Tandem intramolecular photocycloaddition-retro-mannich fragmentation as a route to spiro[pyrrolidine-3,3′-oxindoles]. Total synthesis of (±)-coerulescine, (±)-horsfiline, (±)-elacomine, and (±)-6-deoxyelacomine

Article abstract of DOI:10.1021/jo1002714

Figure presented Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-M

Full text of DOI:10.1021/jo1002714

pubs.acs.org/joc
Tandem Intramolecular Photocycloaddition-Retro-Mannich
Fragmentation as a Route to Spiro[pyrrolidine-3,30-oxindoles].
Total Synthesis of (()-Coerulescine, (()-Horsfiline, (()-Elacomine,
and (()-6-Deoxyelacomine
James D. White,* Yang Li, and David C. Ihle
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003
james.white@oregonstate.edu
Received February 17, 2010
Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue
results in an intramolecular [2 þ 2] cycloaddition to the indole 2,3-double bond. The resultant
cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,30-pyrrolenine]
with relative configuration defined by the orientation of substituents in the transient cyclobutane. The
tandem intramolecular photocycloaddition-retro-Mannich process, abbreviated as TIPCARM, leads
to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation that expels
the malonate unit and generates transiently an indolenine. The latter undergoes rearrangement to a
β-carboline, which upon brominative oxidation undergoes further rearrangement to an oxindole. With
tryptamine as starting material, the entire sequence leads to the alkaloid (()-coerulescine. Starting from
5-methoxytryptamine, a parallel series affords (()-horsfiline. Modification of the malonylidene unit to
include an isobutyl substituent at C3 affords a photosubstrate which also undergoes the TIPCARM
process. In this case, a 20-isobutyl-substituted spiro[indoline-3,30-pyrrolenine] results. This undergoes
stereoselective hydride reduction to give a product with relative orientation at the spiro carbon and
the new stereocenter bearing the isobutyl appendage corresponding to that of the alkaloid elacomine.
From tryptamine, the sequence paralleling that leading to coerulescine and horsfiline terminates at
6-deoxyelacomine, whereas 6-methoxytryptamine as starting material affords (()-elacomine itself.
Introduction
utility of this principle in his elegant construction of
1,4-dicarbonyl systems by irradiating an enolic β-diketone
(1, X=O, Scheme 1) in the presence of an alkene.3 Retro-
aldol cleavage of the resultant cyclobutane 2 led via 3 to 4.
Numerous applications of this concept to the synthesis of
novel substances have evolved from De Mayo’s pioneering
study.4
Photochemical [2 þ 2] cycloaddition of an R,β-unsatu-
rated carbonyl compound to an alkene followed by frag-
mentation of the resultant cyclobutane is a valuable strategy
for building structural complexity from simple subunits.1
The success of the method hinges not only on release
of the >20 kcal/mol of strain energy embedded in the
cyclobutane but also on deployment of functional groups
around the four-membered ring that steers rupture in a
desired direction.2 De Mayo was the first to recognize the
(3) De Mayo, P. Acc. Chem. Res. 1971, 4, 41.
€
(4) (a) Inter alia: Buchi, G.; Carlson, J. A.; Powell, J. E.; Tietze, L.-F.
J. Am. Chem. Soc. 1973, 95, 540. (b) Partridge, J. J.; Chadha, N. K.;
Uskokovic, M. R. J. Am. Chem. Soc. 1973, 95, 532. (c) Oppolzer, W.; Godel,
Y. J. Am. Chem. Soc. 1978, 100, 2583. (d) Baker, R.; Sims, R. J. Chem. Soc.,
Perkin Trans. 1 1981, 3087. (e) Piers, E.; Abeysekera, B. F.; Herbert, D. J.;
Suckling, I. D. Can. J. Chem. 1985, 63, 3418. (f) Disanayala, B. W.; Weedon,
A. C. Chem. Commun. 1985, 1282. (g) Seto, H.; Fujimoto, Y.; Tatsumo, T.;
Yoshioka, H. Synth. Commun. 1985, 15, 1217. (h) Crimmins, M. T.; Gould,
L. D. J. Am. Chem. Soc. 1987, 109, 6199.
(1) Ho, T.-L. Tactics of Organic Synthesis; Wiley: New York, 1994;
pp 138-144.
(2) (a) White, J. D.; Dillon, M. P.; Butlin, R. J. J. Am. Chem. Soc. 1992,
114, 9673. (b) White, J. D.; Kim, J.; Drapela, N. J. Am. Chem. Soc. 2000,
122, 8665.
DOI: 10.1021/jo1002714
r
Published on Web 04/29/2010
J. Org. Chem. 2010, 75, 3569–3577 3569
2010 American Chemical Society

White et al.
JOCArticle
SCHEME 1
SCHEME 2
Vinylogous amides (enaminones, 1, X=NH, Scheme 1)
undergo photochemical cycloaddition to alkenes in a man-
ner analogous to that of enolic β-diketones.5 In this case,
opening of the cyclobutane can occur via retro-Mannich
cleavage to yield a 1,4-imino ketone. The intramolecular
variant of this tandem photocycloaddition-retro-Mannich
fragmentation (which we abbreviate as “TIPCARM”)
was first investigated by Schell6 and subsequently was
exploited broadly by Winkler who employed a TIPCARM
strategy in several alkaloid syntheses.7 Swindell also used a
TIPCARM approach to construct a portion of the taxane
skeleton.8
now been applied to syntheses of oxindole alkaloids (()-
coerulescine (5) from the blue canary grass Phalaris
coerulescens10 and to (()-horsfiline (6), first isolated from
the Malaysian medicinal plant Horsfildea superba Warb.11 It
has been further extended to the β-carboline alkaloid 7 found
in the shrub Elaeagnus commutata Bernh12 and to the 40-
substituted spiro[pyrrolidine-3,30-oxindole] alkaloid (()-
elacomine (8), also from E. commutata.13 There has been
strong interest in the synthesis of spiro[pyrrolidine-3,30-
oxindoles],14 especially horsfiline (6), due to their structural
relationship to the cell cycle inhibitors spirotryprostatins
A and B.15
Recently, we showed that the 2,3-double bond of an indole
can serve as the alkene partner in intramolecular photocy-
cloaddition with a β-amino alkylidenemalonate.9 Subse-
quent retro-Mannich fragmentation of the formed cyclo-
butane led to a spiro[pyrrolinoindoline] skeleton. We now
report that extrapolation of our TIPCARM sequence can
include a second retro-Mannich fragmentation, “[TIPCA-
(RM)2]”, which expels a malonate residue used for the initial
photoaddition step. This second fragmentation, when fol-
lowed by rearrangement of the resulting spiroindolenine to a
β-carboline and then oxidation, provides access to alkaloids
of the spiro[pyrrolidine-3,30-oxindole] class. The method has
(10) (a) Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.;
Flower, K.; Vit, I.; Willing, R. I. Phytochemistry 1998, 45, 437. (b) Anderton,
N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Gardner, D.;
Willing, R. I. Phytochemistry 1999, 51, 153.
(11) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527.
(12) Slywka, G. W. A.; Locock, R. A. Tetrahedron Lett. 1969, 4635.
(13) James, M. N. G.; Williams, G. J. B. Can. J. Chem. 1972, 50, 2407.
(14) Reviews: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748.
(5) Cantrell, T. S. Tetrahedron 1971, 27, 1227.
(6) Schell, F. M.; Cook, P. M. J. Org. Chem. 1984, 49, 4067.
(7) (a) Winkler, J. D.; Muller, C. L.; Scott, R. D. J. Am. Chem. Soc. 1988,
110, 4831. (b) Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989,
111, 4852. (c) Winkler, J. D.; Scott, R. D.; Williard, P. G. J. Am. Chem. Soc.
1990, 112, 8971. (d) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998,
120, 6425.
(8) Swindell, C. S.; Patel, B. P.; DeSolms, S. J.; Springer, J. P. J. Org.
Chem. 1987, 52, 2346.
(9) White, J. D.; Ihle, D. C. Org. Lett. 2006, 8, 1081.
(15) Cui, C.-B.; Kakeya, J.; Osada, J. Tetrahedron 1996, 52, 12651.
3570 J. Org. Chem. Vol. 75, No. 11, 2010

White et al.
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SCHEME 3
spontaneous retro-Mannich fragmentation in which diethyl
malonate was expelled to afford the known β-carboline 1819
(Scheme 3). β-Carbolines such as 18 are conventionally
prepared by Pictet-Spengler condensation of a tryptamine
with an aldehyde20 or by Bischler-Napieralski cyclization of
a tryptamide followed by reduction.21 Our observation that
removal of the Boc group from 17 was necessary in order to
trigger the second retro-Mannich process argues against a
pathway to 18 via indole 19 followed by Pictet-Spengler
cyclization. More likely, 20 leads transiently to spiroindole-
nine 21, and it is this species that rearranges spontaneously in
acid to 18. Oxidation of 18 with N-bromosuccinimide in
aqueous acetic acid following a protocol first published by
Lawson and Withrop and further developed by van Tamelen
as a general route to oxindoles22,23 gave (()-coerulescine (5).
The same oxidative rearrangement of 18 was recently accom-
plished by Danishefsky in his synthesis of (()-(5).24 Our
overall yield of 5 for the nine steps from tryptamine (9)
was 11%.
