Regioselective 6-endo cyclizations of 2-indolylacyl radicals: Total synthesis of the pyrido[4,3-b]carbazole alkaloid guatambuine

Article abstract of DOI:10.1021/jo052428s

A regioselective 6-endo reductive cyclization of 2-indolylacyl radicals constitutes the key step of a straightforward synthetic entry to the olivacine skeleton, illustrated by a total synthesis of the tetrahydropyridine alkaloid guatambuine.

Full text of DOI:10.1021/jo052428s

Regioselective 6-Endo Cyclizations of
2-Indolylacyl Radicals: Total Synthesis of the
Pyrido[4,3-b]carbazole Alkaloid Guatambuine
M.-Llu¨ısa Bennasar,* Toma`s Roca, and Francesc Ferrando
Laboratory of Organic Chemistry, Faculty of Pharmacy,
UniVersity of Barcelona, Barcelona 08028, Spain
bennasar@ub.edu
ReceiVed NoVember 24, 2005
FIGURE 1. Pyrido[4,3-b]carbazole alkaloids.
SCHEME 1. Synthetic Strategy
A regioselective 6-endo reductive cyclization of 2-indolylacyl
radicals constitutes the key step of a straightforward synthetic
entry to the olivacine skeleton, illustrated by a total synthesis
of the tetrahydropyridine alkaloid guatambuine.
The pyrido[4,3-b]carbazole alkaloids, exemplified by the fully
aromatic components ellipticine and its isomer olivacine (Figure
1), constitute a small subgroup of naturally occurring biologi-
cally active compounds that have been known for more than
40 years.1 Owing to their well-established anticancer properties,
ellipticine and, to a lesser extent, olivacine have been the
objective of many total syntheses using a great variety of
approaches.1-3 However, despite the intensive synthetic work,
radical methodologies have been scarcely used to assemble the
linear pyridocarbazole skeleton of these alkaloids.4,5
Our previous experience in the inter-6 and intramolecular7
reactions of 2-indolylacyl radicals with alkenes under reductive
conditions led us to envisage a straightforward approach to the
olivacine skeleton hinging on the cyclization of 3-(tetrahydro-
3-pyridylmethyl)-2-indolylacyl radicals (Scheme 1). This paper
deals with our work in this area, including a concise total
synthesis of the pyridocarbazole alkaloid (()-guatambuine, a
tetrahydro derivative of olivacine isolated from several Aspi-
dosperma species.8,9
Radical reactions have become an important tool for the
construction of nitrogen heterocycles.10,11 In this context, there
are several reports in the literature concerning radical cycliza-
tions upon tetrahydropyridines, most of them leading to
structures with the nitrogen atom in the newly formed ring.12,13
* To whom correspondence should be addressed. Tel: 34 934 024 540. Fax:
34 934 024 539.
(1) (a) Sainsbury, M. Synthesis 1977, 437-448. (b) Joule, J. A. Indoles,
The Monoterpenoid Indole Alkaloids. In The Chemistry of Heterocyclic
Compounds; Saxton, J. E., Weissberger. A.; Taylor, E. C., Eds.; Wiley:
New York, 1983; Part 4, pp 275-286. (c) Gribble, G. W. The Alkaloids;
Brosi, A., Ed.; Academic Press: New York, 1990; Vol. 39, pp 239-352.
(2) For a review, see: Kno¨lker, H.-J.; Reddy, K. R. Chem. ReV. 2002,
102, 4303-4427 and references therein.
(3) For representative syntheses of olivacine since 1990, see: (a)
Ba¨ckvall, J.-E.; Plobeck, N. A. J. Org. Chem. 1990, 55, 4528-4531. (b)
Hogan, I.; Jenkins, P. D.; Sainsbury, M. Tetrahedron 1990, 46, 2943-
2964. (c) Hibino, S.; Sugino, E. J. Heterocycl. Chem. 1990, 27, 1751-
1755. (d) Yokoyama, Y.; Okuyama, N.; Iwadate, S.; Momoi, T.; Murakami,
Y. J. Chem. Soc., Perkin Trans. 1 1990, 1319-1329. (e) Hall, R. J.;
Marchant, J.; Oliveira-Campos, A. M. F.; Queiroz, M.-J. R. P.; Shannon,
P. V. R. J. Chem. Soc., Perkin Trans. 1 1992, 3439-3450. (f) Gribble, G.
W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D. M. J. Org. Chem.
