anal. calcd for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C,
79.98; H, 6.75; N, 8.48.
Major Isomer of cis-16b. IR (KBr) 3387 cm-1; 1H NMR (250 Hz,
CDCl3) δ 0.97 (3H, t, J ) 7.4 Hz), 2.01 (3H, m), 2.31 (1H, m), 2.45
(1H, m), 2.75 (1H, dd, J ) 17.3, 5.4 Hz), 2.87 (1H, d, J ) 5.7 Hz),
3.13 (1H, dd, J ) 16, 5.7 Hz), 3.57 (3H, s), 3.80 (3H, m), 4.02 (2H,
d, J ) 5.6 Hz), 5.30 (1H, m), 5.50 (1H, m), 5.6 (1H, s), 7.30 (9H, m);
13C NMR (62.8 MHz, CDCl3) δ 14.09 (CH3), 20.71 (CH2), 22.93 (CH2),
29.15 (CH3), 29.99 (CH2), 33.31 (CH2), 48.32 (CH), 52.49 (CH), 56.54
(CH2), 73.44 (CH), 105.28 (C), 108.62 (C), 118.10 (CH), 118.80 (CH),
120.06 (CH), 120.83 (CH), 124.60 (CH), 126.95 (CH), 128.22 (CH),
128.72 (CH), 134.72 (CH), 135.71 (C), 137.08 (C), 139.13 (C), 141.42
(C); EIMS (m/e, relative intensity) 412 (M+, 100%).
(6S,10S)-(-)-9-Formyl-12-benzyl-6,7,10,11-tetrahydro-6,10-imino-
5H-cycloocta[b]indole 8a. A solution of diisopropylamine (56.38 mL,
0.4 mol) and n-butyllithium (160 mL, 2.5 M in hexane) in THF (300
mL) was cooled to -78 °C under an atmosphere of argon. R-Chlo-
romethyl phenyl sulfoxide (70 g, 0.4 mol) was dissolved in THF (80
mL) and added to the above chilled solution of freshly generated LDA.
The yellow mixture which resulted was stirred for 30 min at -78 °C,
after which the ketone 7a62,63 (50 g, 0.161 mol) in THF (400 mL) was
added dropwise via a double-ended needle over a period of 1 h. The
reaction solution was stirred for 2 h and then brought to room
temperature and diluted with THF (2000 mL). A solution of aq KOH
(1300 mL, 15 N) was added, and the heterogeneous mixture was stirred
at room temperature for 16 h. The organic layer was removed, and the
aqueous phase was extracted with EtOAc (3 × 1000 mL). The
combined organic fractions were washed with saturated aq NH4Cl (500
mL) and brine (500 mL) and dried with K2CO3. The solvent was
removed under reduced pressure to provide a crude mixture of
diastereomers (1:1) of the phenylsulfinyl oxirane. The crude mixture
was used directly in the next step without further separation and
purification. The mixture of phenylsulfinyl oxirane diastereomers was
added to a solution of dioxane (2500 mL), which contained lithium
perchlorate (20 g). The slurry was heated at reflux under an atmosphere
of argon for 4 days. The reaction was monitored by TLC (silica gel,
EtOAc/hexane ) 2:3) on the basis of the disappearance of oxirane,
which has a lower Rf value. The reaction solution was allowed to cool
to room temperature and diluted with CH2Cl2 (4000 mL). The organic
layer was washed with 10% aq ammonia (500 mL) and brine (500
mL) and dried with K2CO3. The solvent was removed under reduced
pressure. The oil which resulted was chromatographed (silica gel,
EtOAc/hexane ) 20:80) to provide the R,â-unsaturated aldehyde 8a
as an amorphous solid (45 g, 87%): [R]2D7 ) -322.8 (c ) 1.05,
Anal. calcd for C28H32N2O‚1/2H2O: C, 79.81; H, 7.83; N, 6.65.
Found: C, 79.54; H, 7.66; N, 6.63.
Minor Isomer of cis-16b. IR (KBr) 3386 cm-1; 1H NMR (250 Hz,
CDCl3) δ 0.96 (3H, t, J ) 7.5 Hz), 2.05 (3H, m), 2.31 (2H, m), 2.69
(2H, m), 3.09 (1H, dd, J ) 15.7, 5.6 Hz), 3.52 (1H, m), 3.64 (3H, s),
3.72 (2H, dd, J ) 31.9, 13.5 Hz), 4.02 (2H, d, J ) 5.6 Hz), 5.39 (1H,
m), 5.51 (1H, m), 5.71 (1H, s), 7.23 (9H, m); 13C NMR (62.8 Hz,
CDCl3) δ 14.19 (CH3), 20.75 (CH2), 22.85 (CH2), 29.21 (CH3), 29.59
(CH2), 34.99 (CH2), 48.78 (CH), 52.94 (CH), 56.67 (CH2), 72.17 (CH),
105.19 (C), 108.70 (CH), 117.41 (CH), 118.03 (CH), 118.88 (CH),
120.91 (CH), 124.55 (CH), 127.03 (CH), 128.29 (CH), 128.72 (CH),
134,85 (CH), 135.85 (C), 135.85 (C), 137.11 (C), 139.11 (C), 142.61
(C); EIMS (m/e, relative intensity) 412 (M+, 100%).
Anal. calcd for C28H32N2O‚1/3H2O: C, 80.38; H, 7.81; N, 6.69.
Found: C, 80.43; H, 7.68; N, 6.55.
(6S,10S)-5-Methyl-9-(1′-hydroxy-hex-3′-enyl)-12-benzyl-6,7,10,-
11-tetrahydro-6,10-imino-5H-cycloocta[b]indole trans-16b. Lithium
metal (220 mg, 31.7 mmol) was added to a solution of biphenyl (5.04
g, 32.7 mmol) in THF (100 mL) at 0 °C. The solution was allowed to
stir at room temperature for 12 h and then was cooled to -78 °C.
Freshly dried BaI2 (6.04 g, 15.4 mmol) was added to the above solution
at -78 °C. The mixture was stirred at room temperature for 2 h and
then cooled to -78 °C. A solution of trans 1-bromo-2-pentene 14a
(2.14 g, 14.3 mmol) and R,â-unsaturated aldehyde 8b (1.18 g, 3.6
mmol) in THF (60 mL) was added to the above reaction mixture at
-78 °C dropwise over a period of 1 h. The reaction solution was stirred
at -78 °C for 4 h and then was brought to pH 7 with an aqueous
solution of NH4Cl and then extracted with EtOAc (3 × 50 mL). The
organic layer was washed with brine (2 × 50 mL) and dried (K2CO3).
