A new acyl radical-based route to the 1,5-methanoazocino[4,3-b]indole framework of uleine and strychnos alkaloids

Article abstract of DOI:10.1021/jo801998h

(Chemical Equation Presented) C-4 or C-12 ethyl substituted 1,5-methanoazocino[4,3-b]indoles, which constitute the tetracyclic framework of uleine alkaloids as well as the ABDE substructure of the Strychnos alkaloid family, have been synthesized by novel 6-exo and 6-endo cyclizations of selenoester-derived 2-indolylacyl radicals upon 5-ethyl-1,2,3,6- and 3-ethyl-1,2,5,6-tetrahydropyridines, respectively.

Full text of DOI:10.1021/jo801998h

A New Acyl Radical-based Route to the
1,5-Methanoazocino[4,3-b]indole Framework of Uleine and Strychnos
Alkaloids
M.-Llu¨ısa Bennasar,* Toma`s Roca, and Davinia Garc´ıa-D´ıaz
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB),
UniVersity of Barcelona, Barcelona 08028, Spain
bennasar@ub.edu
ReceiVed September 10, 2008
C-4 or C-12 ethyl substituted 1,5-methanoazocino[4,3-b]indoles, which constitute the tetracyclic framework
of uleine alkaloids as well as the ABDE substructure of the Strychnos alkaloid family, have been
synthesized by novel 6-exo and 6-endo cyclizations of selenoester-derived 2-indolylacyl radicals upon
5-ethyl-1,2,3,6- and 3-ethyl-1,2,5,6-tetrahydropyridines, respectively.
Introduction
In the last years we have been involved in the development
of a novel general synthetic entry to indole compounds taking
advantage of the reactions of phenyl selenoester derived
2-indolylacyl radicals.1,2 In particular, we have shown that
several alkaloid structures embodying the 2-acylindole moiety
can be efficiently assembled by intramolecular reactions of these
radical intermediates with a variety of indole-tethered carbon-
carbon double bond acceptors.2b,3 On the basis of our earlier
work, we considered extending this methodology for the
construction of the 1,5-methanoazocino[4,3-b]indole system,
which constitutes the bridged arrangement of the indole alkaloids
of the uleine group4 (uleine, dasycarpidone and their C-20
epimers, Figure 1) as well as the ABDE substructure of the
FIGURE 1. Uleine and Strychnos Alkaloids.
* Tel: 34 934 024 540. Fax: 34 934 024 539.
Strychnos alkaloid family,5 exemplified by the pentacyclic
components tubifolidine or strychnopivotine (strychnan bioge-
netic type) and tubotaiwine (aspidospermatan biogenetic type).
Although these natural products have long attracted the attention
of the synthetic community and, consequently, a great variety
of synthetic approaches have been reported,4,5 radical method-
ologies have been little explored in this field.6
(1) For a review on the chemistry of acyl radicals, see: (a) Chatgilialoglu,
C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991–2069.
(2) (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001, 3,
1697–1700. (b) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004, 6, 759–
762.
(3) (a) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2005, 70, 9077–
9080. (b) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2006, 71, 1746–
1749. (c) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561–564.
(d) Bennasar, M.-L.; Roca, T.; Garc´ıa-D´ıaz, D. J. Org. Chem. 2007, 72, 4562–
4565.
(4) For reviews, see: (a) Joule, J. A. In Indoles. The Monoterpenoid Indole
Alkaloids, Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1983; Vol. 25, Part 4,
Ch 6. (b) Alvarez, M.; Joule, J. A. In Monoterpenoid Indole Alkaloids; Saxton,
J. E., Ed.; The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;Wiley:
Chichester, 1994; Supplement to Vol. 25, Part 4, Ch 6. (c) Alvarez, M.; Joule,
J. A. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2001;
Vol. 57, Ch 4.
(5) For reviews, see: (a) Bosch, J.; Bonjoch, J. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, , Ed.; Elsevier: Amsterdam, 1988; pp 31-88. (b)
Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The
Chemistry of Heterocylic Compounds; Taylor, E. C., Ed.; Wiley: Chichester,
1994; Supplement to Vol. 25, Part 4, Ch 7. (c) Bosch, J.; Bonjoch, J.; Amat, M.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1996; Vol.
48, pp 75-189.
10.1021/jo801998h CCC: $40.75
Published on Web 10/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9033–9039 9033

Bennasar et al.
SCHEME 1. Synthetic Strategy
SCHEME 2. Model 6-Exo Cyclization
As depicted in Scheme 1, our strategy for the assembly of
this bridged tetracyclic framework relies on the closure of the
carbocyclic 6-membered ring by cyclization of 3-(tetrahydro-
2-pyridyl)-2-indolylacyl radicals.7,8 We anticipated that placing
both the double bond acceptor and the required two-carbon
appendage at different positions of the pyridine ring (as depicted
in A and B) would enable two radical cyclization pathways to
generate complementary substituted tetracycles. Thus, either
strychnan (C-4 ethyl) or aspidospermatan (C-12 ethyl) sub-
structures would be produced by regioselective 6-exo or 6-endo
cyclizations upon 1,2,3,6- or 1,2,5,6-tetrahydropyridines, re-
spectively. Critical to the success of our synthetic plan was the
efficient construction of the cyclization substrates. To this end,
we devised two closely related flexible routes starting from the
N-protected indole-3-carbaldehyde 1, which involve an amina-
tion (bond a)-imine allylation or alkenylation (bond b)-ring
closing metathesis (RCM, bond c) sequence. In addition,
carboxylation of a 2-lithioindole derivative (bond d) at some
stage would install the carboxylic acid function from which the
acyl radical precursor selenoester would be prepared.
Results and Discussion
We set out to study the construction of the 6-oxo-1,5-
methanoazocino[4,3-b]indole system by 6-exo cyclization of
2-indolylacyl radicals upon 1,2,3,6-tetrahydropyridines (6-
heptenoyl radicals A). To test the feasibility of the proposal we
first targeted the model selenoester 5, which incorporated an
unsubstituted tetrahydropyridine moiety at the indole 3-position.9
As anticipated, this compound was available from the N-Boc-
protected indole 1, following the synthetic sequence depicted
in Scheme 2. Thus, reaction of 1 with allylamine and alkylation
of the resulting imine with allylmagnesium bromide led to an
unstable secondary amine, which was not isolated10 but was
subsequently acylated with methyl chloroformate to give
carbamate 2 in 68% overall yield. At this point, the carboxy
group could be introduced with high efficiency by treatment
with LDA and reaction of the intermediate 2-lithioindole
derivative with carbon dioxide. The next closure of the
tetrahydropyridine ring of the resulting sensitive carboxylic acid
by RCM was accomplished uneventfully by reaction with the
second generation Grubbs catalyst (Im)(PCy3)2(Cl)2RudCHPh
(6) (a) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873–
7881. (b) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li, Y.-L.; Wang, T.
