General access to the Vinca and Tacaman alkaloids using a Rh(II)-catalyzed cyclization/cycloaddition cascade

Article abstract of DOI:10.1021/jo8001003

(Chemical Equation Presented) The total synthesis of several members of the vinca and tacaman classes of indole alkaloids has been accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of an α-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion of (±)-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize (±)-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (±)-tacamonine and (±)-apotacamine.

Full text of DOI:10.1021/jo8001003

General Access to the Vinca and Tacaman Alkaloids Using a
Rh(II)-Catalyzed Cyclization/Cycloaddition Cascade
Dylan B. England and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed January 15, 2008
The total synthesis of several members of the Vinca and tacaman classes of indole alkaloids has been
accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction
of an R-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent
yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion
of (()-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate
the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize
(()-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (()-tacamonine and
(()-apotacamine.
Introduction
of complex structural variation.9,10 These two families are
characterized by the presence of a common pentacyclic frame-
work 1, containing either a cis- or trans-fused D/E ring system
(Figure 1).11 Prototypical examples of the Vinca alkaloids include
(+)-vincamine (2), as well as its epimer, (()-3H-epivincamine
(3) which have been isolated from several plants of the Vinca
genus.12 Members of the Vinca family all exhibit strong
vasodilation activity which brings about an enhancement of the
overall cerebral blood flow.13 Thus, these compounds along with
their semi-synthetic derivatives have recently been the subject
of intense pharmacological and synthetic studies.14 The structur-
ally related tacaman alkaloids represented by tacamine (4),
tacamonine (5), and apotacamine (6) were isolated from the
Central African plant Tabernaemontana eglandulosa Stapf.15
The development of synthetic methods for constructing indole
alkaloids has attracted much attention for several decades due
to the important pharmacological properties and diverse struc-
tures of this class of natural products.1-8 In particular, both the
Vinca and tacaman families of indole alkaloids occupy a central
place in natural product chemistry because of their wide range
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Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100, 3455. (c) Ohshima, T.; Xu,
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10.1021/jo8001003 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/05/2008
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J. Org. Chem. 2008, 73, 2792-2802

Vinca and Tacaman Alkaloids
Spengler cyclization,19 a Michael-type alkylation of the so-called
“Wenkert enamine”20 or an annulation reaction of a dihydro-
â-carboline derivative.21 The strategies for assembling the
tacaman skeleton are also quite varied and involve such
protocols as a Bischler-Napieralski cyclization,22 a double aza-
Michael reaction,23 radical cyclization chemistry,24 ring closing
metathesis to form a piperidinone ring followed by 1,4-addition
to introduce the requisite side chain,25 as well as other more
classical methods.26 Nevertheless, the search for efficient and
general methods which provide flexible entries to structural
analogues of the pentacyclic core of both the Vinca and tacaman
alkaloids still remains a challenging goal.
Our synthetic approach toward the pentacyclic framework
found in the Vinca and tacaman alkaloids was guided by a long
standing interest in developing new applications of the intramo-
lecular [3+2]-cycloaddition of carbonyl ylide dipoles toward
the synthesis of complex natural products.27 The generation of
onium ylides through the use of transition-metal-promoted
cyclizations has emerged in recent years as an important and
efficient method for the construction of ring systems that are
difficult to prepare by other means.28,29 In earlier work from
our laboratory, we described the formation of push-pull dipoles
from the Rh(II)-catalyzed process involving cyclization of an
electrophilic metallo carbenoid onto an adjacent carbonyl
group.30 Our recent total synthesis of (()-aspidophytine31 nicely
demonstrates the utility of this cascade methodology for the
construction of complex natural products. On the basis of this
FIGURE 1. Common pentacyclic indole framework of the Vinca and
tacaman families.
FIGURE 2. Common synthetic strategies toward the Vinca framework.
The close chemical similarity of these alkaloids with vincamine
(2) has also made them potential hypotensive and cerebral
vasodilator candidates.16 Attachment of an ethyl substituent at
C20 and away from the D/E ring junction of the pentacyclic
framework adds an additional stereocenter, setting all three
methine hydrogens cis to each other (i.e., 4-6), providing a
further degree of complexity to these natural products.
Several strategies for the synthesis of vincamine and its
structural analogues have been reported.17 The most common
route toward this particular family is to first establish the
[ABCD]-type octahydroindolo[2,3-a]-quinolizine ring system
(7) starting from an indole subunit and then complete the
synthesis of the specific target by appending the final E-ring
(Figure 2).18 Methods for building up the requisite gem-
disubstituted tetracyclic framework 7 usually involves a Pictet-
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4745. (b) Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580.
(c) Szabo´, L.; Sa´pi, J.; Kalaus, G.; Argay, G.; Ka´lma´n, A.; Baitz-Ga´cs, E.;
Tama´s, J.; Sza´ntay, C. Tetrahedron 1983, 39, 3737. (d) Nemes, A.; Czibula,
L.; Visky, G.; Farkas, M.; Kreidl, J. Heterocycles 1991, 32, 2329.
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1350. (b) Danieli, B.; Lesma, G.; Palmisano, G. J. Chem. Soc., Chem.
Commun. 1981, 908. (c) Magnus, P.; Pappalardo, P.; Southwell, I.
Tetrahedron 1986, 42, 3215.
(22) Massiot, G.; Oliveira, F. S.; Le´vy, J. Bull. Soc., Chim. Fr. II 1982,
185.
(23) Takasu, K.; Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem.
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Org. Chem. 2001, 3719.
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(26) For some other syntheses of tacaman alkaloids, see: (a) Szabo´, L.;
Ma´rva´nyos, E.; To´th, G.; Sza´ntay, Jr., C.; Kalaus, G.; Sza´ntay, C.
Heterocycles 1986, 24, 1517. (b) Din Belle, D.; Tolvanen, A.; Lounasmaa,
M. Tetrahedron 1996, 52, 11361. (c) Lounasmaa, M.; Karinen, K.; Din
Belle, D.; Tolvanen, A. Tetrahedron 1998, 54, 157. (d) Lounasmaa, M.;
Din Belle, D.; Tolvanen, A. Tetrahedron 1998, 54, 14845. (e) Lounasmaa,
M. Curr. Org. Chem. 1998, 2, 63. (f) Ihara, M.; Setsu, F.; Shohda, M.;
Taniguchi, N.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1994, 59, 5317.
(g) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A.
Tetrahedron Lett. 2001, 42, 7237. (h) Ho, T.-L.; Gorobets, E. Tetrahedron
2002, 58, 4969. (i) Chen, C.-Y.; Chang, B.-R.; Tsai, M.-R.; Chang, M.-Y.;
Chang, N.-C. Tetrahedron 2003, 59, 9383.
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Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (c) Padwa, A.
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1984, 40, 737.
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K.; Thielmann, M; Thielmann, T; Winterfeldt, E. Tetrahedron 1987, 43,
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Org. Chem. 1987, 52, 353. (d) Kaufman, M. D.; Grieco, P. A. J. Org. Chem.
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Mej´ıa-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70, 2206.
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L.; Schlessinger, R. H. J. Am. Chem. Soc. 1974, 96, 3702. (b) Pfa¨ffli, P.;
Oppolzer, W.; Wenger, R.; Hauth, H. HelV. Chim. Acta 1975, 58, 1131. (c)
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Schlessinger, R. H. J. Am. Chem. Soc. 1979, 101, 1540. (d) Langlois, Y.;
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4044.
J. Org. Chem, Vol. 73, No. 7, 2008 2793

England and Padwa
SCHEME 2. Rh(II)-Catalyzed Intramolecular
SCHEME 1. Key Disconnections for the Synthesis of
(()-3H-Epivincamine
[3+2]-Cycloaddition to Generate the Core Pentacyclic
Skeleton
earlier work, we felt that the Rh(II)-catalyzed reaction of the
R-diazo indoloamide precursor (i.e., 8) might allow for a facile
entry to the pentacyclic core skeleton of the Vinca alkaloid 3H-
epivincamine (3) as illustrated in Scheme 1. Reductive ring
opening of the expected [3+2]-cycloadduct 9 would generate
compound 10 which could be considered as a precursor to the
required D/E ring fusion found in the natural product. Functional
group manipulation of 10 would lead to 11, and a base-induced
keto-amide ring contraction reaction32 would complete the
synthesis of 3H-epivincamine (3). A similar strategy was also
contemplated for the synthesis of tacamonine (5) (Vide infra).
