Tandem aza-Michael-condensation-Aldol cyclization reaction: Approach to the construction of DE synthon of (±)-camptothecin

Article abstract of DOI:10.1055/s-0028-1083539

An efficient synthesis of the DE ring of camptothecin, employing a Reformatsky and a tandem one-pot, three-step transformation involving aza-Michael reaction, condensation with ethyl malonyl chloride followed by intramolecular 'aldol' reaction to furnish

Full text of DOI:10.1055/s-0028-1083539

LETTER
2781
Tandem Aza-Michael-Condensation–Aldol Cyclization Reaction: Approach to
the Construction of DE Synthon of ( )-Camptothecin
A
pproach to th
u
e
Constructi
b
on of
D
E
Sy
h
nthon of
(
)-
a
Camptothe
s
cin h P. Chavan,* Abasaheb N. Dhawane, Uttam R. Kalkote
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
E-mail: sp.chavan@ncl.res.in
Received 12 April 2008
The initial exhilaration about camptothecin rapidly dimin-
Abstract: An efficient synthesis of the DE ring of camptothecin,
employing a Reformatsky and a tandem one-pot, three-step trans-
formation involving aza-Michael reaction, condensation with ethyl
malonyl chloride followed by intramolecular ‘aldol’ reaction to fur-
ished due to a problem associated with its lower solubility
and toxicity. But due to its excellent antitumor activity
and unique mechanism of action, regenerated interest in
nish the dihydropyridone derivative from commercially available camptothecins led to the development of its analogues
topotecan4 and irinotecan,5 which are marketed as anti-
starting materials, has been achieved.
cancer drugs. While one of its analogues, foetidine (4), ex-
hibites anti-HIV activity,6 others are in different stages of
clinical trials.7
Key words: natural products, alkaloids, antitumor, Aldol cycliza-
tions, Reformatsky reaction
Several total syntheses of camptothecin8 and its analogues
have been achieved. However, most of the reported syn-
theses have drawbacks involving lengthy routes and/or
expensive starting materials, hazardous reagents or te-
dious reaction conditions, and/or proceed in low overall
yields.
Camptothecin (1, Figure 1) is a well-known pentacyclic
alkaloid, which was first isolated from Camptotheca
acuminata by Wall and Wani in 1966.1 Camptothecin and
its analogues, collectively named camptothecins, have
been isolated from various plant species2 and show potent
antitumor activity. The primary cellular target of camp-
tothecin is the covalent binary complex formed between
DNA and topoisomerase I during the process of DNA re-
laxation, and the stabilization of this complex by camp-
tothecin is believed to lead to cell death.3
To overcome these problems there still exists need to de-
velop a simple, practical, and efficient process for the syn-
thesis of camptothecin.
As a part of our interest in developing an expedient syn-
thesis of this unique molecule possessing excellent bio-
logical activity and challenging pentacyclic structure, we
have directed our efforts towards developing a practical
and efficient synthesis of camptothecin and its analogues.9
R2
A
R1
R3
O
B
N
C
N
D
Herein we report a practical synthesis of the DE synthon
of camptothecin which involves Reformatsky reaction
and a tandem one-pot aza-Michael reaction and condensa-
tion with ethyl malonyl chloride followed by intramolec-
ular cyclization to furnish dihydropyridone starting from
inexpensive commercially available starting materials
such as acrolein, ethyl bromobutyrate, and benzylamine
(Scheme 1).
E
O
OH
O
camptothecin (1) R1, R2, R3 = H
topotecan (2) R1 = H, R2 = CH2NMe2⋅HCl, R3 = OH
irinotecan (3) R1 = Et, R2 = H, R3 = OCOPipPip⋅HCl⋅3H2O
O
According to the proposed retrosynthetic path
(Scheme 1), compound 10 can be prepared by utilizing the
Reformatsky reaction. Thus acrolein 11 reacted with eth-
yl-2-bromo butyrate (12) in the presence of zinc and a cat-
alytic amount of iodine in refluxing THF to afford b-
hydroxy ester 13 in 67% yield (Scheme 2). The b-hydroxy
ester 13 was oxidized with Jones reagent or IBX to give
the required a,b-unsaturated ketone 10 in 85 and 90%
yield, respectively.
N
OH
N
O
O
HO
O
O
HN
NH
foetidine (4)
With the a,b-unsaturated ketone 10 in hand, it was sub-
jected to Michael addition with benzyl amine in CH2Cl2 as
the solvent. As soon as the starting material was complete-
ly consumed (TLC), K2CO3 was added followed by ethyl
malonyl chloride at 0 °C, and the reaction mixture was
stirred at room temperature for eight hours to afford dihy-
Figure 1
SYNLETT 2008, No. 18, pp 2781–2784
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083539; Art ID: G08508ST
© Georg Thieme Verlag Stuttgart · New York
1
4
.1
1
.2
0
0
8

