Asymmetric Total Synthesis of (+)-Apovincamine and a Formal Synthesis of (+)-Vincamine. Demonstration of a Practical "Asymmetric Linkage" between Aromatic Carboxylic Acids and Chiral Acyclic Substrates

Article abstract of DOI:10.1021/jo961603p

Asymmetric syntheses of (+)-apovincamine (la) and (+)-vincamine (2) are described. Construction of the pentacyclic diene lactam 14, a pivotal intermediate for synthesis of the cis-fused vincane-type alkaloids, began by Birch reduction - alkylation of the chiral benzamide 3 to give the 6-ethyl-l-methoxy-4-methyl-l,4-cyclohexadiene 4. Conversion of 4 to 2,5-cyclohexadienone 5 (92percent overall yield from 3) and HPLC analysis of 5 demonstrated the diastereomeric purity resulting from the Birch reduction - alkylation to be > 100:1. Dienone 5 was converted to butyrolactone 9 (47percent overall yield from 3), and 9 was coupled with tryptamine (10) to give the amide lia. Amido keto aldehyde 13 was obtained from 11a, and acid-catalyzed tricyclization and subsequent base-induced elimination of MeOH provided the desired cis-fused pentacyclic diene lactam 14. Examination of the two-step process 13 -14 revealed a novel base-induced epimerization at C(21) which served to interconvert 14 and 17, possibly by the involvement of a homoenolate. Diene lactam 14 was converted to (+)-apovincaminal 20a, an intermediate in the synthesis of (+)-apovincamine (la) reported by Winterfeldt and co-workers. A new procedure for conversion of 20a to la involves conversion of 20a to the acetal 20b and treatment of 20b with NBS/AIBN in CCl₄. The conversion of la to vincamine (2) has been reported by Oppolzer and co-workers.

Full text of DOI:10.1021/jo961603p

J . Org. Chem. 1997, 62, 1223-1229
1223
Asym m etr ic Tota l Syn th esis of (+)-Ap ovin ca m in e a n d a F or m a l
Syn th esis of (+)-Vin ca m in e. Dem on str a tion of a P r a ctica l
“Asym m etr ic Lin k a ge” betw een Ar om a tic Ca r boxylic Acid s a n d
Ch ir a l Acyclic Su bstr a tes
Arthur G. Schultz,* William P. Malachowski, and You Pan
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590
Received August 19, 1996X
Asymmetric syntheses of (+)-apovincamine (1a ) and (+)-vincamine (2) are described. Construction
of the pentacyclic diene lactam 14, a pivotal intermediate for synthesis of the cis-fused vincane-
type alkaloids, began by Birch reduction-alkylation of the chiral benzamide 3 to give the 6-ethyl-
1-methoxy-4-methyl-1,4-cyclohexadiene 4. Conversion of 4 to 2,5-cyclohexadienone 5 (92% overall
yield from 3) and HPLC analysis of 5 demonstrated the diastereomeric purity resulting from the
Birch reduction-alkylation to be >100:1. Dienone 5 was converted to butyrolactone 9 (47% overall
yield from 3), and 9 was coupled with tryptamine (10) to give the amide 11a . Amido keto aldehyde
13 was obtained from 11a , and acid-catalyzed tricyclization and subsequent base-induced
elimination of MeOH provided the desired cis-fused pentacyclic diene lactam 14. Examination of
the two-step process 13 f 14 revealed a novel base-induced epimerization at C(21) which served
to interconvert 14 and 17, possibly by the involvement of a homoenolate. Diene lactam 14 was
converted to (+)-apovincaminal 20a , an intermediate in the synthesis of (+)-apovincamine (1a )
reported by Winterfeldt and co-workers. A new procedure for conversion of 20a to 1a involves
conversion of 20a to the acetal 20b and treatment of 20b with NBS/AIBN in CCl4. The conversion
of 1a to vincamine (2) has been reported by Oppolzer and co-workers.
Sch em e 1. Th e P r ep a r a tion of Key In ter m ed ia tes
in Sever a l Asym m etr ic Syn th eses of th e
Ebu r n a m in e-Vin ca m in e Alk a loid s
The eburnamine-vincamine alkaloids are found in
plants of the dogbane family (Apocynaceae).1 Herein, we
report asymmetric total syntheses of two of the most
important vincane-type alkaloids, (+)-apovincamine (1a )
and (+)-vincamine (2). Ethyl apovincaminate (1b) has
been used for the treatment of cognitive and behavioral
symptoms associated with vascular and degenerative
disorders of the central nervous system2 and has been
reported to have beneficial effects in the treatment of
cerebral ischemia.3 Vincamine (2) is a vasodilator; it is
noteworthy that Sankyo introduced brovincamine fuma-
rate (trade name: Sabromin) in 1986 as a drug to
selectively increase cranial and coronary blood flow for
the treatment of multiinfarct dementia.4
Several strategies for asymmetric syntheses of the
eburnamine-vincamine alkaloids (excluding resolutions)
are highlighted in Scheme 1. The Rapoport5 and Takano6
groups have made direct use of the chiral pool; other
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Lounasmaa, M.; Toluanen, A. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1992; Vol. 42, pp 1-116.
(2) Neuss, N. In Indole and Biogenetically Related Alkaloids; Phil-
lipson, J . D., Zenk, M. H., Eds.; Academic Press: London, 1980; p 294.
(3) King, G. A.; Narcavage, D. Drug Dev. Res. 1986, 9, 225.
(4) Hagstadius, S. Psychopharmacology (Berlin) 1984, 83, 321.
(5) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. J .
Org. Chem. 1990, 55, 3068.
research groups have utilized the chiral auxiliary ap-
proach with modest to good absolute stereocontrol.7
Absolute stereocontrol in our synthesis of 1a has been
accomplished by the Birch reduction-alkylation of the
chiral benzamide 3 to give 4 with a diastereomer distri-
bution of >100:1.8
(6) Takano, S.; Yonaga, M.; Morimoto, M.; Ogasawara, K. J . Chem.
Soc., Perkin Trans. 1 1985, 305.
S0022-3263(96)01603-9 CCC: $14.00 © 1997 American Chemical Society

1224 J . Org. Chem., Vol. 62, No. 5, 1997
Schultz et al.
Sch em e 2a
Resu lts a n d Discu ssion
It was expected that a wide range of vincane-type
alkaloids would be accessible by chemical modification
of the pentacyclic diene lactam 14. The strategy for
construction of 14 involved coupling of tryptamine (10)
with the chiral enantiomerically pure butyrolactone 9,
followed by acid-catalyzed tricyclization and elimination
of MeOH from the amido keto aldehyde 13. Butyrolac-
tone 9 was obtained from the chiral benzamide 3 by a
new process9a that provides a practical “asymmetric
linkage” between aromatic carboxylic acids and chiral
acyclic substrates.9b
a
Reaction conditions: (a) K, NH3, tert-BuOH (1 equiv) -78 °C;
piperylene; EtI (1.1 equiv), -78 °C to 25 °C; (b) PDC (cat.), tert-
BuOOH, Celite, PhH; (c) H2, 5% Pd/C, EtOAc (60 psi); (d) Li, NH3,
tert-BuOH, -78 °C; NH4Cl, -78 °C; (e) TFAA, UHP, CH2Cl2,
Na2HPO4; (f) TsOH, H2O, PhH, reflux.
Sch em e 3a
Con st r u ct ion of Bu t yr ola ct on e 9. A concise and
efficient preparation of butyrolactone 9 from chiral
benzamide 310 is shown in Scheme 2. Birch reduction-
ethylation of 3 (32.5 g scale) provided the 1,4-cyclohexa-
diene 4, which was converted to the 2,5-cyclohexadienone
5 on oxidation with catalytic PDC and t-BuOOH in
benzene in the presence of Celite.11 The overall yield for
this two-step conversion was 92%. Diastereomeric purity
of 5 was determined to be >100:1 by direct HPLC
comparison to a 1:1 mixture of diastereomers prepared
by reductive alkylation of methyl 2-methoxy-5-methyl-
benzoate with ethyl iodide, saponification, coupling of the
resulting cyclohexadienecarboxylic acid to L-prolinol (meth-
yl ether),12 and oxidation to the dienone.
Hydrogenation of the C(5)-C(6) double bond in 5 with
5% Pd/C gave the crystalline vinylogous ester 6 in 90%
yield as a single diastereomer. The C(2)-C(3) double
bond in 6 was resistant to further hydrogenation;13
efficient conversion of 6 to the 3-methoxycyclohexanone
7 required reduction with Li in NH3 in the presence of
tert-BuOH. Baeyer-Villiger oxidation of 7 gave the
caprolactone derivative 8, for which an X-ray structure
a
Reaction conditions: (a) (PhO)2P(O)N3, DMF, Et3N, 0 °C to
25 °C; (b) (tert-BuO2C)2O, CH2Cl2; (c) LiBH4, THF; (d) ClCOCOCl,
DMSO, CH2Cl2, -78 °C; Et3N, -78 °C to 25 °C; (e) CF3CO2H,
CH2Cl2, 25 °C; (f) tert-BuOK, tert-BuOH, reflux
determination provided the absolute configurational as-
signments at C(4), C(5), and C(7).14 Treatment of 8 with
p-toluenesulfonic acid in a refluxing mixture of PhH-
H2O gave the butyrolactone carboxylic acid 9 and re-
leased the chiral auxiliary for reutilization. It is note-
worthy that 9 was prepared from 3 in six steps with an
overall yield of 47%.