The solvent was removed under reduced pressure. The oil which
resulted was chromatographed (silica gel, EtOAc/hexane ) 30:70) to
1
CHCl3); FTIR (NaCl) 1670, 3393 cm-1; H NMR (250 MHz, CDCl3)
δ 2.37 (1H, dd, J ) 19.20, 5.00 Hz), 2.65 (1H, d, J ) 16.40 Hz), 2.95
(1H, dd, J ) 19.20, 5.20 Hz), 3.22 (1H, dd, J ) 16.50, 5.90 Hz), 3.71
(1H, d, J ) 13.40 Hz), 3.85 (1H, d, J ) 13.40 Hz), 4.01 (1H, d, J )
5.50 Hz), 4.22 (1H, d, J ) 5.60 Hz), 6.72 (1H, d, J ) 2.90 Hz), 7.12
(1H, t, J ) 6.75 Hz), 7.17 (1H, t, J ) 6.90 Hz), 7.25-7.50 (6H, m),
7.49 (1H, d, J ) 7.20 Hz), 7.70 (1H, s), 9.33 (1H, s); 13C NMR (62.8
MHz, CDCl3) δ 22.12, 32.96, 49.36, 50.29, 56.40, 106.31, 110.99,
(62) Yu, P., Ph.D. Thesis, University of Wisconsin-Milwaukee, 1999.
(63) Yu, P.; Wang, T.; Li, J.; Cook, J. M. manuscript in preparation.

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7007
provide the allylic alcohol trans-16b (1.28 g, 90%) as a mixture of
135.85, 136.01, 139.10, 140.00, 141.86; CIMS (m/e, relative intensity)
399 (M + 1, 100%).
Anal. calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.48; H, 7.41; N, 6.90.
two diastereomers in a ratio of 4:1.
1
Major Isomer of trans-16b. H NMR (300 MHz, CDCl3) δ 0.97
(3H, t, J ) 7.3 Hz), 2.02 (2H, m), 2.29 (1H, t, J ) 7.4), 2.75 (1H, dd,
J ) 17.0, 7.5 Hz), 2.85 (1H, d, J ) 16 Hz), 3.10 (1H, dd, J ) 16.0,
6.0 Hz), 3.56 (3H, s), 3.68 (2H, dd, J ) 19.0, 14.8 Hz), 3.85 (1H, t, J
) 5.66 Hz), 4.02 (1H, t, J ) 5.8 Hz), 5.27-5.43 (1H, m), 5.56-5.61
(2H, m), 7.06 (1H, t, J ) 7.6 Hz), 7.17 (1H, t, J ) 7.7 Hz), 7.24-7.
36 (6H, m), 7.41 (1H, d, J ) 7.7 Hz); 13C NMR (75 MHz, CDCl3) δ
13.76, 23.04, 25.65, 29.22, 29.98, 38.88, 48.51, 52.58, 56.67, 73.23,
105.43, 108.68, 118.19, 118.86, 119.98, 120.91, 125.05, 127.08, 127.30,
128.30, 128.78, 135.84, 136.06, 137.19, 139.24, 141.47; EIMS (m/e,
relative intensity) 412 (M+, 100%).
Oxy-anion Cope Rearrangement To Convert (6S,10S)-9-(1′-
Hydroxy-3′-hexenyl)-12-benzyl-6,7,10,11-tetrahydro-6,10-imino-5H-
cycloocta[b]indole trans-12a into (6S,10S)-8-(1′-Ethyl-2′-propenyl)-
12-benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-cycloocta[b]indole-
9-carboxaldehydes 17a and 17b. A solution of both diastereomers of
allylic alcohol trans-12a (10.2 g, 25.7 mmol) obtained from the last
step and 18-crown-6 (14.5 g, 54.9 mmol) in dry dioxane (1000 mL)
was added to a suspension of KH (5.60 g, 140 mmol) in dry dioxane
(500 mL). The light yellow-colored mixture which resulted was stirred
at room temperature for 2 h and then heated to reflux under argon for
14 h. The reaction mixture was allowed to cool to room temperature,
after which it was quenched by careful addition of methanol (50 mL)
and then extracted with methylene chloride (3 × 500 mL). The
combined organic extracts were washed with water (200 mL) and brine
(200 mL), dried (K2CO3), and concentrated under reduced pressure.
The residue which resulted was chromatographed on silica gel (EtOAc/
hexane ) 2:8) to provide alkenic aldehydes 17a and 17b which were
the rearrangement products from the R face (8.7 g, 85%); the ratio of
17a to 17b was 4:1 on the basis of the isolated material. Only a trace
of the mixture of alkenic aldehydes which arose from rearrangement
Anal. calcd for C28H32N2O: C, 81.35; H, 7.99; N, 6.78. Found: C,
81.25; H, 8.03; N, 6.57.
1
Minor Isomer of trans-16a. H NMR (300 MHz, CDCl3) δ 0.97
(3H, t, J ) 7.3 Hz), 2.02 (2H, m), 2.20 (1H, t, J ) 7.4), 2.35 (1H, m),
2.60-2.80 (2H, m), 2.71 (1H, d, J ) 16.7 Hz), 3.08 (1H, dd, J )
16.5, 7.5 Hz), 3.57 (3H, s), 3.61 (1H, d, J ) 13.5 Hz), 3.80 (1H, d, J
) 13.5 Hz), 4.03 (1H, d, J ) 6.0 Hz), 5.40-5.72 (3H, m), 7.07 (1H,
t, J ) 7.6 Hz), 7.17 (1H, t, J ) 7.7 Hz), 7.24-7. 36 (6H, m), 7.47
(1H, d, J ) 7.7 Hz); 13C NMR (75 MHz, CDCl3) δ 13.78, 23.00, 25.64,
29.20, 29.51, 40.50, 48.86, 52.95, 56.73, 72.01, 105.30, 108.70, 117.41,
118.06, 118.89, 120.91, 124.91, 127.04, 127.30, 128.31, 128.70, 136.04,
137.16, 139.71, 142.00; EIMS (m/e, relative intensity) 412 (M+, 100%).
1
from the â face was detected by H NMR.
Major Isomer 17a. FTIR (NaCl) 1452, 1708, 2954, 3396 cm-1; 1H
NMR (250 MHz, CDCl3) δ 0.69-0.90 (4H, m), 1.40-1.65 (2H, m),
1.83 (1H, d, J ) 12.70 Hz), 2.16 (1H, dt, J ) 12.70, 4.10 Hz), 2.29
(1H, dq, J ) 9.90, 3.15 Hz), 2.48 (1H, d, 16.80 Hz), 2.49 (1H, d, J )
1.70 Hz), 3.34 (1H, dd, J ) 16.80, 7.40 Hz), 3.59 (1H, s), 3.69 (1H,
dd, J ) 7.20, 1.90 Hz), 4.00 (1H, s), 4.87-5.04 (2H, m), 5.15-5.70
(1H, m), 7.15-7.39 (8H, m), 7.57 (1H, dd, J ) 6.68, 2.10 Hz), 7.75
(1H, s), 9.94 (1H, s); 13C NMR (62.8 MHz, CDCl3) δ 11.55, 21.88,
24.60, 31.85, 33.10, 46.94, 52.41, 53.65, 55.86, 57.78, 107.48, 111.08,
116.79, 118.11, 119.55, 121.56, 127.05, 127.17, 128.38, 128.65, 133.29,
135.84, 139.04, 140.67, 204.66; CIMS (m/e, relative intensity) 399 (M
+ 1, 100%).
