Addition of chiral enolates to N-alkyl-3-acylpyridinium salts. Total synthesis of (+)-16-epivinoxine and (-)-vinoxine

Article abstract of DOI:10.1016/S0957-4166(02)00055-1

Chiral enolates of indolylacetyl derivatives 6a-f undergo addition to pyridinium salt 7 with complete trans-selectivity and varied diastereofacial selectivities to give, after acid-induced cyclization of the intermediate 1,4-dihydropyridines, the vinoxine-related tetracycles 8a-f. Starting from (S)-prolinol indolylacetamide 6e, subsequent elaboration of the ethylidene substituent from tetracycle 8e and removal of the chiral auxiliary has resulted in a straightforward synthesis of (+)-16-epivinoxine and (-)-vinoxine.

Full text of DOI:10.1016/S0957-4166(02)00055-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 95–106
Addition of chiral enolates to N-alkyl-3-acylpyridinium salts.
Total synthesis of (+)-16-epivinoxine and (−)-vinoxine
M.-Llu¨ısa Bennasar,a,* Ester Zulaica,a Yolanda Alonso,a Bernat Vidal,a Jesu´s T. Va´zquezb and
Joan Boscha
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bInstituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, University of La Laguna, 38206-La Laguna, Tenerife, Spain
Received 29 January 2002; accepted 4 February 2002
Abstract—Chiral enolates of indolylacetyl derivatives 6a–f undergo addition to pyridinium salt 7 with complete trans-selectivity
and varied diastereofacial selectivities to give, after acid-induced cyclization of the intermediate 1,4-dihydropyridines, the
vinoxine-related tetracycles 8a–f. Starting from (S)-prolinol indolylacetamide 6e, subsequent elaboration of the ethylidene
substituent from tetracycle 8e and removal of the chiral auxiliary has resulted in a straightforward synthesis of (+)-16-epivinoxine
and (−)-vinoxine. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
blocks for alkaloid synthesis would be significantly
enhanced. In the literature there are several examples of
stereoselective syntheses of chiral non-racemic 1,4-
dihydropyridines8 by diastereofacial-selective addition
of organometallic reagents to N-acylpyridinium salts
bearing chiral auxiliaries at the 3-position of the ring.9
However, the application of similar auxiliary-induced
stereoselective processes in the alkaloid field is far less
common.9e,10 In this context, we have recently described
a biomimetic synthesis of (−)-N(a)-methylervitsine, start-
ing from a chiral N-alkylpyridinium salt.11 On the other
hand, Spitzner has used the addition of a chiral non-
racemic nucleophile to a pyridinium salt in the synthesis
of (−)-isovallesiachotamine and (+)-vallesiachotamine.12
We wish to report herein our work on the stereoselec-
tive synthesis of vinoxine, which has provided access to
(+)-16-epivinoxine and the natural product, (−)-
vinoxine.
The nucleophilic addition of indole-containing enolates
to N-alkyl-3-acylpyridinium salts has been extensively
used in our laboratory as the initial step of a general
scheme for the synthesis of indole alkaloids.1,2 After
suitable manipulation of the resultant indolyl-1,4-dihy-
dropyridine adducts, it is possible to construct complex
polycyclic structures, giving access to alkaloids belong-
ing to different structural types. Thus, starting from the
enolates derived from 1-, 2-, and 3-indoleacetates, we
have synthesized indole alkaloids of the C-mavacurine3
and Strychnos groups,4 as well as tetracyclic akuammi-
line substructures.5 From 2-acetylindole enolates, we
have completed total syntheses of bridged (ervitsine)
and fused 2-acylindole alkaloids of the ervatamine and
silicine groups.6 In a similar manner, we have developed
formal syntheses of the Corynanthean alkaloids geis-
soschizine and akagerine starting from 1-acetylindole
enolates.7 So far, all these syntheses have only been
carried out in the racemic series.
Vinoxine 1 is a C-mavacurine alkaloid isolated in 1967
from Vinca minor L,13 with a tetracyclic bridged
structure14 lacking the tryptamine unit present in the
majority of indole alkaloids. The (3S)-absolute configu-
ration of natural (−)-vinoxine was established by com-
paring its CD curves with those of its pentacyclic
analogue pleiocarpamine.14b The 15-H/16-H relative
configuration, initially reported to be trans, was reas-
signed several years later as cis (Fig. 1).3a,15
We have consequently become interested in exploring
the stereoselective version of the above methodology,
using either chiral non-racemic enolates or chiral non-
racemic pyridinium salts. In this manner, the scope and
potential of 1,4-dihydropyridines as effective building
Scheme 1 outlines our previously described synthesis of
( )-vinoxine.3a The tetracyclic ring system of the alka-
* Corresponding author. Tel.: 34-934024540; fax: 34-934024539;
e-mail: bennasar@farmacia.far.ub.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00055-1

96
M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
Figure 1.
loid was assembled in a straightforward manner, by a
one-pot process involving the addition of the enolate
derived from methyl 1-indoleacetate 2 to pyridinium
salt 3 (formation of C(15)ꢀC(16) bond), followed by the
in situ acid-induced cyclization of the initially formed
1,4-dihydropyridine (formation of C(2)ꢀC(3) bond). As
a result, a 5:1 C(16) epimeric mixture of tetracycles 4
(15-H/16-H trans relative configuration) and 5 (15-H/
16-H cis relative configuration) was obtained in 40%
yield. Subsequent stereoselective elaboration of the (E)-
ethylidene substituent was effected following a classical
procedure in indole alkaloid synthesis,16 by hydrolysis-
decarboxylation of the 3-(tetrahydro-3-pyridyl)acrylate
moiety, reesterification of the C-16 methoxycarbonyl
group, and final reduction with NaBH4. In this manner,
( )-vinoxine and minor amounts of its C(16) epimer,
( )-16-epivinoxine, were obtained in 30% yield.
Scheme 2. Strategies for the stereoselective synthesis of vinox-
ine.
eration of the stereocenter at the pyridine 4-position
C(15). Cyclization of the resultant 1,4-dihydropyridine
onto the indole nucleus would result in the generation
of the C(3) stereocenter, whose configuration would be
determined by that of C(15) because of the bridgehead
character of both carbons. The important role played
by the electron-withdrawing group Y (CHꢁCHCO2-
Me) at the 3-position of the pyridine ring in the
previous racemic synthesis prompted us to study the
feasibility of strategy A, which enabled us to maintain
the same group.
2. Results and discussion
Two strategies can be envisaged for the stereoselective
version of the above racemic synthesis: incorporating a
chiral group either at the indolylacetyl moiety of the
nucleophile (A) or at the 3-position of the pyridine ring
(B) (Scheme 2). In both cases, this group would act as
a chiral auxiliary, thus allowing the stereoselective gen-
Scheme 1. Synthesis of ( )-vinoxine and ( )-16-epivinoxine.

M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
97
Table 1. Addition–cyclization sequence from chiral eno-
lates derived from 6 and pyridinium iodide 7
As chiral analogues of methyl 1-indoleacetate 2, we
selected the indolylacetyl derivatives 6 (Scheme 3),
which contain chiral auxiliaries17 commonly used in
diastereoselective Michael additions to prochiral enones
and a,b-unsaturated esters.18 Thus, (1R)-menthyl and
(1R)-8-phenylmenthyl esters 6a and 6b, N-
acyloxazolidinones 6c and 6d, and (S)-prolinol indolyl-
acetamides 6e and 6f were prepared according to stan-
dard procedures19 (see Section 4), and the behavior of
their corresponding enolates in the nucleophilic addi-
tion–dihydropyridine cyclization sequence with pyri-
dinium iodide 7 was investigated.
Entry
Indolea
Product (%)b
Diastereomeric ratioc
1
2
6a
6b
8a (40)
8b (28)
9b (9)
8b (28)
9b (21)
8c (30)
8d (31)
8e (25)
8f (10)
1:1d
2.5:1d
1:1d
2:1d
1:1d
1.5:1
1.4:1
3:1
3
6b
4
5
6
7
6c
6d
6e
6f
1:1d
The results, summarized in Table 1, present some gen-
eral trends. The best yields (37–49%) of the vinoxine
related tetracycles 8 and 9, the latter resulting from
hydrolysis of the acetate moiety, were obtained when
ester enolates were used as nucleophiles (entries 1–3).
The use of imide (entries 4 and 5) and amide (entries 6
and 7) enolates was less efficient. Although in all cases
the addition–cyclization process took place with com-
plete diastereoselectivity since only tetracycles with 15-
H/16-H trans relative configuration were detected,20 the
above chiral enolates derived from 6 showed moderate
a Generation of the enolate with LDA (LHDMS in entries 1 and 2).
b Isolated yields.
c Approximate ratio calculated by 1H NMR.
d Unseparable diastereomeric mixture.
to low facial diastereoselectivity in their reactions with
pyridinium salt 7.