J. Org. Chem. 1998, 63, 2172–2173. (c) Eichberg, M. J.; Dorta, R. L.; Grotjahn,
D. B.; Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001,
123, 9324–9337.
(7) For a leading review on the synthesis of nitrogen heterocycles by radical
cyclization, see: Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2747–2762.
(8) For relevant radical cyclizations leading to bridged nitrogen heterocycles,
see: (a) Della, E. W.; Knill, A. M. J. Org. Chem. 1996, 61, 7529–7533. (b)
Quirante, J.; Escolano, C.; Massot, M.; Bonjoch, J. Tetrahedron 1997, 53, 1391–
1402. (c) Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J. Org. Chem. 1998,
63, 968–976. (d) Della, E. W.; Smith, P. A. J. Org. Chem. 2000, 65, 6627–
6633. (e) Hoepping, A.; George, C.; Flippen-Anderson, J.; Kozikowski, A. P.
Tetrahedron Lett. 2000, 41, 7427–7432. (f) Tamura, O.; Yanagimachi, T.;
Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427–2429. (g) Quirante, J.;
Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67, 2323–2328. (h) Yu,
J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook,
J. M. J. Org. Chem. 2003, 68, 7565–7581. (i) Bower, J. F.; Szeto, P.; Gallagher,
T. Chem. Commun. 2005, 5793–5795. (j) Bower, J. F.; Szeto, P.; Gallagher, T.
Org. Biomol. Chem. 2007, 5, 143–150. (k) Grainger, R. S.; Welsh, E. J. Angew.
Chem., Int. Ed. 2007, 46, 5377–5380. (l) Dandapani, S.; Duduta, M.; Panek,
J. S.; Porco, Jr., J. A. Org. Lett. 2007, 9, 3849–3852. (m) Yoshimitsu, T.; Atsumi,
C.; Iimori, E.; Nagaoka, H.; Tanaka, T. Tetrahedron Lett. 2008, 49, 4473–4475.
(n) See also ref 6.
(9) For a preliminary report of this part of the work, see: Bennasar, M.-L.;
Roca, T.; Garc´ıa-D´ıaz, D. Synlett 2008, 1487–1490.
(10) All attempts to carry out the amination-imine allylation sequence from
an indole-3-carbaldehyde already incorporating a carboxylic ester at the 2-position
resulted in lactamization.
9034 J. Org. Chem. Vol. 73, No. 22, 2008

1,5-Methanoazocino[4,3-b]indoles by Acyl Radical Cyclization
SCHEME 3. Cyclization of Selenoester 10
at room temperature in CH2Cl2 to give tetrahydropyridine 3 in
85% overall yield from 2. Selective removal of the indole
protecting group under the usual acid (TFA) conditions resulted
in intensive decomposition, but it was also achieved in high
yield (92%) using a basic protocol (MeONa, reflux). Finally,
the resulting tetrahydropyridine carboxylic acid 4 was converted
into selenoester 5 by phenylselenation under Batty and Crich
conditions11 (60%).
With a reliable route to the radical precursor in hand, attention
was focused on the key cyclization step. Satisfactorily, treatment
of selenoester 5 with 2 equiv of n-Bu3SnH in the presence of
Et3B as the initiator at room temperature in benzene (concentra-
tion 0.07 M) led to azocinoindole 6 as the major product in
60% yield. The formation of 6 was consistent with the predicted
6-exo cyclization of the initially formed 2-indolylacyl radical
to give a bridged azabicyclo[3.3.1]nonane ring system after
reduction of the cyclized secondary radical C. Minor amounts
of tetracycle 7, containing the regioisomeric bicyclo[3.2.2]nonane
system derived from the radical attack at the C-5 tetrahydro-
pyridine position instead of C-4, were also obtained (10% yield).
No evidence of acyl radical reduction (i.e., formation of an
aldehyde), either from direct hydrogen abstraction from the
hydride or an eventual [1,5]-hydrogen transfer, was observed.
We experimented with different hydride concentrations to
ascertain if the regiochemical outcome was a reflection of the
kinetic composition of the initially formed cyclized radicals C
and D or the result of a partial equilibration between these
intermediates through one-carbon ring expansion.12 As com-
pounds 6 and 7 were invariably obtained in the same 6:1 ratio
(combined yields 30-40%) working at a higher (0.14 M) or
lower (0.005 M) hydride concentration, we assumed that the
aforementioned equilibration was not included in the reaction
pathway.
Following the success in the model deethyl series, we
endeavored to complete the strychnan core structure (C-4 ethyl)
by extending the chemistry outlined above to a more elaborated
radical precursor (e.g., selenoester 10, Scheme 3). We expected
that the presence of an ethyl substituent at the site of attack on
the tetrahydropyridine double bond would preclude the undesired
cyclization pathway, thus favoring the exclusive formation of
the 6-membered ring. Our synthetic route to 10 began with the
sequential reaction of aldehyde 1 with 2-ethylallylamine,13
allylmagnesium bromide, and methyl chloroformate to give
carbamate 8 in 65% yield. Introduction of the R-carboxy group
was less efficient than in the above series as it suffered from
competitive interaction of the intermediate 2-lithioindole with
the N-(methoxycarbonyl) group, resulting in partial lactamiza-
tion.14 Indeed, after RCM of the rather unstable carboxylic acid,
performed in the presence of benzoquinone to prevent the
unwanted isomerization of the terminal double bond,15 the
N-Boc tetrahydropyridine 9 was obtained in a modest 45% yield
from 8. Changing the order of the synthetic steps, that is, first
performing the RCM of 8 and then the carboxylation at the
tetrahydropyridine stage, resulted in an even higher undesired
lactamization and, consequently, a lower yield of 9 (<10%).14
Finally, removal of the N-Boc group followed by phenylsel-
enation led to selenoester 10 in 62% yield.
We were pleased to find that selenoester 10 upon exposure
to the n-Bu3SnH-Et3B reductive protocol led to tetracycle 1116
(70%), which embodied the expected 4-ethyl-6-oxo-1,5-metha-
noazocino[4,3-b]indole framework with the H-4/H-5 cis relative
configuration of the indole alkaloid tubifolidine. The formation
of 11 as a single regio- and stereoisomer can be rationalized by
considering that, after the predicted 6-exo cyclization of the
initially formed 2-indolylacyl radical upon the less substituted
alkene carbon, the resulting tertiary radical (E) undergoes
stereoselective axial hydrogen abstraction from the stannane.
