Conjugate additions to phenylglycinol-derived unsaturated δ-lactams. Enantioselective synthesis of uleine alkaloids

Article abstract of DOI:10.1021/jo0487101

The stereochemical outcome of the conjugate addition of a variety of stabilized nucleophiles (2-indoleacetic enolates and sulfur-stabilized anions) to the phenylglycinol-derived unsaturated lactams trans-2, cis-2, and its 8-ethyl-substituted analogue 10 i

Full text of DOI:10.1021/jo0487101

Conjugate Additions to Phenylglycinol-Derived Unsaturated
δ-Lactams. Enantioselective Synthesis of Uleine Alkaloids
Mercedes Amat,*,† Maria Pe´rez,† Nu´ria Llor,† Carmen Escolano,† F. Javier Luque,‡
Elies Molins,§ and Joan Bosch*,†
Laboratory of Organic Chemistry and Department of Physical Chemistry, Faculty of Pharmacy,
University of Barcelona, 08028 Barcelona, Spain, and Institut de Cie`ncia de Materials (CSIC),
Campus UAB, 08193 Cerdanyola, Spain
amat@ub.edu; joanbosch@ub.edu
Received July 27, 2004
The stereochemical outcome of the conjugate addition of a variety of stabilized nucleophiles (2-
indoleacetic enolates and sulfur-stabilized anions) to the phenylglycinol-derived unsaturated lactams
trans-2, cis-2, and its 8-ethyl-substituted analogue 10 is studied. The factors governing the exo or
endo facial stereoselectivity are discussed. This methodology provides short synthetic routes to
either cis- or trans-3,4-disubstituted enantiopure piperidines as well as efficient routes for the
enantioselective construction of the tetracyclic ring system of uleine alkaloids, both in the normal
and 20-epi series. The formal total synthesis of several alkaloids of this group is reported.
The alkaloids of the uleine group constitute a com-
paratively small group of indole alkaloids lacking the two-
carbon link between the indole 3-position and the basic
nitrogen atom, present in the greater part of monoter-
penoid indole alkaloids.1 These alkaloids are character-
ized by the presence of a tetracyclic 1,5-methanoazocino-
[4,3-b]indole system bearing an ethyl substituent at the
bridge carbon (Figure 1).
Biogenetically, the alkaloids of the uleine group are
formed from stemmadenine, by fragmentation of the
tryptamine bridge followed by isomerization of the re-
sulting exocyclic iminium species to a more stable
conjugated iminium cation and subsequent electrophilic
cyclization on the indole 3-position2 (Scheme 1). While
the absolute configuration of the bridgehead C-15 posi-
tion3 results from their biogenetic origin from secologa-
nin, there are alkaloids with each of the two possible
configurations at C-20: H15 and H20 are cis, and conse-
quently the ethyl substituent is equatorial with respect
to the piperidine ring, in most of the alkaloids of this
group, but trans in the 20-epi series.
FIGURE 1. Uleine alkaloids.
SCHEME 1. Biosynthesis of Uleine Alkaloids
Although the uleine alkaloids have received consider-
able synthetic attention,1 their enantioselective synthesis
has been little explored, and only one enantioselective
† Laboratory of Organic Chemistry.
‡ Laboratory of Physical Chemistry.
§ Institut de Cie`ncia de Materials.
(1) (a) Joule, J. A. Indoles. The Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1983; Vol. 25,
Part 4, Chapter 6. (b) Alvarez, M.; Joule, J. A. Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocyclic Com-
pounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Suppl. to Vol. 25,
Part 4, Chapter 6. (c) Alvarez, M.; Joule, J. A. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 2001; Vol. 57, Chapter 4.
(2) Atta-ur-Rahman; Basha, A. Biosynthesis of Indole Alkaloids;
Clarendon Press: Oxford, 1983.
total synthesis of alkaloids of this group has been
reported so far.4 A crucial problem associated with the
synthesis of these alkaloids is the control of the absolute
(and relative) configuration at C15 and C20.
(4) (a) Saito, M.; Kawamura, M.; Hiroya, K.; Ogasawara, K. Chem.
Commun. 1997, 765. (b) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc.
2002, 124, 9660. (c) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004,
126, 3534.
(3) The biogenetic numbering is used throughout this paper for all
tetracyclic compounds. Le Men, J.; Taylor, W. I. Experientia 1965, 21,
508.
10.1021/jo0487101 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
J. Org. Chem. 2004, 69, 8681-8693
8681

Amat et al.
SCHEME 2. Synthetic Strategy
FIGURE 2. Stereoelectronic control.
tronic control,8 axial to the electrophilic carbon of the
conjugate double bond (Figure 2). These conjugate addi-
tions constitute the key step of an enantiodivergent
synthesis of both enantiomers of the antidepressant drug
paroxetine (a trans-3,4-disubstituted piperidine).
Results and Discussion
Taking into account that R,â-unsaturated lactams are
poor Michael acceptors9 and that there are few examples
of such conjugate additions to δ-lactams lacking an
additional electron-withdrawing group on the nitrogen
and/or in conjugation with the double bond,10 to check
the viability of the proposed conjugate addition-cycliza-
tion sequence, in our initial studies we examined the
stereochemical outcome of the conjugate addition of
2-indoleacetate enolates to the model lactams cis-2 and
trans-2, which lack the ethyl substituent present in the
natural products.
Reaction of lactam trans-2 with the enolate of methyl
1-methyl-2-indoleacetate (3a) gave (64%) lactam ester 4a
as a mixture of epimers (3:2 ratio) at the isomerizable
stereocenter R to the ester group, which could be sepa-
rated by column chromatography (Scheme 3). The cy-
clization step was carried out in the presence of TiCl4,
using each epimer separately. The major isomer led to
tetracycle (16S)-5a (44%), whereas the minor one led to
the C-16 epimer (16R)-5a (50%),11 thus indicating that
the conjugate addition had taken place on the exo face of
lactam trans-2 with excellent facial selectivity.
In the context of our studies on the enantioselective
synthesis of piperidine-containing derivatives from phe-
nylglycinol-derived bicyclic lactams,5 we devised a gen-
eral synthetic route to the uleine alkaloids, in which the
key step would be the stereocontrolled conjugate addition
of an indolylmethyl anion equivalent to an appropriate
γ-ethyl R,â-unsaturated δ-lactam (bond formed C15-C16).
A subsequent biomimetic cyclization on the indole 3-posi-
tion of the masked acyl iminium ion present in the
resulting enantiopure cis or trans 4,5-disubstituted 2-pi-
peridone (bond formed C7-C21) would lead to the
natural products, either in the normal or epi series,
respectively (Scheme 2).6 As a consequence of the bridge-
head character of the stereocenters at C-15 and C-21, the
absolute configuration of the stereogenic center generated
at the piperidine 4-carbon (C-15) after the conjugate
addition reaction would determine that of C-21 in the
cyclization leading to the tetracyclic system of uleine
alkaloids.
In recent work,5a,7 we have demonstrated that the
diastereomeric unsaturated lactams cis-1 and trans-1
undergo conjugate addition of organocuprates with op-
posite facial selectivity, a result that was rationalized by
considering that the configuration of the C-8a stereo-
center determines the conformation of the six-membered
ring and that the attack of the nucleophile to these
conformationally rigid lactams occurs under stereoelec-
The relative configuration of C-16 in these tetracycles
was deduced from the H15-H16 J value and from the
(8) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983; p 221. (b) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1992; p 25.
(9) (a) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetra-
hedron Lett. 1985, 26, 657. (b) Hagen, T. J. Synlett 1990, 63.
(10) For the addition of organocuprates, see: (a) Overman, L. E.;
Robichaud, A. J. J. Am. Chem. Soc. 1989, 111, 300. (b) Herdeis, C.;
Kaschinski, C.; Karla, R. Tetrahedron: Asymmetry 1996, 7, 867. (c)
Muller, M.; Schoenfelder, A.; Didier, B.; Mann, A.; Wermuth, C.-G.
Chem. Commun. 1999, 683. (d) Deiters, A.; Martin, S. F. Org. Lett.
2002, 4, 3243. (e) Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002,
124, 14826. (f) Hanessian, S.; van Otterlo, W. A. L.; Nilsson, I.; Bauer,
U. Tetrahedron Lett. 2002, 43, 1995. (g) Cossy, J.; Mirguet, O.; Gomez
Pardo, D.; Desmurs, J.-R. New J. Chem. 2003, 27, 475. For the addition
of stabilized anions, see: (h) Stork, G.; Schultz, A. G. J. Am. Chem.
Soc. 1971, 93, 4074. (i) Herrmann, J. L.; Richman, J. E.; Schlessinger,
R. H. Tetrahedron Lett. 1973, 2599. (j) Kametani, T.; Surgenor, S. A.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1981, 920. (k) Takano,
S.; Sato, M.; Ogasawara, K. Heterocycles 1981, 16, 799. (l) Naito, T.;
Miyata, O.; Ninomiya, I. Heterocycles 1987, 26, 1739. (m) Fujii, T.;
Ohba, M.; Sakaguchi, J. Chem. Pharm. Bull. 1987, 35, 3628. (n) Forns,
P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-Bardia, M. Tetrahedron
1996, 52, 3563. (o) Etxarri, B.; Gonza´lez-Temprano, I.; Manteca, I.;
Sotomayor, N.; Lete, E. Synlett 1999, 1486. (p) Hanessian, S.; Go-
mtsyan, A.; Malek, N. J. Org. Chem. 2000, 65, 5623. (q) Hanessian,
S.; Seid, M.; Nilsson, I. Tetrahedron Lett. 2002, 43, 1991.
(5) (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor,
N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem.
2000, 65, 3074. (b) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez,
M.; Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335. (c) Amat, M.; Llor,
N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919.
(d) Amat, M.; Escolano, C.; Lozano, O.; Llor, N.; Bosch, J. Org. Lett.
2003, 5, 3139 and references therein. For reviews, see: (e) Meyers, A.
I.; Brengel, G. P. Chem. Commun. 1997, 1. (f) Groaning, M. D.; Meyers,
A. I. Tetrahedron 2000, 56, 9843.
(6) For a preliminary communication of this part of the work, see:
Amat, M.; Pe´rez, M.; Llor, N.; Martinelli, M.; Molins, E.; Bosch, J.
Chem. Commun. 2004, 1602.
(7) Amat, M.; Pe´rez, M.; Llor, N.; Lago, E.; Molins, E. Org. Lett.
2001, 3, 611.
(11) In both cases, minor amounts of the respective C-16 epimer
were also formed as a consequence of the epimerization occurring at
the ester R carbon during the cyclization step.
8682 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
SCHEME 3. Tetracyclic Ring System of Uleine
Alkaloids
SCHEME 4
conjugate addition of 3a to cis-2 had also occurred on the
exo face, which involves a facial stereoselectivity opposite
to that observed when starting from trans-2. These
results are in agreement with the stereochemical outcome
of the conjugate addition of cyanocuprates to related
lactams cis-1 and trans-15a,7 and can be accounted for by
considering that the process is kinetically controlled.14
Once it was demonstrated that the above approach can
provide straightforward access to the tetracyclic ring
system of uleine alkaloids with the natural configuration
at the bridgehead carbons (e.g., 7), we extended our
studies using the unsaturated lactam 10, which has the
same cis-3,8a configuration as cis-2 and incorporates the
ethyl substituent with the required absolute configura-
tion for the synthesis of alkaloids in the normal C-20
series. This lactam was prepared in 55% overall yield by
cyclocondensation of (R)-phenylglycinol with racemic
methyl 4-formylhexanoate (8), in a process involving a
dynamic kinetic resolution,15 followed by generation of
the carbon-carbon double bond from the resulting lactam
9 via a â-keto sulfoxide (Scheme 4). The addition of the
enolate ester 3a to lactam 10 took place in excellent yield
(83%) and complete facial selectivity to give the epimeric
lactam esters (RS)-11a and (RR)-11a (3:7 ratio). Cycliza-
tion of the major isomer also took place in excellent yield
(81%) to give tetracycle 12a. The absolute configuration
of (RR)-11a was unambiguously established by X-ray
crystallography and indicated that the ethyl substituent
had exerted a dramatic influence on the stereochemical
course of the conjugate addition since it had occurred on
the endo face of the carbon-carbon double bond to give
an all-trans piperidine derivative, instead of the required
cis-4,5-disubstituted 2-piperidone.16
existence or absence of γ-gauche effects on C-14 and C-20
on the NMR spectra,12 whereas the absolute configuration
(C-15 is S) was inferred by comparing the NMR data of
tetracycles 5a with those of 12a, whose absolute config-
uration was known from the X-ray analysis of its precur-
sor (RR)-11a (see below).
The use of the enolate of indoleacetate 3b, unsubsti-
tuted on the indole nitrogen, led to similar results.
Conjugate addition to trans-2 took place again with high
exo facial stereoselectivity to give an epimeric mixture
of lactam esters 4b (3:2 ratio; 51%), which were sepa-
rately cyclized to the respective tetracycles (16S)-5b and
(16R)-5b in ∼70% yield. In this series, epimerization at
C-16 during cyclization occurred to a considerable extent
(see the Experimental Section).
Next we investigated the stereochemical outcome of the
conjugate addition-cyclization sequence from lactam cis-
2. The conjugate addition of ester 3a led again to an
epimeric mixture of lactam esters 6 (3:2 ratio; 53% yield),
which were separately cyclized to the respective tetra-
cycles (16S)-7 (from the major lactam ester) and (16R)-7
without detectable epimerization at C-16. These cycliza-
tions, involving a 3,8a-cis lactam, took place in lower yield
and required harder conditions than the above cycliza-
tions from the 3,8a-trans isomers.13
Comparison of the NMR spectroscopic data of tetra-
cycle (16R)-7 with those of (16S)-5a, both of them with a
trans H15-H16 relationship, made evident that these
compounds were diastereomers and, consequently, that
the absolute configuration of C-15 in (16R)-7 is R. Sim-
ilarly, (16S)-7 and (16R)-5a, both having a cis H15-H16
relationship, are also diastereomers, and therefore, the
configuration at the piperidine 4-position in tetracycle
(16S)-7 is also R. This allowed us to conclude that the
The same stereoselectivity was observed from the
enolate of the N-unsubstituted indoleacetate 3b, although
in this case the conjugate addition only took place in
acceptable yield (40%) in the presence of CuCN to give a
7:3 epimeric mixture of lactam esters (RS)-11b and
(RR)-11b. Both epimers were separately cyclized to
give the same enantiopure tetracycle 12b, thus indicating
that epimerization at C-16 from the major isomer had
occurred during cyclization.
(14) Molecular mechanics (MM.; CVFF91 force field) calculations
provide support to this conclusion because they indicated that the exo
adducts 4a and 6 are less stable that the corresponding C-7 epimers.
(15) For a recent review, see: Pellissier, H. Tetrahedron 2003, 59,
8291.
(16) According to MM calculations, the endo adducts 11a, 24b, 28b,
and 33b were more stable than the respective exo epimers.