Previous studies on the use of cyclohexyl-based chiral
auxiliaries in different reaction types indicate that (1R)-
8-phenylmenthol21 induces high levels of stereocontrol
in comparison with (1R)-menthol, which generally gives
poorer results.22,23 In our case, no diastereoselectivity
was observed when the enolate derived from (1R)-men-
thyl ester 6a, generated with LHDMS, was treated with
pyridinium salt 7 (entry 1), but only slightly better
results were obtained from (1R)-8-phenylmenthyl ester
6b under the same conditions (entry 2). The use of
LDA as the base to generate the enolate of 6b did not
improve the diastereoselectivity, although the overall
yield of tetracycles 8b and 9b increased (entry 3).
The synthetic utility of the above reactions was ham-
pered by the difficulty in separating the diastereomeric
mixtures of tetracycles 8a, 8b or 9b by column chro-
matography. Furthermore, the chiral auxiliary of 8a or
8b could not be removed under the usual (basic hydro-
lysis or methanolysis) conditions or under the acidic
hydrolytic conditions required for the formation of the
(E)-ethylidene substituent from the 3-(tetrahydro-3-
pyridyl)acrylate
moiety.
Thus,
treatment
of
diastereomeric mixtures of 8a or 8b with 4N aqueous
HCl at reflux, followed by NaBH4 reduction gave the
auxiliary-containing (E)-ethylidene derivatives 10a or
10b in 28 and 30% yields, respectively (Scheme 4).
On the other hand, the use of N-acyloxazolidinones 6c
and 6d in the addition–cyclization sequence was unsat-
isfactory as poor diastereomeric ratios of the respective
tetracycles 8c and 8d were obtained in 30% yields
(entries 4 and 5). This result was completely unexpected
since it is well known that substituted 2-oxazolidinones
are excellent chiral auxiliaries,24,25 which have been
used successfully in a variety of diastereoselective trans-
formations.26 The diastereomeric mixtures of 8c or 8d
were easily separated by column chromatography,
although the absolute configuration of the
diastereomers was not determined. Both diastereomers
of 8c were independently treated with LiOOH in order
Scheme 3.

98
M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
Scheme 4.
to remove the chiral auxiliary.27,28 However, although
(S)-4-benzyl-2-oxazolidinone was recovered in both
cases in ꢀ60% yield, only minor amounts (5%) of the
desired tetracycles (+)-11 (from the minor diastereomer
8c) or (−)-11 (from the major diastereomer 8c) were
obtained after esterification of the crude reaction prod-
ucts (Scheme 5).
face to that of the 2-hydroxymethyl substituent), as
generally occurs in the reactions of (S)-prolinol amide
enolates.24
With the major diastereomer (+)-8e in hand, access to
the alkaloid vinoxine only required the removal of the
chiral auxiliary and the elaboration of the (E)-ethyli-
dene substituent by means of the usual hydrolysis–
decarboxylation procedure. Knowing that (S)-prolinol
amides are efficiently hydrolyzed under acidic condi-
tions,24 we initially considered carrying out both trans-
Although less popular than N-acyloxazolidinones, N-
acyl derivatives of (S)-prolinol and their ethers have
also been used as substrates for diastereoselective reac-
tions,24,25 in particular, alkylations.29,30 In our case,
indolylacetamides 6e and 6f behaved quite differently in
their reactions with pyridinium salt 7. Thus, whereas 6f
led to a nearly equimolecular mixture of diastereomers
8f in low yield (10%, entry 7), the addition of the
dianion of 6e to pyridinium salt 7, followed by in situ
acid-induced cyclization afforded a 3:1 diastereomeric
mixture of tetracycles 8e (25% yield, entry 6), which
were easily separated by column chromatography. The
minor diastereomer, a very polar compound, was not
isolated in all runs. The absolute configuration of the
major diastereomer (+)-8e was assigned as 3S,15S since
it was ultimately converted to (+)-16-epivinoxine and
(−)-vinoxine (see below).
formations in
a single synthetic step. However,
treatment of (+)-8e with 4N HCl at reflux followed by
NaBH4 reduction gave the (E)-ethylidene derivative 12
(33%), which contains a 2-pyrrolidinylmethyl ester com-
ing from an intramolecular O-acylation.24 Complete
removal of the auxiliary was accomplished by trans-
esterification of 12 with MeOMgBr to give (+)-16-
epivinoxine 13 in 50% yield (Scheme 7). Then, (+)-16-
epivinoxine 13 could be partially epimerized to a 2:1
1
mixture (calculated by H NMR) of 13 and (−)-vinox-
ine 1 by treatment with t-BuOK in MeOH at reflux.
These synthetic vinoxines showed NMR spectra identi-
cal to those of the racemic materials.3a
After flash chromatography, the above ratio of 13/1
was shifted to 14:86 (calculated by HPLC). Considering
the specific rotation of the isolated components, (+)-13,
[h]D +109 (c 0.11, CHCl3), and (−)-1, [h]D −18.6 (c not
given, CHCl3),14b the specific rotation [h]D +4 (c 0.1,
CHCl3) of this mixture agrees with the levorotatory
character of 1.
The stereochemical course of the above reaction can be
rationalized as follows. The 15-H/16-H trans configura-
tion of both diastereomeric tetracycles 8e (and all tetra-
cycles 8) is
a consequence of the preferred ul
approaches between the dianion derived from 6e and
pyridinium salt 7, as depicted in Scheme 6. On the
other hand, the absolute configuration 3S,15S of the
major diastereomer (+)-8e implies that the Z-configu-
rated, conformationally locked dianion 6e·2Li preferen-
tially reacts with 7 from its Re face (i.e. the opposite
Finally, the (3S)-absolute configuration of both vinoxi-
nes was unambiguously established by comparing their
CD data with those reported for natural (−)-1.14b Thus,
Scheme 5.

M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
99
Scheme 6.
Scheme 7. Synthesis of (+)-16-epivinoxine and (−)-vinoxine.

100
M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
the CD curves displayed an analogous course, exhibit-
ing Cotton effects of the same sign at the typical umax of
the indole chromophore: a negative Cotton effect at
ꢀ225 nm and two broad positive Cotton effects at
ꢀ270 and ꢀ295 nm.
4.3. (1R,3R,4S)-8-Phenylmenthyl 1-indoleacetate 6b
A solution of indole (0.5 g, 4.27 mmol) in DMF (7.5
mL) was added to a suspension of NaH (60%, 0.25 g,
10.6 mmol) in DMF (3 mL) and the resulting mixture
was stirred at rt for 1 h. Then (+)-(1R,3R,4S)-8-phenyl-
menthyl 2-chloroacetate (1.32 g, 4.27 mmol) was added
at 0°C and the mixture was stirred at rt for 3 h. The
reaction mixture was poured into ice-H2O and
extracted with Et2O. Concentration of the ethereal
extracts followed by flash chromatography (8:2 hex-
anes–Et2O) afforded ester 6b (1.3 g, 78%); [h]2D2 +32.5 (c
3. Conclusion
In conclusion, the role of a series of chiral analogues of
methyl 1-indoleacetate in the nucleophilic addition–
dihydropyridine cyclization sequence with pyridinium
salt 7 has been investigated. When the enolate derived
from (S)-prolinol indolylacetamide 6e is used as the
nucleophile, this sequence provides stereoselective
access to (+)-16-epivinoxine and natural (−)-vinoxine.
1
1.2, CCl4); IR (film) 1748; H NMR (assignment aided
by HMQC) l 0.86 (d, J=6.5 Hz, 3H, CH3), 0.94 (m,
2H, 2%- and 6%-H), 1.14 (m, 2H, 5%-H), 1.18, 1.28 (2s, 6H,
CH3), 1.69 (m, 1H, 1%-H), 1.77 (m, 1H, 2%-H), 1.82 (m,
1H, 6%-H), 2.09 (m, 1H, 4%-H), 3.87, 4.15 (2d, J=15 Hz,
2H, NCH2), 4.87 (td, J=11 and 4.4 Hz, 1H, 3%-H), 6.48
(d, J=3 Hz, 1H, 3-H), 6.90 (d, J=3 Hz, 1H, 2-H),
7.06–7.37 (m, 3H, indole), 7.59 (d, J=8 Hz, 1H, 4-H);
13C NMR (assignment aided by HMQC l 21.6 (C-7%),
22.8, 29.6 (C-9%, C-10%), 26.8 (C-5%), 31.0 (C-1%), 34.2
(C-6%), 39.3 (C-8%), 41.4 (C-2%), 47.2 (NCH2), 49.8 (C-4%),
75.3 (C-3%), 101.9 (C-3), 108.8 (C-7), 119.5 (C-4), 120.8
(C-5), 121.6 (C-6), 125.1 (C-2), 125.3, 127.9, 128.3
(C-3a, Ph), 136.2 (C-7a), 151.8 (Ph), 167.8 (CO). Anal.
calcd for C26H31NO2·1/2H2O: C, 78.36; H, 8.09; N,
3.51. Found: C, 78.40; H, 7.97; N, 3.57%.
4. Experimental
4.1. General
All non-aqueous reactions were performed under an
argon atmosphere. All solvents were dried by standard
methods. Reaction courses and product mixtures were
routinely monitored by TLC on silica gel (pre-coated
F254 Merck plates). Drying of organic extracts during
the workup of reactions was performed over anhydrous
Na2SO4. Evaporation of the solvents was accomplished
under reduced pressure with a rotary evaporator. Flash
chromatography was carried out on SiO2 (silica gel 60,
SDS, 0.04–0.06 mm). Melting points are uncorrected.