Con ver sion of 9 to th e P en ta cyclic Dien e La cta m
14. Butyrolactone 9 was coupled to tryptamine (10) as
shown in Scheme 3 to give the chiral amide 11a (83%).
It was necessary to protect the indole NH group as the
tert-butoxycarbonyl derivative 11b because an unpro-
tected intermediate (not shown) underwent oxidative
cyclization at C(2) of the indole ring and the neighboring
(7) (a) Meyers, A. I.; Romine, J .; Robichaud, A. J . Heterocycles 1990,
30, 339. (b) Ihara, M.; Yasui, K.; Taniguchi, N.; Fukumoto, K.
Heterocycles 1990, 31, 1017. (c) Hakam, K.; Thielmann, M.; Thielmann,
T.; Winterfeldt, E. Tetrahedron 1987, 43, 2035. (d) Node, M.; Na-
gasawa, H.; Fuji, K. J . Org. Chem. 1990, 55, 517.
(8) For a complete review of previous syntheses of the eburnamine-
vincamine alkaloids, see: ref 1.
(9) (a) Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron
Lett. 1992, 33, 6611. (b) The first synthesis of racemic eburnamine
involved the “abnormal Reimer-Tiemann reaction” of p-ethylphenol
to give 4-(dichloromethyl)-4-ethyl-2,5-cyclohexadien-1-one in 4% yield;
see: Bartlett, M. F.; Taylor, W. I. J . Am. Chem. Soc. 1960, 82, 5941.
(10) For the preparation and Birch reduction-methylation of benz-
amide 3, see: Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras,
A. G.; Welch, M. J . Am. Chem. Soc. 1988, 110, 7828.
(11) Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetrahedron
Lett. 1988, 29, 3907.
(14) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(12) See ref 10 for details.
(13) Herndon, J . W.; Matasi, J . J . Tetrahedron Lett. 1992, 33, 5725
and references cited therein.

Synthesis of (+)-Apovincamine and (+)-Vincamine
J . Org. Chem., Vol. 62, No. 5, 1997 1225
secondary amide during a subsequent Swern oxidation.
Reduction of the lactone ring in 11b with LiBH4 in THF
provided the diol 12, which was converted to the amido
keto aldehyde 13 on Swern oxidation (68% overall yield
from 11a ). Treatment of 13 with CF3CO2H in CH2Cl2
effected the desired tricyclization, and subsequent base-
induced elimination of MeOH provided the cis-fused
diene lactam 14 as the major reaction product (see
Experimental Section).
Careful examination of the two-step process 13 f 14
revealed several remarkable features that make this
solution to the stereocontrolled construction of the cis-
fused vincane-type alkaloids unique. Separation of reac-
tion products from the acid-catalyzed cyclization of 13
provided cis-fused 15 (47%) and trans-fused 16 (30%).
Treatment of 15 with tert-BuOK in tert-BuOH at reflux
gave the crystalline cis-fused diene lactam 14 in 60%
isolated yield and 12% of the trans-fused diene lactam
17. To our initial surprise, trans-fused 16 also provided
the cis-fused diene lactam 14 (52% isolated yield) under
conditions identical to those utilized for the conversion
of 15 to 14. It was demonstrated in a separate experi-
ment with 17 and tert-BuOK in tert-BuOH at reflux that
epimerization at C(21) occurred to give a 4:1 mixture of
14 and 17.
F igu r e 1. Energy-minimized (MM2 via MacroModel Version
3.0) of a homoenolate possibly involved with the interconver-
sion of 14 and 17.
Sch em e 4a
a
Reaction conditions: (a) LiAlH4, Et2O, reflux; (b) CH3CONHBr
Deuterium labeling experiments were carried out to
help elucidate the mechanism of isomerization at C(21).
In both the cis- and trans-fused pentacyclic lactams 15
and 16 the protons at C(14) readily exchanged (see
Experimental Section for details). With 15, this resulted
in the elimination of MeOH and formation of 14 without
any deuterium incorporation at C(21). With 16, elimina-
tion of MeOH to generate 17 was accompanied by
exchange of the proton at C(21) and epimerization.
Interconversion of 15 and 16 did not occur under the
strongly basic conditions leading to elimination of MeOH
from 15 and 16. Therefore, the R,â-unsaturated lactam
is a structural unit that is required for conversion of
trans-fused 17 into cis-fused 14. It is possible that
interconversion of 14 and 17 is facilitated by the involve-
ment of a homoenolate15 as shown in Figure 1.
Com p letion of th e Syn th esis of (+)-Ap ovin ca m in e
(1a ) a n d a F or m a l Tota l Syn th esis of (+)-Vin ca m in e
(2). Reduction of the diene lactam 14 by the method of
Shamma and Rosenstock16 gave the piperidine 18 (Scheme
4). Electrophilic bromination of the enamine-like double
bond in 18 with 2 equiv of N-bromoacetamide provided
the dibromide 19 in 67% overall yield from 14. Treat-
ment of 19 with AgBF4, DMSO, and Et3N followed by an
aqueous workup procedure gave (+)-apovincaminal 20a
in 83% yield.
(2 equiv), THF; (c) AgBF4, Et3N, DMSO; (d) MeOH, (MeO)3CH,
TsOH, reflux; (e) AIBN, NBS, CCl4, reflux.
The conversion of 20a to (+)-apovincamine (1a ) has
been reported by Winterfeldt and co-workers.7c Aldehyde
20a was reduced to apovincaminol 20c, and a sample of
this material sent to Hannover was found to be identical
to apovincaminol in two TLC systems and by direct 1H
NMR comparison. Although the preparation of 20a
constitutes a formal total synthesis17 of 1a , we opted to
develop a procedure for conversion of 20a to (+)-apovin-
camine (1a ) which avoids the use of metallic oxidants.
Treatment of 20a with MeOH, (MeO)3CH, and p-tolu-
enesulfonic acid gave the acetal 20b and free radical
bromination18 of 20b provided (+)-1a . This substance
was found to be identical (1H and 13C NMR, TLC, IR) to
(+)-apovincamine that had been prepared from natural
vincamine by literature procedures.19 The conversion of
apovincamine to vincamine (2) has been reported by
Oppolzer and co-workers.20
To confirm that the high diastereoselectivity obtained
by Birch reduction-alkylation of 3 to give 4 was main-
(17) Najer, H.; Pascal, Y. German Patent P 236568.3,9 1973; also,
see ref 7c.
(18) Marko´, E.; Mekhalfia, A.; Ollis, D. Synlett 1990, 347.
(19) (a) Troja´nek, J .; Strouf, O.; Holubek, J .; Cekan, Z. Tetrahedron
Lett. 1961, 702. (b) Mokry, J .; Kompis, I. Tetrahedron Lett. 1963, 1917.
(c) Pfa¨fli, P.; Hauth, H. Helv. Chim. Acta 1978, 61, 1682.
(20) Pfa¨ffli, P.; Oppolzer, W.; Wenger, R.; Hauth, H. Helv. Chim.
Acta 1975, 58, 1131.
(15) Nickon, A.; Lambert, J . L. J . Am. Chem. Soc. 1966, 88, 1905.
(16) Shamma, M.; Rosenstock, P. O. J . Org. Chem. 1961, 26, 718.

1226 J . Org. Chem., Vol. 62, No. 5, 1997
Schultz et al.
g, (100%) as a light yellow oil which was used in the next
reaction. Chromatography (silica gel, 30% EtOAc in hexane)
gave 4 as a white solid (mp 34-39 °C). Rf ) 0.54 (EtOAc:
hexane 1:1) UV inactive. 1H NMR (CDCl3) δ 5.0 (1 H, s), 4.75
(1 H, t, J ) 3 Hz), 4.30 (1 H, m), 3.62 (1 H, dd, J ) 10 Hz, 4
Hz), 3.50 (1 H, m), 3.49 (3 H, s), 3.33 (3 H, s), 3.29-3.26 (2 H,
m), 2.77 (1 H, d, J ) 20 Hz), 2.66 (1 H, d, J ) 19 Hz), 2.05 (2
H, m), 1.84-1.75 (2 H, m), 1.74 (3 H, s), 1.73-1.66 (2 H, m),
0.66 (3 H, t, J ) 7 Hz); 13C NMR (CDCl3) δ 171.0, 152.6, 133.4,
121.2, 92.8, 71.8, 58.6, 57.8, 54.0, 53.0, 45.6, 31.4, 28.6, 26.1,
24.7, 22.0, 13.9, 7.7. CI-MS, m/z (relative intensity) 294 (M+
+ 1, 100%).
