6-exo cyclizations of 2-indolylacyl radicals: Access to the uleine alkaloid skeleton

Article abstract of DOI:10.1055/s-2008-1078415

A new straightforward approach to the bridged framework of uleine alkaloids, based on the 6-exo cyclization of sele-noester-derived 3-(tetrahydro-2-pyridyl)-2-indolylacyl radicals under reductive conditions, is described.

Full text of DOI:10.1055/s-2008-1078415

LETTER
1487
6-Exo Cyclizations of 2-Indolylacyl Radicals: Access to the Uleine Alkaloid
Skeleton
Access to the Uleine
A
.
lkaloi
-
dSkeleto
L
n
luïsa Bennasar,* Tomàs Roca, Davinia García-Díaz
Laboratory of Organic Chemistry, Faculty of Pharmacy and Institut de Biomedicina (IBUB), University of Barcelona,
Av. Joan XXIII, sn, 08028 Barcelona, Spain
Fax +34(93)4024539; E-mail: bennasar@ub.edu
Received 1 April 2008
Our strategy for the assembly of the bridged 1,5-metha-
noazocino[4,3-b]indole system hinges on the 6-exo cy-
clization of 2-indolylacyl radicals of general formula A
(Scheme 1) upon double bonds included in tetrahydropy-
ridine rings attached to the 3-position of the indole. The
required tetrahydropyridine substrates would be accessed
by the strategic disconnections depicted in B, which in-
volve an amination–imine allylation–ring-closing metathe-
sis sequence from a suitably protected indole-3-
carbaldehyde. In addition, the acyl radical precursor sele-
noester would be prepared from the corresponding car-
boxylic acid, which could be installed at some stage by
carboxylation of a 2-lithioindole derivative. In this man-
ner the route would be flexible enough to allow eventual
introduction of the two-carbon atom appendage character-
istic of the Strychnos alkaloids with the strychnan skele-
ton (e.g., tubifolidine, strychnopivotine).
Abstract: A new straightforward approach to the bridged frame-
work of uleine alkaloids, based on the 6-exo cyclization of sele-
noester-derived 3-(tetrahydro-2-pyridyl)-2-indolylacyl radicals
under reductive conditions, is described.
Key words: indoles, radical reactions, cyclizations, metathesis, al-
kaloids
In the last years we have reported that 2-indolylacyl radi-
cals generated from the corresponding phenyl
selenoesters1 efficiently participate in synthetically useful
cyclizations, leading to polycyclic compounds embody-
ing the 2-acylindole moiety.2 Thus, five- to eight-mem-
bered monocycles2,3 as well as 5-5 and 5-6 fused
bicycles2,4 have been assembled using a variety of indole-
tethered alkene acceptors under reductive conditions. Our
continuing interest in this area led us to study the use of
these reactive intermediates for the construction of the
1,5-methanoazocino[4,3-b]indole system, which consti-
tutes the bridged arrangement of the indole alkaloids of
the uleine group (uleine, dasycarpidone)5 as well as the
tetracyclic substructure of the Strychnos alkaloid family6
(Figure 1).
X
R2
R1
X
R1
N
N
R2
H
6-exo
H
R1 = CO2Me or Me
R
O
N
N
2 = H or Et
H
H
O
X = H,H or O
Me
A
N
N
H
X
H
R2
R1
RCM
H
N
H
CHO
amination
imine allylation
N
H
X
N
H
H
Y
2-lithioindole
carboxylation
N
N
uleine (X = CH2)
dasycarpidone (X = O)
tubifolidine
PG
O
PG
B
Y = OH
Y = SePh
N
H
Scheme 1 Synthetic strategy
H
O
N
H
Radical reactions have been extensively used for the syn-
thesis of nitrogen heterocycles,7 including bridged sys-
tems either isolated8 or embedded in more complex
structures.9,10 Particularly significant for our work was the
construction of the 6-azabicyclo[3.2.1]octane and the 2-
azabicyclo[2.2.2]octane frameworks by aryl radical cy-
clizations upon pyrrolidine11 and tetrahydropyridine12 ac-
ceptors, respectively. On the other hand, the 6-
azabicyclo[3.2.1]octane13 system as well as its higher ho-
mologue 2-azabicyclo[3.3.1]nonane (morphane)14 have
Ac
strychnopivotine
Figure 1 Uleine and pentacyclic Strychnos alkaloids
SYNLETT 2008, No. 10, pp 1487–1490
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078415; Art ID: G11508ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1488
M.-L. Bennasar et al.