(12) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch,
J. J. Org. Chem. 1990, 55, 1156.
(13) For the different reactivity of 3,8a-cis and trans related lactams
in R-amidoalkylation reactions, see: Amat, M.; Escolano, C.; Llor, N.;
Huguet, M.; Pe´rez, M.; Bosch, J. Tetrahedron: Asymmetry 2003, 14,
1679.
J. Org. Chem, Vol. 69, No. 25, 2004 8683

Amat et al.
in the addition of sulfur-stabilized anions to enones,19
there are few reports concerning the stereoselectivity of
such conjugate addition reactions.19e For this reason, we
became interested in studying the stereochemical out-
come of the conjugate addition of a variety of dithioacetals
to phenylglycinol-derived unsaturated lactams as a tool
for the enantioselective generation of cis or trans 3,4-
disubstituted piperidine derivatives. To explore the influ-
ence on the stereoselectivity of an alkyl substituent next
to the electrophilic carbon of the double bond, in our study
we used lactams cis-2 and 10 as substrates, both with a
cis 3,8a relative configuration. Moreover, to gain further
insight into the factors governing the stereoselectivity of
the reaction we also used lactam trans-2, the C-8a
diastereomer of cis-2. The results are summarized in
Table 1.20
SCHEME 5. Enantioselective Total Synthesis of
20-Epiuleine Derivatives
The addition of 2-lithio-1,3-dithiane (15-Li) to the
diastereomeric unsubstituted lactams trans-2 and cis-2
and the ethyl-substituted lactam 10 at low temperature
(-78 °C), followed by stirring at 0 °C for 20 h in THF in
the presence of HMPA, took place with excellent facial
selectivity to give the corresponding exo adducts 21a, 25a,
and 29a, respectively (entries 1, 6, and 13). Similar
results were observed in the addition of 15-Li to trans-2
in the absence of HMPA (entry 2). However, on raising
the temperature to 25 °C lactam 10 afforded a nearly
equimolecular mixture of isomers 29a and 29b (entry 14).
On the other hand, conjugate addition of the lithium salt
of bis(phenylthio)methane (19-Li) to lactam 10 at 0 °C
took place with low exo stereoselectivity (entry 15),
whereas at 25 °C the endo isomer 30b was the major
component of the reaction mixture (entry 16). The above
results suggest that the addition of lithium salts 15-Li
and 19-Li to 10 is reversible and that, under the same
reaction conditions, 19-Li affords a higher ratio of the
thermodynamic endo isomer b (trans relative configura-
tion of the substituents), presumably as a consequence
of the higher steric hindrance in the corresponding
adduct and the greater anion stability of 19-Li as
compared with 15-Li.21
The reaction of 2-lithio-2-phenyl-1,3-dithiane (16-Li)
with trans-2 at 0 °C for 20 h again led to the correspond-
ing exo isomer 16a (entry 3), although with lower
stereoselectivity than when using 15-Li, whereas starting
from cis-2 an approximately 25:75 mixture of isomers,
in which the endo derivative 26b predominated, was
obtained (entry 7). There was a similar result when the
reaction of 16-Li with cis-2 was carried out at room
temperature (entry 8). However, a reversal in the ster-
eochemical outcome of the reaction was observed when
the addition of 16-Li to cis-2 was performed under kinetic
Unfortunately, the absolute configuration at the pip-
eridine 4-position in 11 and, consequently, at the bridge-
head carbons in tetracycles 12 is the opposite of that
present in uleine alkaloids. However, taking advantage
of the fact that both enantiomers of phenylglycinol are
commercially available, the trans stereoselectivity of the
above conjugate additions can provide access to tetracy-
clic derivatives with the natural configuration in the
20-epi series. It is simply a matter of starting from the
enantiomer of unsaturated lactam 10, which was pre-
pared from (S)-phenylglycinol as in the above R-series
(Scheme 5).
As expected, conjugate addition of the enolate derived
from 3b to ent-10, followed by cyclization of the resulting
epimeric mixture of lactam esters ent-11b, led to tetra-
cycle ent-12b, which was chemoselectively reduced with
Na/liq NH3 to alcohols 13 (64%; epimeric mixture) and
then converted (53%) to the nor-20-epiuleine derivative
14 via the corresponding mesylate.
The enantioselective access to the more widespread
uleine alkaloids with a cis H15-H20 relationship (normal
series) required the preparation of a cis-4,5-disubstituted
2-piperidone by stereocontrolled conjugate addition of an
appropriate nucleophile to unsaturated lactam 10, avoid-
ing the undesired equilibration to the more stable trans
isomers. Taking into account that metalated dithioacetals
have been reported to undergo conjugated addition
reactions to unsaturated amides and lactams in fair
yields,17,18 we decided to investigate the introduction of
the required indolylmethyl substituent on the 4 position
of the piperidine ring of lactam 10 by conjugate addition
of a 2-(2-indolyl)-1,3-dithiane derivative. It should be
mentioned that, although much effort has been devoted
to identifying the factors governing the regioselectivity
(19) (a) Ostrowski, P. C.; Kane, V. V. Tetrahedron Lett. 1977, 3549.
(b) Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51, 3983. (c) Cohen,
T.; Abraham, W. D.; Myers, M. J. Am. Chem. Soc. 1987, 109, 7923. (d)
Page, P. C. B.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45,
7643. (e) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001, 123,
6527. (f) Juaristi, E.; Herna´ndez-Rodr´ıguez, M.; Lo´pez-Ruiz, H.; Avin˜a,
J.; Mun˜oz-Mun˜iz, O.; Hayakawa, M.; Seebach, D. Helv. Chim. Acta
2002, 85, 1999.
(20) For a preliminary account covering part of these results, see:
Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J. Org. Lett. 2002, 4, 2787.
(21) For pKa values of dithioacetals 15, 16, and 19, see: (a) Fraser,
R. R.; Bresse, M.; Mansour, T. S. J. Chem. Soc., Chem. Commun. 1983,
620. (b) Xie, L.; Bors, D. A.; Streitwieser, A. J. Org. Chem. 1992, 57,
4986. (c) Xie, L.; Streitwieser, A. J. Org. Chem. 1995, 60, 1339. (d)
Alnajjar, M. S.; Zhang, X.-M.; Franz, J. A.; Bordwell, F. G. J. Org.
Chem. 1995, 60, 4976.
(17) (a) Mpango, G. B.; Mahalanabis, K. K.; Mahdavi-Damghani,
Z.; Snieckus, V. Tetrahedron Lett. 1980, 21, 4823. (b) Mpango, G. B.;
Snieckus, V. Tetrahedron Lett. 1980, 21, 4827. See also ref 10i,n,o.
(18) For
a recent review on 1,3-dithianes in natural product
synthesis, see: Yus, M.; Na´jera, C.; Foubelo, F. Tetrahedron 2003, 59,
6147.
8684 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
TABLE 1. Conjugate Addition of Sulfur-Stabilized Nucleophilesa
entry
substrate
dithioacetal
product
R1
R2
R3
T (°C) (time (h))
a/b ratiob
yield (%)
1
2
trans-2
trans-2
trans-2
trans-2
trans-2
cis-2
cis-2
cis-2
cis-2
cis-2
cis-2
cis-2
10
15
15
16
17
18
15
16
16
16
16
17
18
15
15
19
19
16
16
16
17
18
20
20
20
20
21
21
22
23
24
25
26
26
26
26
27
28
29
29
30
30
31
31
31
32
33
34
34
34
34
H
H
C6H5
CO2Et
CO2Et
H
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-
-(CH2)3-
-(CH2)3-
C6H5
H
0 (20)
0 (15)c
0 (20)
a
78
71
85
70
72
68
80
81
74
75
66
70
61
54
61
66
79
90
75
60
52
70
40
82
90
H
a
3
H
88:12
>95:5
>95:5
a
4
H
0 (20)
5
H
0 (5)c
6
H
0 (20)
7
C6H5
C6H5
C6H5
C6H5
CO2Et
CO2Et
H
H
0 (20)
25:75
22:78
>95:5
>95:5
86:14
86:14
>95:5
43:57
60:40
16:84
b
8
H
25 (20)
-78 (2)c
-78 (2)
0 (20)
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H
H
H
0 (20)
0 (20)
25 (20)
0 (20)
25 (20)
0 (20)
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
10
H
10
H
10
H
C6H5
10
C6H5
C6H5
C6H5
CO2Et
CO2Et
2-indolyl
2-indolyl
2-indolyl
2-indolyl
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
10
-78 (20)
-78 (20)c
0 (20)
b
b
10
10
<5:95
<5:95
34:66
70:30
57:43
80:20
10
0 (4)c
10
0 (20)
10
-78 (0.5)
-78 (3)
-78 (2)c
10
10
a See the general procedure in the Experimental Section. b Determined by 1H NMR and/or after isolation by column chromatography.
c In the absence of HMPA.
conditions, that is at low temperature (-78 °C) for a short
reaction time (2 h) both in the absence and in the
presence of HMPA (entries 9 and 10). Under these
conditions, compound 26a, resulting from an exo attack
of the nucleophile, was stereoselectively formed. On the
other hand, the addition of 16-Li to lactam 10 stereo-
selectively afforded the thermodynamic endo isomer 31b
under a variety of conditions (entries 17-19). These
results can be rationalized once again by considering the
higher steric hindrance in the adducts resulting from
16-Li and the higher stability of this anion as compared
with 15-Li.21 In fact, when pure isomers 22a and 26a
were stirred in the presence of 4 equiv of 16-Li at 25 °C,
a slow isomerization to the corresponding endo epimers
22b and 26b was observed, thus corroborating the
reversibility of the reaction.
cis-2 at 0 °C for 20 h predominantly afforded the kinetic
exo isomers 23a, 24a (entries 4 and 5) and 27a, 28a
(entries 11 and 12), respectively.16 Again the exo stereo-
selectivity was higher from the unsaturated lactam
trans-2 than from cis-2. In sharp contrast, under the
same conditions, the conjugate addition of the highly
stabilized enolates 17-Li and 18-Li to lactam 10 occurred
with almost complete endo facial selectivity, affording the
endo isomers 32b and 33b (entries 20 and 21).16 The
above results evidenced that, as already observed when
using indoleacetic ester enolates, under the same reaction
conditions the endo/exo ratio using sulfur-stabilized nu-
cleophiles is much higher from the 8-ethyl-substituted
lactam 10 than from the deethyl analogue cis-2. In
contrast, the related lactams cis-1a and cis-1b, the latter
bearing an ethyl substituent at C-8 (see Figure 2),
undergo conjugate addition of cuprates with the same exo
selectivity.5a,7
We also examined the stereoselectivity in the conjugate
addition of sulfur-stabilized enolates 17-Li and 18-Li,
which whould allow the introduction of an acetate chain
at the 4 position of the piperidine ring after desulfuri-
zation. The addition of the masked glyoxylate anions
17-Li and 18-Li to the diastereomeric lactams trans-2 and
To better understand why the conjugate addition of
stabilized nucleophiles to the 8-ethyl-substituted lactam
10 and its deethyl analogue cis-2 takes place with
different facial selectivity we first examined the reactivity
J. Org. Chem, Vol. 69, No. 25, 2004 8685

Amat et al.
TABLE 2. Electrostatic (Eele), Polarization (Epol), van
der Waals (EvW), and Total Interaction (Etot) Energy
Determined from GMIPp Calculations for the Attack of a
Negatively Charged Classical Point Charge to the Two
Faces of the Lactam Ring at C7a
2-(2-indolyl)-1,3-dithiane (20) to lactam 10. When the
reaction was carried out in THF-HMPA at 0 °C for 20
h, a 34:66 mixture of exo and endo isomers, 34a and 34b,
respectively, was obtained in good chemical yield (70%)
(entry 22). Probably as a consequence of the dianionic
character of the nucleophile, the equilibration between
the desired kinetic exo addition product to the thermo-
dynamic endo adduct (a trans 4,5-disubstituted 2-piperi-
done) was slower in this case than in the above experi-
ments with 16-Li. As could be expected, the exo
stereoselectivity leading to the desired cis isomer 34a was
improved (exo/endo 7:3), although the chemical yield was
only moderate (40%), when the reaction was carried out
at lower temperature (-78 °C) for a short time (30 min)
in order to minimize the equilibration process (entry 23).
Longer reaction times (3 h) under the same conditions
resulted in a higher chemical yield but a lower stereo-
selectivity (entry 24). However, to our delight, in the
absence of HMPA the reaction took place at -78 °C in
an extraordinarily high yield (90%) and good stereose-
lectivity from the synthetic standpoint (exo/endo ratio 4:1;
entry 25). After column chromatography the required
enantiopure piperidone cis-34a was isolated in 72% yield.
The stereochemical identity of some adducts obtained
in the above conjugate addition reactions was established
by desulfurization with nickel boride and comparison of
the specific rotation and spectroscopic data of the result-
ing compounds with those of related lactams of known
configuration previously prepared in our laboratory.
Thus, desulfurization of 21a, 25a, and 29a/30a afforded
35, 37, and 39, respectively, which had previously been
prepared5a,7 by conjugate addition reactions of methyl
organocuprates to lactams trans-1 and cis-1a,b fol-
lowed by debenzyloxycarbonylation. On the other hand,
desulfurization of 29b and 30b gave 40, the C-7 epimer
of 39. Treatment of compounds 24a and 28a with nickel
boride afforded 36 and 38, respectively, which are
C-7 diastereomers of bicyclic lactams obtained by cyclo-
condensation of diethyl 3-(2-oxoethyl)glutarate and
(R)-phenylglycinol.5b Similarly, 33b was converted to
lactam 42, which had previously been obtained by cyclo-
condensation of a racemic aldehyde diester and (R)-phenyl-
glycinol.5b Finally, the configuration of 26a, 26b, and 31b
was unambiguously established by X-ray crystallography.
The synthetic usefulness of the above chiral substituted
lactams is illustrated by their conversion to enantiopure
trans-3,4-disubstituted piperidines (Scheme 6). Thus,
desulfurization of 31b followed by lactam reduction with
simultaneous reductive ring opening of the oxazolidine
present in 41 afforded piperidine 43, whose debenzylation
in the presence of (Boc)2O gave the trans-4-benzyl-3-
ethylpiperidine derivative 44. On the other hand, lactam
42 was converted to valuable intermediates for the
synthesis of indolo[2,3-a]- and benzo[a]quinolizidine al-
kaloids.23 Thus, treatment of 42 with borane brought
about both the chemoselective reduction of the lactam
carbonyl group and the reductive opening of the oxazo-
lidine ring affording 4-piperidineacetate 45, whereas
lactam
face
Eele
Epol
EvW
Etot
cis-2b
exo
-4.9
+1.0
-5.2
+1.7
-12.2
-11.6
-11.7
-11.3
+2.5
+2.3
+1.1
+0.8
-14.5
-8.3
-15.9
-8.9
endo
exo
10
endo
a Values are in kcal/mol. b Data taken from ref 5a.