In this report, we document the full results of our studies making
use of this methodology.33
1H NMR spectrum, thus providing support for the formation of
this dipole. The intramolecular [3+2]-cycloaddition reaction
produced the endo cycloadduct solely with regard to the dipole,
and this result is in full accord with earlier observations where
it was noted that the cycloaddition proceeds from the lowest-
energy transition state.35
At this point in our planned approach toward (()-3H-
epivincamine (3), we needed to demonstrate that the [3+2]-
cycloadduct could be converted into a pentacyclic keto-amide
that would be required for a subsequent base-induced ring
contraction reaction.32 The first step in this contemplated
sequence would require reductive ring opening of the oxabi-
cyclic bridge followed by subsequent functional group manipu-
lation. The game plan that we had in mind was easily tested
using the readily available cycloadduct 16. Compound 16 was
treated with BF3‚OEt2 to affect ring opening, and we were
pleased to note that this reaction delivered enamine 17 in 82%
yield (Scheme 3). The next step envisaged the selective removal
of the carboethoxy group, and this decarboxylation was initially
attempted by making use of typical Krapcho conditions (i.e.,
NaCl, LiI, etc.).36 Unfortunately, only a low yield of the desired
product (i.e., 18) was obtained. However, we eventually found
that the carboethoxy group could be easily removed by treating
17 with MgI2 in refluxing acetonitrile that contained a trace
amount of water.37 This resulted in the formation of R-hydroxy
lactam 18 in 70% yield. Attempts to oxidize the secondary
alcohol present in 18 to the desired keto-amide functionality
failed to give tractable material under a variety of oxidizing
conditions. We suspect this problem may be related to the
susceptibility of the molecule to undergo dehydration. Instead,
reduction of the enamino double bond present in 18 was
investigated. The reduction could be accomplished under
catalytic hydrogenation conditions using PtO2 as the catalyst
Results and Discussion
Model Studies. To test the feasibility of the retrosynthetic
strategy outlined in Scheme 1, our initial efforts were focused
on a model substrate. The primary goal was to prepare the core
pentacyclic skeleton of the Vinca and tacaman alkaloids by
omitting the ethyl substituent found at the C14 and C20 positions
to test the feasibility of the tandem cascade process as well as
to investigate specific reactions to be used in a total synthesis
effort. With this in mind, we chose to examine the Rh(II)-
catalyzed cascade reaction of R-diazo indoloamide 14 as a test
substrate. Compound 14 was readily prepared by treating
carboline 12 with pent-4-enoyl chloride under refluxing condi-
tions in toluene followed by reaction of the resulting N-acyl
carboline 13 with sodium hydride and ethyl 2-diazomalonyl
chloride34 (Scheme 2). Heating R-diazo indoloamide 14 with a
catalytic amount of Rh2(OAc)4 was expected to generate a
rhodium carbenoid intermediate that should undergo cyclization
with the neighboring amido carbonyl group to form a transient
carbonyl ylide dipole 15. Indeed, our studies showed that a
subsequent intramolecular [3+2]-cycloaddition of 15 occurred
across the tethered π-bond and furnished cycloadduct 16 in 95%
yield and with complete diastereoselectivity as evidence by its
(32) For conversion of related oxolactams to vincamine derivatives via
this semi-benzylic acid rearrangement, see: (a) Oppolzer, W.; Hauth, H.;
Pfa¨ffli, P.; Wenger, R. HelV. Chim. Acta 1977, 60, 1801. (b) Sza´ntay, C.;
Szabo´, L.; Kalaus, G. Tetrahedron 1977, 33, 1803. (c) Szabo´, L.; Kablaus,
G.; Sza´ntay, C. Arch. Pharm. (Weinheim, Ger.) 1983, 316, 629.
(33) For a preliminary report, see: England, D. B.; Padwa, A. Org. Lett.
2007, 9, 3249.
(35) Weingarten, M. D.; Prein, M.; Price, A. T.; Snyder, J. P.; Padwa,
A. J. Org. Chem. 1997, 62, 2001.
(36) For a review of dealkoxycarbonylations, see: Krapcho, A. P.
Synthesis 1982, 805 and 893.
(34) Marino, J. P.; Osterhout, M. H.; Price, A. T.; Sheehan, S. M.; Padwa,
A. Tetrahedron Lett. 1994, 35, 849.
(37) Hong, X.; Mej´ıa-Oneto, J. M.; Padwa, A. Tetrahedron Lett. 2006,
47, 8387.
2794 J. Org. Chem., Vol. 73, No. 7, 2008

Vinca and Tacaman Alkaloids
Lewis acid.38 However, our initial attempts to reduce the
resulting iminium ion with Et3SiH and other hydride reagents
afforded only recovered starting material. We suspected that
removal of the lactam carbonyl group would help promote the
reduction by enhancing the nucleophilicity of the nitrogen atom
thereby facilitating oxabicyclic ring opening. Accordingly,
cycloadduct 9 was converted into the corresponding thiolactam
22 with Lawesson’s reagent in 95% yield. Reductive removal
of the thiocarbonyl group with Raney-Ni was followed by
treatment of the resulting piperidine with Zn/AcOH to give the
ring opened amide 10 containing the eventually required trans-
D/E ring fusion of 3H-epivincamine in 75% yield over the two
steps. Reduction of the transient iminium ion with zinc occurred
from the least hindered face thereby generating the required
trans-ring junction. We were also interested in determining
whether the cis-isomer could be formed. However, screening a
variety of reducing agents (i.e., H2/PtO2; NaBH4; LiAl(Ot-Bu)4)
resulted only in the formation of the trans-ring stereoisomer.
Next, the carboethoxy group in 10 was selectively removed by
treatment with MgI2 as found with the earlier model studies.
Oxidation of the resulting R-hydroxy lactam to the correspond-
ing keto-amide 11 was carried out using Dess-Martin periodi-
nane in 31% overall yield for the two steps. The conversion of
related oxolactams to vincamine derivatives has been reported
in the literature.32 In our hands, methanolysis of 11 with sodium
carbonate as base gave, after 1 h of stirring at room temperature,
a 95% yield of (()-3H-epivincamine (3) as the only diastere-
omer.
SCHEME 3. Completion of the Model Study
SCHEME 4. Total Synthesis of (()-3H-Epivincamine
Synthesis of (()-Tacamonine (5). The main challenge in
designing any synthetic approach toward the tacaman alkaloids
lies in controlling the relative configurational relationship of
all three stereocenters at C3, C14, and C20 (all cis-hydrogens).
Considering the success we had synthesizing (()-3H-epivin-
camine (3), we decided to use a similar cyclization cascade
strategy for (()-tacamonine (5). However, two major variants
of the approach are necessary for this particular target and which
need to be taken into consideration: (1) the different placement
of the ethyl substituent on the skeleton and (2) the need to
control the stereochemistry of the reductive ring opening of the
oxabicycle to generate the required cis-D/E ring fusion. Our
synthesis of (()-tacamonine (5) began with the preparation of
R-diazo indoloamide 23 containing the ethyl substituent in the
required position. Compound 23 was prepared in 65% yield by
treating carboline 12 with the mixed anhydride of 2-ethyl-pent-
4-enoic acid followed by deprotonation of the indole N-H and
reaction with ethyl 2-diazomalonyl chloride. Subjecting R-diazo
indoloamide 23 to a catalytic amount of Rh2(OAc)4 in refluxing
benzene gave the desired intramolecular [3+2]-cycloadduct 24
in 90% yield as a single diastereomer (Scheme 5). Once again,
the facileness of the cycloaddition shows how effective the Rh-
(II)-catalyzed cascade sequence is for generating the core
pentacyclic skeleton.
to give the cis-fused ring system 19 in 65% yield as a single
diastereomer. Oxidation of 19 with Dess-Martin periodinane was
now straightforward and furnished keto-amide 20 in 72% yield.
With keto-amide 20 in hand, the desired conversion to the ring
contracted vincamine derivative was found to occur in methanol
using sodium carbonate as the base,32 furnishing 21 in 90% yield
as 3:1 mixture of diastereomers at the C16-position.
Synthesis of (()-3H-Epivincamine (3). Having been en-
couraged by the model studies with R-diazo indoloamide 14,
we turned our attention to the preparation of R-diazo indoloa-
mide 8 which would be used to provide the necessary quaternary
ethyl substituent required for the synthesis of (()-3H-epivin-
camine (3). Accordingly, compound 8 was synthesized in 60%
yield by treating the readily available carboline 12 with the
mixed anhydride of 4-methylenehexanoic acid followed by
deprotonation of the indole N-H with sodium hydride and
reaction with ethyl 2-diazomalonyl chloride. Formation of the
desired carbonyl ylide dipole was achieved by treating 8 with
a catalytic amount of Rh2(OAc)4 in refluxing benzene. Subse-
quent intramolecular [3+2]-cycloaddition furnished the key
cycloadduct 9 containing the desired quaternary ethyl substituent
in 95% yield as a single diastereomer (Scheme 4). The uniquely
functionalized oxapolycyclic adduct 9 contains a “masked”
N-acyliminium ion which can be released by treatment with a
Carrying on with the synthesis, cycloadduct 24 was treated
with BF3‚OEt2, as was done previously, to induce oxabicyclic
ring opening and produce the expected enamine 25 in 93% yield.
At this point, we envisioned a catalytic hydrogenation of the
enamine double bond to deliver the required cis-ring fusion of
the target molecule. We also anticipated that hydrogen would
be delivered from the least hindered face opposite the ethyl
substituent thereby setting the required all cis-stereochemistry.
Gratifyingly, when enamine 25 was subjected to hydrogenation
(38) Padwa, A.; Zhang, H. J. Org. Chem. 2007, 72, 2570.
J. Org. Chem, Vol. 73, No. 7, 2008 2795

England and Padwa
SCHEME 5. Total Synthesis of (()-Tacamonine (5)
conditions using catalytic PtO2, we were able to isolate lactam
26 in 70% yield which possesses the correct stereochemistry
(i.e., all hydrogens cis to each other). Single-crystal X-ray
analysis of 26 unequivocally confirmed this assignment.39 Next,
the carboethoxy group was removed with MgI2 and the
secondary alcohol was easily oxidized to the desired keto-amide
27 in 80% yield over the two steps.
