Conjugate addition of 2-acetylindole enolates to unsaturated oxazolopiperidone lactams: Enantioselective access to the tetracyclic ring system of ervitsine

Article abstract of DOI:10.1002/ejoc.201001020

The stereochemical outcomes of the conjugate addition reactions of 2-acetylindole enolates to the unsaturated phenylglycinol-derived oxazolopiperidone lactams 1a-f have been studied. After reduction of the 2-acylindole carbonyl group, the Michael adduct c

Full text of DOI:10.1002/ejoc.201001020

FULL PAPER
DOI: 10.1002/ejoc.201001020
Conjugate Addition of 2-Acetylindole Enolates to Unsaturated
Oxazolopiperidone Lactams: Enantioselective Access to the Tetracyclic Ring
System of Ervitsine
Mercedes Amat,*[a] Begoña Checa,[a] Núria Llor,[a] Maria Pérez,[a] and Joan Bosch[a]
Dedicated to Prof. Carmen Nájera on the occasion of her 60th birthday
Keywords: Alkaloids / Nitrogen heterocycles / Lactams / Asymmetric synthesis / Cyclization / Michael addition
The stereochemical outcomes of the conjugate addition reac-
tions of 2-acetylindole enolates to the unsaturated phenylgly-
cinol-derived oxazolopiperidone lactams 1a–f have been
studied. After reduction of the 2-acylindole carbonyl group,
the Michael adduct cis-6 underwent a Lewis acid-promoted
intramolecular α-amidoalkylation, leading enantioselectively
to the tetracyclic ring system of the indole alkaloid ervitsine.
Introduction
Results and Discussion
Here we report conjugate additions of 2-acetylindole
enolates to unsaturated phenylglycinol-derived oxazolopip-
eridone lactams and the subsequent construction of the
tetracyclic framework of the indole alkaloid ervitsine
through closure of the seven-membered ring by intramolec-
ular α-amidoalkylation at the indole 3-position (Scheme 1).
Phenylglycinol-derived oxazolopiperidone lactams have
proved to be versatile scaffolds that allow the regio- and
stereocontrolled introduction of substituents at the different
positions in the piperidine ring, thus providing access to
enantiopure piperidines bearing virtually any type of substi-
tution pattern and also to more complex piperidine-con-
taining alkaloids, including indole alkaloids.[1] In particular,
the stereoselective introduction of carbon appendages at the
piperidine 4-position through conjugate addition reactions
requires the activation of this position, which can be ac-
complished by generation of a conjugated C=C bond, tak-
ing advantage of the lactam carbonyl group.
In previous work we have exploited conjugate additions
of lower-order alkyl and aryl cyanocuprates to unsaturated
oxazolopiperidone lactams for the enantioselective synthe-
sis of cis-2,4-[2] and cis-3,4-disubstituted piperidines,[3] as
well as 2,4-bridged[2] and cis-3,4-fused piperidine[4] deriva-
tives, including the antidepressant drug (–)-paroxetine[5]
and synthetic intermediates en route to the indole alkaloid
(–)-16-episilicine[6] and alkaloids of the madangamine
group.[7]
Similarly, stereocontrolled conjugate addition reactions
of sulfur-stabilized nucleophiles and indoleacetic acid ester
enolates have been successfully employed as the key steps in
enantioselective formal syntheses of uleine[8] and Strychnos
alkaloids.[9,10]
Scheme 1. Synthetic strategy.
As the starting unsaturated lactams we selected the lac-
tams 1a–f (Figure 1 and Scheme 2), each bearing an ethyl
substituent at the 8-position of the oxazolopiperidone sys-
tem. The preparation of the 3,8a-cis lactams 1a–d[3,6,8] has
[a] Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), University of Barcelona,
Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34-934-024-539
E-mail: amat@ub.edu
Figure 1. Unsaturated oxazolopiperidone lactams.
898
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 898–907

Enantioselective Access to the Tetracyclic Ring System of Ervitsine
been reported previously. The new 3,8a-trans lactams 1e of 5-substituted 5,6-dihydro-2-pyridones leads to the ther-
and 1f were prepared from the known lactams 2a[11] and modynamically more stable trans-4,5-disubstituted deriva-
2b[11] via the respective seleno derivatives 3a and 3b, as out- tives.[12] Accordingly, in the reaction between the lactam 1a
lined in Scheme 2.
and the acetylindole 4b an increase in the proportion of the
isomer cis-6 was observed when the reaction was quenched
after a short reaction time (Table 1, Entry 5).
In clear contrast from the stereochemical standpoint,
similar conjugate addition reactions with the activated lac-
tams 1b–d, each bearing an additional activating alkoxycar-
bonyl substituent, led to the corresponding adducts 7–10 as
diastereoisomeric mixtures in which the C-7/C-8 cis isomers
predominated (Entries 6–10).[13] As in the case of lactam
1a above, the use of excess nucleophile (5 equiv.) in these
reactions resulted in higher yields, lactams 9 and 10 being
formed in 90% (compare Entries 8 and 9) and 87% yields
(Entry 10), respectively, even after shorter reaction times.
The C-7/C-8 cis relative configuration in the major iso-
mer cis-9 was confirmed by its conversion [H2, Pd(OH)2;
then toluene at reflux] into cis-6, the minor isomer obtained
from lactam 1a (Scheme 3).
Scheme 2. Preparation of the unsaturated lactams 1e and 1f.
Table 1 summarizes the results obtained from the conju-
gate addition reactions of the 2-acetylindole enolates 4a and
4b to the unsaturated lactams 1a–d. The initial experiments
were carried out with the enolate of 2-acetyl-1-methylindole
(4a). When starting from the unsaturated lactam 1a, which
lacks the activating electron-withdrawing benzyloxy-
carbonyl group, the use of a slight excess (1.2 equiv.) of the
nucleophile (Entry 1) led to the expected adducts 5 in low
yield (24%) as a 1:2 epimeric mixture of C-7/C-8 cis/trans
isomers. A similar result was observed with the enolate of
2-acetylindole (4b): compound 6 was obtained in 30% yield
as a C-7/C-8 cis/trans epimeric mixture in a 1:3 ratio (En-
try 2). The yields grew progressively higher as the excess of
the nucleophile was increased (Entries 3 and 4), reaching Scheme 3. Removal of the benzyloxycarbonyl substituent.
68% when 5 equiv. of enolate were used.
The relative configurations of the cis and trans isomers
On the other hand, the predominance of the cis isomers
were evident from the shielding of the oxazolopiperidone in the conjugate additions to the lactams 1b–d (R1 = CO2R)
C-6 signal in the 13C NMR spectrum of cis-6 (δ = 37.9 ppm; can be explained by considering that in these cases the
compare with δ = 42.0 ppm in trans-6) resulting from the equilibration takes place to a lesser extent, as a consequence
axial ethyl substituent at C-8.
of the greater stabilities of the initially formed adducts (1,3-
The facial selectivity of the conjugate addition reactions dicarbonyl enolates). The process would then occur mainly
to lactam 1a (R1 = H) can be accounted for by considering under stereoelectronic control,[14] which involves an axial
that the addition of stabilized anions to α,β-unsaturated approach of the nucleophile to the electrophilic C atom of
carbonyl compounds is a reversible process that in the case the conjugate double bond from the exo face of the bicyclic
Table 1. Conjugate addition reactions of 2-acetylindoles to the unsaturated lactams 1a–d.
Entry
Lactam
Indole (equiv.)
Time
R1
R2
Product
H7,H8
cis/trans ratio
Yield
[%][a]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1b
1b
1d
4a (1.2)
4b (1.2)
4b (2.5)
4b (5.0)
4b (5.0)
4a (1.2)
4b (1.2)
4b (1.2)
4b (5.0)
4b (5.0)
16 h
10 h
12 h
24 h
3 h
23 h
16 h
16 h
5 h
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
H
5
6
1:2
1:3
1:2.3
1:2.3
1:1.3
3:1
3:1
4:1
4:1
5:1
24
30
56
68
73
42
38
46
90
87
6
6
6
CO2Bn
CO2Me
CO2Bn
CO2Bn
CO2tBu
7
8
9
9
10
4 h
10
[a] For the relative configuration of the epimerizable C-6 stereocentre, see Exp. section.
Eur. J. Org. Chem. 2011, 898–907
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
899

M. Amat, B. Checa, N. Llor, M. Pérez, J. Bosch
FULL PAPER
system as depicted in Figure 2. In fact, irreversible conju-
gate additions (of organocuprates, for instance) to unsatu-
rated oxazolopiperidone lactams (1a–f or related lactams)
have been reported to occur under stereoelectronic control
with complete exo facial selectivity.[15]
Figure 2. Stereoelectronic control in the conjugate additions.
Similar stereoelectronically controlled facial stereoselec-
tivity was observed in the conjugate additions of the enolate
of 4b to the C-8 epimeric 3,8a-trans lactams 1e and 1f (Fig-
ure 2), with the corresponding exo adducts cis-11 and trans-
12 being formed as the major isomers (Scheme 4).
Scheme 5.
the failure of the cyclization was attributed to the deactivat-
ing effect of the carbonyl group conjugated with the indole
ring. For this reason, the acylindole trans-6 was converted
into the alcohol 16 (Scheme 5) and then into the indolyle-
thyl derivative 18 by hydrogenolysis of the corresponding
acetate 17.
The desired cyclization at the indole 3-position, however,
did not occur from 16 or 18 either, with only extensive de-
composition being observed under a variety of acidic condi-
tions.
Bearing in mind that the closure of the seven-membered
ring of ervitsine and analogues has been successfully
achieved by a related intramolecular iminium ion cycliza-
tion,[19] we reasoned at this point that conformation factors
could be responsible for the reluctance of the above C-7/C-
8 trans derivatives to undergo intramolecular α-amidoalkyl-
ation: cyclization would involve an encumbered conforma-
Scheme 4. Conjugate addition reactions between 2-acetylindole
and the unsaturated lactams 1e and 1f; ind = indolyl.
To study the closure of the seven-membered ring charac- tion in which both C-7 and C-8 substituents should be ax-
teristic of ervitsine, we initially selected the lactam trans-6 ial. To confirm this hypothesis, we decided to study related
(Scheme 5). However, all attempts to promote cyclization α-amidoalkylation reactions from C-7/C-8 cis lactams.
under a variety of acidic conditions (TiCl4, CH2Cl2, reflux;
No cyclized products were detected, however, upon treat-
BF3·Et2O, CH2Cl2, reflux; HCl, MeOH or C6H6) resulted ment of cis-6 with TiCl4, the only isolable product being
in failure. The enamide 13[16] and its 8a-epimer 14 and the the 8a-epimer of cis-6.[20] As in the above C-7/C-8 trans
8,8a-diastereoisomer 15 of trans-6 were the only isolable series, the 2-acylindole cis-6 was reduced to the alcohol 19
products.[17] The stereochemistry of 14 and 15 was con- (Scheme 6) and then converted into the indolylethyl deriva-
firmed when these compounds were unambiguously pre- tive 21 via the corresponding acetate 20.
pared from trans-12 and cis-11, respectively, by debenz-
Although the alcohol 19 underwent extensive decompo-
ylation [H2, Pd(OH)2] followed by decarboxylation.
sition upon acidic treatment, to our delight, when the re-
Because the isolation of compounds 13–15 clearly indi- duced derivative 21 was treated with TiCl4 in CH2Cl2 at
cated that the N-acyliminium cation[18] had been formed, reflux, the tetracycle 22 was isolated in 58% yield.
Scheme 6. Access to the tetracyclic ring system of ervitsine.
900
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 898–907

Enantioselective Access to the Tetracyclic Ring System of Ervitsine
H, 3-H), 7.18–7.70 (m, 30 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 10.5, 10.7 (CH3 ethyl), 23.7, 24.0 (CH2 ethyl),
32.5, 35.2 (C-7), 37.8, 39.3 (C-8), 54.2, 55.6 (C-6), 58.8 (C-3), 67.7,
67.8 (CH2C6H5), 72.1, 72.3 (C-2), 92.0, 92.3 (C-8a), 125.7, 126.1
(C-o), 126.6, 126.7 (C-m), 127.3, 127.5 (C-p), 127.9, 128.0 (C-o),
128.0, 128.1 (C-p), 128.3, 128.4 (C-m), 128.5, 128.6 (C-o), 128.7,
128.8 (C-m), 129.3, 129.5 (C-i), 135.0, 135.1 (C-i), 138.0 (C-p),
138.5, 138.7 (C-i), 164.5, 164.9 (NCO), 169.9, 170.9 (COO) ppm.
