A synthetic approach to ervatamine-silicine alkaloids. Enantioselective total synthesis of (-)-16-episilicine

Article abstract of DOI:10.1021/jo902346j

(Chemical Equation Presented) Starting from an appropriate unsaturated phenylglycinol-derived oxazolopiperidone lactam, the synthesis of (-)-16-episilicine is reported, the key steps being a stereoselective conjugate addition, a stereoselective alkylation, and a ring-closing metathesis reaction. This represents the first enantioselective total synthesis of an alkaloid of the silicine group. 2009 American Chemical Society.

Full text of DOI:10.1021/jo902346j

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A Synthetic Approach to Ervatamine-Silicine Alkaloids. Enantioselective
Total Synthesis of (-)-16-Episilicine†
,‡
Mercedes Amat,* Nuria Llor, Begona Checa, Elies Molins, and Joan Bosch*
‡
‡
§
,‡
ꢀ
~
‡Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB),
University of Barcelona, 08028 Barcelona, Spain and §Institut de Cieꢁncia de Materials de Barcelona (CSIC),
Campus UAB, 08193 Cerdanyola, Spain
amat@ub.edu; joanbosch@ub.edu
Received November 4, 2009
Starting from an appropriate unsaturated phenylglycinol-derived oxazolopiperidone lactam,
the synthesis of (-)-16-episilicine is reported, the key steps being a stereoselective conjugate
addition, a stereoselective alkylation, and a ring-closing metathesis reaction. This represents the
first enantioselective total synthesis of an alkaloid of the silicine group.
Introduction
The ervatamine-silicine alkaloids1 constitute a relatively
numerous group of Corynanthean-type2 2-acylindole alka-
loids with a rearranged skeleton that lacks the characteristic
tryptamine moiety (Ind-C6-C5-N)3 present in most indole
alkaloids, having an unusual Ind-C6-C16-C5-N connectivity
instead (Figure 1).
Biogenetically, these alkaloids derive from secologanin via
a vobasine N-oxide equivalent,2 which undergoes a fragmen-
tation reaction and then a cyclization to form the central
carbocyclic seven-membered ring characteristic of these
natural products (Scheme 1). As a consequence of their
FIGURE 1. Representative alkaloids of the ervatamine-silicine
group.
biogenetic origin, the configuration of the C-15 stereocenter
in these alkaloids is usually S (H-15β),4 the same configura-
tion as for C-15 in secologanin. However, they differ in the
relative stereochemistry of C-16 (cis or trans C/D ring fusion)
and C-20 (there are also C-20 E-ethylidene derivatives), the
oxidation level at C-6 (some are 6-oxo derivatives), and the
presence or absence of a C-16 methoxycarbonyl group.
The alkaloids of the ervatamine-silicine group have
received scarce attention from the synthetic standpoint,5
† Dedicated to Professor Pelayo Camps, University of Barcelona, on the
occasion of his 65th birthday.
(1) (a) Joule, J. A. Indoles. The Monoterpenoid Indole Alkaloids; Saxton, J. E.,
Ed. In The Chemistry of Heterocyclic Compounds; Weissberger, A.;, Taylor, E.
C., Eds.; Wiley: New York, 1983; Vol. 25, part 4, pp 232-239. (b) Danieli, B.;
Palmisano, G. in The Alkaloids, ed. Brossi, A.; Academic Press, Orlando, vol. 27,
1986, pp 1-130. For more recent isolations, see: (c) Zhang, H.; Yue, J.-M. Helv.
Chim. Acta 2005, 88, 2537.
€
(2) Kisakurek, M. V.; Leeuwenberg, A. J. M.; Hesse, M. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1983; Chapter 5.
(3) Biogenetic numbering is used throughout this paper for all tetracyclic
and pentacyclic compounds: Le Men, J.; Taylor, W. I. Experientia 1965, 21,
508.
(4) In a few cases (e.g., C-20 ethylidene derivatives), although the C-15
configuration is the same as in secologanin, it is specified as R as a
consequence of the application of the sequence rule procedure.
(5) (a) Husson, H.-P.; Bannai, K.; Freire, R.; Mompon, B.; Reis, F. A. M.
Tetrahedron 1978, 34, 1363. (b) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org.
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Chem. 1997, 62, 3597. (c) Bennasar, M.-L.; Vidal, B.; Kumar, R.; Lazaro, A.;
Bosch, J. Eur. J. Org. Chem. 2000, 3919. For the synthesis of tetracyclic
structures related to ervatamine-silicine alkaloids, see: (d) Langlois, Y.;
Potier, P. Tetrahedron 1975, 31, 423. (e) Grierson, D. S.; Bettiol, J.-L.; Buck,
I.; Husson, H.-P.; Rubiralta, M.; Diez, A. J. Org. Chem. 1992, 57, 6414.
178 J. Org. Chem. 2010, 75, 178–189
Published on Web 12/07/2009
DOI: 10.1021/jo902346j
r
2009 American Chemical Society

Amat et al.
JOCArticle
SCHEME 1. Biosynthetic Pathway to Ervatamine-Silicine
Alkaloids. Absolute Configuration of C-15
SCHEME 2. Synthetic Strategy
SCHEME 3. First Synthetic Approach. Unexpected Diels-
Alder Reaction
and with the exception of our preliminary report6 on the
synthesis of (-)-16-episilicine, no enantioselective total
syntheses for these alkaloids have been reported so far.
Ervatamines and silicines can be envisaged as enantiopure
3,4,5-trisubstituted piperidines (the former with an addi-
tional methoxycarbonyl substituent) that embody an ethyl
substituent and a seven-membered carbocyclic ring fused on
the c side of the heterocycle.
Bearing in mind the versatility of aminoalcohol-derived
oxazolopiperidone lactams as chiral building blocks for the
enantioselective construction of complex piperidine-con-
taining derivatives,7 the above structural features prompted
us to explore the utility of these lactams as starting scaffolds
for the synthesis of ervatamine-silicine alkaloids. Scheme 2
outlines our synthetic strategy, whose key steps would be
(i) the stereoselective conjugate addition of a vinyl residue to
an unsaturated lactam already incorporating the ethyl sub-
stituent present in the natural targets, (ii) a stereoselective
alkylation to introduce a 2-vinyl-3-indolylmethyl fragment,
and (iii) a ring-closing olefin metathesis (RCM) reaction8 to
construct the carbocyclic seven-membered C ring. Subse-
quent oxidation-reduction and protecting-deprotecting
steps would complete the synthesis of ervatamines. The
alkoxycarbonyl substituent in the starting lactam not only
would facilitate the subsequent conjugate addition9 and
alkylation steps but could also be removed in advanced
stages of the synthesis to provide access to the silicine series.
Results and Discussion
The known10 lactam 1 was selected to carry out our initial
studies. The conjugate addition of the vinyl group was
accomplished in excellent chemical yield and complete exo-
facial selectivity, cis with respect to the ethyl substituent. The
subsequent alkylation of the resulting mixture of C-6 epi-
meric lactams 211 with 3-(bromomethyl)indole 312 took place
stereoselectively on the most accessible face of the piperidine
ring, providing derivative 4 in excellent yield (84%) as a
single stereoisomer (Scheme 3). Surprisingly, treatment of 4
(6) Amat, M.; Checa, B.; Llor, N.; Molins, E.; Bosch, J. Chem. Commun.
2009, 2935.
(7) For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47,
9503. (b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1. (c) Groaning,
M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843. (d) Escolano, C.; Amat, M.;
Bosch, J. Chem.;Eur. J. 2006, 12, 8198. (e) Couty, F.; Evano, G. In Compre-
hensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven,
E. F. V., Taylor, R. J., Eds; Elsevier: Oxford, 2008; Vol 11, pp 409-499. For more
recent work, see: (f ) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano,
(9) (a) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
ꢀ
300. (b) Cossy, J.; Mirguet, O.; Gomez Pardo, D.; Desmurs, J.-R. New J.
Chem. 2003, 27, 475. (c) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org.
Chem. 2006, 71, 6547 and references therein.
ꢀ
ꢀ
C.; Gomez-Esque, A.; Molins, E.; Allin, S. M.; Mckee, V.; Bosch, J. J. Org.
Chem. 2007, 72, 5193. (g) Amat, M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch,
ꢀ
ꢀ
ꢀ
(10) Amat, M.; Perez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E. Org.
Lett. 2001, 3, 611.
(11) For a preliminary communication reporting lactams 2 and 12a, see:
J. Angew. Chem., Int. Ed. 2008, 47, 3348. (h) Amat, M.; Gomez-Esque, A.;
Escolano, C.; Santos, M. M. M.; Molins, E.; Bosch, J. J. Org. Chem. 2009, 74,
1205. (i) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org. Chem. 2009, 74,
1794 and references therein.
ꢀ
Amat, M.; Brunaccini, E.; Checa, B.; Perez, M.; Llor, N.; Bosch, J. Org. Lett.
(8) (a) Handbook of Metathesis; Grubbs, R. H., Ed; Wiley-VCH: Weinheim,
2003; Vols. 1-3. (b) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693.
(c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
2009, 11, 4370.
(12) Mohanakrishnan, P. C.; Srinivasan, P. C. J. Org. Chem. 1995, 60,
1939.
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SCHEME 4. Second Synthetic Approach
SCHEME 6. Control of C-15 Configuration
SCHEME 5. Third Synthetic Approach
derivative 2 with 3-(bromomethyl)indole 6, followed by
Wittig methylenation of the resulting 2-formylindole 7
(Scheme 4). However, heating a toluene solution of 8 in the
presence of the second-generation Grubbs catalyst did not
lead to the expected ring-closing metathesis product either,
giving the Diels-Alder adduct 9 instead.
At this point, we reasoned that the failure in the closure of
the seven-membered ring of the target alkaloids by a RCM
reaction could have a conformational origin due to the steric
crowding caused by the benzyloxycarbonyl substituent on
the quaternary carbon. For this reason, we decided to
prepare diene 14a, i.e., the tert-butyl ester analogue of 8,
from which the tert-butoxycarbonyl group could be easily
removed under nonreductive conditions without affecting
the carbon-carbon double bonds. The synthesis of 14a was
performed as outlined in Scheme 5, following a synthetic
route similar to that previously developed in the above
benzyloxycarbonyl series but starting from the unsaturated
lactam 11a. This was readily accessible by sequential treat-
ment of lactam 10a14 with (TMS)2NLi, di-tert-butyl dicar-
bonate, and PhSeCl, followed by oxidation of the resulting
mixture of selenides. Both the conjugate addition of the vinyl
residue and the alkylation of the resulting lactam 12a11
(mixture of C-6 epimers) took place in excellent chemical
yield and complete stereoselectivity. A subsequent Wittig
methylenation of 2-formylindole 13a led to the new key
intermediate 14a.
Removal of the C-6 tert-butoxycarbonyl group from 14a
was accomplished by treatment with TFA followed by
heating of the resulting keto acid in refluxing toluene to give
6,7-trans oxazolopiperidone 15a in 81% yield. Only trace
amounts of the corresponding 6-epimer were detected.
Gratifyingly, as we had assumed, diene 15a underwent a
ring-closing metathesis reaction on treatment with the sec-
ond-generation Grubbs catalyst in refluxing toluene, leading
to the desired pentacycle 16a in 86% yield. The absolute
configuration of 16a was unambiguously established by
X-ray crystallographic analysis, thus confirming both the
stereochemical outcome of the conjugate addition reaction,
with the second-generation Grubbs catalyst in refluxing
toluene led to hexacycle 5 (33% yield), resulting from an
intramolecular Diels-Alder process,13 instead of the ex-
pected ring-closing metathesis product. A similar result
was obtained using the Hoveyda-Grubbs catalyst. As might
be expected, hexacycle 5 was also obtained (60% yield) when
a solution of 4 in toluene was heated at reflux in the absence
of a RCM catalyst.
To evaluate if the failure of the ring-closing metathesis
reaction could be attributed to the deactivating effect of the
ethoxycarbonyl substituent on the vinylindole moiety, we
turned our attention to diene 8, which bears an unsubstituted
vinyl substituent on the indole ring. This diene was prepared
in excellent overall yield by alkylation of the 1,3-dicarbonyl
(13) For related intramolecular Diels-Alder reactions, in which a
2-vinylindole moiety acts as the diene, see: (a) Kuehne, M. E.; Bornmann,
W. G.; Earley, W. G.; Marko, I. J. Org. Chem. 1986, 51, 2913. (b) Kuehne, M.
E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52,
ꢀ
347. (c) Pindur, U. Heterocycles 1988, 27, 1253. (d) Levy, J.; Sapi, J.; Laronze,
J.-L.; Royer, D.; Toupet, L. Synlett 1992, 601. (e) Abbiati, G.; Canevari, V.;
Facoetti, D.; Rossi, E. Eur. J. Org. Chem. 2007, 517.
(14) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron: Asymmetry
1997, 8, 2237.
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SCHEME 7. Enantioselective Total Synthesis of (-)-16-Episilicine
SCHEME 8. RCM Reaction from Diene 6-epi-15b
which leads to the unnatural configuration at C-15 (H-15R),
and the trans-C/D ring fusion.
In fact, the conjugate addition of organocuprates to
unsaturated oxazolopiperidone lactams is highly stereose-
lective15 as a consequence of the conformational rigidity of
the bicyclic system, occurring under stereoelectronic con-
trol,16 axial to the electrophilic carbon of the conjugate
double bond and, consequently, cis with respect to the
adjacent pseudoequatorial ethyl substituent (see 11a in
Scheme 6). To obtain the natural (H-15β) absolute config-
uration at C-15, an obvious solution was to start from the
enantiomeric lactam ent-11a, which would be accessible
from the S-phenylglycinol-derived lactam ent-10a. However,
taking into account the availability of lactam 10b,17 to access
the natural C-15 absolute configuration we decided to use the
unsaturated lactam 11b, which presumably would also un-
dergo a stereoselective conjugate addition ultimately leading
to H-15β isomers. This lactam incorporates a C-8 ethyl
substituent with the absolute configuration required for the
synthesis of 16-episilicine, an alkaloid isolated in 1975 from
Pandaca caducifolia.18
The synthetic sequence for the preparation of the key
intermediate 16b starting from lactam 10b is outlined in
Scheme 7 and parallels that previously developed starting
from the diastereoisomeric lactam 10a. As expected, the
conjugate addition of the vinyl group to the unsaturated
lactam 11b took place stereoselectively leading to the exo
isomer 12b (mixture of C-6 epimers). A subsequent alkyla-
tion with the N-protected indole derivative 6 afforded 13b
in 75% yield as a single stereoisomer, thus confirming the
facial stereoselectivity of the conjugate addition reaction.