LETTER
been achieved by the alternative cyclization of amino- Thus, reaction of 1 with allylamine and alkylation of the
tethered radicals upon cyclohexene rings.
resulting imine with allylmagnesium bromide (–78 °C to
r.t.) led to an unstable secondary amine (not isolated),16
which was subsequently acylated with methyl chlorofor-
mate (NaH, ClCO2Me, r.t.) to give carbamate 2. At this
point, the carboxy group could be introduced with high ef-
ficiency by treatment with LDA (–78 °C, 30 min) and re-
action of the intermediate 2-lithioindole derivative with
carbon dioxide (–78 °C, 30 min). The next task was to
close the tetrahydropyridine ring by RCM, which was ac-
complished uneventfully by reaction of carboxylic acid 3
To establish the feasibility of our proposed cyclization for
the construction of the core structure of the uleine alka-
loids, we targeted radical precursors that incorporated an
unsubstituted tetrahydropyridine double bond (R2 = H,
H), either unactivated (selenoester 5) or activated by a lac-
tam carbonyl group (selenoester 9), at the indole 3-posi-
tion. As anticipated, both compounds were available from
the N-Boc-protected indole-3-carbaldehyde 115 following
the two similar synthetic sequences depicted in Scheme 2.
with
the
second-generation
Grubbs
catalyst
(Im)(PCy3)2(Cl)2Ru=CHPh (7 mol%, CH2Cl2, r.t., 6 h).
After selective removal of the indole protecting group in
basic conditions (MeONa, MeOH, reflux, overnight),17
the tetrahydropyridine carboxylic acid 4 was obtained in
high yield and then converted into selenoester 518 by
phenylselenation under Batty and Crich conditions19
(Et3N, Bu3P, PhSeCl, r.t., overnight).
CHO
N
Boc
1
1. H2N
1. MeNH2
2. BrMg
2. BrMg
3. ClCO2Me
3. ClCOCH=CH2
On the other hand, the sequential reaction of aldehyde 1
with methylamine, allylmagnesium bromide and acryloyl
chloride led to amide 6, from which we obtained sele-
noester 9 as in the above series, only changing the order
of some synthetic steps. Hence, we first performed the
RCM step and then the carboxylation of the resulting in-
dole lactam 7 through the corresponding 2-lithioindole
derivative, giving access to the carboxylic acid 8 in high
yield. Removal of the N-Boc group at this stage with Me-
ONa–MeOH suffered from unwanted conjugate addition
to the unsaturated lactam leading to products lacking the
double bond. As a consequence, we decided to maintain
this protecting group at the indole nitrogen hoping that it
would not disfavor the key radical cyclization step. Direct
phenylselenation of acid 8 nevertheless proved to be
equally troublesome due to the competitive conjugate ad-
dition of phenylselenolate. After some experimentation it
was found that an additional treatment of the crude reac-
tion mixtures with MCPBA (–40 °C to r.t.) regenerated
the double bond, allowing the isolation of pure selenoester
9,20 although in a moderate yield.
50%
O
68%
Me
N
MeO2C
N
N
N
Boc
2
Boc
6
Grubbs II
CH2Cl2, r.t.
85%
LDA, CO2
74%
O
Me
N
MeO2C
N
OH
N
N
O
Boc
Boc
3
90%
7
1. Grubbs II
96%
LDA, CO2
O
CH2Cl2, r.t.
2. MeONa
Me
With a reliable route to the radical precursors, attention
was focused on the key cyclization step.21 Satisfactorily,
treatment of selenoester 5 with two equivalents of n-
Bu3SnH in the presence of Et3B as the initiator at room
temperature in benzene (concentration 0.07 M) led to azo-
cinoindole 10 (60% yield, Scheme 3) coming from the
predicted 6-exo cyclization of the initially formed 2-in-
dolylacyl radical. Significantly, minor amounts of tetracy-
cle 11, containing the regioisomeric bicyclo[3.2.2]nonane
system derived from the radical attack at the C-5 tetrahy-
dropyridine position instead of C-4, were also obtained
(10% yield). No evidence of radical reduction (i.e., forma-
tion of an aldehyde), either from direct hydrogen abstrac-
tion from the hydride or an eventual [1,5]-hydrogen
transfer, was observed.