Conclusions
In conclusion, conjugate addition reactions of 2-acetyl-
indole enolates to phenylglycinol-derived unsaturated δ-lac-
tams allow the stereocontrolled formation of C–C bonds
at the piperidine 4-position. Depending on the absence or
presence of an additional electron-withdrawing substituent
conjugated with the C–C double bond, the reaction pre-
dominantly leads either to trans- or to cis-4,5-disubstituted
enantiopure 2-piperidone derivatives, respectively.
The synthetic potential of the resulting Michael adducts
has been demonstrated with the enantioselective construc-
tion of the tetracyclic ring system of ervitsine, a minor in-
dole alkaloid isolated from Pandaca boiteaui[21] that lacks
the characteristic tryptamine moiety present in most mono-
terpenoid indole alkaloids. The strategy developed here,
starting from an appropriate lactam bearing a C-8 substitu-
ent precursor of the exocyclic methylene group and involv-
ing a stereoselective conjugate addition and an intramolecu-
lar α-amidoalkylation as the key steps (see Scheme 1), may
be applied to the enantioselective synthesis of ervitsine.[22]
(3R,8S,8aS)-6-(Benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-6-(phen-
ylselenyl)-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (3b): A
mixture of C-6 epimeric selenides (3.46 g, 82%) was obtained as in
the above preparation of 3a, from lactam 2b[11] (2 g, 7.90 mmol) in
THF (100 mL), LiHMDS (17.3 mL of a 1.0 m solution in THF),
benzyl chloroformate (1.2 mL, 8.6 mmol) and C6H5SeCl (1.70 g,
8.80 mmol) in THF (20 mL). Pure isomers were isolated after sub-
sequent flash chromatography (hexane to hexane/EtOAc 9:1).
Data for 3b (Higher Rf Epimer): Orange oil. [α]2D2 = –84.0 (c = 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.82 (t, J =
7.5 Hz, 3 H, CH3 ethyl), 1.29–1.38 (m, 1 H, CH2 ethyl), 1.53–1.63
(m, 1 H, CH2 ethyl), 1.72–1.81 (m, 1 H, 8-H), 1.88–2.02 (m, 1 H,
7-H), 1.99 (dd, J = 12.9, 5.1 Hz, 1 H, 7-H), 3.73 (dd, J = 8.7,
6.9 Hz, 1 H, 2-H), 4.45 (t, J = 8.7 Hz, 1 H, 2-H), 4.60 (d, J =
5.4 Hz, 1 H, 8a-H), 5.09 (d, J = 12.3 Hz, 1 H, CH2C6H5), 5.32 (d,
J = 12.3 Hz, 1 H, CH2C6H5), 5.56 (t, J = 8.1 Hz, 1 H, 3-H), 7.13–
7.55 (m, 15 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ
= 11.4 (CH3 ethyl), 23.3 (CH2 ethyl), 33.6 (C-7), 35.9 (C-8), 54.2
(C-6), 58.1 (C-3), 67.4 (CH2C6H5), 70.8 (C-2), 87.8 (C-8a), 125.6
(C-o), 126.7 (C-m), 127.3 (C-p), 128.1 (C-o), 128.2 (C-m), 128.4 (C-
p), 128.6 (C-o), 129.5 (C-m), 135.2 (C-p), 138.5 (C-i), 139.5 (C-i),
Experimental Section
General: Flash chromatography was carried out on SiO2 (silica
gel 60, SDS, 0.04–0.06 mm) or (when indicated) with a cartridge
containing amine-functionalized silica. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter. High-resolution mass
spectra (HMRS; LC/MSD TOF Agilent Technologies) were per-
formed by the Serveis Científico-Tècnics, Barcelona. Microanalyses
(Carlo–Erba 1106 analyzer) were performed by the Centre d’Inves-
tigació i Desenvolupament (CSIC), Barcelona. Only noteworthy IR
absorptions (cm–1; Perkin–Elmer 1600) are listed. NMR spectra
were recorded at 200, 300, 400 or 500 MHz (1H) and 75.4, 100.6
or 125.9 MHz (13C).
167.1 (NCO), 169.4 (COO) ppm. IR (film): ν = 1664, 1724 cm–1.
˜
C29H29NO4Se (534.51): calcd. C 65.17, H 5.47, N 2.62; found C
65.19, H 5.58, N 2.54.
Data for 3b (Lower Rf Epimer): Orange oil. [α]2D2 = –22.0 (c = 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.81 (t, J =
7.5 Hz, 3 H, CH3 ethyl), 1.12–1.23 (m, 1 H, CH2 ethyl), 1.55–1.67
(m, 1 H, CH2 ethyl), 2.04 (dd, J = 15.0, 4.2 Hz, 1 H, 7-H), 2.22–
2.28 (m, 1 H, 8-H), 2.56 (dd, J = 15.0, 6.6 Hz, 1 H, 7-H), 3.84 (dd,
J = 8.7, 6.3 Hz, 1 H, 2-H), 4.34 (dd, J = 8.7, 7.5 Hz, 1 H, 2-H),
4.85 (d, J = 4.8 Hz, 1 H, 8a-H), 5.18 (s, 2 H, CH2C6H5), 5.35 (t, J
= 6.8 Hz, 1 H, 3-H), 7.06–7.47 (m, 15 H, ArH) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 11.6 (CH3 ethyl), 18.7 (CH2 ethyl),
32.5 (C-7), 37.2 (C-8), 52.7 (C-6), 58.6 (C-3), 67.9 (CH2C6H5), 71.6
(C-2), 89.0 (C-8a), 126.5 (C-o), 126.7 (C-m), 127.6 (C-p), 128.1 (C-
o), 128.4 (CHAr), 128.7 (CHAr), 129.4 (CHAr), 135.2 (C-i), 137.7
(3R,8R,8aS)-6-(Benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-6-(phen-
ylselenyl)-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine
(3a):
Lithium bis(trimethylsilyl)amide (9.4 mL of a 1.0 m solution in
THF, 9.4 mmol) was slowly added at –78 °C to a solution of lactam
2a[11] (1.08 g, 4.24 mmol) in anhydrous THF (50 mL), and the re-
sulting mixture was stirred for 90 min. Benzyl chloroformate
(710 μL, 4.24 mmol) was then added, followed after 2 h of con-
tinuous stirring at –78 °C by a solution of C6H5SeCl (1.14 g,
5.09 mmol) in anhydrous THF (5 mL). The mixture was stirred for
2 h and poured into saturated aqueous NH4Cl. The aqueous layer
was extracted with EtOAc, and the combined organic extracts were
dried and concentrated. Flash chromatography (hexane to hexane/
EtOAc 4:1) of the resulting oil afforded the corresponding selenides
3a as a mixture of C-6 epimers (1.40 g, 62%).
(C-i), 139.2 (C-i), 165.1 (NCO), 170.2 (COO) ppm. IR (film): ν =
˜
1661, 1732 cm–1. C29H29NO4Se (534.51): calcd. C 65.17, H 5.47, N
2.62; found C 64.81, H 5.64, N 2.64.
(3R,8R,8aS)-6-(Benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-3,5,8,8a-
tetrahydro-5H-oxazolo[3,2-a]pyridine (1e): A stream of ozone gas
was bubbled through a cooled (–78 °C) solution of the selenides 3a
(161 mg, 0.30 mmol) in anhydrous CH2Cl2 (50 mL) until the solu-
tion had turned pale blue (5 min). The solution was then purged
with O2, and the temperature was slowly raised to 25 °C. After
30 min of stirring, the mixture was poured intro brine and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were dried and concentrated to give unsaturated lactam 1e,
which because of its instability was used in the next reaction with-
out further purification.
1
Data for 3a: Orange oil. H NMR (300 MHz, CDCl3, 25 °C): δ =
0.74 (t, J = 7.5 Hz, 3 H, CH3 ethyl), 0.80 (t, J = 7.3 Hz, 3 H, CH3
ethyl), 1.12–1.18 (m, 1 H, CH2 ethyl), 1.12–1.22 (m, 1 H, CH2
ethyl), 1.57–1.95 (m, 3 H, CH2 ethyl, 7-H, 8-H), 1.61–1.72 (m, 2
H, CH2 ethyl, 8-H), 1.83–2.00 (m, 2 H, 7-H), 2.33 (dd, J = 13.8,
2.1 Hz, 1 H, 7-H), 3.71 (dd, J = 9.0, 7.8 Hz, 1 H, 2-H), 3.78 (dd,
J = 9.0, 7.5 Hz, 1 H, 2-H), 4.34 (d, J = 8.1 Hz, 1 H, 8a-H), 4.37
1
(dd, J = 9.0, 7.5 Hz, 1 H, 2-H), 4.46 (dd, J = 9.0, 7.8 Hz, 1 H, 2- Data for 1e: Yellow oil. H NMR (300 MHz, CDCl3, 25 °C): δ =
H), 4.67 (d, J = 7.8 Hz, 1 H, 8a-H), 5.20 (d, J = 6.9 Hz, 1 H,
CH2C6H5), 5.20 (s, 2 H, CH2C6H5), 5.24 (d, J = 6.9 Hz, 1 H, 1.81–1.90 (m, 1 H, CH2 ethyl), 2.53–2.61 (m, 1 H, 8-H), 3.94 (dd,
CH2C6H5), 5.25 (d, J = 7.8 Hz, 1 H, 3-H), 5.30 (t, J = 7.5 Hz, 1 J = 9.0, 6.0 Hz, 1 H, 2-H), 4.44 (dd, J = 9.0, 6.9 Hz, 1 H, 2-H),
1.10 (t, J = 7.5 Hz, 3 H, CH3 ethyl), 1.57–1.66 (m, 1 H, CH2 ethyl),
Eur. J. Org. Chem. 2011, 898–907
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
901

M. Amat, B. Checa, N. Llor, M. Pérez, J. Bosch
FULL PAPER
5.10 (d, J = 9.3 Hz, 1 H, 8a-H), 5.26 (d, J = 5.3 Hz, 1 H, a mixture of C-7 epimers as described in the General Procedure,
CH2C6H5), 5.29 (m, 1 H, 3-H), 5.30 (d, J = 5.3 Hz, 1 H, CH2C6H5), from the unsaturated lactam 1a[3b,8] (400 mg, 1.64 mmol) in THF
7.19–7.40 (m, 11 H, 7-H, ArH) ppm.
(30 mL), LDA (11 mL of a 1.5 m solution in cyclohexane,
16.5 mmol) and a solution of 2-acetylindole (4b, 1.3 g, 8.2 mmol)
in THF (50 mL) over 24 h. Flash chromatography (hexane/EtOAc
1:1 to 3:7) afforded trans-6 (316 mg, 48%) and cis-6 (132 mg, 20%).
(3R,8S,8aS)-6-(Benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-3,5,8,8a-
tetrahydro-5H-oxazolo[3,2-a]pyridine (1f): The unsaturated lactam
1f (173 mg, 0.46 mmol) was obtained as in the above preparation of
1e, from a mixture of selenides 3b (246 mg, 0.46 mmol) in CH2Cl2
(15 mL). Because of its instability it was used in the next reaction
without further purification.
The pure lactams trans-6 (201 mg, 42%) and cis-6 (150 mg, 31%)
were also obtained after flash chromatography as above (Table 1,
Entry 5), from the lactam 1a (296 mg, 1.21 mmol) and acetylindole
(4b, 970 mg, 6.12 mmol) after 3 h.