SCHEME 6. Attempts to Directly Reduce Hydroxy Ester 28
into (()-Tacamine (4)
At this point, we subjected keto-amide 27 to the base-induced
ring contraction conditions and obtained the expected hydroxy
ester 28 in 95% yield as a 3:2-mixture of diastereomers. The
mixture of stereoisomers obtained was inconsequential since
the newly formed stereocenter at C16 would ultimately become
a carbonyl group in the final product. To complete the synthesis,
hydroxy ester 28 was treated with an excess amount of lithium
aluminum hydride so as to reduce both the lactam carbonyl and
ester functionalities. Finally, the resulting 3:2-mixture of diols
was subjected to sodium periodate oxidative cleavage to give
(()-tacamonine (5) as a single diastereomer in 63% yield for
the last two steps.
SCHEME 7. Attempted Conversion of [3+2]-Cycloadduct
24 into (()-Tacamine (4)
Attempted Synthesis of (()-Tacamine (4). We considered
the possibility of using the ring contracted hydroxy ester 28 as
a precursor for the synthesis of (()-tacamine (4). What would
be required would be to selectively reduce the lactam carbonyl
group in the presence of the ester functionality and then separate
the resulting diastereomers (Scheme 6). Unfortunately, all of
our attempts to convert 28 into (()-tacamine (4) by selective
reduction of the lactam carbonyl group failed to give any of
the desired product under a variety of reducing conditions (BH3‚
Sme2, BH3‚THF, NaBH4 + BF3‚OEt2, etc.).
Since we were not able to carry out the selective lactam
reduction, we turned our attention to an alternate approach,
which involves removing the lactam carbonyl group earlier on
in the synthesis. Thus, starting from cycloadduct 24, treatment
with Lawesson’s reagent afforded thiolactam 29 in 78% yield,
but unfortunately as a 1:1-mixture of epimers (Scheme 7). It
appears that under the reaction conditions used to convert lactam
(39) We will deposit coordinates for structure 26 with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on request,
from the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
2796 J. Org. Chem., Vol. 73, No. 7, 2008

Vinca and Tacaman Alkaloids
SCHEME 8. Conversion of r-Hydroxy Ester 28 into
(()-Apotacamine (6)
Experimental Section
2-Pent-4-enoyl-2,3,4,9-tetrahydro-â-carbolin-1-one (13). To a
stirred solution containing 2.0 g (10.7 mmol) of carboline 1240 in
30 mL of refluxing toluene was added a solution of pent-4-enoyl
chloride (43 mmol) in 10 mL of toluene via cannula. The resulting
mixture was heated at reflux for 8 h and then the solvent was
removed under reduced pressure. The crude residue was subjected
to flash silica gel chromatography to give 2.1 g (74%) of carboline
13 as a white solid: mp 146-147 °C; IR (neat) 3301, 3064, 2925,
1
1691, and 1663 cm-1; H NMR (400 MHz, CDCl3) δ 2.48-2.54
(m, 2H), 3.07 (t, 2H, J ) 6.4 Hz), 3.20 (t, 2H, J ) 7.3 Hz), 4.35
(t, 2H, J ) 6.4 Hz), 5.02 (dd, 1H, J ) 10.2 and 1.6 Hz), 5.11 (dd,
1H, J ) 17.2 and 1.6 Hz), 5.87-5.97 (m, 1H), 7.19 (t, 1H, J ) 7.9
Hz), 7.38 (t, 1H, J ) 8.3 Hz), 7.46 (d, 1H, J ) 8.3 Hz), 7.64 (d,
1H, J ) 8.6 Hz), and 9.36 (brs, 1H); 13C NMR (100 MHz, CDCl3)
δ 20.9, 29.1, 38.5, 44.1, 112.6, 115.4, 120.8, 121.1, 123.9, 124.8,
126.5, 126.6, 137.3, 138.6, 161.8, and 175.6.
2-Diazo-3-oxo-3-(1-oxo-2-pent-4-enoyl-1,2,3,4-tetrahydro-â-
carbolin-9-yl)-propionic Acid Ethyl Ester (14). To a suspension
of 0.19 g (4.7 mmol) of NaH in 20 mL of THF cooled to 0 °C was
added 1.1 g (3.9 mmol) of carboline 13 dissolved in 20 mL of
THF via cannula. The solution was allowed to stir at 0 °C for 30
min, after which time 1.0 g (5.9 mmol) of ethyl 2-diazomalonyl
chloride34 dissolved in 10 mL of THF was added via cannula. The
resulting mixture was allowed to warm to rt overnight. The solution
was then quenched with water, and extracted with ethyl acetate.
The combined organic layers were washed with brine and dried
over Na2SO4. The organic extracts were filtered and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 1.1 g (70%) of R-diazo indole
14 as a yellow oil: IR (neat) 2137, 1712, 1679, 1646, and 1307
24 into thiolactam 29, epimerization at the C20 position has
occurred. Reductive removal of the thiocarbonyl group with
Raney-Ni does deliver enamine 30 in 73% yield but as a 1:1-
mixture of inseparable epimers. At this point, we envisioned
hydrogenation of the enamino double bond with the hope of
obtaining some facial selectivity for the reduction. However,
examination of the crude reaction mixture obtained from the
hydrogenation reaction showed very little facial selectivity and,
in fact, a mixture of four stereoisomers of 31 were produced.
Although we were somewhat discouraged by this result, we
nevertheless treated 30 with MgI2 in wet acetonitrile to effect
the decarboethoxylation. The resulting alcohol 32 was then
subjected to hydrogenation but, unfortunately, this resulted in
a complex mixture of all four diastereomers of 33. Since we
were unable to effect separation of the various stereoisomers
of 33 by column chromatography, we subsequently abandoned
further work with this synthesis.
Synthesis of (()-apotacamine (6). Even though we had little
success in converting hydroxy ester 28 into (()-tacamine (4),
we thought that we might be able to use this same compound
for the synthesis of the natural product (()-apotacamine (6)
which is devoid of any stereochemistry at the C16 position of
the E-ring. Consequently, the 3:2-mixture of epimers present
in 28 was treated with Meerwein’s reagent at room temperature
and this resulted in a smooth dehydration and formation of the
unsaturated ester 34 in 80% yield (Scheme 8). Conversion of
34 to the natural product involved converting the lactam
carbonyl group to the corresponding thiolactam using Lawes-
son’s reagent followed by reductive removal of the thio group
with Raney-Ni to give (()-apotacamine (6) in 56% yield for
the two steps.
In conclusion, we have developed a concise total synthesis
of several members of the Vinca and tacaman class of indole
alkaloids. The central step in the synthesis consists of an
intramolecular [3+2]-cycloaddition reaction of an R-diazo
indoloamide which delivers the pentacyclic skeleton of the
natural product in excellent yield. The acid lability of the
oxabicyclic structure was exploited to establish the trans-D/E
ring fusion of (()-3H-epivincamine (3). Finally, a base induced
keto-amide ring contraction was utilized to generate the E-ring
of the natural product. A variation of the cascade sequence of
reactions used to synthesize (()-3H-epivincamine (3) was also
employed for the synthesis of the tacaman alkaloids (()-
tacamonine (5) and (()-apotacamine (6). We plan to use this
cascade methodology toward the synthesis of other natural
products, the results of which will be disclosed in due course.
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.22 (t, 3H, J ) 7.3 Hz),
2.41-2.46 (m, 2H), 3.00 (t, 2H, J ) 6.4 Hz), 3.08 (t, 2H, J ) 7.3
Hz), 4.16 (q, 2H, J ) 7.3 Hz), 4.28-4.35 (m, 2H), 5.00 (d, 1H, J
) 10.2 Hz), 5.07 (dd, 1H, J ) 17.2 and 1.6 Hz), 5.82-5.92 (m,
1H), 7.30 (t, 1H, J ) 7.6 Hz), 7.46 (t, 1H, J ) 8.3 Hz), 7.60 (d,
1H, J ) 7.9 Hz), and 7.87 (d, 1H, J ) 8.6 Hz); 13C NMR (100
MHz, CDCl3) δ 14.3, 21.2, 29.0, 38.7, 42.3, 61.7, 114.2, 115.3,
121.0, 123.6, 125.4, 128.5, 128.8, 129.2, 137.3, 139.2, 159.9, 160.3,
161.7, and 175.4.
Rh(II)-Catalyzed Formation of Dipolar Cycloadduct 16. A
1.0 g (2.4 mmol) sample of R-diazo indole 14 was stirred with
rhodium(II) acetate (2 mg) in 20 mL of benzene and the mixture
was heated at reflux for 1 h. At the end of this time, the mixture
was allowed to cool to rt and the solvent was removed under
reduced pressure. The crude residue was subjected to flash silica
gel chromatography to give 0.87 g (95%) of cycloadduct 16 as a
white solid: mp 169-170 °C; IR (neat) 3422, 2936, 1750, 1719,
1
and 1687 cm-1; H NMR (400 MHz, CDCl3) δ 1.35 (t, 3H, J )
7.3 Hz), 1.82-1.88 (m, 1H), 2.04-2.14 (m, 1H), 2.46-2.53 (m,
2H), 2.61-2.85 (m, 4H), 2.96 (dd, 1H, J ) 13.8 and 9.1 Hz), 3.08
(dt, 1H, J ) 12.4 and 3.8 Hz), 4.29-4.45 (m, 2H), 4.87 (dd, 1H,
J ) 13.0 and 4.8 Hz), 7.34-7.42 (m, 2H), 7.53 (d, 1H, J ) 7.0
Hz), and 8.21 (d, 1H, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 14.0, 20.4, 26.5, 29.1, 37.8, 38.9, 39.0, 62.8, 84.1, 88.3, 114.4,
116.1, 119.5, 125.0, 125.9, 128.2, 133.3, 134.7, 165.6, and 173.3;
HRMS Calcd. for [C21H20N2O5 + H+]: 381.1445. Found 381.1455.
