Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of Indolenine Alkaloids: Enantioselective Syntheses of Vincadifformine, ψ- And 20-epi-ψ-Vincadifformines, Tabersonine, Ibophyllidine, and Mossambine

Article abstract of DOI:10.1021/jo971838g

Condensations of the chiral N-ferrocenylethylindoloazepines 4a,b, with the aldehydes 5, 13, 19, 29, and 32, led to tetracyclic vinylogous urethanes 6a,b and 7, 14a and 14b, 21a,c and 21b,d, 30a and 31a, and 30b and 31b. Respectively, 6:1, 5:1, 3:1, 1.7:1, and 2:1 diastereomeric selections provided intermediates which, on cleavage of the chiral auxiliary N-substituent and subsequent elaboration of ring D of the Aspidosperma and Strychnos alkaloids, provided enantiomerically pure (-)-ψ- and (-)-epi-ψ-vincadifformines (1, 2), (4-)-ibophyllidine (12), (+)- and (-)-vincadifformine (16a, 16b), (-)-tabersonine (27), and (-)-mossambine (41).

Full text of DOI:10.1021/jo971838g

2
172
J . Org. Chem. 1998, 63, 2172-2183
Ap p lica tion of F er r ocen yla lk yl Ch ir a l Au xilia r ies to Syn th eses of
In d olen in e Alk a loid s: En a n tioselective Syn th eses of
Vin ca d iffor m in e, ψ- a n d 20-epi-ψ-Vin ca d iffor m in es, Ta ber son in e,
Ibop h yllid in e, a n d Mossa m bin e
Martin E. Kuehne,* Upul K. Bandarage, Abdelhakim Hammach, Yun-Long Li, and
Tiansheng Wang
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received October 6, 1997
Condensations of the chiral N-ferrocenylethylindoloazepines 4a ,b, with the aldehydes 5, 13, 19,
2
9, and 32, led to tetracyclic vinylogous urethanes 6a ,b and 7, 14a and 14b, 21a ,c and 21b,d , 30a
and 31a , and 30b and 31b. Respectively, 6:1, 5:1, 3:1, 1.7:1, and 2:1 diastereomeric selections
provided intermediates which, on cleavage of the chiral auxiliary N-substituent and subsequent
elaboration of ring D of the Aspidosperma and Strychnos alkaloids, provided enantiomerically pure
(
(
-)-ψ- and (-)-epi-ψ-vincadifformines (1, 2), (+)-ibophyllidine (12), (+)- and (-)-vincadifformine
16a , 16b), (-)-tabersonine (27), and (-)-mossambine (41).
The present enantioselective alkaloid syntheses were
Sch em e 1
undertaken in order to ascertain the practical limits of
chiral N-ferrocenylethyl enamine substituents for achiev-
ing enantioselective intramolecular Diels-Alder reac-
tions of the isosecodine type, using methodology by which
we had synthesized a variety of racemic Aspidosperma,
Iboga, and Strychnos alkaloids.
Application of our biomimetic isosecodine chemistry to
syntheses of the racemic ψ- and 20-epi-ψ-vincadifform-
ines (1, 2) had allowed the identification and assignment
of relative stereochemistry of the natural, nonracemic
alkaloid mixture.1 The racemic alkaloids were formed
in a 4:1 ratio from the transient enamine acrylate
(isosecodine) intermediate 3 (Scheme 1) and corresponded
to the 4:1 ratio of natural occurrence. For an enantiose-
lective synthesis of these alkaloids, extension of this
strategy to an intermediate (3) with a defined absolute
stereochemistry at C-20 would result in a 4:1 mixture of
diastereomers with opposite absolute configurations at
C-3, C-7, and C-14. To generate the two ψ- and 20-epi-
ψ-vincadifformine (1, 2) diastereomers with the same
absolute stereochemistry at C-3, C-7, and C-14, and
differing in absolute stereochemistry at C-20, an alterna-
tive synthetic path was required. With the discovery of
complete enantioselectivity (at C-3, C-7, C-14) in the
isolated in equal amounts from the major enantiomeric
product. Heating of these tetracyclic compounds 6a or
6b in acetic acid at 110 °C for 10 min resulted in cleavage
of the chiral auxiliary substituent, epimerization at C-3
and C-7, and cyclization of the transient secondary amino
esters.
Under these conditions, the chiral auxiliary substituent
2
was converted to the corresponding vinylferrocene.
However, when heated to 70 °C in acetic acid, the
tetracyclic intermediates 6a ,b provided mostly the chiral
ferrocenylethyl acetate 8 (for reuse in synthesis of the
reaction of the ferrocenylethyl-substituted indoloazepines
2
4
a with an aldehyde precursor to vinblastine, it seemed
2
that this approach could also provide enantioselective
indoloazepines 4a ) and a mixture of secondary amines
access to the two ψ-vincadifformine epimers 1 and 2
9, derived from incomplete epimerization at C-3 and C-7.
The lactam products 10a and 10b were converted to
thiolactams 11a and 11b with phosphorus pentasulfide,
and these products were desulfurized with Raney nickel
to provide (-)-ψ-vincadifformine (ent-1) and (-)-epi-ψ-
vincadifformine (ent-2) in >99% ee.3 These products can
thus be obtained in four steps (16% and 14% overall
yields) from the racemic aldehyde 5 and the indoloazepines
4, with one chromatographic separation of diastereomers.
(
4
Scheme 2). While either enantiomer of the indoloazepines
a ,4b is available, the enantiomer 4a leading to the ent-
2
(
-)-ψ-vincadifformines was chosen for this study.
A reaction of the indoloazepines 4a with 4-(methoxy-
carbonyl)hexanal (5) was not as highly enantioselective
2
as our earlier example, providing the C-3, C-7, and C-14
enantiomeric pairs 6 and 7 in a 6:1 ratio. No stereose-
lectivity was found at the side chain chiral center, with
the separable C-20 S (6a ) and C-20 R (6b) epimers
4
Use of a single enantiomer of the aldehyde 5 would allow
(
1) Kuehne, M. E.; Kirkemo, C. L.; Matsko, T. H.; Bohnert, J . C. J .
Org. Chem. 1980, 45, 3259.
2) Kuehne, M. E.; Bandarage, U. K. J . Org. Chem. 1996, 61, 1175.
(3) For ee determination by NMR chiral shift, see: Sullivan, G. R.
Topics in Stereochemistry; Eliel, E. L., Allinger, N. L., Eds.; Wiley-
Interscience: New York, 1978; p 287.
(
S0022-3263(97)01838-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2173
Sch em e 2
Sch em e 3
process of Scheme 1, which would give a 4:1 mixture of
(
impure) isomers with [R] < +300. The natural products
D
are thus more likely formed by a dehydrosecodine cy-
clization, followed by a subsequent reduction with gen-
eration of the C-20 chiral center.
A synthesis of (+)-ibophyllidine (12) by the same
general strategy for achieving enantioselection provided
a reaction sequence unencumbered by the formation of
a C-20 (1:1) enantiomeric pair of tetracyclic intermediates
that was encountered in the preceding syntheses of the
ψ-vincadifformines (1, 2). Condensation of the in-
6
doloazepines 4b with 4,4-(ethylenedioxy)hexanal (13)
furnished a 5:1 diastereomeric mixture of tetracyclic
ketals 14a and 14b (Scheme 3). While the aldehyde in
this reaction is γ-disubstituted, analogous to the aldehyde
used in the vinblastine synthesis, which had resulted in
2
a single enantiofacial 4 + 2 cyclization reaction, the
enantioselection was now actually decreased somewhat
relative to that found in the above-described synthesis
of the ψ-vincadifformines (1, 2). Ketal hydrolysis of the
major tetracyclic product 14a was followed by cleavage
of the chiral auxiliary substituent of the ketone 15 in
acetic acid at 70 °C. Epimerization at C-3 and C-7 and
cyclization to a pentacyclic enamine and its hydrogena-
tion followed the sequence developed for the correspond-
the enantioselective synthesis of either product 1 or 2 in
3
0% overall yield.
Comparison of the optical rotation of natural “ψ-
vincadifformine” ([R]
D
) +430, apparently somewhat
5
impure), which was shown to consist of a 4:1 mixture of
6,7
ing racemic compound and provided (+)-ibophyllidine
1
ψ- and epi-ψ-vincadifformines, with the optical rotation
(12) in 60% yield and > 98% ee.
values obtained for the two synthetic ent products above
For further exploration of this new methodology, a
([R]
D
) -506 and -450, respectively), allows one to
synthesis of vincadifformine (16, Scheme 8) offered the
opportunity to determine if a â-disubstituted enamine
intermediate is compatible with the enantioselection
induced by the chiral ferrocenylethyl N-substituent. We
had previously found that racemic tetracyclic esters
conclude that the natural isomers have the same absolute
configuration at C-3, C-7, and C-14 and are epimeric at
C-20. Consequently, they do not arise from cyclization
of a common isosecodine, according to the synthetic
1
7a ,b were formed without selection for E and Z enamine
(
4) See Kuehne and Bornmann (Kuehne, M. E.; Bornmann, W. G.
J . Org. Chem. 1989, 54, 3407) for a synthesis of the racemic aldehyde
and for methodology, which could provide an enantioselective
synthesis of that aldehyde or an equivalent synthon.
5) (a) Zeches, M.; Debray, M. M.; Ledouble, G.; LeMen-Olivier, L.;
intermediates by either the condensation of the N-
benzylated indoloazepine 18 with the aldehyde ester 19
at 110 °C or by fragmentation of the quaternary bridged
5
8
(
LeMen, J . Phytochemistry 1975, 14, 1122. (b) LeMen, J .; Caron-Sigant,
C.; Hugel, G.; LeMen-Olivier, L.; L e´ vy, J . Helv. Chim. Acta 1978, 61,
(6) Kuehne, M. E.; Bohnert, J . C. J . Org. Chem. 1981, 46, 3443.
(7) Kuehne, M. E.; Pitner, J . B. J . Org. Chem. 1989, 54, 4553.
(8) Kuehne, M. E.; Kuehne, S. E. J . Org. Chem. 1993, 58, 4147.
5
66. (c) Kutney, J . P.; Brown, R. T.; Piers, E.; Hadfield, J . R. J . Am.
Chem. Soc. 1970, 92, 1708.

2
174 J . Org. Chem., Vol. 63, No. 7, 1998
Kuehne et al.
Sch em e 4
Sch em e 6
Sch em e 7
Sch em e 5
(+)-21a ,b predominated over the E-enamine-derived
products (+)-21c,d (51%:25%, vide infra) while the C-7S,
C-21R tetracyles (+)-21a ,c predominated over the C-7R,
C-21S tetracycles (+)-21b,d (59%:17%). Maximum selec-
tion for Z vs E enamine reaction was found in the major
enantioselected products (+)-21a > 21c, while the minor
enantioselected products (+)-21b and (+)-21d were formed
in equal amounts analogous to the formation of racemic
products.
In contrast to the lack of E/ Z-enamine selectivity
found with the closely analogous reaction of the N-
benzylindoloazepine 18 with the aldehyde 19 in refluxing
toluene, the preferential formation of Z-enamine inter-
mediates in the present reaction, in refluxing benzene,
may be in part the result of a selectivity allowed by a
lower reaction temperature and interaction between the
enamine nitrogen and the ester carbonyl group. As the
N-benzyl compound 18 failed to react (fragment) at the
indoloazepines 20 (Scheme 4).9 Analogous results were
reported for a related reaction sequence.1
0a
When the indoloazepines 4a and 2-ethyl-4-(methoxy-
carbonyl)butanal (19) were heated at 80 °C in benzene,
four tetracyclic products (+)-21a -d were formed in 76%
yield and isolated as two product pairs: (+)-21a ,b and
(
9) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.; Oliver-
Smith, D. J . Org. Chem. 1981, 46, 2002.
10) (a) Kalaus, Gy.; Greiner, I.; Peredy-Kajtar, M.; Brlik, J .; Szabo,
L. Szantay, Cs. J . Org. Chem. 1993, 58, 1434; (b) 1993, 58, 6076.
(
(+)-21c,d (Scheme 5). The Z-enamine-derived products

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2175
Sch em e 8
An alternative strategy, for conversion of the tetracyles
(-)-21c,d to the N-benzyl esters (-)- and (+)-25, avoided
all acid treatment. The phosphines (-)-21c,d were
oxidized with hydrogen peroxide, and the resulting
phosphine oxides (-)-21e,f (compare ent 21e,f, Scheme
5
) were then N-benzylated in refluxing toluene, resulting
in formation of ferrocenylethylene phosphine oxide 8a
and the partially racemic N-benzyl tetracycle (-)-25
(Scheme 7).
On reaction of the enantiomeric mixture of 3-ox-
ovincadifformine (+/-)-22 with phosphorus pentasulfide,
in THF at room temperature, the corresponding thiolac-
tams (+/-)-26 were formed in 87% yield (Scheme 8).
Reductive desulfurization of the thiolactam mixture with
R/Ni provided (+)-vincadifformine (16a ) in 87% yield and
6
7% ee (as determined by NMR, vide infra). Crystal-
lization of the major thiolactam enantiomer (+)-26 and
its reduction gave (+)-vincadifformine (16a ) in >98% ee.