This satisfactory result motivated us to examine a more
concise approach to an alternative 6-exo cyclization substrate
en route to the so-called isodasycarpidone17,18 (18, Scheme 4).
This approach features the rapid assembly of the required 3-(2-
tetrahydropyridyl)indole moiety by exploiting the venerable
chemistry of N-alkyl-2-cyano-1,2,3,6-tetrahydropyridines,19 which
are synthons for dihydropyridinium salts able to react with the
indole ring.18,20 Thus, tetrahydropyridine 13 could be easily
synthesized in 60% yield by reaction of 2-cyanotetrahydropy-
ridine 1221 with indole in acidic aqueous medium. After
protection of the indole NH with a Boc group, the R-lithiation-
carboxylation sequence cleanly afforded the expected amino acid
(86%), which was isolated as the hydrochloride salt (15). The
(11) Batty, D.; Crich, D. Synthesis 1990, 273–275.
(12) For discussions, see: (a) Beckwith, A. L. J.; O’Shea, D. M.; Westwood,
S. W. J. Am. Chem. Soc. 1987, 110, 2565–2575. (b) Boger, D. L.; Mathvink,
R. J. J. Org. Chem. 1992, 57, 1429–1443. (c) Dowd, P.; Zhang, W. Chem. ReV.
1993, 93, 2091–2115. (d) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Venturini,
A.; Zavitsas, A. A. Chem.sEur. J. 1997, 3, 376–387.
(16) Gra`cia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994,
59, 3939–3951.
(17) Kametani, T.; Suzuki, T. J. Org. Chem. 1971, 36, 1291–1293.
(18) Bosch, J.; Rubiralta, M.; Domingo, A.; Bolo´s, J.; Linares, A.; Minguillo´n,
C.; Amat, M.; Bonjoch, J. J. Org. Chem. 1985, 50, 1516–1522.
(19) Fry, E. M. J. Org. Chem. 1964, 29, 1647–1650.
(20) Feliz, M.; Bosch, J.; Mauleo´n, D.; Amat, M.; Domingo, A. J. Org. Chem.
1982, 47, 2435–2440.
(13) Prepared from 2-ethylallyl methanesulfonate: (a) Plamondon, L.; Wuest,
J. D. J. Org. Chem. 1991, 56, 2066–75, See Supporting Information.
(14) See Supporting Information for details.
(15) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160–17161.
(21) Chapman, R. F.; Phillips, N. I. J.; Ward, R. S. Tetrahedron 1985, 41,
5229–5234.
J. Org. Chem. Vol. 73, No. 22, 2008 9035

Bennasar et al.
SCHEME 4. Synthesis of Isodasycarpidone
SCHEME 5. Cyclization of Selenoesters 21
subsequent indole deprotection under the usual basic conditions
followed by phenylselenation of the resulting amino acid 16
led to the highly unstable N-methyl selenoester (17), which was
directly subjected to our standard radical protocol. Satisfactorily,
the initially formed 2-indolylacyl radical underwent the expected
regio- and stereoselective cyclization leading to isodasycarpi-
done (18), once again possessing the H-4/H-5 cis relationship,
in 40% overall yield from 16.
reductive protocol identical to that used in the above exo series
(n-Bu3SnH, Et3B, concentration 0.07 M) selenoester 21a led to
a nearly equimolecular mixture of 6-endo (22a) and 5-exo (23a)
tetracycles, which could not be separated. We explored the
possibility of increasing the amount of endo product by carrying
out the radical cyclization at lower hydride concentrations (0.01
M, 0.005 M), giving opportunities to an eventual equilibration
of the intermediate cyclized radicals F and G in favor of the
most stable tertiary radical F. However, the product ratio was
not significantly modified and, consequently, we assumed that
the observed exo-endo regioselectivity was a reflection of the
initial kinetic composition of cyclized radicals. On the other
hand, cyclization of the N-(benzyloxycarbonyl) selenoester 21b
was not regioselective either, but the mixture of cyclized
products 22b and 23b could now be separated by column
chomatography. Tetracycle 22b was shown by NMR to embody
the expected 12-ethyl-6-oxo-1,5-methanoazocino[4,3-b]indole
framework with the H-5/H-12 trans relative configuration (12-
ethyl axial with respect to the piperidine ring), which is the
result of the stereoselective equatorial hydrogen abstraction of
the cyclized radical F from the stannane.
At this point we considered examining the behavior of the
2-indolylacyl radical derived from N-methyl selenoester 28
(Scheme 6) to see if changing the carbamate nitrogen atom for
an amine nitrogen atom in the acceptor ring would have any
influence in the regiochemical course of the cyclization. To this
end, aldehyde 1 was allowed to react as above with 3-buteny-
lamine and 1-buten-2-ylmagnesium bromide,22 and the resulting
secondary amine was converted into the tertiary amine 24 in
50% yield by reductive alkylation with formaldehyde. The
assembly of the tetrahydropyridine moiety was accomplished
in 71% yield by RCM of 24, which required its previous
Following our general plan, we sought to elaborate the
aspidospermatan core structure (C-12 ethyl) by tackling the more
challenging 6-endo cyclizations of 2-indolylacyl radicals upon
1,2,5,6-tetrahydropyridines (5-hexenoyl radicals B, Scheme 1).
In this series we planned to directly study the behavior of 3-ethyl
substituted radical precursors since the presence of the two-
carbon appendage was expected to be crucial to sterically
prevent the otherwise favored competitive 5-exo closure.
With the final aim of reaching dasycarpidone alkaloids, we
first targeted selenoesters 21a,b bearing an easily removable
acyl (methoxycarbonyl or benzyloxycarbonyl) group at the
tetrahydropyridine nitrogen. These compounds were prepared
from indole-3-carbaldehyde 1, following the synthetic sequence
outlined in Scheme 5. Reaction of 1 with 3-butenylamine
followed by addition of 1-buten-2-ylmagnesium bromide22 to
the resulting imine led to a secondary allyl homoallyl amine,
which was acylated with methyl or benzyl chloroformate to give
carbamates 19a (56%) or 19b (54%). Since the indole R-lithia-
tion-carboxylation of 19a suffered from competitive lactamiza-
tion as in the above series, we decided to first close the
tetrahydropyridine ring by RCM. Thus, treatment of 19a or 19b
with the second generation Grubbs catalyst in the presence of
benzoquinone led to 1,2,5,6-tetrahydropyridines 20a (72%) or
20b (71%), which were then elaborated into selenoesters 21a
or 21b by carboxylation, indole deprotection, and phenylsel-
enation. Without any intermediate being isolated, the overall
yield of the three-step sequence was 45 or 30%, respectively.