4.4. (S)-N-(1-Indolyl)acetyl-4-benzyl-2-oxazolidinone 6c
Pivaloyl chloride (1.42 mL, 10.5 mmol) was slowly
added to a solution of 1-indoleacetic acid (1.84 g, 10.5
mmol) and TEA (1.6 mL, 11.5 mmol) in THF (26 mL)
cooled at 0°C, and the resulting whitish suspension was
stirred at 0°C for 1 h. In a second flask, n-BuLi (10.5
mmol) was added to a solution of (S)-4-benzyl-2-oxa-
zolidinone (2.16 g, 10.5 mmol) in THF (105 mL) cooled
at −78°C. The mixture was stirred at −78°C for 30 min,
and then added to the above suspension cooled at
−78°C. The reaction mixture was allowed to warm to rt
(2 h), poured into a saturated aqueous NH4Cl solution,
and extracted with Et2O. The organic extracts were
washed with a saturated aqueous NaHCO3 solution,
dried and concentrated. The resulting residue was chro-
matographed (flash, 1:1 hexanes–AcOEt) to afford
compound 6c (2.24 g, 64%); mp 131°C (hexanes–Et2O–
acetone); [h]2D2 +69.7 (c 0.3, MeOH); IR (KBr) 1781,
1
Unless otherwise noted, H and 13C NMR spectra were
recorded in CDCl3 solution at 300 and 75.4 MHz,
respectively, using TMS as an internal reference. Micro-
analyses and HRMS were performed by Centro de
Investigacio´n y Desarrollo (CSIC), Barcelona.
4.2. (1R,3R,4S)-Menthyl 1-indoleacetate 6a
A mixture of 1-indoleacetic acid (0.93 g, 5.3 mmol),
DMAP (0.56 g, 4.25 mmol), DCC (0.72 g, 5.8 mmol),
and (−)-menthol (0.89 g, 5.3 mmol) in CH2Cl2 (30 mL)
was stirred at rt for 6 days and then filtered. The filtrate
was concentrated and the residue was chromatographed
(hexanes and 95:5 hexanes–AcOEt, increasing polarity)
to afford ester 6a (0.95 g, 57%); [h]2D2 −43.5 (c 1,
CHCl3); IR (film) 1749, 1733; 1H NMR (assignment
aided by HMQC) l 0.63, 0.78, 0.88 (3d, J=6.6 Hz, 9H,
7%-, 9%-, and 10%-H), 0.90 (m, 3H), 1.23 (tm, J=12, 12
Hz, 1H, 4%-H), 1.42 (m, 1H, 1%-H), 1.60 (m, 3H), 1.95
(dm, J=12 Hz, 1H, 2%-H), 4.65 (td, J=12, 12, 3.7 Hz,
1H, 3%-H), 4.81 (s, 2H, NCH2), 6.55 (d, J=3 Hz, 1H,
3-H), 7.08–7.23 (m, 4H, indole), 7.60 (d, J=8 Hz, 1H,
4-H); 13C NMR (assignment aided by HMQC l 16.1
(C-7%), 20.6, 21.9 (C-9%, C-10%), 23.2 (C-6%), 26.0 (C-8%),
31.3 (C-1%), 34.0 (C-5%), 40.6 (C-2%), 46.7 (C-4%), 48.1
(NCH2), 75.8 (C-3%), 102.2 (C-3), 108.8 (C-7), 119.6
(C-4), 120.9 (C-5), 121.8 (C-6), 128.4 (C-2), 128.5 (C-
3a), 136.4 (C-7a), 168.0 (CO). Anal. calcd for
C20H27NO2·1/2H2O: C, 74.49; H, 8.74; N, 4.34. Found:
C, 74.40; H, 8.61; N, 4.32%.
1
1712; H NMR l 2.81 (dd, J=13.3, 8.8 Hz, 1H), 3.29
(dd, J=13.3, 3.3 Hz, 1H), 4.30 (m, 2H), 4.67 (m, 1H),
5.46, 5.54 (2d, J=18.4 Hz, 2H), 6.61 (d, J=0.3 Hz,
1H), 7.12–7.32 (m, 8H), 7.66 (d, J=8 Hz, 1H); 13C
NMR l 37.5 (CH2), 49.4 (CH2), 55.1 (CH), 67.1 (CH2),
102.6 (CH), 108.8 (CH), 119.8 (CH), 121.1 (CH), 121.9
(CH), 127.4 (CH), 128.2 (C), 128.9, 129.3, 128.6 (CH),
134.4 (C), 136.6 (C), 153.6 (C), 168.0 (C). Anal. calcd
for C20H18N2O3: C, 71.84; H, 5.42; N, 8.38. Found: C,
71.92, H, 5.43, N, 8.30%.
4.5. (S)-N-(1-Indolyl)acetyl-4-isopropyl-2-oxazolidinone
6d
As in the preparation of oxazolidinone 6c, from 1-
indoleacetic acid (0.2 g, 1.14 mmol), triethylamine (0.17

M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
101
mL, 1.25 mmol), pivaloyl chloride (0.15 mL, 1.25
mmol), (S)-4-isopropyl-2-oxazolidinone (0.16 g, 1.26
mmol) and n-BuLi (1.26 mmol). Purification by flash
chromatography (7:3 hexanes–AcOEt) afforded the
pure oxazolidinone 6d (180 mg, 55%); mp 100°C (Et2O–
hexanes); [h]2D2 +86.2 (c 0.5, CHCl3); IR (KBr) 1792,
NMR l (minor rotamer, most significant signals) 21.5
(CH2), 28.6 (CH2), 45.5 (CH2), 48.3 (CH2), 56.5 (CH),
58.9 (CH3), 74.9 (CH2). Anal. calcd for C16H20N2O2: C,
70.56; H, 7.40; N, 10.28. Found: C, 70.41; H, 7.45; N,
10.12%.
1
1711; H NMR l 0.86, 0.87 (2 d, J=7 Hz, 6H), 2.33
4.8. 2-Iodoethyl acetate
(m, 1H), 4.31 (m, 3H), 5.44, 5.52 (2d, J=18.4 Hz, 2H),
6.57 (d, J=3 Hz, 1H), 7.09–7.25 (m, 4H), 7.63 (dm,
J=7.8 Hz, 1H); 13C NMR l 14.6 (CH3), 17.7 (CH3),
28.1 (CH), 49.4 (CH2), 58.5 (CH), 64.3 (CH2), 102.5
(CH), 108.8 (CH), 119.8 (CH), 121.1 (CH), 121.9 (CH),
128.5 (C), 128.7 (CH), 136.6 (C), 154.3 (C), 167.9 (C).
Anal. calcd for C16H18N2O3: C, 67.12; H, 6.33; N, 9.78.
Found: C, 67.01; H, 6.31; N, 9.75%.
Sodium iodide (9 g, 60 mmol) was added to a solution
of 2-bromoethyl acetate (5 g, 29.9 mmol) in anhydrous
acetone (50 mL) and the resulting mixture was stirred
at rt overnight. The reaction mixture was filtered and
concentrated. The resulting residue was dissolved in
AcOEt and washed with H2O. The solvent was
removed, and the crude residue (5.4 g, 87%) was used
directly in the next reaction.
4.6. (S)-N-(1-Indolyl)acetylprolinol 6e
4.9. 1-(2-Acetoxyethyl)-3-[(E)-2-(methoxycarbonyl)-
Pivaloyl chloride (0.35 mL, 2.86 mmol) was slowly
added to a solution of 1-indoleacetic acid (0.5 g, 2.86
mmol) and triethylamine (0.44 mL, 3.14 mmol) in THF
(20 mL) cooled at 0°C, and the resulting whitish sus-
pension was stirred at 0°C for 1 h. (S)-Prolinol (0.28
mL, 2.86 mmol) was added and the resulting solution
was stirred at rt for 30 min. The reaction mixture was
poured into H2O and extracted with CH2Cl2. Evapora-
tion of the dried organic extracts followed by flash
chromatography (97:3 AcOEt–MeOH) afforded 6e
(0.66 g, 90%); mp 100°C (Et2O–CH2Cl2); [h]2D2 −49 (c 1,
CHCl3); IR (KBr) 3429, 1632; 1H NMR l 1.57 (m, 1H),
1.80–1.99 (m, 3H), 3.30 (m, 1H), 3.39 (m, 1H), 3.59 (m,
2H), 4.15, 4.47 (2m, 2H), 4.77 (s, 2H), 6.55 (d, J=3.3
Hz, 1H), 7.06–7.22 (m, 4H), 7.63 (d, J=7.8 Hz, 1H);
13C NMR l 24.4 (CH2), 27.7 (CH2), 47.2 (CH2), 49.0
(CH2), 61.8 (CH), 66.2 (CH2), 102.3 (CH), 108.9 (CH),
119.7 (CH), 121.1 (CH), 121.9 (CH), 128.4 (CH), 129.0
(C), 136.4 (C), 168.2 (C). Anal. calcd for C15H18N2O2·1/
10H2O: C, 69.26; H, 7.05; N, 10.77. Found: C, 69.11;
H, 7.15; N, 10.84%.