A sequence parallel to that shown in Schemes 2 and 3 but
departing from 5-methoxytryptamine (22) and proceeding
via 23, 24, and 25 led to (()-horsfiline (6) in an overall yield
of 12% (Scheme 3). The photocycloaddition-retro-Man-
nich sequence from 26 via 27 to 28 was both slower and less
efficient than the analogous conversion of 14 to 16, probably
due to partial quenching of the photoexcited malonylidene
unit of 26 by the methoxy substituted indole. On the other
hand, the combined N-methylation and borohydride reduc-
tion of 28 resulted in more efficient preparation of 29 than of
17. Subsequent steps from 29 to (()-horsfiline (6) proceeded
via 30 and 31 to β-carboline 32 which was brominatively
oxidized to the racemic alkaloid. The structures of (()-5 and
Results and Discussion
(()-Coerulescine (5) and (()-Horsfiline (6). For the synthe-
sis of 5,16 tryptamine (9) was first converted to trifluoroa-
cetamide 10 before protection of the indole nitrogen as Boc
derivative 11 (Scheme 2). Removal of the trifluoroacetyl
group and condensation of the liberated amine 12 with
diethyl β-ethoxymethylidenemalonate (13)17 afforded photo
substrate 14. Irradiation of 14 in EtOH with a 450 W
medium-pressure mercury lamp through a Corex filter
(50% transmission at 290 nm)18 led via cycloadduct 15 and
in situ retro-Mannich fragmentation to spiropyrrolenine 16
in good yield. Although formation of 16 was more rapid
when 14 was irradiated through a Vycor filter (90% trans-
mission at 280 nm), decomposition of the product compli-
cated purification in this case. No reaction occurred when 14
was irradiated through Pyrex glass (20% transmission at 290
nm). These experiments confirm that the photocycloaddtion
step in our TIPCARM sequence is sensitive to the energy of
the incident radiation.
1
(()-6 were confirmed by comparison of their H and 13C
NMR spectra with published spectra of coerulescine16b and
horsfiline,16i respectively.
(()-Elacomine (8). The isobutyl substituent located at C40
in elacomine presented our TIPCA(RM)2 strategy with two
new challenges. Since we wished to bring the isobutyl ap-
pendage into our synthetic sequence at an early stage, the
first goal involved incorporation of that substituent into the
aminomalonylidene portion of our photo substrate. A sec-
ond issue concerned the new stereocenter at C40 and speci-
fically whether it would be oriented correctly with respect to
the adjacent spiro carbon at C3. Some precedent for both of
these operations existed in our previous work,9 but it was
unclear whether the more sterically demanding isobutyl
group would impose a constraint on the photocycloaddition
step of TIPCARM which would now generate a more highly
congested cyclobutane intermediate. Our solution to the first
of these tasks was straightforward and required only acyla-
tion of diethyl malonate with isovaleryl chloride followed by
O-methylation of 3425 to provide 35 (Scheme 4).
Treatment of 16 with methyl iodide gave a methiodide
which was reduced with sodium borohydride to saturated
spiro[pyrrolidinoindoline] 17. Removal of Boc protection
from 17 with trifluoroacetic acid under more strenuous
conditions than those used previously9 resulted in a second,
(16) The first synthesis of 5 appears to have been an adventitious one
recorded by Kuehne; Kuehne, M. E.; Roland, D. M.; Hafter, R J. Org.
Chem. 1978, 43, 3705. For subsequent syntheses of 5 and/or 6, see:
(a) Kuehne, M. E.; Roland, D. M.; Hafter, R. Heterocycles 1994, 38, 725.
We chose initially to test our approach to 8 in the con-
text of 6-deoxyelacomine (36, Scheme 6). Although this
€
(b) Pellegrini, C.; Strassler, C.; Weber, M.; Borschberg, H.-J. Tetrahedron:
Asymmetry 1994, 5, 1979. (c) Lakshmaiah, G.; Kawabata, G.; Shang, M.;
Fuji, K. J. Org. Chem. 1999, 64, 1699. (d) Kumar, U. K. S.; Ila, H.; Junjappa,
H. Org. Lett. 2001, 3, 4193. (e) Cravotto, G.; Giovenzana, G. B.; Pilati, T.;
Sisti, M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447. (f) Lizos, D. E.;
Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117. (g) Chang, M.-Y.; Pai, C.-L.;
Kung, Y.-H. Tetrahedron Lett. 2005, 46, 8463. (h) Murphy, J. A.; Tripoli, R.;
Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7, 3287. (i) Trost, B. M.; Brennan,
M. K. Org. Lett. 2006, 8, 2027.
(17) Momose, T.; Tanaka, T.; Yokota, T.; Nagamoto, N.; Yamada, K.
Chem. Pharm. Bull. Jpn. 1978, 26, 2224.
(18) Horspool, W. M., Ed. Synthetic Organic Photochemistry; Plenum
Press: New York, 1984; p 492.
(19) Boekelheide, V.; Ainsworth, C. J. Am. Chem. Soc. 1950, 72, 2132.
(20) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 151.
(21) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74.
(22) Lawson, W. B.; Withrop, B. J. Org. Chem. 1961, 26, 263.
(23) van Tamelen, E. E.; Yardley, J. P.; Miyano, M.; Hinshaw, W. B.
J. Am. Chem. Soc. 1969, 91, 7333.
(24) Li, C.; Chan, C.; Heimann, A.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2007, 46, 1444.
(25) Huffman, J. W.; Garg, S. P.; Cecil, J. H. J. Org. Chem. 1966, 31, 1276.
J. Org. Chem. Vol. 75, No. 11, 2010 3571

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SCHEME 4
SCHEME 6
SCHEME 5
The presence of a secondary amine in 7 prevented its direct
conversion to an oxindole, as was executed successfully with
18 and 32, and therefore, 7 was protected as its carbobenzy-
loxy derivative 41 (Scheme 6). Treatment of 41 with NBS in
an aqueous medium containing THF and acetic acid gave 42
and 43. After separation by chromatography, hydrogenoly-
sis of 42 gave (()-6-deoxyelacomine (36).
For the synthesis of (()-elacomine (8), we chose N-
protected 6-methoxytryptamine 44 as our starting material
with the expectation that judicious timing of the methyl ether
cleavage would need to be made at some point in the
sequence. Tryptamine derivative 44 was prepared by a
known route from indole27 and was condensed with 35 to
furnish photo substrate 45. Irradiation of 45 gave 46 and
subsequent reduction to 47 followed by retro-Manich fission
via 48 yielded β-carboline 49 in a process that closely
paralleled the sequence from 12 to 7. However, in attempting
to advance 49 toward elacomine (8), it became clear that
unmasking the hydroxyl group of the alkaloid as a final step
was problematic. Consequently, we chose 49 as the more
opportune substrate for accomplishing this transformation
and when 49 was reacted with boron tribromide at low
temperature it gave β-carboline 50 in satisfactory yield.
Protection of both the amine and hydroxyl substituent of
50 as bis-carbobenzyloxy derivative 51 followed by bromi-
native oxidation and rearrangement produced oxindole 52.
Final hydrogenolysis then yielded (()-elacomine (8)
substance has not been found in Nature, we foresaw that our
route would pass through the known alkaloid 7, a substance
previously obtained by Borschberg in the course of his
synthesis of (()-elacomine.26 Correlation would provide
assurance that our TIPCA(RM)2 strategy was applicable
to elacomine itself. First, N-Boc tryptamine 12 was con-
densed under basic conditions with 35 to furnish photo
substrate 37 in excellent yield (Scheme 5). Irradiation of 37
under conditions previously used for photolysis of 14 and 26
led directly to spiropyrrolenine 38 which was immediately
subjected to reduction with sodium cyanoborohydride. Our
expectation based on steric grounds was that hydride would
be delivered to imine 38 from the face opposite the C2
branched indoline substituent and our prediction was con-
firmed with the isolation of 39 as a single stereoisomer in high
yield. Exposure of spiropyrrolidine 39 to trifluoroacetic acid
removed Boc protection from N1 and led spontaneously to
retro-Mannich expulsion of the malonate residue to produce
transiently spiroindolenine 40 and then β-carboline 7. The
spectral properties of 7 matched those reported by
Borschberg,26 and data for the hydrochloride of 7 agreed
with those reported by Slywka and Locock for the corre-
sponding salt of the alkaloid isolated from E. commutata.12
1
(Scheme 7). The H and 13C NMR spectra of (()-8 were
identical to corresponding spectra of the racemic alkaloid
published by Horne.28
In summary, a photocycloaddition-retro-Mannich se-
quence applied to tryptamine systems provides a new entry
to spiro[pyrrolidino-3,30-indolines] and thus to correspond-
ing oxindole alkaloids found in Nature. Although a malonyl
unit present in the photosubstrate is subsequently expelled in
(27) (a) Teranishi, K.; Nakatsuka, K.; Goto, T. Synthesis 1994, 1018.
(b) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
Tetrahedron 1958, 2, 1.
(26) Pellegrini, C.; Weber, M.; Borschberg, H.-J. Helv. Chim. Acta 1996,
79, 151.
(28) Miyake, F.; Yakushijin, K.; Horne, D. A. Org. Lett. 2004, 6, 711.