Formation of Ring-Opened Product 17. A 0.7 g (1.8 mmol)
sample of cycloadduct 16 was dissolved in 25 mL of CH2Cl2 and
cooled to 0 °C. To this mixture was added 1.6 mL (12.9 mmol) of
boron trifluoride etherate in CH2Cl2 (10 mL) via cannula. The
mixture was allowed to warm to rt overnight. The solution was
then added to a saturated aqueous solution of NaHCO3, the organic
layer was separated, and the aqueous layer was extracted with CH2-
Cl2. The combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude residue was
(40) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315.
J. Org. Chem, Vol. 73, No. 7, 2008 2797

England and Padwa
subjected to flash silica gel chromatography to give 0.57 g (82%)
of enamine 17 as a white solid: mp 182-184 °C; IR (neat) 3411,
2927, 1731, 1671, and 1652 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.12 (t, 3H, J ) 7.3 Hz), 2.31-2.36 (m, 1H), 2.47-3.10 (m, 7H),
3.17 (dt, 1H, J ) 12.2 and 3.8 Hz), 4.09-4.18 (m, 2H), 4.93-
4.95 (m, 1H), 4.97 (s, 1H), 7.35-7.46 (m, 2H), 7.49 (d, 1H, J )
7.6 Hz), and 8.58 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3)
δ 14.0, 21.5, 27.6, 30.9, 37.7, 37.9, 62.1, 77.6, 113.4, 117.9, 118.9,
122.4, 125.2, 126.4, 127.1, 127.6, 128.4, 138.3, 168.3, 168.9, and
170.1; HRMS Calcd. for [C21H20N2O5 + H+]: 381.1445. Found
381.1444.
CDCl3) δ 20.6, 21.7, 24.9, 26.0, 32.7, 33.4, 35.2, 35.6, 42.8, 43.4,
57.7, 111.2, 117.4, 118.4, 118.7, 124.6, 125.0, 125.4, 126.2, 126.5,
129.9, 130.0, 135.9, 142.4, 162.1, 169.7, 195.2.
5-Hydroxy-1-oxo-1,2,3,3a,4,5,10,11b-octahydro-11H-5a,11a-
diaza-benzo[cd] fluoranthene-5-carboxylic Acid Methyl Ester
(21). To a 0.03 g (0.1 mmol) sample of keto-amide 20 in 5 mL of
methanol was added 0.10 g (1.0 mmol) of anhydrous sodium
carbonate. After stirring at rt for 1 h, the solvent was removed under
reduced pressure, water was added and the mixture was extracted
with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.03 g (90%) as a 3:1 mixture of diastereomers of 21
as an oily foam: IR (neat) 3243, 2952, 2849, 1748, 1621, and 1456
11-Hydroxy-1,2,4,5,11,12-hexahydro-3a,9b-diaza-benzo[a]-
naphtho[2,1,8-cd] azulene-3,10-dione (18). To a 0.5 g (1.3 mmol)
sample of enamine 17 in 25 mL of acetonitrile was added 1.1 g
(3.9 mmol) of magnesium iodide and the mixture was heated at
reflux for 24 h. The solution was then allowed to cool to rt, added
to CH2Cl2 and extracted with a saturated aqueous solution of
NaHCO3. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chromatography
to give 0.28 g (70%) of alcohol 18 as a pale orange solid: mp
cm-1 1H NMR (400 MHz, CDCl3) δ 1.52-1.55, 1.73-1.79
;
(m, 1H), 1.72, 1.93 (dq, 1H, J ) 13.3 and 5.1 Hz), 2.26-2.41 (m,
3H), 2.48-2.74 (m, 3H), 2.91-3.10 (m, 2H), 3.65, 3.89 (s, 3H),
4.75, 4.79 (brd, 1H, J ) 6.4 Hz), 4.92-5.00 (m, 1H), 7.05-7.08
(m, 1H), 7.11-7.17 (m, 2H), and 7.33-7.35, 7.43-7.47 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 20.6, 20.8, 22.6, 23.3, 30.9,
32.5, 33.1, 38.2, 40.3, 41.9, 42.0, 53.5, 54.0, 54.4, 54.6, 81.5, 82.1,
109.5, 109.6, 110.6, 111.7, 118.3, 118.7, 120.6, 120.9, 122.2,
122.5, 128.1, 128.8, 131.3, 131.7, 134.8, 136.1, 169.3, 169.7, 172.3,
173.8; HRMS Calcd. for [C19H20N2O4 + H+]: 341.1496. Found
341.1499.
1
48-50 °C; IR (neat) 3451, 3051, 2924, 1692, and 1667 cm-1; H
NMR (400 MHz, CDCl3) δ 2.24-2.29 (m, 1H), 2.44-2.54 (m,
1H), 2.60-2.84 (m, 4H), 2.91-3.00 (m, 2H), 3.12 (dt, 1H, J )
12.1 and 3.8 Hz), 4.10 (d, 1H, J ) 3.5 Hz), 4.61 (dt, 1H, J ) 12.1
and 3.5 Hz), 5.16 (ddd, 1H, J ) 12.7, 5.1 and 2.2 Hz), 7.35 (t, 1H,
J ) 8.3 Hz), 7.43 (t, 1H, J ) 8.3 Hz), 7.48 (d, 1H, J ) 7.6 Hz),
and 8.55 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ
21.6, 27.0, 30.9, 36.8, 37.7, 69.6, 115.2, 117.3, 118.9, 122.4, 125.0,
126.5, 127.0, 127.3, 128.3, 137.7, 169.0, and 173.3.
2-Diazo-3-[2-(4-methylene-hexanoyl)-1-oxo-1,2,3,4,-tetrahy-
dro-â-carbolin-9-yl]-3-oxo-propionic Acid Ethyl Ester (8). To
a stirred solution of 0.75 g (5.9 mmol) of 4-methylene-hexanoic
acid41 in 25 mL of THF cooled to 0 °C was added 0.6 mL (5.9
mmol) of 4-methylmorpholine, followed by 0.8 mL (5.9 mmol) of
isobutyl chloroformate dropwise. After stirring at 0 °C for 30 min,
the white precipitate that formed was removed by filtration and
was washed with 5 mL of THF. The filtrate was concentrated under
reduced pressure and redissolved in 10 mL of toluene. In a separate
flask, was placed 2.2 g (11.8 mmol) of carboline 12 in 50 mL of
toluene. To this mixture was added the preformed mixed anhydride
via cannula and the resulting solution was stirred at reflux for 12
h. At the end of this time, the mixture was allowed to cool to rt
and the solvent was removed under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to give
0.73 g (42%) of 2-(4-methylene-hexanoyl)-2,3,4,9-tetrahydro-â-
carbolin-1-one as a white solid: mp 123-124 °C; IR (neat)
11-Hydroxy-1,2,4,5,11,12,12a,12b-octahydro-3a,9b-diaza-ben-
zo[a]naphtho [2,1,8-cd]azulene-3,10-dione (19). To a stirred
solution of 0.21 g (0.68 mmol) of alcohol 18 in 3 mL of THF and
3 mL of EtOH was added a catalytic amount of PtO2 (10 mol %).
The resulting mixture was hydrogenated at 5 atm for 24 h, filtered
through a pad of Celite, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chromatography
to give 0.14 g (65%) of alcohol 19 as a white solid: mp 204-
206 °C; IR (neat) 3389, 2924, 1697, 1624, and 1456 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.41-1.52 (m, 1H), 1.71-1.85 (m, 2H),
2.41-2.81 (m, 6H), 2.94-3.03 (m, 1H), 4.03 (d, 1H, J ) 3.2 Hz),
4.57 (d, 1H, J ) 12.1 Hz), 5.04 (dd, 1H, J ) 12.4 and 4.1 Hz),
5.10-5.12 (m, 1H), 7.34-7.43 (m, 2H), 7.47 (d, 1H, J ) 7.9 Hz),
and 8.55 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ
21.5, 26.3, 32.8, 33.4, 36.1, 42.8, 58.1, 67.4, 117.4, 118.2, 122.7,
124.7, 126.0, 129.6, 130.7, 136.3, 170.2, and 173.8; HRMS Calcd.
for [C18H18N2O3 + H+]: 311.1390. Found 311.1386.
1
3308, 3058, 2966, 1692, and 1666 cm-1; H NMR (400 MHz,
CDCl3) δ 1.05 (t, 3H, J ) 7.3 Hz), 2.09 (q, 2H, J ) 7.3 Hz),
2.46 (t, 2H, J ) 7.6 Hz), 3.07 (t, 2H, J ) 6.4 Hz), 3.20 (t, 2H, J
) 7.6 Hz), 4.34 (t, 2H, J ) 6.4 Hz), 4.77 (brs, 2H), 7.19 (t, 1H, J
) 7.0 Hz), 7.38 (t, 1H, J ) 7.3 Hz), 7.45 (d, 1H, J ) 8.3 Hz), 7.64
(d, 1H, J ) 8.3 Hz), and 8.98 (brs, 1H); 13C NMR (100
MHz, CDCl3) δ 12.3, 20.9, 29.0, 31.3, 37.7, 44.2, 108.1, 112.6,
120.8, 121.0, 123.9, 124.8, 126.5, 126.6, 138.5, 150.2, 161.8, and
176.0.