vinyl]pyridinium iodide 7
A mixture of methyl (E)-3-(3-pyridyl)acrylate (6.4 g, 39
mmol) and 2-acetoxyethyl iodide (10 g, 46 mmol) was
heated at 90–100°C for 2 h. The mixture was diluted
with Et2O, and the resulting precipitate was filtered to
afford pyridinium iodide 7 (13.2 g, 90%); mp 161–
1
163°C (acetone–MeOH); H NMR (DMSO-d6) l 2.03
(s, 3H), 3.84 (s, 3H), 4.62 (t, J=5.1 Hz, 2H), 4.92 (t,
J=5.1 Hz, 2H), 7.14 (d, J=16.2 Hz, 1H), 7.85 (d,
J=16.2 Hz, 1H), 8.29 (dd, J=8, 6.1 Hz, 1H), 9.03 (d,
J=8 Hz, 1H), 9.14 (d, J=6.1 Hz, 1H), 9.59 (s, 1H).
Anal. calcd for C13H16NO4I·H2O: C, 39.51; H, 4.59; N,
3.54. Found: C, 39.55; H, 4.19; N, 3.54%.
4.10. (1R,3R,4S)-Menthyl (1R*,2S*,6S*)-5-(2-acetoxy-
ethyl)-3-[(E)-2-(methoxycarbonyl)vinyl]-1,2,5,6-tetra-
hydro-2,6-methano[1,4]diazocino[1,2-a]indole-1-
carboxylate 8a
LHMDS (1.7 mmol) was added to a solution of ester 6a
(0.5 g, 1.6 mmol) in THF (40 mL) cooled at −78°C, and
the resulting solution was stirred at −78°C for 45 min.
Pyridinium iodide 7 (0.6 g, 1.6 mmol) was added in
portions, and the mixture was allowed to rise to −30°C
and stirred at this temperature for 1.5 h. A saturated
C6H6 solution of dry HCl was added dropwise to bring
the pH to 3.5–4, and the reaction mixture was heated at
60°C for 2 h. The reaction mixture was poured into a
saturated aqueous Na2CO3 solution and extracted with
Et2O. Evaporation of the ethereal extracts followed by
flash chromatography (hexanes–AcOEt, increasing
polarity) afforded tetracycles 8a (353 mg, 40%, 1:1
diastereomeric mixture); IR (film) 1741; 1H NMR
(most significant signals from the mixture) l 0.45, 0.65,
0.75, 0.88, 0.95 (5d, J=6.5 Hz, 9H), 2.07 (s, 3H), 3.30
(br s, 1H), 3.70 (s, 3H), 4.10, 4.25 (m, 2H), 4.60 (br s,
1H), 4.70 (m, 1H), 5.05, 5.15 (2s, 1H, 16-H), 5.70, 5.75
(2d, J=15 Hz, 1H), 6.40 (s, 2H), 7.0–7.4 (m, 4H), 7.50
(d, J=8 Hz, 1H); 13C NMR l 15.4, 16.2 (CH3), 20.5
(CH3), 21.6 (CH3), 21.8 (CH3), 22.6 (CH2), 23.4 (CH2),
25.4, 26.5 (CH), 28.9, 29.1 (CH), 31.2 (CH), 33.9 (CH2),
40.4, 40.5 (CH2), 46.5, 46.6 (CH), 48.5 (CH), 50.8
4.7. (S)-N-(1-Indolyl)acetyl-2-(methoxymethyl)-
pyrrolidine 6f
A solution of prolinol 6e (1 g, 3.8 mmol) in THF (40
mL) was added to a suspension of NaH (60%, 0.34 g,
8.57 mmol) in THF (10 mL) at 0°C, and the resulting
suspension was stirred for 30 min at 0°C. MeI (1.5 mL,
14 mmol) was added and the reaction mixture was
stirred at rt for 2 h. The mixture was poured into H2O
and extracted with Et2O. The organic extracts were
dried and concentrated, and the resulting residue was
chromatographed (flash, 3:7 hexanes–AcOEt) to afford
6f (0.87 g, 83%, 3:2 mixture of rotamers); mp 72°C
(Et2O–hexane); [h]2D2 −39.3 (c 1, CHCl3); IR (film) 1655;
1H NMR l 1.80–2.0 (m, 4H), 3.28 (s, 3H), 3.30 (m,
1H), 3.45 (m, 3H), 4.15, 4.21 (2m, 1H), 4.73 (s, NCH2),
4.85, 5.15 (2d, J=15 Hz, NCH2), 6.52 (d, J=3 Hz,
1H), 7.07–7.30 (m, 4H), 5.59 (d, J=7.5 Hz, 1H); 13C
NMR (major rotamer) l 24.1 (CH2), 26.9 (CH2), 46.5
(CH2), 48.9 (CH2), 57.0 (CH), 58.7 (CH3), 71.8 (CH2),
101.8 (CH), 108.9 (CH), 119.4 (CH), 120.6 (CH), 121.6
(CH), 128.5 (CH), 128.7 (C), 136.4 (C), 165.9 (C); 13C

102
M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
(CH3), 51.7 (CH2), 59.2, 59.7 (CH), 61.5, 61.6 (CH2),
75.8, 75.9 (CH), 99.3 (CH), 104.0 (CH), 105.9 (C),
109.0 (CH), 120.2, 120.3 (CH), 120.6, 120.7 (CH),
122.0, 122.1 (CH), 127.6 (C), 134.6, 134.7 (C), 136.5
(C), 144.1 (CH), 144.9 (CH), 168.7, 169.3, 169.7, 170.4
(CO). Anal. calcd for C33H42N2O6·1/3CH2Cl2: C,
67.61; H, 7.26; N, 4.73. Found: C, 67.27; H, 7.26; N,
4.80%.
Method B. Operating as above, but using LDA as the
base, tetracycles 8b (2:1 diastereomeric mixture, 28%)
and 9b (1:1 diastereomeric mixture, 21%) were
obtained.
4.12. (1R,3R,4S)-Menthyl (1R*,2S*,6S*)-(3E)-ethyli-
dene-5-(2-hydroxyethyl)-1,2,5,6-tetrahydro-2,6-methano-
[1,4]diazocino-[1,2-a]indole-1-carboxylate 10a
4.11. Reaction of ester 6b with pyridinium iodide 7
A suspension of tetracycles 8a (1:1 diastereomeric mix-
ture, 0.5 g, 0.88 mmol) in MeOH (12 mL) and aqueous
HCl (4N, 36 mL) was refluxed for 2 h and then
concentrated. The residue was dissolved in a methano-
lic solution of dry HCl (1.5N, 60 mL) and stirred at rt
overnight. The solvent was removed, and the residue
was dissolved in MeOH (45 mL), treated with NaBH4
(120 mg, 3.6 mmol) at 0°C, and stirred at this tempera-
ture for 1 h. The solvent was removed, and the residue
was partitioned between H2O and Et2O and extracted
with Et2O. The organic extracts were dried and con-
centrated, and the resultant residue was chro-
matographed (1:1 hexanes–AcOEt) to give tetracycles
10a (115 mg, 28%. 1:1 diastereomeric mixture); IR
Method A. Ester 6b (0.65 g, 1.67 mmol) in anhydrous
THF (45 mL) was allowed to react with LHMDS (1.84
mmol) and then with pyridinium iodide 7 (0.63 g, 1.67
mmol) as described above. After workup, the crude
residue was chromatographed. Elution with 8:2 hex-
anes–Et2O
afforded
(1R,3R,4S)-8-phenylmenthyl
(1R*,2S*,6S*)-5-(2-acetoxyethyl)-3-[(E)-2-(methoxy-
carbonyl)vinyl]-1,2,5,6-tetrahydro-2,6-methano[1,4]dia-
zocino[1,2-a]indole-1-carboxylate 8b (300 mg, 28%.
