Cyclization of functionalized ketene-N,S-acetals to substituted pyrroles: Applications in the synthesis of marine pyrrole alkaloids

Article abstract of DOI:10.1016/j.tetlet.2004.11.076

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinates with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in the presence of the Vilsmeier reagent to afford alkyl 3-aryl-4-formyl-5- (alkylsulfanyl)-1H-pyrrole-2-carbo

Full text of DOI:10.1016/j.tetlet.2004.11.076

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 475–478
Cyclization of functionalized ketene-N,S-acetals to substituted
pyrroles: applications in the synthesis of marine pyrrole alkaloids
Paulson Mathew and C. V. Asokan*
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam 686 650, Kerala, India
Received 22 September 2004; revised 8 November 2004; accepted 15 November 2004
This paper is dedicated to Professor H. Ila on the occation of her 60th birthday.
Abstract—a-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinates with b-oxodithiocarboxylates followed by alkyl-
ation, underwent cyclization in the presence of the Vilsmeier reagent to afford alkyl 3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-
2-carboxylates in excellent yields. When the reaction was extended to b-oxodithiocarboxylates derived from deoxyanisoin,
3,4-diarylpyrrole-2-carboxylates, the key intermediates in the synthesis of lukianol A and lamellarin Q were formed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Recently, several pyrrole-containing bioactive natural
products like, lukianol A,1 lamellarins,2 ningalins,3
policitones,4 halitulin5 etc., have been isolated and some
of them are in clinical trials as antitumor agents. These
marine alkaloids are a new class of DNA targeting com-
pounds with considerable cytotoxicity and many of
them function as Multi Drug Resistant (MDR) reversal
agents.2,6 They possess in common a 3,4-diarylpyrrole-
2-carboxylate skeleton or can be derived from this
structural unit. The key step in the synthesis of these
alkaloids is the construction of the 3,4-diarylpyrrole-2-
carboxylate unit which is often accomplished in a
multistep sequence involving metal-catalyzed coupling
reactions.7 Herein we report a convenient and efficient
synthesis of highly functionalized pyrroles from readily
available starting materials employing a simple iminium
ion mediated cyclization. The utility of this protocol in
the synthesis of pyrrole-containing marine natural prod-
ucts has been demonstrated by formal total syntheses of
lukianol A and lamellarin Q.
leading to a variety of heterocyclic compounds.9 While
there are several reports on the cyclization of intermedi-
ate iminium salts to six-membered heterocycles such a
pyridines10 and quinolines,11 formation of substituted
pyrroles under Vilsmeier–Haack conditions is less com-
mon.12 Ketene-N,S-acetals are highly versatile enamines
widely used in the synthesis of heterocycles.13 Junjappa
and co-workers have recently reported a synthesis of
substituted quinolines by the cyclization of ketene-
N,S-acetals under Vilsmeier–Haack conditions.14 Kirsch
and co-workers have described cyclodehydration of
functionalized ketene-N,S-acetals leading to thiophenes,
pyrroles and thienopyrroles.15 We found that the reac-
tion of suitably substituted ketene-N,S-acetals leads to
substituted pyrrole-2-carboxylates in the presence of
the Vilsmeier reagent. The key step is an iminium salt
mediated cyclization of a-oxoketene-N,S-acetals 4 pre-
pared from b-oxodithioesters 1 and alkyl glycinate
hydrochlorides 2 followed by alkylation. b-Oxodithio-
esters 1, easily prepared16 by the reaction of enolizable
carbonyl compounds with dimethyl trithiocarbonate,
are valuable synthetic intermediates17 and can be trans-
formed to a-oxoketene dithioacetals, N,S-acetals and
O,S-acetals.13
The Vilsmeier–Haack reaction has been extensively used
for the formylation of various electron-rich aromatic,
aliphatic and heteroaromatic substrates.8 The broad
synthetic utility of the halomethyleniminium salts results
from initial iminoalkylations followed by cyclizations
The condensation of b-oxodithioester 1a with methyl
glycinate hydrochloride in the presence triethylamine
in methanol proceeded smoothly to afford the b-
oxothioamide 3a in 96% yield. Alkylation of the thioa-
mide 3a by ethyl iodide using potassium carbonate, as
the base, in acetone afforded the N,S-acetals 4a in 91%
Keywords: Pyrroles; Marine alkaloids; Iminium ions; Vilsmeier–Haack
reagent; Lamellarins.
*
Corresponding author. Tel.: +91 481 271036; fax: +91 481
2731009; e-mail: asokancv@yahoo.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.076