To a suspension of 86 mg (2.2 mmol) of NaH in 15 mL of THF
cooled to 0 °C was added 0.53 g (1.8 mmol) of the above carboline
dissolved in 10 mL of THF via cannula. The solution was allowed
to stir at 0 °C for 30 min, after which time 0.47 g (2.7 mmol) of
ethyl 2-diazomalonyl chloride dissolved in 8 mL of THF was added
via cannula. The resulting mixture was allowed to warm to rt
overnight, the solution was then quenched with water, and extracted
with ethyl acetate. The combined organic layers were washed with
brine and dried over Na2SO4. The organic extracts were filtered
and concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.47 g (60%)
of R-diazo indole 8 as a yellow oil: IR (neat) 2967, 2937, 2140,
1718, and 1689 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.04 (t, 3H,
J ) 7.6 Hz), 1.22 (t, 3H, J ) 7.3 Hz), 2.07 (q, 2H, J ) 7.6 Hz),
2.41 (t, 2H, J ) 7.6 Hz), 3.00 (t, 2H, J ) 6.4 Hz), 3.12 (t, 2H, J
1,2,5,12,12a,12b-Hexahydro-4H-3a,9b-diaza-benzo[a]naphtho-
[2,1,8-cd] azulene-3,10,11-trione (20). To a 0.22 g (0.52 mmol)
slurry of Dess-Martin periodinane in 5 mL of CH2Cl2 was added 2
drops of tert-butyl alcohol and the mixture was stirred at rt for 15
min. A solution of 0.08 g (0.26 mmol) of alcohol 19 in 3 mL of
CH2Cl2 was then added dropwise and the solution was stirred at rt
for 2 h. At the end of this time, the mixture was diluted with CH2-
Cl2 and poured into a saturated aqueous NaHCO3 solution contain-
ing an excess of Na2S2O3. The mixture was stirred for 10 min, the
organic layer was separated and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography to
give 0.06 g (72%) as a 4:1 mixture of tautomers of keto-amide 20
as an oily foam: IR (neat) 3383, 2929, 1733, 1696, 1643, and 1457
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.69 (dq, 1H, J ) 13.0 and
4.4 Hz), 1.88-1.93(m, 1H), 2.45-2.73 (m, 4H), 2.79-3.01 (m,
2H), 3.02 (dd, 1H, J ) 11.4 and 8.9 Hz), 3.09-3.13 (m, 1H), 4.89
(dd, 1H, J ) 12.7 and 5.7 Hz, enol), 5.01-5.12 (m, 2H), 6.17 (d,
1H, J ) 9.2 Hz, enol), 7.32-7.45 (m, 2H), 7.49 (d, 1H, J ) 7.9
Hz), and 8.44, 8.53 (d, 1H, J ) 7.9 Hz); 13C NMR (100 MHz,
(41) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
2798 J. Org. Chem., Vol. 73, No. 7, 2008

Vinca and Tacaman Alkaloids
) 7.6 Hz), 4.16 (q, 2H, J ) 7.3 Hz), 4.28-4.34 (m, 2H), 4.73 (s,
1H), 4.75 (s, 1H), 7.30 (t, 1H, J ) 7.9 Hz), 7.46 (t, 1H, J ) 8.6
Hz), 7.60 (d, 1H, J ) 7.9 Hz), and 7.87 (d, 1H, J ) 8.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 12.3, 14.2, 21.2, 28.9, 31.2, 37.8, 42.4,
61.7, 108.1, 114.2, 121.0, 123.6, 125.4, 128.5, 128.8, 129.2, 139.2,
150.1, 159.9, 160.3, 161.8, and 175.8.
3.02 (m, 3H), 4.17 (s, 1H), 4.31 (s, 1H), 4.38-4.47 (m, 2H), 7.27-
7.30 (m, 2H), 7.39-7.41 (m, 1H), and 8.33-8.35 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.1, 14.0, 22.0, 22.4, 24.7, 36.9, 38.3,
41.3, 52.5, 56.2, 63.4, 65.7, 80.8, 117.0, 117.7, 119.2, 124.1, 124.7,
129.7, 133.7, 136.6, 169.5, and 172.6; Anal. Calcd. for
C23H28N2O4: C, 69.67; H, 7.12; N, 7.07. Found: C, 69.67; H, 7.22;
N, 6.82.
Rh(II)-Catalyzed Formation of Dipolar Cycloadduct 9. A 0.40
g (0.9 mmol) sample of R-diazo indole 8 was stirred with rhodium-
(II) acetate (2 mg) in 10 mL of benzene and the mixture was heated
at reflux for 1 h. At the end of this time, the mixture was allowed
to cool to rt and the solvent was removed under reduced pressure.
The crude residue was subjected to flash silica gel chromatography
to give 0.35 g (95%) of cycloadduct 9 as a white solid: mp 153-
154 °C; IR (neat) 2970, 1752, 1722, 1690, and 1376 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.87 (t, 3H, J ) 7.3 Hz), 1.00 (dt, 1H, J )
13.7 and 7.3 Hz), 1.22 (dt, 1H, J ) 13.7 and 7.3 Hz), 1.34 (t, 3H,
J ) 7.3 Hz), 1.73-1.81 (m, 1H), 1.99-2.05 (m, 1H), 2.45-2.85
(m, 6H), 3.03 (dt, 1H, J ) 12.4 and 3.5 Hz), 4.28-4.44 (m, 2H),
4.83 (dd, 1H, J ) 13.0 and 4.8 Hz), 7.34-7.42 (m, 2H), 7.52 (d,
1H, J ) 8.3 Hz), and 8.22 (d, 1H, J ) 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 9.0, 14.0, 20.5, 29.3, 29.8, 31.4, 39.6, 42.4, 46.3,
62.8, 82.9, 92.5, 116.2, 117.6, 119.4, 125.0, 125.9, 128.2, 131.1,
134.4, 165.9, and 173.0; Anal. Calcd. for C23H24N2O5: C, 67.63;
H, 5.92; N, 6.86. Found: C, 67.81; H, 6.15; N, 6.61.
12a-Ethyl-2,3,5,12,12a,12b-hexahydro-1H,4H-3a,9b-diaza-
benzo[a]naphtho [2,1,8-cd]azulene-10,11-dione (11). To a 0.05
g (0.13 mmol) sample of amide 10 in 2 mL of acetonitrile con-
taining 3 drops of tert-butyl alcohol was added 0.07 g (0.26 mmol)
of magnesium iodide. The mixture was heated at reflux for 24 h
and then 0.5 mL of DMF was added. The resulting solution was
refluxed for a further 48 h, allowed to cool to rt, added to CH2Cl2
and extracted with a saturated aqueous solution of NaHCO3. The
organic layer was separated and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chromato-
graphy to give 0.026 g (62%) of 12a-ethyl-11-hydroxy-2,3,4,5,-
11,12,12a,12b-octahydro-1H-3a,9b-diaza-benzo[a]naphtho[2,1,8-
cd] azulen-10-one as a white solid: mp 121-123 °C; IR (neat)
3460, 2937, 2804, 2756, 1686, and 1458 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.69 (t, 3H, J ) 7.6 Hz), 0.84 (dt, 1H, J ) 14.6 and 7.6
Hz), 1.47-1.57 (m, 2H), 1.71-1.96 (m, 4H), 2.06 (dt, 1H, J )
14.6 and 7.6 Hz), 2.45 (dt, 1H, J ) 11.4 and 3.2 Hz), 2.56-2.62
(m, 2H), 2.83-2.92 (m, 1H), 2.98-3.04 (m, 2H), 3.46 (s, 1H),
3.98 (d, 1H, J ) 3.8 Hz), 4.71-4.76 (m, 1H), 7.30-7.37 (m, 2H),
7.43 (d, 1H, J ) 7.6 Hz), and 8.55 (d, 1H, J ) 7.3 Hz); 13C NMR
(100 MHz, CDCl3) δ 6.7, 21.9, 22.2, 25.7, 36.2, 37.0, 43.1, 52.1,
56.4, 67.0, 67.5, 117.2, 117.8, 120.1, 124.3, 125.0, 129.7, 132.8,
136.1, and 174.2.
Formation of Thiolactam 22. To a stirred solution of 0.40 g
(1.0 mmol) of cycloadduct 9 in 30 mL of toluene under N2 was
added 0.50 g (1.2 mmol) of Lawesson’s reagent at rt. The mixture
was heated at reflux for 1 h, cooled to rt, and concentrated under
reduced pressure. The crude residue was subjected to flash silica
gel chromatography to give 0.41 g (95%) of thiolactam 22 as a
white solid: mp 174-175 °C; IR (neat) 2971, 2936, 1751, 1723,
1
1663, 1390, and 1376 cm-1; H NMR (400 MHz, CDCl3) δ 0.87
(t, 3H, J ) 7.0 Hz), 0.91-0.97 (m, 1H), 1.15 (dt, 1H, J ) 13.0
and 7.3 Hz), 1.35 (t, 3H, J ) 7.3 Hz), 1.66 (dt, 1H, J ) 13.7 and
3.5 Hz), 1.90-1.95 (m, 1H), 2.61-2.82 (m, 3H), 2.95-3.00 (m,
1H), 3.18 (dt, 1H, J ) 14.6 and 4.1 Hz), 3.30-3.39 (m, 2H), 4.32-
4.42 (m, 2H), 5.71 (dd, 1H, J ) 13.3 and 4.8 Hz), 7.38-7.46 (m,
2H), 7.57 (d, 1H, J ) 7.6 Hz), and 8.26 (d, 1H, J ) 7.3 Hz); 13C
NMR (100 MHz, CDCl3) δ 9.1, 14.0, 20.0, 31.8, 33.9, 40.1, 42.4,
47.2, 47.8, 62.9, 83.0, 91.3, 116.2, 116.4, 119.5, 125.2, 126.1, 127.7,
130.5,134.4,165.3,165.5,and209.9;HRMSCalcd.for[C23H24N2O4S
+ H+]: 425.1530. Found 425.1527.