Treatment of the chromatographically more polar 2:1
mixture of tetracyclic products (+)-21c,d with acetic acid
at 100 °C provided an enantiomeric mixture of lactams
(-/+)-22 in 97% yield. Formation of the corresponding
thiolactams (-/+)-26 and their reduction then gave (-)-
vincadifformine (16b) in 33% ee. The enantiomeric
product ratios 16a /16b in these reaction sequences was
lower reaction temperature of the ferrocenyl analogue 4a
and, conversely, because that compound undergoes de-
structive decomposition at the higher reaction tempera-
ture of the benzyl compound 18, it was not possible to
verify the temperature dependence of E- vs Z-enamine
formation. Since mono-trans-substituted enamine inter-
mediates had been found to give higher enantioselectivity
3
determined by titration with Eu(hfc) and analysis of the
1
3
resulting H NMR shift spectra.
To obtain (-)-vincadifformine (16b) with more favor-
able chiral induction, the aldehyde 19 was condensed
with the enantiomeric indoloazepines 4b. The major, less
polar chromatographic fraction of tetracyclic products (-)-
2
1a ,b, on thiolactam formation, crystallization, and
(
vide supra and ref 2), a Z-alkyl enamine substituent
reduction, furnished (-)-vincadifformine (16b) in 98% ee,
with yields of intermediates and product in good agree-
ment with the enantiomeric reaction sequence starting
from the indoloazepines 4a .
seems detrimental to enantioselectivity (21c/21d , 2:1)
while a Z substituent, which can complex with the
enamine nitrogen, allows better enantioselectivity (21a /
2
1b 5:1).
A synthesis of (-)-tabersonine (27, Scheme 8) was then
obtained by reaction of the intermediate thiolactam (-)-
Structural assignments to the four products (+)-21a -d
were derived from the following experiments: The chro-
matographically less polar fraction (+)-21a ,b (5:1) was
heated in acetic acid at 100 °C for 10 min, resulting in
cleavage of the ferrocenylethyl substituent and cycliza-
tion of the amino ester derived from (+)-21a to form the
lactam (+)-22 and correspondingly cyclization of (+)-21b
to the enantiomeric lactam (-)-22. An enantiomeric
mixture of the same lactam products (unique TLC, NMR)
was also obtained from the more polar fraction of tetra-
cylic product (+)-21c,d (2:1). This partially racemic
product showed a reversed sign and decreased magnitude
of rotation relative to the product derive from the esters
2
6 with p-toluenesulfinyl chloride and N,N-diisopropyl-
N-ethylamine (40% yield), followed by S-methylation of
the resulting unsaturated thiolactam (-)-28 and reduc-
1
0a
tion with sodium borohydride (48% yield, ee> 98%).
We had previously reported alternative enantioselec-
1
1
tive syntheses of vincadifformine and tabersonine.
They were based on the reaction of a mannitol-derived
chiral, cyclic enamine-indoloacrylate intermediate, which
avoided the formation of C-20 diastereomeric intermedi-
ates in the intramolecular Diels-Alder reaction step, and
enantioselectivity was complete. In comparison, the
present route with formation of C-20 diastereomeric
products, and only partial enantioselectivity, suffers an
obvious strategic disadvantage. However, now the more
readily available racemic aldehyde 19 provides a shorter
path to vincadifformine-type alkaloids, where enantiose-
lectivity and diastereoselectivity might be improved by
variation of the recoverable chiral auxiliary that is
attached to nitrogen in the indoloazepine precursors 4a ,b.
For a fourth exploration of enantioselectivity in cy-
clization of ferrocenylethyl enamine indoloacrylates, we
(+)-21a ,b. Here, cyclization requires an initial acid-
catalyzed epimerization at C-3a and C-11b of the second-
ary amine intermediate 24.
To circumvent the ambiguity arising from the foregoing
epimerization on cleavage of the chiral auxiliary sub-
stituent in acid, which could accommodate an exchange
of structures 21b and 21c, a mixture of ent tetracycles
(-)-21c,d (2:1) was treated with trifluoroacetic acid and
trifluoroacetic anhydride. A partially racemic single
diastereomer of the trifluoroacetamide 23 was formed
and this was treated with moist potassium carbonate and
benzyl bromide (Scheme 7). The resulting diastereo-
merically unique, partially racemic N-benzyl tetracylic
ester (-)-25 matched in NMR spectra the corresponding
racemic compound obtained previously by a different
synthesis.9
applied this methodology to a synthesis of the Strychnan-
type alkaloid mossambine.1
2a,b,13
Here, condensation of
(
(
11) Kuehne, M. E.; Podhorez, D. E. J . Org. Chem. 1985, 50, 924.
12) (a) Stauffacher, D. Helv. Chim. Acta 1961, 44, 2006. (b)
Monseur, X.; Goutarel, R.; LeMen, J .; Wilson, J .; Budzikiewicz, H.;
Djerassi, C. Bull. Soc. Chim. Fr. 1962, 1088.

2
176 J . Org. Chem., Vol. 63, No. 7, 1998
Kuehne et al.
Sch em e 9
Sch em e 10
the acetamide alcohol 34. To avoid this acyl migration,
cleavage of the auxiliary substituent was carried out in
trifluoroacetic acid. This resulted in formation of the
trifluoroacetamide acetate 35 as the major product and
the amine acetate 33 as a minor product. The two
products showed the same negative sign of rotation,
indicating that the spirocyclic center had not been
inverted (through protonation of the vinylogous acrylate,
cleavage to an indole-iminium salt and alterfacial cy-
clization). Both products showed the C-3a hydrogen as
an NMR singlet, indicating a near 90° angle with respect
to the hydrogen at C-4, which is also observed in the
above tetracyclic analogues, and both products gave NOE
coupling of the C-11 aromatic hydrogen to the C-3a
hydrogen and to a C-2 hydrogen, indicating the mainte-
nance of the original tetracyclic skeleton. The expected
downfield shift of hydrogens R to N in the trifluoroac-
etamide 35, relative to those in the amine 33, was also
accompanied by a pronounced downfield shift of the C-4
1
H signal (at δ 5.46 for 35 rather than at δ 4.88 for 33).
Alkylation of either tetracyclic product 33 or 35 with
(
Z)-1-bromo-2-iodo-2-butene in the presence of potassium
carbonate (nonanhydrous) furnished the tertiary amine
6. The in situ hydrolysis and alkylation of the trifluo-
3
roacetamide 35 proved advantageous, since its basic
hydrolysis resulted in a low yield of the isolated amine
3
3.
Hydrolysis of the acetate function of the alkylation
product 36 and Swern oxidation of the resultant alcohol
7 to the ketone 38 was followed by its oxidation to the
3
imino ketone 39. This compound was sensitive to race-
mization, in contrast to its precursor 38. Consequently,
the following reaction with tributyltin hydride could not
be carried out at the usual elevated temperature. How-
ever, a photochemical radical cyclization of the vinyl
iodide 39 provided a 1.7:1 E:Z mixture of pentacyclic
ketones. Reduction of the major ketone product 40a with
sodium borohydride and ceric chloride then yielded
mossambine 41, corresponding to the natural enanti-
omer.
the indoloazepines 4b with acetoxyacetaldehyde (29)
resulted in a 90% yield of the diastereomeric tetracycles
3
0a and 31a , which were formed in a 0.6:1 ratio (Scheme
9
). An attempt to increase this ratio to that found with
the monoalkyl-substituted enamines (vide supra) by use
of the corresponding diphenyl-tert-butylsiloxy-substituted
acetaldehyde 32 provided only a marginal increment in
diastereoselection (30b/31b 1:2, Scheme 10). On the
other hand, either oxidation of the diphenylphosphinyl
substituent (4c), or removal of that substituent (4d ) from
the chiral auxiliary, destroyed the enantioselectivity of
the intramolecular Diels-Alder reaction.
Exp er im en ta l Section
(
3a R,4S,11bS a n d 3a S,4R,11bR)-Meth yl 3-[1(S)-[(R)-2-
Cleavage of the chiral auxiliary substituent from the
major tetracyclic product 31a with acetic acid resulted
in a 1:1 mixture of the expected secondary amine 33 and
(
D ip h e n y lp h o s p h e n o )fe r r o c e n y l]e t h y l]-2,3,3a ,4,5,7-
h exa h yd r o-4-[(S a n d R)-2-(m eth oxyca r bon yl)bu tyl]-1H-
p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla tes (6a ,b a n d 7a ,b).
2
A solution of the (S)-(+)-ferrocenylethylindoloazepine (S)-4a
4
(
0.5 g, 0.78 mmol) and methyl 2-ethyl-5-oxopentanoate (5)
(
13) For establishment of relative stereochemistry by synthesis of
the racemate, see: Kuehne, M. E.; Wang, T. J . Org. Chem. 1996, 61,
873.
(0.136 g, 0.85 mmol) in dry benzene (5 mL) was heated at
reflux for 6 h. The benzene was evaporated under reduced
7

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2177
pressure. The residue was dissolved in dry methanol/CH
2
Cl
2
(-)-21-Oxo-20-epi-p seu d ovin ca d iffor m in e (10b). Cleav-
age of the more polar isomer 6b (0.41 g, 0.525 mmol) in glacial
actic acid (5 mL), according to the preceding procedure, gave
4
(1:10, 50 mL), and NaBH (0.1 g) was added with stirring to
reduce excess aldehyde, which contaminated the product. The
mixture was stirred at room temperature for 15 min, and water
2
5
21-oxo-20-epi-pseudovincadifformine 10b (0.17 g, 91%): [R]
D
1
13
(50 mL) was added. The aqueous phase was extracted with
3
-215 (c 0.5, CHCl ). H NMR and C NMR data matched
1
ether (3 × 25 mL), dried over MgSO
4
, filtered, and concen-
those reported for the racemic compound.
trated under reduced pressure. Purification by low-pressure
flash chromatography (silica gel/ether/hexane, 1:1) gave the
major enantiomeric type of diastereomers 6a (0.19 g, 31%) and
(-)-21-Th ioxop seu d ovin ca d iffor m in e (11a ). A mixture
of the lactam 10a (0.40 g, 1.13 mmol) and P S10 (0.80 g, 1.8
4
mmol), in dry THF (75 mL), was stirred at room temparature
for 24 h under nitrogen. After addition of CH Cl (100 mL)
and brine (100 mL), the organic layer was separated and the
aqueous layer was extracted with CH Cl
6
b (0.18 g, 30%) and an inseparable mixture of minor enan-
2
2
tiomeric type diastereomers 7a and 7b (0.06 g, 10%, TLC R
f
)
0.53, silica, ether/hexane, 1:1).
For the less polar isomer 6a : [R]
2
2
(3 × 25 mL). The
2
5
D
+411 (c 0.62, CHCl
3
);
combined organic layers were dried, filtered, and concentrated.
Purification by flash chromatography (silica, ether/hexane (1:
1)) gave 21-thiooxopseudovincadifformine 11a (0.318 g, 76%):
mp 95 °C (decomp); TLC R ) 0.47 (silica gel, hexane/ether,
f
1
:1, CAS blue to purple); UV (EtOH) λmax 216, 232, 300, 330
[R]25
) - 50 (c 0.5, CHCl
1
13
nm; IR (KBr) νmax 3370, 3049, 2958, 2944, 2866, 1725, 1666,
1
1
D
3
). H NMR and C NMR data
4
,10b
594, 1476, 1463, 1437, 1371, 1293, 1267, 1240, 1180, 1096,
matched those reported for the racemic compound.
037, 890, 814, 736, 690 cm-1; H NMR (CDCl
1
) δ 0.50 (m, 1
(-)-21-Th ioxo-20-epi-pseu dovin cadiffor m in e (11b). Op-
erating as described in the preparation of the epimer 11a ,
3
H), 0.64 (t, J ) 7.4 Hz, 3 H), 0.74-0.93 (m, 2 H), 0.80-1.10
(m, 2 H)0.1.22-1.72 (m, 7 H), 1.75 (d, J ) 6.9 Hz, 3 H), 2.10
(m, 1 H), 2.29 (d, J ) 15 Hz, 1 H), 2.35 (m, 1 H), 2.75-2.85
(m, 1 H), 3.70 (s, 6 H), 3.84 (s, 5 H), 4.15 (s, 1 H), 4.44 (m, 2
starting from the lactam 10b (0.44 g, 1.24 mmol) with P
4 10
S
(0.88 g) in THF (75 mL), gave the product 11b (0.292 g, 64%):
[R]25
1
13
D
3
) -71 (c 0.56, CHCl ). H NMR and C NMR data
4
,10b
H), 4.53 (s, 1 H), 6.73 (d, J ) 7.7 Hz, 1 H), 6.79 (d, J ) 4.3 Hz,
matched those reported for the racemic compound.