With selenoesters 21 in hand, we were ready to attempt the
key cyclization step. Disappointingly, upon subjection to a
(22) Sinha, S. C.; Li, L.-S.; Watanabe, S.; Kaltgrad, E.; Tanaka, F.; Rader,
C.; Lerner, R. A.; Barbas, C. F. Chem.sEur. J. 2004, 10, 5467–5472.
9036 J. Org. Chem. Vol. 73, No. 22, 2008

1,5-Methanoazocino[4,3-b]indoles by Acyl Radical Cyclization
SCHEME 6. Synthesis of Dasycarpidones
Experimental Section
Phenyl 3-[(1-Methoxycarbonyl)-1,2,3,6-tetrahydro-2-pyridyl]in-
dole-2-carboselenoate (5). A suspension of carboxylic acid 4 (0.25
g, 0.83 mmol) in anhydrous CH2Cl2 (6 mL) was treated with Et3N
(0.24 mL, 1.68 mmol). After 15 min at rt, the mixture was
concentrated to give the triethylammonium salt. In another flask,
tributylphosphine (1.0 mL, 4.20 mmol) was added under Ar to a
solution of PhSeCl (0.80 g, 4.20 mmol) in anhydrous THF (6 mL),
and the mixture was stirred at rt for 10 min (yellow solution). The
above ammonium salt in THF (6 mL) was added to this solution,
and the resulting mixture was stirred overnight. The reaction mixture
was partitioned between Et2O (20 mL) and H2O (20 mL) and was
extracted with Et2O (3 × 15 mL). The solvent was removed and
the crude product was chromatographed (hexanes and then 75:25
hexanes-AcOEt) to give selenoester 5 as a white solid: 0.22 g
(60%); mp 174-5 °C; 1H NMR (400 MHz) δ 2.48 (br d, J ) 17.2
Hz, 1H), 2.79 (m, 1H), 3.59 (s, 3H), 4.02 (d, J ) 17.6 Hz, 1H),
4.29 (d, J ) 18.0 Hz, 1H), 6.00 (m, 3H), 7.10 (t, J ) 7.2 Hz, 1H),
7.33 (t, J ) 8 Hz, 1H), 7.39 (d, J ) 8.4 Hz, 1H), 7.44 (m, 3H),
7.62 (m, 2H), 7.68 (d, J ) 8 Hz, 1H), 8.74 (br s, 1H); 13C NMR
(75.4 MHz) δ 30.3 (CH2), 42.4 (CH2), 46.9 (CH), 52.7 (CH3), 112.4
(CH), 121.1 (CH), 122.8 (CH), 124.9 (CH), 125.5 (C), 126.0 (C),
126.1 (2 CH), 129.2 (CH), 129.4 (CH), 130.7 (C), 136.2 (CH),
136.8 (C), 156.6 (C), 183.4 (C), indole C-3 not observed. Anal.
calcd for C22H20N2O3Se·1H2O: C, 57.77; H, 4.84; N, 6.12. Found:
C, 57.92; H, 4.52; N, 5.92.
Cyclization of Selenoester 5. n-Bu3SnH (0.18 mL, 0.65 mmol)
and Et3B (1 M in hexanes, 0.65 mL, 0.65 mmol) were added to a
solution of selenoester 5 (0.14 g, 0.32 mmol, previously dried
azeotropically with anhydrous C6H6) in anhydrous C6H6 (9 mL).
The reaction mixture was stirred at rt for 3 h with dry air constantly
supplied by passing compressed air through a short tube of Drierite.
The reaction mixture was concentrated. The residue was partitioned
between hexanes (15 mL) and acetonitrile (15 mL), and the polar
layer was washed with hexanes (3 × 15 mL). The acetonitrile
solution was concentrated, and the crude product was chromato-
graphed (hexanes and then 7:3 hexanes-AcOEt) to give the
following compounds:
conversion into the hydrochloride salt.23 The subsequent indole
R-carboxylation of 25 (71% yield), indole deprotection of 26
(80% yield), and phenylselenation of amino acid 27 led to the
highly unstable N-methyl selenoester 28, which was directly
subjected to the standard radical cyclization protocol. To our
delight, the 5-exo route was completely suppressed since a 2.2:1
mixture of stereoisomeric azocinoindoles 29 and 30 was
obtained in 41% overall yield from 27. After chromatographic
separation, the major product 29 was assigned as (()-20-
epidasycarpidone17,24 (H-5/H-12 trans relative configuration),
which was identical to the material produced by hydrogenolysis-
methylation of the benzyl carbamate 22b.14 On the other hand,
the minor product 30 was assigned as (()-dasycarpidone16,17
(H-5/H-12 cis relative configuration, 12-ethyl equatorial with
respect to the piperidine group). This stereochemical result
indicated that the 6-endo cyclization was now followed by an
incompletely stereoselective hydrogen abstraction of the result-
ing cyclized radical.
Methyl 6-oxo-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-
1
b]indole-2-carboxylate (6): 55 mg (60%); H NMR (400 MHz,
assignment aided by HSQC and COSY, mixture of rotamers) δ
2.02 (m, 2H, 4-H), [2.22 (dt, J ) 12.8, 2.8 Hz) and 2.55 (br d, J
) 10.8 Hz), 2H, 12-H], [2.78 (br t, J ) 12.8 Hz) and 3.8-4.0
(masked), 2H, 3-H], 2.89 (s, 1H, 5-H), 3.68 and 3.88 (2 s, 3H,
OMe), 5.78 and 5.94 (2 s, 1H, 1-H), 7.18 (t, J ) 7.2 Hz, 1H, 10-
H), 7.39 (t, J ) 8.4 Hz, 1H, 9-H), 7.48 (d, J ) 8 Hz, 1H, 8-H),
[7.69 (br d, J ) 6.8 Hz) and 7.91 (d, J ) 7.6 Hz), 1H, 11-H], 9.60
and 9.64 (2 s, 1H, 7-H); 13C NMR (100.6 MHz, assignment aided
by HSQC and HMBC, mixture of rotamers) δ 29.0 (C-4), 35.4
(C-12), 36.5 (C-3), 41.3 (C-5), 43.6 and 44.1 (C-1), 52.7 (OMe),
112.5 and 112.8 (C-8), 121.3 (C-10), 121.7 and 122.7 (C-11), 124.3
(C-11a), 125.4 (C-11b), 127.5 (C-9), 132.6 (C-6a), 138.4 (C-7a),
155.9 and 156.2 (CO2), 193.3 (C-6); ESI-HRMS [M + H]+ calcd
for C16H17N2O3: 285.1233. Found: 285.1232.