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White et al.
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SCHEME 7
7.18 (t, J=7.8 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.43 (d, J=8.0
Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 8.12 (bs, 1H); 13C NMR (100
MHz, CDCl3) δ 24.7, 40.1, 111.4, 111.8, 118.5, 119.8, 122.2,
122.6, 127.0, 136.5; HRMS calcd for C12H11N2F3O m/z
256.0824, found 256.0820.
tert-Butyl 3-(2-(2,2,2-Trifluoroacetamido)ethyl)-1H-indole-1-
carboxylate (11). To a solution of 10 (1.00 g, 3.90 mmol) in THF
(39.0 mL) was added Boc2O (916 mg, 4.68 mmol) followed by
DMAP (24.0 mg, 5 mol %). The solution was warmed to 40 °C
for 1 h and then was diluted with CH2Cl2 and washed with H2O.
The solution was dried (Na2SO4) and filtered, and the filtrate
was concentrated in vacuo. Purification of the residue by
chromatography on silica gel (hexanes/EtOAc 10:1) gave 11 as
a colorless oil (1.25 g, 85%): IR (neat) 3314, 2982, 1723, 1566,
1462, 1380, 1168, 1086, 754 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.70 (s, 9H), 3.05 (t, J=6.7 Hz, 2H), 3.61 (dd, J=6.5, 6.4 Hz,
2H), 6.60 (bs, 1H), 7.22 (t, J=7.8 Hz 1H), 7.34 (t, J=8.0 Hz 1H),
7.42 (s, 1H), 7.52 (d, J=7.8 Hz 1H), 8.15 (d, J=7.8 Hz 1H); 13
C
NMR (100 MHz, CDCl3) δ 24.5, 28.2, 39.6, 83.2, 115.5, 116.5,
118.6, 122.7, 123.4, 124.8, 128.5, 129.3, 135.1, 149.0; HRMS
calcd for C17H19N2F3O3 m/z 356.1348, found 356.1360.
Diethyl 2-((2-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)ethylamino)-
methylene)malonate (14). To a solution of 11 (700 mg, 1.85 mmol)
in MeOH-H2O (18.5 mL, 70:30) was added K2CO3 (900 mg) in
one portion. The mixture was stirred for 48 h and then was poured
into H2O and extracted with CH2Cl2. The extract was dried
(Na2SO4) and filtered, and the filtrate was concentrated in vacuo
to afford crude 12 as a pale yellow oil (880 mg, 96%). This material
was used without further purification in the next reaction.
a second retro-Mannich fragmentation after spiro[pyrro-
linoindoline] formation, retention of the malonyl function
would afford opportunities for accessing more complex
alkaloid skeletons including those of the Strychnos family.
This aspect of our TIPCARM strategy will be the subject of a
future study.
To a solution of 12 obtained above (880 mg, 3.02 mmol) and
diethyl ethoxymethylenemalonate (13, 345 μL, 3.44 mmol) in
EtOH (3 mL) was added K2CO3 (520 mg, 3.94 mmol), and the
mixture was stirred at rt for 5 h. The resulting yellow solution,
which contained a small amount of white solid, was poured into
H2O (50 mL) and was extracted with CH2Cl2 (3 ꢀ 50 mL). The
combined extracts were dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo to afford crude 14 as a yellow
oil. The crude product was purified by chromatography on silica
gel (hexanes/EtOAc 4:1) to give pure 14 as a pale yellow solid
(1.37 g, 90%): mp 58 °C; IR (KBr) 3276, 3192, 3112, 3057, 2979,
2935, 2901, 1734, 1653, 1616, 1456, 1375, 1258, 1217, 1154, 1088,
1033, 802, 747 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=
6.7 Hz, 3H), 1.31 (t, J=6.7 Hz, 3H), 1.66 (s, 9H), 2.98 (t, J=6.8
Hz, 2H), 3.63 (q, J=5.9 Hz, 2H), 4.13 (q, J=6.9 Hz, 2H), 4.21 (q,
J=6.9 Hz, 2H), 7.24 (m, 1H), 7.33 (m, 1H), 7.41 (s, 1H), 7.47 (m,
1H), 7.90 (d, J=8.1 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 9.27 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 14.4, 26.8, 28.1, 49.3,
59.6, 59.8, 83.5, 89.8, 113.2, 116.1, 124.3, 130.6, 135.5, 149.5,
156.0, 165.9, 169.2; HRMS calcd for C23H31N2O6 m/z 431.2182,
found 431.2163.
Experimental Section
General Methods. Infrared spectra were recorded neat unless
otherwise indicated and are reported in cm-1. 1H NMR spectra
were recorded in deuterated solvents and are reported in ppm
relative to tetramethylsilane and referenced internally to the
residually protonated solvent. 13C NMR spectra were recorded
in deuterated solvents and are reported in ppm relative to
tetramethylsilane and referenced internally to the residually
protonated solvent.
Routine monitoring of reactions was performed using silica
gel on aluminum-backed TLC plates. Flash chromatography
was performed with the indicated eluents on 230-400 mesh
silica gel.
Air- and/or moisture-sensitive reactions were performed
under inert atmosphere conditions. Reactions requiring rigor-
ously anhydrous conditions were performed under a blanket of
argon in glassware dried in an oven at 150 °C or by flame and
then cooled under argon. Dry THF and dichloromethane
were obtained from commercial solvent purification system.
All other solvents and commercially available reagents were
either purified via literature procedures or used without further
purification.
N-(2-(1H-Indol-3-yl)ethyl)-2,2,2-trifluoroacetamide (10). To a
solution of tryptamine (9, 1.00 g, 6.24 mmol) in CH2Cl2 (56 mL)
containing pyridine (5.6 mL) at 0 °C under argon was added
dropwise trifluoroacetic anhydride (920 μL, 6.60 mmol). After
5 min, the cold bath was removed, and the mixture was stirred at
rt for 2 h. The mixture was diluted with CH2Cl2, and the solution
was washed with satd aq NaHCO3, aq NH4Cl, and H2O. The
combined extracts were dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo. Purification of the residue by
chromatography on silica gel (hexanes/EtOAc 3:1) afforded 10
as a colorless oil (944 mg, 72%): IR (neat) 3406, 1701, 1560,
1173, 749 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.10 (t, J=6.7
Hz, 2H), 3.73 (dd, J=6.5, 6.4 Hz, 2H), 7.08 (d, J=2.3 Hz, 1H),
Diethyl 2-(1-(tert-Butoxycarbonyl)-40,50-dihydrospiro[indoline-
3,30-pyrrole]-2-yl)malonate (16). A degassed solution of 14
(200 mg, 0.47 mmol) in EtOH (100 mL) was irradiated with a
450 W medium-pressure mercury lamp through a Corex filter
for 12 h. The solution was concentrated in vacuo, and the
resulting yellow oil was purified by chromatography on silica
gel (hexanes/EtOAc 1:1) to afford 16 as a pale yellow oil (164 mg,
82%): IR (neat) 2978, 2936, 2863, 1733, 1700, 1481, 1381, 1305,
1283, 1253, 1165, 1033, 754 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.03 (t, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.57 (s, 9H), 1.99
(ddd, J=12.8, 6.8, 6.8 Hz, 1H), 2.30 (ddd, J=12.8, 6.8, 6.8 Hz, 1H),
3.85 (m, 2H), 3.99 (t, J=6.4 Hz, 2H), 4.15 (m, 2H), 4.22 (d, J=6.4
Hz, 2H), 4.96 (bs, 1H), 6.80 (dt, J=7.6, 1.2 Hz, 1H), 6.95 (dt, J=
7.6, 1.2 Hz, 1H), 7.18 (dt, J=7.8, 1.2 Hz, 1H), 7.79 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 13.6, 13.8, 28.4, 42.1, 52.6, 59.9, 60.0,
61.6, 64.1, 67.8, 115.5, 122.6, 123.5, 128.6, 134.7, 140.2, 166.5,
166.9, 167.0; HRMS calcd for C23H30N2O6 m/z 430.2104, found
430.2115.
J. Org. Chem. Vol. 75, No. 11, 2010 3573

White et al.
JOCArticle
1-(tert-Butoxycarbonyl)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-
10-methyl-40,50-dihydrospiro[indoline-3,30-pyrrol]-10-ium Iodide.
A mixture of methyl iodide (1.10 mL, 2.00 mmol) and 16 (380 mg,
0.88 mmol) was stirred for 48 h. The resulting yellow solution was
concentrated in vacuo, and the residual solid was dried under high
vacuum to afford iodide as a pale yellow solid (475 mg, 94%): IR
(KBr) 3444, 2979, 2935, 1716, 1483, 1382, 1287, 1256, 1162, 1032,
758 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J=7.2 Hz, 3H),
1.27 (t, J=7.2 Hz, 3H), 1.61 (s, 9H), 2.75 (m, 2H), 3.52 (m, 1H), 3.87
(m, 1H), 4.14 (s, 2H), 4.22 (m, 2H), 4.39 (m, 2H), 4.95 (bs, 1H), 4.97
(ddd, J=13.6, 7.2, 7.2 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.28 (t, J=
7.6 Hz, 1H), 7.40 (bs, 1H), 7.85 (bs, 1H), 9.09 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ13.5, 13.9, 27.2, 28.3, 39.8, 44.1, 60.3, 62.4, 63.0,
67.6, 83.6, 115.2, 124.8, 126.1, 129.2, 130.4, 139.5, 151.4, 167.5, 168.3,
178.4. This material was used without further purification in the next
reaction.
in CH2Cl2 (10 mL) containing pyridine (1 mL) at 0 °C under argon
was added dropwise trifluoroacetic anhydride (78 μL, 0.55 mmol).