2
H), 6.98-7.10 (m, 4 H), 7.21 (t, J ) 7 Hz, 2 H), 7.36 (m, 3
(-)-P seu d ovin ca d iffor m in e (1). A mixture of the thi-
olactam 11a (0.125 g, 0.067 mmol) and about 2 g of Raney
nickel in ethanol (10 mL) was stirred for 6 h at room
temparature and filtered. The Raney nickel was washed with
1
3
H), 7.66 (m, 2 H), 8.89 (s, 1 H); C NMR (CDCl
3
) δ 11.82, 18.49,
2
5
7
1
1
1
0.17, 26.21, 32.13, 38.11, 39.84, 44.24, 48.41, 50.61, 51.18,
2.12, 52.21, 55.42, 67.04, 69.02, 69.43, 69.59 (5C), 70.95,
4.82, 89.61, 98.48, 98.71, 108.81, 120.24, 122.69, 127.32,
27.38, 127.58, 127.62, 127.87, 127.93, 128.96, 132.28, 132.43,
35.28, 135.46, 137.54, 139.00, 140.19, 140.25, 142.76, 164.58,
68.90, 176.39; mass spectrum (CI), m/z (rel intensity) 781 (M
CH
2
Cl
2
(3 × 10 mL), and the combined filtrate was concen-
trated. Purification by flash chromatography (silica/ether/
2
5
hexane) gave pseudovincadifformine 1 (0.087 g, 76%): [R]
D
5
25
-503 (EtOH). 1H
- 506 (c 0.62, EtOH, >98% ee); lit. [R]
D
NMR and 1 C NMR data matched those reported for the
3
+
1, 61), 425 (17), 411 (21), 398 (16), 397 (100), 396 (93), 383
10), 268 (13), 267 (23), 266 (42). Anal. Calcd for C46
PFe: C, 70.77; H, 6.32; N, 3.56; P, 3.97; Fe, 7.15. Found: C,
racemic compound.1
,4,10b
(
49 2 4
H N O -
(-)-20-epi-P seu d ovin ca d iffor m in e (2). Operating as
described in the preparation of the epimer 1, starting from
the thiolactam 11b (0.025 g, 0.067 mmol), gave epi-pseudo-
6
9.99; H, 6.13; N, 3.42; P, 3.52; Fe, 7.55.
2
5
For the more polar diastereomer 6b: [R]
D
) +445 (c 0.94,
2
5
CHCl
3
); mp 115 °C (decomp); TLC R
f
) 0.38 (silica gel,hexane/
vincadifformine 2 (0.018 g, 78%): [R]
D
) -450 (c 0.3, EtOH,
>98% ee); lit. [R]25
-433 (c 0.7, EtOH).5 H NMR and
NMR data matched those reported for the racemic com-
1 13
C
ether, 1:1, CAS blue to purple); UV (EtOH) λmax 214, 230, 300,
D
3
1
1
0
1
2
4
6
30 nm; IR (KBr) ν max 3383, 3048, 2966, 2943, 2872, 1727,
pound.1
,4,10b
674, 1598, 1475, 1451, 1422, 1381, 1287, 1270, 1240, 1187,
-
1 1
111, 1035, 906, 818, 735, 694 cm ; H NMR (CDCl
3
) δ 0.60-
(3a S,4R,11bR a n d 3a R,4S,11bS)-Meth yl 3-[1(R)-[(S)-2-
(D ip h e n y lp h o s p h e n o )fe r r o c e n y l]e t h y l]-2,3,3a ,4,5,7-
h exa h yd r o-4-[1-(2,5-d ioxa la n yl)b u t yl]-1H -p yr r olo[2,3-
d ]ca r b a zole-6-ca r b oxyla t e (14a ,b ). A solution of the
.85 (m, including 3 H triplet at δ 0.73, J ) 7.3 Hz, 4 H), 1.19-
.60 (m, 7 H), 1.66 (d, J ) 6.8 Hz, 3 H), 2.00-2.10 (m, 2 H),
.75-2.90 (m, 3 H), 3.44 (s, 3 H), 3.63 (s, 3 H), 3.78 (s, 5 H),
.12 (s, 1 H), 4.33 (s, 1 H), 4.41 (m, 2 H), 6.65-6.80 (m, 4 H),
.90-7.35 (m, 8 H), 7.60 (m, 2 H), 8.76 (s,1 H); 13C NMR
2
indoloazepines (-)-4b (1.00 g, 1.56 mmol) and 4,4-(ethylene-
dioxy)hexanal (13,6 500 mg, 3.16 mmol) in dry benzene (10
mL) was heated at reflux for 18 h. The benzene was removed
by rotary evaporation to give an orange oil. This oil was
dissolved in a methanol/dichloromethane mixture (30 mL, 3:1),
and sodium borohydride was added in small portions to reduce
the excess aldehyde. The mixture was partitioned between
water and ether (150 mL), and the ether extract was washed
with water and dried over magnesium sulfate. The ethereal
extract was concentrated by rotary evaporation to give an
orange oil. 1H NMR analysis of the crude product showed that
this reaction gave a 5:1 ratio of diastereomers (67% de). This
oil was applied to a flash silica column and eluted with a
hexane/ether mixture (2:1) to give the minor diasteromer (-)-
14b, contaminated with the reduced aldehyde, and the major
diastereomer (-)-14a (948 mg, 75% yield).
3
(CDCl ) δ 11.83, 18.50, 20.19, 26.23, 32.16, 38.08, 38.13, 44.26,
4
6
1
1
1
7
8.45, 50.62, 51.20, 52.16, 52.25, 55.45, 67.07, 69.05, 69.45,
9.54 (5C), 69.61, 89.65, 98.53, 98.75, 108.83, 120.26, 122.71,
27.35, 127.40, 127.60, 127.65, 127.89, 127.96, 128.98, 132.31,
32.45, 135.30, 135.48, 137.57, 139.02, 139.09, 140.27, 140.25,
64.60, 168.93, 176.41; mass spectrum (CI), m/z (rel intensity)
+
81 (M + 1, 10), 438 (11), 410 (14), 398 (25), 397 (100), 396
49 2 4
(76), 212 (25). Anal. Calcd for C46H N O PFe: C, 70.77; H,
6
3
.32; N, 3.56; P, 3.97; Fe, 7.15. Found: C, 70.77; H, 6.58; N,
.50; P, 3.60; Fe, 6.73.
(
-)-21-Oxop seu d ovin ca d iffor m in e (10a ). A solution of
the less polar diastereomer 6a (0.93 g, 1.19 mmol) in glacial
acetic acid (15 mL) was heated at 100 °C for 10 min. The
mixture was then poured into crushed ice (5 g) and basified
2
5
with 15% NH
precipitate, which was extracted with ether (4 × 25 mL). The
ether extracts were dried over Na SO , filtered, and concen-
trated. Purification by flash chromatography (silica gel, 5%
methanol in CH Cl ) gave 21-oxopseudovincadifformine 10a
0.411 g, 94%) as a single product. The ferrocenyl moiety was
4
OH in brine (25 mL) to produce a yellow
For the major diastereomer 14a : yellow foam, [R]
D
-403°
(c 0.14, CHCl ); TLC R 0.19 (slica gel, hexane/ether 2:1); IR
3
f
2
4
(NaCl) νmax 3391, 2973, 2943, 2879, 1674, 1610, 1478, 1465,
1435, 1369, 1294, 1279, 1247, 1213, 1203, 1109, 1069, 1001,
-
1 1
2
2
3
946, 821, 749, 698, 666 cm ; H NMR (CDCl ) δ 0.78 (t, J )
(
7.40 Hz, 3 H), 0.89-0.94 (m, 1 H), 1.24 (dd, J ) 4.65, 11.58
Hz, 1 H), 1.43-1.53 (m, 3 H), 1.67 (dd, J ) 3.35, 5.85 Hz, 1
H), 1.72 (d, J ) 6.97 Hz, 3 H), 1.72 (dd, J ) 5.11, 12.08 Hz),
2.33 (br d, J ) 15 Hz, 1 H), 2.68-2.72 (m, 1 H), 2.83 (dd, J )
6.59 Hz, 1 H), 2.89 (s, 1 H), 3.56 (dd, J ) 6.29 Hz, 1 H), 3.60-
3.73 (m, 4 H), 3.65 (s, 3 H), 3.82 (s, 5 H), 4.10 (s, 1 H), 4.33
(dd, J ) 2.36 Hz, 1 H), 4.41 (q, J ) 5.25 Hz, 1 H), 4.55 (d, J )
1.01 Hz, 1 H), 6.66 (d, J ) 2.28 Hz, 1 H), 6.69-6.74 (m, 2 H),
7.01 7.05 (m, 4 H), 7.23 (dd, J ) 1.75, 7.75 Hz, 2 H), 7.31-
2
completely converted to the vinylferrocene 8, and PPFOAC
was not recovered under these conditions. However, while
removal of the ferrocenylethyl moeity at 70 °C produced a
2
considerable amount of PPFOAC, a mixture of tetracyclic
amines (cis and trans) was produced and the lactam 10a was
formed only as a minor product under these conditions. For
2
5
1
5
0a : [R]
D
) -224 (c 0.7, CHCl
3 f
); TLC R ) 0.42, (silica gel,
1
13
% methanol in CH
data matched those reported for the racemic compound.
2
Cl , CAS blue). H NMR and C NMR
2
1
13
7.33 (m, 3 H), 7.60-7.64 (m, 2 H), 8.76 (br s, 1 H); C NMR

2
178 J . Org. Chem., Vol. 63, No. 7, 1998
Kuehne et al.
(
CDCl ) δ 17.97, 18.19, 22.68, 29.63, 31.60, 35.86, 36.07, 41.02,
3
for complexation of a sample of (+)-ibophyllidine showed only
1
3
5
6
9
1
1
(
4
3
(
(
1
(
9.31, 50.76, 55.45, 64.31, 64.57, 68.19, 68.93, 69.06, 69.65,
9.82, 69.86, 70.04, 70.45, 71.10, 71.51, 75.03, 75.11, 91.18,
9.09, 99.31, 108.34, 111.77, 120.21, 122.54, 127.52, 127.74,
27.99, 128.06, 129.07, 132.55, 132.69, 135.35, 135.53, 137.80,
a single enantiomer at δ 3.85 (vide infra). A C NMR spetrum
6 25
matched that of a racemic sample: [R]
D
+141 (c 0.1, CHCl
); TLC R 0.35 (SiO , ethyl
acetate/ethanol, 4:1, CAS blue to purple); H NMR (CDCl ) δ
3
),
1
4,15
25
lit.
[R]
D
+134, +259 (CHCl
3
f
1
2
3
39.02, 139.08, 139.99, 140.05, 143.07, 164.68, 169.37; MS m/z
1.03 (t, J ) 7.42 Hz, 3 H), 1.26-1.32 (m, 1 H), 1.43-1.59 (m,
1 H), 1.81 (dd, J ) 11.22, 15.20 Hz, 1 H), 1.85-1.94 (m, 1 H),
2.00-2.06 (m, 1 H), 2.14-2.20 (m, 2 H), 2.24-2.29 (m, 1 H),
2.80 (q, J ) 9.62 Hz, 1 H), 3.12 (dd, J ) 5.04, 13.58 Hz, 1 H),
3.14-3.19 (m, 1 H), 3.21-3.23 (m, 1 H), 3.50 (d, J ) 8.63 Hz,
1 H), 3.76 (s, 3 H), 6.82 (d, J ) 7.66 Hz, 1 H), 6.93 (ddd, J )
1.00, 7.58, 8.34 Hz, 1 H), 7.14 (ddd, J ) 1.18, 7.64, 8.81 Hz, 1
H), 7.52 (d, J ) 7.58 Hz, 1 H), 9.12 (s, 1 H).
+
rel intensity) 780 (M , 0.6), 426 (2), 425 (5), 413 (1), 412 (3),
11 (2), 410 (4), 399 (3), 398 (20), 397 (65), 396 (58), 395 (24),
94 (3), 384 (9), 383 (6), 332 (3), 331 (14), 330 (3), 329 (7), 319
7), 288 (10), 284 (5), 283 (17), 276 (3), 275 (8), 264 (3), 257
2), 256 (4), 252 (8), 251 (4), 242 (4), 228 (7), 226 (6), 183 (15),
76 (13), 171 (6), 170 (8), 169 (4), 168 (6), 167 (9), 166 (6), 165
14), 159 (7), 157 (7), 154 (7), 153 (6), 152 (7), 149 (14), 129
62), 121 (13), 115 (5), 101 (87), 69 (11), 57 (18).
(
(3a R,11b S)- a n d (3a S,11b R)-Met h yl 3-[1-(S)-[(R)-2-
(D ip h e n y lp h o s p h e n o )fe r r o c e n y l]e t h y l]-2,3,3a ,4,5,7-
h exa h yd r o-4-(R a n d S)-eth yl-4-[2-(m eth oxyca r bon yl)eth -
yl]-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (21a ,b a n d
21c,d ; (+)-Dia ster eom er s). A solution of the indoloazepine
For the minor diastereomer 14b: TLC R
f
0.30 (slica gel,
) δ (visible peaks only) 2.06
br d, J ) 15.26 Hz, 1 H), 2.33 (dd, J ) 6.24, 8.46 Hz, 1 H),
1
hexane/ether 2:1); H NMR (CDCl
(
2
5
7
3
.52-2.53 (m, 1 H), 2.74-2.79 (m, 1 H), 3.68 (s, 3 H), 3.92 (s,
H), 4.31 (dd, J ) 2.42 Hz, 1 H), 4.54 (s, 1 H), 6.74 (d, J )
.60 Hz, 1 H), 6.74 (d, J ) 7.60 Hz, 1 H), 6.84 (dd, J ) 7.43
9
4a (2.0 g, 3.05 mmol) and methyl 4-formylhexanoate (19, 2.0
g, 12.51 mmol) in dry benzene (6 mL) was heated under reflux
for 24 h. The benzene was evaporated under reduced pressure.
Hz, 1 H), 7.05-7.13 (m, 6 H), 7.36-7.38 (m, 4 H), 7.56 (ddd, J
1.98, 7.75, 9.66 Hz, 2 H), 8.83 (s, 1 H).