Wittig methylenation of 13b followed by removal of the
tert-butoxycarbonyl group gave diene 15b in 58% overall
yield. Minor amounts (10%) of the C-6 epimer (6-epi-15b)
were also isolated. The crucial ring-closing metathesis of 15b
was efficiently performed using the second-generation
Grubbs catalyst under refluxing toluene to give the trans-
fused pentacycle 16b in 87% yield. Quite unexpectedly,
a similar treatment from 6-epi-15b led to the anticipated
cis-fused pentacycle 16-epi-16b in only 24% yield, the main
product (50%) being the Diels-Alder adduct 21 (Scheme 8).
As in the failure of the RCM reactions from dienes 4 and 8,
the different behavior of 15b and 6-epi-15b under RCM
reaction conditions can most probably be explained on
conformational grounds. The absolute configuration of
16b, coinciding at C-15 with the natural configuration
(15β-H), and 21 were unambiguously established by X-ray
crystallographic analysis.
ꢀ
(15) (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65,
ꢀ
ꢀ
3074. (b) Amat, M.; Perez, M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins,
E.; Bosch, J. J. Org. Chem. 2004, 69, 8681.
(16) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983; p 221. (b) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992; p 25.
Once the tetracyclic ring system of the target alkaloid, with the
required trans-C15-C16 and cis-C15-C20 configuration, was
assembled, to complete the synthesis from 16b we only needed
to remove the chiral auxiliary and the indole protecting group
and to adjust the oxidation level. Catalytic hydrogenation of the
ꢀ
ꢀ
(17) Amat, M.; Escolano, C.; Gomez-Esque, A.; Lozano, O.; Llor, N.;
Griera, R.; Molins, E.; Bosch, J. Tetrahedron: Asymmetry 2006, 17, 1581.
(18) (a) Zeches, M.; Debray, M. M.; Ledouble, G.; Le Men-Olivier, L.; Le
Men, J. Phytochemistry 1975, 14, 1122. (b) Structural elucidation: Clivio, P.;
ꢁ
Richard, B.; Nuzillard, J.-M.; Zeches-Hanrot, M. Phytochemistry 1995, 40,
987.
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carbon-carbon double bond of 16b followed by treatment with
LiAlH4-AlCl3, which brought about both the reduction of the
lactam carbonyl group and the reductive opening of the oxa-
zolidine ring, gave tetracycle 17 in 64% overall yield. Deprotec-
tion of the indole nitrogen under smooth conditions, followed
by a catalytic debenzylation in the presence of (Boc)2O led to the
N-Boc protected piperidine derivative 19. A chemoselective
oxidation with I2O519 installed the 2-acylindole carbonyl group.
Finally, removal of the Boc protecting group followed by
methylation furnished (-)-16-episilicine, thus completing the
first synthesis of this natural product.
ethyl), 1.74-1.87 (m, 1H, CH2 ethyl), 2.24-2.31 (m, 1H, H-8),
3.02 (dd, J = 7.6, 3.6 Hz, 1H, H-7), 3.50 (d, J = 1.2 Hz, 1H, H-6),
3.99 (dd, J = 9.2, 1.2 Hz, 1H, H-2), 4.12 (dd, J = 9.2, 7.2 Hz, 1H,
H-2), 4.55 (d, J = 10.0 Hz, 1H, H-8a), 4.91-4.95 (m, 1H, H-3),
5.02-5.26 (m, 4H, CH2C6H5, CH2d), 5.83 (ddd, J = 17.2, 10.4,
7.6 Hz, 1H, CHd), 7.19-7.35 (m, 10H, ArH); 13C NMR (CDCl3,
100.6 MHz) δ 10.9 (CH3 ethyl), 20.5 (CH2 ethyl), 40.4 (C-7), 41.0
(C-8), 52.5 (C-6), 59.4 (C-3), 67.0 (CH2C6H5), 73.9 (C-2), 90.1
(C-8a), 118.2 (CHd), 126.4 (C-o), 127.4 (C-m), 128.0 (C-p), 128.2
(C-o), 128.4 (C-m), 128.5 (C-p), 134.1 (CH2d), 140.6 (C-i), 162.0
(NCO), 169.7 (CO). 6-epi-2 (minor epimer): IR (NaCl) 1664,
1735 cm-1 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
;
The 1H and 13C NMR data of our synthetic 16-episilicine
were in complete agreement with those previously repor-
ted18b for the alkaloid. However, the specific rotation of our
δ 1.04 (t, J = 7.4 Hz, 3H, CH3 ethyl), 1.36-1.46 (m, 1H, CH2
ethyl), 1.74-1.87 (m, 1H, CH2 ethyl), 2.24-2.31 (m, 1H, H-8),
3.11 (ddd, J = 10.4, 6.4, 4.0 Hz, 1H, H-7), 3.56 (d, J = 6.4 Hz, 1H,
H-6), 4.05 (dd, J = 9.2, 1.2 Hz, 1H, H-2), 4.13 (dd, J = 9.2, 7.2 Hz,
1H, H-2), 4.67 (d, J = 9.6 Hz, 1H, H-8a), 4.91-4.95 (m, 1H, H-3),
5.02-5.26 (m, 4H, CH2C6H5, CH2d), 5.73 (dt, J = 16.4, 10.8 Hz,
1H, CHd), 7.19-7.35 (m, 10H, ArH); 13C NMR (CDCl3, 100.6
MHz) δ 10.9 (CH3 ethyl), 20.9 (CH2 ethyl), 42.6 (C-7), 44.4 (C-8),
53.9 (C-6), 59.7 (C-3), 66.8 (CH2C6H5), 73.7 (C-2), 89.5 (C-8a),
120.1 (CH2d), 126.4 (C-o), 127.4 (C-m), 128.0 (C-p), 128.2 (C-o),
128.4 (C-m), 128.5 (C-p), 132.4 (CHd), 135.4 (C-i), 162.3 (NCO),
168.4 (COO); HRMS calcd for [C25H27NO4 þ Na] 428.1832,
found 428.1837.
synthetic material {[R]22 -20, c 1.0, CHCl3)}, although
D
coinciding in its absolute value with that reported for
16-episilicine {[R]22D þ20, c 1.0, CHCl3)},18 had the opposite
sign.20 Taking into account that the C-15 configuration
(S, 15β-H) of our synthetic 16-episilicine stems from the
X-ray crystallographic analysis of the advanced intermediate
16b, the discrepancy in the sign of the [R]D values is striking
since it might point to an uncommon 15R-H absolute con-
figuration for the alkaloid 16-episilicine, which would be the
enantiomer of the structure depicted in Figure 1. Hovewer,
this would need to be confirmed with new material isolated
from natural sources.
(3R,6R,7R,8S,8aR)-6-[(1-Benzenesulfonyl-2-(E-ethoxycarbonyl)-
vinyl-3-indolyl)methyl]-6-(benzyloxycarbonyl)-8-ethyl-5-oxo-3-
phenyl-7-vinyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine
(4). NaH (60% dispersion in mineral oil, 60 mg, 1.51 mmol)
was slowly added at 0 °C to a solution of lactams 2 (513 mg,
1.26 mmol) in dry DMF (18 mL), and the mixture was stirred at
0 °C for 1 h. Then, a solution of bromomethylindole 312 (850 mg,
1.9 mmol) in DMF (6 mL) was added at 0 °C, and the resulting
mixture was stirred at room temperature for 24 h. The mixture
was poured into water, the aqueous layer was extracted with
Et2O, and the combined organic extracts were dried and con-
centrated. Flash chromatography of the resulting oil (9:1 hex-
ane-EtOAc to 1:1 hexane-EtOAc) afforded pure compound
Conclusion
In summary, we have accomplished for the first time
the enantioselective total synthesis of an alkaloid of the
silicine group, thus further illustrating the potential and
versatility of phenylglycinol-derived oxazolopiperidone
lactams in the synthesis of enantiopure piperidine-con-
taining complex natural products. The unexpected beha-
vior of dienes 4 and 8 under RCM reaction conditions
represents a serious drawback that precludes the applica-
tion of the developed strategy to the synthesis of ervata-
mine alkaloids.
1
4 (820 mg, 84% yield): IR (film) 1659, 1715 cm-1; H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.72 (t, J = 7.2 Hz, 3H,
CH3 ethyl), 1.12-1.18 (m, 2H, CH2 ethyl, H-8), 1.37 (t, J =
7.2 Hz, 3H, CH3CH2CO), 1.48-1.54 (m, 1H, CH2 ethyl), 2.94
(dd, J = 10.8, 4.4 Hz, 1H, H-7), 3.56 (d, J = 14.8 Hz, 1H,
CH2-ind), 3.66 (d, J = 14.8 Hz, 1H, CH2-ind), 3.92 (dd, J = 9.0,
1.2 Hz, 1H, H-2), 4.00 (dd, J = 9.0, 6.5 Hz, 1H, H-2), 4.28-4.36
(m, 2H, CH3CH2CO), 4.62 (d, J = 9.2 Hz, 1H, H-8a), 4.82 (d,
J = 6.5 Hz, 1H, H-3), 4.92-5.03 (m, 4H, CH2C6H5, HCdCH2),
5.57-5.67 (m, 1H, HCdCH2), 6.26 (d, J = 16.4 Hz, 1 H,
CHdCHCO), 6.69 (m, 1H, H-6 ind), 7.06-7.46 (m, 11H, ArH,
H-5 ind), 7.65 (dd, J = 8.4, 1.2 Hz, 1H, H-7 ind), 8.05 (d, J =
16.4 Hz, 1H, CHdCHCO), 8.11 (d, J = 8.4 Hz, 1H, H-4 ind);
13C NMR (CDCl3, 100.6 MHz) δ 10.5 (CH3 ethyl), 14.3
(CH3CH2CO), 20.1 (CH2 ethyl), 29.7 (CH2-ind), 43.4 (C-8),
46.0 (C-7), 59.9 (C-6), 60.2 (C-3), 60.8 (CH3CH2CO), 67.1
(CH2C6H5), 74.2 (C-2), 88.7 (C-8a), 114.2 (CHdCHCO), 120.1
(HCdCH2), 121.4 (C-7 ind), 121.7 (C-4 ind), 124.6 (C-3 ind),
124.9 (CHdCHCO), 126.0 (C-2 ind), 126.7 (C-6 ind), 126.9
(C-5 ind), 127.5 (C-o), 128.1 (C-m), 128.2 (C-p), 128.5 (C-o),
128.6 (C-m), 129.0 (C-p), 130.4 (C-i), 132.9 (HCdCH2), 133.9
(C-i), 135.0 (C-i), 135.2 (C-o), 136.3 (C-m), 137.9 (C-3a ind),
140.9 (C-7a ind), 165.8 (COO), 165.9 (COO), 170.4 (NCO);
[R]22D -58.3 (c 1.0, CHCl3). Anal. Calcd for C45H44N2O8S: C,
69.93; H, 5.74; N, 3.62; S, 4.15. Found: C, 69.93; H, 5.69; N, 3.55;
S, 4.05.
Experimental Section
(3R,7R,8S,8aR)-6-(Benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-
7-vinyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (2). LiCl
(906 mg, 21.3 mmol) was heated at 80 °C for 3 h under vacuum
(10-15 mmHg) in a three-necked 500 mL round-bottomed flask.
Then, CuI (5.6 g, 29.1 mmol) and THF (40 mL) were added at
room temperature, and the mixture was stirred at rt for 5 min. The
suspension was cooled at -78 °C, and vinylmagnesium bromide
(1 M in THF, 29 mL), TMSCl (3.7 mL, 29.1 mmol), and a solution
of the crude unsaturated lactam 110 (2.88 g) in THF (100 mL) were
successively added. The resulting mixture was stirred at -78 °C for
23 h. The reaction was quenched with saturated aqueous NH4Cl,
and the aqueous layer was extracted with EtOAc. The combined
organic extracts were dried and concentrated. Flash chromato-
graphy (4:1 hexane-EtOAc to 1:1 hexane-EtOAc) gave lactams
2 and 6-epi-2 as a 4:1 mixture (2.80 g, 90% yield from the
crude unsaturated lactam 1). 2 (major epimer): IR (NaCl) 1664,
1735 cm-1 1H NMR (CDCl3, 400 MHz, COSY, HETCOR)
;
δ 0.99 (t, J = 7.3 Hz, 3H, CH3 ethyl), 1.36-1.46 (m, 1H, CH2
Attempted RCM Reaction from 4. Second-generation Grubbs
catalyst (2 mg) was added to a solution of compound 4 (60 mg,
0.08 mmol) in toluene (20 mL), and the resulting mixture was
heated at reflux for 16 days, with an additional 2 mg of catalyst
(19) Yoshida, K.; Goto, J.; Ban, Y. Chem. Pharm. Bull. 1987, 35, 4700.
(20) We acknowledge Dr. J. M. Nuzillard (University of Reims) for
providing us with a recently measured [R]D value (þ19.6, c 1.0, CHCl3) of
the isolated 16-episilicine.
182 J. Org. Chem. Vol. 75, No. 1, 2010

Amat et al.
JOCArticle
being added each 24 h. The solvent was evaporated, and the
resulting residue was chromatographed (99:1 CH2Cl2-EtOAc)
to yield hexacycle 5 (20 mg, 33% yield): IR (film) 1678,
(t, J = 8.0 Hz, 1 H, H-5 ind), 6.87 (d, J = 4.4 Hz, 1 H, ArH),
7.05-7.08 (m, 1H, H-6 ind), 7.24-7.52 (m, 14H, ArH), 7.73
(dd, J = 8.0, 1.6 Hz, 1H, H-7 ind), 7.98 (d, J = 8.0 Hz, 1H, H-4
ind), 10.29 (s, 1H, CHO); 13C NMR (CDCl3, 100.6 MHz)
δ 10.6 (CH3 ethyl), 20.6 (CH2 ethyl), 31.3 (CH2-ind), 42.2
(C-8), 46.1 (C-7), 60.2 (C-6), 60.3 (C-3), 67.1 (CH2C6H5), 74.3
(C-2), 89.1 (C-8a), 114.3 (C-7 ind), 120.0 (HCdCH2), 120.3
(C-6 ind), 123.9 (C-5 ind), 128.4 (C-4 ind), 126.6 (C-3 ind),
126.7 (C-o), 127.4 (C-m), 128.1 (C-p), 128.2 (C-o), 128.4 (C-m),
128.8 (C-p), 129.4 (HCdCH2), 130.8 (C-o), 133.2 (C-m),
134.1 (C-3a ind), 135.0 (C-i), 135.3 (C-i), 137.1 (C-i), 137.8
(C-2 ind), 140.1 (C-7a ind), 165.5 (COO), 170.6 (NCO), 183.9
(CHO); [R]22D -27.7 (c 0.3, CHCl3). Anal. Calcd for C41H38-
N2O7S3 1/2CH2Cl2: C, 66.88; H, 5.27; N, 3.76; S, 4.30. Found:
C, 66.88; H, 5.29; N, 3.85; S, 4.31.