After 5 min, the cold bath was removed, and the mixture was stirred
at rt for 2 h. The mixture was diluted with CH2Cl2, and the solution
was washed with satd aq NaHCO3, aq NH4Cl, and H2O. The
combined extracts were dried (Na2SO4) and filtered, and the filtrate
was concentrated in vacuo. Purification of the residue by chroma-
tography on silica gel (hexanes/EtOAc 3:1) yielded 23 as a colorless
oil (125 mg, 83%): IR (neat) 3335, 1701, 1489, 1216, 1173, 792 cm-1
;
1H NMR (400 MHz, CDCl3) δ3.04 (t, J=6.7, 2H), 3.71 (dd, J=6.3,
6.3 Hz, 2H), 3.91 (s, 3H), 6.39 (bs, 1H), 6.91 (dd, J=8.8, 2.6 Hz 1H),
7.05 (dd, J=8.3, 2.1 Hz, 2H), 7.29 (d, J=8.5 Hz 1H), 8.02 (bs, 1H);
13C NMR (100 MHz, CDCl3) δ 24.7, 40.0, 55.9, 100.1, 111.5, 112.2,
112.8, 123.0, 154.3; HRMS calcd for C13H14N2F3O2 m/z 287.1007,
found 287.1011.
tert-Butyl 5-Methoxy-3-(2-(2,2,2-trifluoroacetamido)ethyl)-
1H-indole-1-carboxylate (24). To a solution of 23 (120 mg,
0.42 mmol) in THF (5 mL) was added Boc2O (98 mg, 0.50 mmol)
followed by DMAP (2.5 mg, 5 mol %). The solution was stirred
at 40 °C for 1 h and then was diluted with CH2Cl2 and washed
with H2O. The solution was dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo. Purification of the residue by
flash chromatography on silica gel (hexanes/EtOAc 10:1) af-
forded 24 as a colorless oil (150 mg, 88%): IR (neat) 2941, 1723,
1481, 1388, 1126, 1081, 1034 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.68 (s, 9H), 2.97 (t, J=6.7 Hz, 2H), 3.71 (dd, J=6.6, 6.6 Hz,
2H), 3.94 (s, 3H), 6.39 (bs, 1H), 6.98 (dd, J=8.2, 2.4 Hz 2H), 7.29
(s, 1H), 8.02 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 24.5, 28.2,
39.6, 55.8, 101.3, 113.4, 116.3, 124.0, 156.0; HRMS calcd for
C18H21N2F3O4 m/z 386.1453, found 386.1470.
tert-Butyl 3-(2-Aminoethyl)-5-methoxy-1H-indole-1-carboxy-
late (25). To a solution of 24 (130 mg, 0.318 mmol) in
MeOH-H2O (70:30, 5 mL) was added K2CO3 (250 mg) in
one portion. The mixture was stirred at rt for 48 h and was
poured into H2O. The mixture was extracted with CH2Cl2, and
the extract was dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo to afford virtually pure 25 as a pale yellow
oil (99 mg, 99%): IR (neat) 2921, 1723, 1478, 1385, 1265, 1009,
792 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.65 (s, 9H), 3.18 (bs,
2H), 3.25 (bs, 2H), 3.84 (s, 3H), 6.90 (dd, J=7.8, 3.0 Hz, 1H),
7.06 (s, 1H), 7.52 (s, 1H), 7.95 (bs, 1H); 13C NMR (100 MHz,
CDCl3) δ 28.2, 29.7, 39.6, 55.9, 101.3, 113.4, 116.3, 156.0;
HRMS calcd for C16H23N2O3 m/z [M þ 1] 291.1709, found
291.1701.
Diethyl 2-(1-(tert-Butoxycarbonyl)-10-methylspiro[indoline-3,30-
pyrrolidine]-2-yl)malonate (17). To a solution of iodide obtained
above (500 mg, 0.873 mmol) in MeOH (10 mL) was added
NaBH4 (50.0 mg, 1.32 mmol) in one portion. The solution
was stirred for 3 h, after which satd aq NH4Cl was added. The
mixture was concentrated by removing solvent in vacuo, and
the residue was extracted with EtOAc (3 ꢀ 5 mL). The combined
extracts were dried (Na2SO4) and filtered, and the filtrate was
concentrated in vacuo. Purification of the residue by chroma-
tography on silica gel (CH2Cl2/MeOH 20:1) gave 17 as a color-
less oil (268 mg, 71%): IR (neat) 3048, 2978, 2938, 2838, 2780,
1733, 1708, 1602, 1481, 1387, 1280, 1254, 1168, 1039, 868, 753 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.08 (t, J=7.2 Hz, 3H), 1.20
(t, J=7.2 Hz, 3H), 1.55 (s, 9H), 1.85 (ddd, J=12.8, 8.0, 8.0 Hz,
1H), 2.18 (ddd, J=12.8, 8.0, 4.0, 1H), 2.56 (s, 3H), 2.70 - 3.10
(m, 3H), 3.31 (m, 1H), 3.75 - 4.00 (m, 3H), 4.11 (m, 2H), 4.99
(d, J=4.8 Hz, 1H), 7.00 (t, J=7.6, 1H), 7.15 (t, J=7.6 Hz, 1H),
7.38 (d, J=7.7 Hz, 1H), 7.49 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.6, 13.9, 28.4, 28.4, 43.7, 54.6, 60.1, 60.6, 61.8, 69.4,
115.2, 123.6, 127.9, 167.6; HRMS calcd for C24H34N2O6 m/z
446.2417, found 446.2493.
2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (18). To
a solution of 17 (200 mg, 0.45 mmol) in CH2Cl2 was added
TFA (1.60 mL), and the solution was stirred for 24 h. Saturated
aq Na2CO3 was added, and the mixture was extracted with CH2Cl2.
The combined extracts were dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo. Purification of the residue by
chromatography on silica gel (CH2Cl2/MeOH 50:1) gave 18 as a
colorless oil (53.4 mg, 62%): IR (neat) 3411, 2927, 2851, 1674,
1457, 738 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 2.85
(m, 4H), 3.58 (s, 2H), 7.13 (m, 2H), 7.30 (m, 1H), 7.50 (d, J=8.0
Hz, 1H), 7.95(bs, 1H); 13C NMR (100 MHz, CDCl3) δ31.9, 45.2,
52.0, 52.9, 107.7, 110.9, 118.0, 119.3, 121.4, 127.1, 131.2, 136.2;
HRMS calcd for C12H14N2 m/z 186.1157, found 186.1159.
(()-Coerulescine (5). To a solution of 18 (33 mg, 0.18 mmol)
in THF-H2O-AcOH (1 mL, 1:1:1.5) was added NBS (18 mg,
0.09 mmol). The mixture was stirred for 15 min at rt, after which
satd aq NaHCO3 was added and the mixture was extracted with
EtOAc-Et3N (6:1, 3 ꢀ 5 mL). The combined extracts were dried
(Na2SO4) and filtered, and the filtrate was concentrated in
vacuo. Purification of the residue by chromatography on silica
gel (CH2Cl2/MeOH 50:1) afforded 5 as a colorless oil (21 mg,
Diethyl 2-((2-(1-(tert-Butoxycarbonyl)-5-methoxy-1H-indol-
3-yl)ethylamino)methylene)malonate (26). To a solution of 25
(100 mg, 0.32 mmol) and diethyl ethoxymethylenemalonate (13,
37 μL, 0.35 mmol) in EtOH (3 mL) was added K2CO3 (55 mg,
0.40 mmol). The mixture was stirred at rt for 5 h, and the
resulting yellow solution was poured into H2O (10 mL). The
mixture was extracted with CH2Cl2 (3 ꢀ 20 mL), and the
combined extracts were dried (Na2SO4) and filtered. The filtrate
was concentrated in vacuo to afford a yellow oil which was
purified by chromatography on silica gel (hexanes/EtOAc 4:1)
to give 26 as a pale yellow oil (134 mg, 91%): IR (neat) 2970,
1
1728, 1658, 1609, 1472, 1385, 1265, 1157, 1075, 803 cm-1; H
NMR (400 MHz, CDCl3) δ 1.28 (m, 6H), 1.66 (s, 9H), 2.97 (t, J=
6.8 Hz, 2H), 3.64 (dd, J=6.8, 6.8 Hz, 2H), 3.86 (s, 3H), 4.15 (q,
J=7.3 Hz, 2H), 4.22(q, J=7.3 Hz, 2H), 6.93 (m, 2H), 7.39 (s,
1H), 7.90 (d, J=8.0 Hz, 1H), 8.04 (m, 1H), 9.26 (bs, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.3, 14.4, 26.8, 28.2, 49.4, 55.7,
59.6, 59.8, 83.5, 89.8, 101.4, 113.2, 116.0, 116.2, 124.2, 130.7,
149.3, 155.9, 159.8, 166.0, 169.2; HRMS calcd for C24H32N2O7
m/z 460.2210, found 460.2216.