3a S,4R,11b R)-Met h yl 3-[1(R)-[(S)-2-(Dip h en ylp h os-
)
The residue was dissolved in dry methanol/CH
2 2
Cl (1:10, 50
(
mL), and NaBH (0.2 g) was added in small portions with
4
p h en o)fer r ocen yl]et h yl]-2,3,3a ,4,5,7-h exa h yd r o-4-[1-(2-
oxobu tyl)]-1H-pyr r olo[2,3-d]car bazole-6-car boxylate (15).
To a solution of the ketal (-)-14a (400 mg, 0.512 mmol) in
THF/MeOH (12 mL, 1:1) at room temperature was added an
aqueous hydrochloric acid solution (6 mL, 10%). This solution
was allowed to stir at ambient temperature for 4 h and then
neutralized with an aqueous NaOH solution (10%) and ex-
tracted with ether. The ethereal extract was washed with
water, dried over magnesium sulfate, and concentrated by
rotary evaporation to give a yellow foam. This foam was
applied to a flash silica column and eluted with a hexane/ether
mixture (1:1) to give the title compound (350 mg, 99%) as a
stirring to reduce excess aldehyde, which contaminated the
product. The mixture was stirred at room temperature for 15
min, and water (15 mL) was added. The aqueous phase was
extracted with dichloromethane (3 × 60 mL), and the extract
4
was dried over MgSO , filtered, and concentrated under
reduced pressure to give a yellow foam. The crude product
was purified by column chromatography (silica, ether/hexane,
1:2) to give an inseparable mixture of less polar diastereomers
(+)-21a and (+)-21b, in a 5:1 ratio, as a yellow foam (1.21 g,
51%). Further elution gave an inseparable mixture of the more
polar diastereomers (+)-21c and (+)-21d , in a 2:1 ratio, as a
yellow foam (0.6 g, 25%).
2
5
For the less polar isomers (+)-21a ,b: [R]25 +360 (c 0.10,
yellow foam: [R]
D
-347 (c 0.10, CHCl
3 f 2
); TLC R 0.41 (SiO ,
D
hexane/ether 2:1, CAS blue to purple); IR (NaCl) νmax 3380,
CHCl ); mp 110-111 °C (decomp); TLC R ) 0.48, (silica gel,
3
f
3
1
6
1
054, 2978, 2934, 2859, 1715, 1675, 1653, 1609, 1540, 1477,
465, 1436, 1371, 1293, 1278, 1247, 1202, 1109, 1049, 822, 742,
hexane/ether, 1:2, CAS blue to purple); UV (EtOH) λ
max
216,
226, 302, 332 nm; IR (KBr) νmax 3380, 3052, 2972, 2953, 2875,
-
1
1
99, 668 cm ; H NMR (CDCl
3
) δ 0.89 (t, J ) 7.32 Hz, 3 H),
1736, 1679, 1610, 1478, 1465, 1434, 1377, 1288, 1271, 1248,
-
1
1
.35-1.42 (dd, J ) 10.73, 16.47 Hz), 1.68-1.74 (m, 1 H), 1.79
1211, 1157, 1107, 1049, 1002, 821, 743, 698 cm ; H NMR
(d, J ) 6.98 Hz, 3 H), 1.96-2.07 (m, 3 H), 2.19 (dd, J ) 3.46,
(CDCl ) δ -0.30 to -0.20 (m, 1 H), 0.1-0.2 (m, 1 H), 0.22 (t,
3
7
2
5
.07 Hz, 1 H), 2.26 (dd, J ) 1.62, 15.50 Hz, 1 H), 2.71 (s, 1 H),
.85-2.89 (m, 1 H), 2.90-2.95 (m, 1 H), 3.66 (s, 3 H), 3.81 (s,
H), 4.29 (d, J ) 1.39 Hz, 1 H), 4.53 (s, 1 H), 4.53 (q, J ) 3.86
J ) 7.9 Hz, 3 H), 1.27-1.30 (m, 1 H), 1.37-1.39 (m, 1 H), 1.83
(d, J ) 6.9 Hz, 3 H), 1.95-2.00 (m, 1 H), 2.02 (d, J ) 15.1 Hz,
1 H), 2.16 (d, 1 H, J ) 15.3 Hz, 1 H), 2.26-2.32 (m, 1 H), 2.51
(s, 1 H), 2.71-2.74 (m, 1 H), 2.92-2.98 (m, 1 H), 3.01-3.08
(m, 1 H), 3.67 (s, 3 H), 3.74 (s, 5 H), 3.81 (s, 3 H), 4.40 (s, 1 H),
4.57-4.59 (m, 1 H), 4.70 (s, 1 H), 4.76 (s, 1 H), 6.07 (d, J ) 7.7
Hz, 1 H), 6.50 (t, J ) 7.1 Hz, 2 H), 6.70-6.71 (m, 2 H), 6.81 (t,
J ) 7.3 Hz, 1 H), 6.92 (t, J ) 7.3 Hz, 2 H), 7.12 (t, J ) 7.1 Hz,
Hz, 1 H), 4.63 (d, J ) 0.99 Hz, 1 H), 6.64 (d, J ) 7.29 Hz, 1 H),
.74 (d, J ) 7.68 Hz, 1 H), 6.80 (dd, J ) 7.51 Hz), 6.85-6.88
m, 2 H), 7.00 (dd, J ) 7.43 Hz, 1 H), 7.11-7.16 (m, 3 H), 7.36-
.38 (m, 3 H), 7.66-7.69 (m, 2 H), 8.91 (s, 1 H); 13C NMR
CDCl ) δ 20.00, 20.21, 21.50, 35.30, 35.65, 36.18, 39.96, 40.11,
6
(
7
(
3
1
3
4
6
9
1
1
2.34, 46.18, 50.52, 50.71, 55.18, 65.95, 66.09, 68.35, 68.87,
9.00, 69.56, 70.38, 70.51, 71.33, 71.58, 74.90, 74.99, 90.33,
6.99, 97.23, 108.82, 120.21, 122.73, 127.38, 127.55, 127.60,
28.01, 129.13, 132.06, 132.21, 132.35, 135.42, 135.60, 137.10,
39.42, 140.56, 140.62, 142.85, 164.42, 169.09, 210.62.
2 H), 7.35-7.39 (m, 2 H), 7.68 (m, 2 H), 8.86 (s, 1 H); C NMR
(CDCl ) (visible peaks only) δ 24.01, 25.64, 28.05, 29.53, 29.55,
3
30.23, 38.86, 42.06, 50.60, 51.39, 57.26, 69.81, 70.78, 70.79,
71.88, 71.91, 89.08, 108.44, 119.80, 124.34, 126.85, 127.09,
127.97, 129.16, 132.12, 132.26, 135.67, 135.85, 136.31, 140.24,
142.74, 168.78, 175.49; mass spectrum (CI), m/z (rel intensity)
781 (M + 1, 52), 566 (16), 412 (17), 398 (76), 397 (35), 396
(100), 212 (22), 199 (25), 127 (10), 111 (10), 89 (13), 71 (16), 69
(10), 59 (31). Anal. Calcd for C H N O PFe: C, 70.77; H,
(
+)-Ibop h yllid in e (12). A solution of the amino ketone
(
-)-15 (70 mg, 0.102 mmol) in acetic acid (2 mL) was heated
to 70 °C for 10 min. This orange solution was quenched with
ice, basified with 15% ammonium hydroxide solution, and
4
6
49
2
4
extracted with CH
2
Cl
2
. The organic layer was washed with
6.32; N, 3.56; P, 3.97. Found: C, 70.37; H, 6.51; N, 3.27; P,
an aqueous HCl solution (3 × 3 mL, 10%). The acid extract
was basified with a sodium hydroxide solution (10%), extracted
with toluene, and dried over magnesium sulfate. The toluene
was removed by rotary evaporation, and the residual oil was
dissolved in acetic acid (1 mL) containing 10% Pd/C (20 mg).
This mixture was allowed to stir at room temperature for 4
days under hydrogen at atmospheric pressure. The catalyst
was filtered off under suction and washed with hot methanol.
The acidic solution was added to ice and then basified with
ammonium hydroxide solution (15%). Subsequent extraction
3.78.
For the more polar diastereomers (+)-21c and 21d : [R]25D
+256 (c 0.10, CHCl ); mp 73-74 °C (decomp); TLC Rf ) 0.33,
3
(silica gel, hexane/ether, 1:2, CAS blue to purple); UV (EtOH)
λmax 216, 226, 302, 332 nm; IR (KBr) νmax 3380, 3053, 2948,
2877, 1737, 1679, 1642, 1602, 1478, 1465, 1434, 1384, 1286,
1247, 1205, 1186, 1119, 1106, 1049, 1026, 1001, 970, 821, 743,
699 cm-1
1
3
; H NMR (CDCl ) (major peaks for major diastere-
omer) δ 0.52-0.60 (m, 1 H), 0.11-0.17 (m, 1 H), 0.94 (t, J )
7.17 Hz, 3 H), 1.84 (d, J ) 7.0 Hz, 3 H), 3.41 (s, 3 H), 3.67 (s,
with CH
evaporation gave a white foam, which was separated by PLC
SiO , ethyl acetate:ethanol 3:1) to give (+)-ibophyllidine (20
mg, 60% yield, in over 98% ee, by chiral shift titration).
Addition of up to five times the required amount of Eu(hfc)
2 2
Cl , drying over magnesium sulfate, and rotary
(14) Khuong-Huu, F.; Cesario, M.; Guilhelm, J .; Gooutarel, R.
(
2
Tetrahedron 1976, 32, 2539.
(15) Kan, C.; Husson, H.-P.; J acquemin, H.; Kan, S.-K.; Lounasmaa,
M. Tetrahedron Lett. 1980, 55.
3

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2179
3
4
8
H), 3.71 (s, 5 H), 4.37 (s, 1 H), 4.60 (m, 1 H), 4.68 (s, 1 H),
1736, 1679, 1610, 1478, 1466, 1435, 1377, 1289, 1271, 1248,
-
1
1
.75 (s, 1 H), 6.07 (d, J ) 7.3 Hz, 1 H), 7.64-7.67 (m, 2 H),
1211, 1158, 1107, 1049, 1002, 821, 743, 698 cm ; H NMR
(CDCl ) δ 0.71 (t, J ) 7.3 Hz, 3 H), 0.96-1.16 (m, 2 H), 1.18-
1
.83 (s, 1 H); H NMR (CDCl
3
) (major peaks for minor
3
diastereomer) δ 1.13 (t, J ) 7.50 Hz, 3 H), 1.68 (d, J ) 6.5 Hz,
3
1
1.21 (m, 1 H), 1.83 (d, J ) 15.6 Hz, 1 H), 1.96 (dd, J ) 6.1,
12.6 Hz, 1 H), 2.02 (dt, J ) 3.5 13.4 Hz, 1 H), 2.08-2.13 (m, 1
H), 2.55 (dt, J ) 3.4, 13.9 Hz, 1 H), 2.73 (dd, J ) 1.5, 15.7 Hz,
1 H), 3.12 (dt, J ) 3.9, 5.4 Hz, 1 H), 3.39 (s, 1 H), 3.70-3.77
(m, 1 H), 3.78 (s, 3 H), 4.61 (dd, J ) 7.94, 13.1 Hz, 1 H), 6.88
(t, J ) 7.8 Hz, 1 H), 6.92 (t, J ) 7.5 Hz, 1 H), 7.19-7.24 (m, 2
H), 3.49 (s, 3 H), 3.70 (s, 3 H), 4.01 (s, 5 H), 7.53-7.56 (m,
H), 8.83 (1 H); mass spectrum (CI), m/z (rel intensity) 781
(
3
M + 1, 28), 566 (33), 413 (12), 411 (23), 397 (100), 396 (89),
94 (13), 212 (12), 180 (12), 70 (12).
3a S,11bR)- a n d (3a R,11bS)-Met h yl 3-[(R)-[(S)-2-(Di-
(
p h en ylp h osp h en o)fer r ocen yl]eth yl]-2,3,3a ,4,5,7-h exa h y-
d r o-4-(R a n d S)-eth yl-4-[2-(m eth oxyca r bon yl)eth yl]-1H-
p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (21a , 21b a n d 21c,
H), 8.99 (br s, 1 H); 13C NMR (CDCl
3
) δ 7.07, 27.38, 29.49,
30.16, 38.84, 40.21, 41.25, 49.47, 50.94, 51.17, 56.42, 70.30,
91.10, 109.63, 121.06, 121.44, 128.68, 135.00, 142.75, 162.90,
168.05.
2
1d , (-)-Dia ster eom er s). By the above procedure, starting
with (-)-ferrocenyl azepine 4b and aldehyde 19, the title
compounds were obtained with similar yield and diastereo-
meric ratio. For the less polar diastereomers (-)-21a and
(-)-3-Th ioxovin ca d iffor m in e (26). Operating as de-
scribed in the preparation of (+)-26, starting from 5:1 (-)-22/
4
(+)-22 (0.44 g, 1.24 mmol) with P S10 (0.88 g) in THF (75 mL)
2
5
2
1b: [R]
D
-361 (c 0.10, CHCl
3
); mp 110-111 °C (decomp);
gave (-)-26 (0.383 g, 84%). The enantiomerically pure product
TLC R
f
) 0.48 (silica gel, hexane/ether, 1:2, CAS blue to
was obtained as described for its enantiomer (vide supra);
purple). For the more polar diastereomers (-)-21c and 21d :
[R]25
D
3
) -50 (c 0.12, CHCl ).