TABLE 3. Energy Changes for the Formation of the
Enolate Adducta
lactam
face
∆E
cis-2
exo
-2.7
-6.7
+2.6
-4.6
endo
exo
10
endo
a Values are in kcal/mol.
pattern of these bicyclic lactams from GMIPp calcula-
tions22 (see the Computational Methods). To this end, we
determined the GMIPp interaction energy profile for the
approach of a negatively charged classical point particle
along the line perpendicular to the six-membered ring
passing through carbon 7. As noted in Table 2, the two
faces of the lactam ring have different susceptibility to
the attack of a nucleophilic reagent. Thus, the exo attack
is found to be energetically more favorable than the endo
attack by 6-7 kcal/mol. Moreover, the results in Table 2
also show that such a preference clearly stems from the
electrostatic term, and that replacement of the hydrogen
atom by an ethyl group has negligible influence on the
intrinsic reactivity of lactams cis-2 and 10.
Table 3 shows the reaction energies corresponding to
the formation of the enolate adducts obtained by nucleo-
philic attack of either a hypothetical methyl anion (a
small nucleophile) or the anion derived from dithiolane
18 (a bulky nucleophile) on the two faces of the unsatur-
ated C-7 carbon of cis-2 and 10. For the attack of the
methyl anion, the adducts are highly favored (by around
82 kcal/mol) compared to the separate reactants, and the
energy difference between the enolates formed upon
addition on the exo or endo faces is less than 1.5 kcal/
mol. However, the energetic stabilization of the enolate
adducts is drastically reduced in the case of the bulky
anion derived from dithiolane 18. In fact, the addition of
this anion on the exo face of the substituted lactam 10 is
even predicted to be energetically disfavored. More
importantly, the relative energy of the two enolates is
clearly different, the adduct formed upon attack on the
endo face being energetically preferred by 4 (cis-2) and 6
(10) kcal/mol.
Consequently, it can be concluded that even though
the intrinsic reactivity of lactams cis-2 and 10 favors a
nucleophilic attack on the exo face owing to a better
electrostatic interaction, the steric hindrance associated
with the enolate resulting from the approach of a bulky
anion to the exo face tends to reverse such a reactivity
preference.
(22) (a) Luque, F. J.; Orozco, M. J. Comput. Chem. 1998, 19, 866.
(b) Orozco, M.; Luque, F. J. In Molecular Electrostatic Potentials:
Concepts and Applications; Murray, J. S., Sen, K., Eds.; Elsevier:
Amsterdam, 1996; pp 181-218.
(23) For reviews, see: (a) Fujii, T.; Ohba, M. Heterocycles 1988, 27,
1009. (b) Fujii, T.; Ohba, M. Heterocycles 1998, 47, 525.
Finally, with our synthetic purpose in mind, we
undertook the conjugate addition of the dilithium salt of
8686 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
SCHEME 6. Synthesis of Enantiopure
trans-3,4-Disubstituted Piperidines
SCHEME 7. Enantioselective Formal Synthesis of
Uleine Alkaloids
reduction of 42 with alane caused the additional reduc-
tion of the ester group yielding 4-piperidineethanol 47.
Debenzylation of 45 and 47 by catalytic hydrogenation
gave trans-3-ethyl-4-piperidineacetate 46 and trans-3-
ethyl-4-piperidineethanol 48, respectively. Alternatively,
hydrogenolysis of the C-N bond of 42 with Ca in liquid
NH3, followed by treatment of the resulting oxylactams
with Et3SiH in THF afforded lactam 49.
to phenylglycinol-derived unsaturated δ-lactams allow
the stereocontrolled formation of C-C bonds at the
piperidine 4-position. Some factors governing the stereo-
selectivity of the process, namely the nature of the
nuclophile, the configuration of the stereocenter at the
angular position (C-8a), and the presence or absence of
a γ-substituent, have been identified. By choosing the
appropriate indole-containing nucleophile, the above
methodology opens short synthetic routes for the enan-
tioselective construction of the bridged tetracyclic system
of uleine alkaloids either in the normal or 20-epi series.
The availability of both enantiomers of phenylglycinol
allows the preparation, in each particular case, of 4-sub-
stituted derivatives in both enantiomeric series.
Finally, conversion of the cis-substituted lactam 34a
into the target tetracyclic alkaloids of the uleine group
required, as the key steps, the closure of the carbocyclic
ring and the removal of the chiral inductor. Treatment
of 34a with TiCl4 under several reaction conditions
afforded in poor yields (∼20%) tetracyclic keto lactam 51
resulting from both deprotection of the dithioacetal
function and intramolecular amidoalkylation (Scheme 7).
A similar TiCl4-promoted cyclization of 50, prepared by
desulfurization of 34a, gave tetracycle 52, again in low
yield (∼20%). For this reason we decided to first remove
the chiral inductor. This was accomplished by treatment
of 34a with sodium in liquid ammonia, which brought
about the reductive desulfurization and cleavage of the
benzylic C-N bond to give an intermediate 6-hydroxy-
lactam, which, without further purification, was cyclized
with TiCl4 to give the tetracyclic lactam 53 in 35% overall
yield. Minor amounts (6%) of the regioisomer 54, result-
ing from cyclization on the indole nitrogen, were also
formed.24 Finally, borane reduction of the lactam carbonyl
group of 53 followed by treatment of the resulting
secondary amine with benzyl chloroformate gave (40%
overall yield) carbamate 55, which had previously been
converted4a into the alkaloids (+)-dasycarpidone and
(+)-uleine. Taking into account previous correlations,25
the above synthesis also represents a formal synthesis
of nordasycarpidone, (-)-dasycarpidol, and (-)-17-hy-
droxydihydrouleine.
Experimental Section
(3R,8aS)-5-Oxo-3-phenyl-2,3,8,8a-tetrahydro-5H-oxazolo-
[3,2-a]pyridine (trans-2). Methyl phenylsulfinate (1.29 g,
8.29 mmol) and KH (1.0 g, 20 wt % dispersion in mineral oil,
25 mmol) were added to a solution of (3R,8aS)-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine5a (950 mg,
4.37 mmol) in THF (15 mL). The suspension was heated at
reflux for 1.5 h and concentrated. The resulting residue was
taken up in 0.5 M aqueous H3PO4 and extracted with CH2Cl2.
The combined organic extracts were dried and concentrated,
and the resulting residue was washed with hexane and
chromatographed (CHCl3) to give (3R,8aS)-5-oxo-3-phenyl-
6-(phenylsulfinyl)-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (1.48 g, 95%) as a mixture of isomers: 1H NMR
(300 MHz, selected resonances) δ 3.46 (masked s, 1 H), 3.48
(dd, J ) 10.6, 7.6 Hz, 1 H), 3.71 (t, J ) 8.5 Hz, 1 H), 3.84 (t,
J ) 8.5 Hz, 1 H), 4.54 (m, 2 H), 5.04 (m, 2 H), 5.27 (t, J ) 8.0
Hz, 1 H), 5.33 (t, J ) 8.0 Hz, 1 H); 13C NMR (75.4 MHz,
selected resonances) δ 12.4 (CH2), 27.1 (CH2), 58.9 (CH), 65.8
(CH), 72.9 (CH2), 88.3 (CH), 164.0 (C). Na2CO3 (2.69 g, 25.3
mmol) was added to a solution of the â-keto sulfoxide (1.53 g,
4.5 mmol) in toluene (54 mL), and the mixture was heated at
reflux for 7 h, filtered through Celite, and concentrated. The
resulting oil was chromatographed (7:3 EtOAc-hexane) to
In conclusion, conjugate addition reactions of indole-
acetic ester enolates and sulfur-stabilized nucleophiles
(24) For a related cyclization, see ref 10n.
(25) (a) Joule, J. A.; Ohashi, M.; Gilbert, B.; Djerasi, C. Tetrahedron
1965, 21, 1717. (b) Gra`cia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J.
J. Org. Chem. 1994, 59, 3939.
J. Org. Chem, Vol. 69, No. 25, 2004 8687

Amat et al.
1
afford trans-2 (820 mg, 89%): IR (KBr) 1660, 1611 cm-1; H
71.75; H, 6.26; N, 6.69. Found: C, 71.49; H, 6.63; N, 6.29. (RR)-
NMR (300 MHz) δ 2.48 (dddd, J ) 17.4, 10.2, 3.2, 2.3 Hz, 1
H), 2.80 (dddd, J ) 17.4, 6.0, 6.0, 0.7 Hz, 1 H), 3.86 (dd, J )
8.8, 7.0 Hz, 1 H), 4.49 (dd, J ) 8.8, 7.0 Hz, 1 H), 5.25 (t, J )
7.0 Hz, 1 H), 5.42 (dd, J ) 10.2, 6.0 Hz, 1 H), 5.99 (ddd, J )
9.9, 3.2, 0.7 Hz, 1 H), 6.48 (ddd, J ) 9.9, 6.0, 2.3 Hz, 1 H),
7.22-7.40 (m, 5 H); 13C NMR (75.4 MHz) δ 29.9 (CH2), 57.9
(CH), 73.0 (CH2), 86.7 (CH), 125.4 (CH), 125.9 (CH), 128.7
(CH), 127.5 (CH), 134.8 (CH), 139.2 (C), 160.7 (C); mp 121-
122 °C (Et2O-hexane); [R]22D +50.5 (c 1.0, EtOH). Anal. Calcd
for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.56;
H, 6.08; N, 6.57.
4a (higher Rf): IR (film) 1734, 1661 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 2.12 (ddd, J ) 14.0, 6.0, 4.5 Hz, 1 H), 2.23 (dd, J
) 17.3, 6.0 Hz, 1 H), 2.31 (m, 1 H), 2.48 (dd, J ) 17.3, 5.2 Hz,
1 H), 2.98 (m, 1 H), 3.69 (s, 3 H), 3.72 (s, 3 H), 3.80 (dd, J )
8.7, 7.5 Hz, 1 H), 3.87 (d, J ) 11.0 Hz, 1 H), 4.52 (tap, J ) 8.3
Hz, 1H), 5.14 (tap, J ) 5.5 Hz, 1 H), 5.37 (tap, J ) 8.0 Hz, 1 H),
6.52 (s, 1 H), 7.10 (ddd, J ) 7.8, 7.0, 1.2 Hz, 1 H), 7.20 (tm, J
) 7.0 Hz, 1 H), 7.25-7.40 (m, 6 H), 7.56 (dm, J ) 7.8 Hz, 1
H); 13C NMR (75.4 MHz) δ 29.8 (CH3), 31.0 (CH2), 32.7 (CH),
35.4 (CH2), 46.6 (CH), 52.7 (CH3), 58.1 (CH), 72.0 (CH2), 86.0
(CH), 101.0 (CH), 109.3 (CH), 119.9 (CH), 120.5 (CH), 121.9
(CH), 125.9 (CH), 128.9 (CH), 125.9 (C), 127.7 (CH), 134.6
(CH), 137.4 (C), 139.7 (C), 168.5 (C), 171.3 (C); mp 240-245
(3R,8aR)-5-Oxo-3-phenyl-2,3,8,8a-tetrahydro-5H-oxazo-
lo[3,2-a]pyridine (cis-2). Operating as described above, from
(3R,8aR)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo-
[3,2-a]pyridine5a (300 mg, 1.4 mmol), THF (10 mL), methyl
phenylsulfinate (437 mg, 2.8 mmol), and KH (840 mg, 20 wt
% dispersion in mineral oil, 21 mmol) was obtained (3R,8aR)-
5-oxo-3-phenyl-6-(phenylsulfinyl)-2,3,6,7,8,8a-hexahydro-
5H-oxazolo[3,2-a]pyridine (487 mg, 97%) as a mixture of
°C (Et2O); [R]22 -123.6 (c 0.5, CHCl3). Anal. Calcd for
D
C25H26N2O4‚1H2O: C, 68.79; H, 6.46; N, 6.41. Found: C, 68.70;
H, 6.18; N, 6.40.
(1S,5S,6S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6-(meth-
oxycarbonyl)-7-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(16S)-5a]. TiCl4 (90 µL, 0.82
mmol) was added to a cooled (0 °C) solution of (RS)-4a (230
mg, 0.55 mmol) in CH2Cl2 (2 mL), and the resulting mixture
was stirred for 2 h, poured into saturated aqueous NaHCO3,
and extracted with CH2Cl2. The combined organic extracts
were dried and concentrated, and the resulting residue was
chromatographed (EtOAc) to give (16S)-5a (100 mg, 44%) and
trace amounts of (16R)-5a and starting material. (16S)-5a: IR
isomers: IR (film) 1661 cm-1 1H NMR (300 MHz, selected
;
resonances for two isomers) δ 3.29 (dd, J ) 6.6, 0.9 Hz, 1 H),
3.35 (dd, J ) 10.5, 7.8 Hz, 1 H), 4.05 (2dd, J ) 9.0, 2.1 Hz, 2
H), 4.18 (2dd, J ) 9.0, 6.9 Hz, 2 H), 4.88 (td, J ) 9.9, 3.0 Hz,
2 H), 5.00 (d, J ) 6.9 Hz, 2 H, H-3); 13C NMR (75.4 MHz,
selected resonances) δ 12.8 (CH2), 16.9 (CH2), 26.5 (CH2), 27.2
(CH2), 59.2 (CH), 59.5 (CH), 65.3 (CH), 65.4 (CH), 73.7 (CH2),
73.8 (CH2), 88.1 (CH), 88.8 (CH), 162.0 (C), 162.2 (C). From
the â-keto sulfoxide (487 mg, 136 mmol), toluene (15 mL), and
Na2CO3 (804 mg) was obtained cis-2 (260 mg, 89%) after flash
chromatography (2:1 EtOAc-CHCl3): IR (film) 1670, 1606
(KBr) 1731, 1621 cm-1 1H NMR (300 MHz) δ 2.12 (dt, J )
;
13.2, 3.3 Hz, 1 H), 2.28 (dm, J ) 13.2 Hz, 1 H), 2.46 (d, J )
18.0 Hz, 1 H), 3.09 (dm, J ) 10.0 Hz, 1 H), 3.17 (dd, J ) 18.0,
9.1 Hz, 1 H), 3.62 (s, 3 H), 3.72 (s, 3 H), 3.81 (d, J ) 1.4 Hz, 1
H), 3.86 (ddd, J ) 14.5, 4.3, 2.6 Hz, 1 H), 4.05 (ddd, J ) 14.5,
9.4, 6.3 Hz, 1 H), 4.63 (br t, J ) 2.7 Hz, 1 H), 4.86 (dd, J ) 9.4,
4.3 Hz, 1 H), 4.92 (dd, J ) 6.3, 2.6 Hz, 1 H), 7.10-7.50 (m, 9
H); 13C NMR (75.4 MHz) δ 29.1 (CH2), 29.6 (CH), 30.2 (CH3),
39.2 (CH2), 46.9 (CH), 51.2 (CH), 52.6 (CH3), 64.6 (CH2), 70.3
(CH), 109.5 (CH), 112.6 (C), 118.3 (CH), 120.1 (CH), 122.1
(CH), 124.6 (C), 127.4 (CH), 127.7 (CH), 128.7 (CH), 130.3 (C),
137.5 (C), 137.6 (C), 170.9 (C), 171.5 (C); mp 205-208 °C
1
cm-1; H NMR (300 MHz) δ 2.60 (dddd, J ) 17.2, 11.7, 3.3,
2.1 Hz, 1 H), 2.82 (dddd, J ) 17.1, 6.6, 4.5, 0.9 Hz, 1 H), 4.10
(dd, J ) 9.0, 1.5 Hz, 1 H), 4.20 (dd, J ) 9.0, 6.9 Hz, 1 H), 5.03
(dd, J ) 6.9, 1.5 Hz, 1 H), 5.11 (dd, J ) 11.7, 4.5 Hz, 1 H),
5.94 (ddd, J ) 9.9, 3.0, 0.9 Hz, 1 H), 6.52 (dd, J ) 9.9, 2.1 Hz,
1 H), 7.10-7.35 (m, 5 H); 13C NMR (75.4 MHz) δ 29.9 (CH2),
57.3 (CH), 74.0 (CH2), 86.8 (CH), 126.1 (CH), 126.2 (CH), 128.3
(CH), 127.3 (CH), 135.9 (CH), 140.7 (C), 161.1 (C); mp 45-50
(Et2O-CH2Cl2); [R]22 -6.1 (c 1.0, CH2Cl2). Anal. Calcd for
°C; [R]22 +5.2 (c 1.0, CHCl3).