Anal. calcd for C28H32N2O: C, 81.35; H, 7.99; N, 6.78. Found: C,
81.00; H, 7.69; N, 7.03.
1,2-Addition of trans-1-Bromo-2-pentene 14a to the R,â-Unsatur-
ated Aldehyde 8a To Provide the Diastereomers of (6S,10S)-9-(1′-
Hydroxy-3′-hexenyl)-12-benzyl-6,7,10,11-tetrahydro-6,10-imino-5H-
cycloocta[b]indole trans-12a. A mixture of lithium metal (1.72 g, 0.248
mol) and biphenyl (40.0 g, 0.260 mol) in freshly distilled THF (400
mL) was stirred at room temperature overnight. Freshly dried BaI2 (47.0
g, 0.120 mol) was then added to the above dark blue solution, and the
mixture which resulted was stirred at room temperature for 1 h. The
dark red solution which formed was cooled to -78 °C in a cooling
bath of dry ice/EtOAc. A solution of R,â-unsaturated aldehyde 8a (10.0
g, 0.0305 mol) and trans-1-bromo-3-pentene (18.8 g, 0.126 mol) in
THF (160 mL) was added dropwise to the above chilled solution of
barium metal after which the mixture was stirred at -78 °C for an
additional 2 h. The reaction mixture was poured into an ice cooled
aqueous solution of NH4OH (10%, 100 mL) and extracted with EtOAc
(3 × 200 mL). The combined organic layers were washed with water
(100 mL) and brine (100 mL) and then dried with K2CO3. The solvent
was concentrated to give a crude oil which was purified by flash
chromatography (EtOAc/hexane ) 20:80) to provide the isomers of
allylic alcohol trans-12a (11.0 g, 90%) as a mixture of two diastereomers
in a ratio of 4:1.
Anal. Calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.48; H, 7.61; N, 6.70.
Minor Isomer 17b. FTIR (NaCl) 1449, 1709, 2913, 2958, 3396
cm-1; 1H NMR (250 MHz, CDCl3) δ 0.78 (3H, t, J ) 7.20 Hz), 0.85-
1.30 (2H, m), 1.35-1.50 (1H, m), 1.70-2.05 (3H, m), 2.57 (1H, d, J
) 17.00 Hz), 2.91 (1H, dt, J ) 11.90, 4.13 Hz), 3.08 (1H, dd, J )
17.10, 6.70 Hz), 3.62 (1H, t, J ) 6.10 Hz), 3.70 (2H, q, J ) 9.40 Hz),
3.89 (1H, t, J ) 3.10 Hz), 4.88-5.03 (2H, m), 5.30-5.50 (1H, m),
7.14-7.39 (8H, m), 7.53 (1H, dd, J ) 6.60, 1.80 Hz), 7.71 (1H, s),
9.75 (1H, d, J ) 3.50 Hz); 13C NMR (62.8 MHz, CDCl3) δ 12.44,
18.99, 22.36, 32.34, 33.12, 49.01, 51.52, 53.29, 56.61, 57.08, 107.30,
111.04, 116.92, 118.16, 119.57, 121.58, 127.05, 127.17, 128.41, 128.65,
133.40, 135.92, 139.01, 140.26, 205.76; CIMS (m/e, relative intensity)
399 (M + 1, 100%).
Major Isomer of trans-12a. FTIR (NaCl) 1457, 1470, 1654, 2958,
3439 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.98 (3H, t, J ) 7.40 Hz),
1.95-2.05 (4H, m), 2.31 (2H, t, J ) 6.30 Hz), 2.67 (1H, dd, J ) 17.20,
5.50 Hz), 2.85 (1H, d, J ) 16.0 Hz), 3.12 (1H, dd, J ) 15.70, 5.20
Hz), 3.70 (1H, d, J ) 13.40 Hz), 3.81 (1H, d, J ) 13.90 Hz), 3.89
(2H, bs), 4.03 (1H, t, J ) 6.10 Hz), 5.25-5.60 (3H, m), 7.15-7.45
(8H, m), 7.50 (1H, d, J ) 7.00 Hz), 7.73 (1H, s); 13C NMR (62.8
MHz, CDCl3) δ 13.64, 22.99, 25.71, 30.69, 38.83, 49.45, 52.66, 56.54,
73.24, 106.14, 110.92, 118.21, 119.35, 120.43, 121.37, 125.05, 127.10,
127.68, 128.35, 128.91, 134.79, 135.93, 136.08; CIMS (m/e, relative
intensity) 399 (M + 1, 100%).
Anal. calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
80.78; H, 7.51; N, 6.65.
Oxy-anion Cope Rearrangement To Convert (6S,10S)-5-Methyl-
9-(1′-hydroxy-hex-3′-enyl)-12-benzyl-6,7,10,11-tetrahydro-6,10-imino-
5H-cycloocta[b]indole cis-16b into (6S,10S)-5-Methyl-8-(1′-ethyl-
2′-propenyl)-12-benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-
cycloocta[b]indole-9-carboxaldehydes 18a, 18c, 19, and 20. A
solution of allylic alcohol cis-16b (100 mg, 0.243 mmol) and 18-
crown-6 (128 mg, 0.48 mmol) in dry dioxane (5 mL) was added to a
suspension of KH (60 mg, 1.54 mmol) in dry dioxane (5 mL). The
light yellow-colored mixture which resulted was stirred at room
temperature for 0.5 h and then heated to reflux under argon for 2 h.
The reaction mixture was allowed to cool to room temperature and
quenched by careful addition of ethanol (2 mL). A saturated solution
of NH4Cl (50 mL) and ethyl acetate (100 mL) was added to the above
mixture. The aqueous layer was extracted with ethyl acetate (3 × 20
mL). The combined organic extracts were washed with water and brine,
dried (K2CO3), and concentrated under reduced pressure. The residue
which formed was chromatographed on silica gel (EtOAc/hexane )
Anal. calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.48; H, 7.41; N, 6.90.