1
1730 cm-1; H NMR (400 MHz, CDCl3, COSY, HETCOR;
see Supporting Information for the numbering system) δ 0.99
(t, J = 7.4 Hz, 3H, CH3 ethyl), 1.31 (t, J = 7.1 Hz, 3H,
CH3CH2CO), 1.36 (d, J = 15.6 Hz, 1H, H-15), 1.65 (d, J =
15.6 Hz, 1H, H-15), 1.79-1.87 (m, 1H, H-8), 1.89-1.99 (m, 2H,
CH2 ethyl), 2.13-2.19 (m, 1H, H-10), 2.46-2.53 (m, 2H, H-8a,
H-9), 2.96-3.01 (m, 1H, H-7), 3.08 (dd, J = 9.6, 4.8 Hz, 1H,
H-8b), 4.07 (d, J = 4.0 Hz, 2H, H-11), 4.17 (d, J = 6.4 Hz, 1H,
CH3CH2CO), 4.21 (d, J = 6.4 Hz, 1H, CH3CH2CO), 4.77 (t,
J = 4.0 Hz, 1H, H-12), 4.88 (d, J = 6.0 Hz, 1H, H-9a), 5.06 (d,
J = 12.0 Hz, 1H, CH2C6H5), 5.16 (d, J = 12.0 Hz, 1H, CH2-
C6H5), 6.38 (d, J = 3.6 Hz, 1H, H-6), 6.56 (d, J = 7.6 Hz, 1H,
H-1), 6.75 (ddd, J = 8.8, 7.6, 1.2 Hz, 1H, H-2), 7.11 (dd, J = 8.4,
1.2 Hz, 1H, ArH), 7.16 (dd, J = 8.4, 1.2 Hz, 1H, ArH),
7.32-7.44 (m, 13H, ArH), 7.50 (dd, J = 8.8, 1.2 Hz, 1H,
H-4), 7.77 (dd, J = 8.8, 0.8 Hz, 1H, H-3); 13C NMR (CDCl3,
100.6 MHz) δ 12.9 (CH3 ethyl), 14.2 (CH3CH2CO), 24.3
(CH2 ethyl), 25.2 (C-8), 39.7 (C-7), 43.0 (C-9), 43.8 (C-8a),
44.0 (C-15), 49.7 (C-8b), 53.2 (C-15a), 58.1 (C-12), 60.3
(C-14a), 61.1 (CH3CH2CO), 67.7 (CH2C6H5), 74.1 (C-11),
93.5 (C-9a), 110.0 (C-6), 113.0 (C-4), 116.9 (C-2), 121.8 (C-3),
125.5 (C-1), 126.4 (C-o), 126.9 (C-m), 127.8 (C-p), 128.0 (C-o),
128.6 (C-m), 128.7 (C-p), 128.8 (C-o), 128.9 (C-m), 133.6 (C-i),
134.9 (C-i), 137.0 (C-i), 138.8 (C-15b), 140.2 (C-4a), 141.6
(C-5a), 144.4 (C-6), 166.0 (NCO), 170.8 (COO), 173.2 (COO);
[R]22D -56.1 (c 0.5, CHCl3). Anal. Calcd for C45H44N2O8S: C,
69.93; H, 5.74; N, 3.62; S, 4.15. Found: C, 69.81; H, 5.76; N,
3.29; S, 3.89.
(3R,6R,7R,8S,8aR)-6-[(1-Benzenesulfonyl-2-vinyl-3-indolyl)-
methyl]-6-(benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (8). KHMDS
(0.5 M in toluene, 2.16 mL, 1.08 mmol) was added to a solution
of methyltriphenylphosphonium bromide (387 mg, 1.08 mmol)
in anhydrous THF, and the mixture was stirred at rt for 30 min.
Thissolution was slowy transferred to a solution of formylindole7
(370 mg, 0.53 mmol) in anhydrous THF (20 mL), and the mixture
was heated at reflux for 4 h. The reaction was quenched by
addition of water, and the mixture was extracted with Et2O. The
combined organic extracts were dried and concentrated. Flash
chromatography (9:1 hexane-CH2Cl2 to 1:1 hexane-CH2Cl2)
gave 8 (323 mg, 87% yield): IR (film) 1658, 1740 cm-1; 1H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.56 (t, J = 7.2 Hz, 3H,
CH3 ethyl), 1.08-1.20 (m, 2H, CH2 ethyl, H-8), 1.47-1.55 (m,
1H, CH2 ethyl), 2.98 (dd, J = 10.8, 4.4 Hz, 1H, H-7), 3.55 (d, J =
15.2 Hz, 1H, CH2-ind), 3.71 (d, J = 15.2 Hz, 1H, CH2-ind), 3.97
(dd, J = 9.2, 1.6 Hz, 1H, H-2), 4.01 (dd, J = 9.2, 6.4 Hz, 1H, H-2),
4.61 (d, J= 9.6 Hz, 1H, H-8a), 4.84 (dd, J = 6.4, 1.6 Hz, 1H, H-3),
4.94 (d, J = 12.4 Hz, 1H, CH2C6H5), 4.95 (dt, J = 8.0, 1.6 Hz, 1H,
CHdCH2), 5.00 (d, J = 1.6 Hz, 1H, CHdCH2), 5.05 (d, J =
12.4 Hz, 1H, CH2C6H5), 5.37 (dd, J = 17.0, 1.6 Hz, 1H, ind-
HCdCH2), 5.51 (dd, J = 11.0, 1.6 Hz, 1H, ind-HCdCH2), 5.63
(dd, J = 17.0, 11.0 Hz, 1H, ind-HCdCH2), 6.80 (td, J = 8.0, 0.8
Hz, 1 H, CHdCH2), 6.80 (td, J = 7.6, 0.8 Hz, 1H, H-5 ind), 6.85
(d, J = 11.6 Hz, 1 H, ArH), 6.88 (d, J = 11.6 Hz, 1 H, ArH),
7.16-7.38 (m, 13H, ArH), 7.45 (tt, J = 7.6, 1.2 Hz, 1H, H-6 ind),
7.70-7.73 (m, 1H, H-7 ind), 8.11 (dd, J = 7.6, 0.4 Hz, 1H, H-4
ind); 13C NMR (CDCl3, 100.6 MHz) δ 10.3 (CH3 ethyl), 20.0
(CH2 ethyl), 28.9 (CH2-ind), 43.2 (C-8), 45.1 (C-7), 60.1 (C-3),
60.2 (C-6), 67.0 (CH2C6H5), 74.2 (C-2), 88.7 (C-8a), 114.0 (C-7
ind), 117.2 (C-5 ind), 119.7 (CHdCH2), 120.9 (C-6 ind), 122.7
(ind-CHdCH2), 124.1 (ind-CHdCH2), 124.9 (C-3 ind), 126.8
(C-4 ind), 127.2 (CHdCH2), 127.5 (C-o), 128.0 (C-m), 128.1
(C-p), 128.2 (C-o), 128.5 (C-m), 128.6 (C-p), 128.9 (C-o), 130.8
(C-3a ind), 133.3 (C-m), 133.6 (C-p), 135.3 (C-i), 135.4 (C-2 ind),
137.1 (C-i), 138.4 (C-i), 140.9 (C-7a ind), 166.3 (COO), 170.9
(NCO); [R]22D -21.5 (c 0.4, CHCl3). Anal. Calcd for C42H40N2-
O6S31/2H2O: C, 67.63; H, 6.08; N, 3.76. Found C, 67.40; H, 5.68;
N, 3.56.
1-(Benzenesulfonyl)-3-(bromomethyl)indole-2-carbaldehyde (6).
Benzoyl peroxide (2 mg, 0.008mmol) was added at rttoa solution
of 1-(benzenesulfonyl)-3-methylindole-2-carbaldehyde21 (250 mg,
0.84 mmol) and NBS (155 mg, 0.87 mmol) in anhydrous CCl4
(20 mL). The mixture was heated at reflux for 4 h, cooled at rt, and
filtered. The solution was concentrated, and the resulting residue
was chromatographed (hexane to 9:1 hexane-EtOAc) to give
1
formylindole 6 (188 mg, 60% yield): IR (film) 1678 cm-1; H
NMR (300 MHz, CDCl3) δ 4.91 (s, 2H, CH2), 7.39-7.74 (m, 8H,
ArH), 8.22 (d, J = 8.7 Hz, 1H, H-4), 10.66 (s, 1H, CHO); 13C
NMR (CDCl3, 75.4 MHz) δ 20.6 (CH2), 115.6 (C-7), 121.6 (C-4),
125.1 (C-6), 126.6 (C-5), 128.1 (C-3), 129.4 (C-o), 129.5 (C-m),
129.7 (C-p), 132.3 (C-2), 134.5 (C-3a), 137.1 (C-7a), 137.2 (C-i),
184.8 (CHO); HRMS calcd for [C16H12NO3SBr þ H] 377.9794,
found 377.9781.
(3R,6R,7R,8S,8aR)-6-[(1-Benzenesulfonyl-2-formyl-3-indolyl)-
methyl]-6-(benzyloxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (7). Operat-
ing as in the above preparation of 4, from lactam 2 (39 mg,
0.1 mmol), NaH (60% dispersion in mineral oil, 4.8 mg,
0.12 mmol), and bromomethylindole 6 (63 mg, 0.16 mmol) in
DMF (2 mL), compound 7 (51 mg, 75% yield) was obtained
after column chromatography (9:1 hexane-EtOAc to 1:1
hexane-EtOAc) as a yellow foam: IR (film) 1661, 1735
cm-1 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
;
Attempted RCM Reaction from 8. Operating as in the
preparation of compound 5, hexacycle 9 was obtained (8 mg,
32% yield) from lactam 8 (25 mg, 0.04 mmol) and the sec-
ond-generation Grubbs catalyst (8 mg; 0.5 mg/day, 16 days) in
toluene (10 mL) after flash chromatography (9:1 CH2Cl2-
δ 0.88 (t, J = 7.6 Hz, 3H, CH3 ethyl), 1.26-1.31 (m, 1H,
CH2 ethyl), 1.61-1.69 (m, 2H, CH2 ethyl, H-8), 3.62 (dd, J =
10.8, 4.4 Hz, 1H, H-7), 3.74 (d, J = 14.0 Hz, 1H, CH2-ind), 3.78
(d, J = 14.0 Hz, 1H, CH2-ind), 3.87 (d, J = 9.2 Hz, 1H, H-2),
4.03 (dd, J = 9.2, 7.2 Hz, 1H, H-2), 4.67 (d, J = 9.2 Hz, 1H,
H-8a), 4.81 (d, J = 6.0 Hz, 1H, H-3), 4.95 (d, J = 12.4 Hz, 1H,
CH2C6H5), 5.00 (d, J = 12.4 Hz, 1H, CH2C6H5), 5.04 (dd, J =
10.0, 1.6 Hz, 1H, HCdCH2), 5.27 (dd, J = 16.0, 1.6 Hz, 1H,
HCdCH2), 5.68 (dt, J = 16.0, 10.0 Hz, 1H, HCdCH2), 6.73
1
EtOAc). 9: IR (film) 1661, 1730 cm-1; H NMR (400 MHz,
CDCl3, COSY, HETCOR; see Supporting Information for the
numbering system) δ 0.84 (t, J = 7.3 Hz, 3H, CH3 ethyl),
1.42-1.78 (m, 6H, CH2 ethyl, H-7, H-8), 2.20-2.25 (m,
1H, H-9), 2.55 (d, J = 16.0 Hz, 1H, H-15), 2.75 (d, J = 16.0
Hz, 1H, H-15), 2.97 (dd, J = 8.8, 4.8 Hz, 1H, H-8b), 3.06 (m,
1H, H-8a), 4.07 (d, J = 4.0 Hz, 2H, H-11), 4.88 (t, J = 4.0 Hz,
1H, H-12), 4.93 (d, J = 5.6 Hz, 1H, H-9a), 5.18 (d, J = 12.0 Hz,
(21) Benzies, D. W. M.; Martinez-Fresneda, P.; Jones, R. A. Synth.
Commun. 1986, 16, 1799.
J. Org. Chem. Vol. 75, No. 1, 2010 183

Amat et al.
JOCArticle
1H, CH2C6H5), 5.23 (d, J = 12.0 Hz, 1H, CH2C6H5), 6.27 (d,
J = 7.6 Hz, 1H, H-6), 6.56 (td, J = 8.0, 0.8 Hz, 1H, H-1), 7.11
(td, J = 8.0, 1.2 Hz, 1H, H-2), 7.36-7.45 (m, 15H, ArH), 7.56
(d, J = 7.6 Hz, 1H, H-4), 8.00 (dd, J = 8.0, 1.6 Hz, 1H, H-3);
13C NMR (CDCl3, 100.6 MHz) δ 12.5 (CH3 ethyl), 24.7
(CH2 ethyl), 21.6 (C-8), 23.6 (C-7), 32.8 (C-15), 42.1 (C-9),
47.6 (C-8a), 49.9 (C-8b), 58.1 (C-12), 59.3 (C-15a), 60.2
(C-14a), 67.9 (CH2C6H5), 74.0 (C-11), 93.7 (C-9a), 101.8
(C-6), 114.5 (C-4), 117.0 (C-2), 123.1 (C-3), 124.7 (C-1), 126.7
(C-o), 127.1 (C-m), 127.7 (C-p), 128.0 (C-o), 128.2 (C-m), 128.7
(C-p), 134.7 (C-i), 137.1 (C-i), 139.2 (C-15b), 140.2 (C-4b),
Hz, 1H, H-3), 7.03 (d, J = 1.4 Hz, 1H, H-7), 7.10-7.20
(m, 5H, ArH).