(2′S,4R)-4-E t h yl-3-m et h oxy-6-m et h yl-4-[[2′-(m et h oxy-
m e t h yl)p yr r olid in yl]ca r b on yl]-2,5-cycloh e xa d ie n -1-
on e (5). To a solution of 4 (19.9 g, 67.9 mmol) in benzene
(600 mL) were added PDC (2.5 g, 6.8 mmol), Celite (2.5 g),
and t-BuOOH (10 mL, 102 mmol). The mixture was stirred
for 7 h at room temperature, and then another portion of PDC
(2.5 g), Celite (2.5 g), and t-BuOOH (10 mL) was added. After
stirring overnight, the mixture was filtered and the solution
was evaporated under reduced pressure. Column chromatog-
raphy (silica gel, 60% EtOAc in hexane) gave 5, 19.28 g (92%),
as a light yellow solid (mp 90-96 °C). Rf ) 0.25 (EtOAc:
hexane 1:1) UV active. HPLC analysis of diastereomers (9:1
hexanes:i-PrOH): retention times ) 8.20 (major diastereomer)
and 9.76 min (minor); ratio of integrated peak areas exceeded
100:1. An analysis of a mixture of the diastereomers prepared
as described in the text had an integration ratio of 1:1. 1H
NMR (CDCl3) δ 6.13 (1 H, s), 5.66 (1 H, s), 4.14 (1 H, br s),
3.62 (3 H, s), 3.40 (1 H, m), 3.27 (1 H, m), 3.20 (3 H, s), 3.07 (1
H, m), 2.90 (1 H, m), 2.14-2.10 (1 H, m), 1.97-1.92 (1 H, m),
1.83 (3 H, s), 1.74-1.71 (3 H, m), 1.59 (1 H, m), 0.45 (3 H, t,
J ) 9 Hz). 13C NMR (CDCl3) δ 187.7, 173.6, 166.1, 138.2,
136.8, 104.4, 71.5, 58.6, 58.3, 56.3, 55.7, 45.1, 29.5, 26.1, 24.4,
15.2, 7.1. IR (CHCl3) 1622, 1603 cm-1. CI-MS, m/z (relative
intensity) 308 (M+ + 1, 40%), 142 (M+ - 166, 100%). Anal.
Calcd for C17H25NO4: C, 66.42; H, 8.20; N, 4.56. Found: C,
66.28; H, 8.32; N, 4.49.
tained during subsequent synthetic conversions, (+)-
apovincaminol (20c) was converted to the Mosher ester.
This derivative was compared to a diastereomeric mix-
ture of the corresponding Mosher ester of racemic apovin-
caminol obtained by Birch reduction-alkylation of the
achiral pyrrolidine amide analogue of 3. 1H NMR
spectroscopy indicated that the Mosher ester of (+)-20c
was a single diastereomer; however, 19F NMR spectros-
copy revealed a small but reproducible resonance at the
chemical shift corresponding to the second diastereomer,
establishing the minimum enantiomeric composition to
be >20:1. It can be concluded, therefore, that the process
resulting in epimerization at C(21) during the conversion
of 16 to 14 does not compromise the absolute configura-
tion at C(20) to any significant degree.
Con clu sion
This highly stereoselective synthesis of (+)-apovincam-
ine (1a ) was carried out in 17 steps from chiral benz-
amide 3. Important general features of this synthesis
are excellent control of absolute configuration at three
stereogenic centers during the conversion of 3 to cyclo-
hexanone 7; complete regioselectivity for the Baeyer-
Villiger oxidation of 7; the efficient release of the chiral
auxiliary by an acid-catalyzed transesterification to give
butyrolactone 9; effective stereocontrol for the sequence
of reactions to convert 13 to the diene lactam 14. It is
expected that the pentacyclic diene lactam 14 also will
serve as an intermediate for synthesis of the 14,15-
dehydrovincane type alkaloids1 and related analogues.
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectroscopies were
performed at 500 and 125 MHz, respectively, with chloroform
used as the internal standard. 19F NMR spectroscopy was
performed at 470 MHz and trifluoroacetic acid (δ ) 0.0) was
used as an external reference. High resolution mass spectra
were obtained from the University of Illinois facilities at
UrbanasChampaign. Thin-layer chromatography was per-
formed with Merck Kieselgel 60 F-254 and Whatman Linear-K
silica gel precoated glass plates. Melting points are reported
without correction. Elemental analyses were obtained from
Quantitative Technologies Inc., Whitehouse, N.J . HPLC
analyses were performed on a Waters (6000A) chromatograph
fitted with a Chiracel OJ (Daicel) column and a refractometer
detection system (R40). Peak areas were measured with a
Hewlett-Packard integrator (HP 3394). Methyl alcohol, tert-
butyl alcohol, dimethyl sulfoxide, and triethylamine were dried
over CaH2 and distilled. Tetrahydrofuran and diethyl ether
were dried over sodium/benzophenone ketyl and distilled.
Methylene chloride and carbon tetrachloride were dried over
P2O5 and distilled. Dimethylformamide and trimethyl ortho-
formate were dried over 4 Å molecular sieves and distilled.
N-Bromoacetamide was recrystallized from methylene chlo-
ride. Tryptamine was recrystallized from toluene. N-Bromo-
succinimide was recrystallized from H2O. All other reagents
were used as purchased. Reactions requiring anhydrous
conditions were performed under a nitrogen atmosphere.
(2′S,6R)-6-E t h yl-1-m et h oxy-4-m et h yl-6-[[2′-(m et h oxy-
m et h yl)p yr r olid in yl]ca r b on yl]-1,4-cycloh exa d ien e (4).
To a solution of benzamide 310 (32.5 g, 123 mmol) and tert-
butyl alcohol (11.6 mL, 123 mmol) in THF (300 mL) and NH3
(1200 mL) at -78 °C was added potassium in small pieces until
a blue coloration was maintained for 30 min. Piperylene was
added to consume the excess metal, and then EtI (11.1 mL,
136 mmol) was added over 10 min. The solution was stirred
at -78 °C for 1.5 h and then slowly warmed to room
temperature to allow the NH3 to evaporate. Water was added
and the mixture was extracted with CH2Cl2. The organic layer
was dried (Na2SO4) and concentrated in vacuo to give 4, 36.8
(2′S,4R,6S)-4-E t h yl-3-m et h oxy-6-m et h yl-4-[[2′-(m et h -
oxym eth yl)pyr r olidin yl]car bon yl]-5-cycloh exen -1-on e (6).
A mixture of 5 (3.07 g, 10.0 mmol) and Pd/C (5%, 2.00 g, 0.940
mmol) in EtOAc (225 mL) was shaken under H2 (60 psi) for 4
h. Filtration and column chromatography (silica gel, 70%
EtOAc in hexane) gave 6, 2.80 g (90%), as colorless crystals
(mp 82-84 °C). Rf ) 0.29 (EtOAc:hexane 7:3) UV active. 1H
NMR (CDCl3) δ 5.38 (1 H, s), 4.27 (1 H, br s), 3.69 (3 H, s),
3.60 (1 H, m), 3.54 (1 H, br s), 3.43 (1 H, m), 3.34 (3 H, s), 3.02
(1 H, m), 2.56 (1 H, m), 2.10 (1 H, m), 2.07 (2 H, m), 1.89 (3 H,
m), 1.15 (3 H, d, J ) 7 Hz), 0.97 (3 H, t, J ) 8 Hz). 13C NMR
(CDCl3) δ 199.7, 178.6, 169.7, 102.0, 72.1, 58.9, 58.0, 55.7, 51.8,
46.7, 38.5, 36.4, 30.4, 26.2, 24.9, 15.1, 10.7. IR (CHCl3) 1632,
1601 cm-1. CI-MS, m/z (relative intensity) 310 (M+ + 1, 100%).
Anal. Calcd for C17H27NO4: C, 65.99; H, 8.80; N, 4.53.
Found: C, 65.72; H, 8.77; N, 4.42.
(2′S,3S,4R,6S)-4-Eth yl-3-m eth oxy-6-m eth yl-4-[[2′-(m eth -
oxym eth yl)p yr r olid in yl]ca r bon yl]-1-cycloh exa n on e (7).