2.5:1 diastereomeric mixture); IR (film): 1742, 1702,
1584; 1H NMR (major isomer, assignment aided by
HMQC) l 0.82 (m, 1H, 6%-H), 0.85 (d, J=6.5 Hz, 3H,
CH3), 0.94 (m, 1H, 2%-H), 1.30, 1.44 (2s, 6H, CH3),
1.42 (m, 1H, 1%-H), 1.59 (m, 1H, 6%-H), 1.91 (m, 1H,
2%-H), 1.94 (m, 1H, 14-H) 2.07 (s, 3H, MeCO), 2.11
(1H, 4%-H), 2.23 (dm, J=15 Hz, 1H, 14-H), 3.21 (m,
2H, 5-H), 3.81 (s, 3H, OMe), 4.12, 4.44 (2m, 2H, 6-H),
4.56 (br s, 1H, 3-H), 4.67 (s, 1H, 16-H), 4.90 (m, 1H,
3%-H), 5.66 (d, J=15 Hz, 1H, 18-H), 6.39 (s, 1H, 7-H),
6.41 (s, 1H, 21-H), 6.99–7.42 (m, 8H, Ar), 7.56 (d, J=8
1
(KBr) 1738; H NMR (from the mixture, assignment
aided by HMQC) l 0.50, 0.59, 0.75, 0.86, 0.92 (5d,
J=6.5 Hz, 9H, 3CH3), 0.90 (masked, 2H, 2%-H and
6%-H), 1.05 (m, 1H, 4%-H), 1.20 (m, 1H, 8%-H), 1.45 (m,
1H, 1%-H), 1.70 (m, 3H, 5%-H and 6%-H), 1.78 (dd,
J=6.9 Hz, 3H, 18-H), 1.90 (m, 1H, 2%-H), 2.05 (dt,
J=14, 3 Hz, 1H, 14-H), 2.35 (m, 2H, 5-H and 14-H),
2.55 (m, 1H, 21-H), 2.80 (m, 1H, 5-H), 3.05 (d, J=15
Hz, 1H, 21-H), 3.45 (br s, 1H, 15-H), 3.65 (m, 2H,
6-H), 4.05 (br s, 1H, 3-H), 4.60, 4.65 (2td, J=11, 3 Hz,
1H, 3%-H), 4.80 and 4.82 (2s, 1H, 16-H), 5.43 (br q,
J=6.9 Hz, 1H, 18-H), 6.31, 6.32 (2s, 1H, 7-H), 7.05–
7.20 (m, 3H), 7.60 (m, 1H, 9-H); 13C NMR (assign-
ment aided by HMQC) l 12.5 (C-18), 15.4, 16.1 (C-7%),
20.6, 20.7, 21.9 (C-9%, C-10%), 22.6, 23.1 (C-5%), 25.0,
26.4 (C-8%), 27.6 (C-14), 31.2, 31.3 (C-15), 31.6 (C-1%),
34.0, 34.1 (C-6%), 40.4, 40.5 (C-2%), 46.6, 46.7 (C-4%),
51.6, 51.7 (C-3), 54.2 (C-21), 56.3 (C-5), 57.7 (C-6),
59.8, 60.0 (C-16), 75.6, 75.9 (C-3%), 101.1 (C-7), 108.6
(C-12), 120.1-121.5 (indole, C-19), 127.9 (C-8), 132.0,
135.1, 136.0 (C-2, C-13, C-20), 170.0, 170.2 (CO);
HRMS calcd for C29H40N2O2 464.3038, found
464.3048.
1
Hz, 1H, 9-H); H NMR (minor isomer) l 4.90 (s, 1H,
16-H), 5.57 (d, J=15 Hz, 1H, 18-H); 13C NMR (major
isomer, assignment aided by HMQC) l 20.8 (MeCO),
21.7, 25.6, 28.3 (C-7%, C-9%, C-10%), 22.9 (C-14), 26.9
(C-5%), 31.2 (C-1%), 34.3 (C-6%), 40.2 (C-8%), 41.5 (C-2%),
48.6 (C-3), 49.9 (C-4%), 51.1 (OMe), 51.8 (C-5), 59.4
(C-16), 61.7 (C-6), 75.2 (C-3%), 99.5 (C-7), 104.5 (C-18),
106.0 (C-20), 109.6 (C-12), 120.4 (C-9), 120.8 (C-10),
122.1 (C-11), 125.1, 128.1 (Ph), 134.6 (C-2), 136.8 (C-
13), 150.7 (Ph), 144.3 (C-21), 145.1 (C-19), 168.9,
169.6, 170.7 (CO). Anal. calcd for C39H48N2O6: C,
73.33; H, 7.26; N, 4.40. Found: C, 73.28; H, 7.25; N,
4.33%. On elution with 97:3 Et2O–MeOH the deacetyl
derivatives 9b were obtained (93 mg, 9%. 1:1
diastereomeric mixture); IR (film) 3400, 1740, 1702,
1
1580; H NMR (most significant signals from the mix-
ture) l 0.85 (d, J=6.5 Hz, 3H), 1.33, 1.45 (2s, 6H),
2.88, 3.26 (2 br s, 1H), 3.10, 3.48 (2 m), 3.70 (m, 2H),
3.76, 3.80 (2s, 6H), 4.59 (br s, 1H), 4.67, 4.90 (2s, 1H,
16-H), 4.85 (m, 1H), 5.53, 5.65 (2d, J=15 Hz, 1H),
6.38 (s, 1H), 6.44, 6.47 (2s, 1H), 6.96–7.42 (m, 8H),
7.53, 7.55 (2d, J=8 Hz, 1H); 13C NMR (from the
mixture) l 21.7 (CH3), 22.9, 23.0 (CH2), 25.2, 25.5
(CH3), 26.8, 27.1 (CH2), 27.1, 27.6 (CH), 27.6, 28.3
(CH3), 31.2, 31.3 (CH), 34.3 (CH2), 40.1 (C), 41.4, 42.0
(CH2), 48.9 (CH), 49.7, 49.8 (CH), 51.1 (CH3), 55.4
(CH2), 59.4, 59.7 (CH), 60.6 (CH2), 75.5, 76.7 (CH),
99.3, 99.4 (CH), 103.6 (CH), 105.5 (C), 109.3, 109.5
(CH), 120.3, 120.4 (CH), 120.8 (CH), 122.0, 122.1
(CH), 125.4 (CH), 125.5 (CH), 127.9 (C), 128.1 (CH),
135.1, 135.0 (C), 136.6, 136.7 (C), 144.9 (CH), 145.4
(CH), 150.4, 150.6 (C), 169.2 (C), 169.7 (C).
4.13. (1R,3R,4S)-8-Phenylmenthyl (1R*,2S*,6S*)-3(E)-
ethylidene-5-(2-hydroxyethyl)-1,2,5,6-tetrahydro-2,6-
methano[1,4]diazocino[1,2-a]indole-1-carboxylate 10b
Operating as above, from tetracycles 8b (2.5:1
diastereomeric mixture, 0.22 g, 0.36 mmol) afforded
the ethylidene derivatives 10b (58 mg, 30%, 2.5:1
diastereomeric mixture) after flash chromatography
(AcOEt); IR (film) 3400, 1744; 1H NMR (from the
mixture, assignment aided by HMQC) l 0.85 (d, J=
6.5 Hz, 3H, CH3), 1.01 (2m, 2H, 2%-H and 6%-H), 1.25,
1.38 (2s, 6H, CH3), 1.45 (m, 1H, 1%-H), 1.65 (dm, 1H,
6%-H), 1.75 (2dd, J=6.8 Hz, 3H, 18-H), 1.90 (m, 3H,
4%-H and 2%-H), 2.05 (dm, J=15 Hz, 1H, 14-H), 2.33
(m, 1H, 14-H), 2.42 (dm, J=12.5 Hz, 1H, 21-H), 2.58,
2.80 (2m, 2H, 5-H), 2.96 (d, J=12.5 Hz, 1H, 21-H),

M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
103
3.39, 3.45 (2 br s, 1H, 15-H), 3.63 (m, 2H, 6-H), 4.02,
4.12 (2t, 1H, 3-H), 4.22, 4.79 (2s, 1H, 16-H), 4.80 (m,
1H, 3%-H), 5.49 (m, 1H, 19-H), 6.30 (s, 1H, 7-H),
7.01–7.65 (m, 9H, Ar); 13C NMR (major diastereomer,
assignment aided by HMQC) l 12.7 (C-18), 21.7, 26.1
27.7 (C-7%, C-9%, C-10%), 26.7 (C-5%), 27.6 (C-14), 31.3
(C-1%, C-15), 34.2 (C-6%), 39.7 (C-8%), 41.3 (C-2%), 50.1
(C-4%), 51.8 (C-3), 54.2 (C-5), 56.3 (C-21), 57.7 (C-6),
59.7 (C-16), 77.6 (C-3%), 101.4 (C-7), 109.2 (C-12),
120.1, 120.6, 121.3, 121.5 (indole, C-19), 125.3–128.1
(Ph), 128.6 (C-8), 131.8, 134.9, 137.4 (C-2, C-13, C-20),
151.3 (Ph), 169.1 (CO); HRMS calcd for C35H44N2O3
540.3351, found 540.3353.