Diethyl 2-(1-(tert-Butoxycarbonyl)-5-methoxy-40,50-dihydros-
piro[indoline-3,30-pyrrole]-2-yl)malonate (28). A degassed solu-
tion of 26 (100 mg, 0.21 mmol) in EtOH (100 mL) was irradiated
with a 450 W medium-pressure mercury lamp through a Corex
62%): IR (neat) 3225, 1712, 1626, 1470, 1190, 1108, 758 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.13 (m, 1H), 2.45(m, 1H), 2.51
(s, 3H), 2.80 (m, 2H), 2.91 (m, 1H), 3.08 (m, 1H), 6.91 (d, J=7.6
Hz, 1H), 7.08 (dt, J=7.6, 1.1 Hz, 1H), 7.23 (dt, J=7.6, 1.2 Hz,
1H), 7.41 (d, J=7.2 Hz, 1H), 8.29 (bs, 1H); 13C NMR (100 MHz,
CDCl3) δ 38.0, 41.9, 53.7, 56.8, 66.4, 109.4, 122.9, 123.4, 127.8,
136.3, 140.0, 182.7; HRMS calcd for C12H14N2O m/z 202.1106,
found 202.1108.
2,2,2-Trifluoro-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide
(23).To a solution of 5-methoxytryptamine (22, 100 mg, 0.52 mmol)
3574 J. Org. Chem. Vol. 75, No. 11, 2010

White et al.
JOCArticle
filter for 12 h. The solution was concentrated in vacuo, and the
resulting yellow oil was purified by chromatography on silica gel
(hexanes/EtOAc 1:1) to give 28 as a pale yellow oil (60 mg, 60%):
Diethyl 2-(3-Methylbutanoyl)malonate (34). In a round-bot-
tom flask were placed Mg (1.25 g, 51.3 mmol), absolute EtOH
(1.25 mL), and CCl4 (0.05 mL). A small portion of a solution of
diethyl malonate (7.8 mL, 50 mmol) in EtOH (4 mL) was added,
and the mixture was gently warmed until H2 evolution began.
The remaining solution of diethyl malonate in EtOH was added
at such a rate that the exothermic reaction proceeded vigorously
but under control. When the reaction moderated, the flask was
cooled in ice-water, and Et2O (30 mL) was added. The mixture
was heated again on a water bath until no further H2 was
evolved. The mixture was cooled to rt, and a solution of
isovaleryl chloride (33, 6.5 mL, 51.5 mmol) in Et2O (20 mL)
was added slowly. The mixture was refluxed for 15 min and
cooled to rt, and dilute acetic acid (10% in water w/v) was added
slowly until the pH was approximately 7. The mixture was
extracted with Et2O, and the extracts were washed with brine,
dried (Na2SO4), and filtered. The filtrate was concentrated in
vacuo, and the residual oil was purified by chromatography
on silica gel (hexanes/EtOAc 20:1) to yield 34 as a colorless
liquid (10.3 g, 84%): IR (neat) 2964, 1738, 1645, 1599, 1241,
1085, 1046 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.95 (dd, J=
6.7, 3.4 Hz, 6 H), 1.31 (m, 6 H), 2.15 (m, 1 H), 2.33 (d, J=6.8 Hz,
1 H), 2.50 (d, J = 6.8 Hz, 1 H), 4.26 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 18.0, 22.3, 23.9, 48.4, 62.1, 67.2,
168.2, 201.9 ; HRMS calcd for C12H20O5 m/z 244.1311, found
244.1315.
1
IR (neat) 2970, 1734, 1494, 1385, 1282, 1162, 1037 cm-1; H
NMR (400 MHz, CDCl3) δ 1.10 (t, J=7.2 Hz, 3H), 1.27 (t, J=
7.2 Hz, 3H), 1.59 (s, 9H), 2.05 (m, 1H), 2.32 (m, 1H), 3.75 (3H, s),
3.94 (m, 2H), 4.02 (dt, J=6.9, 2.2 Hz, 2H), 4.20 (m, 4H), 4.99 (bs,
1H), 6.40 (d, J=2.6 Hz, 1H), 6.75 (dd, J=8.8, 2.5 Hz, 1H), 7.83
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 13.9, 28.4, 42.0,
55.7, 60.1, 61.6, 61.9, 68.0, 108.4, 113.5, 116.1, 156.3, 166.5,
166.9; HRMS calcd for C24H32N2O7 m/z 460.2210, found
460.2213.
1-(tert-Butoxycarbonyl)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-
5-methoxy-10-methyl-40,50dihydrospiro[indoline-3,30-pyrrol]-10-
ium Iodide. A mixture of methyl iodide (370 mg, 2.60 mmol) and
32 (60 mg, 0.130 mmol) was stirred for 48 h. The resulting pale
yellow solution was concentrated in vacuo, and the residue was
dried under high vacuum to afford crude 33. The crude product
was used for the next step without purification.
Diethyl 2-(1-(tert-Butoxycarbonyl)-5-methoxy-10-methylspiro-
[indoline-3,30-pyrrolidine]-2-yl)malonate (29). To a solution of
crude iodide obtained above in MeOH (1 mL) was added
NaBH4 (7.4 mg, 0.20 mmol) in one portion. The solution was
stirred for 3 h, after which satd aq NH4Cl was added. The
solvent was evaporated, the residue was extracted with EtOAc
(3ꢀ10 mL), and the combined extracts were dried (Na2SO4) and
filtered. The filtrate was concentrated in vacuo, and the residue
was purified by chromatography on silica gel (CH2Cl2/MeOH
20:1) to give 29 as a colorless oil (57 mg, 95% from 32): IR (neat)
Diethyl 2-(1-Methoxy-3-methylbutylidene)malonate (35). To a
solution of 34 (1.00 g, 4.11 mmol) in THF (20 mL) at 0 °C was
added KH (329 mg, 8.2 mmol) slowly. The mixture was warmed
to rt and was stirred for 30 min. Dimethyl sulfate (0.77 mL, 8.2
mmol) was added dropwise, and the mixture was stirred for 24 h
at rt. Aqueous NH4Cl was added, the mixture was extracted
with Et2O, and the extracts were washed with brine, dried
(Na2SO4), and filtered. The filtrate was concentrated in vacuo,
and the residue was purified by flash chromatography on silica
gel (hexanes/EtOAc 10:1) to give 35 as a colorless oil (410 mg,
2976, 2832, 1734, 1707, 1494, 1391, 1255, 1162, 1037, 868 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.10 (t, J=7.2 Hz, 3H), 1.27 (t,
J=7.2 Hz, 3H), 1.59 (s, 9H), 1.97 (bs, 2H), 2.22 (bs, 1H), 2.46 (bs,
3H), 2.90 (m, 3H), 3.20 (bs, 1H), 3.80 (s, 3H), 3.94 (m, 3H), 4.16
(m, 2H), 5.00 (bs, 1H), 6.71 (dd, J=9, 3 Hz, 1H), 6.97 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 3.7, 13.9, 28.4, 54.7, 55.8, 61.5, 61.6,
69.6, 115.9, 127.9, 167.2; HRMS calcd for C25H36N2O7 m/z
476.2522, found 476.2525.
1
40%): IR (neat) 2961, 1735, 1710, 1614, 1213, 1093 cm-1; H
NMR (400 MHz, CDCl3) δ 1.03 (d, J=6.6 Hz, 6 H), 1.29 (m,
6 H), 1.98 (m, 1 H), 2.77 (d, J=7.4 Hz, 2 H), 3.78 (s, 3 H), 4.17 (q,
J=7.1 Hz, 2 H), 4.24 (q, J=7.1 Hz, 2 H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 22.3, 27.7, 35.6, 56.2, 60.4, 61.0, 109.5, 165.0,
173.2; HRMS calcd for C13H22O5 m/z 258.1467, found 258.1470.
Diethyl 2-(1-(2-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)ethyl-
amino)-3-methylbutylidene)malonate (37). To a solution of 35
(1.00 g, 3.90 mmol) and 12 (1.00 g, 3.55 mmol) in EtOH (4.0 mL)
was added K2CO3 (638 mg, 4.62 mmol). The reaction vessel was
sealed, and the mixture was stirred at rt for 48 h. The resulting
yellow solution which contained a white precipitate was poured
into H2O (50 mL) and was extracted with CH2Cl2 (3ꢀ50 mL).
The combined extracts were dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo to afford crude 37 as a yellow
oil. The crude product was purified by chromatography on silica
gel (hexanes/EtOAc 4:1) to give 37 (1.37 g, 65%): IR (neat) 3276,
3192, 3112, 3057, 2979, 2935, 2901, 1734, 1653, 1616, 1456, 1375,
6-Methoxy-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(32). To a solution of 29 (150 mg, 0.33 mmol) in CH2Cl2 was
added TFA (200 μL), and the solution was stirred for 24 h.