2
5
[
0
R]
D
-225 (c 0.10, CHCl
.33, (silica gel, hexane/ether, 1:2, CAS blue to purple).
+)-3-Oxovin ca d iffor m in e (22). (a ) A solution of the
3
); mp 73-74 °C (decomp); TLC R
f
)
(-)-Vin ca d iffor m in e (16b). (a ) A mixture of enantiomeri-
cally pure thiolactam (-)-26 (0.050 g, 0.135 mmol) and about
2 g of Raney nickel in ethanol (2 mL) was stirred for 16 h at
room temperature and filtered. The Raney nickel was washed
(
amines (+)-21a and 21b (1.09 g, 1.39 mmol) in glacial acetic
acid (16 mL) was heated at 100 °C for 10 min. The dark
orange mixture was then poured into crushed ice (5 g) and
with CH
2
Cl
2
(3 × 10 mL), and the combined filtrate was
concentrated. Purification by flash chromatography (silica,
basified with 15% NH
precipitate, which was extracted with ether (3 × 50 mL). The
ether extracts were dried over Na SO , filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography (silica, methanol/CH Cl 1:19) gave mostly (+)-3-
4
OH in brine (25 mL) to produce a yellow
ether/hexane 1:1) gave vincadifformine (-)-16b (0.039 g,
2
5
11
87%): [R]
D
-556 (c 0.14, EtOH, >98% ee, vide infra); lit.
[R]25
1
2
4
D
3
-564 (c 0.14, EtOH); mp ) 98-99 °C; H NMR (CDCl )
δ 0.58 (t, J ) 7.1 Hz, 3 H), 0.61-0.64 (m, 1 H), 0.98-1.20 (m,
1 H) 1.28-1.31 (m, 1 H), 1.71-1.79 (m, 1 H), 1.80 (br d, J )
4.1 Hz, 1 H), 1.82 (m, 2 H), 2.05-2.06 (m, 1 H), 2.28 (d, J )
15.3 Hz, 1 H), 2.41-2.45 (m, 2 H), 2.52-2.56 (m, 1 H), 2.73
(d, J ) 15.1 Hz, 1 H), 2.92 (t, J ) 7.0 Hz, 1 H), 3.12 (br d, J )
8.9 Hz, 1 H), 3.76 (s, 3 H), 6.79 (d, J ) 7.2 Hz, 1 H), 6.85 (t, J
) 7.4 Hz, 1 H), 7.12 (t, J ) 7.7 Hz, 1 H) 8.89 (br s, 1 H).
(b) Starting from the more polar tetracyclic ferrocenylethyl
diastereomers (+)-21c and 21d (cleavage, formation of thi-
olactam, desulfurization) produced (-)-16b with 33% enan-
2
2
oxovincadifformine (+)-22 (0.48 g, 97%) as a white foam: mp
2
5
)
214-215 °C (decomp); [R]
0.51 (silica gel, 5% methanol in CH
) δ 0.69 (t, J ) 7.4 Hz, 3 H), 0.98 (q, J ) 7.4 Hz, 2 H),
.32-1.40 (m, 1 H), 1.71 (s, 1 H), 1.82 (dd, J ) 6.4, 12.3 Hz, 1
D
) +178 (c 0.1, CHCl
3 f
); TLC R
Cl , CAS blue); H NMR
2
1
)
2
(CDCl
3
1
H), 1.91 (d, J ) 15.5 Hz, 1 H), 1.95-2.02 (m, 2 H), 2.28-2.36
m, 1 H), 2.38 (dt, J ) 4.32, 15.5 Hz, 1 H), 2.63 (dd, J ) 0.28,
(
1
4
6
.73 Hz, 1 H), 3.41 (dt, J ) 5.54, 12.1 Hz, 1 H), 3.77 (s, 1 H),
.15 (dd,J ) 7.69, 11.71 Hz, 1 H), 6.86 (d, J ) 7.7 Hz, 1 H),
.91 (t, J ) 7.5 Hz, 1 H), 7.16-7.21 (m, 2 H), 8.98 (s, 1 H).
tiomeric excess: [R]25
D
3
) -125 (c 0.3, CHCl ). Here recrys-
tallization was not applied at the thioxovincadifformine stage.
(+)-Vin ca d iffor m in e (16a ). (a ) Operating as described in
the preparation of (-)-16b, starting from unrecrystallized
3-thiooxovincadifformine (+)-26 (0.05 g, 0.135 mmol), gave 16a
(
b) Cleavage of the more polar diastereomers (-)-21c amd
2
1d (0.50 g, 0.64 mmol, vide supra) in glacial acetic acid (5
mL), similar to that (+)-21a and 21b, produced mostly (+)-3-
2
5
oxovincadifformine (+)-22 (0.208 g, 95%): mp 200-205 °C;
(0.038 g, 87%): [R]
D
) + 440 (c 0.3, CHCl
3
, >80% ee, vide
2
5
11
25
[R]
D
+96 (c 0.1, CHCl
3
).
infra); lit. [R]
D
+542 (c 0.04, EtOH).
(
-)-3-Oxovin ca d iffor m in e (22). (a ) Cleavage of the more
(b) Starting from the more polar diastereomers (-)- 21c and
polar diastereomers (+)-21c and 21d (0.50 g, 0.64 mmol) in
glacial acetic acid (5 mL), similar to that for (+)-21a and 21b,
produced mostly (-)-3-oxovincadifformine (-)-22 (0.208 g,
21d (cleavage, formation of thiolactam, desulfurization) pro-
2
5
duced 16a with 33% enantiomeric excess, [R]
CHCl ). Recrystallization was not applied at the thioox-
D
) +124 (c 0.3,
3
2
5
9
5%): mp 200-205 °C; [R]
b) Cleavage of less polar diastereomers (-)- 21a and 21b
0.50 g, 0.64 mmol) in glacial acetic acid (5 mL), similar to
that for (+)-21a and 21b produced mostly (-)-3-oxovincadif-
D
-95 (c 0.1, CHCl
3
).
ovincadifformine stage.
(
(3a S,11bR)- an d (3a R,11bS)-Meth yl 3-(Tr iflu or oacetyl)-
2,3,3a ,4,5,7-h exa h yd r o-4-(R a n d S)-eth yl-4-[2-(m eth oxy-
ca r b on yl)et h yl]-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r b oxy-
la tes ((-)-23). To a solution of 0.172 g (0.22 mmol) of the
(
2
5
formine (-)-22 (0.208 g, 95%): mp 214-215 °C; [R]
D
-180 (c
0
.1, CHCl
+)-3-Th ioxovin ca d iffor m in e (26). A 5:1 mixture of (+)-
2/(-)-22 (0.34 g, 0.96 mmol) and P 10 (0.76 g, 1.71 mmol) in
3
).
ferrocenylethyl tetracycles (-)-21c and 21d , 2/1, low R
f
, [R]
D
(
) -256 (c 0.32, CHCl )) in 5 mL of anhydrous CH Cl , cooled
3
2
2
2
4
S
to 0 °C, was added, under nitrogen, 47 µL (0.33 mmol) of TFAA,
followed by 1 mL of trifluoroacetic acid. The reaction mixture
was allowed to warm to room temperature and stirred at room
temperature for an additional 30 min. Then, the volatile
components were evaporated at reduced pressure. The result-
dry THF (65 mL) was stirred at room temperature for 19 h
under nitrogen. Then water (50 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
CH
over MgSO
2
Cl
2
(3 × 50 mL). The combined organic layers were dried
4
and concentrated under reduced pressure. The
2 2
ing residue was diluted with CH Cl and neutralized by
crude product was purified by flash chromatography (silica gel,
ether/hexane 1:2) to give (+)-26 (0.312 g, 88%) as a white solid.
The white solid was dissolved in a mixture of hexane/ether/
stirring with solid potassium carbonate. After filteration, the
filtrate was concentrated at room temperature under reduced
pressure. The residue was subjected to flash chromatography
on silica gel and eluted with acetone/ethyl acetate, 1:8, to yield
0.091 g (86%) of partially racemic trifluoroacetamide (-)-23:
CH
C for 12 h. The precipitated white crystals were filtered and
dried at room temperature (0. 07 g). This product was found
2 2
Cl (1:2:0.25, 10 mL) with gentle heating and left at -12
°
TLC R
CHCl ); UV (EtOH) λmax 208, 230, 300, 330 nm; IR (KBr) νmax
3373, 2953, 1735, 1681, 1611, 1468, 1438, 1384, 1254, 1203,
f
) 0.58 (silica gel, acetone, CAS blue); [R]
D
-99 (c 0.83,
2
5
to be racemic material, [R ]
87 °C. The mother liquor was concentrated under reduced
pressure to produce white solid, which was enriched with
D
) 0 (c 0.1, CHCl
3
), mp ) 185-
3
1
-
1 1
1134, 1060, 835, 799, 750, 721 cm ; H NMR (CDCl ) δ 8.94
3
2
5
optically pure enantiomer (+)-26 (0.24 g, 68%); [R]
c 0.2, CHCl ); mp ) 150-152 °C; TLC R ) 0.43 (silica gel,
hexane/ether, 1:2, CAS blue to purple); UV (EtOH) λmax 200,
30, 274, 296, 328 nm; IR (KBr) νmax 3380, 3052, 2972, 2875,
D
) +50
(1 H, s), 7.35 (1 H, d, J ) 7.4 Hz), 7.24 (1 H, dd, J ) 7.7 and
7.7 Hz), 6.97 (1 H, dd, J ) 7.4 and 7.4 Hz), 6.88 (1 H, d, J )
7.7 Hz), 3.80 (1 H, s), 3.79 (3 H, s), 3.56 (3 H, s), 3.47 (1 H, br
s), 3.36 (1 H, br s), 2.50 (1 H, d, J ) 16.2 Hz) 2.27 (1 H, d, J
(
3
f
2

2
180 J . Org. Chem., Vol. 63, No. 7, 1998
Kuehne et al.
)
16.2 Hz), 2.18 (1 H, m), 2.09 (1 H, m), 1.99 (2 H, m), 1.66 (1
0.84-0.88 (m, 1 H), 0.96-1.20 (m, 1 H) 1.79 (dd, J ) 3.8, 11.6
Hz, 1 H), 2.05-2.10 (m, 1 H), 2.44 (d, 1 H), 2.54 (dd, J ) 1.8,
15.1 Hz, 1 H), 2.68 (s, 1 H), 2.69-2.73 (m, 1 H), 3.03-3.20 (m,
1 H), 3.44 (dd, J ) 1.3, 4.7 Hz, 1 H), 3.76 (s, 3 H), 5.70 (ddd,
J ) 1.5, 4.7, 9.9 Hz, 1 H), 5.78 (ddd, J ) 1.5, 4.7, 9.9 Hz, 1 H),
6.81 (d, J ) 7.7 Hz, 1 H), 6.86 (m, 1 H), 7.13 (dd, J ) 7.7 Hz,
1 H), 7.23 (d, J ) 7.4 Hz, 1 H) 8.98 (br s,1 H).
H, m), 1.58 (1 H, m), 1.40 (1 H, m), 1.14 (1 H, m), 0.97 (3 H, t,
+
J ) 7.3 Hz); mass spectrum (CI) m/z (rel intensity) 481 (M
+
+
1
1
, 0.5), 480 (M , 0.1), 449 (0.4), 385 (37), 353 (16), 170 (31),
15 (63), 99 (70), 60 (100). This trifluoroacetamide was shown
1
to be a mixture of enantiomeric isomers by H NMR shift
studies using a gradual addition of a 0.1 M solution of Eu-
(
hfc)
.79 was split to give signals at δ 4.11 and 4.04. The indole
proton signal at δ 8.94 was split to give signals at δ 9.32 and
.28. The ratio between the integral of the split signals was
ca. 2:1.
3
in d-chloroform. The ester methyl proton signal at δ
Deter m in a tion of En a n tiom er ic P u r ity. Enantiomeric
3
excesses (ee) of all synthesized natural products were deter-
3
mined by the chiral shift method using Eu(hfc)
3
.
(a )
9
ψ-Vin ca d iffor m in e. The methyl ester singlet at δ 3.76 of
racemic ψ-vincadifformine was split into two broad singlets
(
3aS,11bR)- an d (3aR,11bS)-Meth yl 3-Ben zyl-2,3,3a,4,5,7-
3
when the racemic alkaloid and Eu(hfc) (1:0.2) were complexed.
h exa h yd r o-4-(R a n d S)-eth yl-4-[2-(m eth oxyca r bon yl)eth -
yl)-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (25). (a )To
a solution of 0.125 g (0.16 mmol) of the ferrocenylethyl
The same singlet of enantiomerically pure material was not
3
split when it was complexed with Eu(hfc) at the same
concentration or even higher concentrations.
tetracycles (-)-21c and 21d , low R
f
, [R]
D
) -256 (c 0.32,
3
(b) Ibop h yllid in e. Eu(hfc) (0.01 M) was added to ibo-
CHCl ) in 10 mL of acetone, cooled to 0 °C, was added 0.23
3
phyllidine samples (0.06 M). The first addition to a racemic
ibophyllidine sample caused complexation and splitting of the
methyl ester singlet, which was shifted to δ 3.78 for (-)-
ibophyllidine and to δ 3.79 for (+)-ibophyllidine. When un-
complexed, the methyl ester singlet is found at δ 3.76.
mL (30% w/w, 2.3 mmol) of hydrogen peroxide. The solution
was allowed to warm to room temperature in 30 min. The
excess hydrogen peroxide was reduced by the addition of 10
mL of aqueous sodium thiosulfate solution. The resulting
mixture was extracted with ether. The organic layers were
combined, washed with brine, and dried with sodium sulfate.