(3R,8R,8aS )-6-(tert-Butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-
2,3,8,8a-tetrahydro-5H-oxazolo[3,2-a]pyridine (11b). Operating
as in the above preparation of 11a, from lactam 10b17 (1.56 g,
6.36 mmol) in THF (100 mL), LiHMDS (13.5 mL of a 1.0 M
solution in THF), (Boc)2O (1.47 g, 6.74 mmol) in THF (20 mL),
and PhSeCl (1.64 g, 8.54 mmol) in THF (10 mL), a 7:3 mixture of
C-6 epimeric selenides (2.6 g, 82% yield) was obtained. Pure
isomers were isolated after a subsequent flash chromatography
(9:1 hexane-EtOAc to 4:1 hexane-EtOAc). Higher Rf epimer:
IR (NaCl) 1658, 1735 cm-1 1H NMR (CDCl3, 400 MHz,
;
141.8 (C-5a), 167.7 (COO), 172.2 (NCO); [R]22 þ14.6 (c 0.5,
D
COSY, HETCOR) δ 0.73 (t, J = 7.3 Hz, 3H, CH3 ethyl),
1.12-1.20 (m, 1H, CH2 ethyl), 1.44 [s, 9H, C(CH3)3],
1.64-1.71 (m, 1H, CH2 ethyl), 1.83-1.92 (m, 2H, H-7, H-8),
2.03 (dd, J = 11.2, 2.0 Hz, 1H, H-7), 3.73 (dd, J = 8.8, 0.4 Hz,
1H, H-2), 4.44 (dd, J = 8.8, 7.6 Hz, 1H, H-2), 4.67 (d, J =
8.0 Hz, 1H, H-8a), 5.25 (t, J = 7.6 Hz, 1H, H-3), 7.24-7.40 (m,
8H, ArH), 7.80 (m, 2H, Ar-H); 13C NMR (CDCl3, 100.6 MHz)
δ 10.8 (CH3 ethyl), 24.0 (CH2 ethyl), 27.7 [CH3)3C], 33.3 (C-7),
38.2 (C-8), 57.4 (C-6), 58.6 (C-3), 72.3 (C-2), 82.8 [CH3)3C ], 92.3
(C-8a), 125.8 (C-o), 127.2 (C-m), 127.4 (C-p), 128.6 (C-o), 128.8
(C-m), 129.4 (C-p), 138.1 (C-i), 138.9 (C-i), 165.0 (NCO), 170.0
CHCl3); HRMS calcd for [C42H40N2O6S þ H] 701.8509, found,
701.8504.
(3R,8S,8aR)-6-(tert-Butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-
2,3,8,8a-tetrahydro-5H-oxazolo[3,2-a]pyridine (11a). Lithium
bis(trimethylsilyl)amide (17.4 mL of a 1.0 M solution in THF)
was slowly added at -78 °C to a solution of lactam 10a14
(2 g, 8.1 mmol) in anhydrous THF (100 mL), and the resulting
mixture was stirred for 90 min. Then, (Boc)2O (1.90 g,
8.71 mmol) and, after 2 h of continuous stirring at -78 °C, a
solution of PhSeCl (2.12 g, 11.05 mmol) in anhydrous THF
(10 mL) were added. 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 (1:9 hexane-EtOAc)
of the resulting oil afforded the corresponding selenides as a
mixture of C-6 epimers (3.64 g, 89% yield). Pure isomers were
isolated after a subsequent chromatography. Higher Rf epimer:
(CO); [R]22 - 169.5 (c 1.0, CHCl3); HRMS calcd for
D
[C26H31NO4Se þ Na] 524.1310, found 524.1312. Lower Rf
epimer: IR (NaCl) 1662, 1725 cm-1 1H NMR (CDCl3, 400
;
MHz, COSY, HETCOR) δ 0.93 (t, J = 7.3 Hz, 3H, CH3 ethyl),
1.15-1.22 (m, 1H, CH2 ethyl), 1.47 [s, 9H, C(CH3)3], 1.62-1.83
(m, 2H, CH2 ethyl, H-8), 1.79 (d, J = 12.0 Hz, 1H, H-7), 2.39 (d,
J = 12.0 Hz, 1H, H-7), 3.78 (dd, J = 8.8, 6.8 Hz, 1H, H-2), 4.28
(d, J = 8.0 Hz, 1H, H-8a), 4.37 (dd, J = 8.8, 7.6 Hz, 1H, H-2),
5.31 (t, J = 7.3 Hz, 1H, H-3), 7.11-7.37 (m, 9H, ArH), 7.50 (dd,
J = 8.0, 1.2 Hz, 1H, ArH); 13C NMR(CDCl3, 100.6 MHz) δ 10.8
(CH3 ethyl), 23.9 (CH2 ethyl), 27.7 [CH3)3C], 35.3 (C-7), 39.4
(C-8), 55.8 (C-6), 59.0 (C-3), 72.1 (C-2), 83.2 [CH3)3C ], 92.0
(C-8a), 126.5 (C-o), 126.8 (C-m), 127.5 (C-p), 128.6 (C-o), 128.7
(C-m), 129.1 (C-p), 138.0 (C-i), 138.9 (C-i), 165.5 (NCO), 169.1
(CO); [R]22D -13.1 (c 0.5, CHCl3). Operating as described above
for the preparation of compound 11a, unstable lactam 11b
(1,78 g) was obtained from the corresponding selenides (2.6 g,
IR (NaCl) 1665, 1726 cm-1 1H NMR (CDCl3, 400 MHz,
;
COSY, HETCOR) δ 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.18 (m,
1H, CH2 ethyl), 1.29 [s, 9H, (CH3)3C], 1.66 (m, 1H, CH2 ethyl),
1.76 (t, J = 12.4 Hz, 1H, H-7), 1.81 (m, 1H, H-8), 2.36 (dd, J =
12.4, 1.2 Hz, 1H, H-7), 3.88 (d, J = 8.8 Hz, 1H, H-8a), 3.95 (dd,
J = 9.2, 6.8 Hz, 1H, H-2), 3.98 (dd, J = 9.2, 2.4 Hz, 1H, H-2),
4.81 (dd, J = 6.8, 2.4 Hz, 1H, H-3), 7.20-7.55 (m, 10H, ArH);
13C NMR (CDCl3, 100.6 MHz) δ 10.6 (CH3), 23.4 (CH2 ethyl),
27.5 [(CH3)3C], 36.8 (C-7), 39.8 (C-8), 55.7 (C-6), 59.2 (C-3),
74.0 (C-2), 82.7 [(CH3)3C ], 92.2 (C-8a), 126.9-129.5 (C-o, m, p),
138.3 (C-i), 140.8 (C-i), 163.6 (NCO), 168.9 (COO); HRMS
calcd for [C26H31NO4Se þ H] 502.1484, found 502.1491. Lower
1
5.2 mmol) in CH2Cl2 (100 mL): H NMR (CDCl3, 400 MHz)
Rf epimer: IR (NaCl) 1668, 1725 cm-1 1H NMR (CDCl3,
;
δ 1.11 (t, J = 7.3 Hz, 3H, CH3 ethyl), 1.50 [s, 9H, C(CH3)3],
1.56-1.65 (m, 1H, CH2 ethyl), 1.82-1.89 (m, 1H, CH2 ethyl),
2.53 (dddd, J = 9.6, 8.0, 5.2, 2.0 Hz, 1H, H-8), 3.93 (dd, J =
9.2, 6.0 Hz, 1H, H-2), 4.43 (dd, J = 9.2, 7.2 Hz, 1H, H-2), 5.10 (d,
J = 9.6 Hz, 1H, H-8a), 5.27 (t, J = 6.3 Hz, 1H, H-3), 6.98 (d, J =
2.0 Hz, 1H, H-7), 7.24-7.91 (m, 5H, ArH); 13C NMR (CDCl3,
100.6 MHz) δ 11.0 (CH3 ethyl), 23.5 (CH2 ethyl), 28.0 [C(CH3)3],
42.4 (C-8), 58.3 (C-3), 73.1 (C-2), 82.0 [C(CH3)3], 90.7 (C-8a),
126.3 (C-o), 127.7 (C-p), 128.7 (C-m), 131.5 (C-6), 138.9 (C-i),
144.7 (C-7), 157.8 (NCO), 162.5 (CO).
400 MHz, COSY, HETCOR) δ 0.91 (t, J = 7.2 Hz, 3H, CH3),
1.18 (m, 1H, CH2 ethyl), 1.45 [s, 9H, (CH3)3C)], 1.66 (m,
1H, CH2 ethyl), 1.96 (dd, J = 14.0, 11.2 Hz, 1H, H-7), 2.04
(m, 1H, H-8), 2.13 (dd, J = 14.0, 3.6 Hz, 1H, H-7), 4.06 (dd, J =
9.2, 1.2 Hz, 1H, H-2), 4.16 (dd, J = 9.2, 6.8 Hz, 1H, H-2), 4.57 (d,
J = 8.4 Hz, 1H, H-8a), 4.95 (dd, J = 6.8, 1.2 Hz, 1H, H-3),
7.20-7.55 (m, 10H, ArH); 13C NMR (CDCl3, 100.6 MHz)
δ 10.8 (CH3), 23.9 (CH2 ethyl), 27.8 [(CH3)3C], 34.3 (C-7),
38.5 (C-8), 56.7 (C-6), 59.3 (C-3), 73.9 (C-2), 82.8 [(CH3)3C ],
92.1 (C-8a), 126.7-129.5 (C-o, m, p), 138.1 (C-i), 140.7 (C-i),
163.5 (NCO), 168.6 (COO); HRMS calcd for [C52H62N2O8Se2 þ
Na] 1025.2728, found 1025.2732. A stream of ozone gas was
bubbled through a cooled (-78 °C) solution of the above
selenides (3.64 g, 7.26 mmol) in anhydrous CH2Cl2 (215 mL)
until it turned pale blue (5 min). Then, the solution was
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 11a (2.5 g) as an oil, which due to its
unstability was used in the next reaction without further
purification: 1H NMR (CDCl3, 300 MHz) δ 1.14 (t, J =
7.5 Hz, 3H, CH3), 1.50 [s, 9H, C(CH3)3], 1.64 (m, 1H, CH2
ethyl), 1.88 (m, 1H, CH2 ethyl), 2.72 (m, 1H, H-8), 4.14 (dd,
J = 8.7, 1.5 Hz, 1H, H-2), 4.21 (dd, J = 8.7, 6.3 Hz, 1H,
H-2), 4.85 (d, J = 10.5 Hz, 1H, H-8a), 5.05 (dd, J = 6.3, 1.5
(3R,7R,8S,8aR)-6-(tert-Butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-
7-vinyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (12a).
Operating as in the above preparation of 2, from LiCl (1.23 g,
29.29 mmol), CuI (5.54 g, 29.08 mmol), vinylmagnesium
bromide (1 M in THF, 29.08 mL), TMSCl (3.7 mL, 29.1 mmol),
and a solution of the crude unsaturated lactam 11a (2.5 g,
7.27 mmol) in THF (100 mL), lactam 12a was obtained as a
mixture of C-6 epimers (ratio 77:23, 2.51 g, 83% overall yield
from 10a) after flash chromatography (9:1 hexane-EtOAc
to 4:1 hexane-EtOAc). Higher Rf epimer: IR (NaCl) 1666,
1
1731 cm-1; H NMR (CDCl3, 400 MHz, COSY, HETCOR)
δ 1.07 (t, J = 7.2 Hz, 3H, CH3 ethyl), 1.37 [s, 9H, C(CH3)3], 1.45
(m, 1H, CH2 ethyl), 1.83 (m, 1H, CH2 ethyl), 2.36 (m, 1H, H-8),
3.05 (dd, J = 8.0, 3.6 Hz, 1H, H-7), 3.32 (d, J = 0.8 Hz, 1H, H-
6), 3.98 (dd, J = 9.2, 1.2 Hz, 1H, H-2), 4.11 (dd, J = 9.2, 7.2 Hz,
1H, H-2), 4.52 (d, J = 10.0 Hz, 1H, H-8a), 4.90 (dd, J = 7.2,
1.2 Hz, 1H, H-3), 5.16 (d, J = 17.2 Hz, 1H, HCdCH2), 5.23
184 J. Org. Chem. Vol. 75, No. 1, 2010

Amat et al.