Aqueous Na2CO3 was added, and the mixture was extracted
with CH2Cl2. The combined extracts were dried (Na2SO4) and
filtered, and the filtrate was concentrated in vacuo. Purification
of the residue by chromatography on silica gel (CH2Cl2/MeOH
50:1) afforded 32 as a colorless oil (28 mg, 40%): IR (neat) 3462,
1
2943, 2829, 1483, 1456, 1216, 1151, 835, 786 cm-1; H NMR
(400 MHz, CDCl3) δ 2.52 (s, 3H), 2.84 (s, 4H), 3.58 (s, 2H), 3.87
(s, 3H), 6.80 (dd, J=8.7, 2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H),
7.18 (d, J=8.7 Hz, 1H), 7.94(bs, 1H); 13C NMR (100 MHz,
CDCl3) δ 29.7, 45.5, 52.3, 53.0, 55.3, 100.4, 107.8, 111.0, 111.4,
113.8, 127.6, 131.2, 154.0; HRMS calcd for C13H16N2O m/z
216.1263, found 216.1269.
(()-Horsfiline (6). To a solution of 32 (16.0 mg, 0.073 mmol)
in THF-H2O-AcOH (1 mL, 1:1:1.5) was added NBS (14 mg,
0.078 mmol), and the mixture was stirred for 15 min at rt.
Aqueous NaHCO3 was added, and the solution was extracted
with a mixture of EtOAc and Et3N (6:1, 3ꢀ5 mL). The combined
extracts were dried (Na2SO4) and filtered, and the filtrate was
concentrated in vacuo. Purification of the residue by chroma-
tography on silica gel (CH2Cl2/MeOH 50:1) afforded 6 as a
colorless oil (13.5 mg, 80%): IR (neat) 3232, 2943, 2834, 1707,
1483, 1304, 1200, 808 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.10
(m, 1H), 2.42 (m, 1H), 2.47 (s, 3H), 2.75 (m, 1H), 2.87 (d, J=
1.6 Hz, 1H), 2.91 (m, 1H), 3.03 (m, 1H), 3.82 (s, 3H), 6.74 (dd, J=
8.4, 2.3 Hz, 1H), 6.77 (m, 1H), 7.05 (d, J=2.5 Hz, 1H), 7.59 (bs,
1H); 13C NMR (100 MHz, CDCl3) δ 29.7, 38.2, 41.8, 54.1, 55.9,
56.7, 66.5, 109.6, 110.4, 112.4, 133.1, 137.7, 156.2; HRMS calcd
for C13H16N2O2 m/z 232.1212, found 232.1219.
1
1258, 1217, 1154, 1088, 1033, 802, 747 cm-1; H NMR (400
MHz, CDCl3) 0.94 (m, 6H), 1.29 (m, 6H), 1.69 (s, 9H), 1.84 (m,
1H), 2.42 (d, J=7.4 Hz, 2H), 2.98 (t, J=7.3 Hz, 2H), 3.60 (q, J=
5.9 Hz, 2H), 4.21 (m, 4H), 7.24 (m, 1H), 7.41 (s, 1H), 7.47 (m,
1H), 8.14 (d, J=7.7 Hz, 1H), 9.85 (bs, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.3, 14.3, 26.7, 28.1, 49.3, 59.5, 59.7, 83.6, 89.7, 115.4,
116.1, 118.4, 122.5, 123.6, 124.6, 129.8, 135.5, 149.5, 159.8,
165.9, 169.2; HRMS calcd for C27H38N2O6 m/z 487.2781, found
487.2788.
Diethyl 2-((2S,3S)-1-(tert-Butoxycarbonyl)-20-isobutyl-40,50-
dihydrospiro[indoline-3,30-pyrrole]-2-yl)malonate (38). A degassed
solution of 37 (400 mg, 0.82 mmol) in EtOH (100 mL) was
irradiated with a Hanovia 450 W medium-pressure mercury lamp
through a Corex filter for 12 h. The solution was concentrated in
J. Org. Chem. Vol. 75, No. 11, 2010 3575

White et al.
JOCArticle
vacuo, and the resulting yellow oil was purified by chromatogra-
phy on silica gel (hexanes/EtOAc 5:1) to afford 38 as a pale yellow
oil (248 mg, 62%): IR (neat) 2980, 1727, 1700, 1478, 1376, 1305,
1162, 750 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.98 (d, J=6.4 Hz,
6H), 1.25 (tt, J=7.4, 7.1 Hz, 6H), 1.55 (s, 9H), 1.87 (m, 2H), 2.05
(m, 2H), 2.23 (m, 1H), 2.41 (m, 1H), 3.60 (d, J=9.3 Hz, 1H), 3.85
(m, 1H), 4.11 (m, 4H), 5.18 (d, J=9.0 Hz, 1H), 6.98 (dt, J=7.4, 0.8
Hz, 1H), 7.18 (dt, J=7.4, 1.0 Hz, 1H), 7.28 (m, 1H), 7.56 (d, J=8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 13.9, 21.0, 22.7,
23.3, 28.2, 40.9, 44.4, 53.2, 57.6, 60.4, 61.7, 65.3, 66.2, 82.1, 116.5,
123.5, 123.9, 128.3, 134.9, 141.9, 152.3, 166.5, 166.9, 175.5; HRMS
calcd for C27H38N2O6 m/z 486.2730, found 486.2722.
Diethyl 2-((2S,20S,3R)-1-(tert-Butoxycarbonyl)-20-isobutylspiro-
[indoline-3,30-pyrrolidine]-2-yl)malonate (39). To a solution of 38
(300 mg, 0.62 mmol) in a mixture of MeOH and AcOH (3:1, 12 mL)
was added NaBH3CN (85.0 mg, 1.35 mmol) in one portion. The
mixture was stirred at rt for 1 h, after which satd aq NaHCO3 was
added slowly. The mixture was concentrated by removing volatiles
in vacuo, and the residual oil was extracted with EtOAc (3ꢀ). The
combined extracts were dried (Na2SO4) and filtered, and the filtrate
was concentrated. Purification of the residue by chromatography
on silica gel (hexanes/EtOAc 1:1 and 10% Et3N) gave 39 as a
colorless oil (271 mg, 90%): IR (neat) 2956, 1731, 1700, 1490, 1377,
1163, 1049, 753 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.87 (d, J=
6.4 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H),1.21 (m, 6H), 1.24 (m, 1H),
1.55 (s, 9H), 1.75 (m, 2 H), 1.89 (m, 2 H), 2.25 (dt, J=12.5, 7.3, 1H),
3.06 (m, 2 H), 3.29 (d, J=9.8, 1H), 3.9 (d, J=7.0 Hz, 1H), 4.11 (m, 4
H), 5.10 (d, J=7.0 Hz, 1H), 7.00 (t, J=7.7, 1H), 7.20 (t, J=7.6 Hz,
1H), 7.29 (d, J=7.6 Hz, 1H), 7.59 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 21.1, 24.2, 26.4, 28.3, 42.3, 43.6, 44.4, 52.5, 57.7,
58.9, 61.6, 67.4, 81.7, 116.2, 122.7, 125.2, 127.4, 136.1, 141.6, 152.2,
167,1, 168.1; HRMS calcd for C27H41N2O6 m/z [M þ 1] 489.2965,
found 489.2936.
vigorous stirring in the dark for 2 h at rt, the mixture was poured
slowly into aq NaHCO3 and was extracted with a mixture of
EtOAc and Et3N (6:1, 3ꢀ5 mL). The combined extracts were
dried (Na2SO4) and filtered, and the filtrate was concentrated in
vacuo. Purification of the residue by chromatography on silica
gel (hexanes/EtOAc 2:1) gave 42 as a colorless oil (28 mg, 57%)
and 43 (15 mg, 30%). Data for 42: IR (neat) 3420, 2945, 1715,
1613, 1462, 1445, 1407, 1352, 1328, 1109 cm-1; 1H NMR (400
MHz, DMSO) δ 0.72 (m, 3 H), 0.78 (m, 3 H), 1.31 (m, 1H), 1.71
(m, 2 H), 2.06 (m, 1 H), 2.31 (m, 1H), 3.78 (m, 2 H), 4.00 (m, 1H),
5.02 (m, 2H), 6.90 (m, 1H), 6.98 (m, 1H), 7.21 (m, 2 H), 7.30 (m,
5H), 9.20 (bs, d, 1H); 13C NMR (100 MHz, DMSO) δ 22.3,
22.9, 25.2, 34.7, 39.9, 44.6, 55.8, 63.7, 67.1, 109.6, 122.5, 123.1,
128.0, 128.3, 134.2, 136.9, 140.0, 155.0, 178.7; HRMS calcd for
C23H27N2O3 m/z [M þ 1] 379.2022, found 379.2031.
6-Deoxyelacomine (36). To a solution of 42 (40.0 mg, 0.11 mmol)
in MeOH (4 mL) was added 10% Pd/C (4 mg). The mixture was
stirred vigorously under an atmosphere of H2 at 1 bar for 3 h and
then filtered through Celite. The filtrate was evaporated, and the
residue was chromatographed on silica gel (EtOAc/MeOH 5:1) to
afford 36 as a colorless oil (24 mg, 93%): IR (neat) 3420, 2957, 1705,
1620, 1471, 1346, 920 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.75
(d, J=6.6 Hz, 3 H), 0.78 (d, J=6.6 Hz, 3 H), 0.95 (ddd, J=12.2, 8.8,
3.7Hz, 1H), 1.47(ddd, J=14.0, 9.0, 5.0 Hz, 1H), 1.63 (m, 1 H), 2.31
(ddd, J=13.4, 8.8, 6.8 Hz, 1 H), 2.34 (ddd, J=13.4, 8.8, 6.8 Hz, 1H),
3.37 (ddd, J=12.0, 9.6, 5.7 Hz, 1H), 3.45 (dd, J=10.2, 3.6 Hz, 1H),
3.54 (m, 1H), 6.96 (dd, J=7.8, 1.0 Hz, 1H), 7.07 (td, J=8.0, 1.0 Hz,
1H),7.24(m,2H) ;13C NMR (100 MHz, CDCl3) δ21.8, 23.5, 25.8,
37.7, 38.0, 46.2, 58.1, 68.8, 109.6, 122.5, 122.8, 128.0, 131.2, 140.9,
181.4; HRMS calcd for C15H20N2O m/z 244.1576, found 244.1585.