N
MeO2C
N
OH
OH
N
O
Boc
N
O
H
8
4
1. Et3N
Et3N
Bu3P, PhSeCl
Bu3P, PhSeCl
2. MCPBA
60%
40%
O
6
5
MeO2C
Me
N
2
N
4
3
SePh
SePh
N
N
O
H
O
Boc
5
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 be-
9
Scheme 2 Preparation of selenoesters 5 and 9
Synlett 2008, No. 10, 1487–1490 © Thieme Stuttgart · New York

LETTER
Access to the Uleine Alkaloid Skeleton
1489
tween these intermediates through an intramolecular rear- bon skeleton of the natural products using suitably
rangement,22 we experimented with different hydride substituted radical precursors.
concentrations. As the same cyclized product ratio (6:1)
was invariably obtained working at a higher (0.14 M) or
lower (0.005M) concentration, we assumed that the afore-
Acknowledgment
We thank the Ministerio de Educación y Ciencia, Spain, for finan-
cial support (project CTQ2006-00500/BQU) and a predoctoral
grant (FPU program) to D.G.D.
mentioned rearrangement was not included in the reaction
pathway.
MeO2C
N
References and Notes
(1) For a review on the chemistry of acyl radicals, see:
Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
Rev. 1999, 99, 1991.
O
(2) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004, 6,
759.
(3) Bennasar, M.-L.; Roca, T.; García-Díaz, D. J. Org. Chem.
2007, 72, 4562.
(4) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2006,
71, 1746.
MeO2C
MeO2C
N
N
n-Bu3SnH
+
5
Et3B
O
(0.07 M)
(5) For reviews, see: (a) Joule, J. A. Indoles, The
Monoterpenoid Indole Alkaloids, In The Chemistry of
Heterocyclic Compounds, Vol. 25; Weissberger, A.; Taylor,
E. C., Eds.; Wiley: New York, 1983. (b)Alvarez, M.;Joule,
J. A. Monoterpenoid Indole Alkaloids, In The Chemistry of
Heterocyclic Compounds, Supplement to Vol. 25; Taylor, E.
C., Ed.; Wiley: Chichester, 1994, Part 4 Chap. 6.
(c) Alvarez, M.; Joule, J. A. In The Alkaloids, Vol. 57;
Cordell, G. A., Ed.; Academic Press: New York, 2001,
Chap. 4.
(6) For reviews, see: (a) Bosch, J.; Bonjoch, J. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1988, 31–88. (b) Sapi, J.; Massiot, G.
Monoterpenoid Indole Alkaloids, In The Chemistry of
Heterocyclic Compounds, Supplement to Vol. 25; Taylor, E.
C., Ed.; Wiley: Chichester, 1994, Part 4 Chap. 7. (c) Bosch,
J.; Bonjoch, J.; Amat, M. In The Alkaloids, Vol. 48; Cordell,
G. A., Ed.; Academic Press: New York, 1996, 75–189.
(7) For a leading review, see: Bowman, W. R.; Fletcher, A. J.;
Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1 2002, 2747.
(8) (a) Della, E. W.; Knill, A. M. J. Org. Chem. 1996, 61, 7529.
(b) Della, E. W.; Smith, P. A. J. Org. Chem. 2000, 65, 6627.
(9) (a) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem.
1996, 61, 7873. (b) Kuehne, M. E.; Bandarage, U. K.;
Hammach, A.; Li, Y.-L.; Wang, T. J. Org. Chem. 1998, 63,
2172. (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.
O
D
C
MeO2C
H
MeO2C
H
N
N
+
H
H
O
N
H
N
H
O
10 (60%)
11 (10%)
Scheme 3 Cyclization of selenoester 5
On the other hand, cyclization21 of the N-Boc-protected 2-
indolylacyl radical derived from selenoester 9 also took
place productively under the above mild reductive proto-
col to give azocinoindole 12 as the only cyclization prod-
uct in 75% yield. Clearly, the formation of a seven-
membered ring was completely suppressed by the pres-
ence of the lactam carbonyl group acting as a 6-exo direct-
ing functionality. Finally, removal of the indole protecting
group smoothly afforded tetracyclic keto lactam 13
(Scheme 4).23
(10) (a) Hoepping, A.; George, C.; Flippen-Anderson, J.;
Kozikowski, A. P. Tetrahedron Lett. 2000, 41, 7427.