Minor Isomer of trans-12a. FTIR (NaCl) 1457, 1470, 1654, 2958,
3439 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.98 (3H, t, J ) 7.50 Hz),
1.98-2.10 (4H, m), 2.20-2.50 (2H, m), 2.67 (1H, d, J ) 16.0 Hz),
2.95-3.15 (1H, m), 3.05 (1H, s), 3.56 (1H, d, J ) 5.63 Hz), 3.69 (1H,
d, J ) 13.60 Hz), 3.80 (1H, d, J ) 13.60 Hz), 3.92 (1H, d, J ) 4.43
Hz), 4.15 (1H, bs), 4.80-5.70 (3H, m), 7.10-7.45 (8H, m), 7.46 (1H,
d, J ) 4.75 Hz), 7.67 (1H, s); 13C NMR (62.8 MHz, CDCl3) δ 13.62,
22.88, 25.69, 30.26, 40.52, 49.60, 53.01, 56.60, 71.90, 106.30, 110.83,
117.78, 118.11, 119.39, 121.39, 124.90, 127.11, 127.69, 128.34, 128.81,

7008 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
20:80) to provide alkenic aldehydes 18a, 19, 20, and 18c in a ratio of
2:3:3:2. The combined yield for the rearrangement was 83%.
20. IR (KBr) 1722 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.69 (3H,
t, J ) 7.3 Hz), 1.12 (1H, m), 1.78 (2H, m), 2.05 (2H, m), 2.50 (1H, d,
J ) 17.1 Hz), 2.91 (1H, m), 3.09 (1H, dd, J ) 6.9, 17.1 Hz), 3.58 (3H,
s), 3.59 (1H, m), 3.61 (1H, d, J ) 13.4 Hz), 3.71 (1H, d, J ) 13.4 Hz),
3.98 (1H, m), 4.91 (1H, dd, J ) 1.8, 17 Hz), 5.12 (1H, dd, J ) 2.1,
10.2 Hz), 5.56 (1H, m), 7.23 (8H, m), 7.50 (1H, d, J ) 7.4 Hz), 9.74
(1H, d, J ) 2.3 Hz); 13C NMR (62.8 MHz, CDCl3) δ 12.07, 19.00,
25.27, 28.97, 29.26, 32.00, 46.70, 50.34, 52.12, 56.62, 57.35, 106.56,
108.86, 117.67, 118.13, 119.02, 121.01, 126.24, 127.11, 128.32, 128.67,
134.01, 138.10, 139.92, 204.53; EIMS (m/e, relative intensity) 412 (M+,
100%).
18a. IR (KBr) 1718 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.69 (3H,
t, J ) 7 Hz), 1.61 (3H, m), 1.74 (1H, m), 2.12 (1H, dd, J ) 4.2, 12.7
Hz), 2.25 (1H, m), 2.45 (1H, m), 2.46 (1H, d, J ) 16.9 Hz), 3.31 (1H,
dd, J ) 7.5, 16.9 Hz), 3.54 (1H, d, J ) 4.4 Hz), 3.55 (1H, m) 3.55
(3H, s), 3.68 (1H, dd, J ) 2.1, 7.3 Hz), 4.06 (1H, m), 4.86 (1H, dd, J
) 2.3, 16.8 Hz), 5.00 (1H, dd, J ) 2.3, 10.2 Hz), 5.18 (1H, m), 7.2
(8H, m), 7.56 (1H, d, 7.4 Hz), 9.92 (1H, t, J ) 1.5 Hz); 13C NMR
(62.8 MHz, CDCl3) δ 11.46, 21.90, 24.54, 28.91, 31.19, 32.87, 46.94,
50.96, 53.63, 55.73, 57.86, 106.12, 108.95, 116.71, 118.08, 118.98,
121.02, 126.12, 127.13, 128.31, 128.67, 134.44, 138.97, 140.61, 204.49;
EIMS (m/e, relative intensity) 412 (M+, 100%).
19. IR (KBr) 1721 cm-1; 1H NMR (250 MHz, CDCl3) δ 0.69 (3H,
t, J ) 7.3 Hz), 1.55 (3H, m), 1.68 (1H, m), 1.97 (1H, dd, J ) 4.2, 12.8
Hz), 2.11 (1H, m), 2.48 (1H, d, J ) 16.8 Hz), 2.49 (1H, m), 3.39 (1H,
dd, J ) 7.5, 16.9 Hz), 3.51 (1H, m), 3.56 (3H, s), 3.62 (1H, d, J ) 8.5
Hz), 3.69 (1H, d, J ) 4.4 Hz), 4.06 (1H, m), 4.82 (2H, m), 5.09 (1H,
m), 7.2 (8H, m), 7.52 (1H, d J ) 7.2 Hz), 10.06 (1H, t, J ) 0.7 Hz);
EIMS (m/e, relative intensity) 412 (M+, 100%).
18c was composed of a mixture of two isomers which were not
separable by chromatography. 1H NMR (250 MHz, CDCl3) δ 2.6 (1H,
dd, J ) 4.9, 17.2 Hz), 3.05 (1H, m), 3.19 (1H, m), 5.61 (1H, m), 9.97
(1H, s).
2-Epihydroxydiacetylajmaline 29. 21-O-Acetylajmalal A ethylene
acetal 29 (100 mg, 0.244 mmol) was added to a mixture of acetic acid
(3 mL) and aqueous concentrated HCl (0.2 mL), and the mixture which
resulted was stirred for 3 h at room temperature. Acetic anhydride (3
mL) was then added, and the reaction mixture was saturated with HCl
gas and then stirred at room temperature for 2 days. The solvent was
removed under reduced pressure. The residue which resulted was
dissolved in a mixture of CH2Cl2 and NaHCO3 (2:1, 150 mL), and the
aqueous layer was extracted with CH2Cl2 (20 mL × 3). The combined
organic layers were washed with brine (30 mL), dried (K2CO3), and
concentrated under reduced pressure. The crude product was chro-
matographed on silica gel (hexane/ethyl acetate ) 3:7) to obtain 88.3
mg of the hydroxyl compound 29 as a single diastereomer (85%). The
structure of this material was confirmed by X-ray crystallography.30
1
29. IR (KBr) 1471, 1738, 3187, 3495 cm-1; H NMR (250 MHz,
CDCl3) δ 0.94 (3H, t, J ) 7.1 Hz), 1.4 (4H, m), 1.93 (3H, s), 1.97
(1H, t, J ) 6.0 Hz), 2.11 (3H, s), 2.30 (2H, d, J ) 2.7 Hz), 2.38 (2H,
m), 2.72 (3H, s), 2.82 (1H, s), 3.23 (1H, m), 3.40 (1H, d, J ) 10 Hz),
5.14 (1H, s), 5.31 (1H, s), 6.59 (1H, d, J ) 7.8 Hz), 6.75 (1H, t, J )
7.5 Hz), 7.09 (1H, d, J ) 7.4 Hz), 7.15 (1H, t, J ) 7.7 Hz); 13C NMR
(62.8 MHz, CDCl3) δ 12.12, 21.09, 21.26, 24.42, 25.67, 27.90, 28.53,
31.18, 39.48, 47.06, 53.01, 57.08, 61.72, 78.58, 87.94, 97.14, 108.46,
118.58, 124.34, 127.68, 128.46, 151.77, 169.28, 169.88; HR EIMS
C24H30N2O5 requires (m/e, relative intensity) 426.2154, found 426.2140-
(100%).