12a-Ethyl-11-hydroxy-10-oxo-2,3,5,10,11,12,12a,12b-octahy-
dro-1H,4H-3a,9b-diaza-benzo[a]naphtho[2,1,8-cd]azulene-11-
carboxylic Acid Ethyl Ester (10). An excess amount of Raney
nickel (ca 1.5 g) in a 50 mL round-bottom flask under N2 was
washed three times with water, twice with dry methanol, and finally
three times with dry THF. A 0.15 g (0.35 mmol) sample of
thiolactam 22 in 3 mL of THF was then added dropwise to the
Raney nickel suspension in 5 mL of THF. The mixture was stirred
vigorously for 24 h under 1 atm of hydrogen gas, then filtered
through a pad of Celite, and concentrated under reduced pressure.
The crude residue was not purified but was immediately carried
onto the next reaction.
To a 0.13 g (0.30 mmol) slurry of Dess-Martin periodinane in 5
mL of CH2Cl2 was added 0.5 mL of pyridine and the mixture was
stirred at rt for 5 min. A solution of 0.05 g (0.15 mmol) of the
above alcohol in 3 mL of CH2Cl2 was added dropwise and the
solution was stirred at rt for 1 h. At the end of this time, the mixture
was diluted with CH2Cl2 and poured into a saturated aqueous
NaHCO3 solution containing an excess of Na2S2O3. The mixture
was stirred for 10 min, the organic layer was separated and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.025 g (50%) as a 1.6:1 mixture
of tautomers of keto-amide 11 as an oily foam: IR (neat) 3411,
2932, 2805, 2753, 1727, 1696, and 1458 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.77, 0.79 (t, 3H), 1.21-1.30 (m, 2H), 1.40-1.63 (m,
2H), 1.80-2.05 (m, 2H), 2.29-2.66 (m, 4H), 2.80-3.02 (m, 3H),
3.41, 3.50 (brs, 1H), 5.76 (s, 1H, enol), 6.76 (s, 1H, enol), 7.30-
7.46 (m, 3H), and 8.42, 8.48 (d, 1H); 13C NMR (100 MHz, CDCl3)
δ 7.0, 8.3, 21.8, 21.9, 22.2, 24.5, 25.8, 34.5, 35.1, 39.3, 41.6, 50.8,
51.6, 52.7, 55.7, 56.2, 66.6, 68.2, 117.1, 117.8, 118.0, 118.3, 119.8,
120.8, 122.5, 124.4, 125.0, 125.2, 125.3, 129.9, 130.2, 132.2, 135.6,
137.0, 140.0, 162.6, 163.4, and 197.4.
To a 0.14 g (0.35 mmol) sample of the above adduct in 4 mL of
AcOH and 8 mL of H2O was added 0.4 g of Zn dust. The result-
ing mixture was stirred vigorously at rt for 24 h and filtered through
a pad of Celite. The filtrate was added to CH2Cl2 and extracted
with a saturated aqueous solution of NaHCO3. The organic
layer was separated and the aqueous layer was extracted twice with
CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude re-
sidue was subjected to flash silica gel chromatography to give 0.10
g (75% over 2 steps) of amide 10 as a white solid: mp 54-56 °C;
IR (neat) 3459, 2938, 2805, 2775, 1736, 1687, and 1457 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.75 (t, 3H, J ) 7.6 Hz), 1.07 (dt, 1H,
J ) 14.6 and 7.6 Hz), 1.41 (t, 3H, J ) 7.3 Hz), 1.45-1.75
(m, 4H), 1.85-1.89 (m, 1H), 2.04 (dt, 1H, J ) 14.6 and 7.6 Hz),
2.46 (dt, 1H, J ) 12.1 and 2.5 Hz), 2.60-2.70 (m, 3H), 2.84-
(()-3H-Epivincamine (3). To a 0.02 g (0.06 mmol) sample of
keto-amide 11 in 5 mL of methanol was added 0.06 g (0.60 mmol)
of anhydrous sodium carbonate. After stirring at rt for 1 h, the
solvent was removed under reduced pressure, water was added
and the mixture was extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.02 g (95%) of (()-3H-
epivincamine (3) as white crystals: mp 155-156 °C (lit.20a
mp 163-163.5 °C); IR (neat) 3499, 2933, 2851, 2794, 2744, 1733,
1459, and 1444 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.84 (t, 3H,
J ) 7.3 Hz), 1.06 (dt, 1H, J ) 13.3 and 2.9 Hz), 1.27-1.33
(m, 1H), 1.57-1.61 (m, 1H), 1.82-2.03 (m, 4H), 2.24-2.31
(m, 2H), 2.53 (dt, 1H, J ) 11.4 and 4.4 Hz), 2.68-2.73 (m, 1H),
J. Org. Chem, Vol. 73, No. 7, 2008 2799

England and Padwa
2.90-2.98 (m, 2H), 3.07-3.13 (m, 2H), 3.82 (s, 3H), 4.59 (s, 1H),
7.08-7.14 (m, 3H), and 7.44-7.47 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 7.3, 19.6, 21.1, 21.2, 32.1, 36.0, 43.8, 53.0, 54.2, 55.9,
67.1, 82.3, 106.3, 110.7, 118.4, 120.1, 121.3, 128.7, 132.5, 134.7,
and 174.3.
1.82-1.85 (m, 2H), 1.99-2.05 (m, 1H), 2.44-2.52 (m, 2H), 2.66-
2.74 (m, 1H), 2.80-2.86 (m, 2H), 2.97 (dd, 1H, J ) 13.7 and 9.2
Hz), 3.09 (dt, 1H, J ) 12.1 and 3.8 Hz), 4.29-4.46 (m, 2H), 4.91
(dd, 1H, J ) 13.0 and 3.2 Hz), 7.34-7.42 (m, 2H), 7.53 (d, 1H, J
) 7.6 Hz), and 8.22 (d, 1H, J ) 7.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 11.6, 14.0, 20.4, 22.2, 32.0, 38.0, 38.1, 38.9, 62.8, 84.1,
87.9, 113.9, 116.1, 119.5, 125.0, 125.8, 128.2, 133.5, 134.7, 165.6,
165.8, and 175.4; Anal. Calcd. for C23H24N2O5: C, 67.63; H, 5.92;
N, 6.86. Found: C, 67.52; H, 5.96; N, 6.83.
2-(2-Ethyl-pent-4-enoyl)-2,3,4,9-tetrahydro-â-carbolin-1-
one. To a stirred solution of 1.2 g (9.3 mmol) of 2-ethyl-pent-4-
enoic acid42 in 50 mL of THF cooled to 0 °C was added 1 mL (9.3
mmol) of 4-methylmorpholine, followed by 1.2 mL (9.3 mmol) of
isobutyl chloroformate dropwise. After stirring at 0 °C for 30 min,
the white precipitate that formed was removed by filtration and
was washed with 10 mL of THF. The filtrate was concentrated
under reduced pressure and redissolved in 20 mL of toluene. In a
separate flask was placed 2.6 g (14.0 mmol) of carboline 12 in
100 mL of toluene. To this mixture was added the preformed mixed
anhydride via cannula and the resulting solution was stirred at reflux
for 12 h. At the end of this time, the mixture was allowed to cool
to rt and the solvent was removed under reduced pressure. The
crude residue was subjected to flash silica gel chromatography to
give 1.1 g (40%) of 2-(2-ethyl-pent-4-enoyl)-2,3,4,9-tetrahydro-â-
carbolin-1-one as a white solid: mp 86-87 °C; IR (neat) 3311,
Formation of Ring-Opened Cycloadduct 25. A 0.46 g (1.12
mmol) sample of cycloadduct 24 was dissolved in 25 mL of CH2-
Cl2 and cooled to 0 °C. To this mixture was added 1 mL (7.8 mmol)
of boron trifluoride etherate in CH2Cl2 (10 mL) via cannula. The
mixture was allowed to warm to rt overnight. The solution was
then added to a saturated aqueous solution of NaHCO3, the organic
layer was separated, and the aqueous layer was extracted three times
with CH2Cl2. The combined organic layers were dried over Na2-
SO4, filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to give
0.43 g (93%) of 25 as a white solid: mp 142-143 °C; IR (neat)
3416, 2966, 2934, 1732, 1669, and 1455 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.83-0.90 (m, 1H), 1.02 (t, 3H, J ) 7.3 Hz), 1.10 (t,
3H, J ) 7.0 Hz), 1.46-1.55 (m, 1H), 1.99-2.08 (m, 1H), 2.24-
2.35 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.81 (m, 1H), 2.88-2.92
(m, 1H), 3.00-3.12 (m, 2H), 4.12 (dq, 2H, J ) 7.3 and 1.6 Hz),
4.98 (s, 1H), 5.07-5.12 (m, 1H), 7.37 (t, 1H, J ) 7.3 Hz), 7.44
(dt, 1H, J ) 7.6 and 1.3 Hz), 7.48 (d, 1H, J ) 7.9 Hz), and 8.58
(d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 11.5, 14.0,
21.6, 22.4, 32.5, 37.7, 38.1, 40.7, 62.1, 77.5, 113.0, 117.8, 118.9,
122.3, 125.2, 126.0, 127.0, 127.7, 128.4, 138.3, 168.2, 170.1, and
171.1; HRMS Calcd. for [C23H24N2O5 + H+]: 409.1758. Found
409.1755.