To a solution of 6 (9.95 g, 32.2 mmol) and t-BuOH (9.6 mL,
96.6 mmol) in THF (200 mL) and NH3 (1500 mL) at -78 °C
was added Li until the blue coloration was maintained for 15-
20 min at -78 °C. The enolate was quenched with NH4Cl (∼5
g), and the mixture was warmed to room temperature while
NH3 evaporated. Water was added, and the mixture was
extracted with CH2Cl2; the organic layer was dried (Na2SO4)
and concentrated in vacuo. Chromatography (silica gel, 50%,
70% EtOAc in hexane) provided 7, 8.83 g (88%), as a white
solid (mp 90-91 °C). Rf ) 0.30 (EtOAc:hexane 7:3) UV
inactive. 1H NMR (CDCl3) δ 4.42 (1 H, m), 4.15 (1 H, m), 3.61
(1 H, m), 3.57 (1 H, m), 3.49 (1 H, m), 3.42 (1 H, m), 3.31 (3 H,
s), 3.27 (3 H, s), 2.69 (1 H, dd, J ) 15 Hz, 3 Hz), 2.48 (1 H, dd,
J ) 15 Hz, 3 Hz), 2.40 (1 H, m), 2.22 (2 H, d, J ) 10 Hz), 2.04
(1 H, m), 1.92-1.82 (5 H, m), 1.05 (3 H, d, J ) 6 Hz), 0.95 (3
H, t, J ) 8 Hz); 13C NMR (CDCl3) δ 210.4, 172.1, 83.0, 72.1,
58.6, 58.5, 56.3, 52.4, 47.5, 40.0, 39.8, 35.7, 26.0, 25.3, 24.0,
14.2, 8.4. IR (CHCl3) 1713, 1606 cm-1. CI-MS, m/z (relative
intensity) 312 (M+ + 1, 100%). Anal. Calcd for C17H29NO4:
C, 65.56; H, 9.39; N, 4.50. Found: C, 65.71; H, 9.56; N, 4.48.

Synthesis of (+)-Apovincamine and (+)-Vincamine
J . Org. Chem., Vol. 62, No. 5, 1997 1227
(2′S,4S,5R,7S)-5-Eth yl-4-m eth oxy-7-m eth yl-5-[[2′-(m eth -
oxym e t h yl)p yr r olid in yl]ca r b on yl]oxa cycloh e p t a n -2-
on e (8). Na2HPO4 (7.39 g, 52.0 mmol) and urea hydrogen
peroxide (UHP, 5.44 g, 57.8 mmol) were added to a solution of
7 (1.80 g, 5.78 mmol) in CH2Cl2 (40 mL). The mixture was
cooled to 0 °C, treated with trifluoroacetic anhydride (2.05 mL,
14.5 mmol), and then allowed to warm to room temperature
with stirring. After 2.5 h, another portion of trifluoroacetic
anhydride (1.00 mL, 7.08 mmol) was added at 0 °C, and the
mixture was stirred at room temperature for 16 h and then
cooled to 0 °C and quenched with saturated NaHCO3. The
organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with H2O, dried (Na2SO4), and concentrated at reduced
pressure. Chromatography (silica gel, hexanes, 70% EtOAc/
hexanes, and EtOAc) provided 8, 1.56 g (83%), as a white solid
(mp 182.5-185 °C). Rf ) 0.18 (EtOAc:hexane 7:3) UV inactive.
1H NMR (CDCl3) δ 4.43 (1 H, m), 4.33 (1 H, m), 3.92 (1 H, d,
J ) 7 Hz), 3.55 (1 H, m), 3.48 (1 H, m), 3.40-3.34 (2 H, m),
3.34 (3 H, s), 3.22 (3 H, s), 3.04-2.99 (1 H, dd, J ) 15 Hz, 8
Hz), 2.84 (1 H, d, J ) 15 Hz), 2.39 (1 H, dd, J ) 16 Hz, 10 Hz),
1.98 (2 H, d, J ) 16 Hz), 1.86-1.60 (5 H, m), 1.33 (3 H, d, J )
6 Hz), 0.77 (3 H, t, J ) 7 Hz). 13C NMR (CDCl3) δ 171.4, 171.1,
71.9, 70.6, 58.8, 58.5, 56.9, 56.0, 53.5, 47.4, 36.0, 33.4, 25.8,
25.2, 23.6, 22.8, 7.8. IR (CHCl3) 1717, 1606, 1203 cm-1. CI-
MS, m/z (relative intensity) 328 (M+ + 1, 100%). Anal. Calcd
for C17H29NO5: C, 62.36; H, 8.93; N, 4.28. Found: C, 62.03;
H, 8.77; N, 4.24.
residue (silica gel, 70% EtOAc in hexane) afforded 11b, 1.30 g
(93%). Rf ) 0.39 (EtOAc:hexane 7:3) UV active. 1H NMR
(CDCl3) δ 8.03 (1 H, br s), 7.47 (1 H, d, J ) 8 Hz), 7.35 (1 H,
s), 7.22 (1 H, t, J ) 8 Hz), 7.14 (1 H, t, J ) 8 Hz), 6.48 (1 H,
m), 4.42 (1 H, m), 3.91 (1 H, dd, J ) 8 Hz, 3 Hz), 3.51 (2 H,
m), 3.25 (3 H, s), 2.84 (2 H, m), 2.31-2.28 (2 H, m), 2.13 (1 H,
dd, J ) 14 Hz, 8 Hz), 1.57 (9 H, s), 1.54-1.43 (2 H, m), 1.25 (3
H, d, J ) 6 Hz), 1.25 (1 H, m), 0.81 (3 H, t, J ) 8 Hz). 13C
NMR (CDCl3) δ 179.9, 170.4, 149.4, 135.3, 130.1, 124.2, 122.8,
122.3, 118.7, 117.4, 115.0, 83.3, 82.4, 74.4, 59.3, 54.4, 39.0, 37.8,
34.2, 27.9, 26.5, 24.8, 21.4, 8.3. IR (CHCl3) 1747, 1730, 1667,
1514 cm-1. CI-MS, m/z (relative intensity) 473 (M+ + 1, 100%).
HRMS (CI) calcd for C26H36N2O6 (M+ + 1) 472.2573, found
472.2569.
Diol 12. To a solution of 11b (5.15 g, 10.9 mmol) in THF
(130 mL) at room temperature was added LiBH4 (0.712 g, 32.7
mmol) which was followed by stirring for 12 h. Additional
portions of LiBH4 (0.30 g, 14 mmol) were added each 8-12 h
until the reaction was complete. Water was added, and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4), and the solvent was
removed in vacuo to give a white foam. Flash chromatography
of the residue (silica gel, 85% EtOAc in hexane) provided 12,
4.07 g (78%), as a white crystalline solid (mp 41.5-45 °C). Rf
) 0.24 (EtOAc:hexane 7:3) UV active. 1H NMR (CDCl3) δ 8.10
(1 H, br s), 7.55 (1 H, d, J ) 8 Hz), 7.42 (1 H, s), 7.33 (1 H, t,
J ) 7 Hz), 7.25 (1 H, t, J ) 7 Hz), 6.41 (1 H, br s), 3.91 (1 H,
m), 3.85 (1 H, m), 3.74 (2 H, m), 3.52 (2 H, d, J ) 12 Hz), 3.38
(1 H, d, J ) 12 Hz), 3.27 (3 H, s), 2.93 (2 H, m), 2.63 (1 H, dd,
J ) 16 Hz, 4 Hz), 2.19 (1 H, dd, J ) 16 Hz, 6 Hz), 1.85 (1 H,
m), 1.67 (9 H, s), 1.62 (1 H, m), 1.37-1.25 (3 H, m), 1.19 (3 H,
d, J ) 6 Hz), 0.79 (3 H, t, J ) 8 Hz). 13C NMR (CDCl3) δ
173.6, 149.9, 135.4, 130.4, 124.6, 123.1, 122.6, 118.9, 117.8,
115.3, 83.9, 81.3, 67.1, 63.5, 58.4, 44.3, 43.2, 39.0, 37.8, 28.2,
27.8, 25.4, 25.1, 24.8, 7.6. IR (CHCl3) 3500-3100, 1724, 1650,
1518 cm-1. CI-MS, m/z (relative intensity) 477 (M+ + 1, 4%),
377 (M+ + 1 - 100, 100%). HRMS (CI) Calcd for C26H41N2O6
(M+ + 1) 477.2965, found 477.2975.
(1′S,3R,5S)-3-Eth yl-3-(1′-2′-ca r boxyeth yl)-5-m eth ylox-
a cyclop en ta n -1-on e (9). A solution of 8 (2.27 g, 6.94 mmol)
and 1.0 g (5.3 mmol) of TsOH‚H2O in benzene (100 mL) and
water (14 mL) was heated at reflux for 7 h. Another 1 g of
TsOH‚H2O was added, and the solution was heated overnight.