1992, 57, 5891-5899. (g) Miki, Y.; Tsuzaki, Y.; Hibino, H.; Aoki, Y. Synlett
2004, 2206-2208.
(6) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001, 3,
1697-1700.
(7) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004, 6, 759-
762.
(8) Guatambuine was isolated as the (+)-, (-)-, and (()-forms: (a)
Ondetti, M. A.; Deulofeu, V. Tetrahedron 1961, 15, 160-166. (b) Burnell,
R. H.; Della Casa, D. Can. J. Chem. 1967, 45, 89-92.
(9) For previous syntheses of (()-guatambuine, see: (a) Besselie`vre, B.;
Husson, H.-P. Tetrahedron 1981, 37, Suppl. No. 1, 241-246. Through
olivacine: (b) Kutney, J. P.; Noda, M.; Lewis, N. G.; Monteiro, B.;
Mostowicz, D.; Worth, B. R. Can. J. Chem. 1982, 60, 2426-2430.
(10) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001. (b) Zhang, W. Tetrahedron 2001, 57, 7237-
7262. (c) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2747-2762. (d) Srikanth, G. S. C.; Castle, S. L.
Tetrahedron 2005, 61, 10377-10441. (e) Majumdar, K. C.; Basu, P. K.;
Mukhopadhyay, P. P. Tetrahedron 2005, 61, 10603-10642.
(4) For a radical cascade protocol leading to ellipticine, see: Pedersen,
J. M.; Bowman, W. R.; Elsegood, M. R. J.; Fletcher, A. J.; Lovell, P. J. J.
Org. Chem. 2005, 70, 10615-10618.
(5) For the synthesis of ellipticine quinones by intramolecular homolytic
acylation of pyridines, see: Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org.
Chem. 2005, 70, 9077-9080.
10.1021/jo052428s CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/12/2006
1746
J. Org. Chem. 2006, 71, 1746-1749

SCHEME 2. Model Studies
SCHEME 3. Synthesis of (()-Guatambuine
selenoster 4 upon exposure to the standard reductive conditions
(tributyltin hydride-AIBN, benzene, reflux, slow addition, final
concentration 0.06 M) led to the expected pyrido[4,3-b]carbazole
5 as a 2:1 mixture of trans-cis stereoisomers in 75% yield. No
5-exo cyclization product was detected by NMR.
This regiochemical outcome is probably the result of a direct
6-endo cyclization of the initially formed acyl radical to give
the fused radical adduct A, although a partial 5-exo attack
followed by ring expansion of the highly strained radical adduct
B cannot be completely ruled out under the reaction conditions.15
Further hydrogen abstraction of the bridgehead radical A from
tributyltin hydride in an incompletely stereoselective way would
account for the formation of the trans-cis mixture 5. This
mixture could be quantitatively transformed into the thermo-
dynamically more stable trans-fused piperidine compound by
treatment with sodium methoxide in methanol.
At this point, the synthesis of the pyridocarbazole alkaloid
guatambuine required the extension of the chemistry outlined
above to related substrates unsubstituted at the indole nitrogen.
Additionally, at some stage, we had to be able to introduce the
C-1 and C-5 methyl groups of the alkaloid. To this end, we
focused our attention on pyridylmethylindole 65 (Scheme 3),
which was converted as above into N-methylpyridinium salt 7.
Reaction of 7 with methylmagnesium chloride efficiently
accomplished the introduction of the first (C-1) methyl group.
Significantly, the addition of the organometallic reagent took
place in a totally regioselective manner at the C-2 position of
the ring16 to give, after reduction of the intermediate 2,3-
disubstituted 1,2-dihydropyridine with NaBH4, tetrahydropyri-
dine 8 as the sole product in a yield as high as 90%. Its
subsequent hydrolysis followed by phenylselenation led to
In our initial design there were two distinct ways to close the
central carbocyclic ring, namely, a 6-endo cyclization of a
5-hexenoyl radical (1,2,5,6-tetrahydropyridine) or a 6-exo
cyclization of a 6-heptenoyl radical (1,2,3,6-tetrahydropyridine).
As the required starting substrates appeared to be more
accessible from pyridine derivatives through conventional
reductive protocols, we focused our attention on the first
approach. Considering the precedents on related cyclizations
involving acyl radicals,7,14 we expected that the higher alkene
substitution at the 3-position of the ring would probably retard
the competitive 5-exo cyclization mode, thus favoring the
desired formation of the 6-membered ring.