1
Data for 1f: Orange oil. H NMR (300 MHz, CDCl3, 25 °C): δ =
Data for trans-6: Yellow foam. [α]2D2 = –7.0 (c = 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.04 (t, J = 7.2 Hz, 3 H, CH3
ethyl), 1.64–1.88 (m, 3 H, CH2 ethyl, 8-H), 2.16 (dd, J = 16.5,
7.6 Hz, 1 H, CH2CO), 2.57 (m, 1 H, 7-H), 2.68 (dd, J = 16.5,
6.0 Hz, 1 H, 6-H), 2.79 (dd, J = 16.5, 9.2 Hz, 1 H, CH2CO), 3.00
(dd, J = 16.5, 4.5 Hz, 1 H, 6-H), 4.10 (dd, J = 9.0, 1.2 Hz, 1 H, 2-
H), 4.18 (dd, J = 9.0, 6.6 Hz, 1 H, 2-H), 4.71 (d, J = 8.1 Hz, 1 H,
3-H), 4.98 (d, J = 5.7 Hz, 1 H, 8a-H), 6.87 (d, J = 1.5 Hz, 1 H, 3-
H ind), 7.04–7.08 (m, 1 H, 6-H ind), 7.18–7.25 (m, 1 H, 5-H ind),
7.28–7.41 (m, 7 H, ArH, 4-H ind), 10.05 (s, 1 H, NH) ppm. 13C
NMR (75.4 MHz, CDCl3, 25 °C): δ = 10.1 (CH3 ethyl), 22.4 (CH2
ethyl), 30.8 (C-7), 37.2 (CH2CO), 42.0 (C-6), 44.6 (C-8), 58.3 (C-
3), 73.8 (C-2), 90.7 (C-8a), 109.3 (C-3 ind), 112.5 (C-7 ind), 120.3
(C-4 ind), 122.6 (C-6 ind), 125.8 (C-5 ind), 126.7 (C-o), 127.0 (C-
3a ind), 127.5 (C-m), 128.5 (C-p), 135.0 (C-7a ind), 137.7 (C-i),
0.99 (t, J = 7.5 Hz, 3 H, CH3 ethyl), 1.38–1.48 (m, 1 H, CH2 ethyl),
1.83–1.92 (m, 1 H, CH2 ethyl), 2.76–2.81 (m, 1 H, 8-H), 4.00 (dd,
J = 8.4, 5.7 Hz, 1 H, 2-H), 4.47 (dd, J = 8.4, 6.9 Hz, 1 H, 2-H),
5.22–5.26 (m, 3 H, CH2C6H5, 3-H), 5.50 (d, J = 5.4 Hz, 1 H, 8a-
H), 7.24–7.62 (m, 11 H, 7-H, ArH) ppm.
General Procedure for the Conjugate Addition Reactions: LDA was
added to a cooled (–78 °C) solution of a 2-acetylindole (4a or 4b)
in THF, and the mixture was stirred at this temperature for 1 h. A
solution of an unsaturated lactam 1 in THF was then added to
the solution (–78 °C). The resulting mixture was stirred at room
temperature until the disappearance of the starting material was
observed by TLC. The reaction was quenched by the addition of
saturated aqueous NH4Cl, and the mixture was extracted with
EtOAc. The combined extracts were dried and concentrated to give
a residue, which was purified by chromatography.
141.3 (C-2 ind), 167.2 (NCO), 190.4 (CO) ppm. IR (film): ν = 1657,
˜
1735, 3312 cm–1. C25H26N2O3·1/4EtOAc (424.52): calcd. C 73.56,
(3R,7R,8S,8aR)-8-Ethyl-7-[2-(1-methyl-2-indolyl)-2-oxoethyl]-5-
oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine
(trans-5) and Its 7S Epimer (cis-5): Compound 5 was obtained as
a mixture of C-7 epimers as described in the General Procedure,
from the lactam 1a[3b,8] (200 mg, 0.82 mmol) in THF (30 mL), LDA
(0.65 mL of a 1.5 m solution in cyclohexane, 0.98 mmol) and a solu-
tion of the indole 4a (170 mg, 0.98 mmol) in THF (30 mL) over
16 h. Flash chromatography (hexane/EtOAc from 1:1 to 3:7) af-
forded trans-5 (53 mg, 16%) and cis-5 (27 mg, 8%).
H 6.65, N 6.60; found C 73.77, H 6.63, N 6.47.
Data for cis-6: Yellow foam. [α]2D2 = –70.4 (c = 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.10 (t, J = 7.3 Hz, 3 H, CH3
ethyl), 1.45–1.54 (m, 1 H, CH2 ethyl), 1.89–2.03 (m, 2 H, CH2 ethyl,
8-H), 2.45 (m, 2 H, CH2CO), 3.00 (m, 3 H, 2ϫ6-H, 7-H), 4.04
(dd, J = 9.3, 4.3 Hz, 1 H, 2-H), 4.18 (dd, J = 9.3, 6.9 Hz, 1 H, 2-
H), 4.68 (d, J = 9.3 Hz, 1 H, 3-H), 4.94 (d, J = 5.7 Hz, 1 H, 8a-
H), 6.87 (d, J = 1.5 Hz, 1 H, 3-H ind), 7.11–7.36 (m, 9 H, ArH, H
ind), 7.68 (dd, J = 8.1, 0.9 Hz, 1 H, 4-H ind), 9.50 (s, 1 H,
NH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 11.3 (CH3
ethyl), 21.2 (CH2 ethyl), 29.0 (C-7), 36.5 (CH2CO), 37.9 (C-6), 43.6
(C-8), 59.4 (C-3), 73.8 (C-2), 90.2 (C-8a), 109.4 (C-3 ind), 112.4 (C-
7 ind), 120.8 (C-4 ind), 122.8 (C-6 ind), 126.2 (C-5 ind), 126.3 (C-
o), 127.2 (C-3a ind), 127.4 (C-m), 128.4 (C-p), 135.0 (C-7a ind),
137.6 (C-i), 141.3 (C-2 ind), 166.8 (NCO), 190.7 (CO) ppm. IR
Data for trans-5: Yellow foam. [α]2D2 = 13.0 (c = 0.5, CHCl3). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.07 (t, J = 7.4 Hz, 3 H, CH3
ethyl), 1.65–1.89 (m, 3 H, CH2 ethyl, 8-H), 2.16 (dd, J = 18.2,
9.2 Hz, 1 H, 6-H), 2.50–2.60 (m, 2 H, 6-H, 7-H), 2.87 (dd, J = 16.2,
7.6 Hz, 1 H, CH2CO), 3.10 (dd, J = 16.2, 5.2 Hz, 1 H, CH2CO),
4.05 (s, 3 H, NCH3), 4.09 (d, J = 9.0 Hz, 1 H, 2-H), 4.18 (dd, J =
9.0, 6.8 Hz, 1 H, 2-H), 4.73 (d, J = 7.6 Hz, 1 H, 8a-H), 4.96 (dd, J
= 6.8, 1.2 Hz, 1 H, 3-H), 7.11 (s, 1 H, 3-H ind), 7.13–7.20 (m, 1 H,
7-H ind), 7.26–7.40 (m, 7 H, 5-H, 6-H ind, ArH), 7.67 (dd, J =
8.2, 1.2 Hz, 1 H, 4-H ind) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 10.2 (CH3 ethyl), 22.7 (CH2 ethyl), 32.2 (C-7), 37.5 (C-
6), 43.7 (CH2CO), 44.8 (C-8), 58.4 (C-3), 73.9 (C-2), 91.1 (C-8a),
110.3 (C-3 ind), 111.8 (C-7 ind), 120.7 (C-4 ind), 122.9 (C-6 ind),
125.6 (C-5 ind), 126.2 (C-2 ind), 126.7 (C-o), 128.6 (C-m), 127.6
(C-p), 134.7 (C-i), 140.2 (C-3a ind), 141.2 (C-7a ind), 166.7 (NCO),
(film): ν = 1657, 1735, 3325 cm–1. C H N O ·1/2H O (411.19):
˜
25 26
2
3
2
calcd. C 73.78, H 6.56, N 6.88; found C 73.40, H 6.27, N 6.98.
(3R,6R,7R,8S,8aR)-6-(Benzyloxycarbonyl)-8-ethyl-7-[2-(1-methyl-2-
indolyl)-2-oxoethyl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (cis-7): Compound 7 was obtained as a mix-
ture of diastereoisomers as described in the General Procedure,
from the crude product obtained from the unsaturated lactam 1b[3a]
(500 mg, 1.32 mmol) in THF (10 mL), LDA (0.8 mL of a 2.0 m
solution in THF/diethyl ether, 1.6 mmol) and a solution of the in-
dole 4a (274 mg, 1.58 mmol) in THF (20 mL) over 23 h. Flash
chromatography (hexane/EtOAc 9:1 to 1:1) afforded cis-7 (228 mg,
32%) and trans-7 (mixture of C-6 epimers; 76 mg, 10%).
Data for cis-7: Yellow foam. [α]2D2 = –69.8 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.02 (t, J = 7.5 Hz, 3 H, CH3
ethyl), 1.40–1.50 (m, 1 H, CH2 ethyl), 1.85–1.94 (m, 1 H, CH2
ethyl), 2.42–2.51 (m, 1 H, 8-H), 2.95 (dd, J = 16.2, 11.1 Hz, 1 H,
CH2CO), 3.13 (dd, J = 16.2, 2.4 Hz, 1 H, CH2CO), 3.15–3.19 (m,
192.0 (CO) ppm. IR (film): ν = 1644, 1661 cm–1. HRMS: calcd. for
˜
C26H29N2O3 [M + H]+: 417.2178; found 417.2172.
1
Data for cis-5: Yellow foam. H NMR (200 MHz, CDCl3, 25 °C):
δ = 1.11 (t, J = 7.4 Hz, 3 H, CH3 ethyl), 1.38–1.63 (m, 1 H, CH2
ethyl), 1.87–2.06 (m, 2 H, CH2 ethyl, 8-H), 2.33–2.48 (m, 2 H, 6-
H, 7-H), 2.94–3.03 (m, 3 H, 2ϫCH2CO, 6-H), 4.06–4.22 (m, 2 H,
2-H), 4.08 (s, 3 H, NCH3), 4.68 (d, J = 9.6 Hz, 1 H, 8a-H), 4.94
(d, J = 5.8 Hz, 1 H, 3-H), 7.12–7.43 (m, 9 H, ArH, ind-H), 7.69
(d, J = 8.0 Hz, 1 H, 4-H ind) ppm.
(3R,7R,8S,8aR)-8-Ethyl-7-[2-(2-indolyl)-2-oxoethyl]-5-oxo-3-phenyl- 1 H, 7-H), 3.45 (d, J = 0.3 Hz, 1 H, 6-H), 4.01–4.12 (m, 1 H, 2-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (trans-6) and Its
7S Epimer (cis-6): Compound 6 (Table 1, Entry 4) was obtained as
H), 4.05 (s, 3 H, NCH3), 4.18 (dd, J = 9.0, 6.9 Hz, 1 H, 2-H), 4.67
(d, J = 9.6 Hz, 1 H, 8a-H), 4.95 (t, J = 5.7 Hz, 1 H, 3-H), 5.06 (d,
902
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 898–907

Enantioselective Access to the Tetracyclic Ring System of Ervitsine
J = 12.3 Hz, 1 H, CH2C6H5), 5.13 (d, J = 12.3 Hz, 1 H, CH2C6H5), scribed in the General Procedure, from the crude product obtained
7.15–7.40 (m, 14 H, ArH, ind-H), 7.68 (dd, J = 7.8 Hz, 1 H, ind-
from the unsaturated lactam 1b[3a] (1.55 g, 4.11 mmol) in THF
H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 11.1 (CH3 (50 mL), LDA (27.4 mL of a 1.5 m solution in THF, 41.1 mmol)
ethyl), 20.8 (CH2 ethyl), 32.2 (NCH3), 33.1 (C-7), 37.4 (CH2CO), and a solution of 2-acetylindole (4b, 3.27 g, 20.5 mmol) in THF
40.2 (C-8), 53.4 (C-6), 59.7 (C-3), 66.9 (CH2C6H5), 74.0 (C-2), 90.3 (100 mL) over 5 h. Flash chromatography (hexane to hexane/
(C-8a), 110.5 (C-3 ind), 114.4 (C-7 ind), 120.9 (C-5 ind), 122.9 (C-
EtOAc 1:1) afforded cis-9 (accompanied by trace amounts of the
4 ind), 125.6 (CAr), 126.3 (CHAr), 126.4 (CHAr), 127.5 (CAr), C-6 epimer; 1.53 g, 69%) and trans-9 (457 mg, 21%).