Anal. calcd for C24H30N2O5: C, 67.61; H, 7.04; N, 6.57. Found: C,
67.38; H, 7.19; N, 6.28.
2-Epidiacetylajmaline 30 and Diacetylajmaline 31. 2-Epihydroxy-
diacetylajmaline 29 (50 mg, 0.12 mmol) was dissolved in dry CH2Cl2
(5 mL), and BF3‚etherate (0.4 mL) was added dropwise over 5 min,
after which PtO2 (30 mg) was added. The mixture was hydrogenated
(benchtop) under 1 atm H2 for 24 h. The reaction mixture was diluted
with CH2Cl2 (100 mL), washed with an aqueous solution of NaHCO3
(10%, 30 mL) and brine (30 mL), and dried (MgSO4). The solvent
was removed under reduced pressure. The residue was separated by
preparative TLC (silica gel, hexane/ethyl acetate ) 3:7) to provide
2-epidiacetylajmaline (30) (25.6 mg, 53.4%) and diacetylajmaline (31)
(17.1 mg, 35.6%).
(6S,10S)-5-Methyl-8-(1′-ethyl-pent-2′-enyl)-12-benzyl-6,7,8,9,10,-
11-hexahydro-6,10-imino-cycloocta[b]indole-9-carboxaldehydes23a,b,c,d,
26a,b, and 27a,b were prepared following the procedure reported in
ref 37. The spectral properties of these bases were identical to the
reported values.37
1
30. IR (KBr) 1463, 1609, 1738, 2930 cm-1; H NMR (250 MHz,
CDCl3) δ 0.95 (3H, t, J ) 7.3 Hz), 1.4 (2H, m), 1.52 (2H, m), 1.72
(1H, d, J ) 11.8 Hz), 1.93 (3H, s), 2.01 (1H, m), 2.11 (3H, s), 2.35
(2H, m), 2.49 (1H, dd, J ) 11.7, 4.9 Hz), 2.63 (3H, s), 3.18 (2H, dd,
J ) 11.1, 5.7), 3.65 (1H, d, J ) 9.8, 4.8 Hz), 5.12 (1H, s), 5.26 (1H,
s), 6.63 (1H, d, J ) 7.5 Hz), 6.75 (1H, t, J ) 7.3), 7.09 (1H, d J ) 7.5
Hz), 7.19 (1H, dt, J ) 7.7, 1.3); 13C NMR (62.8 MHz, CDCl3) δ 12.17,
21.17, 21.31, 23.54, 25.49, 25.91, 34.14, 37.21, 40.04, 47.51, 47.91,
55.89, 57.00, 74.90, 78.33, 88.65, 109.10, 118.81, 123.87, 128.27,
129.78, 154.39, 169.39, 170.03; HR EIMS C24H30N2O4 requires (m/e,
relative intensity) 410.2207, found 410.2227 (100%).
21-O-Acetylajmalal A Ethylene Acetal 28. The S-aldehyde 27a
(100 mg, 0.218 mmol)37 was dissolved in dry DME (5 mL), and the
Pd/C catalyst (10%, 10 mg) was added. The slurry which resulted was
allowed to stir at room temperature under 1 atm of H2 for 48 h.
Examination of the mixture by TLC (silica gel, hexane/EtOAc ) 1:1)
indicated the disappearance of starting 27a and the appearance of a
new component (lower Rf). Acetic anhydride (44.5 mg, 0.436 mmol)
and DMAP (26.7 mg, 0.218 mmol) were then added directly to the
flask, and this mixture was stirred for an additional 2 h. The catalyst
was filtered from the reaction mixture and washed with DME (5 mL
× 3), and the filtrate was concentrated under reduced pressure. The
residue which resulted was dissolved in CHCl3 (150 mL) and washed
with a solution of aq NaHCO3 (10%, 40 mL) and brine (40 mL). The
CHCl3 layer was dried (MgSO4), and the solvent was concentrated under
reduced pressure. The residue was passed through a short wash column
of silica gel (hexane/EtOAc ) 4:1) to provide 81.4 mg of 21-O-
acetylajmalal A ethylene acetal 28 (91%).
28. IR (KBr) 1467, 1740, 2932 cm-1; 1H NMR (250 MHz, CDCl3)
δ 0.95 (3H, t, J ) 6.8 Hz), 1.48-1.72 (5H, m), 1.78 (1H, t, J ) 10.5
Hz), 1.98 (1H, t, J ) 9 Hz), 2.08 (1H, s), 2.12 (3H, s), 3.01 (1H, dd,
J ) 16.2, 6.4 Hz), 3.31 (1H, d, J ) 16.3 Hz), 3.65 (2H, m), 3.66 (3H,
s), 3.82 (2H, m), 4.45 (1H, dd, J ) 3.8, 6.8 Hz), 4.48 (1H, d, J ) 8.3
Hz), 5.39 (1H, d, J ) 3.8 Hz), 7.06 (1H, dt, J ) 7.8, 1.1 Hz), 7.19
(1H, dt, J ) 7.8, 1.1 Hz), 7.26 (1H, d, J ) 7.6 Hz), 7.48 (1H, d, J )
7.3); 13C NMR (62.8 MHz, CDCl3) δ 11.68, 21.44, 22.76, 24.61, 27.21,
29.23, 30.39, 37.43, 42.20, 45.98, 49.85, 64.04, 64.62, 89.18, 103.34,
104.87, 108.55, 118.43, 118.73, 120.62, 126.49, 137.46, 138.46, 168.48;
HR EIMS C24H30N2O4 requires (m/e, relative intensity) 410.2205, found
410.2214 (100%).
Anal. calcd for C24H30N2O4: C, 70.24; H, 7.32; N, 6.83. Found: C,
70.28; H, 7.40; N, 6.73.
1
31. IR (KBr) 1611, 1738, 3052, 3187, 3495 cm-1; H NMR (250
MHz, CDCl3) δ 0.95 (3H, t, J ) 7.1 Hz), 1.42 (1H, m), 1.47 (1H, m),
1.70 (1H, m), 1.74 (1H, m), 1.77 (1H, m), 1.93 (1H, dd, J ) 12.7, 5.5
Hz), 2.07 (1H, m), 2.10 (3H, s), 2.15 (1H, d, J ) 12 Hz), 2.21 (3H, s),
2.50 (1H, m), 2.72 (1H, s), 2.78 (3H, s), 3.05 (1H, t, J ) 5.9 Hz), 3.63
(1H, d, J ) 8 Hz), 5.25 (1H, s), 5.28 (1H, s), 6.68 (1H, d, J ) 7.8 Hz),
6.80 (1H, t, J ) 7.6 Hz), 7.1 (1H, t, J ) 7.6 Hz), 7.30 (1H, d, J ) 7.3
Hz);13C NMR (62.8 MHz, CDCl3) δ 12.17, 21.23, 21.34, 25.11, 27.40,
31.91, 34.63, 36.22, 43.11, 43.76, 48.53, 53.66, 54.50, 79.36, 80.16,
88.91, 109.78, 119.33, 122.45, 127.73, 132.23, 153.99, 169.13, 170.43;
HR EIMS C24H30N2O4 requires (m/e, relative intensity) 410.2205, found
410.2232 (100%).