We first carried out a model study to probe the feasibility of
the proposal using selenoester 4, which incorporated the required
1,2,5,6-tetrahydropyridine moiety, as the radical precursor
(Scheme 2). As anticipated, this compound was easily accessible
from the known pyridylmethylindole 15 by quaternization with
methyl iodide, reduction of the resulting pyridinium salt 2 with
NaBH4 in a protic solvent (EtOH), and the subsequent phen-
ylselenation of the tetrahydropyridine methyl ester 3 through
the corresponding carboxylic acid. We were pleased to find that
(11) For recent examples of the synthesis of fused azacycles: (a) Miranda,
L. D.; Zard, S. Org. Lett. 2002, 4, 1135-1138. (b) Vila, X.; Quirante, J.;
Paloma, L.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 4661-4664. (c) Padwa,
A.; Rashatasakhon, P.; Ozdemir, A. D.; Willis, J. J. Org. Chem. 2005, 70,
519-528. (d) Taniguchi, T.; Tamura, O.; Uchiyama, M.; Muraoka, O.;
Tanabe, G.; Ishibashi, H. Synlett 2005, 1179-1181.
(12) See inter alia: (a) Mangeney, P.; Hamon, L.; Raussou, S.; Urbain,
N.; Alexakis, A. Tetrahedron 1998, 54, 10349-10362. (b) Della, E. W.;
Smith, P. A. J. Org. Chem. 2000, 65, 6627-6633. (c) Zhang, W.; Pugh, G.
Tetrahedron 2003, 59, 3009-3018. (d) Bressy, C.; Menant, C.; Piva, O.
Synlett 2005, 577-582.
(13) For radical cyclizations upon tetrahydropyridines where a carbocycle
is created, see: (a) Jenkinson, J. J.; Parsons, P. J.; Eyley, S. C. Synlett
1992, 679-680. (b) Ripa, L.; Hallberg, A. J. Org. Chem. 1998, 63, 84-
91. (c) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1999, 40, 8503-
850(71.4) (a) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429-
1443. (b) For a review, see: Chatgilialoglu, C.; Crich, D.; Komatsu, M.;
Ryu, I. Chem. ReV. 1999, 99, 1991-2069.
(15) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Venturini, A.; Zavitsas,
A. A. Chem.sEur. J. 1997, 3, 376-387.
(16) For a discussion on the origin of this regioselectivity, see: (a)
Sundberg, R. J.; Hamilton, G.; Trindle, C. J. Org. Chem. 1986, 51, 3672-
3679. For a recent example, see: (b) Lemire, A.; Grenon, M.; Pourashraf,
M.; Charette, A. B. Org. Lett. 2004, 6, 3517-3520.
J. Org. Chem, Vol. 71, No. 4, 2006 1747

was chromatographed (96:3:1 CH2Cl2-MeOH-diethylamine) to
give 5 as an oil: 94 mg (75%, 2:1 mixture of trans-cis stereoiso-
mers). This mixture was quantitatively converted into the pure trans
compound by treatment with MeONa (38 mg, 0.70 mmol) in MeOH
(5 mL): 1H NMR (400 MHz) δ 1.62 (qd, J ) 4, 12.4, 12.4, 12.4
Hz, 1H), 1.98 (m, 2H), 2.14 (td, J ) 2.7, 12, 12 Hz, 1H), 2.31 (m,
2H), 2.32 (s, 3H), 2.62 (dd, J ) 11.6, 16, Hz, 1H), 3.05 (m, 2H),
3.06 (dd, J ) 3.6, 16 Hz, 1H), 4.06 (s, 3H), 7.13 (ddd, J ) 1.2,
7.2, 8 Hz, 1H), 7.32 (d, J ) 8.4 Hz, 1H), 7.38 (ddd, J ) 1.2, 7.2,
8 Hz, 1H), 7.61 (d, J ) 8 Hz, 1H); 13C NMR (100.6 MHz) δ 25.5
(CH2), 26.1 (CH2), 31.3 (CH3), 41.1 (CH), 46.2 (CH3), 50.1 (CH),
55.7 (CH2), 62.1 (CH2), 110.2 (CH), 120.0 (CH), 121.0 (CH), 124.5
(C), 126.5 (CH), 127.0 (C), 129.8 (C), 139.7 (C), 192.5 (C). Anal.