2782
S. P. Chavan et al.
LETTER
H
N
O
O
O
D
A
B
N
N
C
Br
A
B
N
+
D
E
Br
O
E
HO
O
5
1
6
OH
O
Ph
Ph
Ph
H
N
O
N
O
N
O
N
O
COOEt
COOEt
COOEt
O
O
COOEt
HO
HO
O
6
O
7
8
9
O
O
O
CHO
+
O
O
Br
11
10
12
Scheme 1
O
OH
O
O
O
i
ii
+
CHO
11
O
O
O
Br
12
13
10
Ph
Ph
Ph
O
N
O
N
O
N
O
iii
iv
O
COOEt
COOEt
OEt
COOEt
COOEt
11a
COOEt
9
8
Scheme 2 Reagents and conditions: i) Zn (3 equiv), iodine (cat.), THF, reflux, 8 h, 67%; ii) Jones reagent, acetone, 0 °C to r.t., 85%, IBX,
EtOAc, reflux, 4 h, 90%; iii) BnNH2 (1 equiv), CH2Cl2, 0.5 h, K2CO3, (4 equiv), CH2Cl2, ethyl malonyl chloride (1.1 equiv), 8 h, 70%; iv) DDQ
(1.1 equiv), dioxane, reflux, 24 h, 92%.
dropyridone 9 in 70% yield. It is noteworthy that the syn- duced in 80% yield. The use of two equivalents of
thesis of 9, which involves a tandem three-step DIBAL-H at –60 °C led to the formation of a mixture of
transformation – viz. aza-Micheal addition, condensation products (Scheme 3). Our efforts to get aldehyde 14 as the
with ethyl malonyl chloride, and cyclization, was sole product were unsuccessful. Aldehyde 14 on reduction
achieved in one pot. We isolated compound 11a which with NaBH4 resulted in the formation of lactone 18 in
was characterized by 1H NMR spectroscopy. The analysis 93% yield via the intermediacy of the corresponding alco-
showed that 11a exists as a mixture of rotamers. Com- hol, which underwent facile intramolecular transesterifi-
pound 9 was subjected to aromatization employing DDQ cation (Scheme 4).
as an oxidant in refluxing dioxane to furnish pyridone 8 in
To overcome the problems encountered in the reduction
of the pyridine ester with DIBAL-H, lactone 18 was alter-
92% yield.14
With diester 8 in hand, the next goal was to build a lactone natively synthesized from diester 8. The exhaustive hy-
ring by selective reduction of the heteroaromatic ester de- drolysis of diester 8 using excess lithium hydroxide in
scribed earlier by us.9a Accordingly, ester 8 was subjected ethanol at room temperature furnished diacid 16 in 80%
to reduction using DIBAL-H under the reaction condi- yield. The selective monoesterification of aliphatic acid in
tions previously described. Surprisingly, treatment of 8 the presence of aromatic acid was achieved using nickel
with three equivalents of DIBAL-H at –60 °C in THF fur- chloride as a catalyst in refluxing methanol for 12 hours
nished the required aldehyde 14 along with overreduced and afforded ester 17 in 76% yield10 (Scheme 5).
product (alcohol 15) in a 1:3 ratio. In order to get aldehyde
14 exclusively, we varied the reaction conditions. Accord-
ingly, ester 8 was subjected to treatment with one equiva-
Monoacid 17 was then subjected to treatment with methyl
chloroformate in THF at 0 °C to form mixed anhydride
whose subsequent reduction with NaBH4 led to the forma-
lent of DIBAL-H which surprisingly led to the formation
tion of an alcohol which underwent spontaneous lacton-
of 9,14,15 where one of the double bond of pyridone was re-
ization to furnish lactone 18 in 84% yield11 (Scheme 4).
Synlett 2008, No. 18, 2781–2784 © Thieme Stuttgart · New York