476
P. Mathew, C. V. Asokan / Tetrahedron Letters 46 (2005) 475–478
O
S
O
S
OR2
OR2
SMe
+
H2N
HCl
a
b
N
H
O
R1
O
R1
1
2
1
3a: R = H, R = CH (96%)
2
3
1
2
3b: R = Cl,
R = C H (97%)
2 5
1
2
3c: R = CH , R = C H (96%)
3
2
5
R1
O
O
O
H
OR2
CHO
R1
c
R1
N
R2O
OR2
SR3
R3S
N
H
SR3
N
H
O
O
1
2
3
1
2
3
1
2
3
5a: R = H, R = CH
R
= C H (82%)
6a: R = H, R = CH
R
= C H
= C H
2
3,
2
5
3,
5
4a: R = H, R = CH
R
= C H (91%)
3,
2 5
1
2
3
1
2
3
1
2
3
6b: R = Cl,
R
R
= CH
5b: R = Cl,
R
= C H
R
= CH (90%)
2
5,
3
2
5,
3
4b: R = Cl,
R = C H R = CH (95%)
2 5, 3
1
2
3
1
2
3
1
2
3
6c: R = CH , R = C H
R
= CH
3
5c: R = CH , R = C H
R
= CH (87%)
3
3
2
5,
3
2
5,
4c: R = CH , R = C H
R = CH (92%)
3
3
2
5,
Scheme 1. Reagents and conditions: (a) Et3N, R2OH, rt, 5 h; (b) K2CO3, acetone, reflux, 0.5 h, cooled to 0 ꢁC, R3I, 3 h; (c) POCl3, DMF, rt, 6 h,
80 ꢁC, 2 h.
R1
tuted pyrroles 6. However when the N,S-acetals 4 were
treated with the Vilsmeier–Haack reagent prepared from
POCl3 and DMF,18 the product mixture after hydrolysis
with saturated aqueous potassium carbonate solution
gave the substituted pyrroles 5 exclusively in 82–90%
Me
yields (Scheme 1).19 The reaction was carried out at
room temperature for 4 h, and then at 80 ꢁC for 2 h.
Interestingly the carbonyl group of the aroyl moiety
was involved in the cyclization despite an iminoalkyl-
ation at the b-position of the ketene-N,S-acetal moiety.
The formation of 5 could have resulted from the
cyclization of an intermediate 7,that could have been
easily derived from 4 on treatment with the chloro-
methyleniminium salt, followed by hydrolysis. The elec-
tron-withdrawing nature of the iminium salt moiety in 7
should facilitate the cyclization. The conversion of the
enaminoketone moiety to the chlorosubstituted vinami-
dium intermediate 7 circumvents possible stereochemi-
cal constraints on the cyclization process.13c Base
N
Cl
OR2
Me
R3S
N
O
7
yield. The other ketene-N,S-acetals 4b and 4c were also
prepared in a similar fashion employing appropriate
dithioesters 1b–c, alkyl glycinates and alkylating agents
via 3b–c (Scheme 1).
We envisaged that treatment of the ketene-N,S-acetal 4
with the Vilsmeier–Haack reagent would lead to imino-
alkylation followed by cyclization to afford the substi-
R1
R1
O
O
HCl
H2N
O
a
+
OR2
OR2
R1
S
SCH3
R1
S
N
H
O
1
8a: R = H
1
2
9a: R = H, R = C H (98%)
9b: R = OCH , R = CH (95%)
2
5
1
8b: R = OCH
R1
1
2
3
3
3
R1
R1
R1
O
H
b
c
R2O
N
SCH3
SCH3
R2O
N
H
O
O
1
2
1
2
11a: R = H, R = C H (78%)
10a: R = H, R = C H (90%)
2 5
2
5
1
2
1
2
11b: R = OCH , R = CH (73%)
3
3
10b: R = OCH , R = CH (87%)
3
3
Scheme 2. Reagents and conditions: (a) Et3N, EtOH, rt, 5 h; (b) K2CO3, acetone, reflux, 0.5 h, cooled to 0 ꢁC, CH3I, 3 h; (c) POCl3, DMF, rt, 6 h,
80 ꢁC, 7 h.