127.8 (CHAr), 128.0 (CAr), 128.4 (CHAr), 128.5 (CHAr), 134.5
Data for cis-9: Yellow foam. [α]2D2 = –87.0 (c = 0.2, CHCl3). 1H
(C-i), 135.6 (C-2 ind), 140.3 (C-3a ind), 140.6 (C-7a ind), 162.1
NMR (300 MHz, CDCl3, 25 °C): δ = 1.02 (t, J = 7.6 Hz, 3 H, CH3
(NCO), 169.5 (COO), 190.8 (CO) ppm. IR (film): ν = 1660,
˜
ethyl), 1.40–1.50 (m, 1 H, CH2 ethyl), 1.83–1.94 (m, 1 H, CH2
ethyl), 2.42–2.51 (m, 1 H, 8-H), 2.92 (dd, J = 16.2, 11.1 Hz, 1 H,
CH2CO), 3.10 (dd, J = 16.2, 2.7 Hz, 1 H, CH2CO), 3.16 (m, 1 H,
7-H), 3.47 (d, J = 1.2 Hz, 1 H, 6-H), 4.03 (dd, J = 9.0, 1.5 Hz, 1
1735 cm–1. C34H34N2O5·1/3EtOAc (579.73): calcd. C 73.18, H 6.37,
N 4.83; found C 72.97, H 6.24, N 5.06.
(3R,6S,7R,8S,8aR)-8-Ethyl-7-[2-(2-indolyl)-2-oxoethyl]-6-(meth-
oxycarbonyl)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo- H, 2-H), 4.19 (dd, J = 9.0, 7.2 Hz, 1 H, 2-H), 4.67 (d, J = 9.6 Hz,
[3,2-a]pyridine (cis-8) and Its 6R,7S Diastereoisomer (trans-8): Com-
pound 8 was obtained as a mixture of diastereoisomers as de-
scribed in the General Procedure, from the crude product obtained
from the unsaturated lactam 1c[3a] (657 mg, 2.18 mmol) in THF
(10 mL), LDA (3.84 mL of a 1.5 m solution in THF, 5.76 mmol)
and a solution of 2-acetylindole (4b, 417 mg, 2.61 mmol) in THF
1 H, 8a-H), 4.97 (dd, J = 7.2, 1.5 Hz, 1 H, 3-H), 5.03 (d, J =
16.8 Hz, 1 H, CH2C6H5), 5.08 (d, J = 16.8 Hz, 1 H, CH2C6H5),
7.12–7.41 (m, 14 H, ArH), 7.69 (dd, J = 8.4, 1.2 Hz, 1 H, 4-H ind),
9.22 (s, 1 H, NH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ =
11.1 (CH3 ethyl), 20.7 (CH2 ethyl), 33.4 (C-7), 35.8 (CH2CO), 40.1
(C-8), 53.1 (C-6), 59.5 (C-3), 66.7 (CH2C6H5), 73.8 (C-2), 90.0 (C-
(30 mL) over 16 h. Flash chromatography (hexane to hexane/ 8a), 109.3 (C-3 ind), 112.6 (C-7 ind), 120.6 (C-2 ind), 122.5 (C-6
EtOAc 9:1) afforded cis-8 (290 mg, 29%) and trans-8 (90 mg, 9%). ind), 126.1 (C-5 ind), 126.2 (C-4 ind), 126.9, 127.2, 127.5, 127.7,
127.9, 128.1 (C-o, m, p), 134.6 (C-3a ind), 135.2 (C-7a ind), 140.5
Data for cis-8: Yellow foam. [α]2D2 = –65.3 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.11 (t, J = 7.6 Hz, 3 H, CH3
ethyl), 1.44–1.54 (m, 1 H, CH2 ethyl), 1.89–1.99 (m, 1 H, CH2
ethyl), 2.46–2.55 (m, 1 H, 8-H), 2.93 (dd, J = 16.2, 11.1 Hz, 1 H,
CH2CO), 3.12 (dd, J = 16.2, 2.7 Hz, 1 H, CH2CO), 3.17–3.21 (m,
(C-i), 137.7 (C-i), 162.2 (COO), 169.2 (NCO), 189.9 (CO) ppm. IR
(film): ν = 1655, 1735, 3320 cm–1. C H N O ·1/4EtOAc (558.65):
˜
33 32
2
5
calcd. C 73.10, H 6.13, N 5.01; found C 73.08, H 6.00, N 4.99.
Data for trans-9: Yellow foam. 1H NMR (400 MHz, CDCl3, 25 °C):
1 H, 7-H), 3.41 (d, J = 10.5 Hz, 1 H, 6-H), 3.60 (s, 3 H, OCH3), δ = 0.99 (t, J = 7.6 Hz, 3 H, CH3 ethyl), 1.71–2.04 (m, 3 H, CH2
4.06 (dd, J = 9.0, 1.5 Hz, 1 H, 2-H), 4.20 (dd, J = 9.0, 7.2 Hz, 1
H, 2-H), 4.68 (d, J = 9.9 Hz, 1 H, 8a-H), 4.97 (dd, J = 7.2, 1.5 Hz,
ethyl, 8-H), 2.87–3.18 (m, 3 H, 2 ϫ CH2CO, 7-H), 3.56 (d, J =
5.6 Hz, 1 H, 6-H), 4.01–4.20 (m, 2 H, 2-H), 4.71 (d, J = 8.4 Hz, 1
1 H, 3-H), 7.13–7.40 (m, 9 H, ArH, ind-H), 7.68 (dd, J = 8.1, H, 8a-H), 4.97 (d, J = 6.0 Hz, 1 H, 3-H), 5.09 (d, J = 11.6 Hz, 1
0.9 Hz, 1 H, 4-H ind), 9.27 (s, 1 H, NH) ppm. 13C NMR H, CH2C6H5), 5.14 (d, J = 11.6 Hz, 1 H, CH2C6H5), 6.95 (d, J =
(75.4 MHz, CDCl3, 25 °C): δ = 11.2 (CH3 ethyl), 20.0 (CH2 ethyl),
33.4 (C-7), 35.8 (CH2CO), 40.1 (C-8), 52.4 (C-6), 53.1 (OCH3), 59.7
1.6 Hz, 1 H, 3-H ind), 7.12–7.41 (m, 13 H, ArH), 7.65 (d, J =
7.6 Hz, 1 H, 4-H ind), 9.09 (br. s, 1 H, NH) ppm. 13C NMR
(C-3), 74.0 (C-2), 90.3 (C-8a), 109.6 (C-3 ind), 112.5 (C-7 ind), (100.6 MHz, CDCl3, 25 °C): δ = 10.4 (CH3 ethyl), 23.1 (CH2 ethyl),
121.0 (C-4 ind), 122.9 (C-5 ind), 126.5 (C-6 ind), 126.6 (C-o), 127.3
(C-2 ind), 127.5 (C-m), 128.3 (C-p), 134.8 (C-i), 137.7 (C-3a ind),
34.9 (C-7), 41.1 (CH2CO), 44.7 (C-8), 55.0 (C-6), 58.9 (C-3), 67.3
(CH2C6H5), 73.8 (C-2), 90.4 (C-8a), 109.7 (C-3 ind), 112.3 (C-7
140.6 (C-7a ind), 162.4 (NCO), 170.2 (COO), 190.1 (CO) ppm. IR ind), 120.9 (C-2 ind), 123.0 (C-6 ind), 126.4 (C-5 ind), 126.5 (C-4
(film): ν = 1655, 1736, 3324 cm–1. C H N O ·1/2EtOAc (504.58): ind), 126.9–128.6 (C-o, m, p), 134.8 (C-3a ind), 137.5 (C-7a ind),
˜
27 28
2
5
calcd. C 69.03, H 6.39, N 5.55; found C 68.99, H 6.16, N 5.59.
140.6 (C-i), 140.8 (C-i), 162.7 (COO), 169.9 (NCO), 190.0
(CO) ppm.
Data for trans-8: Yellow foam. [α]2D2 = +3.6 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.11 (t, J = 7.5 Hz, 3 H, CH3 (3R,6R,7R,8S,8aR)-6-(tert-Butoxycarbonyl)-8-ethyl-7-[2-(2-
ethyl), 1.63–1.75 (m, 1 H, CH2 ethyl), 1.75–1.87 (m, 1 H, CH2 indolyl)-2-oxoethyl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-
ethyl), 1.96–2.01 (m, 1 H, 8-H), 2.89–2.98 (m, 1 H, 7-H), 3.02–3.06
oxazolo[3,2-a]pyridine (cis-10): Compound 10 was obtained as a
(m, 2 H, CH2CO), 3.52 (d, J = 7.2 Hz, 1 H, 6-H), 3.69 (s, 3 H, mixture of diastereoisomers as described in the General Procedure,
OCH3), 4.12 (dd, J = 9.3, 1.2 Hz, 1 H, 2-H), 4.21 (dd, J = 9.3,
6.6 Hz, 1 H, 2-H), 4.83 (d, J = 8.4 Hz, 1 H, 8a-H), 4.98–5.00 (m,
from the crude unsaturated lactam 1d[6] (1.0 g, 2.90 mmol) in THF
(50 mL), LDA (19.5 mL of a 1.5 m solution in cyclohexane,
1 H, 3-H), 7.01 (d, J = 1.8 Hz, 1 H, 3-H ind), 7.11–7.45 (m, 8 H, 29 mmol) and a solution of 2-acetylindole (4b, 2.3 g, 14.5 mmol) in
ArH, ind-H), 7.66 (d, J = 8.1 Hz, 1 H, 4-H ind), 9.32 (s, 1 H, THF (100 mL) over 4 h. Flash chromatography (hexane to hexane/
NH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 10.3 (CH3 EtOAc 1:1) afforded cis-10 (1.17 g, 80%) and trans-10 (mixture of
ethyl), 23.1 (CH2 ethyl), 33.7 (C-7), 41.1 (CH2CO), 44.7 (C-8), 52.6
(OCH3), 54.9 (C-6), 59.0 (C-3), 73.8 (C-2), 90.4 (C-8a), 109.6 (C-3
ind), 112.3 (C-7 ind), 120.9 (C-4 ind), 122.9 (C-5 ind), 126.8 (C-6
ind), 126.6 (C-o), 127.3 (C-2 ind), 127.5 (C-p), 128.5 (C-m), 134.8
(C-i), 137.6 (C-3a ind), 140.8 (C-7a ind), 162.7 (NCO), 170.0
C-6 epimers; 230 mg, 7%).
Data for cis-10: Yellow foam. [α]2D2 = –21.5 (c = 0.2, CHCl3). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.11 (t, J = 7.6 Hz, 3 H, CH3
ethyl), 1.34 [s, 9 H, (CH3)3C], 1.43–1.52 (m, 1 H, CH2 ethyl), 1.88–
1.96 (m, 1 H, CH2 ethyl), 2.56 (ddd, J = 13.6, 9.2, 4.8 Hz, 1 H, 8-
H), 2.91 (dd, J = 16.0, 10.8 Hz, 1 H, CH2CO), 3.08 (dd, J = 16.0,
2.4 Hz, 1 H, CH2CO), 3.20 (m, 1 H, 7-H), 3.30 (s, 1 H, 6-H), 4.04
(d, J = 8.4 Hz, 1 H, 2-H), 4.19 (dd, J = 8.4, 7.2 Hz, 1 H, 2-H), 4.66
(d, J = 9.6 Hz, 1 H, 8a-H), 4.97 (d, J = 6.4 Hz, 1 H, 3-H), 7.12–
7.40 (m, 9 H, ArH), 7.68 (d, J = 8.4 Hz, 1 H, 4-H ind), 9.36 (br. s,
1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.2
(CH3 ethyl), 20.8 (CH2 ethyl), 27.8 [C(CH3)3], 32.9 (C-7), 36.0
(COO), 190.1 (CO) ppm. IR (film): ν = 1656, 1737, 3310 cm–1
.
˜
C27H28N2O5·3/4 H2O (474.04): calcd. C 68.41, H 6.27, N 5.91;
found C 68.12, H 6.10, N 5.64.