JOCArticle
(d, J = 10.8 Hz, 1H, HCdCH2), 5.82 (ddd, J = 17.2, 10.8,
8.0 Hz, 1H, HCdCH2), 7.20-7.35 (m, 5H, ArH); 13C NMR
(CDCl3, 100.6 MHz) δ 11.0 (CH3 ethyl), 20.5 (CH2 ethyl),
27.8 [C(CH3)3], 40.6 (C-8), 40.8 (C-7), 53.6 (C-6), 59.4 (C-3),
74.0 (C-2), 81.9 [C(CH3)3], 90.1 (C-8a), 118.0 (HCdCH2), 126.4,
128.3 (C-o, m), 127.3 (C-p), 134.6 (HCdCH 2), 140.9 (C-i), 162.4
(NCO), 168.6 (COO). Lower Rf epimer: 1H NMR (CDCl3, 400
MHz, COSY, HETCOR) δ 1.04 (t, J = 7.6 Hz, 3H, CH3 ethyl),
1.38 [s, 9H, C(CH3)3], 1.45 (bs, 1H, CH2 ethyl), 1.83 (bs, 2H,
CH2 ethyl, H-8), 3.08 (dd, J = 6.0, 3.2 Hz, 1H, H-7), 3.36 (d, J =
6.0 Hz, 1H, H-6), 4.02 (dd, J = 9.2, 0.8 Hz, 1H, H-2), 4.13 (dd,
J = 9.2, 8.8 Hz, 1H, H-2), 4.66 (d, J = 9.2 Hz, 1H, H-8a), 4.92
(bs, 1H, H-3), 5.21 (bs, 2H, HCdCH2), 5.76 (dt, J = 16.8,
10.8 Hz, 1H; HCdCH 2), 7.20-7.35 (m, 5H, ArH); 13C NMR
(CDCl 3, 100.6 MHz) δ 10.9 (CH3 ethyl), 20.9 (CH2 ethyl), 28.0
[C(CH3)3], 42.4 (C-7), 44.6 (C-8), 54.6 (C-6), 59.7 (C-3), 73.7
(C-2), 81.5 [C(CH3)3], 89.6 (C-8a), 119.6 (HCdCH2), 126.5
(C-o), 127.4 (C-m), 127.5 (C-p), 132.9 (HCdCH2), 141.2 (C-i),
δ 0.85 (t, J = 7.4 Hz, 3H, CH3 ethyl), 1.26-1.47 (m, 2H, CH2
ethyl, H-8), 1.38 [s, 9H, C(CH3)3], 1.62-1.69 (m, 1H, CH2 ethyl),
3.65-3.74 (m, 3H, CH2-ind, H-7), 3.85 (d, J = 8.8 Hz, 1H, H-2),
4.04 (dd, J = 8.8, 6.4 Hz, 1H, H-2), 4.69 (d, J = 9.6 Hz, 1H, H-8a),
4.79 (d, J = 6.4 Hz, 1H, H-3), 5.20 (dd, J = 10.4, 1.6 Hz, 1H,
HCdCH2), 5.44 (dd, J= 16.8, 1.6 Hz, 1H, HCdCH2),5.83(dt,J=
16.8, 10.4 Hz, 1H, HCdCH2), 6.69 (t, J = 7.6 Hz, 1 H, H-5 ind),
6.78-6.83 (m, 3H, ArH, H-7 ind), 7.05 (ddd, J = 8.8, 6.0, 2.4 Hz,
1H, H-6 ind), 7.26-7.82 (m, 7H, ArH), 8.01 (d, J= 8.4 Hz, 1H, H-4
ind), 10.32 (s, 1H, CHO); 13C NMR (CDCl3, 100.6 MHz) δ 10.5
(CH3 ethyl), 20.3 (CH2 ethyl), 27.9 [(CH3)3C], 31.1 (CH2-ind),
43.0 (C-8), 44.8 (C-7), 60.0 (C-6), 60.2 (C-3), 74.2 (C-2), 82.4
[(CH3)3C], 88.9 (C-8a), 114.2 (C-7 ind), 120.3 (HCdCH2), 124.2
(C-6 ind), 124.8 (C-5 ind), 126.4 (C-o), 126.7 (C-m), 127.2 (C-p),
128.2 (C-o), 128.8 (C-p), 129.4 (C-m), 130.0 (C-3 ind), 131.2 (C-2
ind), 133.5 (HCdCH2), 134.2 (C-4 ind), 135.0 (C-3a ind), 137.1
(C-ipso), 137.9 (C-7a ind), 141.2 (C-ipso), 166.3 (COO), 169.6
(NCO), 183.7 (CHO); [R]22 þ19.2 (c 1.0, CHCl3). Anal. Calcd for
C38H40N2O7S: C, 68.24; H, 6.03; N, 4.19. Found: C, 67.85; H, 5.97;
N, 3.76.
162.9 (COO), 167.7 (NCO). Anal. Calcd for C22H29NO4
1/2H2O: C, 69.45; H, 7.95; N, 3.68. Found C, 69.35; H, 7.93;
N, 3.73.
3
(3R,6S,7S,8R,8aS )-6-[(1-Benzenosulfonyl-2-formyl-3-indolyl)-
methyl]-6-(tert-butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (13b). Operating
as described for the preparation of 13a, pure compound 13b (680 g,
75% yield) was obtained from the mixture of lactams 12b and
6-epi-12b (500 mg, 1.35 mmol), NaH (65 mg, 1.62 mmol), and
formylindole 6 (1.02 g, 2.70 mmol) in DMF (45 mL) after flash
chromatography (9:1 hexane-EtOAc to 1:1 hexane-EtOAc).
(3R,7S,8R,8aS)-6-(tert-Butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-
7-vinyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (12b).
Operating as in the above preparation of 12a, from LiCl (0.88 g,
20.8 mmol), CuI (3.95 g, 20.8 mmol), vinylmagnesium bromide
(1 M in THF, 20.8 mL), TMSCl (2.7 mL, 20.8 mmol), and a
solution of the crude unsaturated lactam 11b (1.78 g, 5.2 mmol)
in THF (100 mL), lactam 12b was obtained as a mixture of C-6
epimers (ratio 4:1, 1.98 g, 84% overall yield from 10b) after flash
chromatography (hexane to 1:9 hexane-EtOAc). Pure isomers
were isolated after a subsequent chromatography. Higher Rf
epimer: 1H NMR (CDCl3, 400 MHz, COSY, HETCOR) δ 1.01
(t, J = 7.3 Hz, 3H, CH3 ethyl), 1.36-1.64 (m, 1H, CH2 ethyl),
1.47 [s, 9H, (CH3)3C], 1.70-1.80 (m, 1H, CH2 ethyl), 2.02-2.09
(m, 1H, H-8), 2.97 (ddd, J = 8.0, 3.6, 1.2 Hz, 1H, H-7), 3.45 (d,
J = 1.2 Hz, 1H, H-6), 3.70 (dd, J = 13.6, 9.0 Hz, 1H, H-2), 4.51
(dd, J = 13.6, 8.4 Hz, 1H, H-2), 4.63 (d, J = 8.8 Hz, 1H, H-8a),
5.20-5.30 (m, 3H, H-3, HCdCH2), 5.79-5.90 (m, 1H,
HCdCH2), 7.20-7.35 (m, 5H, Ar-H); 13C NMR (CDCl3,
100.6 MHz) δ 11.1 (CH3 ethyl), 21.2 (CH2 ethyl), 27.8
[(CH3)3C], 40.8 (C-8), 41.0 (C-7), 53.4 (C-6), 58.7 (C-3), 72.5
(C-2), 82.0 [(CH3)3C ], 90.5 (C-8a), 118.1 (HCdCH2), 125.8
(C-o), 127.4 (C-m), 128.7 (C-p), 134.3 (HCdCH2), 139.4 (C- i),
164.2 (NCO), 169.2 (CO); HRMS calcd for [C22H29NO4 þ H]
372.2169, found 372.2166. Lower Rf epimer: 1H NMR (CDCl3,
400 MHz, COSY, HETCOR) δ 1.03 (t, J = 7.4 Hz, 3H, CH3
ethyl), 1.36-1.64 (m, 1H, CH2 ethyl), 1.42 [s, 9H, (CH3)3C],
1.70-1.80 (m, 1H, CH2 ethyl), 2.02-2.09 (m, 1H, H-8), 3.06
(ddd, J = 10.8, 6.0, 3.2 Hz, 1H, H-7), 3.48 (d, J = 6.0 Hz, 1H,
H-6), 3.69 (t, J = 8.5 Hz, 1H, H-2), 4.53 (dd, J = 8.5, 4.8 Hz, 1H,
H-2), 4.66 (d, J = 9.2 Hz, 1H, H-8a), 5.19 (t, J = 1.2 Hz, 1H,
H-3), 5.20-5.37 (m, 2H, HCdC H2), 5.79-5.90 (m, 1H,
HCdCH2), 7.20-7.35 (m, 5H, Ar-H); 13C NMR (CDCl3,
100.6 MHz) δ 11.0 (CH3 ethyl), 21.6 (CH2 ethyl), 27.9 [(CH 3)3C],
42.2 (C-8), 44.4 (C-7), 54.6 (C-6), 58.1 (C-3), 72.2 (C-2), 81.7
[(CH3)3C], 90.4 (C-8a), 120.2 (HCdCH2), 125.4 (C-o), 127.3
(C-m), 128.7 (C-p), 132.4 (HCdCH2), 139.0 (C-i), 164.9 (NCO),
167.7 (CO); HRMS calcd for [C44H58N2O8 þ Na] 765.4085, found
765.4080.
1
13b: IR (KBr) 1671, 1727 cm-1; H NMR (400 MHz, CDCl3,
COSY, HETCOR) δ 0.87 (t, J = 7.3 Hz, 3H, CH3 ethyl), 1.22 [s,
9H, (CH3)3C], 1.27-1.37 (m, 1H, CH2 ethyl), 1.68-1.74 (m,
1H, CH2 ethyl), 2.00 (ddd, J = 13.2, 9.0, 3.6 Hz, 1H, H-8), 2.86
(dd, J = 10.0, 3.6 Hz, 1H H-7), 3.66 (t, J = 8.4 Hz, 1H, H-2), 3.70
(d, J = 13.2 Hz, 1H, CH2-ind), 3.85 (d, J = 13.2 Hz, 1H, CH2-ind),
4.49 (t, J = 8.4 Hz, 1H, H-2), 4.68 (d, J = 9.0 Hz, 1H, H-8a), 5.04
(t, J = 8.4 Hz, 1H, H-3), 5.22 (dd, J= 10.0, 1.6 Hz, 1H, HCdCH2),
5.25 (dd, J = 17.6, 1.6 Hz, 1H, HCdCH2), 5.81 (dt, J = 17.6,
10.0 Hz, 1 H, HCdCH2), 7.20-7.30 (m, 7H, ArH, H-7 ind), 7.39
(dd, J = 8.0, 1.2 Hz, 2H, ArH), 7.43 (dd, J = 8.0, 1.2 Hz, 1H,
H-5 ind), 7.74-7.76 (m, 2H, ArH), 8.00 (d, J = 8.0 Hz, 1H,
H-6 ind), 8.09 (d, J = 8.8 Hz, 1H, H-4 ind), 10.52 (s, 1H, CHO); 13
C
NMR (CDCl3, 100.6 MHz) δ 10.8 (CH3 ethyl), 21.4 (CH2 ethyl),
27.8 [CH3)3C], 31.5 (CH2-ind), 40.5 (C-8), 48.9 (C-7), 59.1 (C-3),
59.7 (C-6), 72.1 (C-2), 82.5 [(CH3)3C], 90.4 (C-8a), 115.0 (C-7 ind),
120.6 (HCdCH2), 123.9 (C-6 ind), 124.1 (C-5 ind), 125.7 (C-4 ind),
126.8 (C-o), 127.2 (C-m), 128.4 (C-p), 128.7 (C-o), 129.0 (C-m),
129.9 (C-3 ind), 132.0 (C-2 ind), 132.7 (HCdCH2), 133.8
(C-p), 134.8 (C-3a ind), 137.3 (C-i), 137.6 (C-7a ind), 139.4 (C-i),
166.0 (NCO), 170.3 (CO), 184.8 (CHO); [R]22 -137.7 (c 0.5,
D
CHCl3); HRMS calcd for [C38H40N2O7S þ Na] 691.2447, found
691.2448.
(3R,6R,7R,8S,8aR)-6-[1-(1-Benzenosulfonyl-2-vinyl-3-indolyl)-
methyl]-6-(tert-butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (14a). Operating
as described for the preparation of 8, vinylindole 14a was obtained
(181 mg, 70% yield) from methyltriphenylphosphonium bromide
(542 mg, 1.52 mmol), KHMDS (0.5 M in toluene, 3.0 mL,
1.52 mmol), and lactam 13a (259 mg, 0.38 mmol) in THF
(30 mL) after column chromatography (9:1 hexane-CH2Cl2 to
1
(3R,6R,7R,8S,8aR)-6-[(1-Benzenesulfonyl-2-formyl-3-indolyl)-
methyl]-6-(tert-butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (13a). Operating
as described above for the preparation of 4, from lactam 12a
(500 mg, 1.35 mmol), NaH (60% dispersion in mineral oil, 65 mg,
1.62 mmol), and formylindole 6 (2.55 mg, 6.76 mmol) in DMF
(60 mL), compound 13a (827 mg, 92% yield) was obtained after
flash chromatography (9:1 hexane-EtOAc): IR (film) 1658,
1:1 hexane-CH2Cl2). 14a: IR (film) 1658, 1736 cm-1; H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.57 (t, J = 7.2 Hz, 3H,
CH3 ethyl), 1.01-1.16 (m, 2H, CH2 etthyl, H-8), 1.41 (s, 9H,
(CH3)3C), 1.49-1.55 (m, 1H, CH2 ethyl), 2.99 (dd, J = 10.8,
4.8 Hz, 1H, H-7), 3.51 (d, J = 14.8 Hz, 1H, CH2-ind), 3.63 (d,
J=14.8Hz, 1H, CH2-ind), 3.97(dd,J= 9.1, 1.2 Hz, 1H, H-2), 4.05
(dd, J = 9.1, 6.6 Hz, 1H, H-2), 4.66 (d, J = 9.6 Hz, 1H, H-8a), 4.83
(dd, J = 6.6, 1.2 Hz, 1H, H-3), 5.09 (dd, J = 6.7, 1.6 Hz, 1H,
CH-CHdCH2), 5.12 (m, 1H, CH-CHdCH2), 5.39 (dd, J = 18.0,
1736 cm-1 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
;
J. Org. Chem. Vol. 75, No. 1, 2010 185

Amat et al.
JOCArticle
1.6 Hz, 1H, ind-CHdCH2), 5.53 (dd, J = 11.2, 1.6 Hz, 1H,
ind-CHdCH2), 5.75-5.85 (m, 1H, CH-CHdCH2), 6.73 (dd,
J = 7.2, 0.8 Hz, 1 H, H-5 ind), 6.92 (dd, J = 18.0, 11.2 Hz, 1H,
ind-CHdCH 2), 7.12-7.35 (m, 9 H, ArH, H-ind), 7.44-7.73
(m, 2H, ArH, H-ind), 8.12 (d, J = 8.4 Hz, 1H, H-4 ind); 13C
NMR (CDCl3, 100.6 MHz) δ 10.2 (CH3 ethyl), 19.6 (CH2 ethyl),
27.9 [(CH3)3C], 28.6 (CH2-ind), 43.9 (C-8), 44.4 (C-7), 60.0 (C-6),
60.3 (C-3), 74.3 (C-2), 82.2 [(CH3)3C], 88.5 (C-8a), 113.9 (C-7 ind),
117.5 (C-5 ind), 119.5 (CH-CHdCH2), 121.2 (C-4 ind), 122.7
(ind-CHdCH2), 124.1 (C-6 ind), 124.8 (C-3 ind), 126.7 (C-o), 127.1
(C-m), 127.4 (C-p), 128.1 (ind-CHdCH2), 128.5 (C-o), 128.9 (C-m),
130.8 (C-2 ind), 133.6 (C-p), 133.8 (CH-CHdCH2), 135.4 (C-3a
ind), 136.9 (C-7a ind), 138.4 (C-i), 141.0 (C-i), 166.9 (NCO), 169.9
5.69 (dd, J = 11.4, 1.7 Hz, 1H, ind-CHdCH2), 7.13 (dd, J = 17.8,
11.4 Hz, 1H, ind-CHdCH2), 7.18-7.55 (m, 12H, ArH, H-ind),
7.69 (dd, J = 8.4, 1.2 Hz, 1 H, H-6 ind), 8.19 (d, J = 8.4 Hz, 1H,
H-4 ind); 13C NMR (CDCl3, 100.6 MHz) δ 11.2 (CH3 ethyl),
20.9 (CH2 ethyl), 26.9 (CH2-ind), 39.5 (C-7 and C-8), 46.0 (C-6),
59.3 (C-3), 73.8 (C-2), 90.3 (C-8a), 115.1 (C-7 ind), 117.4
(CHHCdCH2), 119.8 (C-5 ind), 120.4 (ind-CHdCH2), 121.0
(C-4 ind), 123.9 (C-6 ind), 125.4 (C-3 ind), 126.2 (C-o), 126.6
(C-m), 127.5 (C-p), 127.9 (ind-CHdCH2), 128.6 (C-o), 128.9
(C-m), 130.3 (C-2 ind), 133.6 (C-p), 135.6 (CHHCdCH 2), 135.7
(C-3a ind), 136.2 (C-7a ind), 138.1 (C-i), 141.9 (C-i), 168.9
(NCO); [R]22D þ145.3 (c 0.3, CHCl3); HRMS calcd for [C34H34-
N2O4S þ H] 567.2312, found 567.2316.