P. Mathew, C. V. Asokan / Tetrahedron Letters 46 (2005) 475–478
477
Acknowledgements
MeO
OMe
MeO
OMe
We thank MK University, Madurai and SIF, Bangalore
for providing spectral and analytical data. P.M. thanks
the UGC for assistance under the Faculty Improvement
Program.
a
H3CO
H3CO
74%
SMe
N
H
N
H
O
O
12
11b
References and notes
MeO
OMe
1. Yoshida, W. Y.; Lee, K. K.; Carroll, A. R.; Sceuer, P. J.
Helv. Chem. Acta 1992, 75, 1721–1726.
2. Bailly, C. Curr. Med. Chem.––Anti-Cancer Agents 2004, 4,
363–378.
3. Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262.
4. Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu,
Y.; Schleyer, M.; Kashman, Y. J. Org. Chem. 1994, 59,
999–1003.
HO
O
OH
H3CO
N
O
O
N
O
5. Kashman, Y.; Koren-Goldshlager, G.; Gravalos, M. D.
G.; Schleyer, M. Tetrahedron Lett. 1999, 40, 997–1000.
6. Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 54–62.
7. (a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int.
Ed. 1997, 36, 155–156; (b) Banwell, M.; Flynn, B.; Hamel,
E.; Hockless, D. Chem. Commun. 1997, 207–208.
8. (a) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 373–
384; (b) Marson, C. M. Tetrahedran 1992, 48, 3659–3726;
(c) Jutz, C. In Advances in Organic Chemistry; Taylor, E.
C., Ed.; John Wiley & Sons: New York, 1976; Vol. 9, pp
225–342.
OMe
lamellarin O dimethyl ether (13)
OH
lukianol A (14)
Scheme 3. Reagents and conditions: (a) Raney Ni, EtOH, reflux, 3 h.
catalyzed alkylation of ketene-N,S-acetals has been
found to proceed with spontaneous cyclodehydration
to pyrroles.15 However similar cyclization was not
observed during the preparation of ketene-N,S-acetal 4.
9. (a) Meth-Cohn, O. Heterocycles 1993, 35, 539–557; (b)
Meth-Cohn, O. Adv. Heterocycl. Chem. 1996, 65, 1–39; (c)
Meth-Cohn, O.; Taylor, D. L. J. Chem. Soc., Chem.
Commun. 1995, 1463–1464; (d) Jackson, A.; Meth-Cohn,
O. J. Chem. Soc., Chem. Commun. 1995, 22, 1319; (e)
Cheng, Y.; Liu, Q.-X.; Meth-Cohn, O. Tetrahedron Lett.
2000, 41, 3475–3478; (f) Majo, V. J.; Perumal, P. T. J. Org.
Chem. 1998, 63, 7136–7142; (g) Majo, V. J.; Perumal, P. T.
Tetrahedron Lett. 1997, 38, 6889–6892; (h) Amaresh, R.
R.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3837–3840;
(i) Akila, S.; Selvi, S.; Balasubramaniyan, K. Tetrahedron
2001, 57, 3465–3469.
10. (a) Thomas, A. D.; Asokan, C. V. Tetrahedran Lett. 2002,
43, 2273–2275; (b) Thomas, A. D.; Asokan, C. V. J. Chem.
Soc., Perkin Trans. 1 2001, 2583–2587; (c) Thomas, A. D.;
Josemin; Asokan, C. V. Tetrahedron 2004, 60, 5069–5076;
(d) Katrizky, A. R.; Denisenko, A.; Arend, M. J. Org.
Chem. 1999, 64, 6076–6079.
Gupton et al. have utilized reactions of vinylogous imi-
nium salts with a-aminocarbonyl compounds for the
synthesis of substituted pyrroles.20 This protocol has
recently been used for the total synthesis such as ninga-
lin B hexamethyl ether and lukianol A.21 We envisaged
that cyclodehydration of ketene-N,S-acetals 10 derived
from readily available substituted deoxybenzoins would
lead to a rapid access of 3,4-diarylpyrrole-2-carboxy-
lates which are the key precursors for the synthesis of
marine pyrrole alkaloids. The efficient cyclization of 4
to 5 under Vilsmeier–Haack conditions prompted us
to employ this reagent for the cyclization of 10 to 11
as well. We found that the cyclization does not proceed
effectively in the presence of bases.
11. (a) Amerash, R. R.; Perumal, P. T. Indian J. Chem. 1997,
36B, 541–544; (b) Meth-Cohn, O.; Narine, B.; Tarnawski,
B. J. Chem. Soc., Perkin Trans. 1 1981, 1520–1530.
12. Balasundaram, B.; Venugopal, M.; Perumal, P. T. Tetra-
hedron Lett. 1993, 34, 4249–4252.
13. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990,
46, 5423–5506; (b) Ila, H.; Junjappa, H.; Mohanata, P. K.
In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: New York, 2001; Vol.
13, Chapter 1, pp 1–24; (c) Barun, O.; Mohanta, P. K.; Ila,
H.; Junjappa, H. Synlett 2000, 653–657; (d) SyamKumar,
U. K.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3, 4193–4296.
14. Mahata, P. K.; Venkatesh, C.; SyamKumar, U. K.; Ila,
H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966–3975.
15. Sommen, G.; Comel, A.; Kirsch, G. Tetrahedron 2003, 59,
1557–1564.
The ketene-N,S-acetals 10 were prepared from the corre-
sponding dithiocarboxylates 8 on treatment with alkyl
glycinate followed by alkylation. The ketene N,S-acetals
10a and 10b underwent smooth cyclization to afford the
corresponding 3,4-diaryl pyrroles 11a and 11b in good
yields under Vilsmeier–Haack conditions (Scheme 2).
Reductive removal of the alkylsulfanyl group from
11busing Raney Ni afforded the Furstner intermediate
¨
12 (lamellarin Q dimethyl ether) in 74% yield which
has previously been transformed into lukianol A and
22
lamellarin O dimethyl ether (Scheme 3).
In summary, we have developed a straightforward and
simple protocol for highly functionalized pyrrole deriva-
tives. We have also extended the scope of the method for
the efficient total synthesis lukianol A and lamellarin Q.
We are currently investigating the total synthesis of several
other pyrrole-containing marine natural products using this
protocol and the results will be published in due course.
16. Singh, G.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H.
Synthesis 1982, 693–694.
17. (a) Roy, A.; Nandi, S. S.; Ila, H.; Junjappa, H. Org. Lett.
2001, 3, 229–232; (b) Tominaga, Y.; Okuda, H.; Kohra, S.;
Mazume, H. J. Heterocycl. Chem. 1991, 5, 1245–1256; (c)