(+)-Ajmaline 1. Diacetylajmaline 31 (20 mg, 0.049 mmol) was
dissolved in CH3OH (3 mL), and a solution of aq K2CO3 (20%, 0.5
mL) was added, after which the reaction mixture was stirred at room
temperature for 2 days. The solvent was removed under reduced
pressure. The residue which resulted was dissolved in a mixture of
CH2Cl2 and H2O (1:1, 150 mL), and the aqueous layer was extracted
with CH2Cl2 (20 × 3). The combined CH2Cl2 extracts were washed
with brine (30 mL), dried (K2CO3), and concentrated under reduced
Anal. calcd for C24H30N2O4: C, 70.24; H, 7.32; N, 6.83. Found: C,
70.05; H, 7.51; N, 6.67.

(+)-Ajmaline, Alkaloid G, and NorsuaVeoline
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7009
pressure to provide 14.8 mg of (+)-ajmaline (1) (93%), which was
identical in all respects (co-TLC, NMR, optical rotation)1,13 with that
of an authentic sample (purchased from Sigma Company).
(1H, m), 6.22 (1H, d, J ) 5.9 Hz), 7.03 (1H, ddd, J ) 7.9, 7.0, 0.9
Hz), 7.14 (1H, ddd, J ) 8.0, 7.2, 1.0 Hz), 7.42(1H, d, J ) 8.0 Hz),
7.51(1H, d, J ) 7.6 Hz); 13C NMR (62.8 MHz, DMSO-d6) δ 12.46,
25.08 28.69, 29.36, 30.80, 46.59, 55,76, 69.36, 88.02, 98.37, 105.54,
109.99, 118.24, 119,39, 120.85,126.22, 136,99; EIMS (m/e, relative
intensity) 340 (100%).
1
1. IR (KBr) 1463, 1605, 2952, 3402 cm-1; H NMR (250 MHz,
CDCl3) δ 0.97 (3H, t, J ) 7 Hz), 1.36 (1H, m), 1.46 (1H, m), 1.48
(2H, m), 1.84 (1H, dd, J ) 14, 10 Hz), 1.95 (1H, dd, J ) 12, 5 Hz),
2.02 (1H, m), 2.04 (1H, m), 2.27 (1H, m), 2.62 (1H, s), 2.76 (3H, s),
3.03 (1H, m), 3.58 (1H, d, J ) 10 Hz), 4.21 (1H, s), 4.41 (1H, s), 6.62
(1H, d, J ) 7.7 Hz), 6.73 (1H, t, J ) 7.4 Hz), 7.10 (1H, t, J ) 7.7 Hz),
7.43 (1H, d, J ) 7.4 Hz); 13C NMR (62.8 MHz, CDCl3) δ 15.35, 26.67,
31.55, 34.76, 37.29, 37.97, 46.38, 48.62, 51.32, 56.00, 59.46, 81.19,
82.57, 91.46, 112.66, 122.29, 125.85, 130.45, 136.46, 157.01; EIMS
(m/e, relative intensity) 326 (100%). The spectral data for 1 were
identical to the published values including the optical rotation; [R]D27
) +145.8 (c ) 0.48, CHCl3), lit.14 [R]D20 ) +144 (c ) 0.8, CHCl3).
21-O-Acetylajmalal A 32. 21-O-Acetylajmalal A ethylene acetal
28 (100 mg, 0.244 mmol) was dissolved in acetone (6 mL), and p-TSA
hydrate (19 mg, 0.101 mmol) was added. The reaction mixture was
stirred at room temperature for 14 h. The solvent was removed under
reduced pressure. The residue which resulted was dissolved in a mixture
of CH2Cl2 and aqueous NaHCO3 (2:1, 150 mL). The aqueous layer
was extracted with CH2Cl2 (20 mL × 3). The combined organic layers
were washed with brine (30 mL), dried (K2CO3), and concentrated under
reduced pressure. The residue was chromatographed on silica gel (ethyl
acetate/hexane ) 1:4) to provide 79.9 mg of pure 21-O-acetylajmalal
A 32 in 89% yield.
(6S,10S)-8-(1′-Ethyl-2′-propenyl)-9-(2′,5′-dioxacyclopentanyl)-12-
benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-cycloocta[b]indole 34.
The alkenic aldehyde 17a62,63 (4.66 g, 11.72 mmol) and ethylene glycol
(6.68 g, 127.6 mmol) were dissolved in benzene (200 mL), and
p-toluenesulfonic acid monohydrate (2.24 g, 11.8 mmol) was added.
The mixture which resulted was heated at reflux with a DST for 20 h
under argon. Examination of the reaction mixture by TLC (silica gel,
EtOAc/hexane ) 2:8) indicated the disappearance of starting aldehyde.
The solution was then cooled to room temperature and concentrated
under reduced pressure. The residue which formed was dissolved in a
mixture of EtOAc/saturated aqueous NaHCO3. The aqueous layer was
extracted with ethyl acetate (3 × 200 mL). The combined organic layers
were washed with water and brine, dried (K2CO3), and concentrated
under reduced pressure to provide alkenic acetal 34 (4.92 g, 95%).
34. FTIR (NaCl) 1110, 1308, 1453 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.64 (3H, t, J ) 6.90 Hz), 0.69-0.95 (1H, m), 1.26 (1H, d,
J ) 2.00 Hz), 1.55 (1H, d, J ) 1.80 Hz), 1.63 (1H, d, J ) 12.70 Hz),
1.85-2.10 (2H, m), 2.31 (1H, s), 2.41 (1H, d, J ) 20.40 Hz), 3.26
(1H, dd, J ) 16.80, 7.40 Hz), 3.49 (1H, d, J ) 13.80 Hz), 3.62 (1H,
d, J ) 13.81 Hz), 3.70 (1H, d, J ) 7.20 Hz), 3.82-3.93 (4H, m), 4.22
(1H, s), 4.87-5.05 (2H, m), 5.25-5.45 (1H, m), 5.48 (1H, d, J ) 8.30
1
32. IR (KBr) 1463, 1698, 1736, 2934 cm-1; H NMR (250 MHz,
Hz), 7.12-7.35 (8H, m), 7.53 (1H, d, J ) 6.60 Hz), 7.62 (1H, s); 13
C
CDCl3) δ 0.95 (3H, t, J ) 7.1 Hz), 1.46 (1H, dt, J ) 12.8, 7.4 Hz),
1.54 (2H, m), 1.72 (1H, dt, J ) 12.6, 6.5 Hz), 1.80 (2H, m), 2.15 (3H,
s), 2.25 (1H, s), 2.52 (1H, dd, J ) 8.9, <1 Hz), 3.12 (2H, d, J ) 4.3
Hz), 3.61 (3H, s), 3.75 (1H, m), 4.50 (1H, dd, J ) 9.2, 3.2 Hz), 5.43
(1H, d, J ) 2.8 Hz), 7.06 (1H, t, J ) 7.7 Hz), 7.17 (1H, t, J ) 6.8 Hz),
7.24 (1H, d, J ) 6.8 Hz), 7.41 (1H, d, J ) 7.6 Hz), 9.32 (1H, s); 13C
NMR (62.8 MHz, CDCl3) δ 11.78, 21.28, 23.62, 25.27, 26.11, 29.19,
29.37, 42.87, 43.41, 46.27, 50.63, 88.49, 103.58, 108.86, 118.13, 119.28,
121.48, 126.11, 137.89, 138.14, 169.22, 202.54; HR EIMS C22H27N2O3
requires (m/e, relative intensity) 366.1943, found 366.1958 (100%).