(b) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-
Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68,
7565.
(11) (a) Tamura, O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi,
H. Org. Lett. 2001, 3, 2427. (b) Bower, J. F.; Szeto, P.;
Gallagher, T. Chem. Commun. 2005, 5793. (c) Bower, J. F.;
Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143.
(12) Dandapani, S.; Duduta, M.; Panek, J. S.; Porco, J. A. Jr. Org.
Lett. 2007, 9, 3849.
Me
O
Me
O
N
N
H
H
n-Bu3SnH
Et3B
H
MeONa
85%
H
9
(0.07 M)
75%
O
N
H
O
N
Boc
12
13
Scheme 4 Cyclization of selenoester 9
(13) (a) Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org.
Chem. 2002, 67, 2323. (b) Grainger, R. S.; Welsh, E. J.
Angew. Chem. Int. Ed. 2007, 46, 5377.
In conclusion, cyclization of 2-indolylacyl radicals upon
tetrahydropyridine double bonds opens a conceptually
new synthetic route for the rapid construction of the
bridged tetracyclic system of uleine alkaloids. This ap-
proach should be amenable to the completion of the car-
(14) Quirante, J.; Escolano, C.; Massot, M.; Bonjoch, J.
Tetrahedron 1997, 53, 1391.
(15) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z.
J. Org. Chem. 2005, 75, 5840.
Synlett 2008, No. 10, 1487–1490 © Thieme Stuttgart · New York

1490
M.-L. Bennasar et al.
LETTER
(16) All attempts to carry out the amination–imine allylation
sequence from an indole-3-carbaldehyde already
155.9, 156.2 (CO2), 193.3 (C-6). HRMS (ESI): m/z [M + H]+
calcd for C16H17N2O2: 285.1233; found: 285.1232.
incorporating a carboxylic acid or ester at the 2-position
resulted in lactamization.
(17) Removal of the Boc group under the usual acidic conditions
(TFA, r.t.) resulted in decomposition.
Methyl 5-Oxo-2,3,4,5-tetrahydro-1,4-ethanoazepino[4,3-
b]-1H-indole-2-carboxylate (11): yield: 10%. 1H NMR
(400 MHz, CDCl3; assignment aided by HSQC and COSY,
mixture of rotamers): d = 1.90 (m, 2 H, 11-H, 12-H), 2.13
(m, 1 H, 12-H), 2.41 (m, 1 H, 11-H), [3.21 (t, J = 5.2 Hz) and
3.26 (br t), 1 H, 4-H], [3.51 (d, J = 12.8 Hz) and 3.65 (m), 2
H, 3-H], 3.64, 3.65 (2 × s, 3 H, OMe), [5.79 (dd, J = 2.4, 5.6
Hz)and 5.98 (dd, J = 2.0, 5.2 Hz), 1 H, 1-H], 7.22 (t, J = 7.6
Hz, 1 H, 9-H), 7.41 (m, 2 H, 7-H, 8-H), [7.79 (d, J = 8.0 Hz)
and 7.91 (d, J = 7.6 Hz), 1 H, 10-H], 8.96, 8.99 (2 × s, 1 H,
6-H). 13C NMR (100.6 MHz, CDCl3; assignment aided by
HSQC and HMBC, mixture of rotamers): d = 18.7 (C-12),
26.9, 27.0 (C-11), 42.3, 42.5 (C-3), 45.0, 45.5 (C-1), 46.5 (C-
4), 52.6, 52.7 (MeO), 112.2, 112.4 (C-7), 120.7, 121.0 (C-
10), 121.2 (C-9), 124.6, 124.8 (C-10a), 127.0, 127.2 (C-8),
130.7, 131.2 (C-10b), 132.8, 132.9 (C-5a), 137.2, 137.3 (C-
6a), 155.6, 155.9 (CO2), 194.0 (C-5). HRMS (ESI): m/z
[M + H]+ calcd for C16H17N2O2: 285.1233; found: 285.1233.