Concentration under vacuum gave the corresponding phos-
phine oxide compounds 21e and 21f as a yellow foam (0.127
Addition of up to five times the required amount of Eu(hfc)
3
for complexation of a sample of (+)-ibophyllidine showed only
a single enantiomer at δ 3.85.
3
(c) Vin ca d iffor m in e. A vincadifformine to Eu(hfc) 1:0.1
g, 100%): [R]
D
-157 (c 0.1, CHCl
3
).
molar ratio was used. The methyl ester singlet of racemic
vincadifformine at δ 3.76 when uncomplexed was split to give
signals at δ 4.33 for the (+) enantiomer and at δ 4.21 for the
(-) enantiomer.
Meth yl3-[1(S)-[(R)-2-(Dip h en ylp h osp h in yl)fer r ocen yl]-
eth yl]-1,2,3,4,5,6-h exa h yd r oa zep in o[4,5-b]in d ole-5ú-ca r -
b oxyla t es (4c). To a solution of (+)-ferrocenylethylin-
doloazepines 4a (1.00 g, 1.56 mmol) in acetone (18 mL) was
added dropwise hydrogen peroxide (30%, 1.26 mL, 11.1 mmol).
After 30 min of stirring at room temperature, aqueous sodium
thiosulfate was added to decompose an excess of the hydrogen
peroxide. The reaction mixture was extracted with ether. The
The crude phosphine oxide product was suspended with
benzyl bromide (39 µL, 0.32 mmol) and lithium iodide (0.022
g, 0.16 mmol) in THF-toluene (10 mL, 1:1). The mixture was
heated at reflux for 4 h and then cooled to room temperature,
diluted with ether, and washed with water. The ether extracts
were dried over sodium sulfate and concentrated by rotary
evaporation. The residue was applied to silica gel and eluted
with ethyl ether/hexane (1:2) to afford the benzyl compound
(-)-25 (0.035 g, 46%): [R]
D
3
- 72.5 (c 0.15, CHCl ). The proton
NMR data matched those given below. Further elution with
ether/hexane (1:1) gave the ferrocenylethylene phosphine oxide
1
6
25
8
a , [R]
D
+364 (c 0.79, CHCl
3
), followed by unreacted
4
combined extracts were washed with water, dried over MgSO ,
1
3
1
starting phosphine oxides 21e,f. The C and H NMR spectra
and concentrated under reduced pressure. Purification of the
residue by short-column chromatography on alumina, eluting
with ethyl acetate, gave the title phosphine oxide (0.95 g, 93%)
of the ferrocenylethylene 8a matched those reported.16
(
b) A mixture of the above trifluoroacetamide (-)-23 (58 mg,
0
0
.12 mmol), benzyl bromide (22 µL, 0.18 mmol), water (6 µL,
.34 mmol), and potassium carbonate (0.082 g, 0.59 mmol) in
as an inseparable mixture of isomers: TLC R
(silica gel, EtOAc, CAS green); mp 147-150 °C; [R]
0.35, CHCl ); UV (EtOH) λmax 212, 226, 266 nm; IR (KBr) νmax
3374, 3185, 3066, 2959, 1728, 1602, 1457, 1437, 1250, 1180,
f
) 0.33, 0.40
D
+266 (c
dry THF (5 mL) was heated at reflux overnight under nitrogen.
After cooling, and filtration of the inorganic materials, the
filtrate was concentrated. The residue was separated by
chromatography on silica gel, eluting with ethyl ether/hexane
3
-
1 1
1146, 1117, 1072, 1000, 838, 750, 702 cm
3
; H NMR (CDCl )
δ 8.53, 8.51 (1 H, 2s), 7.83-7.76 (2 H, m), 7.67-7.53 (2 H, m),
7.48-7.42 (3 H, m), 7.39-7.27 (1 H, m), 7.23-7.19 (1 H, m),
7.12-6.94 (5 H, m), 4.73-4.68 (1 H, m), 4.52-4.43 (1 H, m),
4.37-4.31 (1 H, m), 4.15-3.97 (2 H, m), 5.15, 4.14 (5 H, 2s),
3.77, 3.72 (3 H, 2s), 3.29-1.97 (6 H, m), 1.32-1.23 (3 H, m);
(
1:1) to give the benzyl compound (-)-25 (0.025 g, 44%).
Further elution with acetone/ethyl acetate (1:1) gave the
starting trifluoroacetamide (0.030 g). For the partially racemic
benzyl compound (-)-25: TLC R
f
) 0.31 (silica gel, ethyl ether/
- 73 (c 0.2, CHCl );
) δ 8.92 (1 H, s), 7.46 (1 H, d, J ) 7.5 Hz),
+
hexane, 1:1, CAS blue faded to yellow); [R]
D
3
mass spectrum (EI) m/z (rel intensity) 657 (M + 1, 37), 656
1
+
H NMR (CDCl
3
(M , 100), 413 (ferrocenyl, 28), 347 (14), 245 (23), 244 (in-
7
7
.36 (1 H, dd, J ) 7.2 and 7.7 Hz), 7.28 (1 H, dd, J ) 7.2 and
doloazepinyl, 32), 242 (51), 202 (45), 154 (68).
.4 Hz), 7.16 (1 H, dd, J ) 7.6 and 7.6 Hz), 7.01 (1 H, d, 7.3
(3a R,4R,11bR)- a n d (3a S,4S,11bS)-Meth yl 3-[1(S)-[[R]-
2-(Dip h en ylp h osp h in yl)fer r ocen yl]et h yl]-2,3,3a ,4,5,7-
h exa h yd r o-4-a cetoxy-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r -
b oxyla t es (30c a n d 31c). A solution of the above ferro-
cenylethylindoloazepine phosphine oxide (4c, 0.450 g, 0.685
Hz), 6.88 (1 H, dd, J ) 7.2 and 7.6 Hz), 4.27 (1 H, d, J ) 13.5
Hz), 3.78 (3 H, s), 3.73 (1 H, d, J ) 13.5 Hz), 3.53 (3 H, s), 2.98
(
(
2
1 H, dd, J ) 6.6 and 9.4 Hz), 2.94 (1 H, d, J ) 1.2 Hz), 2.46
1 H, dd, J ) 1.2 and 15.5 Hz), 2.24 (1 H, d, J ) 15.5 Hz),
.14-2.05 (3 H, m), 1.92 (1 H, m), 1.78 (1 H, m), 1.63 (1 H, dd,
2 2
mmol) and acetoxyacetaldehyde (29, 1.43 N in CH Cl , 0.60
J ) 5.0 and 12.1 Hz), 1.26 (1 H, m), 1.16 (1 H, m), 0.99 (3 H,
t, J ) 7.5 Hz). These values matched those previously reported
for the racemic compound, which was obtained by alternative
mL, 0.86 mmol) in dry benzene (4.5 mL) was heated at reflux
for 12 h. The solvent was removed by rotary evaporation, and
the residue was chromatographed on silica gel and eluted by
EtOAc/hexane (1:1 to 2:1) to give tetracycle 30c (0.224 g) and
31c (0.233 g) as yellow solids; total yield 90%. For 30c: TLC
8
,10
synthesis.
(
-)-Ta ber son in e (27). Operating as described in the
10
preparation of racemic tabersonine but starting from ena-
R
f
) 0.38 (silica gel, EtOAc/hexane, 2:1, CAS blue to brown);
mp 152-154 °C dec (ethyl ether/hexane); [R] +282 (c 0.22,
CHCl ); UV (EtOH) λmax 210, 300, 328 nm; IR (KBr) νmax 3374,
3065, 2983, 2952, 1731, 1679, 1610, 1438, 1247, 1193, 1117,
tiomerically pure (-)-3-oxovincadifformine ((-)-22a , 0.10 g,
D
2
5
0
.27 mmol) gave (-)-tabersonine (27, 0.017 g, 19%): [R]
D
)
3
-
248 (c 0.09, CHCl
3
, >98% ee, vide infra); reported [R]25
D
-240
) δ 0.62 (t, J ) 7.4 Hz, 3 H),
1
1 1
-1
1
(
c 0.15, EtOH); H NMR (CDCl
3
912, 729, 701 cm ; H NMR (CDCl
7
3
) δ 8.92 (1 H, s), 7.95-
.92 (2 H, m), 7.87-7.83 (2 H, m), 7.52 (3 H, br s), 7.40 (3 H,
t, J ) 2.3 Hz), 7.14 (1 H, t, J ) 7.6 Hz), 7.07 (1 H, d, J ) 7,4
Hz), 6.86 (1 H, t, J ) 7.4 Hz), 6.78 (1 H, d, J ) 7.7 Hz), 4.93
(1 H, q, J ) 6.9 Hz), 4.56 (1 H, s), 4.38 (1 H, d, J ) 2.0 Hz),
(
16) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Na-
gashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.;
Yamamoto, K.; Kumada, M. Bull. Chem. Soc. J pn. 1980, 53, 1138.

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2181
4
2
(
.20-4.09 (3 H, m), 4.13 (5 H, s), 3.70 (3 H, s), 3.24 (1 H, s),
.88 (2 H, br d, J ) 6.1 Hz), 2.46 (1 H, br d, J ) 14.6 Hz), 1.74
mmol) in dry benzene (4 mL) was heated at reflux for 12 h.
The solvent was removed by distillation under vacuum. The
resulting residue (30a , 31a ) was dissolved in acetone (7 mL),
and hydrogen peroxide (40%, 0.25 mL, 2.94 mmol) was added
dropwise. After 30 min of stirring at room temperature,
aqueous Na S O was added to decompose an excess of
3 H, s), 1.69 (3 H, d, J ) 6.9 Hz), 1.38-1.24 (2 H, m); 13
C
NMR (CDCl
3
) δ 168.93, 168.03, 163.00, 143.15, 136.97, 135.62,
1
1
7
5
34.92, 134.78, 134.05, 131.30, 131.23, 131.15, 131.04, 128.35,
28.13, 127.77, 122.60, 120.48, 109.07, 97.62, 97.53, 88.25,
3.32, 73.12, 70.91, 70.32, 70.24, 70.04, 69.95, 69.90, 64.20,
2
2
3
hydrogen peroxide. The reaction mixture was extracted with
5.27, 51.52, 50.82, 50.41, 39.31, 30.86, 22.83, 21.14, 13.74;
ether, dried (MgSO ), and purified by chromatography on silica
4
+
mass spectrum (EI) m/z (rel intensity) 455 (M - Ph
CH
3
0
2
PO -
gel (EtOAc/hexane 1:1 to 2:1) to afford tetracyle 31e (0.234 g)
and its diastereoisomer 30e (0.140 g) successively; total yield
3
CO, 4), 414 (20), 413 (ferrocenyl, 49), 412 (72), 347 (17),
26 (3), 121 (60), 84 (100). Anal. Calcd for C42 PFe‚
.5H O: C, 67.29; H, 5.60; N, 3.74; P, 4.13; Fe, 7.45. Found:
41 2 5
H N O
8
1%. For 31e: TLC R
CAS blue to brown); mp 152-154 °C dec (ethyl ether/hexane);
R] -286 (c 0.32, CHCl ). This tetracycle has identical
spectroscopica data with its enantiomer 31c. Anal. Calcd for
PFe‚0.5H O: C, 67.29; H, 5.60; N, 3.74; P, 4.13.
Found: C, 67.41; H, 5.58; N, 3.62; P, 4.01.
For 30e: TLC R ) 0.22 (silica gel, EtOAc/hexane, 2:1, CAS
blue); mp 156-158 °C dec (ethyl ether/hexane); [R] +6.9 (c
.28, CHCl ). This tetracycle has identical spectroscopica data
with its enantiomer 30c. Anal. Calcd for C42 PFe‚
.5H O: C, 67.29; H, 5.60; N, 3.74; P, 4.13. Found: C, 67.50;
H, 5.62; N, 3.60; P, 4.12.
3a R,4R,11bR)-Meth yl 3-(Tr iflu or oacetoxy)-2,3,3a,4,5,7-
f
) 0.38 (silica gel, EtOAc/hexane, 2:1,
2
C, 67.09; H, 5.62; N, 3.52; P, 4.18; Fe, 7.27.