After a third addition of TsOH‚H2O (1 g), the mixture was
refluxed for 7 h. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. Flash chromatog-
raphy of the residue (silica gel, 60% EtOAc in hexane) gave 9,
1.24 g (78%), as a colorless oil. Rf ) streak from baseline
(EtOAc:hexane 7:3) UV inactive. 1H NMR (CDCl3) δ 10.0 (1
H, br s), 4.60 (1 H, m), 4.00 (1 H, m), 3.40 (3 H, s), 2.58 (1 H,
dd, J ) 16 Hz, 4 Hz), 2.49-2.43 (2 H, m), 1.65-1.60 (2 H, m),
1.38 (3 H, d, J ) 6 Hz), 1.32 (1 H, m), 0.93 (3 H, t, J ) 7 Hz).
13C (CDCl3) δ 180.0, 176.5, 81.9, 74.8, 59.3, 54.6, 36.1, 34.1,
26.5, 21.5, 8.3. IR (CDCl3) 3400-2500, 1765, 1713 cm-1. CI-
MS, m/z (relative intensity) 231 (M+ + 1, 100%). Anal. Calcd
for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.49; H, 7.64.
Am id e 11a . A solution of 9 (3.09 g, 13.4 mmol) in DMF
(75 mL) was treated with Et3N (4.67 mL, 33.5 mmol). The
solution was cooled to 0 °C, and diphenylphosphoryl azide (3.47
mL, 16.1 mmol) and tryptamine (2.58 g, 16.1 mmol) were
added. The mixture was warmed to room temperature and
stirred overnight. Quenching with H2O was followed by
extraction with Et2O and drying with Na2SO4. Concentration
in vacuo and chromatography (silica gel, 70% EtOAc/hexanes)
afforded 11a as a white crystalline solid (mp 42-45 °C), 4.13
g (83%). Rf ) 0.21 (EtOAc:hexane 3:1) UV active. 1H NMR
(CDCl3) δ 8.29 (1 H, br s), 7.60 (1 H, d, J ) 8 Hz), 7.37 (1 H,
d, J ) 8 Hz), 7.20 (1 H, t, J ) 8 Hz), 7.12 (1 H, t, J ) 7 Hz),
7.05 (1 H, s), 5.83 (1 H, br s), 4.46 (1 H, m), 3.92 (1 H, m), 3.63
(2 H, m), 3.29 (3 H, s), 2.99 (2 H, m), 2.37 (1 H, dd, J ) 15 Hz,
3 Hz), 2.35-2.30 (1 H, m), 2.11 (1 H, dd, J ) 15 Hz, 8 Hz),
1.61-1.51 (2 H, m), 1.37 (3 H, d, J ) 6 Hz), 1.26 (1 H, m), 0.88
(3 H, t, J ) 8 Hz). 13C NMR (CDCl3) δ 180.1, 170.4, 136.4,
127.2, 122.1, 122.0, 119.2, 118.5, 112.4, 111.4, 82.6, 74.6, 59.7,
54.6, 39.9, 38.1, 34.4, 26.7, 25.1, 21.7, 8.6. IR (CHCl3) 1754,
Am id o Keto Ald eh yd e 13. A solution of oxalyl chloride
(81 mg, 0.63 mmol) in CH2Cl2 (5.8 mL) at -78 °C was treated
with DMSO (98 mg, 1.3 mmol) in CH2Cl2 (1 mL). The mixture
was stirred at -78 °C for 5 min, and then diol 12 (60 mg, 0.13
mmol) in CH2Cl2 (2 mL) was added. The reaction mixture was
stirred at -78 °C for 25 min and was then treated with Et3N.
After stirring at -78 °C for 5 min, the solution was warmed
to room temperature. The reaction mixture was washed with
water and extracted with CH2Cl2. The combined organic
layers were dried (Na2SO4), and the solvent was removed
under reduced pressure to give a colorless oil. Flash chroma-
tography of the residue (silica gel, 70% EtOAc in hexane)
afforded 13, 56 mg (94%), as a colorless oil. The product was
used immediately in the next reaction because of decomposi-
tion. Rf ) 0.39 (EtOAc:hexane 7:3) UV active. 1H NMR
(CDCl3) δ 9.58 (1 H, s), 8.16 (1 H, br s), 7.59 (1 H, d, J ) 8
Hz), 7.47 (1 H, s), 7.36 (1 H, t, J ) 7 Hz), 7.30 (1 H, t, J ) 7
Hz), 5.95 (1 H, br s), 4.16 (1 H, m), 3.64 (2 H, m), 3.33 (3 H, s),
2.95 (2 H, m), 2.81-2.70 (2 H, q, J ) 17 Hz), 2.46 (1 H, dd, J
) 15 Hz, 4 Hz), 2.20 (1 H, m), 2.16 (3 H, s), 1.86 (1 H, m), 1.76
(1 H, m), 1.70 (9 H, s), 0.83 (3 H, t, J ) 7 Hz). 13C NMR
(CDCl3) δ 206.9, 203.9, 170.8, 149.5, 135.4, 130.1, 124.3, 123.0,
122.4, 118.7, 117.4, 115.1, 83.4, 79.8, 59.3, 55.9, 42.6, 39.0, 37.7,
30.6, 28.0, 24.9, 22.9, 8.03. IR (CHCl3) 1723, 1664, 1518 cm-1
.
CI-MS, m/z (relative intensity) 473 (M+ + 1, 6%), 455 (M+
1 - H2O, 100%).
+
P en ta cyclic La cta m s 15 a n d 16. A solution of 13 (960
mg, 2.03 mmol) and CF3CO2H (10 mL) in CH2Cl2 (100 mL)
was stirred at room temperature for 15 h, after which
saturated NaHCO3 was added and then solid NaHCO3 until
the aqueous solution was a neutral pH. The aqueous layer
was extracted with CH2Cl2. The combined extracts were dried
(Na2SO4) and concentrated to give a mixture of 15 and 16 (1H
NMR analysis). Chromatography (silica gel, 30% EtOAc in
hexane) provided 15, 319 mg (47%), and 16, 208 mg (30%).
15: yellow solid, mp 144.5-146.5 °C. Rf ) 0.65 (EtOAc:hexane
3:1) UV active. 1H NMR (CDCl3) δ 7.66 (1 H, d, J ) 8 Hz),
7.44 (1 H, d, J ) 8 Hz), 7.18 (1 H, t, J ) 7 Hz), 7.12 (1 H, t, J
1662, 1522 cm-1. CI-MS, m/z (relative intensity) 373 (M+
+
1, 100%). HRMS (CI) calcd for C21H29N2O4 (M+ + 1) 373.2127,
found 373.2122.
N-Boc-In d ole 11b. To a solution of 11a (1.10 g, 2.96 mmol)
and (t-BuO2C)2O (0.77 g, 3.6 mmol) in CH2Cl2 (60 mL) was
added DMAP (36 mg, 0.30 mmol). The mixture was stirred
at room temperature for 30 min, washed with water, and
extracted with CH2Cl2. The organic layer was dried (Na2SO4),
and the solvent was removed in vacuo to give a white
crystalline solid (mp 44-46 °C). Flash chromatography of the

1228 J . Org. Chem., Vol. 62, No. 5, 1997
Schultz et al.
) 7 Hz), 4.98 (1 H, m), 4.82 (1 H, s), 4.78 (1 H, s), 3.33 (1 H,
dd, J ) 12 Hz, 5 Hz), 3.25 (3 H, s), 3.04 (2 H, m), 2.73 (1 H,
dd, J ) 17 Hz, 5 Hz), 2.65 (1 H, d, J ) 12 Hz), 2.58 (3 H, s),
2.46 (1 H, dd, J ) 17 Hz, 12 Hz), 1.86 (1 H, m), 1.70 (1 H, m),
1.03 (3 H, t, J ) 7 Hz). (C6D6) δ 7.40 (1 H, m), 7.35 (1 H, m),
7.15-7.10 (2 H, m), 5.03 (1 H, dd, J ) 13 Hz, 6 Hz), 4.60 (1 H,
s), 4.28 (1 H, s), 3.07 (1 H, m), 3.03 (1 H, dd, J ) 12 Hz, 5 Hz),
2.73 (1 H, dd, J ) 16 Hz, 5 Hz), 2.70 (3 H, s), 2.47 (1 H, dt, J
) 12 Hz, 5 Hz), 2.33 (1 H, dd, J ) 16 Hz, 12 Hz), 2.22 (1 H,
dd, J ) 15 Hz, 3 Hz), 2.03 (3 H, s), 1.78 (1 H, m), 1.41 (1 H,
m), 0.78 (3 H, t, J ) 7 Hz). 13C NMR (DEPT): δ 168.3 (s),
134.8 (s), 133.0 (s), 131.2 (s), 128.5 (s), 122.7 (d), 120.2 (d),
118.7 (d), 112.2 (d), 110.5 (d), 110.4 (s), 78.3 (d), 57.8 (q), 54.7
(d), 43.0 (t), 34.4 (t), 29.7(s), 21.1 (t), 20.7 (q), 20.3 (t), 8.7 (q).