Diethyl 2-(1-(2-(1-(tert-Butoxycarbonyl)-6-methoxy-1H-in-
dol-3-yl)ethylamino)-3-methylbutylidene)malonate (45). To a so-
lution of 44 (160 mg, 0.62 mmol) and 35 (160 mg, 0.51 mmol) in
EtOH (1.0 mL) was added K2CO3 (92 mg, 0.70 mmol). The
reaction vessel was sealed, and the mixture was stirred at rt for
48 h. The resulting yellow solution which contained residual
K2CO3 was poured into H2O (50 mL) and was extracted with
CH2Cl2 (3ꢀ20 mL). The combined extracts were dried (Na2SO4)
and filtered, and the filtrate was concentrated in vacuo to afford
crude 53 as a yellow oil. The crude product was purified by
chromatography on silica gel (hexanes/EtOAc 4:1) to give pure
45 (1.37 g, 65%) as a pale yellow oil: IR (neat) 2977, 1730, 1648,
1597, 1488, 1444, 1383, 1256, 1159, 1110, 1040 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.94 (m, 6 H), 1.23 (m, 6 H), 1.68 (s, 9H),
1.86 (m, 1 H), 2.44 (d, J=7.4 Hz, 2 H), 2.95 (t, J=7.0 Hz, 2H),
3.58 (tt, J=5.8, 6.9 Hz, 2H), 3.89 (s, 9H), 4.21 (m, 5 H), 6.90 (m,
1H), 7.28 (m, 1H), 7.36 (m, 2H), 7.76 (s, 1H), 9.85 (bs, s, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.2, 14.4, 22.4, 26.3, 27.6, 28.2,
37.1, 43.3, 55.6, 59.3, 60.4, 92.7, 116.7, 118.9, 122.1, 158.0, 166.4,
168.0, 169.2; HRMS calcd for C28H40N2O7 m/z 516.2836, found
516.2851.
1-Isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (7). To a
solution of 39 (150 mg, 0.31 mmol) in CH2Cl2 (1 mL) was added
TFA (200 μL), and the solution was stirred for 24 h. Aqueous
Na2CO3 was added, and the mixture was extracted with CH2Cl2.
The combined extracts were dried (Na2SO4) and filtered, and the
filtrate was concentrated in vacuo. Purification of the residue by
chromatography on silica gel (CH2Cl2/MeOH 50: 1) afforded 7
as a colorless oil (45 mg, 40%): IR (neat) 3462, 2943, 2929, 1483,
1456 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.6 Hz, 3
H), 1.05, (d, J=6.6 Hz, 3H), 1.63 (m, 3 H), 2.00 (m, 1 H), 2.75 (m,
2H), 3.04 (ddd, J=13.3, 7.5, 5.8 Hz, 1 H), 3.36 (dt, J=12.8, 4.8
Hz, 1 H), 4.12 (ddt, J=8.3, 6.2, 1.8 Hz, 1 H), 7.11 (ddd, J=7.3,
6.9, 1.2 Hz, 1H), 7.16 (ddd, J=7.3, 6.9, 1.2 Hz, 1H), 7.33 (dd, J=
7.3, 1.4 Hz, 1H), 7.50 (dd, J=7.2, 1.5 Hz, 1 H), 7.79 (bs, s, 1 H);
13C NMR (100 MHz, CDCl3) δ 21.7, 22.8, 23.9, 24.6, 42.5, 44.5,
50.5, 108.8, 110.7, 118.0, 119.4, 121.5, 127.6, 135.6, 136.8;
HRMS calcd for C15H20N2 m/z 228.1627, found 228.1623.
Benzyl 1-Isobutyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-
carboxylate (41). To a solution of 7 (60 mg, 0.26 mmol) and
Et3N (0.1 mL) in CH2Cl2 (3 mL) at -10 °C was added benzyl
chloroformate (0.06 mL, 0.37 mmol). The mixture was stirred
for 75 min at rt and was poured into H2O. The mixture was
extracted with CH2Cl2, and the combined extracts were washed
with aq NaHCO3 and brine, dried (Na2SO4), and filtered. The
filtrate was concentrated in vacuo, and the residual oil was
purified by chromatography on silica gel (hexanes/EtOAc 5:1)
to afford 41 as a colorless oil (86 mg, 91%): IR (neat) 3324, 2954,
1671, 1423, 1441, 1222, 1086 cm-1; 1H NMR (400 MHz, CDCl3)
and 13C NMR (100 MHz, CDCl3) showed severe line broad-
ening with doubling of certain signals due to the presence of
rotational conformers; HRMS calcd for C23H26N2O2 m/z
363.2073, found 363.2069.
Diethyl 2-((2S,3S)-1-(tert-Butoxycarbonyl)-20-isobutyl-6-met-
hoxy-40,50-dihydrospiro[indoline-3,30-pyrrole]-2-yl)malonate (46).
A degassed solution of 45 (200 mg, 0.41 mmol) in EtOH (100 mL)
was irradiated with a Hanovia 450 W medium-pressure mercury
lamp through a Corex filter for 12 h. The solution was concentrated
in vacuo, and the resulting yellow oil was purified by chromatogra-
phy on silica gel (hexanes/EtOAc 5:1) to afford 46 as a pale yellow oil
(116 mg, 58%): IR (neat) 2957, 1733, 1706, 1616, 1597, 1500, 1453,
1369, 1306, 1256, 1226, 1161, 1035, 860, 733 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 0.98 (dd, J=6.5, 1.8 Hz, 6 H), 1.26 (dd, J=
7.1, 6.8 z, 6H), 1.55 (s, 9H), 1.87 (m, 1 H), 2.38 (m, 2H), 3.02 (m, 2H),
3.58 (d, J=9.2 Hz, 2 H), 3.82 (s, 3 H), 4.15 (m, 4H), 6.83 (d, J=8.4
Hz, 1H), 7.22 (s, 1 H), 7.35 (m, 1H), 7.76 (s, 1H), 9.85 (s, 1 H); 13
C
NMR (100 MHz, CDCl3) δ 13.8, 13.9, 22.7, 23.3, 26.3, 28.2, 40.9,
44.3, 53.2, 55.5, 57.5, 61.7, 65.6, 66.0, 82.1, 102.6, 109.6, 124.3, 126.8,
143.2, 152.2, 160.2, 166.5, 166.9, 175.8; HRMS calcd for C28H40-
N2O7 m/z 516.2836, found 516.2841.
(20S,3R)-Benzyl 20-Isobutyl-2-oxospiro[indoline-3,30-pyrrolidine]-
10-carboxylate (42). To a solution of 41 (47.0 mg, 0.13 mmol) in
THF/AcOH/H2O (3 mL, 1:1:1) was added NBS (25 mg). After
3576 J. Org. Chem. Vol. 75, No. 11, 2010

White et al.
JOCArticle
Diethyl 2-((2S,20S,3R)-1-(tert-Butoxycarbonyl)-20-isobutyl-6-
methoxyspiro[indoline-3,30-pyrrolidine]-2-yl)malonate (47). To a
solution of 46 (170 mg, 0.33 mmol) in MeOH and AcOH (3:1,
4 mL) was added NaBH3CN (45 mg, 0.66 mmol) in one portion.