For 31c: TLC R ) 0.22 (silica gel, EtOAc/hexane, 2:1, CAS
blue); mp 156-158 °C dec (ethyl ether/hexane); [R] - 6.3 (c
); UV (EtOH) λmax 210, 300, 328 nm; IR (KBr) νmax
586, 3378, 3065, 2990, 2824, 1747, 1682, 1596, 1437, 1371,
[
D
3
f
D
C
H
N
O
42
41
2
5
2
0
3
1
.21, CHCl
3
-
1
1
f
247, 1204, 1039, 911, 703 cm ; H NMR (CDCl ) δ 8.84 (1
3
D
H, s), 7.73 (2 H, dd, J ) 7.2 and 11.6 Hz), 7.53-7.43 (5 H, m),
.37 (1 H, dd, J ) 6.9 and 7.4 Hz), 7.29 (2 H, m), 7.12 (2 H,
dd, J ) 6.9 and 7.4 Hz), 6.84 (1 H, dd, J ) 7.4 and 7.4 Hz),
.75 (1 H, d, J ) 7.7 Hz), 5.32 (1 H, s), 5.22 (1 H, q, J ) 6.5
Hz), 4.63 (1 H, s), 4.36 (1 H, d, J ) 1.8 Hz), 4.21 (1 H, m), 4.16
5 H, s), 3.95 (1 H, s), 3.68 (3 H, s), 3.33 (1 H, s), 2.80 (1 H, m),
.33 (1 H, br d, J ) 12.4 Hz), 2.27 (1 H, dd, J ) 6.6 and 8.3
Hz), 1.77 (3 H, s), 1.62 (3 H, d, J ) 6.5 Hz), 1.31 (1 H, dd, J )
0
3
7
41 2 5
H N O
0
2
6
(
(
2
h exa h yd r o-4-a cetoxy-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r -
boxyla te (35). To a solution of the tetracycle 31e (3.0 g, 4.05
.3 and 11.5 Hz), 1.10 (1 H, m); 1 C NMR (CDCl
3
mmol) in dry CH Cl2 (30 mL), at 0 °C under nitrogen, was
4
1
1
1
7
4
3
) δ 170.65,
2
69.05, 163.24, 143.30, 137.56, 136.88, 136.04, 135.48, 134.65,
31.78, 131.70, 131.33, 131.08, 127.91, 127.81, 127.70, 122.26,
20.23, 109.07, 96.19, 96.12, 89.65, 73.94, 73.82, 71.52, 70.93,
0.39, 70.03, 69.70, 69.10, 66.10, 60.32, 54.60, 50.79, 49.45,
2.46, 39.99, 22.58, 21.46, 20.98, 14.16, 9.71; mass spectrum
added dropwise trifluoroacetic acid (3 mL). The reaction
mixture was allowed to warm to room temperature and stirred
for 6 h; then the volatile component was evaporated at reduced
2 2
pressure. The residue was diluted with CH Cl , potassium
carbonate was added, and the mixture was stirred for 15 min
to neutralize any residual acid and filtered. The filtrate was
concentrated at room temperature under reduced pressure.
The resulting residue was subjected to chromatography on
silica gel and eluted with MeOH/EtOAc (1:20) to give trifluo-
roacetamide 35 (1.10 g, 64%) and the corresponding free amine
(
EI) m/z (rel intensity) 413 (ferrocenyl, 37), 412 (100), 347 (9),
28 (21), 269 (33), 215 (33), 1665 (22), 72 (29). Anal. Calcd
for C42 PFe‚0.5H O: C, 67.29; H, 5.60; N, 3.74; P, 4.13;
Fe, 7.45. Found: C, 67.12; H, 5.62; N, 3.54; P, 4.15; Fe, 7.10.
3a R,4R,11bR)- a n d (3a S,4S,11bS)-Meth yl 3-[1(S)-[[R]-
-(Dip h e n ylp h osp h e n o)fe r r oce n yl]e t h yl]-2,3,3a ,4,5,7-
h exa h yd r o-4-(ter t-b u t yld ip h en ylsilyloxy)-1H -p yr r olo-
2,3-d ]ca r ba zole-6-ca r boxyla tes (30b a n d 31b). A solution
3
H
41
N
2
O
5
2
(
1
2
33 (0.226 g, 17%). The ratio was determined as ca. 3:1 by H
NMR. For trifluoroacetamide 35: TLC R
methanol/ethyl acetate, 1:10, CAS blue), R
acetone); [R] -144 (c 0.3, CHCl ); UV (EtOH) λmax 238, 298,
f
) 0.40 (silica gel,
) 0.55 (silica gel,
[
f
of ferrocenylindoloazepine 4a (0.320 g, 0.50 mmol) and silyloxy
aldehyde 32 (0.179 g, 0.60 mmol) in dry benzene (3.2 mL) was
heated at reflux for 20 h. After evaporation of the solvent
under reduced pressure, the resulting residue was dissolved
in a mixture of dry CH
this mixture was added NaBH
D
3
328 nm; IR (KBr) νmax 3376, 3018, 2953, 1733, 1682, 1612,
-
1
1
1469, 1440, 1251, 1205, 1136, 753 cm ; H NMR (CDCl ) δ
3
9.11 (1 H, s), 7.44 (1 H, d, J ) 7.4 Hz), 7.25 (1 H, dd, J ) 7.7
and 7.9 Hz), 6.97 (1 H, dd, J ) 7.5 and 7.5 Hz), 6.90 (1 H, d,
J ) 7.8 Hz), 5.46 (1 H, s), 4.02 (1 H, s), 3.79 (3 H, s), 3.59-
3.53 (2 H, m), 3.12 (1 H, d, J ) 16.8 Hz), 2.64 (1 H, d, J ) 15.6
2
Cl
2
(2 mL) and dry MeOH (2 mL). To
(0.05 g) with stirring to reduce
4
excess aldehyde. The reaction mixture was stirred at room
temperature for 15 min, and then water (25 mL) was added.
The aqueous phase was extracted with ether (3 × 10 mL), and
13
Hz), 2.27 (1 H, m), 2.06 (1 H, m), 1.90 (3 H, s); C NMR
(
1
CDCl
43.09, 133.81, 129.20, 122.33, 121.58, 116.39 (q, J ) 289.8
Hz), 109.73, 89.36, 69.69, 65.35, 54.27, 43.85, 40.20, 30.83,
4.00, 20.88; mass spectrum (EI) m/z (rel intensity) 424 (M ,
), 328 (7), 296 (10), 268 (19), 214 (37), 167 (34), 154 (38), 69
3
) δ 171.10, 168.24, 162.59 (q, J ) 36.3 Hz), 160.12,
4
the extracts were dried over MgSO and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography on silica gel, eluting with ether/
hexane (1:2) to give an inseparable mixture of diastereoisomers
of 30b and 31b (0.396 g, 86%) in a 1:2 ratio, on the basis of
indole NH singlets in the H NMR spectrum: TLC R
+
2
1
(100).
1
f
) 0.62
For the free amine 33: TLC R
ethyl acetate, 1:10, CAS blue); [R]
f
) 0.33 (silica gel, methanol/
-225 (c 0.1, CHCl ); UV
EtOH) λmax 240, 298, 326 nm; IR (KBr) νmax 3374, 2961, 2925,
(
(
λ
1
7
silica gel, ether/hexane, 1:1, CAS brown); mp 136-139 °C dec
ethyl ether/hexane); [R] +148 (c 0.35, CHCl ); UV (EtOH)
max 224, 300, 328 nm; IR (KBr) νmax 3383, 3073, 2931, 2856,
675, 1610, 1466, 1436, 1289, 1276, 1247, 1198, 1111, 909, 822,
D
3
D
3
(
2
854, 1731, 1683, 1610, 1467, 1438, 1246, 1204, 1133, 750
-
1
1
-
1
1
cm ; H NMR (CDCl
3
) δ 9.06 (1 H, s), 7.22-7.17 (2 H, m),
.91 (1 H, dd, J ) 6.7 and 7.7 Hz), 6.87 (1 H, d, J ) 8.1 Hz),
.88 (1 H, s), 3.78 (3 H, s), 3.63 (1 H, s), 3.24 (1 H, m), 3.16 (1
38, 701 cm ; H NMR (CDCl ) δ 9.05, 9.02 (1 H, 2s), 7.72 (1
3
6
4
H, m), 7.61 (1 H, m), 7.52 (2 H, m), 7.44 (4 H, m), 7.39 (4 H,
m), 7.34 (2 H, m), 7.25 (3 H,), 7.15 (2 H, m), 7.08 (3 H, m),
6
3
H, dd, J ) 7.1 and 9.3 Hz), 2.96 (1 H, dd, J ) 3.2 and 16.1
Hz), 2.55 (1 H, dd, J ) 2.5 and 16.0 Hz), 2.02 (1 H, m), 1.86 (3
.88 (1 H, m), 6.83 (1 H, m), 4.33 (1 H, m), 3.95 (1 H, br s),
.88 (1 H, br s), 3.81 (1 H, s), 3.79 (5 H, s), 3.66 (2 H, s), 3.59
H, s), 1.81 (1 H, dd, J ) 5.2 and 12.1 Hz); 13C NMR (CDCl
) δ
70.68, 169.17, 163.84, 143.34, 136.47, 128.07, 122.04, 120.82,
3
(3 H, s), 3.48 (1 H, m), 3.35 (1 H, s), 2.90 (1 H, m), 2.84 (1 H,
1
1
2
m), 1.34 (3 H, d, J ) 6.7 Hz), 1.27 (2 H, m), 0.73 (9 H, s); mass
spectrum (EI) m/z (rel intensity) 397 (ferrocenyl, 6), 396 (14),
2
1
09.35, 88.74, 74.15, 65.15, 54.83, 44.78, 42.14, 30.90, 23.77,
+
1.29; mass spectrum (EI) m/z (rel intensity) 328 (M , 10), 268
2
88 (tetracyclyl-t-BuPh SiO, 4), 268 (17), 242 (39), 232 (59),
99 (100), 135 (45).
+
(M
- AcOH, 69), 215 (52), 195 (39), 168 (36), 154 (54), 114
(
31), 72 (100).
Clea va ge of F er r ocen yleth yl Gr ou p w ith TF A-CH
a n d TF AA. To a solution of tetracycle 31e (0.020 g, 0.027
mmol) in 5 mL of dry CH Cl , cooled at 0 °C, was added TFAA
(
3a S,4S,11bS)- a n d (3a R,4R,11bR)-Meth yl 3-[1(R)-[[S]-
2
-(Dip h en ylp h osp h in yl)fer r ocen yl]et h yl]-2,3,3a ,4,5,7-
2 2
Cl
h exa h yd r o-4-a cetoxy-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r -
boxyla tes (30a , 31a ) a n d P h osp h in e Oxid es (30e, 31e). A
solution of ferrocenylindoloazepine 4b (0.400 g, 0.624 mmol)
2
2
(3.8 µL, 0.0405 mmol) under nitrogen, followed by 1 mL of
trifluoroacetic acid. The mixture was allowed to warm to room
and acetoxyacetaldehyde (29, 1.43 N in CH
2
Cl
2
, 0.55 mL, 0.78

2
182 J . Org. Chem., Vol. 63, No. 7, 1998
Kuehne et al.
m), 2.08 (1 H, m), 1.82 (1 H, d, J ) 6.2 Hz), 1.73 (1 H, dd, J )
4.7 and 12.1 Hz).
(3a R,11bR)-Meth yl 3-((Z)-2-Iod obu t-2-en -1-yl)-2,3,3a ,4,
COCF3
3.56
N
2
.27
7.44
4.02 OAc
.46
2
.06
5
,7-h exa h yd r o-4-oxo-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r -
6.97
5
boxyla te (38). To a solution of DMSO (0.31 mL, 4.4 mmol)
in dichloromethane (30 mL) at -70 °C was added dropwise
trifluoroacetic anhydride (0.60 mL, 4.3 mmol). After the
solution was stirred for 20 min, alcohol 37 (0.663 g, 1.42 mmol)
in dichloromethane (15 mL) was added at -70 °C. Stirring
was continued at the same temperature for 1 h before addition
of triethylamine (2.01 mL, 14.23 mmol). After being stirred
for 2 h, the reaction mixture was gradually warmed to room
temperature. The mixture was diluted with 100 mL of
dichloromethane, washed with saturated aqueous sodium
7
.25
3.12
2.64
N
H
6.90
CO2Me
9
.11
NOESY of trifluoroacetamide 35
temperature and stirred for an additional 4 h. Workup and
purification, as above, gave the trifluoroacetamide 35 (0.011
g, 92%).
3aR,4R,11bR)-Meth yl 3-((Z-2-Iodobu t-2-en -1-yl)-2,3,3a,4,
,7-h exa h yd r o-4-a cet oxy-1H -p yr r olo[2,3-d ]ca r b a zole-6-
ca r boxyla te (36). A mixture of trifluroacetamide 35 (1.33 g,
.14 mmol), (Z)-1-bromo-2-iodobut-2-ene (1.59 g, 6.09 mmol)
and potassium carbonate (2.73 g, 19.8 mmol) in THF (10 mL)
was heated at reflux overnight under nitrogen. After filter-
ation of the inorganic materials, the filtrate was concentrated
and chromatographed on silica gel (1:2 ethyl ether:hexane) to
yield the title compound 36 (1.46 g, 92%): TLC R
gel, ethyl ether/hexane, 2:1, CAS blue to gray); mp 164-166
); UV (EtOH) λmax 208, 240,
00, 328 nm; IR (KBr) νmax 3376, 2947, 2801, 1728, 1681, 1612,
479, 1466, 1438, 1372, 1248, 1201, 1143, 1090, 1034, 752
(
5
bicarbonate, and dried (MgSO
residue by flash column (2:1 hexane:ethyl ether) gave ketone
38 (0.561 g, 85%): TLC R ) 0.43 (silica gel, ethyl ether/
hexane, 1:1, CAS greenish blue); mp 132-134 °C (ether/
hexane); [R] -538 (c 0.24, CHCl ); UV (EtOH) λmax 240, 298,
332 nm; IR (KBr) νmax 3365, 2983, 2952, 2858, 1717, 1682,
4
). Purification of the evaporated
3
f
D
3
-
1 1
1610, 1479, 1467, 1437, 1244, 1210, 1137, 749 cm ; H NMR
(CDCl ) δ 9.14 (1 H, s), 7.45 (1 H, d, J ) 7.4 Hz), 7.19 (1 H,
f
) 0.40 (silica
3
dd, J ) 7.4 and 7.6 Hz), 6.93 (1 H, dd, J ) 7.6 and 7.7 Hz),
6.82 (1 H, d, J ) 7.7 Hz), 5.95 (1 H, q, J ) 6.4 Hz), 3.77 (1 H,
d, J ) 14.0 Hz), 3.74 (3 H, s), 3.72 (1 H, dd, J ) 1.1 and 14.0
Hz), 3.52 (1 H, d, J ) 17.2 Hz), 3.22 (1 H, d, J ) 1.1 Hz), 3.05-
3.01 (2 H, m), 2.55 (1 H, dt, J ) 8.6 and 12.6 Hz), 2.04 (1 H,
ddd, J ) 2.9, 12.6 and 12.6 Hz), 1.80 (3 H, d, J ) 6.4 Hz).