IR (KBr) 1648, 1406 cm-1. CI-MS, m/z (relative intensity) 337
(M+ + 1, 100%). HRMS (CI) calcd for C21H25N2O2 (M+ + 1)
337.1916, found 337.1912. 16: Rf ) 0.53 (EtOAc:hexane 3:1)
UV active. 1H NMR (CDCl3) δ 7.64 (1 H, d, J ) 8 Hz), 7.48 (1
H, d, J ) 8 Hz), 7.20 (1 H, t, J ) 7 Hz), 7.15 (1 H, t, J ) 7 Hz),
5.30 (1 H, s), 4.85 (1 H, dd, J ) 13 Hz, 5 Hz), 4.40 (1 H, s),
3.64 (1 H, t, J ) 7 Hz), 3.41 (3 H, s), 3.12 (1 H, m), 3.07 (1 H,
dd, J ) 18 Hz, 7 Hz), 2.85 (2 H, m), 2.57 (3 H, s), 2.52 (1 H,
dd, J ) 18 Hz, 10 Hz), 1.48 (1 H, m), 1.02 (1 H, m), 0.56 (3 H,
t, J ) 7 Hz). 13C NMR (CDCl3) δ 169.9, 135.5, 134.4, 130.6,
128.3, 122.4, 120.2, 118.7, 112.0, 110.4, 108.7, 80.3, 57.2, 55.7,
42.4, 39.3, 36.2, 20.1, 19.7, 19.6, 9.1. CI-MS, m/z (relative
intensity) 337 (M+ + 1, 100%).
Deu ter iu m Exch a n ge Exp er im en ts. A solution of 15 (5
mg, 0.02 mmol) and t-BuOK (4 mg, 0.03 mmol) in t-BuOD (2
mL) was heated at reflux for 2 days. Water was added to the
reaction mixture, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo to give a yellow oil.
Flash chromatography (silica gel, 30% EtOAc in hexane)
afforded 14-14-d (1 mg) and 15-14-d2 (4 mg). 14-14-d: Rf )
0.57 (EtOAc:hexane ) 7:3). 1H NMR (C6D6) δ 7.34-7.29 (2
H, m), 7.20-7.08 (2 H, m), 5.49 (1 H, s), 4.93 (1 H, dd, J ) 13
Hz, 6 Hz), 4.32 (0.7 H, s), 4.05 (1 H, s), 3.22 (1 H, m), 2.60 (1
H, dddd, J ) 11 Hz, 7 Hz, 5 Hz, 5 Hz), 2.18 (1 H, ddd, J ) 15
Hz, 5 Hz, 2 Hz), 1.96 (3 H, s), 1.44-1.30 (2 H, m), 0.76 (3 H,
t, J ) 7 Hz). 15-14-d2: Rf ) 0.44 (EtOAc:hexane ) 7:3). 1H
NMR (CDCl3) δ 7.66 (1 H, d, J ) 8 Hz), 7.44 (1 H, d, J ) 8
Hz), 7.18 (1 H, t, J ) 7 Hz), 7.12 (1 H, t, J ) 7 Hz), 4.98 (1 H,
m), 4.82 (1 H, s), 4.78 (1 H, s), 3.33 (1 H, s), 3.25 (3 H, s), 3.04
(2 H, m), 2.65 (1 H, d, J ) 12 Hz), 2.58 (3 H, s), 1.86 (1 H, m),
1.70 (1 H, m), 1.03 (3 H, t, J ) 7 Hz).
A mixture of 14-14-d and 15-14-d2 (5 mg, 0.02 mmol) and
t-BuOK (4 mg, 0.03 mmol) in t-BuOD (2 mL) was heated at
reflux for 3 days. Water was added to the reaction mixture,
and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4) and concentrated
in vacuo to give a yellow oil. Flash chromatography (silica
gel, hexane followed by 30% EtOAc in hexane) afforded 14-
14-d (0.9 mg) as a light yellow oil and 15-14-d2 (0.4 mg).
A solution of 16 (6 mg, 0.02 mmol) and t-BuOK (5 mg, 0.05
mmol) in t-BuOD (2 mL) was heated at reflux for 3 days.
Water was added to the reaction mixture, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to give a yellow
oil. Flash chromatography (silica gel, hexane followed by 30%
EtOAc in hexane) afforded 14-21-d,14-d (0.7 mg), a mixture
of 14-21-d,14-d, 17-21-d,14-d (2.9 mg), and a third fraction
containing 16-14-d2 (0.8 mg). 14-21-d,14-d: Rf ) 0.57 (EtOAc:
hexane ) 7:3). 1H NMR (C6D6) δ 7.34-7.29 (2 H, m), 7.20-
7.08 (2 H, m), 5.49 (1 H, s), 4.93 (1 H, dd, J ) 13 Hz, 6 Hz),
4.32 (0.1 H, s), 4.05 (1 H, s), 3.22 (1 H, m), 2.60 (1 H, dddd, J
) 11 Hz, 7 Hz, 5 Hz, 5 Hz), 2.18 (1 H, ddd, J ) 15 Hz, 5 Hz,
2 Hz), 1.96 (3 H, s), 1.44-1.30 (2 H, m), 0.76 (3 H, t, J ) 7
Hz).
P en ta cyclic Dien e La cta m s 14 a n d 17. A solution of 15
(275 mg, 0.817 mmol) and t-BuOK (208 mg, 1.85 mmol) in
t-BuOH (25 mL) was refluxed for 2 days. Water was added to
the reaction mixture, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give a yellow oil. Flash chromatog-
raphy (silica gel, 30% EtOAc in hexane) afforded 14, 150 mg
(60%), as a light yellow foam, 17, 29 mg (12%), and recovered
15, 27 mg (10%). 14 was crystallized from Et2O on standing,
mp 157-160 °C.
F r om 16. Procedure identical to that from 15: 14 mg (0.042
mmol) of 16, 10 mg (0.092 mmol) of t-BuOK, and 3 mL of
t-BuOH were used. The procedure afforded 14, 6.8 mg (52%),
and 17, 2.3 mg (18%).
F r om a m ixtu r e of 15 a n d 16. Procedure identical to that
from 15: 1.19 g (3.54 mmol) of a mixture of 15 and 16, 0.873
g (7.78 mmol) of t-BuOK, and 100 mL of t-BuOH were used.
The procedure afforded 14, 0.599 g (55%), 17, 98 mg (9%), and
recovered 15, 78 mg (7%). 14: Rf ) 0.75 (EtOAc:hexane 3:1)
UV active. 1H NMR (CDCl3) δ 7.61 (1 H, d, J ) 8 Hz), 7.43 (1
H, d, J ) 8 Hz), 7.15 (1 H, t, J ) 7 Hz), 7.10 (1 H, t, J ) 7 Hz),
6.02 (1 H, d, J ) 10 Hz), 5.72 (1 H, d, J ) 10 Hz), 4.89 (1 H,
m), 4.87 (1 H, s), 4.62 (1 H, s), 3.20-3.12 (2 H, m), 2.62 (1 H,
br d, J ) 15 Hz), 2.55 (3 H, s), 1.81 (1 H, m), 1.72 (1 H, m),
1.06 (3 H, t, J ) 7 Hz). (C6D6) δ 7.34-7.29 (2 H, m), 7.20-
7.08 (2 H, m), 5.78 (1 H, d, J ) 10 Hz), 5.49 (1 H, dd, J ) 10
Hz, 1.5 Hz), 4.93 (1 H, dd, J ) 13 Hz, 6 Hz), 4.32 (1 H, s), 4.05
(1 H, s), 3.22 (1 H, m), 2.60 (1 H, dddd, J ) 11 Hz, 7 Hz, 5 Hz,
5 Hz), 2.18 (1 H, ddd, J ) 15 Hz, 5 Hz, 2 Hz), 1.96 (3 H, s),
1.44-1.30 (2 H, m), 0.76 (3 H, t, J ) 7 Hz). 13C NMR (CDCl3)
δ 165.5, 144.3, 134.6, 134.4, 131.3, 128.8, 122.6, 121.3, 120.3,
118.8, 112.3, 110.6, 108.3, 57.2, 44.2, 37.8, 33.5, 20.9, 19.4, 8.1.
IR (CHCl3) 1665, 1609 cm-1. CI-MS, m/z (relative intensity)
17-21-d,14-d: Rf ) 0.44 (EtOAc:hexane ) 7:3). 1H NMR
(C6D6) δ 7.39 (1 H, d, J ) 8 Hz), 7.34 (1 H, d, J ) 8 Hz), 7.16-
7.06 (2 H, m), 6.20 (1 H, s), 4.73 (1 H, ddd, J ) 13 Hz, 6 Hz,
2 Hz), 4.59 (1 H, s), 2.96 (1 H, dddd, J ) 11 Hz, 7 Hz, 5 Hz, 5
Hz), 2.60 (1 H, m), 2.35 (1 H, ddd, J ) 16 Hz, 5 Hz, 2 Hz), 1.95
(3 H, s), 1.36-1.29 (2 H, m), 0.47 (3 H, t, J ) 7 Hz). 16-14-d2:
Rf ) 0.26 (EtOAc:hexane ) 7:3). 1H NMR (CDCl3) δ 7.64 (1
H, d, J ) 8 Hz), 7.48 (1 H, d, J ) 8 Hz), 7.20 (1 H, t, J ) 7 Hz),
7.15 (1 H, t, J ) 7 Hz), 5.30 (1 H, s), 4.85 (1 H, dd, J ) 13 Hz,
5 Hz), 3.64 (1 H, s), 3.41 (3 H, s), 3.12 (1 H, m), 2.85 (2 H, m),
2.57 (3 H, s), 1.48 (1 H, m), 1.02 (1 H, m), 0.56 (3 H, t, J ) 7
Hz).