The mixture was stirred at rt for 1 h, after which satd aq
NaHCO3 was added slowly. The mixture was concentrated by
removing volatiles in vacuo, and the residue was extracted with
EtOAc (3ꢀ). The combined extracts were dried (Na2SO4) and
filtered, and the filtrate was concentrated. Purification of the
residue by chromatography on silica gel (hexanes/EtOAc 1:1
and 10% Et3N) gave 47 as a colorless oil (155 mg, 90%): IR
(neat) 2956, 1707, 1498, 1369, 1163, 1036, 733 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.92 (dd, J=21.5, 6.1 Hz, 6 H), 1.24 (tt, J=
7.9, 7.2 Hz, 6 H), 1.56 (s, 9H), 1.72 (m, 2 H), 1.91 (m, 2 H), 2.23
(m, 1H), 3.03 (m, 2 H), 3.26 (dd, J=10.8, 1.6 Hz, 1H), 3.80 (t,
1H), 3.81 (s, 3H), 4.15 (m, 4 H), 5.10 (d, J=7.0 Hz, 1H), 6.54 (m,
1H), 7.18 (d, J=8.0 Hz, 1H), 7.25 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 21.0, 24.2, 26.3, 28.3, 42.5, 43.5, 44.2, 52.5, 55.4,
58.7, 61.6, 67.9, 81.7, 102.4, 108.2, 120.5, 124.3, 125.5, 127.9,
144.1, 153.1 159.4, 167.1, 168.1; HRMS calcd for C28H42N2O7
m/z 518.2992, found 518.2982.
combined extracts were washed with aq NaHCO3 and brine,
dried (Na2SO4), and filtered. The filtrate was concentrated in
vacuo, and the residue was purified by chromatography on silica
gel (hexanes/EtOAc 5:1) to give 51 as a colorless oil (260 mg,
65%): IR (neat) 3351, 2954, 1695, 1456, 1423, 1227, 1095 cm-1
;
1H NMR (400 MHz, DMSO, severe line broadening and
doubling of certain signals), δ 0.92 (d, J=6.0 Hz, 2 H), 0.99
(d, J=6.0 Hz, 2H), 1.1 (d, J=6.0 Hz, 2H), 1.52 (m, 2 H), 1.77 (m,
2 H), 2.73 (m, 2H), 3.19 (m, 1 H), 4.44 (d, J=7.9 Hz, 1 H), 5.28
(m, 5H), 6.91 (m, 1H), 7.10 (m, 1H), 7.46 (m, 10 H), 7.80 (m, 1H);
13C NMR (100 MHz, DMSO, severe line broadening and
doubling of certain signals), δ 20.9, 21.5, 22.4, 23.4, 24.9, 25.1,
37.9, 38.2, 43.9, 44.3, 49.8, 49.9, 67.3, 67.6, 70.3, 103.6, 108.0,
108.6, 113.0, 118.3, 118.5, 125.1, 127.8, 128.0, 128.2, 128.7,
134.9, 135.5, 135.9, 146.8, 154.6, 155.9; HRMS calcd for
C31H32N2O5 m/z 512.2311, found 512.2322.
(20S,3R)-Benzyl 6-(Benzyloxycarbonyloxy)-20-isobutyl-2-oxo-
spiro[indolin-3,30-pyrrolidine]-10-carboxylate (52). To a solution
of 51 (150 mg) in THF/AcOH/H2O (18 mL, 1:1:1) was added
NBS (58 mg, 0.33 mmol). After being stirred vigorously in the
dark for 2 h at rt, the mixture was poured slowly into aq
NaHCO3 and was extracted with a mixture of EtOAc and
Et3N (6:1, 3ꢀ15 mL). The combined extracts were dried (Na2SO4)
and filtered, and the filtrate was concentrated in vacuo. Pur-
ification of the residue by chromatography on silica gel
(hexanes/EtOAc 2:1) afforded 52 as a colorless oil (78 mg,
1-Isobutyl-7-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(49). To a solution of 47 (80 mg, 0.31 mmol) in CH2Cl2 (1 mL)
was added TFA (100 μL), and the solution was stirred for 24 h.
Aqueous Na2CO3 was added, and the mixture was extracted
with CH2Cl2. The combined extracts were dried (Na2SO4) and
filtered, and the filtrate was concentrated in vacuo. Purification
of the residue by chromatography on silica gel (CH2Cl2/MeOH
50: 1) gave 49 as a colorless solid (24 mg, 38%): mp 146 - 149 °C;
48%): IR (neat) 3247, 2957, 1712, 1458, 1412, 1230, 1110 cm-1
;
1H NMR (400 MHz, DMSO) δ 0.75 (m, 6H), 0.71 (m, 1H), 1.30
(bs, 2H), 1.68 (m, 2H), 2.08 (m, 1H), 2.27 (m, 1H), 3.78 (m, 2H),
3.98 (m, 1H), 5.30 (m, 4H), 6.77 (m, 1H), 7.03 (m, 1H), 7.30 (m,
10 H); 13C NMR (100 MHz, DMSO) δ 22.1, 22.9, 24.7, 24.8,
25.2, 35.2, 40.9, 45.4, 61.4, 67.1, 70.6, 71.0, 104.0, 114.5, 125.8,
127.0, 128.0, 128.4, 128.5, 128.6, 128.7, 128.9, 134.6, 141.8,
151.3, 153.5, 155.7, 180.8; HRMS (FAB) calcd for C31H32-
N2O6 m/z [M þ Na] 551.2158, found 551.2139.
1
IR (neat) 3462, 2954, 1699, 1628, 1465, 1155 cm-1; H NMR
(400 MHz, CDCl3) δ 1.00 (d, J=6.5 Hz, 3H), 1.05, (d, J=6.5 Hz,
3H), 1.61 (m, 1 H), 1.66 (m, 1H), 1.94 (m, 1 H), 2.71 (m, 2H), 3.04
(ddd, J=12.7, 8.0, 5.5 Hz, 1H), 3.36 (dt, J=12.7, 4.7 Hz, 1 H),
3.85 (s, 3H), 4.11 (ddt, J=8.7, 5.5, 2.1 Hz, 1H), 6.75 (dd, J=8.6,
2.2 Hz, 1H), 6.84 (d, J=2.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.61
(bs, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8, 22.7, 23.9, 24.6,
42.4, 44.5, 50.5, 55.8, 95.0, 108.6, 108.7, 118.5, 122.1, 134.8,
136.6, 156.1; HRMS calcd for C16H22N2O m/z 258.1732, found
258.1732.
7-Hydroxy-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(50). To a solution of 49 (170 mg) in CH2Cl2 (3 mL) was added
dropwise BBr3 (1.7 mL, 1 M in CH2Cl2) at rt under argon. The
solution was stirred for 12 h, MeOH was added, and the mixture
was poured into H2O (10 mL). The mixture was extracted with
CH2Cl2 and Et3N (3ꢀ20 mL, 2 mL), and the combined extracts
were dried (Na2SO4) and filtered. The filtrate was concentrated
in vacuo, and the residue was purified by chromatography on
silica gel (CH2Cl2/MeOH 50:1) to provide 50 as an unstable
solid (125 mg, 78%): IR (neat) 3462, 2954, 1629, 1456, 1152,
1124 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=10.8 Hz,
3 H), 1.02, (d, J=10.8 Hz, 3H), 1.62 (m, 2 H), 1.97 (m, 1 H), 2.71
(m, 2H), 3.04 (m, 2 H), 3.36 (dt, J=12.7, 4.7 Hz, 2 H), 4.07 (m,
1 H), 6.67 (dd, J=8.4, 2.1 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 7.31
(OH, 1H), 7.52 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.8,
22.7, 23.9, 24.6, 42.4, 44.3, 50.5, 97.0, 108.5, 109.3, 118.5, 121.8,
135.1, 136.6, 152.3; HRMS calcd for C15H20N2O m/z 244.1576,
found 244.1571.
(()-Elacomine (8). To a solution of 52 (70 mg, 0.13 mmol) in
MeOH (20 mL) was added 10% Pd/C (7 mg), and the suspension
was stirred vigorously under an atmosphere of H2 at 1 bar for
3 h. The suspension was filtered through Celite, the filtrate was
concentrated, and the residue was chromatographed on silica
gel (EtOAc/MeOH 5:1) to afford 8 as a colorless solid (24 mg,
93%): mp 173-177 °C dec; IR (neat) 3264, 2957, 1699, 1632,
1468, 1346, 1156, 1113 cm-1 1H NMR (400 MHz, CDCl3)
;
δ 0.75 (d, J=6.6 Hz, 3 H), 0.78 (d, J=6.6 Hz, 3 H), 0.95 (ddd, J=
13.8, 9.0, 4.3 Hz, 1 H), 1.36 (ddd, J=13.8, 9.5, 5.4 Hz, 1H), 1.51
(m, 1 H), 2.21 (ddd, J=13.3, 9.4, 6.1 Hz, 1 H), 2.25 (ddd, J=13.3,
8.8, 5.5 Hz, 1H), 3.14 (ddd, J=11.8, 9.4, 6.0 Hz, 1H), 3.21 (dd,
J=9.2, 4.3 Hz, 1H), 3.37 (ddd, J=12.0, 8.4, 6.2, 1H), 6.40 (d, J=
2.1 Hz, 1 H), 6.47 (dd, J=8.0, 2.1 Hz, 1H), 7.05 (d, J=8.3, 1 H);
13C NMR (100 MHz, CDCl3) δ 20.9, 22.3, 25.2, 37.0, 38.3, 45.1,
57.4, 67.0, 97.8, 108.7, 121.5, 122.7, 142.8, 157.7, 182.9; HRMS
calcd for C15H20N2O2 m/z 260.1525, found 260.1531.
Acknowledgment. We are grateful to the National Insti-
tute of General Medical Sciences (Grant No. GM058889) for
support of this work.
Benzyl 7-(Benzyloxycarbonyloxy)-1-isobutyl-3,4-dihydro-1H-
pyrido[3,4-b]indole-2(9H)-carboxylate (51). To a solution of 50
(180 mg, 0.74 mmol) and Et3N (0.5 mL) in CH2Cl2 (25 mL) at
-10 °C was added benzyl chloroformate (1.5 mL, 2.4 mmol).
The mixture was stirred for 75 min at rt and was poured into
H2O. The mixture was extracted with CH2Cl2 (3ꢀ), and the
Supporting Information Available: Experimental proce-
dures and characterization data not included in the Experimen-
tal Section; 1H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 11, 2010 3577