tert-Butyl 2-Methyl-3,6-dioxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole-7-carboxylate (12): yield:
72%. 1H NMR (400 MHz, CDCl3; assignment aided by
HSQC and COSY): d = 1.62 (s, 9 H, Boc), 2.51 (dt, J = 3.2,
3.2, 13.2 Hz, 1 H, 12-H), 2.67 (dm, J = 13.2 Hz, 1 H, 12-H),
2.69 (d, J = 19.2 Hz, 1 H, 4-H), 2.93 (dd, J = 8.0, 18.4 Hz, 1
H, 4-H), 3.10 (s, 3 H, NMe), 3.17 (dt, J = 3.2, 3.2, 8.0 Hz, 1
H, 5-H), 4.79 (t, J = 3.2 Hz, 1 H, 1-H), 7.34 (t, J = 7.6 Hz, 1
H, 10-H), 7.51 (ddd, J = 1.2, 8, 8.8 Hz, 1 H, 9-H), 7.73 (d,
(18) Selenoester 5: mp 174–175 ºC. 1H NMR (400 MHz, CDCl3):
d = 2.48 (br d, J = 17.2 Hz, 1 H), 2.79 (m, 1 H), 3.59 (s, 3 H),
4.02 (d, J = 17.6 Hz, 1 H), 4.29 (d, J = 18.0 Hz, 1 H), 6.00
(m, 3 H), 7.10 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H),
7.39 (d, J = 8.4 Hz, 1 H), 7.44 (m, 3 H), 7.62 (m, 2 H), 7.68
(d, J = 8.0 Hz, 1 H), 8.74 (br s, 1 H). 13C NMR (75.4 MHz,
CDCl3): d = 30.3 (CH2), 42.4 (CH2), 46.9 (CH), 52.7 (Me),
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
was not observed. Anal. Calcd for C22H20N2O3Se·H2O: C,
57.77; H, 4.84; N, 6.12. Found: C, 57.92; H, 4.52; N, 5.92.
(19) Batty, D.; Crich, D. Synthesis 1990, 273.
(20) Selenoester 9: 1H NMR (400 MHz, CDCl3): d = 1.65 (s, 9 H),
2.66 (dddd, J = 1.2, 5.4, 6.9, 18.3 Hz, 1 H), 2.83 (s, 3 H), 2.89
(dddd, J = 2.7, 3.0, 11.4, 18.6 Hz, 1 H), 5.14 (dd, J = 6.9, 11.4
Hz, 1 H), 6.08 (ddd, J = 0.9, 2.7, 9.6 Hz, 1 H), 6.56 (ddd, J =
3.0, 5.1, 9.9 Hz, 1 H), 7.29 (ddd, J = 0.9, 7.2, 8.1 Hz, 1 H),
7.43 (m, 3 H), 7.46 (ddd, J = 1.2, 7.5, 8.4 Hz, 1 H), 7.61 (m,
2 H), 7.75 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H). 13
C
NMR (100.6 MHz, CDCl3): d = 28.0 (Me), 31.0 (CH2), 31.9
(Me), 53.5 (CH), 86.2 (C), 115.8 (CH), 120.7 (C), 121.6
(CH), 124.0 (CH), 124.9 (CH), 125.9 (C), 126.2 (C), 127.1
(CH), 129.4 (CH), 129.6 (CH), 134.6 (C), 135.3 (CH), 136.3
(C), 138.1 (CH), 148.6 (C), 165.7 (C), 188.4 (C).
J = 8.0 Hz, 1 H, 11-H), 8.08 (d, J = 8.8 Hz, 1 H, 8-H). 13
C
NMR (100.6 MHz, CDCl3; assignment aided by HSQC and
HMBC): d = 27.6 (Me), 33.3 (C-12), 34.6 (NMe), 35.4 (C-
4), 42.9 (C-5), 50.7 (C-1), 85.0 (C), 115.2 (C-8), 120.6 (C-
11), 123.8 (C-10), 125.0 (C-11a), 129.3 (C-9), 130.3 (C-6a),
135.7 (C-11b), 139.1 (C-7a), 149.1 (CO2), 167.8 (C-3),
188.8 (C-6). HRMS (ESI): m/z [M + H]+ calcd for
C20H23N2O4: 355.1652; found: 355.1649. Anal. Calcd for
C20H22N2O4·1/4H2O: C, 66.94; H, 6.32; N, 7.80. Found: C,
66.64; H, 6.27; N, 7.56.