D
D
C25H26N2O4: C, 71.75; H, 6.26; N, 6.69. Found: C, 71.66; H,
6.27; N, 6.62.
Methyl (3R,7S,8aS)-r-(1-Methyl-2-indolyl)-5-oxo-3-phen-
yl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine-7-
acetate (4a). LDA was prepared by addition of diisopropyl-
amine (0.31 mL, 2.22 mmol) to a cooled (-78 °C) solution of
n-BuLi (1.3 mL of a 1.6 M solution in hexanes, 2.08 mmol) in
THF (4 mL). The mixture was stirred at -78 °C for 5 min and
at 0 °C for 5 min, and cooled at -78 °C. Then, a solution of
ester 3a12 (422 mg, 2.08 mmol) in THF (30 mL) was added
dropwise, and the mixture was stirred at -78 °C for 30 min.
A solution of trans-2 (300 mg, 1.39 mmol) in THF (5 mL) was
added via cannula, and the mixture was stirred at 0 °C for 4
h, poured into saturated aqueous NaHCO3, and extracted with
EtOAc. The combined organic extracts were dried and con-
centrated to give an oil. Flash chromatography (Et2O) afforded
230 mg of (RS)-4a and 140 mg of (RR)-4a (overall yield 64%).
(RS)-4a (lower Rf): IR (NaCl) 1737, 1663 cm-1; 1H NMR (300
MHz) δ 1.97 (dt, J ) 14.0, 5.0 Hz, 1 H, H-8), 2.06 (ddd, J )
14.0, 7.5, 5.2 Hz, 1 H, H-8), 2.43 (dd, J ) 17.0, 7.0 Hz, 1 H,
H-6), 2.72 (ddd, J ) 17.0, 5.0, 0.8 Hz, 1 H, H-6), 3.07 (m, 1 H,
H-7), 3.67 (s, 3 H, CH3N), 3.72 (dd, J ) 8.5, 7.0 Hz, 1 H, H-2),
3.77 (s, 3 H, CH3O), 3.82 (d, J ) 11.0 Hz, 1 H, CHCO2Me),
4.45 (tap, J ) 8.5 Hz, 1 H, H-2), 4.83 (tap, J ) 5.3 Hz, 1 H,
H-8a), 5.41 (tap, J ) 7.5 Hz, 1 H, H-3), 6.52 (s, 1H, H-3 ind),
7.12 (tm, J ) 7.8 Hz, 1 H, H-5 ind), 7.23 (tm, J ) 7.5 Hz, 1 H,
H-6 ind), 7.24-7.42 (m, 6 H, ArH), 7.57 (dm, J ) 7.8 Hz, 1 H,
H-4 ind); 13C NMR (75.4 MHz) δ 30.0 (CH3N), 30.0 (C-8); 31.3
(C-7), 37.0 (C-6), 47.2 (CHCO2Me), 52.6 (CH3O), 58.0 (C-3), 71.7
(C-2), 85.7 (C-8a), 101.5 (C-3 ind), 109.3 (C-7 ind), 119.9 (C-4
ind), 120.6 (C-5 ind), 121.9 (C-6 ind), 125.8, 128.9 (C-o, m),
126.0 (C-3a ind), 127.7 (C-p), 134.2 (C-2 ind), 137.5 (C-i), 139.6
(C-7a ind), 168.7 (NCO), 171.2 (COO); mp 65-69 °C (Et2O);
(1S,5S,6R)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6-(meth-
oxycarbonyl)-7-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(16R)-5a]. Operating as de-
scribed above, starting from (RR)-4a (50 mg, 0.12 mmol) in
CH2Cl2 (4 mL) and TiCl4, (20 µL, 0.18 mmol) at rt for 5 h, pure
(16R)-5a (25 mg, 50%), trace amounts of (16S)-5a, and starting
material (10 mg) were obtained after flash chromatography
1
(EtOAc). (16R)-5a: IR (film) 1733, 1620 cm-1; H NMR (300
MHz) δ 2.00 (m, 1 H), 2.30 (dt, J ) 13.2, 3.3 Hz, 1 H), 2.54 (d,
J ) 19.0 Hz, 1 H), 2.87 (dd, J ) 19.0, 8.2 Hz, 1 H), 3.15 (m, 1
H), 3.57 (s, 3 H), 3.85 (s, 3 H), 3.90 (ddd, J ) 13.5, 4.7, 2.9 Hz,
1 H), 4.03 (ddd, J ) 13.5, 9.3, 6.4 Hz, 1 H), 4.18 (d, J )
6.0 Hz, 1 H), 4.58 (m, 1 H), 4.78 (m, 1 H), 4.85 (dd, J ) 6.1,
2.4 Hz, 1 H), 7.10-7.50 (m, 9 H); 13C NMR (75.4 MHz) δ 29.6
(CH), 30.5 (CH3), 32.8 (CH2), 35.5 (CH2), 46.2 (CH), 50.8 (CH),
52.6 (CH3), 64.7 (CH2), 70.1 (CH), 109.5 (CH), 112.4 (C), 117.9
(CH), 120.3 (CH), 122.2 (CH), 124.5 (C), 125.5 (CH), 127.7
(CH), 128.8 (CH), 131.3 (C), 137.7 (C), 138.0 (C), 170.2 (C),
172.0 (C).
Methyl(3R,7S,8aS)-r-(2-Indolyl)-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3,2-a]pyridine-7-acetate (4b).
LDA (3.72 mL of a 1.5 M solution in cyclohexane, 5.58 mmol)
was added to a solution of ester 3b26 (520 mg, 2.75 mmol) in
THF (48 mL) at -78 °C. After 1 h, a solution of trans-2 (400
mg, 1.86 mmol) in THF (5 mL) was added via cannula, and
the mixture was stirred at -78 °C for 5 h. The resulting
mixture was poured into saturated aqueous NaHCO3 and
(26) Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1
1990, 673.
[R]22 +53.8 (c 0.5, CHCl3). Anal. Calcd for C25H26N2O4: C,
D
8688 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
extracted with EtOAc. The combined organic extracts were
dried and concentrated to give an oil. Flash chromatography
(Et2O) afforded (RS)-4b and (RR)-4b (380 mg, overall yield
51%, 63:37 ratio). (RS)-4b (lower Rf): IR (film) 3300, 1734, 1646
cm-1; 1H NMR (300 MHz) δ 1.90 (m, 2 H), 2.34 (dd, J ) 17.0,
7.0 Hz, 1 H), 2.64 (dd, J ) 17.0, 5.0 Hz, 1 H), 2.83 (m, 1 H),
3.73 (dd, J ) 8.7, 7.5 Hz, 1 H), 3.74 (s, 3 H), 3.80 (d, J ) 10.5
Hz, 1 H), 4.44 (tap, J ) 8.5 Hz, 1 H), 4.97 (tap, J ) 5.2 Hz, 1 H),
5.38 (tap, J ) 7.8 Hz, 1 H), 6.44 (d, J ) 2.0 Hz, 1 H), 7.11 (tm,
J ) 7.5 Hz, 1 H), 7.19 (tm, J ) 7.2 Hz, 1 H), 7.22-7.41 (m, 6
H), 7.56 (d, J ) 7.7 Hz, 1 H), 8.75 (br s, 1 H); 13C NMR (75.4
MHz) δ 29.6 (CH2), 32.7 (CH), 36.5 (CH2), 48.9 (CH), 52.6
(CH3), 58.0 (CH), 71.7 (CH2), 85.7 (CH), 102.7 (CH), 111.1 (CH),
119.9 (CH), 120.2 (CH), 122.1 (CH), 125.7 (CH), 128.8 (CH),
127.6 (CH), 127.6 (C), 131.8 (CH), 136.4 (C), 139.4 (C), 168.6
5), 373 (3), 284 (30), 268 (5), 245 (87), 225 (25), 193 (35); HMRS
calcd for C24H24N2O4 404.1736, found 404.1735.
Methyl (3R,7R,8aR)-r-(1-Methyl-2-indolyl)-5-oxo-3-phen-
yl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine-7-
acetate (6). Operating as described for the preparation of 4a,
from n-BuLi (2.2 mL of a 1.6 M solution in hexanes, 3.5 mmol),
diisopropylamine (495 µL, 3.5 mmol), 3a (708 mg, 3.5 mmol),
and cis-2 (500 mg, 2.32 mmol), epimers (RS)-6 and (RR)-6 (520
mg, 53%, 63:37 ratio) were obtained after flash chromatogra-
phy (2:1 EtOAc-hexane). (RS)-6 (higher Rf): IR (film) 1736,
1662 cm-1; 1H NMR (300 MHz) δ 2.09 (dd, J ) 17.0, 7.2 Hz, 1
H), 2.24 (ddd, J ) 14.0, 9.3, 7.2 Hz, 1 H), 2.37 (ddd, J ) 17.0,
6.0 Hz, 1 H), 2.40 (m, 1 H), 3.00 (m, 1 H), 3.72 (s, 3 H), 3.73 (s,
3 H), 3.85 (d, J ) 11.0 Hz, 1 H), 4.10 (dd, J ) 9.0, 0.9 Hz, 1
H), 4.24 (dd, J ) 9.0, 6.0 Hz, 1 H), 4.94 (dd, J ) 6.0, 0.9 Hz,
1 H), 5.11 (dd, J ) 9.3, 4.5 Hz, 1 H), 6.50 (s, 1 H), 7.09 (tm, J
) 7.8 Hz, 1 H), 7.15-7.38 (m, 7 H), 7.56 (d, J ) 7.8 Hz, 1 H);
13C NMR (75.4 MHz) δ 29.9 (CH3), 31.7 (CH2), 32.9 (CH), 35.4
(CH2), 47.7 (CH), 52.6 (CH3), 58.4 (CH), 74.3 (CH2), 86.0 (CH),
101.1 (CH), 109.3 (CH), 119.9 (CH), 120.5 (CH), 121.9 (CH),
126.3 (CH), 128.6 (CH), 127.4 (C), 127.7 (CH), 134.8 (C), 137.4
(C), 172.4 (C); [R]22 +12.2 (c 0.5, EtOH); HMRS calcd for
D
C24H24N2O4 404.1736, found 404.1734. (RR)-4b (higher Rf): IR
(film) 3300, 1734, 1647 cm-1; 1H NMR (300 MHz) δ 2.09 (dt, J
) 14.2, 5.0 Hz, 1 H), 2.19 (ddd, J ) 14.2, 7.7, 5.5 Hz, 1 H),
2.23 (dd, J ) 17.0, 7.5 Hz, 1 H), 2.40 (dd, J ) 17.0, 5.0 Hz, 1
H), 2.76 (m, 1 H), 3.77 (s, 3 H), 3.77 (masked, 1 H), 3.80 (d, J
) 10.2 Hz, 1 H), 4.48 (tap, J ) 8.5 Hz, 1 H), 5.07 (tap, J ) 5.2
Hz, 1 H), 5.37 (tap, J ) 8.0 Hz, 1 H), 6.40 (d, J ) 2.0 Hz, 1 H),
7.09 (tm, J ) 7.5 Hz, 1 H), 7.17 (tm, J ) 7.3 Hz, 1 H), 7.20-
7.39 (m, 6 H), 7.54 (d, J ) 7.7 Hz, 1 H), 8.70 (br s, 1 H); 13C
NMR (75.4 MHz) δ 31.0 (CH2), 33.0 (CH), 35.1 (CH2), 48.9
(CH), 52.6 (CH3), 58.1 (CH), 71.8 (CH2), 85.8 (CH), 103.1 (CH),
111.0 (CH), 120.0 (CH), 120.3 (CH), 122.2 (CH), 125.8 (CH),
128.8 (CH), 127.5 (C), 127.6 (CH), 131.7 (CH), 136.4 (C), 139.5
(C), 168.7 (C), 172.4 (C); mp 168-171 °C (Et2O-acetone-
hexane); [R]22D -45.1 (c 0.2, EtOH). Anal. Calcd for C24H24N2O4‚
1/2H2O: C, 69.71; H, 6.09; N, 6.77. Found: C, 69.73; H, 5.90;
N, 6.80.
(C), 140.9 (C), 166.5 (C), 171.3 (C); mp 132-140 °C; [R]22
D
-10.5 (c 1.0, CHCl3); MS-EI m/z 418 (M+, 13), 325 (57), 136
(45), 108 (76); HMRS calcd for C25H26N2O4 418.1892, found
418.1891. (RR)-6 (lower Rf): IR (NaCl) 1736, 1666 cm-1 1H
;
NMR (300 MHz) δ 2.03 (ddd, J ) 14.0, 9.0, 7.5 Hz, 1 H), 2.21
(dt, J ) 14.0, 4.5 Hz, 1 H), 2.28 (dd, J ) 17.0, 7.0 Hz, 1 H);
2.61 (dd, J ) 17.0, 5.7 Hz, 1 H), 3.14 (m, 1 H), 3.66 (s, 3 H),
3.79 (s, 3 H), 3.85 (d, J ) 10.8 Hz, 1 H), 4.03 (dd, J ) 9.3, 0.9
Hz, 1 H), 4.15 (dd, J ) 9.3, 6.6 Hz, 1 H), 4.88 (dd, J ) 9.0, 4.5
Hz, 1 H), 4.94 (d, J ) 6.6 Hz, 1 H), 6.52 (s, 1 H), 7.14 (tm, J )
7.8 Hz, 1 H), 7.20-7.38 (m, 7 H), 7.60 (d, J ) 7.8 Hz, 1 H); 13
C
NMR (75.4 MHz) δ 30.0 (CH3), 30.9 (CH2), 31.6 (CH), 36.3
(CH2), 48.0 (CH), 52.6 (CH3), 58.5 (CH), 74.2 (CH2), 85.9 (CH),
101.5 (CH), 109.3 (CH), 119.9 (CH), 120.5 (CH), 121.9 (CH),
126.3 (CH), 128.6 (CH), 127.5 (C), 127.7 (CH), 134.4 (C), 137.5
(C), 140.9 (C), 166.5 (C), 171.3 (C); [R]22D -18.8 (c 1.0, CHCl3);
MS-EI m/z 418 (M+, 96), 325 (17), 287 (100), 203 (76); HMRS
calcd for C25H26N2O4 418.1892, found 418.1891.