J=15.4 Hz, 1H, 18-H), 6.46 (s, 1H, 21-H), 6.48 (s, 1H,
7-H), 6.58 (d, J=1.3 Hz, 1H, 16-H), 7.06–7.28 (m, 9H,
Ar, 19-H), 7.59 (d, J=7.5 Hz, 1H, 9-H); 13C NMR
(assignment aided by HMQC) l 20.8 (COMe), 22.0
(C-14), 28.8 (C-15), 37.1 (CH2Ph), 48.7 (C-3), 51.1
(OMe), 51.5 (C-5), 56.2 (C-4), 58.2 (C-16), 61.8 (C-6),
66.6 (C-5%), 99.7 (C-7), 105.1 (C-18), 105.4 (C-20),
109.1 (C-12), 120.7 (C-9), 121.0 (C-10), 122.4 (C-11),
128.0 (C-8), 127.3, 128.8, 129.4, 134.5 (Ph), 135.5 (C-
2), 137.0 (C-13), 144.9 (C-21), 145.3 (C-19), 152.9,
169.2, 170.7 (CO). Anal. calcd for C33H33N3O7·H2O: C,
65.88; H, 5.86; N, 6.98. Found: C, 65.82; H, 5.77; N,
7.00%.
4.15. Methyl (1R*,2S*,6S*)-5-(2-acetoxyethyl)-1-[(4S)-
isopropyl-2-oxo-1,3-oxazolidinylcarbonyl]-1,2,5,6-tetra-
hydro-2,6-methano[1,4]diazocino[1,2-a]indole-(3E)-
acrylate 8d
4.14. Methyl (1R*,2S*,6S*)-5-(2-acetoxyethyl)-1-[(4S)-
benzyl-2-oxo-1,3-oxazolidinylcarbonyl]-1,2,5,6-tetra-
hydro-2,6-methano[1,4]diazocino[1,2-a]indole-(3E)-
acrylate 8c
Operating as in the preparation of tetracycles 8a, from
oxazolidinone 6d (0.37 g, 1.3 mmol), and pyridinium
iodide 7 (0.49 g, 1.29 mmol), a residue was obtained
and then chromatographed. Elution with 1:1 hexanes–
AcOEt afforded tetracycle 8d (70 mg, 13%, minor
diastereomer); mp 158°C (Et2O–hexanes); [h]2D2 +849 (c
0.5, CHCl3); IR (KBr) 1777, 1737, 1698, 1582; 1H
NMR l 0.87, 0.93 (2d, J=6.8 Hz, 6H), 1.90 (dt,
J=13.1, 3.3 Hz, 1H), 2.08 (s, 3H), 2.25 (m, 1H), 2.45
(dt, J=13.1, 2.5 Hz, 1H), 3.20 (m, 1H), 3.25 (br s, 1H),
3.61 (dt, J=16, 4.5 Hz, 1H), 3.74 (s, 3H), 4.11 (m,
1H), 4.39 (m, 4H), 4.60 (br s, 1H), 6.05 (d, J=15 Hz,
1H), 6.44, 6.46 (2s, 2H), 6.56 (s, 1H, 16-H), 7.10–7.26
(m, 4H), 7.60 (d, J=7.8 Hz, 1H); 13C NMR l 15.0,
17.7 (CH3), 20.8 (CH3), 21.9 (CH2), 28.4 (CH), 29.2
(CH), 48.7 (CH), 51.1 (CH3), 51.6 (CH2), 58.2 (CH),
58.9 (CH), 61.7 (CH2), 64.2 (CH2), 99.8 (CH), 105.4
(CH), 105.5 (C), 109.7 (CH), 120.7 (CH), 121.0 (CH),
122.5 (CH), 128.1 (C), 135.4 (C), 137.3 (C), 144.9
(CH), 145.4 (CH), 153.7, 169.4, 170.5 (C). Anal. calcd
for C29H33N3O7·1/2H2O: C, 63.96; H, 6.29; N, 7.72.
Found: C, 64.03; H, 6.65; N, 7.43%. Elution with 4:6
hexane–AcOEt afforded tetracycle 8d (98 mg, 18%,
major diastereomer); mp 195°C (Et2O–hexanes); [h]D22
−962 (c 0.5, CHCl3); IR (film) 1778, 1738, 1697, 1582;
1H NMR (assignment aided by HMQC) l 0.75, 0.80
(2d, J=7 Hz, 6H, CH3), 1.86 (dt, J=13, 3 Hz, 1H,
14-H), 2.06 (s, 3H, COMe), 2.11 (m, 1H, CH), 2.61 (dt,
J=13, 2.4 Hz, 1H, 14-H), 3.20 (m, 2H, 15-H, 5-H),
3.60 (dt, J=15, 4 Hz, 1H, 5-H), 3.72 (s, 3H, OMe),
4.11 (m, 1H, 6-H), 4.35 (m, 4H, 4%-H, 5%-H, 6-H), 4.60
(br s, 1H, 3-H), 5.94 (d, J=15 Hz, 1H, 18-H), 6.43,
6.46 (2s, 2H, 21-H, 7-H), 6.57 (s, 1H, 16-H), 7.06–7.25
(m, 4H, indole, 19-H), 7.55 (d, J=7.8 Hz, 1H, 9-H);
13C NMR (assignment aided by HMQC) l 14.1, 17.7
(Me), 20.8 (MeCO), 21.9 (C-14), 27.6 (CH), 28.5 (C-
15), 48.7 (C-3), 51.0 (OMe), 51.5 (C-5), 58.1 (C-16),
59.2 (C-4%), 61.7 (C-6), 63.6 (C-5%), 99.6 (C-7), 105.3
(C-18), 105.5 (C-20), 109.0 (C-12), 120.7 (C-9), 121.0
(C-10), 122.3 (C-11), 128.1 (C-8), 135.5 (C-2), 136.9
(C-13), 144.9 (C-21), 145.4 (C-19), 156.6, 169.3, 170.4,
170.7 (CO).
Oxazolidinone 6c (0.3 g, 0.89 mmol) was allowed to
react with LDA (0.97 mmol) in THF (30 mL) at −78°C
for 30 min, and then with pyridinium iodide 7 (0.34 g,
0.89 mmol) as described for the preparation of tetra-
cycles 8a. After the usual workup, the resulting residue
was chromatographed. Elution with 1:1 hexanes–
AcOEt afforded tetracycle 8c (62 mg, 12%, minor
diastereomer); mp 166°C (Et2O–hexanes); [h]2D2 +508 (c
1, CHCl3), +471 (c 0.5, acetone); IR (KBr) 1778, 1736,
1698, 1581; ms, m/z (rel. intensity) 583 (M+, 18), 379
(100); 1H NMR (500 MHz, assignment aided by
NOESY and HMQC) l 1.86 (dt, J=13, 3.2 Hz, 1H,
14-H), 2.07 (s, 3H, COMe), 2.47 (dt, J=13, 2.7 Hz,
1H, 14-H), 2.73 (dd, J=13.2, 9.5 Hz, 1H, CH2Ph),
3.18 (m, 1H, 15-H), 3.20 (m, 2H, CH2Ph and 5-H),
3.59 (dt, J=15, 4.1 Hz, 1H, 5-H), 3.73 (s, 3H, OMe),
4.12 (m, 1H, 6-H), 4.26 (m, 2H, 5%-H), 4.15 (m, 1H,
6-H), 4.60 (br s, 1H, 3-H), 4.63 (m, 1H, 4%-H), 5.98 (d,
J=15.4 Hz, 1H, 18-H), 6.44, 6.45 (2s, 2H, 21-H, 7-H),
6.53 (d, J=1.6 Hz, 1H, 16-H), 7.06–7.32 (m, 9H, Ar,
19-H), 7.57 (dm, J=8 Hz, 1H, 9-H); 13C NMR (assign-
ment aided by HMQC) l 20.8 (MeCO), 21.9 (C-14),
28.8 (C-15), 38.3 (CH2Ph), 48.7 (C-3), 51.0 (OMe), 51.5
(C-5), 54.8 (C-4%), 58.5 (C-16), 61.8 (C-6), 67.3 (C-5%),
99.8 (C-7), 105.3 (C-20), 105.4 (C-18), 108.9 (C-12),
120.7 (C-9), 121.0 (C-10), 122.5 (C-11), 128.1 (C-8),
127.5, 128.1, 128.9, 134.5 (Ph), 135.5 (C-2), 144.9 (C-
21), 145.3 (C-19), 153.2, 169.3, 170.6 (CO), 170.7 (CO).
Anal. calcd for C33H33N3O7: C, 67.91; H, 5.69; N, 7.20.