478
P. Mathew, C. V. Asokan / Tetrahedron Letters 46 (2005) 475–478
Curphey, T. J.; Joyner, H. H. Tetrahedron Lett. 1993, 34,
7231–7234.
J = 7.2 Hz), 2.62 (s, 3H), 4.19 (q, 2H, J = 7.2 Hz), 7.33 (d,
J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 2H), 9.42 (brs, 1H), 9.62
(s, 1H); 13C NMR (75.47 MHz, CDCl3) d = 14.38, 15.56,
61.39, 120.73, 123.01, 128.27, 130.45, 132.28, 133.70,
134.45, 138.91, 160.88, 186.33; EI-MS m/z (%) = 325
(M+ + 2, 39) 323 (M+, 100), 276 (38), 244 (20), 216 (42),
179 (20), 161 (5), 113 (3). Anal. Calcd for C15H14ClNO3S:
C, 55.64; H, 4.36; N, 4.33. Found: C, 55.60; H, 4.45; N,
4.42.
18. General procedure for the synthesis of alkyl 3-aryl-4-formyl-
5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates 5: The Vils-
meier reagent was prepared by mixing ice cold, dry DMF
(25 mL) and POCl3 (2 mL, 20 mmol). The mixture was
then stirred for 30 min at room temperature. The N,S-
acetal 4 (3.25 g, 10 mmol) was dissolved in dry DMF
(10 mL) and added over 10 min at 0–5 ꢁC. The reaction
mixture was stirred for 6 h at room temperature and
heated to 80 ꢁC for 2 h with stirring. The reaction mixture
was then cooled and poured into cold, saturated aq
K2CO3 (200 mL) and extracted with diethyl ether
(3 · 50 mL). The organic layer was washed with water,
dried over anhydrous Na2SO4 and evaporated to afford
the crude product, which was chromatographed over silica
gel using hexane–ethyl acetate (10:1) as eluent to give alkyl
3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxyl-
ates 5.
20. (a) Gupton, J.; Krumpe, K.; Burnham, B.; Dwornik, K.;
Petrich, S.; Du, K.; Bruce, M.; Vu, P.; Vargas, M.;
Keertikar, K.; Housein, K.; Jones, C.; Sikorski, J. Tetra-
hedron 1998, 54, 5075–5088; (b) Gupton, J.; Petrich, S.;
Smith, L.; Bruce, M.; Vu, P.; Du, K.; Dueno, E.; Jones,
C.; Sikorski, J. Tetrahedron 1996, 52, 6879–6892.
21. (a) Gupton, J.; Clough, S.; Miller, R.; Lukens, J.; Henry,
C.; Kanters, R. P.; Sikorski, J. A. Teterahedron 2003, 59,
207–215; (b) Gupton, J.; Krumpe, K.; Burnham, B.;
Webb, T.; Shuford, J.; Sikorski, J. Tetrahedron 1999, 55,
14515–14522.
19. Spectroscopic data for ethyl 3-(4-chlorophenyl)-4-formyl-5-
(methylsulfanyl)-1H-pyrrole-2-carboxylate 5b: mp 118–
119 ꢁC; 1H NMR (300 MHz, CDCl3) d = 1.15 (t, 3H,
22. Furstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem.
¨
1995, 60, 6637–6641.