Conclusion
Methyl 5-Oxo-2,3,4,5-tetrahydro-1,4-ethanoazepino[4,3-b]in-
dole-2-carboxylate (7): 9 mg (10%); 1H NMR (400 MHz,
assignment aided by HSQC and COSY, mixture of rotamers) δ
1.90 (m, 2H, 11-H, 12-H), 2.13 (m, 1H, 12-H), 2.41 (m, 1H, 11-
H), [3.21 (t, J ) 5.2 Hz) and 3.26 (br t), 1H, 4-H], [3.51 (d, J )
12.8 Hz) and 3.65 (m), 2H, 3-H], 3.64 and 3.65 (2 s, 3H, OMe),
[5.79 (dd, J ) 2.4, 5.6 Hz) and 5.98 (dd, J ) 2, 5.2 Hz), 1H, 1-H],
7.22 (t, J ) 7.6 Hz, 1H, 9-H), 7.41 (m, 2H, 7-H, 8-H), [7.79 (d, J
) 8 Hz) and 7.91 (d, J ) 7.6 Hz), 1H, 10-H], 8.96 and 8.99 (2 s,
1H, 6-H); 13C NMR (100.6 MHz, assignment aided by HSQC and
HMBC, mixture of rotamers) δ 18.7 (C-12), 26.9 and 27.0 (C-11),
42.3 and 42.5 (C-3), 45.0 and 45.5 (C-1), 46.5 (C-4), 52.6 and 52.7
(OMe), 112.2 and 112.4 (C-7), 120.7 and 121.0 (C-10), 121.2 (C-
9), 124.6 and 124.8 (C-10a), 127.0 and 127.2 (C-8), 130.7 and 131.2
A conceptually new route to the bridged tetracyclic frame-
work of uleine and Strychnos alkaloids, featuring 6-exo or
6-endo cyclizations of 2-indolylacyl radicals upon tetrahydro-
pyridines, has been developed. The usefulness of the approach
is established by the synthesis of isodasycarpidone and dasy-
carpidones, thus illustrating the considerable potential of 2-in-
dolylacyl radical intermediates for the total synthesis of indole
alkaloids.
(23) For a recent review discussing RCM of amine-containing dienes, see:
Compain, P. AdV. Synth. Catal. 2007, 349, 1829–1846.
(24) Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-Bardia, M.
Tetrahedron 1996, 52, 3563–3574.
J. Org. Chem. Vol. 73, No. 22, 2008 9037

Bennasar et al.
(C-10b), 132.8 and 132.9 (C-5a), 137.2 and 137.3 (C-6a), 155.6
and 155.9 (CO2), 194.0 (C-5); ESI-HRMS [M + H]+ calcd for
C16H17N2O3: 285.1233. Found: 285.1233.
1.20 and 1.41 (2 m, 2H, CH2CH3), 1.74 (t, J ) 12.4 Hz, 1H, 3-H),
2.00 (m, 1H, 4-H), 2.29 (dt, J ) 12, 3.2 Hz, 1H, 12-H), 2.30 (s,
3H, NMe), 2.56 (dt, J ) 12.7, 3.2 Hz, 1H, 12-H), 2.61 (dd, J )
12.4, 4.8 Hz, 1H, 3-H), 2.77 (q, J ) 3.2 Hz, 1H, 5-H), 4.34 (t, J )
3.2 Hz, 1H, 1-H), 7.18 (t, J ) 8 Hz, 1H, 10-H), 7.37 (t, J ) 8 Hz,
1H, 9-H), 7.48 (d, J ) 8 Hz, 1H, 8-H), 7.70 (d, J ) 7.6 Hz, 1H,
11-H), 9.56 (s, 1H, 7-H); 13C NMR (100.6 MHz, assignment aided
by HSQC and HMBC) δ 11.6 (CH2CH3), 24.8 (CH2CH3), 38.2 (C-
12), 44.1 (NMe), 41.5 (C-4), 44.8 (C-5), 52.0 (C-1), 52.6 (C-3),
112.6 (C-8), 121.0 (C-10), 121.8 (C-11b), 122.0 (C-11), 126.7 (C-
9), 126.8 (C-11a), 133.5 (C-6a), 137.8 (C-7a), 192.5 (C-6); ESI-
HRMS [M + H]+ calcd for C17H21N2O: 269.1648. Found:
269.1653. Anal. calcd for C17H20N2O·HCl·1/2H2O: C, 65.06; H,
7.07; N, 8.92. Found: C, 64.94; H, 7.12; N, 8.56.