21-O-acetylalkaloid G 33. The aldehyde 32 (30 mg, 0.082 mmol)
was dissolved in a mixture of THF/H2O (THF/H2O ) 9:1, 3 mL). DDQ
(21 mg, 0.093 mmol) was added to the above solution in one portion
with stirring.58 The reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was then diluted with EtOAc (100
mL), and the solution which resulted was washed with aqueous NH4-
OH (10%, 30 mL) and brine (30 mL) and dried (MgSO4). The solvent
was removed under reduced pressure, and the residue was passed
through a short column of silica gel to provide the 21-O-acetyl alkaloid
G 33 (29.4 mg, 94%).18
NMR (75 MHz, CDCl3) δ 11.51, 22.60, 24.14, 28.55, 32.89, 47.77,
49.11, 51.98, 56.72, 64.59, 64.66, 104.50, 105.51, 107.47, 110.71,
115.65, 118.02, 119.34, 121.26, 126.69, 128.09, 128.43, 134.86, 135.87,
139.97, 143.08; CIMS (m/e, relative intensity) 443 (M + 1, 100%).
(6S,10S)-8-(1′-Ethyl-2′-acetyl)-9-(2′,5′-dioxacyclopentanyl)-12-
benzyl-6,7,8,9,10,11-hexahydro-6,10-imino-5H-cycloocta[b]indole 35.
The alkenic acetal 34 (2.31 g, 5.22 mmol) was dissolved in freshly
distilled THF (100 mL) which contained distilled pyridine (35 mL)
and was then added to a cold solution of OsO4 (1.22 g, 4.80 mmol) in
THF (25 mL) and pyridine (20 mL) at 0 °C under argon. The black
solution which resulted was allowed to stir at 0 °C for an additional
20 h. An aqueous solution of NaHSO3 (15 g, 50 mL) was added, and
the mixture was allowed to warm to room temperature and stirred
overnight. The reaction mixture was diluted with EtOAc (200 mL).
The organic layer was concentrated under reduced pressure to provide
the crude acetal diol (2.236 g, 90%). The acetal diol was not subjected
to further characterization but used directly in the next step. Acetal
diol (2.236 g, 4.72 mmol) was dissolved in methanol (100 mL) and
cooled to 0 °C. An aqueous solution of NaIO4 (2.70 g in 80 mL of
H2O) was then added to the above solution. The reaction flask was
covered by aluminum foil to exclude light. The mixture was stirred at
0 °C for 16 h and then concentrated under reduced pressure. The residue
was dissolved in EtOAc/H2O (5:1, 200 mL). The aqueous layer was
extracted with EtOAc (3 × 100 mL). The organic layers were combined,
washed with water (50 mL) and brine (50 mL), and dried (K2CO3).
The solvent was removed under reduced pressure, and the crude material
was chromatographed (silica gel, EtOAc/hexane ) 8:2) to provide pure
acetal aldehyde 35 (1.75 g, 85%).
33. IR (KBr) 1742, 3373 cm-1;1H NMR (250 MHz, CDCl3) δ 0.94
(3H, t, J ) 6.9 Hz), 1.46 (4H, m), 1.81 (2H, m), 1.92 (1H, m), 2.08
(3H, s), 3.52 (3H, s), 3.87 (1H, dd, J ) 8.2, 11.3 Hz), 4.09 (1H, dd, J
) 3.9, 10.4 Hz), 4.68 (1H, m), 4.75 (1H, m), 5.30 (1H, d, J ) 4.0 Hz),
5.60 (1H, d, J ) 8.0 Hz), 7.14 (3H, m), 7.54 (1H, d, J ) 7.4 Hz); 13
C
NMR (62.8 MHz, CDCl3) δ 11.59, 21.31, 24.63, 28.27, 29.23, 30.75,
39.78, 41.10, 44.75, 56.27, 70.33, 87.94, 98.72, 106.63, 108.72, 118.36,
119.94, 121.51, 126.03, 138.12, 142.81, 170.34; EIMS (m/e, relative
intensity) 382 (100%).
35. FTIR (NaCl) 1134, 1446, 1609, 1666, 1715, 2952, 3385 cm-1
;
Alkaloid G 2. 21-O-Acetylalkaloid G 33 (20 mg, 0.052 mmol) was
dissolved in CH3OH (3 mL), and an aqueous solution of K2CO3 (20%,
0.5 mL) was added, after which the reaction mixture was stirred at
room temperature for 2 h. The solvent was removed under reduced
pressure. The residue which resulted was dissolved in a mixture of
CH2Cl2 and H2O (1:1, 150 mL), and the aqueous layer was extracted
with CH2Cl2 (20 mL × 3). The combined CH2Cl2 extracts were washed
with brine (30 mL), dried (K2CO3), and concentrated under reduced
pressure to provide 16.2 mg of alkaloid G 2 (91%). The spectral data
for 2 were identical to the published values.18
2. IR (KBr) 1463, 2918, 3373 cm-1;1H NMR (250 MHz, DMSO-
d6) δ 0.96 (3H, t, J ) 7.03 Hz), 1.29 (1H, m), 1.39 (1H, m), 1.50 (2H,
m), 1.63 (1H, m), 1.69 (1H, m), 1.76 (1H, m), 1.84 (1H, m), 3.63 (3H,
s), 3.77 (1H, dd, J ) 11.1, 8.1 Hz), 4.09 (1H, m), 4.34 (1H, dd, J )
10.3, 4.0 Hz), 4.93 (1H, d, J ) 5.3 Hz), 5.48 (1H, d, J ) 8.0 Hz), 5.67
1H NMR (300 MHz, CDCl3) δ 0.64 (3H, t, J ) 7.48 Hz), 1.30 (1H,
m), 1.50 (1H, m), 1.61 (1H, dt, J ) 12.56, 3.82 Hz), 1.88 (1H, t, J )
4.00 Hz), 1.97 (1H, dt, J ) 12.71, 4.09 Hz), 2.16 (1H, tt, J ) 10.41,
2.57 Hz), 2.48 (1H, d, J ) 16.89 Hz), 2.72 (1H, m), 3.29 (1H, dd, J )
16.90, 7.73 Hz), 3.50 (1H, d, J ) 13.77 Hz), 3.63 (1H, d, J ) 13.77
Hz), 3.73 (1H, d, J ) 7.75 Hz), 3.84-3.92 (5H, m), 5.49 (1H, d, J )
7.62 Hz), 7.11-7.20 (2H, m), 7.21-7.34 (6H, m), 7.55 (1H, dd, J )
6.44, 2.36 Hz), 7.67 (1H, s), 9.63 (1H, d, J ) 2.26 Hz); 13C NMR (75
MHz, CDCl3) δ 10.39, 20.69, 22.42, 28.59, 30.83, 47.18, 51.22, 53.01,
53.64, 57.56, 63.76, 64.91, 104.17, 108.14, 110.82, 118.18, 119.25,
121.17, 126.76, 127.09, 128.04, 128.56, 132.95, 135.63, 139.69, 205.52;
CIMS (m/e, relative intensity) 445 (M + 1, 100%).