(3R,6R,7R,8S,8aR)-6-(Benzyloxycarbonyl)-8-ethyl-7-[2-(2-indolyl)-
2-oxoethyl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (cis-9) and Its 6S,7S Diastereoisomer (trans-9): Com-
pound 9 was obtained as a mixture of diastereoisomers as de-
Eur. J. Org. Chem. 2011, 898–907
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
903

M. Amat, B. Checa, N. Llor, M. Pérez, J. Bosch
(CH2CO), 40.3 (C-8), 54.4 (C-6), 59.6 (C-3), 74.1 (C-2), 81.9 128.3, 128.4, 128.8, (C-o, C-m, C-p, C-3a ind), 134.7 (C-2 ind),
FULL PAPER
[C(CH3)3], 90.3 (C-8a), 109.5 (C-3 ind), 112.3 (C-7 ind), 121.0 (C-
135.5 (C-7a ind), 139.1 (C-i), 166.0 (NCO), 169.6 (COO), 190.3
5 ind), 123.0 (C-6 ind), 126.5 (C-o), 126.6 (C-2 ind), 127.4 (C-m), (CO) ppm. IR (film): ν = 1655, 1736, 3324 cm–1. HRMS: calcd. for
˜
128.4 (C-p), 134.9 (C-3a ind), 137.5 (C-7a ind), 140.8 (C-i), 162.5 C33H32N2NaO5 [M + Na]+: 559.2203; found 559.2207.
(NCO), 168.3 (COO), 190.1 (CO) ppm. IR (KBr): ν = 1662, 1728,
˜
Data for trans-12 (Minor 6R Epimer): 1H NMR (400 MHz, CDCl3,
25 °C): δ = 1.00 (t, J = 7.4 Hz, 3 H, CH3 ethyl), 1.30–1.42 (m, 2
H, CH2 ethyl), 3.15–3.20 (m, 2 H, 7-H, 8-H), 3.25 (dd, J = 16.0,
7.2 Hz, 1 H, CH2CO), 3.30 (dd, J = 16.0, 5.6 Hz, 1 H, CH2CO),
3.74 (dd, J = 8.7, 7.6 Hz, 1 H, 2-H), 3.78 (d, J = 5.6 Hz, 1 H, 6-
H), 4.52 (t, J = 8.4 Hz, 1 H, 2-H), 5.07 (d, J = 12.4 Hz, 1 H,
CH2C6H5), 5.13 (d, J = 12.4 Hz, 1 H, CH2C6H5), 5.16 (masked, 1
H, 8a-H), 5.38 (t, J = 7.6 Hz, 1 H, 3-H), 7.00 (d, J = 1.4 Hz, 1 H,
3-H ind), 7.10–7.42 (m, 13 H, ArH, ind-H), 7.68 (t, J = 8.6 Hz, 1 H,
ind-H), 9.07 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 11.6 (CH3 ethyl), 19.5 (CH2 ethyl), 32.0 (C-7), 38.4
(CH2CO), 39.6 (C-8), 50.5 (C-6), 58.1 (C-3), 67.3 (CH2C6H5), 71.9
(C-2), 87.6 (C-8a), 109.5 (C-3 ind), 112.2 (C-7 ind), 121.1 (C-4 ind),
123.2 (C-5 ind), 125.6 (C-6 ind), 126.6, 127.5, 128.4, 128.5, 128.6,
128.8, 128.9 (C-o, C-m, C-p, C-3a ind), 135.1 (C-2 ind), 134.8 (C-
7a ind), 137.3 (C-i), 164.8, (NCO), 169.2 (COO), 190.1 ppm.
2958 cm–1. HRMS: calcd. for C30H35N2O5 [M + H]+: 503.2540;
found 503.2541.
(3R,6R,7S,8R,8aS)-6-(Benzyloxycarbonyl)-8-ethyl-7-[2-(2-indolyl)-
2-oxoethyl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (cis-11): Compound 11 was obtained as a mixture of
diastereoisomers as described in the General Procedure, from the
crude unsaturated lactam 1e (161 mg, 0.43 mmol) in THF (10 mL),
LDA (2.86 mL of a 1.5 m solution in THF, 4.3 mmol) and a solu-
tion of 2-acetylindole (4b, 342 mg, 2.15 mmol) in THF (15 mL)
over 20 h. Flash chromatography (hexane/EtOAc 9:1 to EtOAc) af-
forded cis-11 (110 mg, 48%) and trans-11 (1:1 mixture of C-6 epi-
mers; 32 mg, 14%).
1
Data for cis-11: Yellow foam. [α]2D2 = –101.1 (c = 1.2, CHCl3). H
NMR (300 MHz, CDCl3, 25 °C): δ = 0.98 (t, J = 7.5 Hz, 3 H, CH3
ethyl), 1.61 (m, 1 H, CH2 ethyl), 1.76 (m, 1 H, CH2 ethyl), 1.91 (m,
1 H, 8-H), 2.91 (m, 1 H, 7-H), 3.12 (dd, J = 5.4, 2.4 Hz, 2 H,
CH2CO), 3.67 (d, J = 9.3 Hz, 1 H, 6-H), 3.73 (dd, J = 9.0, 7.8 Hz,
1 H, 2-H), 4.49 (dd, J = 9.0, 7.8 Hz, 1 H, 2-H), 4.93 (d, J = 8.4 Hz,
1 H, 8a-H), 5.04 (d, J = 12.3 Hz, 1 H, CH2C6H5), 5.13 (d, J =
12.3 Hz, 1 H, CH2C6H5), 5.29 (t, J = 7.8 Hz, 1 H, 3-H), 7.12–7.37
(m, 14 H, ArH, ind-H), 7.67 (d, J = 8.1 Hz, 1 H, 4-H ind), 9.21
(br. s, 1 H, NH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ =
9.9 (CH3 ethyl), 21.5 (CH2 ethyl), 33.4 (C-7), 38.6 (CH2CO), 40.3
(C-8), 55.4 (C-6), 58.7 (C-3), 67.4 (CH2C6H5), 72.6 (C-2), 90.6 (C-
8a), 109.4 (C-3 ind), 112.3 (CH ind), 121.0 (CH ind), 123.1 (CH
ind), 125.7 (CHAr), 126.5 (CHAr), 127.4 (C-i), 127.6 (CHAr),
128.0 (CHAr), 128.2 (CHAr), 128.4 (CHAr), 128.8 (CHAr), 134.8
(C-i), 135.2 (C-2 ind), 137.4 (C-3a ind), 138.6 (C-7a), 164.1 (NCO),
Conversion of cis-9 into cis-6: A solution of cis-9 (200 mg,
0.43 mmol) in EtOAc (10 mL) containing Pd(OH)2 (20 mg) was hy-
drogenated with vigorous stirring at room temperature and atmo-
spheric pressure for 24 h. The catalyst was removed by filtration,
and the solvent was evaporated to give an oil, which was dissolved
in toluene (30 mL). The resulting solution was heated at reflux for
16 h and concentrated to dryness. The residue was chromato-
graphed (hexane/EtOAc 4:1 to EtOAc) to give cis-6 (97 mg, 65%).
(3R,7R,8S,8aS)-8-Ethyl-7-[2-(2-indolyl)-2-oxoethyl]-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (14): Compound
14 (452 mg, 67%) was obtained as above, from trans-12 (900 mg,
1.68 mmol) and Pd(OH)2 (30%, 270 mg) in EtOAc (50 mL), with
subsequent heating at reflux in toluene (100 mL), after column
chromatography (hexane to hexane/EtOAc 1:1).
170.1 (COO), 190.0 (CO) ppm. IR (KBr): ν = 1656, 1735 cm–1.
˜
C33H32N2O5 (536.62): calcd. C 73.86, H 6.01, N 5.22; found C
73.46, H 6.08, N 5.34.
Data for 14: Yellow foam. [α]2D2 = –21.6 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.01 (t, J = 7.4 Hz, 3 H, CH3 ethyl),
1.21–1.28 (m, 1 H, CH2 ethyl), 1.71–1.79 (m, 1 H, CH2 ethyl), 2.18
(ddd, J = 14.0, 6.0, 4.8 Hz, 1 H, 8-H), 2.36 (dd, J = 18.4, 3.2 Hz,
1 H, CH2CO), 2.63 (dd, J = 18.4, 6.4 Hz, 1 H, CH2CO), 2.84 (m,
1 H, 7-H), 3.09–3.11 (m, 2 H, 6-H), 3.79 (dd, J = 8.8, 7.6 Hz, 1 H,
2-H), 4.48 (t, J = 8.8 Hz, 1 H, 2-H), 5.23 (d, J = 4.4 Hz, 1 H, 8a-
H), 5.30 (t, J = 7.6 Hz, 1 H, 3-H), 7.14–7.41 (m, 9 H, ArH), 7.69
(d, J = 8.0 Hz, 1 H, 4-H ind), 9.35 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 11.6 (CH3 ethyl), 18.7 (CH2 ethyl),
29.6 (C-7), 33.7 (CH2CO), 40.7 (C-8), 41.9 (C-6), 58.3 (C-3), 72.2
(C-2), 88.0 (C-8a), 109.5 (C-3 ind), 112.3 (C-7 ind), 121.1 (C-5 ind),
123.1 (C-6 ind), 126.0 (C-o), 126.7 (C-2 ind), 127.7 (C-m), 128.9
(C-p), 134.9 (C-3a ind), 137.5 (C-7a ind), 139.6 (C-i), 168.1 (NCO),
[3R,6R/6S),7S,8S,8aS]-6-(Benzyloxycarbonyl)-8-ethyl-7-[2-(2-
indolyl)-2-oxoethyl]-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (trans-12): Compound 12 was obtained as a
mixture of diastereoisomers as described in the General Procedure,
from the crude product obtained from the unsaturated lactam 1f
(1 g, 2.65 mmol) in THF (50 mL), LDA (26.5 mL of a 1 m solution
in THF, 26.5 mmol) and a solution of 2-acetylindole (4b, 2.11 g,
13.25 mmol) in THF (100 mL) over 5 h. Flash chromatography
(hexane/EtOAc 9:1 to EtOAc) afforded trans-12 (9:1 mixture of C-
6 epimers; 1.02 g, 72 %) and cis-12 (mixture of C-6 epimers;
211 mg, 14%).
Data for trans-12 (Major 6S Epimer): Yellow foam. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.95 (t, J = 7.2 Hz, 3 H, CH3 ethyl),
1.26–1.41 (m, 1 H, CH2 ethyl), 1.64–1.71 (m, 1 H, CH2 ethyl), 2.23–
2.31 (m, 1 H, 8-H), 2.98–3.04 (m, 1 H, 7-H), 3.09 (dd, J = 12.4,
6.0 Hz, 1 H, CH2CO), 3.13 (dd, J = 12.4, 6.4 Hz, 1 H, CH2CO),
3.66 (d, J = 8.8 Hz, 1 H, 6-H), 3.86 (dd, J = 8.8, 6.8 Hz, 1 H, 2-
H), 4.45 (dd, J = 8.8, 8.0 Hz, 1 H, 2-H), 5.09 (d, J = 9.2 Hz, 1 H,
8a-H), 5.16 (d, J = 12.5 Hz, 1 H, CH2C6H5), 5.19 (d, J = 12.5 Hz,
1 H, CH2C6H5), 5.33 (t, J = 7.6 Hz, 1 H, 3-H), 7.10 (d, J = 1.4 Hz,
1 H, 3-H ind), 7.15–7.42 (m, 13 H, ArH, ind-H), 7.69 (t, J = 8.0 Hz,
1 H, ind-H), 9.09 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
190.7 (CO) ppm. IR (KBr): ν = 1649, 3312 cm–1. HRMS: calcd.
˜
for C25H27N2O3 [M + H]+: 403.2016; found 403.2014.
(3R,7R,8R,8aS)-8-Ethyl-7-[2-(2-indolyl)-2-oxoethyl]-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (15):
Compound 15 (288 mg, 62%) was obtained as above, from cis-11
(620 mg, 1.15 mmol) and Pd(OH)2 (20 %, 124 mg) in MeOH
(40 mL), with subsequent heating at reflux in toluene (70 mL), after
column chromatography (hexane to hexane/EtOAc 1:1).