Calcd for C17H20N2O‚1/2H2O: C, 73.61; H, 7.63; N, 10.09. Found:
C, 73.24; H, 7.39; N, 9.74.
FIGURE 2. Diketopiperazine 11.
selenoester 9, which was subjected to the radical protocol
previously used in the model series (tributyltin hydride, AIBN,
slow addition) with the hope that the initially formed 2-indoly-
lacyl radical would initiate the desired 6-endo cyclization
without interference from the indole NH group.17
Methyl 3-(1,2-Dimethyl-1,2,5,6-tetrahydro-3-pyridylmethyl)-
1H-2-indolecarboxylate (8). Pyridinium salt 7 (0.62 g, 1.50 mmol)
was added under Ar to a cooled (-78 °C) solution of MeMgCl (3
M in THF, 1.75 mL, 5.25 mmol) in THF (35 mL), and the mixture
was stirred at -78 °C for 20 min and at 0 °C for 6 h. The reaction
mixture was poured into a 1:1 mixture of 20% NH4OH and a
saturated aqueous NH4Cl solution (30 mL) and extracted with CH2-
Cl2 (3 × 25 mL). The organic extracts were concentrated to dryness,
and the resulting residue (0.47 g) was dissolved in MeOH (35 mL).
NaBH4 (0.16 g, 3.95 mmol) was added to the solution, and the
mixture was stirred at rt for 4 h. The solvent was removed, and the
resulting residue was partitioned between CH2Cl2 (30 mL) and a
saturated aqueous Na2CO3 solution (30 mL) and extracted with CH2-
Cl2 (2 × 25 mL). The organic extracts were dried and concentrated
Owing to the lower solubility of 9 in benzene, the first
attempts were performed using a 1:1 mixture of benzene-
acetonitrile as the solvent system. However, under these
conditions, a fast dimerization of the substrate took place, most
likely through a ketene intermediate, to give diketopiperazine
11 (Figure 2) as the only product in 63% yield.18 The presence
of the polar solvent was clearly responsible for this unwanted
process19 since when we worked with more diluted benzene
solutions of 9 (final concentration 0.02 M) the radical reaction
took place satisfactorily, giving access to pyridocarbazole 10
(mixture of stereoisomers) in approximately 75% yield. Without
further purification, 10 was elaborated into (()-guatambuine
by reaction with methyllithium, which accomplished the intro-
duction of the second (C-5) methyl group, followed by TFA-
Pd/C promoted dehydration of the resulting carbinol with
concomitant dehydrogenation to the carbazole ring. The overall
yield from selenoester 9 was 45%.
1
to give 8 as a brown oil: 0.40 g (90%); H NMR (200 MHz) δ
1.28 (d, J ) 6.6 Hz, 3H), 1.95-2.10 (m, 2H), 2.34 (s, 3H), 2.44
(dt, J ) 5.6, 5.6, 11.8 Hz, 1H), 2.81 (ddd, J ) 5.4, 7.2, 12.8 Hz,
1H), 2.94 (q, J ) 6.2 Hz, 1H), 3.82 (br s, 2H), 3.93 (s, 3H), 5.27
(m, 1H), 7.10 (ddd, J ) 1.8, 6.6, 8.2 Hz, 1H), 7.30-7.35 (m, 2H),
7.66 (d, J ) 8 Hz, 1H), 8.91 (br s, 1H); 13C NMR (75.4 MHz) δ
15.5 (CH3), 24.0 (CH2), 29.8 (CH2), 42.4 (CH3), 46.7 (CH2), 51.7
(CH3), 58.4 (CH), 111.7 (CH), 119.6 (CH), 120.0 (CH), 121.5 (CH),
121.6 (C), 123.5 (C), 125.5 (CH), 128.4 (C), 135.9 (C), 139.1 (C),
162.7 (C). Anal. Calcd for C18H22N2O2‚H2O: C, 68.33; H, 7.64;
N, 8.85. Found: C, 68.39; H, 7.26; N, 8.61.