P en ta cyclic Am in e 18. To a solution of 14 (20 mg, 0.066
mmol) in Et2O (10 mL) was added LiAlH4 (10 mg, 0.26 mmol).
The mixture was stirred and refluxed for 1 h. The reaction
was quenched with water, and the mixture was extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give a colorless oil. Flash chroma-
tography (silica gel, EtOAc and 10% MeOH in CH2Cl2) afforded
18, 14 mg (73%), as a colorless oil, which solidified after a few
days. Rf ) 0.17 (EtOAc:hexane 7:3) UV active. 1H NMR
(CDCl3) δ 7.63 (1 H, d, J ) 8 Hz), 7.46 (1 H, d, J ) 8 Hz),
7.15-7.08 (2 H, m), 4.76 (1 H, s), 4.15 (1 H, s), 3.35 (1 H, dd,
J ) 14 Hz, 6 Hz), 3.25 (1 H, dt, J ) 12 Hz, 5 Hz), 3.03 (1 H,
m), 2.70 (1 H, dt, J ) 12 Hz, 3 Hz), 2.65 (1 H, br d, J ) 11 Hz),
2.51 (1 H, m), 2.49 (3 H, s), 1.89 (1 H, m), 1.71 (2 H, m), 1.40
(2 H, t, J ) 13 Hz), 1.13 (1 H, dt, J ) 14 Hz, 4 Hz), 0.98 (3 H,
t, J ) 7 Hz). 13C NMR (CDCl3) δ 134.4, 131.9, 129.0, 121.6,
119.5, 118.3, 115.2, 112.0, 107.2, 62.7, 56.3, 51.7, 45.2, 36.4,
305 (M+ + 1, 100%). HRMS (CI) calcd for C20H21N2O (M+
+
1) 305.1654, found 305.1657. Anal. Calcd for C20H20N2O: C,
78.92; H, 6.62; N, 9.21. Found: C, 78.81; H, 6.55; N, 9.13.
17: Rf ) 0.71 (EtOAc:hexane 3:1) UV active. 1H NMR
(CDCl3) δ 7.63 (1 H, d, J ) 8 Hz), 7.52 (1 H, d, J ) 8 Hz), 7.21
(1 H, t, J ) 7 Hz), 7.17 (1 H, t, J ) 7 Hz), 6.83 (1 H, d, J ) 10
Hz), 6.02 (1 H, d, J ) 10 Hz), 5.21 (1 H, s), 4.66 (1 H, dd, J )
13 Hz, 8 Hz), 4.62 (1 H, s), 3.29 (1 H, m), 2.93 (2 H, m), 2.54
(3 H, s), 1.46 (1 H, m), 0.78 (1 H, m), 0.74 (3 H, t, J ) 7 Hz).
(C6D6) δ 7.39 (1 H, d, J ) 8 Hz), 7.34 (1 H, d, J ) 8 Hz), 7.16-
7.06 (2 H, m), 6.20 (1 H, d, J ) 10 Hz), 6.04 (1 H, d, J ) 10
Hz), 4.73 (1 H, ddd, J ) 13 Hz, 6 Hz, 2 Hz), 4.59 (1 H, s), 4.24
(1 H, s), 2.96 (1 H, dddd, J ) 11 Hz, 7 Hz, 5 Hz, 5 Hz), 2.60 (1
H, m), 2.35 (1 H, ddd, J ) 16 Hz, 5 Hz, 2 Hz), 1.95 (3 H, s),
1.36-1.29 (2 H, m), 0.47 (3 H, t, J ) 7 Hz). CI-MS, m/z
(relative intensity) 305 (M+ + 1, 100%).
30.1, 27.5, 20.7, 20.6, 16.3, 8.7. IR (CHCl3) 1450 cm-1
. CI-
MS, m/z (relative intensity) 293 (M+ + 1, 100%). HRMS calcd
for C20H25N2 (M+ + 1): 293.2018, found 293.2013.
Dibr om id e 19. Amine 18 (83 mg, 0.28 mmol) was dissolved
in THF (20 mL) and treated with N-bromoacetamide (82 mg,

Synthesis of (+)-Apovincamine and (+)-Vincamine
J . Org. Chem., Vol. 62, No. 5, 1997 1229
0.60 mmol) at 0 °C. The reaction mixture was allowed to
slowly warm to room temperature. After 45 min, saturated
NaHCO3 was added, and the mixture was extracted with CH2-
Cl2, dried (Na2SO4), and concentrated in vacuo to afford a
yellowish white foam. Chromatography (silica, 70% EtOAc/
hexane) afforded 19 as a yellow oil, 114 mg (91%). Rf ) 0.33
(EtOAc:hexane 7:3) UV active. 1H NMR (CDCl3) δ 7.66 (1 H,
d, J ) 8 Hz), 7.52 (1 H, d, J ) 8 Hz), 7.27 (1 H, t, J ) 7 Hz),
7.22 (1 H, t, J ) 7 Hz), 6.66 (1 H, s), 5.47 (1 H, s), 4.20 (1 H,
br s), 3.35 (2 H, m), 2.95 (1 H, m), 2.67-2.58 (2 H, m), 2.51 (1
H, dt, J ) 12 Hz, 3 Hz), 2.42 (1 H, m), 1.85-1.77 (2 H, m),
1.57 (1 H, d, J ) 14 Hz), 1.47 (1 H, d, J ) 14 Hz), 0.99 (2 H,
m), 0.94 (3 H, t, J ) 8 Hz). 13C NMR (CDCl3) δ 138.1, 134.5,
130.8, 130.3, 122.7, 121.6, 118.9, 113.3, 108.5, 90.4, 58.0, 54.2,
50.8, 44.7, 40.5, 24.8, 22.7, 21.4, 16.7, 6.4. CI-MS, m/z (relative
organic layers were dried (Na2SO4) and evaporated to provide
a yellow-white foam. Purification by column chromatography
(silica, 10% MeOH in CH2Cl2) afforded 20c, 9 mg (75%).
Rf ) 0.33 (CH2Cl2:MeOH 90:10). UV active. 1H (CDCl3) δ
7.70 (1 H, d, J ) 9 Hz), 7.47 (1 H, d, J ) 7 Hz), 7.22 (1 H, t,
J ) 7 Hz), 7.16 (1 H, t, J ) 7 Hz), 5.14 (1 H, s), 4.88 (1 H, d,
J ) 13 Hz), 4.62 (1 H, d, J ) 13 Hz), 4.28 (1 H, bs), 3.40 (1 H,
dd, J ) 14 Hz, 6 Hz), 3.29 (1 H, dt, J ) 12 Hz, 7 Hz), 3.00 (1
H, m), 2.78 (2 H, bs), 2.49 (1 H, dd, J ) 14 Hz, 6 Hz), 1.97 (1
H, m), 1.84 (2 H, m), 1.47 (2 H, t, J ) 12 Hz), 1.17 (1 H, t, J
) 14 Hz), 1.01 (3 H, t, J ) 7 Hz). See text for additional
characterization at Hannover.
Mosh er Ester of (+)-Ap ovin ca m in ol. To a CH2Cl2 (5 mL)
solution of (S)-(-)-R-methoxy-R-(trifluoromethyl)phenylacetic
acid (21 mg, 0.088 mmol) wwew added DMAP (2 mg, 0.015
mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
drochloride (20 mg, 0.102 mmol), and 20c (9 mg, 0.029 mmol)
in CH2Cl2 (5 mL). The solution was stirred for 15 h and then
concentrated under reduced pressure to afford a yellow film.