Found: C, 67.80; H, 5.76; N, 7.13%. Elution with 4:6
hexane–AcOEt afforded tetracycle 8c (93 mg, 18%,
major diastereomer); [h]2D2 −539 (c 1, CHCl3), −387.6 (c
0.5, acetone); IR (KBr) 1778, 1737, 1696, 1578; ms,
1
m/z (rel. intensity) 583 (M+, 15), 379 (100); H NMR
(500 MHz, assignment aided by NOESY and HMQC)
l 1.91 (dt, J=13, 3.5 Hz, 1H, 14-H), 2.09 (s, 3H,
COMe), 2.64 (dt, J=13, 2.5 Hz, 1H, 14-H), 2.70 (dd,
J=13.5, 9.5 Hz, 1H, CH2Ph), 3.02 (dd, J=14, 2.5 Hz,
1H, CH2Ph), 3.20 (br s, 1H, 15-H), 3.24 (m, 1H, 5-H),
3.64 (dt, J=15, 4.4 Hz, 1H, 5-H), 3.71 (s, 3H, OMe),
4.15 (m, 1H, 6-H), 4.30 (m, 2H, 5%-H), 4.40 (m, 1H,
6-H), 4.57 (m, 1H, 4%-H), 4.64 (br s, 1H, 3-H), 5.87 (d,

104
M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
1
4.16. Methyl (1R*,2S*,6S*)-5-(2-hydroxyethyl)-1-
(methoxycarbonyl)-1,2,5,6-tetrahydro-2,6-methano[1,4]-
diazocino[1,2-a]indole-(3E)-acrylate 113a
cycle 8e (35 mg, 6%, minor diastereomer); H NMR
(most significant signals) l 2.04 (s, 3H), 2.7 (m, 1H),
3.73 (s, 3H), 4.05 (br s, 1H), 5.23 (br s, 1H, 16-H), 5.76
(d, J=15 Hz, 1H), 6.28 (s, 1H), 6.32 (s, 1H), 6.88–7.26
(m, 4H), 7.47 (d, J=7.5 Hz, 1H); 13C NMR l 20.8
(CH3), 24.1 (CH2), 24.6 (CH2), 25.5 (CH), 27.6 (CH2),
47.7 (CH2), 50.5 (CH), 50.9 (CH3), 53.0 (CH2), 61.3
(CH), 61.5 (CH2), 61.8 (CH), 65.1 (CH2), 99.7 (CH),
104.6 (CH), 107.9 (CH), 108.6 (C), 120.4 (CH), 121.0
(CH), 121.1 (CH), 128.5 (C), 136.4 (2C), 141.5 (CH),
144.2 (CH), 168.3 (C), 169.9 (C), 170.6 (CO).
Aqueous hydrogen peroxide (33%, 0.2 mL, 1.76 mmol)
and LiOH·H2O (0.024 g, 0.55 mmol) were added to a
solution of tetracycle 8c (major diastereomer, 0.1 g,
0.17 mmol) in THF (3 mL) and H2O (1 mL), cooled at
0°C, and the resulting mixture was stirred at 0°C for 45
min. The reaction mixture was poured into an aqueous
Na2SO3 solution, acidified with aqueous HCl (4N) and
extracted with AcOEt. The organic extracts were dried
and concentrated. The resulting residue was dissolved
in a methanolic solution of dry HCl (1.5N, 20 mL) and
stirred at rt for 15 h. The solvent was removed and the
residue was partitioned between a saturated aqueous
Na2CO3 solution and Et2O, and extracted with Et2O.
The organic extracts were dried and concentrated and
the residue was chromatographed (flash, 1:1 Et2O–
CH2Cl2). Initial elution gave (S)-4-benzyl-2-oxazolidi-
none (17 mg, 56%). Further elution gave tetracycle
(−)-11 (4 mg, 5%); [h]2D2 −285 (c 0.15, CHCl3). Similarly,
starting from tetracycle 8c (minor diastereomer, 0.1 g,
0.17 mmol) tetracycle (+)-11 was obtained: 4 mg (5%);
[h]2D2 +300 (c 0.17, CHCl3).
4.18. Methyl (1R*,2S*,6S*)-5-(2-acetoxyethyl)-1-[(2S)-
(methoxymethyl)pyrrolidinylcarbonyl]-1,2,5,6-tetrahydro-
2,6-methano[1,4]diazocino[1,2-a]indole-(3E)-acrylate 8f
Indole 6f (0.2 g, 0.73 mmol) in THF (7 mL) was
allowed to react with LDA (0.80 mmol) in THF (4 mL)
and then with pyridinium iodide 7 (0.27 g, 0.73 mmol)
and HMPA (0.2 mL, 0.73 mmol) as described for the
preparation of 8e. After workup the resulting crude
residue was chromatographed (flash, 4:6 hexanes–
AcOEt) to give tetracycles 8f (38 mg, 10%, 1:1
diastereomeric mixture); mp 130°C (Et2O–hexanes); IR
(film) 1741, 1696, 1646; 1H NMR (most significant
signals from the mixture) l 2.07 (s, 3H), 3.15 (br s, 1H),
3.31 (s, 3H), 3.75 (s, 3H), 4.61 (br s, 1H), 5.09, 5.18 (2s,
1H, 16-H), 6.40 (s, 1H), 6.41 (s, 1H), 6.85–7.3 (m, 4H),
7.55 (d, J=7.5 Hz, 1H); 13C NMR (from the mixture)
l 20.8 (CH3) 21.9, 22.0 (CH2), 25.3, 24.7 (CH2), 26.9,
27.3 (CH2), 28.8, 28.2 (CH), 47.7 (CH2), 49.0, 48.9
(CH), 51.0 (CH3), 51.7 (CH2), 57.0 (CH), 57.6 (CH),
58.8, 59.0 (CH3), 61.8 (CH2), 71.9, 71.7 (CH2), 99.2,
99.0 (CH), 103.2 (CH), 106.3, 106.4 (C), 108.6, 108.9
(CH), 120.3, 120.5 (CH), 121.0 (CH), 121.8, 122.0
(CH), 127.9, 128.0 (C), 135.6 (C), 136.4, 136.7 (C),
145.2 (CH), 146.1 (CH), 167.9, 167.6, 168.7, 168.0,
170.7 (C). Anal. calcd for C29H35N3O6·H2O: C, 64.54;
H, 6.81; N, 7.78. Found: C, 64.82; H, 6.59; N, 7.90%.
4.17. Methyl (1R*,2S*,6S*)-5-(2-acetoxyethyl)-1-[(2S)-
(hydroxymethyl)pyrrolidinylcarbonyl]-1,2,5,6-tetrahydro-
2,6-methano[1,4]diazocino[1,2-a]indole-(3E)-acrylate 8e
A solution of amide 6e (0.3 g, 1.16 mmol) in THF (10
mL) was added to a solution of LDA (2.4 mmol) in
THF (6 mL) cooled at 0°C, and the mixture was stirred
at 0°C for 1 h. The resulting solution was cooled at
−60°C and pyridinium iodide 7 (0.44 g, 1.16 mmol) was
added portionwise. The reaction mixture was allowed
to rise to −40°C, HMPA (0.17 mL, 1.16 mmol) was
added and the mixture was stirred at −40°C for 1.5 h,
and then cooled again at −70°C. A saturated C6H6
solution of dry HCl was added to bring the pH to 3–4,
and the mixture was stirred at rt for 4 h. The reaction
mixture was poured into a 10% aqueous Na2CO3 solu-
tion and extracted with Et2O. After concentration of
the organic extracts the resulting residue was chro-
matographed. Elution with AcOEt afforded tetracycle
(+)-8e (110 mg, 19%, major diastereomer); mp 107°C
(Et2O); [h]2D2 +608 (c 0.5, CHCl3); IR (NaCl) 3432,
4.19. (S)-(2-Pyrrolidinyl)methyl (1R,2S,6S)-(3E)-ethyli-
dene-5-(2-hydroxyethyl)-1,2,5,6-tetrahydro-2,6-meth-
ano[1,4]diazocino[1,2-a]indole-1-carboxylate 12
A suspension of tetracycle (+)-8e (major diastereomer,
60 mg, 0.12 mmol) in EtOH (2 mL) and aqueous HCl
(4N, 5 mL) was heated under reflux for 2 h and then
concentrated. The residue was dissolved in MeOH (5
mL), treated with NaBH4 (40 mg, excess) at 0°C, and
stirred at this temperature for 1 h. The solvent was
removed, and the residue was partitioned between H2O
and Et2O, and extracted with Et2O. The organic
extracts were dried and concentrated, and the residue
was chromatographed (flash, 8:1:1 Et2O–EtOH–DEA)
to give 12 (15 mg, 33%); IR (KBr) 1736, 3300; 1H
NMR l 1.62 (m, 4H), 1.80 (dd, J=6.9 and 2 Hz, 3H),
2.05–2.85 (m, 8H), 3.10 (m, 2H), 3.63 (m, 4H), 3.82 (dd,
J=11 and 6.6 Hz, 1H), 4.07 (br s, 1H), 4.22 (dd, J=11
and 4.4 Hz, 1H), 4.86 (s, 1H, 16-H), 5.45 (q, J=6.9 Hz,
1H), 6.33 (s, 1H), 7.11–7.20 (m, 3H), 7.59 (d, J=8 Hz,
1H); 13C NMR l 12.9 (CH3), 24.6 (CH2), 27.6 (CH2),
28.1 (CH2), 29.6 (CH), 51.8 (CH), 54.6 (CH2), 56.3
1
1738, 1694, 1640; H NMR l 1.73–2.15 (m, 4H), 1.87
(dt, J=12.9, 3.6 Hz, 1H), 2.07 (s, 3H), 2.90 (dm,
J=12.9, 1H), 3.14 (br s, 1H), 3.20 (m, 1H), 3.46 (dd,
J=8.5 and 6.3 Hz, 1H), 3.59–3.67 (m, 3H), 3.73 (s,
3H), 3.86 (m, 2H), 4.12 (m, 2H), 4.63 (br s, 1H), 5.14
(br s, 1H, 16-H), 5.52 (d, J=15.4 Hz, 1H), 6.39 (s, 1H),
6.43 (s, 1H), 6.99–7.26 (m, 4H), 7.57 (d, J=7.5 Hz,
1H); 13C NMR l 20.8 (CH3), 22.1 (CH2), 24.8 (CH2),
27.5 (CH), 28.1 (CH2), 48.0 (CH2), 48.9 (CH), 51.1
(CH3), 51.7 (CH2), 59.0 (CH), 61.9 (CH2), 62.2 (CH),
66.0 (CH2), 99.4 (CH), 103.1 (CH), 106.0 (C), 108.4
(CH), 120.0 (CH), 121.2 (CH), 122.4 (CH), 127.9 (C),
135.5 (C), 136.5 (C), 145.2 (CH), 146.1 (CH), 168.7 (C),
169.7 (C), 170.7 (C). Anal. calcd for C28H33N3O6·H2O:
C, 63.98; H, 6.71; N, 7.99. Found: C, 63.84; H, 6.45; N,
7.92. Elution with 95:5 AcOEt–MeOH afforded tetra-

M.-L. Bennasar et al. / Tetrahedron: Asymmetry 13 (2002) 95–106
105
(CH2), 56.3 (CH2), 56.4 (CH2), 57.3 (CH2), 60.0 (CH),
62.1 (CH), 65.8 (CH2), 101.3 (CH), 108.0 (CH), 120.4
(CH), 120.6 (CH), 120.9 (CH), 121.0 (CH), 127.7 (C),
135.5 (C), 135.6 (C), 136.5 (C), 169.9 (C); HRMS
calcd for C24H31N3O3 409.2365, found 409.2363.