1
2964, 2932, 1681, 1661, and 1479 cm-1; H NMR (400 MHz,
CDCl3) δ 0.95 (t, 3H, J ) 7.3 Hz), 1.59-1.67 (m, 1H), 1.78-1.87
(m, 1H), 2.28-2.35 (m, 1H), 2.50-2.57 (m, 1H), 3.05 (t, 2H, J )
6.4 Hz), 3.83 (tt, 1H, J ) 7.3 and 6.0 Hz), 4.33 (t, 2H, J ) 6.4
Hz), 4.99 (dd, 1H, J ) 10.2 and 1.9 Hz), 5.07 (dd, 1H, J ) 17.2
and 1.9 Hz), 5.77-5.87 (m, 1H), 7.19 (t, 1H, J ) 7.0 Hz), 7.38 (t,
1H, J ) 7.3 Hz), 7.45 (d, 1H, J ) 8.3 Hz), 7.64 (d, 1H, J ) 8.3
Hz), and 9.20 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9, 21.5,
25.5, 36.8, 45.0, 47.4, 112.8, 116.8, 121.1, 121.3, 124.3, 125.1,
126.9, 136.3, 138.8, 162.3, and 179.8.
2-Diazo-3-[2-(2-ethyl-pent-4-enoyl)-1-oxo-1,2,3,4,-tetrahydro-
â-carbolin-9-yl]-3-oxo-propionic Acid Ethyl Ester (23). To a
suspension of 0.10 g (2.7 mmol) of NaH in 15 mL of THF cooled
to 0 °C was added 0.67 g (2.3 mmol) of the above carboline
dissolved in 10 mL of THF via cannula. The solution was allowed
to stir at 0 °C for 30 min, after which time 0.60 g (3.4 mmol) of
ethyl 2-diazomalonyl chloride34 dissolved in 5 mL of THF was
added via cannula. The resulting mixture was allowed to warm to
rt overnight. The solution was then quenched with water, and
extracted with ethyl acetate. The combined organic layers were
washed with brine and dried over Na2SO4. The organic extracts
were filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to give
0.64 g (65%) of R-diazo indole 23 as a yellow oil: IR (neat) 2966,
2935, 2140, 1719, and 1686 cm-1; 1H NMR (400 MHz, CDCl3) δ
0.90 (t, 3H, J ) 7.3 Hz), 1.21 (t, 3H, J ) 7.3 Hz), 1.53-1.60 (m,
1H), 1.72-1.79 (m, 1H), 2.22-2.28 (m, 1H), 2.42-2.49 (m, 1H),
2.97 (t, 2H, J ) 6.4 Hz), 3.83 (tt, 1H, J ) 7.3 and 6.0 Hz), 4.15 (q,
2H, J ) 7.3 Hz), 4.28-4.35 (m, 2H), 4.97 (dd, 1H, J ) 10.2 and
1.6 Hz), 5.04 (dd, 1H, J ) 17.2 and 1.6 Hz), 5.72-5.82 (m, 1H),
7.30 (t, 1H, J ) 7.3 Hz), 7.46 (t, 1H, J ) 7.3 Hz), 7.59 (d, 1H, J
) 7.9 Hz), and 7.89 (d, 1H, J ) 8.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 11.4, 14.2, 21.4, 24.9, 36.3, 42.8, 47.2, 61.6, 114.2, 116.4,
120.9, 123.6, 125.4, 128.5, 129.0, 129.2, 136.0, 139.2, 159.9, 160.4,
161.8, and 179.1.
2-Ethyl-11-hydroxy-3,10-dioxo-2,3,5,10,11,12,12a,12b-octahy-
dro-1H,4H-3a,9b-diaza-benzo[a]naphtho[2,1,8-cd]azulene-11-
carboxylic Acid Ethyl Ester (26). To a stirred solution of 0.20 g
(0.49 mmol) of enamine 25 in 5 mL of THF and 5 mL of EtOH
was added a catalytic amount of PtO2 (10 mol %). The resulting
mixture was hydrogenated at 5 atm for 2 h, filtered through a pad
of Celite, and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to give
0.14 g (70%) of lactam 26 as a white solid: mp 161-162 °C; IR
(neat) 3290, 2934, 1748, 1691, and 1628 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.89 (t, 3H, J ) 7.6 Hz), 1.38 (t, 3H, J ) 7.1 Hz), 1.34-
1.41 (m, 1H), 1.48-1.54 (m, 1H), 1.75-1.78 (m, 1H), 1.95-2.02
(m, 1H), 2.27-2.33 (m, 2H), 2.39 (dd, 1H, J ) 15.2 and 7.1 Hz),
2.63-2.89 (m, 4H), 4.32 (s, 1H), 4.36-4.48 (m, 2H), 5.05 (dd,
1H, J ) 12.4 and 4.8 Hz), 5.58 (brd, 1H, J ) 7.1 Hz), 7.30-7.35
(m, 2H), 7.45 (d, 1H, J ) 7.6 Hz), and 8.32 (d, 1H, J ) 8.1 Hz);
13C NMR (100 MHz, CDCl3) δ 11.1, 14.0, 22.1, 23.6, 31.0, 31.9,
35.5, 42.6, 42.9, 57.6, 63.5, 78.3, 117.3, 118.2, 121.9, 124.5, 125.5,
130.0, 131.2, 136.9, 169.5, 172.2, and 172.4; Anal. Calcd. for
C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C, 66.81; H, 6.39;
N, 6.70.
2-Ethyl-1,2,5,12,12a,12b-hexahydro-4H-3a,9b-diaza-benzo[a]-
naphtho[2,1,8-cd]azulene-3,10,11-trione (27). To a 0.14 g (0.34
mmol) sample of lactam 26 in 5 mL of acetonitrile was added 0.19
g (0.68 mmol) of magnesium iodide and the mixture was heated at
reflux for 24 h. The solution was then allowed to cool to rt, added
to a saturated aqueous solution of NaHCO3 and extracted with CH2-
Cl2. The organic layer was separated and the aqueous layer was
extracted twice with CH2Cl2. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was immediately used in the next
reaction.
Rh(II)-Catalyzed Formation of Dipolar Cycloadduct 24. A
0.50 g (1.15 mmol) sample of R-diazo indoloamide 23 was stirred
with rhodium(II) acetate (2 mg) in 25 mL of benzene and the
mixture was heated at reflux for 1 h. At the end of this time, the
mixture was allowed to cool to rt and the solvent was removed
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.42 g (90%) of cycloadduct 24
as a white solid: mp 151-152 °C; IR (neat) 2937, 1751, 1720,
1
1686, 1662, and 1377 cm-1; H NMR (400 MHz, CDCl3) δ 1.01
To a 0.12 g (0.34 mmol) sample of the above alcohol dissolved
in 10 mL of CH2Cl2 was added 0.29 g (0.7 mmol) of Dess-Martin
periodinane and the reaction was stirred at rt for 2 h. At the end of
this time, the mixture was diluted with CH2Cl2 and poured into a
saturated aqueous NaHCO3 solution containing an excess of
(t, 3H, J ) 7.6 Hz), 1.35 (t, 3H, J ) 7.0 Hz), 1.41-1.48 (m, 1H),
(42) Kuehne, M.; Okuniewicz, F. J.; Kirkemo. C. L.; Bohnert, J. C. J.
Org. Chem. 1982, 47, 1335.
2800 J. Org. Chem., Vol. 73, No. 7, 2008

Vinca and Tacaman Alkaloids
Na2S2O3. The mixture was stirred for 10 min, the organic layerwas
separated and the aqueous layer was extracted twice with CH2Cl2.
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.09 g (80%)
as an 8:1 mixture of tautomers of keto-amide 27 as an orange oily
foam: IR (neat) 3277, 2965, 2934, 2876, 1730, 1693, 1621, and
of THF. The mixture was stirred vigorously for 24 h under 1 atm
of hydrogen gas, filtered through a pad of Celite, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.11 g (73%) as a 1:1 mixture of
diastereomers of 30 and was immediately used in the next reaction.
To a 0.11 g (0.28 mmol) sample of 30 in 5 mL of acetonitrile
was added 0.16 g (0.56 mmol) of magnesium iodide and the mixture
was heated at reflux for 24 h. The solution was then allowed to
cool to rt, added to a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2. The organic layer was separated and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.07 g (77%) as a 1:1 mixture of
diastereomers of the amido alcohol 32 as a clear oil: IR (neat)
3468, 2958, 2921, 2825, 1686, and 1455 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.96, 0.98 (t, 3H, J ) 7.6 Hz), 1.31-1.49 (m, 2H), 1.83-
2.06 (m, 2H), 2.20-2.54 (m, 2H), 2.62-3.22 (m, 7H), 4.07 (brs,
1H), 4.50-4.57 (m, 1H), 7.29-7.38 (m, 2H), 7.43 (d, 1H, J ) 7.9
Hz), 8.52, 8.54 (d, 1H, J ) 7.9 Hz); 13C NMR (100 MHz, CDCl3)
δ 11.3, 11.7, 21.9, 22.3, 26.0, 27.1, 33.8, 34.4, 37.1, 37.3, 37.4,
37.6, 50.0, 50.5, 55.8, 57.0, 69.9, 70.1, 108.2, 108.8, 117.2, 117.5,
118.27, 118.3, 120.8, 121.3, 124.5, 126.0, 129.0, 129.7, 132.2,
132.4, 137.7, 174.1, 174.3; HRMS Calcd. for [C20H20N2O2 + H+]:
323.1754. Found 323.1754.
1
1456 cm-1; H NMR (400 MHz, CDCl3) δ 0.78, 0.89 (t, 3H, J )
7.3 Hz), 1.48 (q, 1H, J ) 13.0 Hz), 1.51-1.60 (m, 1H), 1.89-
2.03 (m, 2H), 2.32-2.40 (m, 1H), 2.63-2.71 (m, 2H), 2.85-2.95
(m, 2H), 3.02 (dd, 1H, J ) 11.4 and 9.2 Hz), 3.08-3.13 (m, 1H),
5.00-5.10 (m, 2H), 6.17 (d, 1H, J ) 9.2 Hz, enol), 7.33-7.45 (m,
2H), 7.48 (d, 1H, J ) 7.9 Hz), and 8.43, 8.54 (d, 1H, J ) 8.3 Hz);
13C NMR (100 MHz, CDCl3) δ 11.0, 21.9, 23.6, 30.7, 34.8, 42.9,
43.1, 43.6, 58.0, 117.4, 118.7, 124.6, 125.4, 126.5, 129.3, 130.1,
135.9, 162.2, 172.2, and 195.3.