[1S,5S,6S(and 6R)]-2-[(1R)-2-Hydroxy-1-phenylethyl]-
6-(methoxycarbonyl)-3-oxo-1,2,3,4,5,6-hexahydro-1,5-meth-
anoazocino[4,3-b]indole [(16S)-5b and (16R)-5b]. TiCl4 (90
µL, 0.82 mmol) was added to a cooled (0 °C) solution of (RS)-
4b (100 mg, 0.25 mmol) in CH2Cl2 (3 mL), and the mixture
was stirred at rt for 5 h, poured into saturated aqueous
NaHCO3, and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated, and the resulting
residue was chromatographed (EtOAc) to give (16S)-5b and
(16R)-5b (60 mg, 60%, 58:42 ratio). Similarly, starting from
(RR)-4b (125 mg, 0.31 mmol), CH2Cl2 (4 mL), and TiCl4 (50
µL, 0.46 mmol), tetracycles (16S)-5b and (16R)-5b (88 mg, 70%,
13:87 ratio) were obtained after flash chromatography (EtOAc).
(1R,5R,6S)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6-(meth-
oxycarbonyl)-7-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(16S)-7]. TiCl4 (35 µL, 0.32
mmol) was added to a solution of (RS)-6 (135 mg, 0.32 mmol)
in CH2Cl2 (2 mL) at rt, and the resulting mixture was heated
at reflux for 2 h. TiCl4 (35 µL, 0.32 mmol) was added twice
after 2 and 6 h, and the mixture was heated at reflux for an
additional 18 h. The mixture was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2. The combined
organic extracts were dried and concentrated, and the result-
ing residue was chromatographed (4:1 EtOAc-hexane to
EtOAc) to give (16S)-7 (34 mg, 25%): IR (film) 3350, 1735,
1620 cm-1; 1H NMR (300 MHz) δ 1.90 (dm, J ) 13.0 Hz, 1 H),
2.24 (dt, J ) 13.0, 3.3 Hz, 1 H), 2.52 (d, J ) 19.0 Hz, 1 H),
2.85 (dd, J ) 19.0, 8.1 Hz, 1 H), 3.13 (m, 1 H), 3.54 (s, 3 H),
3.83 (s, 3 H), 4.14 (d, J ) 6.3 Hz, 1 H), 4.18-4.25 (m, 2 H),
4.54 (dd, J ) 3.6, 2.6 Hz, 1 H), 5.67 (t, J ) 7.0 Hz, 1 H), 7.10-
7.50 (m, 9 H); 13C NMR (75.4 MHz) δ 29.3 (CH), 30.4 (CH3),
33.6 (CH2), 34.9 (CH2), 46.2 (CH), 47.4 (CH), 52.6 (CH3), 62.3
(CH), 63.1 (CH2), 109.3 (CH), 113.0 (C), 118.0 (CH), 119.8 (CH),
122.0 (CH), 124.4 (C), 127.5 (CH), 127.6 (CH), 128.6 (CH),
131.6 (C), 136.6 (C), 137.3 (C), 170.8 (C), 172.3 (C); mp 118 °C
1
(16S)-5b (lower Rf): IR (film) 1734, 1617 cm-1; H NMR (300
MHz) δ 2.17 (dt, J ) 13.2, 3.4 Hz, 1 H), 2.28 (dm, J ) 13.2 Hz,
1 H), 2.46 (d, J ) 16.5 Hz, 1 H), 3.13 (m, 1 H), 3.13 (m, 1 H),
3.73 (s, 3 H), 3.78 (br s, 1 H), 3.85 (dm, J ) 12.4 Hz, 1 H), 4.04
(ddd, J ) 12.4, 9.4, 6.2 Hz, 1 H), 4.57 (tap, J ) 3.0 Hz, 1 H),
4.86 (dd, J ) 6.2, 2.5 Hz, 1 H), 4.90 (m, 1 H), 7.10-7.50 (m, 9
H), 8.50 (br s, 1 H); 13C NMR (75.4 MHz) δ 28.1 (CH), 29.7
(CH2), 39.2 (CH2), 47.0 (CH), 51.0 (CH), 52.6 (CH3), 64.7 (CH2),
70.4 (CH), 111.4 (CH), 113.9 (C), 118.1 (CH), 120.6 (CH), 122.7
(CH), 125.1 (C), 127.4 (CH), 128.8 (CH), 127.7 (CH), 128.2 (C),
136.2 (C), 137.6 (C), 170.8 (C), 171.0 (C); [R]22 -2.0 (c 0.55,
D
EtOH); MS-EI m/z 404 (M+, 10), 268 (10), 245 (34), 225 (70),
193 (100), 161 (75), 148 (33); HMRS calcd for C24H24N2O4
404.1736, found 404.1739. (16R)-5b (higher Rf): IR (film) 1733,
1
1620 (NCO) cm-1; H NMR (300 MHz) δ 2.05 (dm, J ) 13.0
(Et2O-CH2Cl2); [R]22 +40.5 (c 1.0, CHCl3).
D
Hz, 1 H), 2.27 (ddd, J ) 13.0, 4.5, 3.0 Hz, 1 H), 2.40 (d, J )
19.0 Hz, 1 H), 3.00 (dd, J ) 19.0, 9.0 Hz, 1 H), 3.20 (m, 1 H),
3.87 (s, 3 H), 3.91 (dm, J ) 14.0 Hz, 1 H), 4.05 (d, J ) 4.3 Hz,
1 H), 4.11 (ddd, J ) 14.0, 9.3, 6.6 Hz, 1 H), 4.59 (tap, J ) 2.7
Hz, 1 H), 4.81 (dd, J ) 9.3, 4.4 Hz, 1 H), 4.93 (dd, J ) 6.6, 2.5
Hz, 1 H), 7.10-7.45 (m, 9 H), 9.00 (br s, 1 H); 13C NMR (75.4
MHz) δ 28.3 (CH), 32.8 (CH2), 35.6 (CH2), 46.8 (CH), 50.9 (CH),
52.7 (CH3), 64.6 (CH2), 70.2 (CH), 111.5 (CH), 112.5 (C), 118.1
(CH), 120.4 (CH), 122.4 (CH), 125.0 (C), 127.5 (CH), 128.8
(CH), 127.8 (CH), 129.0 (C), 136.3 (C), 137.7 (C), 171.4 (C),
171.5 (C); mp 202-206 °C (Et2O-hexane); MS-EI m/z 404 (M+,
(1R,5R,6R)-2-[(1R)-2-Hydroxy-1-phenylethyl]-6-(meth-
oxycarbonyl)-7-methyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole [(16R)-7]. TiCl4 (125 µL, 0.12
mmol) was added to a solution of (RR)-6 (190 mg, 0.45 mmol)
in CH2Cl2 (10 mL), and the resulting mixture was heated at
reflux 17 h. TiCl4 (50 µL, 0.45 mmol) was added, and the
mixture was heated at reflux for an additional 4 h, poured
into saturated solution NaHCO3, and extracted with CH2Cl2.
The combined organic extracts were dried and concentrated,
and the resulting residue was chromatographed (4:1 EtOAc-
J. Org. Chem, Vol. 69, No. 25, 2004 8689

Amat et al.
hexane, 4.9:0.1 EtOAc-EtOH) to afford (16R)-7 (38 mg,
20%): IR (film) 3375, 1733, 1624 cm-1; 1H NMR (300 MHz) δ
2.00 (dt, J ) 13.0, 3.0 Hz, 1 H), 2.20 (dm, J ) 13.0 Hz, 1 H),
2.47 (d, J ) 18.6 Hz, 1 H), 3.05 (dm, J ) 9.6 Hz, 1 H), 3.16
(dd, J ) 18.6, 9.3 Hz, 1 H), 3.38 (br s, 1 H), 3.58 (s, 3 H), 3.68
(s, 3 H), 3.80 (d, J ) 1.2 Hz, 1 H), 4.25 (m, 2 H), 4.52 (t, J )
(m, 1 H), 1.80 (m, 1 H), 1.82 (m, 1 H), 2.00 (dd, J ) 16.0, 2.5
Hz, 1 H), 2.11 (dd, J ) 16.0, 4.5 Hz, 1 H), 2.64 (dm, J ) 12.0
Hz, 1 H), 2.90 (s, 3 H), 3.51 (d, J ) 12.0 Hz, 1 H), 3.68 (s, 3 H),
4.20 (dd, J ) 9.3, 6.3 Hz, 1 H), 4.25 (dd, J ) 9.3, 1.5 Hz, 1 H),
4.65 (d, J ) 6.3 Hz, 1 H), 4.93 (dd, J ) 6.3, 1.5 Hz, 1 H), 6.40
(s, 1 H), 7.00 (ddd, J ) 8.0, 6.0, 2.0 Hz, 1 H), 7.11 (ddd, J )
8.0, 8.0, 1.0 Hz, 1 H), 7.33 (d, J ) 7.2 Hz, 1 H), 7.40-7.54 (m,
5 H), 7.47 (dt, J ) 8.0, 1.0 Hz, 1 H); 13C NMR (75.4 MHz) δ
11.2 (CH3), 27.0 (CH2), 28.7 (CH3), 33.2 (CH2), 40.9 (CH), 45.1
(CH), 47.3 (CH), 52.3 (CH3), 57.3 (CH), 73.9 (CH2), 91.5 (CH),
99.6 (CH), 109.5 (CH), 119.3 (CH), 120.0 (CH), 121.2 (CH),
127.4 (C), 127.6 (CH), 128.6 (CH), 127.7 (CH), 135.3 (C), 136.9
(C), 141.0 (C), 167.1 (C), 171.8 (C); mp 166-169 °C (Et2O);
2.4 Hz, 1 H), 5.57 (t, J ) 6.3 Hz, 1 H), 7.00-7.40 (m, 9 H); 13
C
NMR (75.4 MHz) δ 29.6 (CH), 29.8 (CH2), 30.1 (CH3), 38.5
(CH2), 47.2 (CH), 47.5 (CH), 52.5 (CH3), 63.3 (CH), 63.7 (CH2),
109.2 (CH), 112.5 (C), 118.3 (CH), 119.6 (CH), 121.9 (CH),
124.5 (C), 127.6 (CH), 127.7 (CH), 128.6 (CH), 130.6 (C), 136.4
(C), 137.3 (C), 171.5 (C), 171.5 (C); [R]22D +35.6 (c 1.0, CHCl3).
(3R,8S,8aR)-8-Ethyl-5-oxo-3-phenyl-2,3,8,8a-tetrahydro-
5H-oxazolo[3,2-a]pyridine (10). Operating as described for
the preparation of trans-2, starting from 927 (500 mg, 2.04
mmol), THF (20 mL), methyl phenylsulfinate (636 mg, 4.08
mmol) and KH (400 mg, 20 wt % dispersion in mineral oil, 10
mmol), (3R,8S,8aR)-8-ethyl-5-oxo-3-phenyl-6-(phenylsulfi-
nyl)-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (715
mg, 95%) was obtained as a mixture of isomers. Major
[R]22 -49.0 (c 1.0, EtOH). Anal. Calcd for C27H30N2O4: C,
D
72.62; H, 6.77; N, 6.27. Found: C, 72.74; H, 6.83; N, 6.28.
(1S,5R,6R,12S)-12-Ethyl-2-[(1R)-2-hydroxy-1-phenyl-
ethyl]-6-(methoxycarbonyl)-7-methyl-3-oxo-1,2,3,4,5,6-
hexahydro-1,5-methanoazocino[4,3-b]indole (12a). TiCl4
(120 µL, 1.08 mmol) was added to a solution of (RR)-11a (160
mg, 0.36 mmol) in CH2Cl2 (8 mL), and the resulting mixture
was heated at reflux for 5 h. The mixture was poured into
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated, and
the resulting residue was chromatographed (8:2 EtOAc-
hexane) to give 12a (140 mg, 81%): IR (KBr) 3375, 1736, 1628
isomer: IR (film) 1658 cm-1 1H NMR (300 MHz, selected
;
resonances) δ 0.93 (t, J ) 7.2 Hz, 3 H), 3.37 (dd, J ) 10.5, 7.8
Hz, 1 H), 4.08 (dd, J ) 9.0, 1.2 Hz, 1 H), 4.17 (dd, J ) 9.0, 6.9
Hz, 1 H), 4.58 (d, J ) 8.7, 1 H), 4.99 (d, J ) 6.9 Hz, 1 H); 13C
NMR (75.4 MHz) δ 10.7 (CH3), 18.3 (CH2), 23.9 (CH2), 39.8
(CH), 59.6 (CH), 65.7 (CH), 73.6 (CH2), 91.4 (CH), 140.6 (C),
141.2 (C), 161.7 (C). A solution of the â-keto sulfoxide (600
mg, 1.62 mmol) in toluene (15 mL) was heated in the presence
of NaCO3 (1.0 g, 9.0 mmol) to give 10 (335 mg, 85%) after flash
chromatography (7:3 EtOAc-hexane): IR (film) 1670 cm-1; 1H
NMR (300 MHz) δ 1.10 (t, J ) 7.8 Hz, 3 H), 1.59 (m, 1 H),
1.85 (m, 1 H), 2.67 (m, 1 H), 4.11 (dd, J ) 9.0, 1.5 Hz, 1 H),
4.19 (dd, J ) 9.0, 6.6 Hz, 1 H), 4.81 (d, J ) 10.8 Hz, 1 H), 5.04
(dd, J ) 6.6, 1.5 Hz, 1 H), 5.93 (dd, J ) 9.9, 3.0 Hz, 1 H), 6.39
(dd, J ) 9.9, 1.8 Hz, 1 H), 7.10-7.35 (m, 5 H); 13C NMR (75.4
MHz) δ 10.8 (CH3), 23.1 (CH2), 42.4 (CH), 57.5 (CH), 74.1
(CH2), 91.0 (CH), 125.5 (CH), 126.3 (CH), 128.4 (CH), 127.4
cm-1 1H NMR (300 MHz) δ 0.61 (t, J ) 7.5 Hz, 3 H, CH3),
;
1.39 (m, 2 H, CH2), 1.80 (m, 1 H, H-12), 2.40 (d, J ) 19.0 Hz,
1 H, H-4), 2.76 (dd, J ) 19.0, 8.7 Hz, 1 H, H-4), 2.86 (m, 1 H,
H-5), 3.57 (s, 3 H, CH3N), 3.85 (s, 3 H, CH3O), 3.91 (dd, J )
12.5, 2.7 Hz, 1 H, H-2′), 4.00 (dd, J ) 12.5, 5.4 Hz, 1 H, H-2′),
4.15 (d, J ) 6.0 Hz, 1 H, H-6), 4.42 (m, 1 H, H-1), 4.69 (dd, J
) 5.4, 2.7 Hz, 1 H, H-1′), 4.90 (br s, 1 H, OH), 7.10-7.52 (m,
8 H, ArH), 7.65 (dm, J ) 7.8 Hz, 1 H, H-11); 13C NMR (75.4
MHz) δ 11.1 (CH3), 23.7 (CH2), 30.5 (CH3N), 32.0 (C-4), 33.5
(C-5), 42.8 (C-12), 47.3 (C-6), 52.5 (CH3O), 53.8 (C-1), 64.7
(C-2′), 70.6 (C-1′), 109.5 (C-8), 114.3 (C-11b), 117.7 (C-11), 120.0
(C-10), 121.9 (C-9), 124.5 (C-11a), 127.7 (C-p), 128.2, 128.3
(C-o, m), 131.3 (C-6a), 137.3 (C-7a), 137.8 (C-i), 169.9 (NCO),
171.8 (COO); mp 115-117 °C; [R]22D -10.5 (c 1.0, EtOH). Anal.