Phenyl 3-[5-Ethyl-(1-methoxycarbonyl)-1,2,3,6-tetrahydro-
2-pyridyl]indole-2-carboselenoate (10). Tetrahydropyridine 9 (0.16
g, 0.37 mmol) in MeOH (2 mL) was allowed to react with a solution
of MeONa, previously prepared from Na (42 mg, 1.85 mmol) in
MeOH (10 mL), at reflux temperature overnight. The reaction
mixture was concentrated, and the residue was partitioned between
2 M aqueous HCl (15 mL) and CH2Cl2 (15 mL) and extracted with
CH2Cl2 (2 × 10 mL). After concentration of the organic extracts,
the resulting material (0.11 g) was dissolved in anhydrous CH2Cl2
(3 mL) and then treated with Et3N (0.09 mL, 0.66 mmol),
tributylphosphine (0.40 mL, 1.65 mmol), and PhSeCl (0.32 g, 1.65
mmol) as described for the preparation of selenoester 5. After flash
chromatography of the crude product (hexanes and 8:2 hexanes-
Phenyl 3-[(3-Ethyl-1-(methoxycarbonyl)-1,2,5,6-tetrahydro-
2-pyridyl]indole-2-carboselenoate (21a). n-BuLi (1.6 M in hexane,
0.52 mL, 0.82 mmol) was added under Ar to a cooled (-78 °C)
solution of diisopropylamine (0.12 mL, 0.82 mmol) in anhydrous
THF (5 mL), and the resulting solution was stirred at -78 °C for
30 min. Tetrahydropyridine 20a (0.21 g, 0.55 mmol) in anhydrous
THF (5 mL) was then added, and the resulting red mixture was
stirred at -78 °C for 30 min. CO2 (gas) was bubbled through the
reaction mixture, which immediately turned orange. After 15 min
at -78 °C, the reaction mixture was quenched with H2O (5 mL),
acidified with 1 M aqueous HCl, and extracted with CH2Cl2 (3 ×
10 mL). Concentration of the organic extracts gave the crude
carboxylic acid (0.20 g). A solution of this acid in MeONa,
previously prepared from Na (56 mg, 2.40 mmol) in MeOH (10
mL), was heated at reflux overnight. The reaction mixture was
concentrated, and the residue was partitioned between 2 M aqueous
HCl (15 mL) and CH2Cl2 (15 mL) and extracted with CH2Cl2 (2
× 15 mL). The organic extracts were concentrated, and the resulting
residue (0.13 g) was dissolved in CH2Cl2 (3 mL) and then treated
with Et3N (0.11 mL, 0.78 mmol), tributylphosphine (0.48 mL, 1.95
mmol), and PhSeCl (0.37 g, 1.95 mmol) as described for the
preparation of selenoester 5. After flash chromatography of the
crude product (hexanes and then 8:2 hexanes-AcOEt), selenoester
1
AcOEt), selenoester 10 was obtained as an oil: 0.11 g (62%); H
NMR (300 MHz) δ 1.08 (t, J ) 7.2 Hz, 3H), 2.15 (q, J ) 7.2 Hz,
2H), 2.44 (dt, J ) 16.5, 5.1 Hz, 1H), 2.75 (m, 1H), 3.59 (s, 3H),
3.95 (d, J ) 16.8 Hz, 1H), 4.20 (d, J ) 16.5 Hz, 1H), 5.64 (m,
1H), 5.91 (dd, J ) 7.2, 4.5 Hz, 1H), 7.08 (ddd, J ) 8.1, 6.6, 1.2
Hz, 1H), 7.31 (t, J ) 7.5 Hz, 1H), 7.37 (d, J ) 8.4 Hz, 1H), 7.43
(m, 3H), 7.58 (d, J ) 8.1 Hz, 1H), 7.61 (m, 2H), 8.87 (s, 1H); 13
C
NMR (75.4 MHz) δ 11.8 (CH3), 28.0 (CH2), 30.5 (CH2), 45.4
(CH2), 47.4 (CH), 52.7 (CH3), 112.3 (CH), 118.4 (CH), 120.9 (CH),
122.7 (CH), 125.4 (C), 126.2 (CH), 126.6 (C), 129.2 (CH), 129.4
(CH), 130.5 (C), 136.2 (CH), 136.7 (C), 138.4 (C), 156.6 (C), 183.2
(C), indole C-3 not observed; ESI-HRMS [M + H]+ calcd for
C24H25N2O3Se: 469.1024. Found: 469.1022.
(1RS, 4RS, 5RS) Methyl 4-Ethyl-6-oxo-1,2,3,4,5,6-hexahydro-
1,5-methanoazocino[4,3-b]indole-2-carboxylate (11).16 Following
the protocol described for selenoester 5, selenoester 10 (0.10 g,
0.21 mmol) gave tetracycle 11 after flash chromatography (8:2
hexanes-AcOEt): 46 mg (70%); 1H NMR (400 MHz, assignment
aided by HSQC, mixture of rotamers) δ 1.06 (t, J ) 7.2 Hz, 3H,
CH2CH3), 1.24 and 1.40 (2 m, 2H, CH2CH3), 1.94 (m, 1H, 4-H),
2.19 (dt, J ) 13.2, 3.2 Hz, 1H, 12-H), 2.41 (q, J ) 12.8 Hz, 1H,
3-H), 2.60 (br d, J ) 12 Hz, 1H, 12-H), 2.91 (q, J ) 3.2 Hz, 1H,
5-H), 3.70 and 3.89 (2 s, 3H, OMe), [3.86 (masked dd) and 4.02
(dd, J ) 4.8, 13.6 Hz), 1H, 3-H], 5.77 and 5.92 (2 s, 1H, 1-H),
7.18 (t, J ) 7.6 Hz, 1H, 10-H), 7.39 (t, J ) 8.4 Hz, 1H, 9-H), 7.48
(d, J ) 8.4 Hz, 1H, 8-H), [7.68 (d, J ) 8 Hz) and 7.91 (d, J ) 8
Hz), 1H, 11-H], 9.67 and 9.71 (2 s, 1H, 7-H); 13C NMR (100.6
MHz, assignment aided by HSQC, mixture of rotamers) δ 11.4
(CH2CH3), 24.4 (CH2CH3), 36.2 and 36.5 (C-12), 41.3 (C-4), 42.4
and 42.6 (C-3), 43.6 and 44.0 (C-1), 44.9 (C-5), 52.7 and 52.9
(OMe), 112.5 and 112.9 (C-8), 121.2 (C-10), 121.6 and 122.6 (C-
11), 124.2 (C-11a), 124.4 and 124.9 (C-11b), 127.3 (C-9), 133.0
(C-6a), 138.3 (C-7a), 155.7 and 155.9 (CO2), 191.9 (C-6); ESI-
HRMS [M + H]+ calcd for C18H21N2O3: 313.1546. Found:
313.1552.
1
21a was obtained as a white solid: 0.11 g (45%); H NMR (400
MHz) δ 0.97 (t, J ) 7.6 Hz, 3H), 1.88 (m, 2H), 2.30 (m, 1H), 2.43
(m, 1H), 3.34 (m, 1H), 3.65 (s, 3H), 4.25 (m, 1H), 5.83 (d, J ) 4
Hz, 1H), 6.25 (s, 1H), 7.10 (t, J ) 7.2 Hz, 1H), 7.33 (t, J ) 8 Hz,
1H), 7.40 (d, J ) 8.8 Hz, 1H), 7.45 (m, 3H), 7.63 (m, 2H), 7.89
(d, J ) 8 Hz, 1H), 8.88 (s, 1H); 13C NMR (100.6 MHz) δ 12.1
(CH3), 24.7 (CH2), 26.8 (CH2), 38.9 (CH2), 49.7 (CH), 52.6 (CH3),
112.3 (CH), 119.0 (CH), 119.3 (C), 121.0 (CH), 122.7 (CH), 125.8
(C), 125.9 (CH), 127.4 (C), 129.3 (CH), 129.5 (CH), 133.5 (C),
136.0 (CH), 136.4 (C), 138.0 (C), 156.1 (C), 184.2 (C). Anal. calcd
for C24H24N2O3Se: C, 61.67; H, 5.18; N, 5.99. Found: C, 61.39;
H, 5.24; N, 6.12.