Data for 15: Yellow foam. [α]2D2 = –74.7 (c = 0.67, CHCl3). 1H NMR
CDCl3, 25 °C): δ = 11.3 (CH3 ethyl), 19.9 (CH2 ethyl), 33.1 (C-7), (400 MHz, CDCl3, 25 °C): δ = 1.08 (t, J = 7.6 Hz, 3 H, CH3 ethyl),
40.5 (CH2CO), 42.1 (C-8), 53.8 (C-6), 58.8 (C-3), 67.2 (CH2C6H5),
1.45–1.54 (m, 1 H, CH2 ethyl), 1.75–1.90 (m, 2 H, CH2 ethyl, 8-
72.3 (C-2), 88.0 (C-8a), 109.5 (C-3 ind), 112.2 (C-7 ind), 121.1 (C-
H), 2.54–2.66 (m, 2 H, 6-H, 7-H), 2.90 (m, 1 H, 6-H), 2.97 (d, J =
4 ind), 123.2 (C-5 ind), 125.6 (C-6 ind), 126.3, 126.7, 127.8, 128.1, 11.8 Hz, 1 H, CH2CO), 3.08 (d, J = 11.8 Hz, 1 H, CH2CO), 3.80
904
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 898–907

Enantioselective Access to the Tetracyclic Ring System of Ervitsine
(t, J = 8.4 Hz, 1 H, 2-H), 4.56 (t, J = 8.4 Hz, 1 H, 2-H), 4.78 (d, J meric mixture of acetates 17 (86 mg, 57%), which was used in the
= 9.2 Hz, 1 H, 8a-H), 5.35 (t, J = 8.0 Hz, 1 H, 3-H), 7.12–7.41 (m,
9 H, ArH, H ind), 7.66 (d, J = 8.4 Hz, 1 H, ind-H), 9.26 (br. s, 1
H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.5
(CH3 ethyl), 22.1 (CH2 ethyl), 29.0 (C-7), 36.1 (CH2CO), 37.4 (C-
6), 44.0 (C-8), 58.3 (C-3), 72.4 (C-2), 90.9 (C-8a), 109.4 (C-3 ind),
112.3 (C-7 ind), 121.1 (C-4 ind), 123.0 (C-5 ind), 125.9 (C-o), 126.7
(C-6 ind), 127.4 (C-2 ind), 127.8 (C-m), 129.0 (C-p), 135.0 (C-i),
137.5 (C-3a), 139.7 (C-7a), 168.3 (NCO), 190.9 (CO) ppm. IR
next reaction without further purification.
1
Data for 17: Yellow foam. H NMR (400 MHz, CDCl3, 25 °C): δ
= 0.87 (t, J = 7.2 Hz, 3 H, CH3 ethyl), 1.04 (t, J = 7.4 Hz, 3 H,
CH3 ethyl), 1.12–1.17 (m, 2 H, 7-H), 1.23–2.21 (m, 8 H, CH2 ethyl,
CH2CHO, 8-H), 2.20 (s, 3 H, CH3CO), 2.25 (s, 3 H, CH3CO), 2.55–
2.63 (m, 2 H, CH2CHO), 2.34 (dd, J = 14.0, 6.8 Hz, 1 H, 6-H),
3.32–3.49 (m, 3 H, 6-H), 4.01 (d, J = 9.0 Hz, 1 H, 2-H), 4.05 (d, J
= 8.8 Hz, 1 H, 2-H), 4.07 (d, J = 8.8 Hz, 1 H, 2-H), 4.17 (dd, J =
9.0, 6.8 Hz, 1 H, 2-H), 4.47–4.54 (m, 3 H, CH2CHO, 8a-H), 4.70
(d, J = 8.4 Hz, 1 H, 8a-H), 4.90 (d, J = 6.4 Hz, 1 H, 3-H), 4.95 (d,
J = 6.0 Hz, 1 H, 3-H), 6.33 (s, 1 H, 3-H ind), 6.44 (s, 1 H, 3-H
ind), 7.10 (dd, J = 14.8, 7.2 Hz, 1 H, ind-H), 7.17 (dd, J = 14.8,
7.2 Hz, 1 H, ind-H), 7.07–7.59 (m, 18 H, ArH, ind-H), 8.30 (br. s,
1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 9.6, 9.9
(CH3 ethyl), 15.2, 15.3 (CH2 ethyl), 21.5, 21.6 (COCH3), 30.3, 30.9
(C-7), 36.9, 37.4 (C-6), 44.8, 44.9 (CH2CO), 58.7, 58.7 (C-3), 64.3,
64.5 (CHOAc), 73.9, 74.0 (C-2), 90.7, 91.1 (C-8a), 100.4, 102.1 (C-
3 ind), 110.9, 111.0 (C-7 ind), 119.8, 119.9 (C-5 ind), 120.4, 120.5
(C-4 ind), 121.8, 122.1 (C-6 ind), 126.4, 126.5 (C-o), 127.5 (C-p),
128.0, 128.2 (C-2 ind), 128.6 (C-m), 135.9, 136.2 (C-3a ind), 137.7,
139.4 (C-3a ind), 141.2, 141.3 (C-i), 166.6 (NCO), 166.8
(COO) ppm.
(KBr): ν = 1648 cm–1. HRMS: calcd. for C H N O [M + H]+:
˜
25 27
2
3
403.2016; found 403.2018. C25H26N2O3·1/2H2O (411.50): calcd. C
72.97, H 6.61, N 6.81; found C 72.94, H 6.61, N 6.45.
(3R,7R,8S,8aR)-8-Ethyl-7-[2-hydroxy-2-(2-indolyl)ethyl]-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (16):
NaBH4 (117 mg, 3.11 mmol) was slowly added at 0 °C to a solution
of trans-6 (128 mg, 0.31 mmol) in MeOH (11 mL). The mixture
was stirred at 0 °C for 1 h and the temperature was slowly raised
to 25 °C. The mixture was concentrated, water was added, and the
aqueous layer was extracted with Et2O. The combined organic ex-
tracts were dried and concentrated to give a foam, which was chro-
matographed (hexane/EtOAc 1:1 to EtOAc) to afford the alcohol
16 as a mixture of epimers (115 mg, 90%).
Data for 16 (Higher Rf Epimer): Yellow foam. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.80 (t, J = 7.4 Hz, 3 H, CH3 ethyl), 1.37–1.62
(m, 5 H, CH2 ethyl, CH2CHOH, 7-H, 8-H), 1.88 (dd, J = 16.8,
7.2 Hz, 1 H, 6-H), 1.97 (dd, J = 10.4, 8.0 Hz, 1 H, CH2CHOH),
2.22 (br. s, 1 H, OH), 2.43 (dd, J = 16.8, 4.4 Hz, 1 H, 6-H), 3.92
(dd, J = 8.8, 1.6 Hz, 1 H, 2-H), 3.96 (dd, J = 8.8, 6.0 Hz, 1 H, 2-
H), 4.20 (d, J = 7.6 Hz, 1 H, 8a-H), 4.59 (m, 1 H, CHOH), 4.77
(d, J = 5.2 Hz, 1 H, 3-H), 6.20 (s, 1 H, 3-H ind), 7.02–7.27 (m, 8
H, ArH, ind-H), 7.50 (d, J = 7.2 Hz, 1 H, 4-H ind), 9.16 (br. s, 1
H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 9.5 (CH3
ethyl), 21.2 (CH2 ethyl), 31.2 (C-7), 37.4 (C-6), 40.5 (CH2CHOH),
44.4 (C-8), 58.7 (C-3), 66.6 (CHOH), 73.7 (C-2), 90.5 (C-8a), 98.9
(C-3 ind), 111.3 (C-7 ind), 119.6 (C-5 ind), 120.3 (C-4 ind), 121.7
(C-6 ind), 126.5 (C-o), 127.6 (C-p), 128.0 (C-2 ind), 128.5 (C-m),
136.0 (C-3a ind), 140.8 (C-7a ind), 141.2 (C-i), 167.6 (NCO) ppm.
(3R,7R,8S,8aR)-8-Ethyl-7-[(2-indolyl)ethyl]-5-oxo-3-phenyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (18): A solution
of acetates 17 (160 mg, 0.36 mmol) in EtOAc (25 mL) containing
Pd-C (20%, 17 mg) was hydrogenated at room temp. for 4 d at at-
mospheric pressure. The catalyst was removed by filtration, and the
solvent was evaporated to give an oil. Flash chromatography (hex-
ane/EtOAc 9:1 to 4:1) afforded 18 (70 mg, 50%).
1
Data for 18: Yellow foam. H NMR (400 MHz, CDCl3, 25 °C): δ
= 0.99 (t, J = 7.6 Hz, 3 H, CH3 ethyl), 1.63–2.18 (m, 7 H, CH2
ethyl, 7-H, 8-H, indCH2CH2, indCH2CH2), 2.49–2.64 (m, 1 H,
indCH2CH2), 2.53 (dd, J = 15.0, 6.0 Hz, 1 H, 6-H), 2.77 (ddd, J =
15.0, 9.6, 4.8 Hz, 1 H, 6-H), 4.06 (dd, J = 9.2, 1.2 Hz, 1 H, 2-H),
4.16 (dd, J = 9.2, 6.8 Hz, 1 H, 2-H), 4.63 (d, J = 8.4 Hz, 1 H, 8a-
H), 4.94 (d, J = 5.6 Hz, 1 H, 3-H), 6.20 (s, 1 H, 3-H ind), 7.03–
7.57 (m, 9 H, ArH, ind-H), 8.22 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 10.0 (CH3 ethyl), 22.0 (CH2 ethyl),
24.9 (C-6), 33.2 (C-7, indCH2CH2), 36.8 (indCH2), 45.1 (C-8), 58.7
(C-3), 74.0 (C-2), 91.0 (C-8a), 99.5 (C-3 ind), 110.4 (C-7 ind), 119.5
(C-5 ind), 119.7 (C-4 ind), 121.0 (C-6 ind), 126.4, 126.6 (C-o), 127.6
(C-p), 128.6 (C-m), 128.7 (C-2 ind), 135.9 (C-3a ind), 138.6 (C-7a
ind), 141.2 (C-i), 167.0 (NCO) ppm.
Data for 16 (Lower Rf Epimer): Yellow foam. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.91 (t, J = 7.3 Hz, 3 H, CH3 ethyl), 1.19–1.26
(m, 1 H, CH2CHOH), 1.41–1.45 (m, 1 H, 8-H), 1.49–1.59 (m, 1 H,
CH2 ethyl), 1.68 (ddd, J = 14.4, 7.2, 4.0 Hz, 1 H, CH2 ethyl), 1.88–
1.92 (m, 1 H, 6-H), 1.95–2.04 (m, 2 H, CH2CHOH, 7-H), 2.21 (br.
s, 1 H, OH), 2.55 (dd, J = 16.4, 4.8 Hz, 1 H, 6-H), 3.91–3.97 (m,
2 H, 2-H), 4.29 (d, J = 9.2 Hz, 1 H, 8a-H), 4.73 (d, J = 9.2 Hz, 1
H, CHOH), 4.78 (d, J = 4.8 Hz, 1 H, 3-H), 6.18 (s, 1 H, 3-H ind),
7.04 (dd, J = 6.4, 1.2 Hz, 1 H, 7-H ind), 7.08 (dd, J = 7.6, 1.6 Hz,
1 H, 5-H ind), 7.09–7.24 (m, 6 H, ArH, 6-H ind), 7.53 (d, J =
8.0 Hz, 1 H, 4-H ind), 9.24 (br. s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 9.3 (CH3 ethyl), 20.5 (CH2 ethyl),
29.2 (C-7), 36.5 (C-6), 39.7 (CH2CHOH), 44.2 (C-8), 59.0 (C-3),
64.4 (CHOH), 73.7 (C-2), 90.6 (C-8a), 97.5 (C-3 ind), 111.1 (C-7
ind), 119.4 (C-5 ind), 120.2 (C-4 ind), 121.3 (C-6 ind), 126.4 (C-o),
127.6 (C-p), 128.2 (C-2 ind), 128.6 (C-m), 135.8 (C-3a ind), 141.2
(C-7a ind), 142.4 (C-i), 167.7 (NCO) ppm.
(3R,7S,8S,8aR)-8-Ethyl-7-[2-hydroxy-2-(2-indolyl)ethyl]-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (19): As in
the above reduction of trans-6, a foam was obtained from a solu-
tion of cis-6 (1.05 mg, 2.60 mmol) in THF (50 mL) and NaBH4
(148 mg, 3.91 mmol) for 3 h. Flash chromatography (hexane/
EtOAc 1:1 to EtOAc) gave two epimeric alcohols 19 (higher Rf
epimer: 462 mg, 44%; lower Rf epimer: 308 mg, 29%).