(21) Typical Procedure for the Radical Cyclization: n-Bu3SnH
(0.13 mL, 0.50 mmol) and Et3B (1 M in hexanes, 0.50 mL,
0.50 mmol) were added to a solution of the phenyl
selenoester 5 or 9 (0.25 mmol, previously dried
azeotropically with anhyd benzene) in anhyd benzene (7
mL). The reaction mixture was stirred at r.t. for 2–4 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
(10 mL) and MeCN (10 mL), and the polar layer was washed
with hexanes (3 × 10 mL). The MeCN solution was
concentrated and the crude product was chromatographed
(SiO2, flash, hexanes–EtOAc, 7:3 or 8:2).
(22) For discussions, see: (a) Beckwith, A. L. J.; O’Shea, D. M.;
Westwood, S. W. J. Am. Chem. Soc. 1987, 110, 2565.
(b) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57,
1429. (c) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091.
(d) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Venturini,
A.; Zavitsas, A. A. Chem. Eur. J. 1997, 3, 376.
Methyl 6-Oxo-1,2,3,4,5,6-hexahydro-1,5-
methanoazocino[4,3-b]indole-2-carboxylate (10): yield:
60%. 1H NMR (400 MHz, CDCl3; assignment aided by
HSQC and COSY, mixture of rotamers): d = 2.02 (m, 2 H,
4-H), [2.22 (dt, J = 2.8, 2.8, 12.8 Hz) and 2.55 (br d, J = 10.8
Hz), 2 H, 12-H], [2.78 (br t, J = 12.8 Hz) and 3.80–4.00
(masked), 2 H, 3-H], 2.89 (s, 1 H, 5-H), 3.68, 3.88 (2 × s, 3
H, OMe), 5.78, 5.94 (2 × s, 1 H, 1-H), 7.18 (t, J = 7.2 Hz, 1
H, 10-H), 7.39 (t, J = 8.4 Hz, 1 H, 9-H), 7.48 (d, J = 8.0 Hz,
1 H, 8-H), [7.69 (br d, J = 6.8 Hz) and 7.91 (d, J = 7.6 Hz),
1 H, 11-H], 9.60, 9.64 (2 × s, 1 H, 7-H). 13C NMR (100.6
MHz, CDCl3; assignment aided by HSQC and HMBC,
mixture of rotamers): d = 29.0 (C-4), 35.4 (C-12), 36.5 (C-
3), 41.3 (C-5), 43.6, 44.1 (C-1), 52.7 (OMe), 112.5, 112.8
(C-8), 121.3 (C-10), 121.7, 122.7 (C-11), 124.3 (C-11a),
125.4 (C-11b), 127.5 (C-9), 132.6 (C-6a), 138.4 (C-7a),
(23) Tetracycle 13: 1H NMR (300 MHz, CDCl3): d = 2.56 (dt,
J = 3.3, 3.3, 13.2 Hz, 1 H, 12-H), 2.69 (m, 1 H, 12-H), 2.69
(m, 1 H, 4-H), 3.01 (dd, J = 8.4, 18.9 Hz, 1 H, 4-H), 3.11 (s,
3 H, NMe), 3.20 (dt, J = 3.0, 3.0, 8.4 Hz, 1 H, 5-H), 4.83 (t,
J = 3.0 Hz, 1 H, 1-H), 7.21 (ddd, J = 0.9, 7.2, 8.4 Hz, 1 H,
10-H), 7.39 (ddd, J = 0.9, 6.6, 7.8 Hz, 1 H, 9-H), 7.49 (dt, J
= 0.9, 0.9, 8.1 Hz, 1 H, 8-H), 7.75 (d, J = 8.1 Hz, 1 H, 11-H),
9.86 (br s, 1 H, 7-H). 13C NMR (100.6 MHz, CDCl3): d =
34.3 (C-12), 34.4 (NMe), 35.4 (C-4), 42.0 (C-5), 50.9 (C-1),
113.2 (C-8), 120.7 (C-11), 121.7 (C-10), 124.5 (C-11a),
127.6 (C-9), 129.0 (C-11b), 129.6 (C-6a), 138.1 (C-7a),
168.0 (C-3), 192.1 (C-6). Anal. Calcd for C15H14N2O4·1/
2H2O: C, 68.43; H, 5.74; N, 10.64. Found: C, 68.49; H, 5.68;
N, 10.30.
Synlett 2008, No. 10, 1487–1490 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.