Pyrek, J. S.; Shi, Y.-J.; Sultana, M.; Vankar, Y. D. J.
Org. Chem. 1986, 51, 2995–3000.
3. (a) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica,
E.; Bosch, J. J. Org. Chem. 1990, 55, 1156–1168; (b)
Bennasar, M.-L.; Zulaica, E.; Jime´nez, J.-M.; Bosch, J. J.
Org. Chem. 1993, 58, 7756–7767.
4. (a) Alvarez, M.; Salas, M.; de Veciana, A.; Lavilla, R.;
Bosch, J. Tetrahedron Lett. 1990, 31, 5089–5092; (b)
Amat, M.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55,
6299–6312.
5. (a) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch, J.
J. Org. Chem. 1996, 61, 1239–1251; (b) Bennasar, M.-L.;
Zulaica, E.; Ram´ırez, A.; Bosch, J. Tetrahedron 1999, 55,
3117–3128.
6. (a) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem.
1997, 62, 3597–3609; (b) Bennasar, M.-L.; Vidal, B.;
Kumar, R.; La´zaro, A.; Bosch, J. Eur. J. Org. Chem.
2000, 3919–3925.
7. Bennasar, M.-L.; Jime´nez, J.-M.; Vidal, B.; Sufi, B. A.;
Bosch, J. J. Org. Chem. 1999, 64, 9605–9612.
8. For the synthesis of chiral non-racemic 1,2-dihydropy-
ridines, see: (a) Comins, D. L.; Joseph, S. P. In Advances
in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI Press:
London, 1996; Vol. 2, pp. 251–294. For more recent
work, see: (b) Comins, D. L.; LaMunyon, D. H.; Chen,
X. J. Org. Chem. 1997, 62, 8182–8187; (c) Comins, D. L.;
Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem.
1999, 64, 2184–2185; (d) Comins, D. L.; Zhang, Y.-M.;
Joseph, S. P. Org. Lett. 1999, 1, 657–659; (e) Comins, D.
L.; Williams, A. L. Tetrahedron Lett. 2000, 41, 2839–
2842; (f) Kuethe J. T.; Comins, D. L. Org. Lett. 2000, 2,
855–857. See also: (g) Ge´nisson, Y.; Marazano, C.; Das,
B. C. J. Org. Chem. 1993, 58, 2052–2057.
9. Oxazoline: (a) Meyers, A. I.; Natale, N. R.; Wettlaufer,
D. G.; Rafii, S.; Clardy, J. Tetrahedron Lett. 1981, 22,
5123–5126; (b) Meyers, A. I.; Natale, N. R. Heterocycles
1982, 18, 13–19; (c) Meyers, A. I.; Oppenlaender, T. J.
Chem. Soc., Chem. Commun. 1986, 920–921; (d) Meyers,
A. I.; Oppenlaender, T. J. Am. Chem. Soc. 1986, 108,
1989–1996. Aminal: (e) Mangeney, P.; Gosmini, R.;
Raussou, S.; Commerc¸on, M.; Alexakis, A. J. Org. Chem.
1994, 59, 1877–1888; (f) Raussou, S.; Gosmini, R.; Man-
geney, P.; Alexakis, A.; Commerc¸on, M. Tetrahedron
Lett. 1994, 35, 5433–5436. See also: (g) Rezgui, F.; Man-
geney, P.; Alexakis, A. Tetrahedron Lett. 1999, 40, 6241–
6244. [(h5-C5H5)Fe(CO)(PPh3)]: (h) Davies, S. G.; Skerlj,
R. T.; Whittaker, M. Tetrahedron Lett. 1990, 31, 3213–
3216; (i) Beckett, R. P.; Burgess, V. A.; Davies, S. G.;
Whittaker, M. Tetrahedron Lett. 1993, 34, 3617–3620.
Amides derived from (S)-thiazolidine-2-thiones and (S)-
oxazolidinones: (j) Yamada, S.; Ichikawa, M. Tetra-
hedron Lett. 1999, 40, 4231–4234; (k) Yamada, S.;
Misono, T.; Ichikawa, M.; Morita, C. Tetrahedron 2001,
57, 8939–8949.
4.20. (+)-16-Epivinoxine 13
A solution of CH3MgBr in Et2O (3 M, 0.4 mmol) was
added to anhydrous MeOH at 0°C, and the mixture
was stirred for 15 min at this temperature. The result-
ing suspension was added to a solution of tetracycle
12 (15 mg, 0.037 mmol) in MeOH (1 mL) and CH2Cl2
(1 mL) cooled at 0°C. The reaction mixture was
heated under reflux for 2 h, quenched with H2O, and
extracted with CH2Cl2. The organic extracts were con-
centrated and the residue was purified by flash chro-
matography (8:1:1 Et2O–EtOH–DEA) to give 13: 6 mg
(50%); [h]2D2 +109 (c 0.11, CHCl3); CD (EtOH, c=5
mM) umax (nm) 227.8 (Dm −4.6), 269.4 (Dm +1.5), 298.6
(Dm +0.9).
4.21. Epimerization of (+)-16-epivinoxine 13
t-BuOK (0.5 g, 4.5 mmol) was added to a solution of
13 (0.023 g, 0.06 mmol) in MeOH (10 mL), and the
resulting mixture was heated under reflux for 5 h. The
suspension was cooled at 0°C, a solution of dry HCl
in MeOH (5N) was added to bring the pH to 3–4, and
the mixture was stirred at rt overnight. The solvent
was removed and the resultant residue was diluted
with
a saturated aqueous Na2CO3 solution and
extracted with Et2O. The organic extracts were dried
and concentrated to give a 2:1 (1H NMR) mixture of
(+)-epivinoxine 13 and (−)-vinoxine 1 (17 mg, 74%).
After flash chromatography (25:1 AcOEt–MeOH) the
ratio (+)-13/(−)-1 of the mixture was shifted to 14:86
(HPLC): [h]2D2 +4 (c 0.1, CHCl3), lit.14b for (−)-vinoxine
[h]2D4 −18.6 (c not given, CHCl3); CD (EtOH, c=0.18
mM) umax (nm) 223.6 (Dm −1.9), 266.4 (Dm +0.22),
297.4 (Dm +0.12).
Acknowledgements
Financial support from the ‘Ministerio de Ciencia y
Tecnolog´ıa’ (Spain, project BQU2000-0785) is grate-
fully acknowledged. We also thank the ‘Comissionat
per
a
Universitats
i
Recerca’ (Generalitat de
Catalunya) for Grant 2001SGR00084. One of us
(Y.A.) also thanks the ‘Ministerio de Educacio´n, Cul-
tura y Deporte’ for a grant.
10. For the synthesis of chiral non-racemic tetracyclic struc-
tures related to Strychnos alkaloids, see: Amat, M.; Coll,
M.-D.; Bosch, J. Tetrahedron 1995, 51, 10759–10770.
11. Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Mata, I.;
Molins, E.; Bosch, J. Chem. Commun. 2001, 1166–1167.
12. (a) Amann, R.; Spitzner, D. Angew. Chem., Int. Ed. 1991,
30, 1320–1321; (b) Amann, R.; Arnold, K.; Spitzner, D.;
Majer, Z.; Snatzke, G. Liebigs Ann. 1996, 349–355.
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