Data for 19 (Higher Rf Epimer): Yellow foam. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.03 (t, J = 7.4 Hz, 3 H, CH3 ethyl), 1.38–2.49
(m, 8 H, CH2 ethyl, CH2CHOH, 6-H, 7-H, 8-H), 3.14 (br. s, 1 H,
OH), 3.94–4.04 (m, 2 H, 2-H), 4.50 (d, J = 8.4 Hz, 1 H, 8a-H),
4.81 (m, 2 H, CHOH, 3-H), 6.29 (s, 1 H, 3-H ind), 7.07 (t, J =
(3R,7R,8S,8aR)-7-[2-Acetyl-2-(2-indolyl)ethyl]-8-ethyl-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (17):
DMAP (8 mg, 0.06 mmol) and Ac2O (140 μL, 1.48 mmol) were 7.4 Hz, 1 H, ind-H), 7.13 (t, J = 7.4 Hz, 1 H, ind-H), 7.21–7.31 (m,
added to a cooled (0 °C) solution of the alcohols 16 (135 mg,
0.34 mmol) in CH2Cl2 and pyridine (2 mL, 4:1). The mixture was
stirred at room temp. for 4 h, diluted with CHCl3 and successively
washed with aqueous HCl (1 n) and saturated aqueous NaHCO3.
The organic solution was dried and concentrated to afford an epi-
6 H, ArH, ind-H), 7.54 (d, J = 7.6 Hz, 1 H, 4-H ind), 8.78 (br. s,
1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.2
(CH3 ethyl), 20.7 (CH2 ethyl), 28.6 (C-7), 35.4 (C-6), 36.9
(CH2CHOH), 43.8 (C-8), 59.3 (CHOH), 65.3 (C-3), 73.8 (C-2),
90.3 (C-8a), 98.1 (C-3 ind), 111.0 (C-7 ind), 119.7 (C-5 ind), 120.4
Eur. J. Org. Chem. 2011, 898–907
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
905

M. Amat, B. Checa, N. Llor, M. Pérez, J. Bosch
FULL PAPER
(C-4 ind), 121.7 (C-6 ind), 126.3 (C-o), 127.6 (C-p), 128.2 (C-2 ind), (3R,7S,8S,8aR)-8-Ethyl-7-[(2-indolyl)ethyl]-5-oxo-3-phenyl-
128.6 (C-m), 135.7 (C-3a ind), 141.4 (C-7a ind), 141.6 (C-i), 167.7 2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (21): A solution
(NCO) ppm.
of the acetates 20 (150 mg, 0.34 mmol) in EtOAc (20 mL) contain-
ing Pd(OH)2 (20 %, 30 mg) was hydrogenated at room temp.
(400 psi pressure) for 2 d. The catalyst was removed by filtration,
and the solvent was evaporated to give a foam. Flash chromatog-
raphy (hexane/EtOAc 9:1 to 1:1) afforded 21 (71 mg, 54%).
Data for 19 (Lower Rf Epimer): Yellow foam. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.83 (t, J = 7.4 Hz, 3 H, CH3 ethyl), 1.34–2.72
(m, 8 H, CH2 ethyl, CH2CHOH, 6-H, 7-H, 8-H), 3.87–4.00 (m, 2
H, 2-H), 4.51 (d, J = 6.8 Hz, 1 H, 8a-H), 4.62–4.78 (m, 2 H,
CHOH, 3-H), 6.27 (s, 1 H, 3-H ind), 7.66–7.28 (m, 8 H, ArH, ind-
H), 7.54 (d, J = 7.6 Hz, 1 H, 4-H ind), 9.20 (br. s, 1 H, NH) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.2 (CH3 ethyl), 20.8
(CH2 ethyl), 29.7 (C-7), 30.8 (C-6), 38.0 (CH2CHOH), 44.2 (C-8),
59.3 (CHOH), 68.2 (C-3), 73.8 (C-2), 90.3 (C-8a), 99.2 (C-3 ind),
111.3 (C-7 ind), 119.6 (C-5 ind), 120.3 (C-4 ind), 121.8 (C-6 ind),
126.3 (C-o), 127.6 (C-p), 127.9 (C-2 ind), 128.6 (C-m), 136.2 (C-3a
ind), 141.0 (C-7a ind), 141.4 (C-i), 170.2 (NCO) ppm.
Data for 21: Yellow foam. [α]2D2 = –42.5 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.98 (t, J = 7.6 Hz, 3 H, CH3 ethyl),
1.45–1.56 (m, 2 H, CH2 ethyl, indCH2CH2), 1.82–1.93 (m, 2 H,
CH2 ethyl, indCH2CH2), 1.95–2.02 (m, 1 H, 8-H), 2.09–2.14 (m, 1
H, 7-H), 2.40 (dd, J = 18.0, 5.2 Hz, 1 H, indCH2), 2.52 (dd, J =
18.0, 2.0 Hz, 1 H, indCH2), 2.66 (ddd, J = 14.8, 10.0, 7.2 Hz, 1 H,
6-H), 2.95 (ddd, J = 14.8, 10.0, 4.8 Hz, 1 H, 6-H), 3.99 (dd, J =
9.2, 1.2 Hz, 1 H, 2-H), 4.11 (dd, J = 9.2, 7.2 Hz, 1 H, 2-H), 4.61
(d, J = 9.6 Hz, 1 H, 1 H, 8a-H), 4.89 (d, J = 6.0 Hz, 1 H, 3-H),
6.24 (d, J = 1.2 Hz, 1 H, 3-H ind), 7.05–7.53 (m, 9 H, ArH, ind-
H), 8.07 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 11.3 (CH3 ethyl), 20.9 (CH2 ethyl), 26.5 (C-6), 27.5
(indCH2CH2), 32.4 (C-7), 36.8 (indCH2), 44.1 (C-8), 59.3 (C-3),
73.8 (C-2), 90.3 (C-8a), 99.9 (C-3 ind), 110.4 (C-7 ind), 119.7 (C-5
ind), 119.8 (C-4 ind), 121.2 (C-6 ind), 126.3 (C-o), 127.5 (C-p),
128.6 (C-m), 128.7 (C-2 ind), 135.9 (C-3a ind), 138.3 (C-7a ind),
(3R,7S,8S,8aR)-7-[2-Acetyl-2-(2-indolyl)ethyl]-8-ethyl-5-oxo-3-
phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (20): The
two epimeric acetates 20 (higher Rf epimer: 440 mg, 52%; lower Rf
epimer: 300 mg, 35%) were obtained as in the above preparation of
17 (reaction time 14 h), from the alcohols 19 (770 mg, 1.90 mmol),
DMAP (8 mg, 0.06 mmol) and Ac2O (0.8 mL, 7.61 mmol) in
CH2Cl2 and pyridine (12.5 mL, 4:1), after column chromatography
(hexane to hexane/EtOAc 9:1).
141.5 (C-i), 171.5 (NCO) ppm. IR (KBr): ν = 1642 cm–1. HRMS:
˜
Data for 20 (Higher Rf Epimer): Yellow foam. [α]2D2 = +47.5 (c =
1.0, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 1.11 (t, J =
calcd. for C25H29N2O2 [M + H]+: 389.2224; found 389.2224.
1
(1R,5S,13S)-13-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-3-oxo-
2,3,4,5,6,7-hexahydro-3H-1,5-methanoazocine[4,3-b]indole (22):
TiCl4 (1 mL of a 1.0 m solution in CH2Cl2, 1.0 mmol) was added
at room temp. to a solution of 21 (38 mg, 0.10 mmol) in CH2Cl2
(2 mL), and the resulting mixture was heated at reflux for 24 h.
TiCl4 (1 mL of a 1.0 m solution in CH2Cl2, 1.0 mmol) was then
once again added after a further 24 h, and the mixture was main-
tained at reflux for an additional 48 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 with a cartridge containing
amine functionalized silica (hexane/EtOAc 1:1 to EtOAc/MeOH
1:1) to give 22 (22 mg, 58%).
7.3 Hz, 3 H, CH3 ethyl), 1.54–1.63 (m, 1 H, CH2 ethyl), 1.79 (dd,
J = 11.2, 2.8 Hz, 1 H, 6-H), 1.92–1.99 (m, 2 H, CH2 ethyl, 8-H),
2.10 (s, 3 H, CH3CO), 2.26–2.31 (m, 1 H, 7-H), 2.35–2.45 (m, 3 H,
CH2CHO, 6-H), 2.54 (d, J = 17.6 Hz, 1 H, CH2CHO), 3.99 (dd, J
= 9.2, 1.2 Hz, 1 H, 2-H), 4.12 (dd, J = 9.2, 6.8 Hz, 1 H, 2-H), 4.62
(d, J = 9.2 Hz, 1 H, 8a-H), 4.89 (d, J = 6.8 Hz, 1 H, 3-H), 6.03
(dd, J = 10.8, 2.4 Hz, 1 H, CH2CHO), 6.49 (d, J = 2.4 Hz, 1 H, 3-
H ind), 7.08–7.32 (m, 8 H, ArH, ind-H), 7.58 (d, J = 7.2 Hz, 1 H,
ind-H), 9.18 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 11.0 (CH3 ethyl), 20.6 (CH2 ethyl), 21.1 (OCH3), 28.9
(C-7), 32.3 (C-6), 37.1 (CH2CHO), 43.7 (C-8), 59.4 (C-3), 67.5
(CH2CHO), 73.9 (C-2), 90.1 (C-8a), 100.2 (C-3 ind), 111.4 (C-4
ind), 119.8 (C-5 ind), 120.6 (C-4 ind), 122.3 (C-6 ind), 126.3 (C-o);
127.5, 127.6 (C-p, C-2 ind), 128.6 (C-m), 136.0 (C-3a ind), 137.0
(C-3a ind), 141.5 (C-i), 166.8 (NCO), 171.2 (COO) ppm. IR (KBr):
Data for 22: Yellow foam. [α]2D2 = –88.2 (c = 0.5, CHCl3). 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 0.72 (t, J = 7.5 Hz, 3 H, CH3 ethyl),
1.11 (td, J = 7.5, 7.5, 2.0 Hz, 2 H, CH2 ethyl), 1.73 (ddd, J = 14.0,
7.0, 5.0 Hz, 1 H, 6-H), 1.95 (dt, J = 14.0, 2.5 Hz, 1 H, 6-H), 2.05–
2.10 (m, 1 H, 13-H), 2.42–2.50 (m, 1 H, 5-H), 2.55 (ddd, J = 16.0,
ν = 1641, 1739, 3267 cm–1. HRMS: calcd. for C H N O [M +
˜
27 31
2
4
H]+: 447.2278; found 447.2300.
Data for 20 (Lower Rf Epimer): Yellow foam. [α]2D2 = +4.6 (c = 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.95 (t, J = 5.0, 3.0 Hz, 1 H, 7-H), 2.75 (d, J = 18.5 Hz, 1 H, 4-H), 3.00 (dd, J
7.3 Hz, 3 H, CH3 ethyl), 1.48–1.52 (m, 1 H, CH2 ethyl), 1.83–1.95 = 18.5, 8.5 Hz, 1 H, 4-H), 3.12 (m, 1 H, 7-H), 3.54 (m, 1 H,
(m, 3 H, CH2 ethyl, 6-H, 8-H), 2.05 (s, 3 H, CH3CO), 2.05–2.11
C6H5CHCH2), 3.80–3.83 (m, 1 H, C6H5CHCH2), 4.51 (d, J =
(m, 1 H, 7-H), 2.31–2.38 (m, 1 H, 6-H), 2.35 (d, J = 17.6, 5.6 Hz, 5.0 Hz, 1 H, 1-H), 5.74 (m, 1 H, C6H5CHCH2), 6.98–7.31 (m, 9 H,
1 H, CH2CHO), 2.59 (d, J = 17.6 Hz, 1 H, CH2CHO), 3.40 (dd, J ArH, ind-H), 8.03 (br. s, 1 H, NH) ppm. 13C NMR (125.9 MHz,
= 8.8, 1.2 Hz, 1 H, 2-H), 4.13 (dd, J = 9.2, 8.8 Hz, 1 H, 2-H), 4.65
(d, J = 9.2 Hz, 1 H, 8a-H), 4.92 (d, J = 6.8 Hz, 1 H, 3-H), 5.96
CDCl3, 25 °C): δ = 11.7 (CH3 ethyl), 23.0 (CH2 ethyl), 23.4 (C-
6), 26.9 (C-7), 33.8 (C-5), 38.4 (C-4), 41.7 (C-13), 53.0 (C-1), 60.5
(dd, J = 9.2, 6.0 Hz, 1 H, CH2CHO), 6.52 (d, J = 2.0 Hz, 1 H, 3- (C6H5CHCH2), 63.2 (C6H5CHCH2), 110.6 (C-12b), 110.8 (C-9),
H ind), 7.11 (td, J = 7.6, 0.8 Hz, 1 H, ind-H), 7.17–7.32 (m, 7 H,
ArH, ind-H), 7.59 (d, J = 8.4 Hz, 1 H, ind-H), 8.98 (br. s, 1 H,
117.4 (C-12), 119.6 (C-11), 121.0 (C-10), 127.6 (C-m), 128.1 (C-o),
128.2 (C-7a), 128.3 (C-p), 133.9 (C-12a), 136.9 (C-8a), 138.5 (C-i),
NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 11.4 (CH3 172.1 (NCO) ppm. IR (KBr): ν = 1608, 2926 cm–1. HRMS: calcd.