Phenyl 3-[1-(Benzyloxycarbonyl)-3-ethyl-1,2,5,6-tetrahydro-
2-pyridyl]indole-2-carboselenoate (21b). Operating as above,
tetrahydropyridine 20b (0.28 g, 0.62 mmol) was allowed to react
with n-BuLi (1.6 M in hexane, 0.58 mL, 0.93 mmol), diisopropy-
lamine (0.13 mL, 0.93 mmol), and CO2 (gas) to give a crude
carboxylic acid (0.26 g). After the usual deprotection with MeONa
(2.30 mmol), the resulting crude material was treated with Et3N
(0.14 mL, 1.0 mmol), tributylphosphine (0.62 mL, 2.50 mmol), and
PhSeCl (0.48 g, 2.50 mmol) as described for the preparation of
selenoester 5. After flash chromatography (hexanes and then 8:2
hexanes-AcOEt), selenoester 21b was obtained as an oil: 0.10 g
Isodasycarpidone (18).17,18 Amino acid hydrochloride 16 (0.13
g, 0.41 mmol) was treated with Et3N (0.14 mL, 1.02 mmol),
tributylphosphine (0.50 mL, 2.05 mmol), and PhSeCl (0.39 g, 2.05
mmol) following the protocol described for the preparation of 5.
The reaction mixture was partitioned between CH2Cl2 (10 mL) and
H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
extracts were concentrated, and the resulting residue was dissolved
in Et2O (10 mL) and then treated with a saturated solution of HCl
in Et2O (0.5 mL). The solvent was removed and the resulting oil
was successively triturated with hexanes (4 × 10 mL) and Et2O (4
× 10 mL) to give crude selenoester 17 as the hydrochloride salt
(0.12 g, impurified with 15% tributylphosphine oxide). As this
compound slowly underwent hydrolisis on standing, it was im-
mediately converted into the free base and then subjected to the
cyclization protocol described for selenoester 5. After flash chro-
matography (98:2 AcOEt-diethylamine), isodasycarpidone (18)
was obtained: 44 mg (40% from 16); 1H NMR (400 MHz,
assignment aided by HSQC) δ 1.02 (t, J ) 7.2 Hz, 3H, CH2CH3),
1
(30%); H NMR (300 MHz) δ 0.95 (t, J ) 7.5 Hz, 3H), 1.87 (m,
2H), 2.27 (m, 1H), 2.40 (m, 1H), 3.41 (m, 1H), 4.20 (m, 1H), 5.02
(d, J ) 12.6 Hz, 1H), 5.21 (br d, J ) 12.3 Hz, 1H), 5.79 (br s,
1H), 6.32 (s, 1H), 7.09 (ddd, J ) 8.1, 6.9, 0.9 Hz, 1H), 7.20-7.43
(m, 10H), 7.52 (m, 2H), 7.89 (d, J ) 8.1 Hz, 1H), 8.77 (s, 1H);
13C NMR (75.4 MHz) δ 12.0 (CH3), 24.7 (CH2), 26.7 (CH2), 38.7
(CH2), 50.1 (CH), 66.8 (CH2), 112.2 (CH), 118.9 (CH), 121.0 (CH),
122.7 (CH), 125.7 (C), 125.9 (C), 127.3 (C), 127.6 (CH), 127.8
(CH), 128.2 (CH), 129.1 (C), 129.4 (CH), 133.4 (C), 136.0 (CH),
9038 J. Org. Chem. Vol. 73, No. 22, 2008

1,5-Methanoazocino[4,3-b]indoles by Acyl Radical Cyclization
136.3 (C), 137.1 (C), 138.1 (C), 155.4 (C), 183.8 (C), indole C-3
not observed; ESI-HRMS [M + H]+ calcd for C30H29N2O3Se:
545.1337. Found: 545.1331.
Cyclization of Selenoester 21a. Selenoester 21a (0.12 g, 0.25
mmol) was subjected to the protocol described for selenoester 5.
Afterflashchromatography(hexanesandthen85:15hexanes-AcOEt),
a nearly equimolecular mixture of tetracycles 22a and 23a was
obtained: 55 mg (71%).
The reaction mixture was partitioned between CH2Cl2 (10 mL) and
H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
extracts were treated with a saturated solution of HCl in Et2O (0.5
mL). The solvent was removed, and the resulting oil was triturated
with Et2O (4 × 10 mL) to give crude selenoester 28 as the
hydrochloride salt (0.10 g, impurified with 20% tributylphosphine
oxide). This material was immediately converted into the free base
and then subjected to the cyclization protocol described for
selenoester 5. Flash chromatography (hexanes and then 80:19:1
hexanes-AcOEt-diethylamine) gave the following compounds.
(()-20-Epidasycarpidone (29):17,24 26 mg (28% from 27); 1H
NMR (400 MHz, assignment aided by HSQC) δ 1.08 (t, J ) 7.6
Hz, 3H, CH2CH3), 1.67 (br d, J ) 13.6 Hz, 1H, 4-H), 1.71 (m, 1H,
CH2CH3), 2.01 (m, 2H, CH2CH3, 3-H), 2.25 (m, 2H, 3-H, 12-H),
2.26 (s, 3H, NMe), 2.47 (dd, J ) 10.8, 5.2 Hz, 1H, 3-H), 2.59 (s,
1H, 5-H), 4.15 (s, 1H, 1-H), 7.20 (ddd, J ) 8.0, 6.8, 1.2 Hz, 1H,
10-H), 7.37 (td, J ) 7.2, 7.2, 1.2 Hz, 1H, 9-H), 7.45 (d, J ) 8 Hz,
1H, 8-H), 7.71 (d, J ) 7.6 Hz, 1H, 11-H), 8.87 (br s, 1H, 7-H);
13C NMR (100.6 MHz, assignment aided by HSQC and HMBC) δ
11.7 (CH2CH3), 23.3 (CH2CH3), 23.9 (C-4), 44.6 (NMe), 45.0 (C-
5), 46.1 (C-12), 46.2 (C-3), 54.8 (C-1), 112.4 (C-8), 121.0 (C-10),
122.1 (C-11), 124.2 (C-11a), 126.8 (C-9), 126.9 (C-11b), 133.3
(C-6a), 137.6 (C-7a), 194.9 (C-6); ESI-HRMS [M + H]+ calcd
for C17H21N2O: 269.1648. Found: 269.1658.