Se-Phenyl 3-(1,2-Dimethyl-1,2,5,6-tetrahydro-3-pyridylmethyl)-
1H-2-indolecarboselenoate (9). A solution of methyl ester 8 (0.30
g, 1 mmol) and LiOH‚H2O (50 mg, 1.20 mmol) in a 3:1 mixture
of THF-H2O (8 mL) was stirred at 65 °C for 5 h. The reaction
mixture was concentrated, acidified with aqueous 1 N HCl until
pH ) 4, and concentrated to dryness. The resulting residue was
digested with anhydrous MeOH. The methanolic solution was
concentrated to give the crude carboxylic acid hydrochloride. A
suspension of the above carboxylic acid in anhydrous CH2Cl2 (7
mL) was treated with Et3N (2 mmol). After 15 min at rt, the mixture
was concentrated under reduced pressure to give the triethylam-
monium salt.
1
Our synthetic material displayed H NMR data identical to
those previously reported,8,9 and its 13C NMR and analytical
data were in full agreement with the proposed structure.
Considering that guatambuine had been transformed into
olivacine by further dealkylative aromatization,8a,9a the synthesis
reported here also constitutes a formal synthesis of this fully
aromatic alkaloid.
In conclusion, we have shown that the cyclization of
3-(tetrahydro-3-pyridylmethyl)-2-indolylacyl radicals under re-
ductive conditions takes place with total 6-endo regioselectivity,
providing a novel synthetic entry to the pyrido[4,3-b]carbazole
skeleton characteristic of olivacine.
Experimental Section
2,6-Dimethyl-1,2,3,4,4a,6,11,11a-octahydropyrido[4,3-b]car-
bazole-5-one (5). n-Bu3SnH (0.16 mL, 0.61 mmol) and AIBN (8
mg, 0.05 mmol) in C6H6 (3 mL) were added over a period of 1 h
(syringe pump) to a heated (reflux) solution of selenoester 4 (0.20
g, 0.47 mmol) and AIBN (8 mg, 0.05 mmol) in C6H6 (5 mL). After
an additional 2 h at reflux, the solution was concentrated, the
resulting residue was partitioned between hexanes (10 mL) and
acetonitrile (10 mL), and the polar layer was washed with hexanes
(3 × 10 mL). The solvent was removed, and the crude product
In another flask, tributylphosphine (1.24 mL, 5 mmol) was added
under Ar to a solution of PhSeCl (0.96 g, 5 mmol) in anhydrous
THF (7 mL), and the mixture was stirred at rt for 10 min (yellow
solution). Then, the above triethylammonium salt in THF (7 mL)
was added to this solution, and the resulting mixture was stirred
overnight. The reaction mixture was partitioned between Et2O (25
mL) and H2O (25 mL) and extracted with Et2O (3 × 15 mL). The
solvent was removed, and the crude product was chromatographed
(CH2Cl2 and 90:9:1 CH2Cl2-MeOH-diethylamine) to give sele-
(17) We had observed that the indole NH group inhibited the radical
cyclization of a related selenoester upon pyridines, probably by interfering
at the rearomatization step: see ref 5.
(18) For a related dimerization involving 2-indolylacyl chlorides, see:
Boger, D. L.; Fink, B. E.; Hedrick, M. P. Biorg. Med. Chem. Lett. 2000,
10, 1019-1020.
(19) Simple heating of selenoester 9 in 1:1 benzene-acetonitrile for 3 h
led to a 3:1 mixture of 9 and 11. In contrast, heating of 9 in benzene for 6
h led to a 10:1 mixture of 9 and 11.
1
noester 9 as a brown oil: 0.27 g (65%); H NMR (200 MHz) δ
1.39 (d, J ) 6.6 Hz, 3H), 2.05 (m, 2H), 2.45 (s, 3H), 2.51 (dd,
J ) 6, 12 Hz, 1H), 2.87 (dt, J ) 5.8, 5.8, 12.2 Hz, 1H), 3.10 (q,
J ) 6.2 Hz, 1H), 3.79 (br d, J ) 17.6 Hz, 1H), 3.96 (br d, J )
16.8 Hz, 1H), 5.17 (br s, 1H), 7.03 (d, J ) 8 Hz, 1H), 7.11 (t, J )
8 Hz, 1H), 7.26 (t, J ) 8 Hz, 1H), 7.45 (m, 3H), 7.65 (m, 3H),
9.82 (br s, 1H); 13C NMR (75.4 MHz) δ 16.2 (CH3), 24.1 (CH2),
1748 J. Org. Chem., Vol. 71, No. 4, 2006

30.4 (CH2), 42.7 (CH3), 47.5 (CH2), 59.5 (CH), 112.5 (CH), 120.4
(2 CH), 121.2 (C), 121.4 (CH), 125.4 (C), 126.5 (CH), 128.5 (C),
129.1 (CH), 129.4 (CH), 132.5 (C), 136.5 (C), 136.6 (CH), 137.8
(C), 184.4 (C). Anal. Calcd for C23H24N2OSe‚3/2H2O: C, 61.33;
H, 6.04; N, 6.23. Found: C, 61.29; H, 5.66; N, 5.97.