(CO); [R]22 -41.8 (c 0.5, CHCl3); HRMS calcd for [C39H42N2-
(3R,6R,7S,8R,8aS )-6-[(1-Benzenesulfonyl-2-vinyl-3-indolyl)-
methyl]-8-ethyl-5-oxo-3-phenyl-7-vinyl-2,3,6,7,8,8a-hexahydro-
5H-oxazolo[3,2-a]pyridine (15b). Operating as above, com-
pounds 15b (756 mg, 77% yield) and 6-epi-15b (136 mg, 14%
yield) were obtained from lactam 14b (1.15 g, 1.73 mmol)
in CH2Cl2 (150 mL) and TFA (5 mL, 0.06 mol) in toluene (250
mL) after flash chromatography (hexane to 9:1 hexane-EtOAc).
D
O6S þ Na] 689.2662, found 689.2662.
(3R,6S,7S,8R,8aS )-6-[(1-Benzenesulfonyl-2-vinyl-3-indolyl)-
methyl]-6-(tert-butoxycarbonyl)-8-ethyl-5-oxo-3-phenyl-7-vinyl-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (14b). Operating
as in the above preparation of 14a, vinylindole 14b was obtained
(1.1 g, 76% yield) from methyltriphenylphosphonium bromide
(1.52 g, 4.27 mmol), KHMDS (0.5 M in toluene, 8.48 mL, 4.24
mmol) in THF (20 mL), and lactam 13b (1.45 g, 2.17 mmol) in THF
(20 mL) after flash chromatography (9:1 hexane-EtOAc to
15b (6R, major): IR (KBr) 1653 cm-1 1H NMR (400 MHz,
;
CDCl3, COSY, HETCOR) δ 1.12 (t, J = 7.2 Hz, 3H, CH3 ethyl),
1.46-1.56 (m, 1H, CH2 ethyl), 1.87-1.95 (m, 2H, CH2 ethyl, H-8),
2.45 (dd, J = 8.0, 2.4 Hz, 1H, H-7), 3.06 (dd, J = 12.0, 3.2 Hz,
1H, H-6), 3.23 (dd, J = 14.0, 12.0 Hz, 1H, CH2-ind), 3.55 (dd,
J = 14.0, 3.2 Hz, 1H, CH2-ind), 3.86 (t, J = 8.5 Hz, 1H, H-2),
4.69 (t, J = 8.5 Hz, 1H, H-2), 4.81 (d, J = 8.8 Hz, 1H, H-8a),
4.87 (d, J = 16.8 Hz, 1H, HCdCH2), 5.15 (d, J = 10.4 Hz,
1H, HCdCH2), 5.41 (d, J = 8.5 Hz, 1H, H-3), 5.67 (dd, J = 17.6,
1.5 Hz, 1H, ind-HCdCH2), 5.84 (dd, J = 11.2, 1.5 Hz, 1H,
ind-HCdCH2), 5.82-5.92 (m, 1H, HCdCH2), 7.31 (dd, J =
17.6, 11.2 Hz, 1H, ind-HCdCH2), 7.38-7.54 (m, 9H, ArH,
H-7 ind), 7.63-7.67 (m, 2H, ArH), 7.79 (d, J = 8.0 Hz, 1H, H-5
ind), 7.90 (dd, J = 8.0, 1.2 Hz, 1H, H-6 ind), 8.40 (d, J = 8.4 Hz,
1H, H-4 ind); 13C NMR (CDCl3, 100.6 MHz) δ 11.4 (CH3 ethyl),
21.7 (CH2 ethyl), 26.1 (CH2-ind), 39.3 (C-7), 40.0 (C-8), 45.7 (C-6),
58.9 (C-3), 72.8 (C-2), 90.9 (C-8a), 115.1 (C-7 ind), 117.5
(HCdCH2), 119.8 (C-6 ind), 120.6 (C-2 ind), 121.2 (ind-
HCdCH2), 123.9 (C-4 ind), 125.4 (C-5 ind), 126.0 (C-o), 126.6
(C-m), 127.6 (ind-HCdCH2), 127.8 (C-p), 128.9 (C-o), 128.9 (C-
m), 130.3 (C-3 ind), 133.6 (C-p), 135.5 (HCdCH2), 135.8 (C-3a
1
1:1 hexane-EtOAc). 14b: IR (film) 1655, 1729 cm-1; H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.56 (t, J = 7.4 Hz, 3H,
CH3 ethyl), 0.97-1.09 (m, 1H, CH2 ethyl), 1.26-1.38 (m, 2H, CH2
ethyl, H-8), 1.36 [s, 9H, (CH3)3C], 2.73 (dd, J= 11.2, 4.0 Hz, 1H, H-
7), 3.58 (dd, J = 8.4, 7.6 Hz, 1H, H-2), 3.64 (d, J = 14.8 Hz, 1H,
CH2-ind), 3.97 (d, J = 14.8 Hz, 1H, CH2-ind), 4.08 (t, J = 8.4 Hz,
1H, H-2), 4.54 (d, J = 9.2 Hz, 1H, H-8a), 5.09-5.14 (m, 2H,
HCdCH2), 5.19(t,J= 7.6 Hz, 1H, H-3), 5.58 (dd, J= 18.0, 1.2 Hz,
1H, ind-HCdCH2), 5.69-5.78 (m, 1H, HCdCH2), 5.77 (dd, J =
11.6, 1.2 Hz, 1H, ind-HCdCH2), 7.12 (dd, J = 18.0, 11.6 Hz, 1H,
ind-HCdCH2), 7.22-7.38 (m, 10H, ArH), 7.48 (t, J = 7.6 Hz, 1 H,
H-7 ind), 7.70 (d, J = 8.0 Hz, 1H, H-5 ind), 7.75 (d, J = 7.6 Hz, 1H,
H-6 ind), 8.21 (d, J = 8.4 Hz, 1H, H-4 ind); 13C NMR (CDCl3,
100.6 MHz) δ 10.3 (CH3 ethyl), 20.9 (CH2 ethyl), 28.0 [C(CH3)3],
30.4 (CH2-ind), 41.6 (C-8), 46.1 (C-7), 59.0 (C-3), 59.3 (C-6), 71.7
(C-2), 82.6 [C(CH3)3], 89.4 (C-8a), 114.8 (C-7 ind), 118.4 (C-3 ind),
119.7 (HCdCH2), 121.2 (C-4 ind), 122.6 (ind-HCdCH2), 123.5
(C-5 ind), 125.4 (C-6 ind), 125.9 (C-o), 126.8 (C-m), 127.4 (C-p),
127.6 (C-o), 128.6 (C-m), 131.1 (C-2 ind), 133.2 (C-p), 133.7
(ind-HCdCH2), 135.7 (C-i), 136.9 (C-3a ind), 138.3 (C-7a ind),
139.0 (HCdCH2), 168.2 (NCO), 170.3 (CO); [R]22D þ18.6 (c 0.5,
CHCl3); HRMS calcd for [C39H42N2O6S þ Na] 689.2662, found
689.2655.
ind), 136.2 (C-7a ind), 138.1 (C-i), 139.6 (C-i), 170.2 (NCO); [R]22
D
-96.0 (c 0.5, CHCl3); HRMS calcd for [C34H34N2O4S þ H]
567.2312, found 567.2316. 6-epi-15b (6S, minor): IR (KBr) 1656
cm-1; 1H NMR (400 MHz, CDCl3, COSY, HETCOR) δ 0.85 (t,
J = 7.3 Hz, 3H, CH3 ethyl), 1.24-1.36 (m, 1H, CH2 ethyl),
1.48-1.64 (m, 2H, CH2 ethyl, H-8), 2.30 (dt, J = 6.4, 3.6 Hz, 1H,
H-7), 2.83 (m, 1H, CH2-ind), 2.90 (dd, J = 12.4, 4.4 Hz, 1H, H-6),
3.59 (d, J = 13.2 Hz, 1H, CH2-ind), 3.71 (t, J = 8.5 Hz, 1H, H-2),
4.52 (t, J = 8.5 Hz, 1H, H-2), 4.62 (d, J = 8.8 Hz, 1H, H-8a), 4.98
(dd, J = 17.0, 1.4 Hz, 1H, HCdCH2), 5.26 (t, J = 8.5 Hz, 1H,
H-3), 5.32 (dd, J = 10.0, 1.4 Hz, 1H, HCdCH2), 5.39 (dd, J =
17.8, 1.6 Hz, 1H, ind-CHdCH2), 5.55 (dd, J = 11.4, 1.6 Hz, 1H,
ind-CHdCH2), 5.62 (dt, J = 17.0, 10.0 Hz, 1H, HCdCH2), 7.04
(dd, J = 17.8, 11.4 Hz, 1H, ind-CHdCH2), 7.22 (dt, J = 8.0,
1.2 Hz, 1H, H-7 ind), 7.25-7.39 (m, 9H, ArH), 7.47 (dt, J = 7.2,
1.2 Hz, 1H, H-5 ind), 7.57 (d, J = 8.0 Hz, 2H, ArH), 7.72 (dd, J =
8.0, 1.2 Hz, 1H, H-6 ind), 8.21 (d, J = 8.4 Hz, 1H, H-6 ind);
13C NMR (CDCl3, 100.6 MHz) δ 11.4 (CH3 ethyl), 22.7 (CH2
ethyl), 23.0 (CH2-ind), 42.1 (C-7), 44.9 (C-8), 47.1 (C-6), 58.9
(C-3), 73.0 (C-2), 91.6 (C-8a), 115.0 (C-7 ind), 119.9 (C-4 ind),
120.8 (C-3 ind), 121.4 (CH2dCH), 122.0 (ind-CHdCH2), 123.6
(C-5 ind), 125.1 (C-6 ind), 126.0 (C-o), 126.7 (C-m), 127.6 (C-p),
127.7 (C-p), 128.8 (C-o), 128.9 (C-m), 130.6 (C-2 ind), 132.9
(HCdCH2), 133.5 (ind-CHdCH2), 135.6 (C-i), 136.2 (C-i), 138.2
(3R,6S,7R,8S,8aR)-6-[(1-Benzenesulfonyl-2-vinyl-3-indolyl)-
methyl]-8-ethyl-5-oxo-3-phenyl-7-vinyl-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (15a). TFA (100 μL, 1.58 mmol) was added
to a solution of 14a (260 mg, 0.39 mmol) in CH2Cl2 (50 mL),
and the mixture was stirred at room temperature for 2 h. Saturated
aqueous Na2CO3 was added to the reaction to reach pH 6-7, and
the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried and concentrated to give an oil, which
was dissolved in toluene (30 mL). The resulting solution was heated
at reflux for 6 h and concentrated to dryness. The residue was
chromatographed (1:1 hexane-CH2Cl2 to CH2Cl2) to afford
lactam 15a (178 mg, 81% yield): IR (film) 1655 cm-1; 1H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.93 (t, J = 7.2 Hz, 3H,
CH3 ethyl), 1.22-1.41 (m, 1H, CH2 ethyl), 1.72-1.86 (m, 1H, CH2
ethyl), 1.94-2.03 (m, 1H, H-8), 2.26 (dd, J= 8.1, 3.6 Hz, 1H, H-7),
2.75 (dd, J = 10.9, 4.2 Hz, 1H, H-6), 2.95 (dd, J = 14.5, 10.9 Hz,
1H, CH2-ind), 3.01 (dd, J = 14.5, 4.2 Hz, 1H, CH2-ind), 4.00 (dd,
J = 9.2, 1.4 Hz, 1H, H-2), 4.11 (dd, J = 9.2, 6.9 Hz, 1H, H-2), 4.52
(d, J = 9.6 Hz, 1H, H-8a), 4.66 (dt, J = 17.2, 1.2 Hz, 1H,
CHHCdCH2), 4.88 (dd, J = 6.9, 1.4 Hz, 1H, H-3), 4.95 (d, J =
10.5 Hz, 1H, CHHCdCH2), 5.47 (dd, J = 17.8, 1.7 Hz, 1H, ind-
CHdCH2), 5.64 (ddd, J = 17.2, 10.4, 8.1 Hz, 1H, CHHCdCH2),
(C-3a ind), 140.0 (C-7a ind), 167.0 (NCO); [R]22 -16.0 (c 0.2,
D
CHCl3); HRMS calcd for [C34H34N2O4S þ Na] 589.2131, found
589.2132.
186 J. Org. Chem. Vol. 75, No. 1, 2010

Amat et al.