Cyclization of Selenoester 21b. Selenoester 21b (0.13 g, 0.25
mmol) was subjected to the protocol described for selenoester 5.
After flash chromatography (hexanes and then 7:3 hexanes-AcOEt),
a 1:1 mixture of tetracycles 22b and 23b was obtained: 83 mg
(86%). Additional flash chromatography (9:1 hexanes-AcOEt to
8:2 hexanes-AcOEt) gave pure samples of both compounds.
(1RS, 5RS, 12SR)-Benzyl 12-ethyl-6-oxo-1,2,3,4,5,6-hexahy-
dro-1,5-methanoazocino[4,3-b]indole-2-carboxylate (22b): 1H
NMR (400 MHz, assignment aided by HSQC, mixture of rotamers)
δ 1.01 and 1.06 (2 t, J ) 7.2 Hz, 3H, CH3CH2), 1.58 and 1.82 (2
m, 2H, CH3CH2), 1.65 and 2.20 (2 m, 2H, 4-H), 2.32 and 2.41(2
m, 1H, 12-H), 2.65-2.80 (m, 2H, 3-H, 5-H), [3.85 (dd, J ) 14.7,
6.9 Hz) and 3.97 (dd, J ) 13.2, 6.3 Hz), 1H, 3-H], [5.08 (d, J )
12.3 Hz), 5.17 (d, J ) 12.6 Hz), 5.24 (d, J ) 12 Hz) and 5.34 (d,
J ) 12.3 Hz), 2H, PhCH2], 5.67 and 5.81 (2 br s, 1H, 1-H), [7.01
(t, J ) 7.2 Hz) and 7.20 (t, J ) 7.6 Hz), 1H, 10-H], 7.30-7.50 (m,
7.5 H, 8-, 9-, 11-H, Ph), 7.92 (d, J ) 8 Hz, 0.5 H, 11-H), 9.08 (s,
1H, 7-H); 13C NMR (signals from the HSQC experiment, mixture
of rotamers, only CH, CH2, and CH3 are shown) δ 11.5 (CH3CH2),
22.6 (CH3CH2), 23.0 (C-4), 36.3 (C-3), 44.0 (C-12), 45.1 (C-5),
46.3 and 46.4 (C-1), 67.4 and 67.5 (PhCH2), 112.8 (C-8), 121.4
and 121.5 (C-10), 122.1 and 122.8 (C-11), 128.0-128.5 (C-9 and
Ph); ESI-HRMS [M + H]+ calcd for C24H25N2O3: 389.1859. Found:
389.1864.
Benzyl 4a-ethyl-3,4,4a,5,6,10c-hexahydro-5-oxo-2H-pyrido[2′,3′:
3,4]cyclopenta[1,2-b]indole-1-carboxylate (23b, cis relative con-
figuration tentatively assigned): 1H NMR (400 MHz, mixture of
rotamers) δ [0.85 (t, J ) 7.2 Hz) and 0.87 (t, J ) 7.6 Hz), 3H],
1.60-2.05 (m, 6H), 2.85 and 2.97 (2 m, 1H), 3.78 and 3.93 (m,
1H), [5.23 (d, J ) 12.4 Hz), 5.30 (d, J ) 12 Hz), 5.37 (d, J ) 12
Hz), and 5.42 (d, J ) 12.4 Hz), 2H], 5.72 and 5.78 (2 br s, 1H),
[7.08 (t, J ) 8 Hz) and 7.13 (t, J ) 7.6 Hz), 1H], 7.30-7.50 (m,
7H), 7.55 (d, J ) 7.6 Hz, 1H), 9.18 and 9.22 (2 s, 1H); 13C NMR
(signals from the HSQC experiment, mixture of rotamers, only CH,
CH2, and CH3 are shown) δ 8.43 (CH3), 18.3 (CH2), 29.5 (CH2),
29.7 (CH2), 39.8 and 40.0 (CH2), 52.7 (CH), 67.5 (CH2), 112.8
and 113.5 (CH), 121.6 (CH), 122.0 (CH), 122.9 (CH), 128.0-128.5
(3 CH); ESI-HRMS [M + H]+ calcd for C24H25N2O3: 389.1859.
Found: 389.1867.
(()-Dasycarpidone (30):16,17 12 mg (13% from 27); 1H NMR
(400 MHz, assignment aided by HSQC) δ 0.88 (t, J ) 7.2 Hz, 3H,
CH2CH3), 1.29 (m, 2H, CH2CH3), 1.92 (br d, J ) 10.4 Hz, 1H,
4-H), 2.15 (m, 2H, 3-H, 4-H), 2.36 (s, 3H, NMe), 2.49 (tm, J )
7.2, 1H, 12-H), 2.65 (m, 1H, 3-H), 2.70 (m, 1H, 5-H), 4.35 (d, J )
2.4 Hz, 1H, 1-H), 7.20 (t, J ) 7.6 Hz, 1H, 10-H), 7.39 (ddd, J )
8.0, 7.2, 1.2 Hz, 1H, 9-H), 7.49 (d, J ) 8.4 Hz, 1H, 8-H), 7.70 (d,
J ) 8 Hz, 1H, 11-H), 9.39 (br s, 1H, 7-H); 13C NMR (100.6 MHz,
assignment aided by HSQC) δ 11.7 (CH2CH3), 24.9 (CH2CH3),
29.7 (C-4), 43.8 (NMe), 46.0 (C-3), 46.1 (C-5), 49.1 (C-12), 56.4
(C-1), 112.7 (C-8), 119.0 (C-11b), 121.3 (C-10), 121.7 (C-11), 126.9
(C-9), 127.5 (C-11a), 132.9 (C-6a), 138.0 (C-7a), 192.9 (C-6); ESI-
HRMS [M + H]+ calcd for C17H21N2O: 269.1648. Found:
269.1661.
Acknowledgment. We thank the Ministerio de Educacio´n y
Ciencia, Spain, for financial support (project CTQ2006-00500/
BQU) and a predoctoral grant (FPU program) to D.G.D.
Supporting Information Available: General experimental
protocols and detailed experimental procedures for synthetic
intermediates 2-4, 8, 9, 13-16, 19a,b, 20a,b, and 24-27.
Characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Cyclization of Selenoester 28. Amino acid hydrochloride 27
(0.11 g, 0.34 mmol) was treated with Et3N (0.11 mL, 0.77 mmol),
tributylphosphine (0.48 mL, 1.93 mmol), and PhSeCl (0.37 g, 1.93
mmol) following the protocol described for the preparation of 5.
JO801998H
J. Org. Chem. Vol. 73, No. 22, 2008 9039