Calcd for C27H30N2O4‚1CH2Cl2: C, 68.23; H, 6.44; N, 5.80.
Found: C, 68.23; H, 6.51; N, 5.71.
(CH), 140.8 (C), 141.3 (CH), 161.1 (C); [R]22 +116.1 (c 1.0,
D
CHCl3).
Methyl (3R,7R,8S,8aR)-8-Ethyl-r-(1-methyl-2-indolyl)-
5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]-
pyridine-7-acetate (11a). A solution of 3a (499 mg, 2.46
mmol) in THF (7 mL) was added dropwise to a cooled solution
(-78 °C) of LDA (1.64 mL of a 1.5 M solution in cyclohexane,
2.46 mmol) in THF (6 mL). After the mixture was stirred at
-78 °C for 1 h, HMPA (432 µL, 2.46 mmol) and a solution of
10 (300 mg, 1.23 mmol) in THF (4 mL) were added via cannula
at -78 °C. The mixture was stirred at 0 °C for 3 h and at rt
for 18 h, poured into saturated aqueous NH4Cl, and extracted
with EtOAc. The combined organic extracts were washed with
water, dried, and concentrated to give an oil. Flash chroma-
tography (8:2 EtOAc-hexane) afforded (RS)-11a and (RR)-11a
(458 mg, 83%, 3:7 ratio). (RS)-11a (lower Rf): IR (film) 1736,
Methyl (3R,7R,8S,8aR)-8-Ethyl-r-(2-indolyl)-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine-
7-acetate (11b). A solution of 3b (1.55 g, 8.22 mmol) in THF
(25 mL) was added to a cooled (-78 °C) solution of LDA (10.9
mL of 1.5 M solution in cyclohexane, 16.4 mmol) in THF (20
mL). After the mixture was stirred at -78 °C for 1 h, HMPA
(1.44 mL, 8.2 mmol) and CuCN (734 mg, 8.22 mmol) were
added. Then, a solution of 10 (1.0 g, 4.11 mmol) in THF (5
mL) was added via cannula at -78 °C. The mixture was stirred
at -78 °C for 30 min, at 0 °C for 1 h, and at rt for 15 h. The
resulting mixture was poured into saturated aqueous NH4Cl
and extracted with CH2Cl2. The combined organic extracts
were washed with saturated aqueous NaHCO3, dried, and
concentrated to give an oil. Flash chromatography (6:4 EtOAc-
hexane to EtOAc) afforded (RS)-11b and (RR)-11b (706 mg,
40%, 7:3 ratio), 10 (325 mg), and 5-ethyl-1-[(1R)-2-hydroxy-
1-phenylethyl]-1H-2-pyridone (56; 140 mg). (RS)-11b (lower
1661 cm-1 1H NMR (300 MHz) δ 0.94 (t, J ) 7.5 Hz, 3 H),
;
1.62 (m, 1 H), 1.70 (m, 1 H), 1.76 (m, 1 H), 2.44 (dd, J ) 17.1,
7.0 Hz, 1 H), 2.60 (dd, J ) 17.1, 4.2 Hz, 1 H), 2.59 (m, 1 H),
3.55 (s, 3 H), 3.57 (s, 3 H), 3.76 (d, J ) 8.7 Hz, 1 H), 4.18 (m,
2 H), 4.70 (d, J ) 8.0 Hz, 1 H), 4.98 (t, J ) 4.0 Hz, 1 H), 6.46
(s, 1 H), 7.10 (tm, J ) 7.8 Hz, 1 H), 7.21 (tm, J ) 8.1 Hz, 1 H),
7.28-7.44 (m, 6 H), 7.56 (dm, J ) 7.8 Hz, 1 H); 13C NMR (75.4
MHz) δ 10.3 (CH3), 25.1 (CH2), 29.8 (CH3), 35.0 (CH2), 37.6
(CH), 42.8 (CH), 46.5 (CH), 52.3 (CH3), 57.6 (CH), 73.9 (CH2),
91.0 (CH), 101.6 (CH), 109.1 (CH), 119.7 (CH), 120.4 (CH),
121.6 (CH), 126.8 (CH), 128.6 (CH), 127.3 (C), 127.6 (CH),
134.7 (C), 137.3 (C), 140.9 (C), 167.1 (C), 171.2 (C); mp 149-
1
Rf): IR (KBr) 3268, 1733, 1665 cm-1; H NMR (300 MHz) δ
0.79 (t, J ) 7.5 Hz, 3 H, CH3), 1.50 (m, 2 H, CH2), 1.90 (m, 1
H, H-8), 2.41 (m, 2 H, H-6), 2.45 (m, 1 H, H-7), 3.58 (s, 3 H,
CH3O), 3.65 (d, J ) 9.0 Hz, 1 H, CHCO2Me), 4.16 (m, 2 H,
H-2), 4.65 (d, J ) 8.4 Hz, 1 H, H-8a), 4.98 (m, 1 H, H-3), 6.37
(s, 1 H, H-3 ind), 7.09 (t, J ) 7.8 Hz, 1 H, H-5 ind), 7.17 (t, J
) 7.8 Hz, 1 H, H-6 ind), 7.33-7.43 (m, 6 H, ArH), 7.57 (d, J )
7.8 Hz, 1 H, H-4 ind), 8.70 (br s, 1 H, NH); 13C NMR (75.4
MHz) δ 10.1 (CH3), 24.7 (CH2), 35.1 (C-6), 39.6 (C-7), 42.6
(C-8), 48.6 (CHCO2Me), 52.4 (CH3O), 57.8 (C-3), 74.1 (C-2), 91.1
(C-8a), 102.8 (C-3 ind), 111.0 (C-7 ind), 120.0 (C-4 ind), 120.2
(C-5 ind), 122.1 (C-6 ind), 126.8, 128.6 (C-o, m), 127.8 (C-p),
128.6 (C-3a ind), 132.6 (C-2 ind), 136.2 (C-i), 140.9 (C-7a ind),
166.6 (NCO), 172.8 (COO); [R]22D -123.6 (c 0.55, EtOH). Anal.
152 °C (EtOAc-hexane); [R]22 -70.0 (c 1.0, EtOH). Anal.
D
Calcd for C27H30N2O4: C, 72.62; H, 6.77; N, 6.27. Found: C,
72.35; H, 6.77; N, 6.12. (RR)-11a (higher Rf): IR (KBr) 1751,
1
1676 cm-1; H NMR (300 MHz) δ 1.11 (t, J ) 7.2, 3 H), 1.71
(27) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron: Asym-
metry 1997, 8, 2237.
8690 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
Calcd for C26H28N2O4‚1/2H2O: C, 70.73; H, 6.62; N, 6.34.
Found: C, 71.05; H, 7.02; N, 6.05. (RR)-11b (higher Rf): IR
J ) 14.0, 7.2 Hz, 1 H), 1.67 (dt, J ) 14.0, 7.2 Hz, 1 H), 1.96 (t,
J ) 7.2 Hz, 1 H), 2.06 (d, J ) 18.0 Hz, 1 H), 2.39 (d, J ) 8.4
Hz, 1 H), 2.45 (dd, J ) 18.0, 8.4 Hz, 1 H), 3.23 (dt, J ) 9.2, 4.8
Hz, 1 H), 3.83 (m, 2 H), 4.45 (t, J ) 3.0 Hz, 1 H), 6.73 (d, J )
4.4 Hz, 1 H), 7.06-7.10 (m, 2 H), 7.24 (dd, J ) 6.8, 2.4 Hz, 1
H), 7.48 (dd, J ) 6.8, 2.4 Hz, 1 H), 8.97 (s, 1 H); 13C NMR
(100.6 MHz) δ 11.6 (CH3), 23.7 (CH2), 29.0 (CH2), 33.5 (CH),
42.3 (CH), 42.4 (CH), 46.1 (CH), 64.8 (CH2), 111.2 (CH), 114.6
(C), 117.0 (CH), 119.7 (CH), 121.6 (CH), 124.8 (C), 135.1 (C),
1
(film) 3298, 1732, 1664 cm-1; H NMR (500 MHz) δ 1.09 (t, J
) 7.2 Hz, 3 H, CH3), 1.77 (m, 2 H, CH2), 1.82 (m, 1 H, H-8),
2.13 (dd, J ) 16.0, 4.2 Hz, 1 H, H-6), 2.24 (dd, J ) 16.0, 5.7
Hz, 1 H, H-6), 2.47 (m, 1 H, H-7), 3.65 (d, J ) 10.0 Hz, 1 H,
CHCO2Me), 3.76 (s, 3 H, CH3O), 4.14 (dd, J ) 9.0, 1.0 Hz, 1
H, H-2), 4.21 (dd, J ) 9.0, 6.6 Hz, 1 H, H-2), 4.70 (d, J ) 7.2
Hz, 1 H, H-8a), 4.94 (d, J ) 6.6, 1.0 Hz, 1 H, H-3), 6.27 (d, J
) 1.2 Hz, 1 H, H-3 ind), 7.04 (td, J ) 7.2, 1.2 Hz, 1 H, H-5
ind), 7.11 (tm, J ) 7.2 Hz, 1 H, H-6 ind), 7.24-7.33 (m, 6 H,
ArH), 7.48 (d, J ) 8.1 Hz, 1 H, H-4 ind), 8.62 (br s, 1 H, NH);
13C NMR (75.4 MHz) δ 10.7 (CH3), 25.3 (CH2), 33.8 (C-6), 40.1
(C-7), 44.2 (C-8), 49.0 (CHCO2Me), 52.5 (CH3O), 58.0 (C-3), 74.2
(C-2), 91.3 (C-8a), 102.6 (C-3 ind), 111.1 (C-7 ind), 119.7 (C-4
ind), 120.2 (C-5 ind), 121.9 (C-6 ind), 126.7, 128.6 (C-o, m),
127.8 (C-p), 128.4 (C-3a ind), 132.0 (C-2 ind), 136.1 (C-i), 140.6
136.0 (C), 173.2 (C); [R]22 -152.4 (c 1.1, EtOH); MS-EI m/z
D
284 (M+, 47), 253 (41), 208 (41), 195 (100), 180 (50); HMRS
calcd for C17H20N2O2 284.1525, found 284.1521. (16R)-13: 1H
NMR (300 MHz, selected resonances) δ 1.01 (t, J ) 7.5 Hz, 3
H), 2.08 (d, J ) 18.3 Hz, 1 H), 2.75 (dd, J ) 18.3, 8.7 Hz, 1 H),
2.79 (t, J ) 6.9 Hz, 1 H), 3.77 (m, 2 H), 4.39 (d, J ) 0.9 Hz, 1
H), 9.23 (br s, 1 H); 13C NMR (75.4 MHz) δ 11.5 (CH3), 23.5
(CH2), 32.2 (CH), 35.6 (CH2), 37.5 (CH), 45.3 (CH), 46.0 (CH),
64.4 (CH2), 111.0 (CH), 115.0 (C), 116.9 (CH), 119.3 (CH), 121.4
(CH), 124.7 (C), 134.9 (C), 136.2 (C), 173.8 (C). When the
reaction time was 5 min instead of 3 h, 13 (50%) and
(1R,5S,6S,12R)-12-ethyl-6-(hydroxymethyl)-2-[(1S)-2-hy-
droxy-1-phenylethyl]-3-oxo-1,2,3,4,5,6-hexahydro-1,5-meth-
anoazocino[4,3-b]indole (57, 15%) were obtained after flash
chromatography (EtOAc to 95:5 EtOAc-EtOH). 57: IR (film)
(C-7a ind), 167.1 (NCO), 172.5 (COO); [R]22 -348.5 (c 0.2,
D
EtOH); MS-EI m/z 432 (M+, 21), 244 (100), 149 (25), 124 (33).
HMRS calcd for C26H28N2O4 432.2049, found 432.2040. 56: IR
1
(film) 3330, 1668 cm-1; H NMR (300 MHz) δ 1.08 (t, J ) 7.5
Hz, 3 H), 2.31 (q, J ) 7.5 Hz, 2 H), 4.13 (m, 1 H), 4.30 (dd, J
) 11.4, 4.8 Hz, 1 H), 6.29 (dd, J ) 7.2, 4.8 Hz, 1 H), 6.53 (d, J
) 9.3 Hz, 1 H), 7.04 (dm, J ) 1.8 Hz, 1 H), 7.22 (dd, J ) 9.3,
2.7 Hz, 1 H), 7.26-7.39 (m, 5 H); 13C NMR (75.4 MHz) δ 14.7
(CH3), 24.9 (CH2), 60.0 (CH), 63.2 (CH2), 120.1 (CH), 121.8 (C),
127.8 (CH), 128.8 (CH), 128.1 (CH), 132.0 (CH), 136.8 (C),
140.7 (CH), 162.8 (C). Anal. Calcd for C15H17NO2‚1/2H2O: C,
71.79; H, 7.38; N, 5.40. Found: C, 71.62; H, 7.21; N, 5.59.
1
3305, 2932, 1613 cm-1; H NMR (400 MHz) δ 0.76 (t, J ) 7.6
Hz, 3 H, CH3), 1.33 (m, 2 H, CH2), 1.83 (t, J ) 7.6 Hz, 1 H,
H-12), 2.28 (d, J ) 19.2 Hz, 1 H, H-4), 2.39 (dd, J ) 8.4, 5.2
Hz, 1 H, H-5), 2.63 (dd, J ) 19.2, 8.8 Hz, 1 H, H-4), 3.22 (dt,
J ) 8.8, 5.2 Hz, 1 H, H-6), 3.88 (m, 3 H, CH2OH, H-2′), 4.00
(dd, J ) 9.2, 6.0 Hz, 1 H, H-2′), 4.42 (d, J ) 0.8 Hz, 1 H, H-1),
4.72 (dd, J ) 6.0, 2.8 Hz, 1 H, H-1′), 5.00 (d, J ) 6.0 Hz, 1 H,
OH), 7.11-7.40 (m, 7 H, ArH), 7.49 (dd, J ) 6.8, 1.6 Hz, 1 H,
H-8), 7.60 (dd, J ) 6.8, 2.0 Hz, 1 H, H-11), 9.07 (s, 1 H, NH);
13C NMR (75.4 MHz) δ 11.2 (CH3), 23.9 (CH2), 30.7 (C-4), 32.9
(C-5), 42.4 (C-6), 43.5 (C-12), 55.3 (C-1), 64.7 (CH2OH), 64.9
(C-2′), 71.2 (C-1′), 111.4 (C-8), 112.7 (C-11b), 117.6 (C-11), 120.1
(C-10), 121.7 (C-9), 124.8 (C-11a), 127.8 (C-p), 128.3, 128.5 (C-
(1S,5R,6R,12S)-12-Ethyl-2-[(1R)-2-hydroxy-1-phenyl-
ethyl]-6-(methoxycarbonyl)-3-oxo-1,2,3,4,5,6-hexahydro-
1,5-methanoazocino[4,3-b]indole (12b). Operating as de-
scribed for the preparation of 12a, starting from (RS)-11b (650
mg, 1.5 mmol) in CH2Cl2 (30 mL) and TiCl4 (500 µL, 4.5 mmol),
tetracycle 12b (225 mg, 35%) was obtained after flash chro-
matography (7:3 EtOAc-hexane). Similarly, treatment of (RR)-
11b (550 mg, 1.27 mmol) in CH2Cl2 (26 mL) with TiCl4 (420
µL, 3.81 mmol) gave 12b (228 mg, 51%) after flash chroma-
tography (7:3 EtOAc-hexane). 12b: IR (KBr) 3254, 3409,
o, m); 136.0 (C-6a), 136.2 (C-7a), 137.7 (C-i), 171.5 (NCO); [R]22
D
-6.1 (c 0.56, EtOH); MS-EI m/z 404 (M+, 30), 373 (35), 284
(30), 268 (63), 196 (100), 168 (86); HMRS calcd for C25H28N2O3
404.2100, found 404.2099.