JOCArticle
(1R,3aR,4S,4aR,12aS )-7-(Benzenesulfonyl)-4-ethyl-13-oxo-
1-phenyl-1,2,3a,4,4a,12,12a,13-octahydrooxazolo[200,300:60,10]-
pyrido[30,40:4,5]cyclohepta[1,2-b]indole (16a). Operating as
described for the preparation of 5, pentacycle 16a was ob-
tained (31 mg, 86% yield) from compound 15a (38 mg, 0.07
mmol) and the second-generation Grubbs catalyst (12 mg;
1.7 mg/day, 7 days) in toluene (25 mL) after column chroma-
tography (CH2Cl2): IR (KBr) 1655 cm-1; 1H NMR (400 MHz,
CDCl3, COSY, HETCOR) δ 0.99 (t, J = 7.2 Hz, 3H, CH3
ethyl), 1.62-1.76 (m, 2H, CH2 ethyl), 2.12 (q, J = 8.0 Hz, 1H,
H-4), 2.50 (ddd, J = 12.4, 8.4, 4.0 Hz, 1H, H-12a), 2.78 (dd,
J = 17.6, 12.0 Hz, 1H, H-12), 2.79-2.85 (m, 1H, H-4a), 3.45
(dd, J = 17.6, 4.0 Hz, 1H, H-12), 4.15 (dd, J = 9.2, 1.2 Hz, 1H,
H-2), 4.24 (dd, J = 9.2, 6.4 Hz, 1H, H-2), 4.78 (d, J = 8.0 Hz,
1H, H-3a), 4.93 (d, J = 6.1 Hz, 1H, H-1), 6.18 (dd, J = 12.0,
6.0 Hz, 1H, H-5), 7.19-7.41 (m, 12H, ArH, H-6, H-10), 7.46
(tt, J = 7.5, 1.2 Hz, 1H, H-9), 7.66 (dd, J = 8.4, 1.2 Hz, 1H, H-
8), 8.24 (d, J = 8.4 Hz, 1H, H-11); 13C NMR (CDCl3, 100.6
MHz) δ 11.5 (CH3 ethyl), 20.5 (CH2 ethyl), 25.2 (C-12),
40.2 (C-4), 44.9 (C-4a), 45.2 (C-12a), 58.9 (C-1), 74.4 (C-2),
90.3 (C-3a), 115.6 (C-8), 118.8 (C-9), 120.3 (C-11), 123.6
(C-6a), 124.2 (C-10), 125.6 (C-11a), 126.2 (C-11b), 126.5
(C-o), 126.8 (C-m), 127.7 (C-p), 128.6 (C-o), 128.8 (C-m),
131.0 (C-11a), 132.5 (C-5), 133.5 (C-p), 136.8 (C-7a), 138.1
(C-i), 141.0 (C-i), 168.5 (NCO); mp 195-144 °C (CH3Cl,
3.31 (dt, J = 7.2, 5.2 Hz, 1H, H-12a), 3.63 (dd, J = 8.8, 8.4 Hz,
1H, H-2), 4.50 (dd, J = 8.8, 8.4 Hz, 1H, H-2), 4.78 (d, J = 9.2
Hz, 1H, H-3a), 5.20 (t, J = 8.0 Hz, 1H, H-1), 6.21 (dd, J = 11.6,
5.2 Hz, 1H, H-5), 6.88-7.79 (m, 14H, ArH, H-6, H-8, H-9,
H-10), 8.20 (d, J = 8.4 Hz, 1H, H-11); 13C NMR (CDCl3, 100.6
MHz) δ 11.4 (CH3 ethyl), 22.1 (CH2 ethyl), 25.4 (C-12), 38.6
(C-4a), 43.6 (C-4), 54.2 (C-12a), 58.3 (C-1), 72.6 (C-2), 90.7
(C-3a), 114.6 (C-8), 119.1 (C-9), 123.0 (C-6a), 124.0 (C-11),
124.2 (C-10), 125.2 (C-o), 125.3 (C-p), 126.5 (C-m), 127.0
(C-11a), 127.3 (C-11b), 128.7 (C-o), 129.2 (C-m), 130.1 (C-p),
130.6 (C-6), 133.6 (C-5), 136.2 (C-7a ind), 138.7 (C-i), 138.8
(C-i), 169.9 (NCO); [R]22D -252.0 (c 0.3, CHCl3); HRMS calcd
for [C32H30N2O4S þ H] 539.1999, found 539.1997. 21: IR (film)
1655 cm-1; 1H NMR (400 MHz, CDCl3, COSY, HETCOR; see
Supporting Information for the numbering system) δ 1.02 (dd,
J = 13.2, 8.4 Hz, 1H, H-15), 1.10 (t, J = 7.4 Hz, 3H, CH3 ethyl),
1.25-1.33 (m, 1H, H-15), 1.30 (d, J = 13.2 Hz, 1H, H-8),
1.56-1.69 (m, 1H, CH2 ethyl), 1.71 (d, J = 13.2 Hz, 1H, H-8),
1.84 (ddd, J = 13.2, 9.2, 4.0 Hz, 1H, H-9), 1.99 (ddd, J = 13.6,
8.4, 2.4 Hz, 1H, CH2 ethyl), 2.04 (dt, J = 13.2, 2.8 Hz, 1H, H-7),
2.17 (dt, J = 12.4, 2.8 Hz, 1H, H-7), 2.39 (t, J = 8.4 Hz, 1H, H-
14a), 2.50 (ddd, J = 10.4, 6.0, 3.6 Hz, 1H, H-8b), 2.57 (dd, J =
10.4, 6.0 Hz, 1H, H-8a), 4.14 (dd, J = 9.2, 6.8 Hz, 1H, H-11),
4.44 (dd, J = 9.2, 8.0 Hz, 1H, H-11), 5.18 (d, J = 8.4 Hz, 1H,
H-9a), 5.27 (t, J = 7.4 Hz, 1H, H-12), 6.03 (dt, J = 7.2, 0.8 Hz,
1H, H-1), 6.30 (dd, J = 8.0, 0.8 Hz, 1H, H-2), 6.35 (dd, J = 8.4,
2.8 Hz, 1H, H-6), 6.95 (dt, J = 8.0, 1.2 Hz, 1H, H-3), 7.35-7.70
(m, 11H, ArH, H-4); 13C NMR (CDCl3, 100.6 MHz) δ 11.7
(CH3 ethyl), 19.0 (C-7), 22.9 (CH2 ethyl), 28.3 (C-8), 41.0 (C-8b),
41.5 (C-8a), 42.7 (C-9), 45.7 (C-14a), 47.1 (C-15), 59.5 (C-12),
71.8 (C-11), 90.3 (C-9a), 114.6 (C-6), 115.3 (C-4), 121.8 (C-2),
124.5 (C-1), 127.0 (C-o), 127.4 (C-p), 128.2 (C-p), 128.6 (C-m),
128.8 (C-15b), 128.9 (C-o), 129.1 (C-m), 133.4 (C-3), 138.1
(C-4a), 138.4 (C-5a), 139.0 (C-15a), 139.3 (C-i), 146.7 (C-i),
hexane); [R]22 þ73.4 (c 0.2, CHCl3). Anal. Calcd for
D
C32H30N2O4S 1/4CHCl3: C, 68.14; H, 5.36; N, 4.93. Found
3
C, 67.88; H, 5.60; N, 4.59.
(1R,3aS,4R,4aS,12aR)-7-Benzenesulfonyl-4-ethyl-13-oxo-
1-phenyl-1,2,3a,4,4a,12,12a,13-octahydrooxazolo[200,300:60,10]-
pyrido[30,40:4,5]cyclohepta[1,2-b]indole (16b). Operating as
described in the above preparation of 16a, pentacycle 16b
was obtained (1.09 g, 87% yield) from lactam 15b (1.31 g,
2.32 mmol) and the second-generation Grubbs catalyst
(265 mg; 53 mg/day, 5 days) in toluene (300 mL) after flash
chromatography (hexane to 1:1 hexane-EtOAc): IR (KBr)
169.9 (NCO); mp 193-195 °C (MeOH); [R]22 -85.5 (c 0.6,
D
CHCl3); HRMS calcd for [C34H34N2O4S þ H] 567.2312, found
1
1656 cm-1; H NMR (400 MHz, CDCl3, COSY, HETCOR)
567.2310.
δ 0.99 (t, J = 7.4 Hz, 3H, CH3 ethyl), 1.53-1.64 (m, 2H,
CH2 ethyl), 1.89-1.95 (m, 1H, H-4), 2.62 (dt, J = 10.0, 3.6 Hz,
1H, H-12a), 2.77 (ddd, J = 10.0, 5.4, 2.1 Hz, 1H, H-4a),
2.87 (dd, J = 16.8, 10.0 Hz, 1H, H-12), 3.46 (dd, J = 16.8,
3.6 Hz, 1H, H-12), 3.84 (dd, J = 9.0, 6.6 Hz, 1H, H-2),
4.40 (dd, J = 9.0, 7.8 Hz, 1H, H-2), 4.92 (d, J = 4.8 Hz,
1H, H-3a), 5.31 (t, J = 6.9 Hz, 1H, H-1), 6.10 (dd, J = 11.7,
5.1 Hz, 1H, H-5), 7.23-7.50 (m, 13H, ArH, H-6, H-9,
H-10), 7.66 (dd, J = 8.4, 1.2 Hz, 1H, H-8), 8.24 (d, J =
8.1 Hz, 1H, H-11); 13C NMR (CDCl3, 100.6 MHz) δ 12.1
(CH3 ethyl), 19.9 (CH2 ethyl), 24.3 (C-12), 39.8 (C-4a),
43.8 (C-4), 44.3 (C-12a), 58.6 (C-1), 71.8 (C-2), 90.2 (C-3a),
115.5 (C-8), 118.9 (C-9), 121.1 (C-6a), 123.8 (C-11), 124.1
(C-10), 125.5 (C-11a), 126.1 (C-11b), 126.4 (C-o), 127.6 (C-m),
128.7 (C-p), 128.8 (C-o), 130.8 (C-6), 132.6 (C-5), 132.8 (C-m),
133.5 (C-p), 136.7 (C-i), 137.9 (C-7a), 139.4 (C-i), 170.8
(1R,3aS,4R,4aS,12aR)-7-Benzenesulfonyl-4-ethyl-13-oxo-1-
phenyl-1,2,3a,4,4a,5,6,12,12a,13-decahydrooxazolo[200,300:60,10]-
pyrido[30,40:4,5]cyclohepta[1,2-b]indole (Dihydro-16b). A solu-
tion of lactam 16b (500 mg, 0.93 mmol) in EtOAc (15 mL)
containing 20% PtO2 (100 mg) was hydrogenated at room
temperature for 24 h. The catalyst was removed by filtration
and washed with hot MeOH. The combined solution was
concentrated, and the residue was chromatographed (9:1
hexane-EtOAc) to give dihydro-16b (360 mg, 72% yield):
IR (KBr) 1662 cm-1 1H NMR (400 MHz, CDCl3, COSY,
;
HETCOR) δ 1.00 (t, J = 7.6 Hz, 3H, CH3 ethyl), 1.43-1.62
(m, 2H, CH2 ethyl), 1.75 (ddd, J = 18.0, 9.2, 3.6 Hz, 1H, H-5),
1.87-1.95 (m, 2H, H-4, H-5), 2.08-2.16 (m, 1H, H-4a), 2.57
(ddd, J = 11.2, 8.4, 4.0 Hz, 1H, H-12a), 2.87 (dd, J = 16.0,
8.4 Hz, 1H, H-12), 3.21 (ddd, J = 17.2, 9.2, 4.4 Hz, 1H, H-6),
3.41-3.50 (m, 1H, H-6), 3.43 (dd, J = 16.0, 4.0 Hz, 1H, H-12),
3.78 (dd, J = 9.2, 7.2 Hz, 1H, H-2), 4.38 (t, J = 8.4 Hz, 1H,
H-2), 4.74 (d, J = 2.8 Hz, 1H, H-3a), 5.36 (t, J = 7.4 Hz, 1H,
H-1), 7.23-7.55 (m, 11H, ArH, H-8, H-9, H-10), 7.70 (dd, J =
8.8, 1.2 Hz, 2H, ArH), 8.19 (dd, J = 6.4, 1.6 Hz, 1H, H-11);
13C NMR (CDCl3, 100.6 MHz) δ 12.6 (CH3 ethyl), 19.6 (CH2
ethyl), 22.2 (C-12), 25.3 (C-6), 28.1 (C-5), 37.6 (C-4a), 41.2
(C-12a), 44.6 (C-4), 58.5 (C-1), 71.4 (C-2), 89.8 (C-3a), 114.8
(C-8), 118.5 (C-9), 119.5 (C-6a), 123.6 (C-10), 124.2 (C-11),
126.0 (C-o), 126.2 (C-m), 127.6 (C-p), 128.8 (C-o), 129.2
(C-m), 130.7 (C-11b), 133.5 (C-p), 136.4 (C-11a), 136.6 (C-
7a), 139.2 (C-i), 139.9 (C-i), 172.1 (NCO); [R]22D -22.5 (c 1.0,
CHCl3); HRMS calcd for [C32H32N2O4S þ H] 541.2155,
(NCO); mp 161-163 °C (MeOH); [R]22 -244.0 (c 0.3,
D
CHCl3). Anal. Calcd for C32H30N2O4S 1/2H2O: C, 70.57;
H, 5.67; N, 5.14; S, 5.89. Found C, 70.53; H, 5.74; N, 5.09;
S, 5.89.
3
RCM Reaction from 6-epi-15b. Operating as in the prepara-
tion of compound 5, pentacycle 6-epi-16b (240 mg, 24% yield)
and hexacycle 21 (540 mg, 50% yield) were obtained from diene
6-epi-15b (1.08 g, 1.91 mmol) and the second-generation
Grubbs catalyst (480 mg; 30 mg/day, 16 days) in toluene
(500 mL) after flash chromatography (9:1 hexane-EtOAc to
4:1 hexane-EtOAc). 16-epi-16b: IR (film) 1655 cm-1; 1H NMR
(400 MHz, CDCl3, COSY, HETCOR) δ 0.97 (t, J = 7.4 Hz, 3H,
CH3 ethyl), 1.46-1.73 (m, 2H, CH2 ethyl), 1.89 (ddd, J = 14.0,
7.6, 5.2 Hz, 1H, H-4), 2.89-2.95 (m, 1H, H-4a), 2.92 (dd, J =
14.4, 10.4 Hz, 1H, H-12), 3.18 (dd, J = 14.4, 5.2 Hz, 1H, H-12),
found 541.2160. Anal. Calcd for C32H32N2O4S 1/3CHCl3:
3
C, 66.94; H, 5.62; N, 4.83; S, 5.53. Found C, 66.57; H, 5.81; N,
4.58; S, 5.13.