LETTER
Approach to the Construction of DE Synthon of ( )-Camptothecin
2783
Ph
N
O
i
COOEt
COOEt
9
Ph
Ph
Ph
Ph
N
O
N
O
N
O
N
O
ii
+
+
OH
COOEt
COOEt
COOEt
CHO
COOEt
COOEt
COOEt
8
14
9
15
Ph
O
Ph
O
N
N
iii
+
OH
CHO
COOEt
COOEt
14
15
Scheme 3 Reagents and conditions: i) DIBAL-H (1 equiv), THF, –60 °C, 1.5 h, 80%; ii) DIBAL-H (2 equiv), THF, –60 °C, 2 h; iii) DIBAL-
H (3 equiv), THF, –60 °C, 2 h.
Lactone 18 on reaction with CuCl2 and catalytic amounts
Ph
Ph
H
of dimethyl amine under oxygen atmosphere afforded a-
hydroxy lactone 7 in 92% yield (Scheme 4).12 The N-de-
benzylation was effected employing catalytic amounts of
palladium hydroxide in ethanol at 50 °C and furnished the
desired DE-ring synthon 6 in 72% yield. This synthon 6 is
the same common intermediate in Comins synthesis of
camptothecin, and its spectral properties were in agree-
ment with those reported by Comins13,14 and by us.9f
i
17
14
N
O
O
N
O
O
N
O
O
v
iii
iv
( )-1
HO
HO
ii
O
O
O
18
7
6
H
N
O
In conclusion, we have achieved a synthesis of the ( )-DE
synthon of camptothecin (1) in 13% overall yield utilizing
tandem mild and efficient reaction conditions from com-
mercially available and cheap starting materials. This
route and its reaction conditions offer a practical synthet-
ic route for camptothecin and its analogues.
ref. 8s
O
HO
6a
O
Scheme 4 Reagents and conditions: i) a) Et3N (1.0 equiv), methyl-
chloroformate (1.0 equiv), anhyd THF, 0 °C, 1 h; b) NaBH4 (4.0
equiv), –78 °C 3 h, 10% HCl, r.t., 12 h, 84%; ii) NaBH4 (1 equiv),
THF–H2O (10:1), 30 min, 10% HCl, 93%; iii) CuCl2 (4.0 equiv),
Me2NH, O2, DMF, r.t., 24 h, 92%; iv) Pd(OH)2, H2, EtOH, 50 °C, 5
h, 72%; v) ref. 13.
Acknowledgment
AND thanks CSIR, New Delhi, India for the fellowship and SPC
thanks the DST, New Delhi, India for funding.
References and Notes
Ph
Ph
Ph
(1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.;
MacPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88,
3888.
N
O
N
O
N
O
ii
i
(2) (a) Hecht, S. M.; Newman, D. J.; Kingston, D. G. I. J. Nat.
Prod. 2000, 63, 1273. (b) Das, B.; Madhusudan, P.; Reddy,
P. V.; Anita, Y. Indian J. Chem., Sect. B 2001, 40, 453.
(c) Kitajima, M.; Yoshida, S.; Yamagata, K.; Nakamura, M.;
Takayama, H.; Saito, K.; Seki, H.; Aimi, N. Tetrahedron
2002, 58, 9169. (d) Puri, S. C.; Verma, V.; Amna, T.; Quzi,
G. N.; Spiteller, M. J. Nat. Prod. 2005, 68, 1717.
COOEt
COOH
COOH
COOEt
COOH
COOMe
8
16
17
Scheme 5 Reagents and conditions: i) excess LiOH, EtOH, r.t.,
24 h, 80%; ii) NiCl2 (0.1 equiv), MeOH, reflux, 12 h, 76%.
Synlett 2008, No. 18, 2781–2784 © Thieme Stuttgart · New York