1
1736, 1620 cm-1; H NMR (500 MHz) δ 0.58 (t, J ) 7.0 Hz, 3
H, CH3), 1.27 (m, 1 H, CH2), 1.35 (m, 1 H, CH2), 1.82 (m, 1 H,
H-12), 2.27 (d, J ) 19.0 Hz, 1 H, H-4), 2.83 (dd, J ) 19.0, 8.7
Hz, 1 H, H-4), 2.86 (m, 1 H, H-5), 3.84 (s, 3 H, CH3O), 3.84 (m,
1 H, H-2′), 3.86 (m, 1 H, H-2′), 4.01 (d, J ) 4.5 Hz, 1 H, H-6),
4.43 (m, 1 H, H-1), 4.67 (dd, J ) 6.0, 2.5 Hz, 1 H, H-1′), 4.85
(br s, 1 H, OH), 7.19-7.39 (m, 7 H, ArH), 7.47 (dd, J ) 8.0,
1.0 Hz, 1 H, H-8), 7.60 (dd, J ) 8.5, 2.0 Hz, 1 H, H-11), 9.02
(br s, 1 H, NH); 13C NMR (75.4 MHz) δ 11.2 (CH3), 24.1 (CH2),
32.8 (C-5), 33.1 (C-4), 42.9 (C-12), 47.8 (C-6), 52.6 (CH3O), 54.6
(C-1), 64.9 (C-2′), 71.4 (C-1′), 111.6 (C-8), 114.4 (C-11b), 117.9
(C-11), 120.3 (C-10), 122.3 (C-9), 124.8 (C-11a), 127.8 (C-p),
128.4, 128.4 (C-o, m), 129.1 (C-6a), 136.5 (C-7a), 137.8 (C-i),
171.0 (NCO), 171.2 (COO); mp 176-180 °C (Et2O); [R]22D -8.8
(c 0.5, EtOH). Anal. Calcd for C26H28N2O4‚1/4H2O: C, 71.46;
H, 6.57; N, 6.41. Found: C, 71.20; H, 6.39; N, 6.26.
(1R,5S,12R)-12-Ethyl-6-methylene-3-oxo-1,2,3,4,5,6-
hexahydro-1,5-methanoazocino[4,3-b]indole (14). Mesyl
chloride (43 µL, 0.55 mmol) and Et3N (91 µL, 0.66 mmol) were
added to a cooled (0 °C) solution of 13 (107 mg, 0.37 mmol) in
CH2Cl2 (18 mL). The mixture was stirred at 0 °C for 2 h,
diluted with CH2Cl2, dried, and concentrated to give the
mesylate derivative (150 mg), which was used without further
purification in the next step. DBU (60 µL, 0.4 mmol) was added
to a solution of the mesylate (150 mg) in THF (2 mL), and the
mixture was heated at reflux for 24 h. Additional DBU (60
µL, 0.4 mmol) was added, and the mixture was heated at reflux
for 24 h. The mixture was concentrated, and the residue was
taken up in EtOAc and washed with cool aqueous H2SO4. The
aqueous layer was extracted with EtOAc, and the combined
organic extracts were dried and concentrated to give an oil.
Flash chromatography (95:5 EtOAc-EtOH) gave 14 (53.1 mg,
53%): 1H NMR (400 MHz) δ 1.07 (t, J ) 7.2 Hz, 3 H, CH3),
1.64 (m, 1 H, CH2), 1.72 (m, 1 H, CH2), 2.12 (t, J ) 7.2 Hz, 1
H, H-12), 2.27 (d, J ) 18.8 Hz, 1 H, H-4), 2.86 (dd, J ) 18.8,
8.0 Hz, 1 H, H-4), 2.98 (d, J ) 8.0 Hz, 1 H, H-5), 4.52 (m, 1 H,
H-1), 5.01 (s, 1 H, CH2d), 5.15 (s, 1 H, CH2d), 6.58 (br s, 1 H,
NH), 7.10 (td, J ) 8.0, 0.8 Hz, 1 H, H-10), 7.19 (td, J ) 8.0,
1.2 Hz, 1 H, H-9), 7.29 (d, J ) 8.4 Hz, 1 H, H-8), 7.49 (d, J )
7.6 Hz, 1 H, H-11), 8.23 (s, 1 H, NH); 13C NMR (100.6 MHz) δ
11.5 (CH3), 23.5 (CH2), 36.1 (C-4), 39.3 (C-5), 42.0 (C-12), 46.5
(C-1), 105.3 (CH2)), 111.2 (C-8), 118.1 (C-11), 119.5 (C-11b),
120.2 (C-10), 123.6 (C-9), 125.2 (C-11a), 131.5 (C-6a), 136.7
(1R,5S,12R)-12-Ethyl-6-(hydroxymethyl)-3-oxo-
1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-b]indole
(13). Into a three-necked, 100 mL round-bottomed flask
equipped with a coldfinger condenser charged with dry ice-
acetone were condensed 30 mL of NH3 at -78 °C. The
temperature was raised to -33 °C, and sodium metal was
added in small portions until the blue color persisted. After
the mixture was stirred at -33 °C for 5 min, a solution of ent-
12b (250 mg, 0.58 mmol) in THF (3 mL) was added, and the
mixture was stirred at -33 °C for 3 h. The reaction was
quenched by addition of solid NH4Cl until the blue color
disappeared, and the mixture was stirred at rt for 4 h. The
resulting residue was digested at rt with CH2Cl2, and the
resulting suspension was filtered and concentrated. Flash
chromatography (EtOAc) afforded (16S)-13 and (16R)-13 (105
mg, 64%, 2:1 ratio). (16S)-13: IR (film) 3286, 2960, 2930, 1650
cm-1; 1H NMR (400 MHz) δ 1.04 (t, J ) 7.2 Hz, 3 H), 1.56 (dt,
(C-7a), 141.7 (C-6), 172.5 (NCO); [R]22 +87.1 (c 0.4, EtOH).
D
General Procedure for Conjugate Addition Reactions.
n-BuLi (1.6 M solution in hexanes) or LDA (1.5 M solution in
cyclohexane, 1.5-5 mmol) and HMPA (0-2 mmol) were added
J. Org. Chem, Vol. 69, No. 25, 2004 8691

Amat et al.
to a cooled solution (-78 °C) of the dithioacetal (15-19; 1.5-5
mmol) in THF. After the mixture was stirred at -78 °C for 1
h, a solution of the unsaturated lactam trans-2, cis-2, or 10 (1
mmol) in THF was added via cannula, and the mixture was
stirred at the temperature for the reaction time indicated in
Table 1. The resulting mixture was poured into saturated
NH4Cl and extracted with EtOAc. The combined organic
extracts were dried and concentrated, and the resulting
residue was chromatographed to afford 21-33 (see the Sup-
porting Information for details).
dine (50). Following the above general procedure, from
dithioacetal 34a (150 mg, 0.31 mmol) in 1:3 THF-MeOH (10
mL), NiCl2‚6H2O (745 mg, 3.1 mmol), and NaBH4 (356 mg,
9.4 mmol) at 0 °C for 2 h was obtained compound 50 (70 mg,
60%) after flash chromatography (3:7 EtOAc-hexane): IR
(film) 1640 cm-1;1H NMR (300 MHz) δ 1.10 (t, J ) 7.5 Hz, 3
H, CH3), 1.57 (m, 1 H, CH2), 1.94 (m, 2 H, CH2, H-8), 2.26 (dd,
J ) 18.3, 5.5 Hz, 1 H, H-6), 2.30-2.50 (m, 3 H, H-6, H-7, CH2-
In), 2.96 (d, J ) 12.3 Hz, 1 H, CH2In), 4.00 (dd, J ) 9.0, 1.0
Hz, 1 H, H-2), 4.12 (dd, J ) 9.0, 7.0 Hz, 1 H, H-2), 4.64 (d, J
) 9.3 Hz, 1 H, H-8a), 4.90 (br d, J ) 6.0 Hz, 1 H, H-3), 6.22 (d,
J ) 2.1 Hz, 1 H, H-3 ind), 7.06 (m, 3 H, ArH), 7.25 (m, 5 H,
ArH), 7.49 (m, 1 H, ArH), 8.62 (br s, 1 H, NH); 13C NMR (75.4
MHz) δ 11.4 (CH3), 21.1 (CH2), 27.1 (CH2In), 34.1 (C-7), 37.0
(C-6), 43.8 (C-8), 59.4 (C-3), 73.8 (C-2), 90.0 (C-8a), 100.4 (C-3
ind), 110.6 (C-7 ind), 119.5 (CH), 119.6 (C-4 ind), 121.0 (CH),
126.2 (CH), 127.5 (CH), 128.5 (CH), 128.6 (C-3a ind), 135.9
[3R,7S(and 7R),8S,8aR]-8-Ethyl-7-[2-(2-indolyl)-1,3-
dithian-2-yl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (34a and 34b). n-BuLi (15.4 mL of
a 1.6 M solution in cyclohexane, 22.6 mmol) was added to a
cooled solution (-78 °C) of 2-(2-indolyl)-1,3-dithiane28 (20; 2.9
g, 12.3 mmol) in THF (40 mL). The mixture was stirred at
-30 °C for 2 h and added to a cooled solution (-78 °C) of 10
(600 mg, 2.46 mmol) in THF (10 mL). The resulting mixture
was stirred at 0 °C for 20 h, poured into saturated aqueous
NH4Cl, and extracted with EtOAc. The combined organic
extracts were dried and concentrated to give and oil. Flash
chromatography (2:8 to 7:3 EtOAc-hexane) afforded 34a (843
mg, 72%) and 34b (207 mg, 18%). 34a: IR (film) 3280, 1650
(C-2 ind), 137.0 (C-i), 141.3 (C-7a ind), 167.0 (NCO); [R]22
D
+13.8 (c 0.55, MeOH). Anal. Calcd for C24H26N2O2‚1/2H2O: C,
70.58; H, 6.53; N, 6.72. Found: C, 70.66; H, 6.59; N, 6.67.
(1R,5S,12S)-12-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
3,6-dioxo-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-
b]indole (51). TiCl4 (70 µL, 0.62 mmol) was added to a
solution of dithioacetal 34a (100 mg, 0.2 mmol) in CH2Cl2 (5
mL), and the resulting mixture was heated at reflux 6 h,
poured into saturated solution NaHCO3, and extracted with
CH2Cl2. The combined organic extracts were dried and con-
centrated, and the resulting residue was chromatographed
(EtOAc) to afford tetracycle 51 (16 mg, 20%) and starting
material (22 mg). 51: IR (film) 1652, 1640 cm-1; 1H NMR (400
MHz) δ 0.64 (t, J ) 7.2 Hz, 3 H, CH3), 1.06 (m, 1 H, CH2), 1.25
(m, 1 H, CH2), 2.40 (m, 1 H, H-12), 2.85 (d, J ) 19.0 Hz, 1 H,
H-4), 2.99 (dm, J ) 8.5 Hz, 1 H, H-5), 3.15 (dd, J ) 18.8, 8.6
Hz, 1 H, H-4), 4.10 (m, 1 H, H-2′), 4.24 (dd, J ) 10.5, 4.2 Hz,
1 H, H-2′), 4.49 (m, 1 H, H-1), 5.86 (dd, J ) 8.0, 4.2 Hz, 1 H,
H-1′), 7.13-7.32 (m, 8 H, ArH), 7.51 (dd, J ) 11.2, 1.2 Hz, 1
H, ArH), 9.20 (br s, 1 H, NH); 13C NMR (100.6 MHz) δ 11.5
(CH3), 23.9 (CH2), 36.1 (C-4), 45.9 (C-5), 48.3 (C-12), 49.6
(C-1), 61.5 (C-1′), 63.2 (C-2′), 113.1 (C-8), 120.6 (CH), 121.5
(CH), 124.8 (C-11b), 127.0 (C-11a), 127.4 (CH), 127.7 (CH),
128.0 (CH), 128.9 (CH), 129.1 (C-6a), 136.2 (C-7a), 138.0
(C-i), 170.6 (NCO), 191.4 (CO). Anal. Calcd for C24H24N2O3‚
H2O: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.72; H, 6.20; N,
6.58.