J. Org. Chem. Vol. 75, No. 1, 2010 187

Amat et al.
JOCArticle
(4R,4aS,12aR)-7-Benzenesulfonyl-4-ethyl-2-[(1R)-2-hydroxy-
1-phenylethyl]-1,3,4,4a,5,6,12,12a-octahydropyrido[30,40:4,5]-
cyclohepta[1,2-b]indole (17). LiAlH4 (436 mg, 11.5 mmol) was
slowly added to a suspension of AlCl3 (498 mg, 3.73 mmol) in
THF (50 mL) at 0 °C. After the mixture was stirred at 25 °C
for 30 min and cooled to -78 °C, a solution of dihydro-16b
(940 mg, 1.74 mmol) in anhydrous THF (10 mL) was slowly
added. The stirring was continued at -78 °C for 10 min and at
0 °C for 1 h 30 min. The reaction was quenched with water.
The aqueous layer was extracted with EtOAc, and the com-
bined organic extracts were dried and concentrated to give a
foam, which was chromatographed (9:1 hexane-EtOAc to
4:1 hexane-EtOAc) to afford compound 17 (805 mg, 88%
(hexane to 4:1 hexane-EtOAc) afforded 19 (91 mg, 60% yield):
IR (KBr) 1667 cm-1 1H NMR (400 MHz, CDCl3, COSY,
;
HETCOR) δ 0.94 (t, J = 7.2 Hz, 3H, CH3 ethyl), 1.12-1.45
(m, 3H, CH2 ethyl, H-4), 1.47 [s, 3H, C(CH3)3], 1.60-1.74 (m, 4H,
H-4a, H-5, H-12a), 2.29 (dd, J = 15.2, 10.0 Hz, 1H, H-6),
2.43-2.46 (m, 1H, H-1), 2.70-2.92 (m, 4H, H-3, H-6, H-12),
4.16 (d, J = 12.4 Hz, 1H, H-3), 4.30 (d, J = 12.0 Hz, 1H, H-1),
7.07-7.09 (m, 2H, H-9, H-10), 7.24-7.25 (m, 1H, H-8), 7.40-7.47
(m, 1H, H-11), 7.82 (sa, 1H, NH); 13C NMR (CDCl3, 100.6 MHz)
δ 12.7 (CH3 ethyl), 17.2 (CH2 ethyl), 27.9 (C-3), 28.4 [C(CH3)3],
29.7 (C-5), 32.8 (C-6), 35.8 (C-4a), 44.2 (C-12a), 46.7 (C-3),
49.7 (C-1), 49.9 (C-3), 79.2 [C(CH3)3], 110.3 (C-8), 110.6 (C-6a),
117.4 (C-9), 119.2 (C-10), 120.6 (C-11), 128.8 (C-11b), 134.2
(C-11a), 138.0 (C-7a), 155.1 (NCO); [R]22 -0.4 (c 0.7,
yield): IR (KBr) 3441 cm-1 1H NMR (400 MHz, CDCl3,
;
D
CHCl3); HRMS calcd for [C46H64N4O4 þ H] 737.4844, found
COSY, HETCOR) δ 0.90 (t, J = 7.2 Hz, 3H, CH3 ethyl),
1.17-1.54 (m, 7H, CH2 ethyl, H-4, H-4a, H-5, H-12a), 2.10
(dd, J = 15.2, 10.8 Hz, 1H, H-3), 2.28 (d, J = 11.6 Hz, H-12),
2.57 (dd, J = 15.2, 1.6 Hz, 1H, H-3), 2.66 (dd, J = 15.2, 10.8
Hz, 1H, H-6), 2.85 (d, J = 8.8 Hz, 1H, H-1), 2.95 (d, J = 11.6
Hz, 1H, H-12), 3.62-3.77 (m, 3H, H-6, NCH, CH2O),
4.01-4.09 (m, 1H, CH2O), 7.19-7.51 (m, 11H, ArH, H-8,
H-9, H-10), 7.66 (dd, J = 8.4, 0.8 Hz, 2H, ArH), 8.20-8.23
(m, 1H, H-11); 13C NMR (CDCl3, 100.6 MHz) δ 12.7
(CH3 ethyl), 18.8 (CH2 ethyl), 25.4 (C-12), 28.8 (C-6), 31.5
(C-5), 35.3 (C-4a), 43.7 (C-12a), 49.7 (C-4), 53.4 (C-3), 55.6
(C-1), 60.2 (CH2O), 70.0 (NCH), 115.3 (C-8), 117.7 (C-9),
121.1 (C-6a), 123.4 (C-10), 123.9 (C-11), 126.2 (C-o), 127.9
(C-p), 128.2 (C-m), 128.9 (C-o), 129.1 (C-m), 130.4 (C-11b),
133.5 (C-p), 135.2 (C-11a), 136.3 (C-7a), 139.3 (C-i), 139.6
737.4835.
(4R,4aS,12aR)-2-(tert-Butoxycarbonyl)-4-ethyl-6-oxo-1,3,4,4a,
5,6,12,12a-octahydropyrido[30,40:4,5]cyclohepta[1,2-b]indole (20).
I2O5 (84 mg, 0.25 mmol) was added to a solution of compound
19 (78 mg, 0.21 mmol) in THF-H2O (9:1, 10 mL) at 0 °C, and the
mixture was stirred at room temperature for 5 h 30 min. The
mixture was poured into saturated aqueous NaHCO3, and the
aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with 20% aqueous Na2S2O3 and brine,
dried, filtered, and concentrated. The resulting oil was chromato-
graphed (CH2Cl2) affording compound 20 (67 mg, 83% yield): IR
1
(KBr) 1692, 1729 cm-1; H NMR (400 MHz, CDCl3, COSY,
HETCOR) δ 1.00 (t, J = 7.2 Hz, 3H, CH3 ethyl), 1.24-1.34 (m,
2H, CH2 ethyl), 1.46 [s, 3H, C(CH3)3], 1.60 (m, 1H, H-4),
1.91-2.00 (m, 1H, H-4a), 2.02-2.11 (m, 1H, H-12a), 2.47-
2.53 (m, 1H, H-1), 2.72-2.87 (m, 2H, H-5), 2.77 (dd, J = 15.6,
7.2 Hz, 1H, H-3), 2.84 (dd, J = 16.4, 4.8 Hz, 1H, H-12), 3.16 (dd,
J = 16.4, 6.0 Hz, 1H, H-12), 4.10 (dd, J = 10.4, 2.8 Hz, 1H,
H-3), 4.31 (d, J = 12.0 Hz, 1H, H-1), 7.16 (ddd, J = 8.0, 6.0,
1.2 Hz, 1H, H-11), 7.33-7.39 (m, 2H, H-9, H-10), 7.64 (d, J =
8.0 Hz, 1H, H-8), 8.86 (sa, 1H, NH); 13C NMR (CDCl3, 100.6
MHz) δ 12.8 (CH3 ethyl), 17.9 (CH2 ethyl), 26.7 (C-12), 29.1
[C(CH3)3], 36.2 (C-12a), 42.6 (C-4a), 43.2 (C-4), 46.3 (C-5), 46.8
(C-1), 49.8 (C-3), 79.6 [C(CH3)3], 112.0 (C-8), 120.4 (C-10), 120.8
(C-11), 123.0 (C-11b), 126.6 (C-9), 127.6 (C-11a), 132.6 (C-6a),
(C-i); [R]22 þ73.2 (c 0.37, CHCl3); HRMS calcd for [C32H36
-
N2O3S þ DH] 529.2519, found 529.2526. Anal. Calcd for
C32H36N2O3S: C, 72.70; H, 6.86; N, 5.30. Found C, 72.62;
H, 7.12; N, 5.01.
(4R,4aS,12aR)-4-Ethyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
1,3,4,4a,5,6,12,12a-octahydropyrido[30,40:4,5]cyclohepta[1,2-b]-
indole (18). Mg turnings (207 mg, 8.50 mmol) were added to a
solution of compound 17 (805 mg, 1.53 mmol) in anhydrous
MeOH (60 mL) at 0 °C. The resulting mixture was warmed to
room temperature and vigorously stirred for 4 h. The reaction
was quenched with water, and the resulting solution was
extracted with CH2Cl2. The combined organic extracts were
washed with saturated aqueous NaCl, dried, and concentrated.
The resulting residue was chromatographed (hexane to 4:1
hexane-EtOAc) to give the N-unsubstituted indole 18 (480
136.4 (C-7a), 155.5 (NCO), 193.9 (CO); [R]22 -22.9 (c 0.24,
D
CHCl3); HRMS calcd for [C23H30N2O3 þ H] 383.2329, found
383.2329.
(-)-16-Episilicine. TFA (50 μL, 0.79 mmol) was added to a
solution of indole 20 (67 mg, 0.18 mmol) in anhydrous CH2Cl2
(10 mL). The mixture was stirred at room temperature for 5 h
and brought to pH 7 by addition of saturated aqueous NaH-
CO3. The aqueous layer was extracted with CH2Cl2, and the
combined organic extracts were dried and concentrated to give
the corresponding amine, which was used in the next reaction
without further purification. The residue was dissolved in
anhydrous CH3CN (5 mL), MeI (18 μL, 0.29 mmol) was added,
and the mixture was stirred at room temperature for 3 h. The
solution was washed with saturated aqueous NaHCO3, and the
aqueous phase was extracted with EtOAc. The combined
organic extracts were dried, filtered, and concentrated. Flash
chromatography using a cartridge containing amine func-
tionalized silica (EtOAc to EtOAc-MeOH 4:1) afforded pure
(-)-16-episilicine (30 mg, 55% yield): 1H NMR (400 MHz,
CDCl3, COSY, HETCOR) δ 0.97 (t, J = 7.2 Hz, 3H, CH3
ethyl), 1.34-1.46 (m, 2H, CH2 ethyl), 1.56-2.02 (m, 5H, H-15,
H-20, H-21, H-5), 2.20-2.40 (m, 1H, H-16), 2.29 (sa, 3H,
NCH3), 2.81 (d, J = 6.4 Hz, 2H, H-14), 2.84 (dd, J = 17.2,
4.8 Hz, H-21), 2.90-3.09 (m, 2H, H-5, H-6), 3.18 (dd, J = 16.4,
6.4 Hz, 1H, H-6), 7.14 (ddd, J = 8.0, 6.8, 1.0 Hz, 1H, H-10), 7.33
(ddd, J = 8.0, 6.4, 1.0 Hz, 1H, H-11), 7.37 (d, J = 8.0 Hz, 1H, H-
12), 7.65 (d, J = 8.4 Hz, 1H, H-9), 8.79 (sa, 1H, NH); 13C NMR
(CDCl3, 100.6 MHz) δ 12.9 (C-18), 18.9 (C-19), 27.1 (C-6), 35.7
mg, 81% yield): IR (KBr) 3411, 2925 cm-1 1H NMR (400
;
MHz, CDCl3, COSY, HETCOR) δ 0.94 (t, J = 7.2 Hz, 3H,
CH3 ethyl), 1.21-1.74 (m, 7H, CH2 ethyl, H-4, H-4a, H-5, H-
12a), 2.22 (dd, J = 14.8, 11.2 Hz, 1H, H-12), 2.32 (d, J = 12.4
Hz, 1H, H-3), 2.72-2.84 (m, 3H, H-1, H-12), 2.94-3.01 (m, 2H,
H-3, H-6), 2.65-3.75 (m, 2H, NCH, CH2O), 4.07-4.16 (m, 1H,
CH2O), 7.08-7.46 (m, 9H, ArH, H-8, H-9, H-10, H-11), 7.75
(sa, 1H, NH); 13C NMR (CDCl3, 100.6 MHz) δ 12.8 (CH3
ethyl), 18.8 (CH2 ethyl), 27.9 (C-12), 29.4 (C-6), 32.5 (C-5), 36.5
(C-4a), 44.2 (C-12a), 49.4 (C-4), 53.6 (C-3), 55.6 (C-1), 60.3
(CH2O), 70.1 (NCH), 110.3 (C-8), 110.9 (C-6a), 117.4 (C-9),
119.2 (C-10), 120.6 (C-11), 127.9 (C-11b), 128.2 (C-o), 128.8
(C-p), 129.0 (C-m), 134.1 (C-11a), 135.3 (C-7a), 138.0 (C-i);
[R]22D þ8.3 (c 0.29, CHCl3); HRMS calcd for [C26H32N2O þ H]
389.2594, found 389.2599. Anal. Calcd for C26H32N2O
1/4EtOAc: C, 78.99; H, 8.35; N, 6.82. Found: C, 79.03; H,
8.41; N, 6.67.
3
(4R,4aS,12aR)-2-(tert-Butoxycarbonyl)-4-ethyl-1,3,4,4a,5,6,12,
12a-octahydropyrido[30,40:4,5]cyclohepta[1,2-b]indole (19). A solu-
tion of indole 18 (160 mg, 0.41 mmol) and di-tert-butyl dicarbo-
nate (94 mg, 0.43 mmol) in EtOAc (25 mL) containing 30%
Pd(OH)2-C (48 mg) was hydrogenated at rt for 16 h at atmo-
spheric pressure. The catalyst was removed by filtration, and the
solvent was evaporated to give an oil. Flash chromatography
188 J. Org. Chem. Vol. 75, No. 1, 2010

Amat et al.
JOCArticle
(C-16), 41.9 (C-15), 43.0 (C-20), 46.2 (NCH3), 46.8 (C-14), 57.8
(C-21), 63.4 (C-5), 112.1 (C-12), 120.3 (C-10), 120.7 (C-9), 123.1
(C-7), 126.5 (C-11), 127.7 (C-8), 132.6 (C-2), 136.4 (C-13), 194.3
(CO); [R]22D -20.0 (c 1.0, CHCl3).
2009-SGR-1111) is gratefully acknowledged. Thanks are
also due to the Ministry of Education and Science (Spain) for
a fellowship to B.C.
1
Supporting Information Available: Copies of the H and
13C NMR spectra of all compounds and X-ray crystallo-
graphic data for compounds 16a, 16b, and 21. This material
is available free or charge via the Internet at http://pubs.
acs.org.
Acknowledgment. Financial support from the Ministry
of Education and Science, Spain (Projects CTQ2006-
02390/BQU and CTQ2009-07021/BQU) and the AGAUR,
Generalitat de Catalunya (Grants 2005-SGR-0603 and
J. Org. Chem. Vol. 75, No. 1, 2010 189