2784
S. P. Chavan et al.
LETTER
Lett. 2004, 45, 3113. (c) Chavan, S. P.; Pasupathy, K.;
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45, 3941. (e) Chavan, S. P.; Venkatraman, M. S. Arkivoc
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Tetrahedron Lett. 2007, 48, 6561. (g) Chavan, S. P.; Pathak,
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13C NMR, and MS analysis.
(6) Priel, E.; Showalter, S. D.; Blair, D. G. AIDS Res. Hum.
Retroviruses 1991, 7, 65.
Spectral Data
(7) (a) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67,
232. (b) Butler, M. S. J. Nat. Prod. 2005, 22, 162.
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(a) Hutchison, C. R. Tetrahedron 1981, 37, 1047. (b) Wall,
M. E.; Wani, M. C. In The Alkaloids, Vol. 50; Cordell,
G. A., Ed.; Academic Press: San Diego CA, 1998, Chap. 13,
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A.; Husson, H. P. Eur. J. Org. Chem. 2004, 5, 1128.
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Hecht, S. M. Org. Lett. 2005, 7, 835. (h) Anderson, R. J.;
Raolji, G. B.; Kanazawa, A.; Greene, A. E. Org. Lett. 2005,
7, 2989. (i) Brunin, T.; Hénichart, J.-P.; Rigo, B.
Compound 8: 1H NMR (200 MHz, CDCl3): d = 0.90 (t,
J = 7.4 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.40 (t, J = 7.3 Hz,
3 H), 1.70–1.81 (m, 1 H), 1.92–2.04 (m, 1 H), 3.5 (t, J = 7.4
Hz, 1 H), 4.13 (q, J = 7.1, 2 H), 4.45 (q, J = 7.3 Hz, 2 H),
5.09 (d, J = 14.4 Hz, 1 H), 5.17 (d, J = 14.4 Hz, 1 H), 6.28
(d, J = 7.2 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.29–7.35 (s,
5 H).
Compound 9: 1H NMR (200 MHz, CDCl3): d = 0.92 (t,
J = 7.4 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.35 (t, J = 7.3 Hz,
3 H), 1.51–1.71 (m, 2 H), 1.82–1.96 (m, 1 H), 2.21–2.50 (m,
1 H), 3.22–3.42 (m, 2 H), 3.60–3.73 (m, 1 H), 4.15 (q,
J = 7.2 Hz, 2 H), 4.36 (q, J = 7.3 Hz, 2 H), 4.49 (d, J = 14.7
Hz, 1 H), 4.66 (d, J = 14.7 Hz, 1 H), 7.24–7.30 (m, 5 H).
Compound 14: 1H NMR (200 MHz, CDCl3): d = 0.96 (t,
J = 7.4 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.60–1.77 (m,
1 H), 1.92–2.10 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.96 (t,
J = 7.3 Hz, 1 H), 5.13 (s, 2 H), 6.30 (d, J = 7.2 Hz, 1 H), 7.42
(d, J = 7.2 Hz, 1 H), 7.31–7.38 (m, 5 H), 10.52 (s, 1 H).
Compound 6: 1H NMR (400 MHz; CD3OD): d = 0.93 (t,
J = 7.3 Hz, 3 H), 1.86 (q, J = 7.2 Hz, 2 H), 5.22 (d, J = 16.2
Hz, 1 H), 5.41 (d, J = 16.2 Hz, 1 H), 6.63 (d, J = 6.8 Hz,
1 H), 7.46 (d, J = 6.8 Hz, 1 H).
Tetrahedron 2005, 61, 7916. (j) Tangirala, R. S.; Dixon, R.;
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(15) Typical Procedure for Compound 9
To a stirred solution of keto compound 10 (5 g, 29.4 mmol)
in dry CH2Cl2 benzyl amine (3.21 mL, 29.4 mmol) was
added dropwise at r.t. and allowed to stir for 20 min. After
the completion of the reaction (TLC), K2CO3 (14.2 g, 102.9
mmol) was added followed by dropwise addition of ethyl
malonyl chloride (4.89 mL, 38.22 mmol) at 0 °C. The
mixture was stirred at r.t. until completion (1 h, TLC), and
then was filtered, and the residue was washed with CH2Cl2
(3 × 30 mL). The organic layer was washed with H2O, brine,
dried over anhyd Na2SO4, filtered, and concentrated on a
rotary evaporator under diminished pressure. The resulting
residue was purified by flash column chromatography (silica
gel) using EtOAc–PE (3:7) as an eluent, affording the
dihydropyridone 9 as a colorless liquid (7.6 g, 70% yield).
(9) (a) Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett.
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Synlett 2008, No. 18, 2781–2784 © Thieme Stuttgart · New York

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