(()-Tacamonine (5). To a 0.02 g (0.06 mmol) sample of keto-
amide 27 in 3 mL of methanol was added 0.064 g (0.6 mmol) of
anhydrous sodium carbonate. After stirring at rt for 1 h, the solvent
was removed under reduced pressure, water was added and the
mixture was extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue containing 28 was immediately used
in the next reaction.
To a stirred solution of 0.02 g (0.06 mmol) of the above mixture
in 4 mL of THF cooled to 0 °C was added 0.3 mL (0.3 mmol) of
lithium aluminum hydride. Once the addition was complete, the
reaction was heated at reflux for 1 h, slowly quenched with water,
followed by the addition of Rochelle salt and stirred for 30 min.
The mixture was then partitioned between ethyl acetate and water.
The organic layer was separated and the aqueous layer was extracted
twice with ethyl acetate. The combined organic layers were washed
with water, brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was immediately used
in the next reaction.
2-Ethyl-1-oxo-1,2,3,3a,10,11b-hexahydro-11H-5a,11a-diaza-
benzo[cd] fluoranthene-5-carboxylic Acid Methyl Ester (34). To
a stirred solution of 0.02 g (0.054 mmol) of hydroxy ester 28 in 4
mL of CH2Cl2 was added 0.02 g (0.14 mmol) of trimethyloxonium
tetrafluoroborate and the mixture was stirred at rt overnight. At
the end of this time, the solution was diluted with H2O and extracted
with CH2Cl2. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chromatography
to give 0.015 g (80%) of lactam 34 as a white solid: mp 175-176
To a 0.02 g (0.06 mmol) sample of the above mixture dissolved
in 3 mL of THF and 1 mL of H2O was added 0.064 g (0.3 mmol)
of sodium periodate and the reaction mixture was stirred vigorously
at rt for 4 h. At the end of this time, the mixture was extracted
with ethyl acetate. The combined organic layers were washed with
a saturated aqueous solution of Na2SO3, water, brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography to
give 0.01 g (60% over 3 steps) of (()-tacamonine (5) as white
needles: mp 140-141 °C, (lit.22 mp 143 °C); IR (neat) 2917, 1700,
1
°C; IR (neat) 2929, 1731, 1644, 1455, and 1427 cm-1; H NMR
(400 MHz, CDCl3) δ 0.85 (t, 3H, J ) 7.3 Hz), 1.14 (q, 1H, J )
13.0 Hz), 1.35-1.42 (m, 1H), 1.86-2.01 (m, 2H), 2.23-2.29 (m,
1H), 2.66-2.69 (m, 1H), 2.93-3.06 (m, 3H), 3.99 (s, 3H), 4.91
(brd, 1H, J ) 7.6 Hz), 4.96-5.04 (m, 1H), 6.29 (d, 1H, J ) 7.0
Hz), 7.14-7.27 (m, 3H), and 7.47 (d, 1H, J ) 7.3 Hz); 13C NMR
(100 MHz, CDCl3) δ 11.4, 20.6, 23.0, 28.6, 32.2, 42.8, 43.5, 52.7,
53.3, 112.5, 112.8, 118.5, 119.8, 120.9, 122.9, 128.9, 130.0, 130.4,
134.7, 163.5, and 171.6; HRMS Calcd. for [C21H22N2O3 + H+]:
351.1703. Found 351.1700.
1
1635, 1453, and 1383 cm-1; H NMR (400 MHz, CDCl3) δ 0.57
(q, 1H, J ) 13.0 Hz), 0.85 (t, 3H, J ) 7.3 Hz), 1.07-1.15 (m,
2H), 1.49-1.57 (m, 1H), 1.67 (brd, 1H, J ) 13.0 Hz), 2.04 (t, 1H,
J ) 11.1 Hz), 2.43-2.53 (m, 2H), 2.63-2.67 (m, 1H), 2.67 (dd,
1H, J ) 17.2 and 2.5 Hz), 2.86-2.95 (m, 1H), 3.01 (dd, 1H, J )
17.2 and 5.1 Hz), 3.34-3.38 (m, 2H), 4.35-4.37 (m, 1H), 7.27-
7.35 (m, 2H), 7.45 (dd, 1H, J ) 7.0 and 1.9 Hz), and 8.38 (dd, 1H,
J ) 7.3 and 1.9 Hz); 13C NMR (100 MHz, CDCl3) δ 11.3, 16.3,
26.8, 31.9, 34.4, 37.6, 39.7, 50.3, 50.5, 53.3, 112.8, 116.3, 118.1,
123.8, 124.3, 129.9, 131.5, 134.4, and 167.4.
2-Ethyl-11-hydroxy-2,3,4,5,11,12-hexahydro-1H-3a,9b-diaza-
benzo[a] naphtho[2,1,8-cd]azulen-10-one (32). To a stirred solu-
tion of 0.2 g (0.49 mmol) of cycloadduct 24 in 15 mL of toluene
under N2 was added 0.2 g (0.49 mmol) of Lawesson’s reagent at
rt. The mixture was heated at reflux for 30 min, cooled to rt, and
concentrated under reduced pressure. The crude thiolactam was
subjected to flash silica gel chromatography to give 0.16 g (78%)
as a 1:1 mixture of diastereomers of 29 and was immediately used
in the next reaction.
(()-Apotacamine (6). To a stirred solution of 0.02 g (0.057
mmol) of lactam 34 in 3 mL of toluene under N2 was added 0.02
g (0.057 mmol) of Lawesson’s reagent at rt. The mixture was heated
at reflux for 1 h, cooled to rt, and concentrated under reduced
pressure. The crude thiolactam was subjected to flash silica gel
chromatography and immediately used in the next reaction.
An excess amount of Raney nickel (ca. 0.25 g) in a 25 mL round-
bottom flask under N2 was washed three times with water, twice
with dry methanol, and finally three times with dry THF. A 0.02
g (0.057 mmol) sample of the above thiolactam in 2 mL of THF
was then added dropwise to the Raney nickel suspension in 3 mL
of THF. The mixture was stirred vigorously for 24 h under 1 atm
of hydrogen gas, filtered through a pad of Celite, and concentrated
under reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.01 g (56% over 2 steps) of
(()-apotacamine (6)15 as a light-yellow oil: IR (neat) 2922, 2851,
1
1731, 1635, and 1455 cm-1; H NMR (400 MHz, CDCl3) δ 0.48
(q, 1H, J ) 12.7 Hz), 0.85 (t, 3H, J ) 7.3 Hz), 1.04-1.18 (m,
2H), 1.48-1.57 (m, 1H), 1.73 (brd, 1H, J ) 12.7 Hz), 2.23 (t, 1H,
J ) 11.1 Hz), 2.56-2.61 (m, 1H), 2.70-2.72 (m, 1H), 2.77-2.85
(m, 1H), 2.97-3.06 (m, 1H), 3.35-3.38 (m, 2H), 3.95 (s, 3H),
4.48-4.50 (m, 1H), 6.40 (d, 1H, J ) 7.3 Hz), 7.12-7.25 (m, 3H),
and 7.48 (d, 1H, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ
An excess amount of Raney nickel (ca. 2.0 g) in a 50 mL round-
bottom flask under N2 was washed three times with water, twice
with dry methanol, and finally three times with dry THF. A 0.16
g (0.38 mmol) sample of the above thiolactam in 10 mL of THF
was then added dropwise to the Raney nickel suspension in 15 mL
J. Org. Chem, Vol. 73, No. 7, 2008 2801

England and Padwa
11.2, 16.2, 26.8, 31.3, 33.1, 36.7, 50.6, 50.7, 51.8, 52.5, 108.6,
112.5, 118.3, 120.3, 122.1, 123.4, 128.8, 129.1, 129.9, 134.3, and
163.6.
Supporting Information Available: 1H and 13C NMR data of
various key compounds lacking CHN analyses together with an
ORTEP drawing for compound 26 as well as the corresponding
CIF files. We will deposit atomic coordinates for compound 26
with the Cambridge Crystallographic Data Centre. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the
National Science Foundation (CHE-0450779). We thank our
colleague, Dr. Kenneth Hardcastle, for his assistance with the
X-ray crystallographic studies.
JO8001003
2802 J. Org. Chem., Vol. 73, No. 7, 2008