(() Guatambuine. n-Bu3SnH (0.10 mL, 0.35 mmol) and AIBN
(5 mg, 0.03 mmol) in C6H6 (5 mL) were added over a period of 2
h (syringe pump) to a heated (reflux) solution of selenoester 9 (115
mg, 0.27 mmol) and AIBN (5 mg, 0.03 mmol) in C6H6 (10 mL).
After an additional 1 h at reflux, the solution was concentrated,
and the resulting residue was partitioned between hexanes (10 mL)
and acetonitrile (10 mL). The polar layer was washed with hexanes
(3 × 10 mL) and concentrated to give ketone 10.
and HMBC) δ 1.52 (d, J ) 6.3 Hz, 3H, Me), 2.41 (s, 3H, Me),
2.54 (s, 3H, NMe), 2.79 (ddd, J ) 5.7, 6, 11.7 Hz, 1H, 3-H), 2.94
(m, 2H, 4-H), 3.19 (ddd, J ) 5.7, 6, 11.7 Hz, 1H, 3-H), 3.89 (q,
J ) 6.3 Hz, 1H, 1-H), 7.19 (ddd, J ) 1.2, 6.6, 7.8 Hz, 1H, 9-H),
7.37 (ddd, J ) 1.2, 6.6, 8.1 Hz, 1H, 8-H), 7.42 (dd, J ) 1.2, 8.1
Hz, 1H, 7-H), 7.70 (s, 1H, 11-H), 7.85 (br s, 1H, NH), 8.00 (d,
J ) 7.8 Hz, 1H, 10-H); 13C NMR (100.6 MHz, HSQC and HMBC)
δ 12.9 (Me), 20.3 (Me), 25.0 (C-4), 42.0 (NMe), 48.1 (C-3), 59.7
(C-1), 110.6 (C-7), 115.9 (C-11), 116.9 (C-5), 119.2 (C-9), 120.1
(C-10), 121.3 (C-10b), 123.7 (C-10a), 125.5 (C-8), 128.8 (C-4a),
130.0 (C-11a), 138.1 (C-5a), 139.9 (C-6a); HRMS calcd for
C18H20N2 264.1626, found 264.1628. Anal. Calcd for C18H20N2‚
HCl: C, 71.86; H, 7.04; N, 9.31. Found: C, 71.63; H, 6.85; N,
9.08.
A solution of crude 10 in anhydrous THF (7 mL) was added
dropwise under Ar to a cooled (-10 °C) solution of MeLi (1.6 M
in Et2O, 2.50 mL, 4.0 mmol) in anhydrous THF (7 mL), and the
resulting mixture was stirred at rt for 3 h. The reaction mixture
was poured into an ice-cold saturated aqueous NH4Cl solution (30
mL) and extracted with CH2Cl2 (3 × 15 mL). The organic extracts
were dried and concentrated. 10% Pd/C (85 mg) was added to the
resulting residue dissolved in TFA (4 mL), and the suspension was
stirred at rt for 3 h. The reaction mixture was filtered through Celite,
the cake was washed with CH2Cl2 (20 mL), and the organic solution
was washed with a saturated aqueous NaHCO3 solution (3 × 20
mL). The organic extracts were concentrated, and the crude product
was chromatographed (92:7:1 CH2Cl2-MeOH-diethylamine) to
give (()-guatambuine: 32 mg (45%); 1H NMR (300 MHz, HSQC
Acknowledgment. Financial support from the Ministerio de
Ciencia y Tecnolog´ıa (MCYT-FEDER, Spain) through project
BQU2003-04967-C-02-02 is gratefully acknowledged. F.F. also
thanks the University of Barcelona for a grant.
Supporting Information Available: General experimental
protocols and detailed experimental procedures for the preparation
of synthetic intermediates 2, 3, 4, and 7. Characterization data of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052428S
J. Org. Chem, Vol. 71, No. 4, 2006 1749