(3a R,11bR)-Meth yl 3-((Z)-2-Iod obu t-2-en -1-yl)-2,3,3a ,4-
tetr a h yd r o-4-oxo-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxy-
la te (39). To a solution of the ketone 38 (0.419 g, 0.903 mmol)
and triethylamine (0.176 mL, 1.26 mmol) in dichloromethame
(30 mL) at 0 °C was added dropwise tert-butyl hypochlorite
(0.129 mL, 1.08 mmol). The reaction mixture was stirred at
0 °C for 10 min and then brought to room temperature, diluted
with 50 mL of dichloromethane, and washed with brine. After
°
3
1
C (EtOH); [R]
D
-252 (c 0.5, CHCl
3
-
1 1
cm ; H NMR (CDCl ) δ 9.01 (1 H, s), 7.18 (1 H, dd, J ) 7.7
3
and 8.0 Hz), 7.15 (1 H, d, J ) 7.4 Hz), 6.90 (1 H, dd, J ) 7.4
and 8.0 Hz), 6.85 (1 H, d, J ) 7.7 Hz), 5.96 (1 H, q, J ) 6.2
Hz), 5.05 (1 H, s), 4.03 (1 H, d, J ) 13.8 Hz), 3.78 (3 H, s), 3.53
(
1 H, d, J ) 13.8 Hz), 3.14 (1 H, s), 3.00 (2 H, m), 2.68 (2 H,
m), 2.09 (1 H, m), 1.84 (3 H, s), 1.81 (3 H, d, J ) 6.2 Hz), 1.75
(
1 H, dd, J ) 4.7 and 8.5 Hz).
P r ep a r a tion of Alk yla tion P r od u ct 36 fr om th e Am in e
3. The free amine (0.040 g, 0.12 mmol) was subjected to the
above alkylation conditions in reagent-pure THF to produce
the alkylation product (0.058 g, 94%). This product had
identical spectroscopica data to the product prepared by
alkylation of the trifluoroacetamide, but a relatively low optical
3
4
drying (MgSO ) and evaporation under vacuum, the residue
was subjected to silica gel chromatography, eluting with 1:1
ether: hexane, to yield imino ketone 39 (0.417 g, 100%): TLC
rotation: [R]
D
-230 (c 0.5, CHCl
3
).
R
f
) 0.38 (silica gel, ethyl ether/hexane, 3:1, CAS blue faded
to greenish yellow); [R] +112 (c 0.4, CHCl ); IR (KBr) νmax
2950, 1733, 1684, 1609, 1406, 1437, 1244, 751 cm ; H NMR
(CDCl ) δ 7.97 (1 H, d, J ) 7.4 Hz), 7.82 (1 H, d, J ) 7.7 Hz),
Alk yla tion Rea ction of Tr ifu or oa ceta m id e 35. A mix-
ture of trifuoroacetamide 35 (44 mg, 0.104 mmol), (Z)-1-bromo-
D
3
-
1 1
2
-iodobut-2-ene (0.041 g, 0.156 mmol) and dry potassium
3
carbonate (0.070 g, 0.507 mmol) in dry THF (5 mL) was heated
at reflux for 4 h under nitrogen. There was no reaction, as
monitored by TLC. Water (∼2 µL, 0.104 mmol) was added.
The reaction mixture was heated for another 2 h. The desired
alkylation product was seen to appear in the TLC; neither free
amine 33 nor alcohol from hydrolysis of acetate was detected.
More water (8 µL, 4 equiv) was added, and refluxing was
continued for 24 h. Workup and purification as above yielded
the alkylated amine 36 (0.049 g, 93%). To test the stability of
the acetate group, compound 36 (0.010 g) and potassium
7.42 (1 H, m), 7.33 (1 H, m), 6.84 (1 H, s), 6.01 (1 H, q, J ) 6.4
Hz), 4.24 (1 H, d, J ) 13.9 Hz), 3.99 (3 H, s), 3.97 (1 H, d, J )
13.9 Hz), 3.49 (1 H, s), 3.35 (1 H, m), 2.91 (1 H, m), 2.43 (1 H,
m), 2.02 (1 H, m), 1.79 (3 H, d, J ) 6.4 Hz).
Ep im er iza tion Stu d ies on Im in o Keton e 39. Imino
ketone 39 (0.012 g, [R]
benzene (7 mL) for 12 h. After removal of the solvent, the
). Prolonged
D
+112) was heated at reflux in dry
imino ketone showed [R]
D
+71 (c 0.4, CHCl
3
heating (64 h) induced decomposition of the imino ketone, and
a 30% yield of imino ketone was recovered after flash chro-
carbonate (0.015 g) were heated at reflux in a H
mL, 1:10) mixture for 30 min. No corresponding alcohol was
detected in TLC. On heateng at reflux in 1:1 H O-THF for 1
h, the acetate cleavage product 37 was detected by TLC.
3aR,4R,11bR)-Meth yl 3-((Z)-2-Iodobu t-2-en -1-yl)-2,3,3a,
2
O-THF (5
matography. It showed [R]
D
3
+12 (c 0.1, CHCl ).
(-)-(18,19(E a n d Z))-14-Oxoa k u a m m icin e (40a , 40b). A
mixture of imino ketone 39 (0.034 mg, 0.074 mmol), tributyl
tinhydride (0.022 mL, 0.081 mmol), and AIBN (0.008 g) in dry
benzene (7 mL) was degassed with argon and then irradiated
with a Pen-Ray Ps-1 UV lamp at room temperature for 1 h.
The solvent was removed under reduced pressure. The
resulting residue was purified by flash column chromatogra-
phy on silica gel, eluting with 75:25:0.5 ethyl acetate:hexane:
triethylamine, to afford a Z/E mixture in a ratio of 1:1.7 as
2
(
4
6
,5,7-h exa h yd r o-4-h yd r oxy-1H-p yr r olo[2,3-d ]ca r ba zole-
-ca r boxyla te (37). A mixture of acetate 36 (0.785 g, 1.55
mmol), potassium carbonate (0.226 g, 1.64 mmol) in methanol
25 mL), and water (1.6 mL) was heated at reflux for 30 min.
(
The reaction mixture was cooled and concentrated. To the
1
residue was added 50 mL of water. After extracting with 3 ×
determined by H NMR (11 mg, 44%). After crystallization of
5
0 mL of dichloromethane, drying (MgSO
4
), and concentration,
the mixture from methanol, a 9:1 mixture was obtained with
the residue was purified on a flash column (SiO
2
), eluting with
the desired E-isomer enriched. One more crystallization from
4
:1 diethyl ether:hexane, to afford alcohol 37 (0.691 g, 96%):
methanol yielded pure E-40a : TLC R
f
) 0.41 (silica gel, ethyl
TLC R
f
) 0.30 (silica gel, ethyl ether/hexane, 5:1, CAS blue);
-314 (c 0.1, CHCl ); UV (EtOH)
max 214, 300, 328 nm; IR (KBr) νmax 3388, 2918, 2854, 1674,
609, 1466, 1438, 1284, 1249, 1199, 1120, 747 cm-1; 1H NMR
) δ 9.04 (1 H, s), 7.18 (2 H, m), 6.90 (1 H, t, J ) 7.0 Hz),
.85 (1 H, d, J ) 7.8 Hz), 5.94 (1 H, q, J ) 6.1 Hz), 4.11 (1 H,
acetate/hexane/triethylamine, 9:1:0.5, CAS blue); mp 214-216
1
mp 172-174 °C (EtOH); [R]
D
3
°C; [R]
D
3 3
-774 (c 0.1, CHCl ); H NMR (CDCl ) δ 9.09 (1 H, s),
λ
7.17-7.14 (2 H, m), 6.90 (1 H, dd, J ) 7.6 and 7.6 Hz), 6.79 (1
H, d, J ) 8.1 Hz), 5.57 (1 H, qt, J ) 1.8 and 7.0 Hz), 4.22 (1 H,
s), 3.85 (1 H, d, J ) 2.4 Hz), 3.80 (3 H, s), 3.74 (1 H, dd, J )
1.7 and 15.3 Hz),3.41 (1 H, m), 3.28 (1 H, m), 3.20 (1 H, d, J
) 15.3 Hz), 3.06 (1 H, m), 2.04 (1 H, m), 1.63 (3 H, dt, J ) 1.6
and 7.0 Hz).
1
(CDCl
3
6
br s), 3.82 (1 H, d, J ) 13.8 Hz), 3.78 (3 H, s), 3.54 (1 H, d, J
)
13.8 Hz), 3.11 (1 H, s), 3.04-2.95 (2 H, m), 2.73-2.63 (2 H,

Syntheses of Indolenine Alkaloids
J . Org. Chem., Vol. 63, No. 7, 1998 2183
(
-)-Mossa m bin e (41). To a stirred mixture of ketone (-)-
167.88, 144.49, 135.47, 132.03, 127.88, 124.05, 121.26, 120.00,
109.76, 97.91, 70.41, 65.23, 58.56, 54.63, 53.95, 51.17, 44.62,
4
0a (0.007 g, 0.022 mmol) and CeCl ‚7H O (0.011 g, 0.030
3
2
+
mmol) in methanol (1.5 mL) and THF (1.5 mL), cooled in an
ice bath, was added sodium borohydride (0.020 g, 0.53 mmol)
by portions. The reaction mixture was allowed to warm to
room temperature, and saturated aqueous sodium biscarbon-
ate (15 mL) was added. Extraction with 4 × 10 mL of
36.26, 12.65; mass spectrum (EI) m/z (rel intensity) 339 (M
+ 1, 8), 338 (M , 19), 321 (M - OH, 1), 279 (M+ - CO
+
+
Me,
2
5), 252 (9), 206 (10), 149 (54), 121 (100).
Ack n ow led gm en t. This work was supported by the
Cancer Institute of the National Institutes of Health
with Grant RO1 CA 12010. We are indebted to Robert
Bennett and Patrick J okiel of our group for low-
resolution mass spectra.
4
chloroform, followed by drying (MgSO ) and evaporation, gave
the crude product, which was purified by column chromatog-
raphy (eluted with 70:30:0.5 ethyl acetate:methanol:triethyl-
amine) to afford the R/â-hydroxy mixture in a ratio of 1:5 as
1
determined by H NMR. Crystallization of the mixture from
methanol gave (-)-mossambine (41) as white crystals (4.5 mg,
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
6
0%): TLC R
f
) 0.24 (silica gel, ethyl acetate/methanol, 1:1,
NMR spectra for compounds 6a , 6b, 10b, 11a , 11b, 14a , 14b,
CAS blue); mp 219-211 °C; [R]
D
-494 (c 0.05, CHCl
482; UV (EtOH) λmax 206, 298, 330 nm; IR (KBr) νmax 3366,
925, 2861, 1670, 1603, 1464, 1463, 1235, 1200, 1104, 748
3
), reported
1
1
5, 16a , 21a -f, 30a , and 31a and H NMR spectra for
1
3
-
compounds 1, 2, 10a , 12, 22, 25, 27, 28, and 33/34 (45 pages).
2
Spectra of other intermediates in the mossambine synthesis
-
1
1
cm ; H NMR (CDCl ) δ 8.83 (1 H, s), 7.19 (1 H, d, J ) 7.3
3
match those of corresponding racemic compounds. They are
Hz), 7.15 (1 H, dd, J ) 7.7 and 7.7 Hz), 6.91 (1 H, dd, J ) 7.4
and 7.5 Hz), 6.81 (1 H, d, J ) 7.7 Hz), 5.75 (1 H, q, J ) 6.6
Hz), 3.95 (1 H, d, J ) 3.2 Hz), 3.86 (1 H, br s), 3.77 (3 H, s),
13
available from the previous publication.
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.
3
.73 (1 H, t, J ) 3.1 Hz), 3.51 (1 H, d, J ) 13.1 Hz), 3.16 (1 H,
d, J ) 12.8 Hz), 3.00 (1 H, dd, J ) 7.1 and 14.7 Hz), 2.94-
.89 (2 H, m), 2.45 (1 H, br s), 1.87 (1 H, dd, J ) 6.9 and 12.6
2
1
3
Hz), 1.79 (3 H, d, J ) 6.8 Hz); C NMR (CDCl
3
) δ 169.54,
J O971838G