˜
ethyl), 20.9 (CH2 ethyl), 21.2 (OCH3), 30.2 (C-7), 31.8 (C-6), 37.5 for C25H29N2O2 [M + H]+: 389.2224; found 389.2222.
(CH2CHO), 44.2 (C-8), 59.4 (C-3), 69.2 (CH2CHO), 73.9 (C-2),
90.1 (C-8a), 101.0 (C-3 ind), 111.4 (C-4 ind), 120.0 (C-5 ind), 120.8
(C-4 ind), 122.6 (C-6 ind), 126.3 (C-o), 127.5, 127.6 (C-p, C-2 ind),
Acknowledgments
128.6 (C-m), 135.8 (C-3a ind), 135.9 (C-3a ind), 141.4 (C-i), 166.7
(NCO), 171.0 (COO) ppm. IR (KBr): ν = 1645, 1732, 3261 cm–1. Financial support from the Spanish Ministerio de Ciencia e
˜
HRMS: calcd. for C27H30N2NaO4 [M + Na]+: 469.2098; found Innovación (MICINN) (project number CTQ2009-07021/BQU),
469.2113.
and the AGAUR, Generalitat de Catalunya (grant number 2009-
906
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 898–907

Enantioselective Access to the Tetracyclic Ring System of Ervitsine
CH3 ethyl), 1.94–1.99 (m, 2 H, CH2 ethyl), 2.62 (dd, J = 16.0,
2.2 Hz, 1 H, CH2CO), 2.76 (dd, J = 16.0, 6.0 Hz, 1 H,
CH2CO), 2.76–2.82 (m, 2 H, 3-H), 2.89–2.95 (m, 1 H, 4-H),
4.11–4.17 (m, 2 H, 2Ј-H), 5.85 (t, J = 7.2 Hz, 1 H, 1Ј-H), 5.94
(s, 1 H, 6-H), 6.75 (d, J = 1.6 Hz, 1 H, 3-H ind), 7.25–7.42 (m,
8 H, ArH, H ind), 7.58 (d, J = 8.4 Hz, 1 H, 4-H ind), 9.53 (br.
s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ =
12.6 (CH3 ethyl), 25.5 (CH2 ethyl), 31.2 (C-4), 37.3 (CH2CO),
39.5 (C-3), 57.9 (C-1Ј), 62.1 (C-2Ј), 110.0 (C-3 ind), 112.2 (C-
7 ind), 120.5 (C-6), 120.8 (C-4 ind), 123.0 (C-5 ind), 125.9 (C-
5), 126.4 (C-6 ind), 127.3 (C-3a ind), 127.6 (C-o), 127.9 (C-p),
128.8 (C-m), 135.2 (C-i), 137.6 (C-2 ind), 137.7 (C-7a ind),
SGR-1111) is gratefully acknowledged. Thanks are also due to the
MICINN for a fellowship to B. C.
[1] For reviews, see: a) D. Romo, A. I. Meyers, Tetrahedron 1991,
47, 9503–9569; b) A. I. Meyers, G. P. Brengel, Chem. Commun.
1997, 1–8; c) M. D. Groaning, A. I. Meyers, Tetrahedron 2000,
56, 9843–9873; d) C. Escolano, M. Amat, J. Bosch, Chem. Eur.
J. 2006, 12, 8198–8207.
[2] M. Amat, M. Pérez, A. T. Minaglia, J. Bosch, J. Org. Chem.
2008, 73, 6920–6923.
[3] a) M. Amat, M. Pérez, N. Llor, J. Bosch, E. Lago, E. Molins,
Org. Lett. 2001, 3, 611–614; b) M. Amat, M. Pérez, N. Llor, J.
Bosch, Org. Lett. 2002, 4, 2787–2790.
[4] a) M. Amat, M. Pérez, A. T. Minaglia, N. Casamitjana, J.
Bosch, Org. Lett. 2005, 7, 3653–3656; b) M. Amat, M. Pérez,
A. T. Minaglia, B. Peretto, J. Bosch, Tetrahedron 2007, 63,
5839–5848; c) M. Amat, E. Brunaccini, B. Checa, M. Pérez, N.
Llor, J. Bosch, Org. Lett. 2009, 11, 4370–4373.
169.5 (NCO), 191.2 (CO) ppm. IR (KBr): ν = 1635 cm–1.
˜
HRMS: calcd. for C25H27N2O3 [M + H]+: 403.2016; found
403.2016.
[17] For the isomerization of 3,8a-cis-oxazolopiperidone lactams to
the more stable 3,8a-trans isomers, see: a) M. Amat, C. Escol-
ano, A. Gómez-Esqué, O. Lozano, N. Llor, R. Griera, E. Mol-
ins, J. Bosch, Tetrahedron: Asymmetry 2006, 17, 1581–1588; b)
M. Amat, M. M. M. Santos, O. Bassas, N. Llor, C. Escolano,
A. Gómez-Esqué, E. Molins, S. M. Allin, V. McKee, J. Bosch,
J. Org. Chem. 2007, 72, 5193–5201; c) M. Amat, M. Pérez,
A. T. Minaglia, D. Passarella, J. Bosch, Tetrahedron: Asym-
metry 2008, 19, 2406–2410; see also ref.[5]
[5] M. Amat, J. Bosch, J. Hidalgo, M. Cantó, M. Pérez, N. Llor,
E. Molins, C. Miravitlles, M. Orozco, J. Luque, J. Org. Chem.
2000, 65, 3074–3084.
[6] M. Amat, N. Llor, B. Checa, E. Molins, J. Bosch, J. Org. Chem.
2010, 75, 178–189.
[7] M. Amat, M. Pérez, S. Proto, T. Gatti, J. Bosch, Chem. Eur. J.
2010, 16, 9438–9441.
[8] M. Amat, M. Pérez, N. Llor, C. Escolano, F. J. Luque, E. Mol-
ins, J. Bosch, J. Org. Chem. 2004, 69, 8681–8693.
[9] M. Amat, N. Llor, B. Checa, M. Pérez, J. Bosch, Tetrahedron
Lett. 2007, 48, 6722–6725.
[18] For recent reviews on the chemistry of N-acyliminium ions, see:
a) W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56,
3817–3856; b) B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J.
Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431–1628.
[19] For the total synthesis of ervitsine in the racemic series, see: a)
M.-Ll. Bennasar, B. Vidal, J. Bosch, J. Org. Chem. 1997, 62,
3597–3609; for the enantioselective synthesis of N-methylervit-
sine, see: b) M.-Ll. Bennasar, E. Zulaica, Y. Alonso, J. Bosch,
Tetrahedron: Asymmetry 2003, 14, 469–479; c) M.-Ll. Benna-
sar, B. Vidal, J. Bosch, Chem. Commun. 1996, 2756–2757.
[20] Data for the 8a epimer of cis-6: Yellow foam. [α]2D2 = –38.0 (c
[10] For conjugate addition reactions to polycyclic unsaturated lac-
tams, see: a) E. García, E. Lete, N. Sotomayor, J. Org. Chem.
2006, 71, 6776–6784; b) S. M. Allin, J. S. Khera, J. Wither-
ington, M. R. J. Elsegood, Tetrahedron Lett. 2006, 47, 5737–
5739; c) S. M. Allin, J. S. Khera, C. I. Thomas, J. Witherington,
K. Doyle, M. R. J. Elsegood, M. Edgar, Tetrahedron Lett. 2006,
47, 1961–1964; d) C. Camarero, I. González-Temprano, E.
Lete, N. Sotomayor, Synlett 2007, 1101–1105; e) C. Camarero,
I. González-Temprano, A. Gómez-SanJuan, S. Arrasate, E.
Lete, N. Sotomayor, Tetrahedron 2009, 65, 5787–5798.
[11] M. Amat, N. Llor, J. Hidalgo, J. Bosch, Tetrahedron: Asym-
metry 1997, 8, 2237–2240.
[12] a) T. Fujii, M. Ohba, J. Sakaguchi, Chem. Pharm. Bull. 1987,
35, 3628–3640; b) A. Deiters, M. Pettersson, S. F. Martin, J.
Org. Chem. 2006, 71, 6547–6561; see also ref.[3b,8,9]
[13] For the relative configuration at the epimerizable C-6 ste-
reocenter, see the Exp. Section. The relative configuration at
C-6 was deduced from the 6-H/7-H coupling constant of 6-H
in the NMR spectra.
1
= 0.2, CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 1.06
(t, J = 7.2 Hz, 3 H, CH3 ethyl), 1.16–1.83 (m, 8 H, CH2 ethyl,
6-H, 7-H, 8-H, CH2CO), 3.77 (t, J = 8.4 Hz, 1 H, 2-H), 4.50
(t, J = 8.4 Hz, 1 H, 2-H), 4.89 (m, 1 H, 8a-H), 5.22 (m, 1 H,
3-H), 7.15–7.43 (m, 9 H, ArH, ind-H), 7.73 (d, J = 8.0 Hz, 1
H, ind-H), 9.09 (br. s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 10.0 (CH3 ethyl), 21.3 (CH2 ethyl), 29.7 (C-
7), 30.4 (CH2CO), 40.3 (C-6), 41.5 (C-8), 58.3 (C-3), 72.7 (C-
2), 91.2 (C-8a), 112.2 (C-H ind), 135.0 (C-i), 137.4 (C-3a ind),
139.7 (C-7a ind), 167.9 (NCO), 190.8 (CO) ppm. IR (KBr): ν =
˜
1652 cm–1. HRMS: calcd. for C25H27N2O3 [M + H]+: 403.2016;
found 403.2014.
[21] M. Andriantsiferana, R. Besselièvre, C. Riche, H.-P. Husson,
Tetrahedron Lett. 1977, 18, 2587–2590.
[14] a) P. Deslongchamps, Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press, Oxford, 1983, p. 221; b) P. Perlmutter,
Conjugate Addition Reactions in Organic Synthesis, Pergamon
Press, Oxford, 1992, p. 25.
[22] For the chemoselective oxidation of a 2-indolylmethyl to a 2-
acylindole moiety, see: a) Y. Ban, K. Yoshida, J. Goto, T. Oishi,
J. Am. Chem. Soc. 1981, 103, 6990–6992; b) Y. Ban, K. Yosh-
ida, J. Goto, T. Oishi, E. Takeda, Tetrahedron 1983, 39, 3657–
3668; c) T. Fujii, M. Ohba, J. Sakaguchi, Chem. Pharm. Bull.
1987, 35, 3628–3640; d) J. Gracia, N. Casamitjana, J. Bonjoch,
J. Bosch, J. Org. Chem. 1994, 59, 3939–3951.
[15] See ref.[2,3a,4b,4c,5–7] For a discussion of the stereochemical out-
come (kinetic vs. thermodynamic control) in conjugate ad-
dition reactions to unsaturated δ-lactams, see ref.[3b,8,9]
1
[16] Data for 13: Yellow foam. [α]2D2 = –14.4 (c = 0.35, CHCl3). H
Received: July 19, 2010
NMR (400 MHz, CDCl3, 25 °C): δ = 0.95 (t, J = 7.6 Hz, 3 H,
Published Online: December 14, 2010
Eur. J. Org. Chem. 2011, 898–907
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
907