Purification by column chromatography (silica, CH2Cl2, 2%
MeOH/CH2Cl2, and 5% MeOH/CH2Cl2) provided 15 mg (quan-
titative yield) of the Mosher ester. Rf ) 0.22 (CH2Cl2:MeOH
95:5). UV active. 1H NMR (CDCl3) δ 7.47 (2 H, d, J ) 8 Hz),
7.43 (1 H, d, J ) 8 Hz), 7.37-7.27 (4 H, m), 7.07 (1 H, t, J )
7 Hz), 7.01 (1 H, t, J ) 8 Hz), 5.61 (1 H, d, J ) 13 Hz), 5.27 (1
H, s), 5.17 (1 H, d, J ) 13 Hz), 4.17 (1 H, s), 3.44 (3 H, s), 3.37
(1 H, dd, J ) 14 Hz, 6 Hz), 3.27 (1 H, dt, J ) 13 Hz, 5 Hz),
3.01 (1 H, m), 2.68 (2 H, bs), 2.53 (1 H, bd, J ) 17 Hz), 1.94 (1
H, m), 1.75 (2 H, m), 1.42 (2 H, bs), 1.08 (1 H, dt, J ) 14 Hz,
4 Hz), 0.97 (3 H, t, J ) 7 Hz). 13C NMR (CDCl3) δ 166.2, 133.5,
131.9, 129.8, 129.6, 128.9, 128.3, 127.1, 124.3, 122.6, 122.3,
122.0, 120.1, 118.4, 111.5, 108.3, 64.6, 55.8, 55.5, 51.6, 46.5,
45.0, 37.0, 29.4, 27.2, 20.4, 16.3, 8.7. 19F NMR (CDCl3) δ 4.12
(major diastereomer), 4.23 (minor). The ratio of integrated
areas of the 19F signals was 22:1. A mixture of the diastere-
omers also was prepared (see text). 19F NMR (CDCl3) δ 4.11,
4.21 (ratio of integrated areas ) 1:1).
intensity) 453 (M+ + 3, 50%), 451 (M+ + 1, 100%), 449 (M+
-
1, 50%). HRMS (EI) calcd for C20H22Br2N2 (M+ - 2): 448.01497,
found 448.01480.
(+)-Ap ovin ca m in a l (20a ). To a solution of 19 (115 mg,
0.254 mmol) in DMSO (15 mL) were added AgBF4 (250 mg,
1.2 mmol) and Et3N (0.20 mL, 1.4 mmol) under strictly
anhydrous conditions. The reaction mixture was heated at
90 °C for 9 h. After cooling to room temperature, the mixture
was partitioned between H2O and CH2Cl2. The organic layer
was separated, and the aqueous layer was neutralized with
saturated NaHCO3 and then extracted with CH2Cl2. The
combined organic layers were washed with H2O, dried (Na2-
SO4), and concentrated under reduced pressure to provide a
brown foam. Column chromatography (silica, CH2Cl2, 70%
EtOAc in hexane, and 5% MeOH in CH2Cl2) gave 20a , 65 mg,
83%. Rf ) 0.26 (CH2Cl2:MeOH 95:5). UV (CH3OH) λmax 310,
280, 221, 210 nm.7c 1H NMR (CDCl3) δ 9.53 (1 H, s), 7.61 (1 H,
d, J ) 8 Hz), 7.45 (1 H, d, J ) 8 Hz), 7.21 (1 H, t, J ) 7 Hz),
7.14 (1 H, t, J ) 7 Hz), 6.20 (1 H, s), 4.16 (1 H, s), 3.37 (1 H,
dd, J ) 14 Hz, 6 Hz), 3.28 (1 H, dt, J ) 12 Hz, 7 Hz), 3.03 (1
H, m), 2.67 (2 H, d, J ) 7 Hz), 2.54 (1 H, br d, J ) 13 Hz), 2.03
(1 H, m), 1.95 (1 H, m), 1.78 (1 H, m), 1.56 (1 H, d, J ) 8 Hz),
1.46 (1 H, d, J ) 13 Hz), 1.07 (1 H, m), 1.05 (3 H, t, J ) 7 Hz).
13C NMR (CDCl3) δ 186.1, 140.5, 137.6, 134.4, 129.1, 122.5,
120.6, 118.1, 114.3, 109.5, 55.5, 51.4, 44.8, 38.5, 28.5, 27.0, 20.2,
16.3, 8.8. IR (CHCl3) 1697, 1600 cm-1. CI-MS, m/z (relative
intensity) 307 (M+ + 1, 100%). HRMS calcd for C20H23N2O
(M+ + 1): 307.1810, found 307.1810.
(+)-Ap ovin ca m in e (1a ). To a solution of 20b (25 mg, 0.071
mmol) in CCl4 (30 mL) were added AIBN (7 mg, 0.04 mmol)
and NBS (15 mg, 0.085 mmol). The mixture was immediately
immersed in an oil bath at 95 °C and heated for 0.5 h. After
cooling to room temperature, the reaction was concentrated
under reduced pressure. Column chromatography (silica,
EtOAc, 5% MeOH/CH2Cl2) gave (+)-apovincamine (1a ), 11 mg
(47%). Rf ) 0.28 (CH2Cl2/MeOH 95:5) UV active. 1H NMR
(CDCl3) δ 7.48 (1 H, d, J ) 8 Hz), 7.24-7.14 (3 H, m), 6.15 (1
H, s), 4.32 (1 H, bs), 3.96 (3 H, s), 3.51 (1 H, m), 3.37 (1 H, dt,
J ) 13 Hz, 5 Hz), 3.06 (1 H, m), 2.85 (1 H, bd, J ) 11 Hz),
2.72 (1 H, m), 2.03 (2 H, m), 1.89 (1 H, m), 1.58 (1 H, d, J ) 14
Hz), 1.49 (1 H, d, J ) 14 Hz), 1.07 (1 H, m), 1.04 (3 H, t, J )
7 Hz). 13C NMR (CDCl3) δ 163.5, 134.3, 128.5, 128.3, 127.4,
122.6, 120.7, 118.4, 112.6, 108.4, 56.1, 52.7, 51.5, 44.8, 37.9,
27.8, 27.2, 19.4, 16.1, 8.6. IR (CHCl3) 1731, 1636, 1610, 1456,
(+)-Ap ovin ca m in a l Dim eth yl Aceta l (20b). 20a (120
mg, 0.39 mmol) was dissolved in anhydrous methanol (70 mL)
and treated with (MeO)3CH (4.3 mL, 39 mmol) and TsOH‚H2O
(0.35 g, 2.0 mmol). The solution was heated at reflux for 0.5
h and then cooled to room temperature. Saturated NaHCO3
was added, and the mixture was extracted with CH2Cl2; the
organic layer was dried (Na2SO4) and concentrated in vacuo
to provide a light brown oil. Column chromatography (silica,
5% MeOH in CH2Cl2) afforded 20b, 90 mg (66%). Rf ) 0.23
(CH2Cl2:MeOH 95:5) UV active. 1H NMR (CDCl3) δ 7.74 (1
H, d, J ) 8 Hz), 7.44 (1 H, d, J ) 8 Hz), 7.17 (1 H, t, J ) 7 Hz),
7.10 (1 H, t, J ) 7 Hz), 5.54 (1 H, s), 5.44 (1 H, s), 4.19 (1 H,
s), 3.48 (3 H, s), 3.36 (1 H, dt, J ) 14 Hz, 6 Hz), 3.33 (3 H, s),
3.26 (1 H, dt, J ) 13 Hz, 5 Hz), 3.03 (1 H, m), 2.71 (2 H, m),
2.52 (1 H, bd, J ) 4 Hz), 1.97 (1 H, m), 1.79 (1 H, m), 1.76 (1
H, m), 1.49 (1 H, bd, J ) 14 Hz), 1.42 (1 H, bd, J ) 11 Hz),
1.14 (1 H, dt, J ) 14 Hz, 3 Hz), 1.01 (3 H, t, J ) 7 Hz). 13C
NMR (CDCl3) δ 133.9, 131.5, 129.0, 121.9, 119.8, 118.0, 117.9,
113.6, 108.0, 99.8, 56.1, 53.6, 52.2, 51.6, 45.1, 36.6, 29.8, 27.5,
20.5, 16.4, 8.9. IR (CHCl3) 1455 cm-1. CI-MS, m/z (relative
intensity) 352 (M+, 75%), 321 (M+ - CH3O, 100%). HRMS
1266 cm-1
. See text for additional discussion of product
characterization.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 26568). We thank
Dr. Fook S. Tham for the X-ray structure determination
of 8, Degussa AG for a generous gift of L-proline, and
Professor E. Winterfeldt for comparison of 20c to his
previously prepared apovincaminol.
+
(CI) calcd for C22H29N2O2 (M+): 352.2151, found 352.2156.
Su p p or tin g In for m a tion Ava ila ble: Copies of proton and
carbon NMR spectra (20 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(+)-Ap ovin ca m in ol (20c). 20a (12 mg, 0.039 mmol) was
dissolved in MeOH (3 mL) and added to a cooled (0 °C) solution
of NaBH4 (6 mg, 0.12 mmol) in MeOH (4 mL). After 30 min,
saturated sodium bicarbonate (1 mL) was added at 0 °C. The
methanol was removed in vacuo, and the concentrated reaction
material was partitioned between H2O and CH2Cl2. The
aqueous layer was washed with CH2Cl2, and the combined
J O961603P