cm-1 1H NMR (300 MHz) δ 0.87 (t, J ) 7.2 Hz, 3 H, CH3),
;
1.26 (m, 1 H, CH2), 1.58 (m, 1 H, CH2), 1.86 [m, 2 H, CH2-
(CH2S)2], 2.03 (m, 1 H, H-8), 2.64 (m, 3 H, H-6, CH2S), 2.79
(m, 1 H, H-7), 2.88 (masked, 2 H, CH2S), 2.90 (dd, J ) 15.6,
6.0 Hz, 1 H, H-6), 3.95 (dd, J ) 9.0, 1.5 Hz, 1 H, H-2), 4.13
(dd, J ) 9.0, 7.2 Hz, 1 H, H-2), 4.80 (dd, J ) 7.2, 1.5 Hz, 1 H,
H-3), 4.85 (d, J ) 6.6 Hz, 1 H, H-8a), 6.84 (dd, J ) 2.4, 1.2 Hz,
1 H, H-3 ind), 7.13 (td, J ) 7.2, 1.2 Hz, 1 H, H-5 ind), 7.19-
7.27 (m, 7 H, ArH), 7.38 (dd, J ) 8.1, 1.2 Hz, 1 H, H-7 ind),
7.59 (d, J ) 7.2 Hz, 1 H, H-4 ind), 8.57 (br s, 1 H, NH); 13C
NMR (75.4 MHz) δ 12.5 (CH3), 21.0 (CH2), 24.2 [CH2(CH2S)2],
27.9, 28.5 (CH2S), 35.3 (C-6), 44.8 (C-8), 46.9 (C-7), 57.5 (CS2),
58.5 (C-3), 74.0 (C-2), 91.0 (C-8a), 106.4 (C-3 ind), 111.1 (C-7
ind), 120.0 (C-4 ind), 120.6 (C-5 ind), 122.4 (C-6 ind), 126.3,
128.4 (C-o, m), 127.1 (C-p), 128.4 (C-3a ind), 136.0 (C-2 ind),
136.9 (C-i), 141.3 (C-7a ind), 167.5 (NCO); [R]22D +17.1 (c 0.5,
MeOH). Anal. Calcd for C27H33N2S2O2‚1/2H2O: C, 66.50; H,
6.41; N, 5.74. Found: C, 66.63; H, 6.38; N, 5.87. 34b: 1H NMR
(300 MHz) δ 0.88 (t, J ) 7.5 Hz, 3 H, CH3), 1.19 (m, 1 H, CH2),
1.40 (m, 1 H, CH2), 1.78 [m, 2 H, CH2(CH2S)2], 2.23 (m, 2 H,
H-6, H-7), 2.53 (m, 5 H, CH2S, H-8), 2.87 (d, J ) 15.3 Hz, 1 H,
H-6), 4.16 (dd, J ) 9.3, 2.1 Hz, 1 H, H-2), 4.21 (dd, J ) 9.3, 5.7
Hz, 1 H, H-2), 4.67 (d, J ) 9.0 Hz, 1 H, H-8a), 4.96 (dd, J )
5.7, 2.1 Hz, 1 H, H-3), 6.81 (dd, J ) 2.1, 0.9 Hz, 1 H, H-3 ind),
7.09 (td, J ) 7.2, 1.2 Hz, 1 H, H-5 ind), 7.16 (td, J ) 7.2, 1.5
Hz, 1 H, H-6 ind), 7.22-7.32 (m, 6 H, ArH), 7.50 (dd, J ) 7.8,
0.9 Hz, 1 H, H-7 ind), 7.57 (d, J ) 7.5 Hz, 1 H, H-4 ind), 8.71
(br s, 1 H, NH); 13C NMR (75.4 MHz) δ 10.3 (CH3), 24.1 [CH2-
(CH2S)2], 26.5 (CH2), 27.5, 27.6 (CH2S), 34.3 (C-6), 41.6 (C-8),
48.2 (C-7), 58.1 (C-3), 60.9 (CS2), 74.4 (C-2), 90.7 (C-8a), 105.5
(C-3 ind), 111.1 (C-7 ind), 119.7 (C-4 ind), 120.3 (C-5 ind), 121.9
(C-6 ind), 127.4 (C-p), 127.4, 127.9 (C-o, m), 128.5 (C-3a ind),
135.9 (C-2 ind), 137.5 (C-i), 140.0 (C-7a ind), 167.5 (NCO);
[R]22D +99.3 (c 0.5, MeOH). Anal. Calcd for C27H33N2S2O2: C,
67.71; H, 6.32; N, 5.85. Found: C, 67.71; H, 6.62; N, 5.62.
General Procedure for Desulfurization Reactions.
NiCl2‚6H2O (7-10 mmol) was added to a cooled solution (0
°C) of the dithioacetal (1 mmol) in 1:3 THF-MeOH (ca. 50
mL). When the dissolution was complete, NaBH4 (21-30
mmol) was added portionwise, and the mixture was stirred at
0-25 °C for 1-8 h and filtered through Celite. The filtrate
was concentrated and partitioned between saturated aqueous
NaCl and CH2Cl2. The combined organic extracts were dried
and concentrated to give the desired product 35-42 (see the
Supporting Information for details).
(1R,5S,12S)-12-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
3-oxo-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-b]in-
dole (52). Operating as described above, from TiCl4 (75 µL,
0.68 mmol) and 50 (85 mg, 0.23 mmol) in CH2Cl2 (7 mL) for 7
h were obtained tetracycle 52 (15 mg, 17%) and starting
material (10 mg) after flash chromatography (EtOAc). 52: IR
1
(film) 1670 cm-1; H NMR (400 MHz) δ 0.63 (t, J ) 7.2 Hz, 3
H, CH3), 0.98 (m, 1 H, CH2), 1.12 (m, 1 H, CH2), 2.02 (m, 1 H,
H-12), 2.48 (d, J ) 19.0 Hz, 1 H, H-4), 2.55 (m, 1 H, H-5), 2.62
(d, J ) 17.2 Hz, 1 H, H-6), 2.97 (dd, J ) 17.2, 5.6 Hz, 1 H,
H-6), 3.08 (dd, J ) 19.0, 8.4 Hz, 1 H, H-4), 4.18-4.30 (m, 3 H,
H-2′, H-1), 5.74 (dd, J ) 8.0, 5.6 Hz, 1 H, H-1′), 7.00-7.40 (m,
9 H, ArH), 8.10 (br s, 1 H, NH); 13C NMR (100.6 MHz) δ 11.7
(CH3), 22.6 (CH2), 28.2 (C-6), 29.0 (C-5), 40.6 (C-4), 43.4
(C-12), 49.8 (C-1), 62.0 (C-1′), 63.5 (C-2′), 110.8 (C-8), 117.5
(CH), 119.7 (CH), 121.6 (CH), 126.4 (C), 127.7 (CH), 127.8
(CH), 127.9 (CH), 128.7 (C), 132.5 (C), 136.1 (C-7a), 136.6
(C-i), 173.0 (NCO); MS-EI m/z 374 (M+, 4), 343 (7), 238 (16),
195 (96), 180 (100); HMRS calcd for C24H26N2O2 374.1994,
found 374.1986.
(1R,5S,12S)-12-Ethyl-3-oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole (53). Operating as described
for the preparation of 13, from liquid NH3 (30 mL), sodium,
and 34a (300 mg, 0.62 mmol) in THF (8 mL) at -33 °C for 25
min was obtained an intermediate 6-hydroxylactam (200 mg,
94%) as an oil, which was used without further purification
in the next reaction. TiCl4 (103 µL, 0.94 mmol) was added to
a cooled (0 °C) solution of the oil in CH2Cl2 (150 mL), and the
(3R,7S,8S,8aR)-8-Ethyl-7-(2-indolylmethyl)-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyri-
(28) Rubiralta, M.; Casamitjana, N.; Grierson, D. S.; Husson, H.-P.
Tetrahedron 1988, 44, 443.
8692 J. Org. Chem., Vol. 69, No. 25, 2004

Enantioselective Synthesis of Uleine Alkaloids
mixture was stirred at rt for 1 h, poured into saturated
aqueous NaHCO3, and extracted with CH2Cl2. The combined
organic extracts were dried and concentrated, and the result-
ing residue was chromatographed (99:1 CH2Cl2-MeOH) to
give tetracycles 53 (55 mg, 35%) and 54 (10 mg, 6%). 53: IR
fined by a nonpolarizable point charge of -1 units of electron
and van der Waals parameters of a carbon atom. The param-
eters ꢀAB and R*AB were computed from the atomic parameters
using the relationships ꢀAB ) (ꢀAꢀB)1/2 and R*AB ) R*A + R*B.
GMIPp calculations were performed on the most stable
conformation of the lactams. To this end, a preliminary
exploration was performed at the molecular mechanical level
using the CVFF9131 force field implemented in the Insight-
II32 program, and the geometry of the selected conformers was
subsequently optimized at the HF/6-31G(d) level. GMIPp
calculations were performed using MOPETE program.33
1
(film) 3256, 1650 cm-1; H NMR (400 MHz) δ 0.96 (t, J ) 7.5
Hz, 3 H, CH3), 1.36 (m, 2 H, CH2), 2.24 (m, 1 H, H-12), 2.25
(d, J ) 18.4 Hz, 1 H, H-4), 2.52 (dd, J ) 17.2, 1.2 Hz, 1 H,
H-6), 2.56 (m, 1 H, H-5), 2.86 (dd, J ) 18.4, 8.4 Hz, 1 H, H-4),
3.06 (dd, J ) 17.2, 6.0 Hz, 1 H, H-6), 4.43 (m, 1 H, H-1), 6.79
(br s, 1 H, NH), 7.07-7.15 (m, 2 H, H-9, H-10), 7.28 (d, J )
6.0 Hz, 1 H, H-8), 7.45 (d, J ) 7.6 Hz, 1 H, H-11), 7.85 (br s,
1 H, NH); 13C NMR (100.6 MHz) δ 12.1 (CH3), 22.8 (CH2), 27.5
(C-6), 29.2 (C-5), 39.7 (C-4), 41.4 (C-12), 46.6 (C-1), 110.7
(C-8), 112.3 (C-11b), 117.0 (C-9), 119.7 (C-11), 121.5 (C-10),
occ
ZA
1
GMIPp )
-
Pµν φµ
φν
+
∑
∑∑∑
|
|
|RB - RA|
|RB - r|
A
i
µ
ν
126.2 (C-11a), 130.9 (C-6a), 136.0 (C-7a), 173.5 (NCO); [R]22
occ vir
2
D
1
1
-82.2 (c 0.3, CHCl3); MS-EI m/z 254 (M+, 75), 195 (76), 180
(100), 168 (51); HMRS calcd for C16H18N2O 254.1419, found
254.1457. 54: IR (film) 1667 cm-1; 1H NMR (400 MHz) δ 1.05
(t, J ) 7.5 Hz, 3 H, CH3), 1.57 (m, 2 H, CH2), 2.35 (m, 1 H,
H-12), 2.44 (d, J ) 18.4 Hz, 1 H, H-4), 2.58 (m, 1 H, H-5), 2.84
(dd, J ) 18.4, 7.2 Hz, 1 H, H-4), 2.90 (d, J ) 17.6 Hz, 1 H,
H-6), 3.31 (dd, J ) 17.6, 6.4 Hz, 1 H, H-6), 5.52 (br s, 1 H,
H-1), 6.28 (br s, 1 H, H-7), 6.63 (br s, 1H, NH), 7.09-7.18 (m,
2 H, H-8, H-9), 7.27 (d, J ) 8.4 Hz, 1 H, H-11), 7.51 (d, J ) 7.6
Hz, 1 H, H-10); 13C NMR (75.4 MHz) δ 11.6 (CH3), 22.2 (CH2),
26.5 (C-6), 27.2 (C-5), 39.1 (C-4), 39.9 (C-12), 60.2 (C-1), 101.5
(C-7), 108.3 (C-11), 119.8 (C-10), 120.2 (C-8), 120.6 (C-9), 129.2
(C-6a), 131.2 (C-11a), 135.5 (C-7a), 171.9 (NCO); [R]22D -105.8
(c 2.0, CHCl3); MS-EI m/z 254 (M+, 27), 183 (100), 154 (24),
130 (30); HMRS calcd for C16H18N2O 254.1419, found 254.1416.
cµicνj φµ
R*AB
φν
+
∑∑
∑∑
|
|
{
}
êi - êj
|RB - r|
i
j
µ
ν
12
6
R*AB
ꢀAB
- 2
(1)
∑
(
[
)
(
)
]
|RB - RA|
|RB - RA|
A
The energetics of the conjugate addition of the anion derived
from 18 to the lactams was examined from B3LYP34 calcula-
tions using the 6-31G(d) basis set. For the sake of complete-
ness, calculations were also performed for the addition of
methyl anion to the lactams. The geometry of the reactants
and the enolate adducts formed from the conjugate addition
reaction were fully optimized, and in all cases the minimum
energy nature of the optimized geometries was confirmed from
the inspection of the harmonic vibrational frequencies. Cal-
culations were performed using Gaussian-98.35
(1R,5S,12S)-N-(Benzyloxycarbonyl)-12-ethyl-3-oxo-
1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-b]indole
(55). BH3‚Me2S (100 µL of a 5 M solution in Et2O, 0.49 mmol)
was added to a cooled solution (0 °C) of 53 (120 mg, 0.47 mmol)
in toluene (2.5 mL), and the mixture was heated at reflux for
6 h. Then, the mixture was cooled, 10% aqueous CaCO3 (2 mL)
was added, and stirring was continued for 20 min. The layers
were separated, and the organic layer was dried and concen-
trated to give 110 mg (97%) of the tetracyclic amine. To a
solution of this amine (110 mg, 0.46 mmol) in CH2Cl2 (7 mL)
were added CaCO3 (164 mg) and benzyloxycarbonyl chloride
(236 µL of a 50% solution in toluene, 0.7 mmol). The mixture
was stirred at rt for 90 min, poured into water, and extracted
with CH2Cl2. The combined organic extracts were dried and
concentrated to give and oil, which was chromatographed (4:6
Et2O-hexane) to afford 55 (72 mg, 41%): [R]22D +89.0 (c 0.33,
Acknowledgment. Financial support from the DGI-
CYT, Spain (Project No. BQU2003-00505), and the CUR,
Generalitat de Catalunya (Grant No. 2001SGR-0084),
is gratefully acknowledged. Thanks are also due to the
Ministry of Education, Culture and Sport for a fellow-
ship to M.P. and to DSM Deretil (Almer´ıa, Spain) for
the generous gift of (R)-phenylglycine.
Supporting Information Available: X-ray crystallo-
graphic data for compounds RR-11a, 26a, 26b, and 31b (CIF),
complete details of computational methods, and general
experimental procedures and experimental details and char-
acterization data for compounds ent-9-ent-12, 21-33, and
35-49. This material is available free of charge via the
Internet at http://pubs.acs.org.
CHCl3) (lit.4a [R]22 +89.4 (c 0.4, CHCl3)).
D
JO0487101
Computational Methods
(29) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(30) Alhambra, C.; Luque, F. J.; Orozco, M. J. Phys. Chem. 1995,
99, 3084.
The generalized molecular interaction potential with polar-
ization (GMIPp)22 was used to investigate the reactivity
pattern of unsaturated lactams cis-2 and 10. The GMIPp
functional computes the interaction energy between the mol-
ecule, which is treated at the quantum mechanical (QM) level,
and a classical probe. Such an interaction energy is expressed
as the addition of three terms (see eq 1): (i) the electrostatic
contribution between the QM charge distribution of the
isolated molecule and the classical particle; (ii) a polarization
contribution determined from perturbation theory; and (iii) a
classical dispersion-repulsion term. In eq 1, RA and RB stand
for the positions of the nuclei (ZA) in the molecule and of the
atoms in the classical probe, Cµi denotes the coefficient of
atomic orbitals in the molecular orbital-linear combination
of atomic orbitals, Pµν is the first-order density matrix, φ is
the set of atomic orbitals, ê denotes the energy of molecular
orbitals, and ꢀ and R* are the van der Waals parameters. The
QM molecule was described at the Hartree-Fock (HF) level
using the 6-31G(d) basis,29 and the van der Waals parameters
were taken from an in-house quantum mechanical-molecular
mechanical parametrization.30 The classical particle was de-
(31) Maple, J. R.; Dinur, U.; Hagler, A. T. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 5350.
(32) Insight-II (version 97.0), Molecular Simulations, San Diego,
1997.
(33) Mopete. Luque, F. J.; Alhambra, C.; Orozco, M. University of
Barcelona, 2001.
(34) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(35) Gaussian 98. Rev. A.7. Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V.
G.; Montgomery, J. A., Jr.; Stratmann R. E.; Burant, J. C.; Dapprich,
S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas,
O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P.
Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian, Inc., Pittsburgh,
PA, 1998.
J. Org. Chem, Vol. 69, No. 25, 2004 8693