(-)-Nb-Benzylnorsuaveoline 36. The acetal aldehyde 35 (300 mg,
0.68 mmol) and p-toluenesulfonic acid (1.50 g, 7.9 mmol) were

7010 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Li et al.
dissolved in acetone (75 mL). The mixture which resulted was stirred
at reflux for 2 days under argon. The solution was then cooled to room
temperature and concentrated under reduced pressure. The residue was
dissolved in absolute EtOH (40 mL), and hydroxylamine hydrochloride
(500 mg, 7.19 mmol) was added. The reaction mixture was heated to
reflux for 2 d under an argon atmosphere. The solution which resulted
was allowed to cool to room temperature, and the solvent was removed
under reduced pressure. The residue was dissolved in a mixture of
EtOAc/saturated aqueous NaHCO3 (4:1, 250 mL). The aqueous layer
was extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with water (50 mL) and brine (50 mL) and then dried
(K2CO3). The solvent was removed under reduced pressure, and the
crude material was flash chromatographed (silica gel, EtOAc/hexane
) 6:4) to provide pure Nb-benzylnorsuaveoline (210 mg, 88%).
36. [R]2D7 ) -143.2 (c ) 1.00, CHCl3); FTIR (NaCl) 1458, 2910
hydrogen for 12 h. Analysis by TLC (silica gel plate was exposed to
NH3 vapors) indicated the absence of starting material 36. The catalyst
was removed by filtration and was washed with EtOH (3 × 25 mL).
The solvent was removed under reduced pressure. The residue was
dissolved in a mixture of CHCl3 and aqueous NH4OH (5:1, 60 mL).
The aqueous layer was extracted with CHCl3 (3 × 20 mL). The
combined organic layers were washed with brine (20 mL), dried (K2-
CO3), and flash chromatographed on silica gel (CHCl3/EtOH ) 9:1)
to provide pure norsuaveoline 360 (28 mg, 92%).
3. [R]2D7 ) -3.2 (c ) 1.00, CHCl3); FTIR (NaCl) 1416, 1447,
1589, 3052, 3184 cm-1; 1H NMR (250 MHz, CDCl3) δ 1.12 (3H, t, J
) 7.55 Hz), 2.44 (2H, q, J ) 7.53 Hz), 2.81 (1H, s), 2.83 (1H, d, J )
14.90 Hz), 2.86 (1H, d, J ) 15.0 Hz), 3.19 (1H, dd, J ) 17.10, 5.70
Hz), 3.34 (1H, dd, J ) 15.80, 5.45 Hz), 4.60 (1H, d, J ) 5.40 Hz),
4.66 (1H, d, J ) 5.20 Hz), 7.05 (1H, t, J ) 7.40 Hz), 7.12 (1H, t, J )
7.30 Hz), 7.28 (1H, d, J ) 8.30 Hz), 7.39 (1H, d, J ) 7.50 Hz), 8.14
(1H, s), 8.31 (1H, s), 8.54 (1H, s); 13C NMR (62.8 MHz, CDCl3) δ
13.90, 22.84, 31.15, 31.92, 45.78, 48.40, 105.99, 111.02, 118.21, 119.67,
121.99, 127.32, 134.25, 135.11, 136.06, 137.11, 139.91, 146.17, 147.03;
CIMS (m/e, relative intensity) 290 (M + 1, 100%).
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.05 (3H, t, J ) 7.30 Hz), 2.38
(2H, q, J ) 7.28 Hz), 2.63 (1H, d, J ) 16.04 Hz), 2.82 (1H, d, J )
17.14 Hz), 3.18 (1H, dd, J ) 17.20, 5.64 Hz), 3.42 (1H, dd, J ) 16.03,
5.20), 3.73 (1H, d, J ) 13.37 Hz), 3.85 (1H, d, J ) 13.35 Hz), 4.24
(1H, d, J ) 4.90 Hz), 4.35 (1H, d, J ) 4.93 Hz), 6.99 (1H, t, J ) 7.00
Hz), 7.05 (1H, t, J ) 6.77 Hz), 7.18-7.35 (7H, m), 7.99 (1H, s), 8.20
(1H, s), 8.26 (1H, bs); 13C NMR (75 MHz, CDCl3) δ 13.92, 23.23,
26.27, 32.48, 49.89, 53.75, 56.77, 105.27, 111.45, 118.60, 120.03,
122.33, 127.44, 127.93, 128.93, 129.26, 133.40, 136.00, 136.53, 138.00,
138.34, 142.96, 144.51, 144.90; CIMS (m/e, relative intensity) 380 (M
+ 1, 100%).
Anal. calcd for C26H25N3: C, 82.29; H, 6.64; N, 11.07. Found: C,
82.78; H, 6.41; N, 11.19.
(-)-Norsuaveoline 3. (-)-Nb-Benzylnorsuaveoline 36 (40 mg, 0.11
mmol) was dissolved in ethanolic HCl (5%, 8 mL), after which Pd on
activated carbon (10%, 60 mg) was added. The mixture which resulted
was allowed to stir at room temperature under an atmosphere of
Anal. calcd for C19H19N3: C, 78.86; H, 6.62; N, 14.52. Found: C,
78.59; H, 6.44; N, 14.16.
Supporting Information Available: Unsuccessful attempts
to convert ketone 7 (see 7b-7f, Schemes 15-17) or R,â-
unsaturated aldehyde 8 (see 8b-8d, Scheme 18) into 1,5-
dialdehyde 6 or a related derivative and unsuccessful approaches
to conversion of 29 into 30 (Table 1), as well as preparations
of 7a and 11a. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA990184L