Total synthesis of nothapodytine B and (±)-mappicine

Article abstract of DOI:10.1016/j.tetlet.2004.03.089

A novel, efficient total synthesis of the naturally occurring antiviral nothapodytine B (2, mappicine ketone) is reported. The approach is based on the successful implementation of the Johnson orthoester rearrangement of allylic alcohol 7 for assembly of a pyridone D ring precursor with the necessary functionalities. Nothapodytine B is converted into mappicine by NaBH₄ reduction.

Full text of DOI:10.1016/j.tetlet.2004.03.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3941–3943
Total synthesis of nothapodytine B and ( )-mappicine
Subhash P. Chavan* and Rasapalli Sivappa
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, Maharashtra, India
Received 21 October 2003; revised 7 March 2004; accepted 16March 2004
Abstract—A novel, efficient total synthesis of the naturally occurring antiviral nothapodytine B (2, mappicine ketone) is reported.
The approach is based on the successful implementation of the Johnson orthoester rearrangement of allylic alcohol 7 for assembly of
a pyridone D ring precursor with the necessary functionalities. Nothapodytine B is converted into mappicine 3 by NaBH4
reduction.
Ó 2004 Elsevier Ltd. All rights reserved.
Nothapodytine A (1), and B (2), have recently been
isolated from Nothapodytis foetida.1 Structurally noth-
apodytine B (2) is an E-ring decarboxylated analogue of
camptothecin (4),2 a topoisomerase inhibitor whose
derivatives are antitumour lead compounds, and an
oxidized derivative of mappicine (3).3
to nothapodytine B6 as well as related analogues.4
Attracted by its impressive biological activity coupled
with our interest in the parent molecule of this family
that is, camptothecin,7 we set out to develop a synthesis
and herein we delineate a novel and efficient approach to
2 and 3. We envisaged that a Johnson orthoester rear-
rangement8 of 7 would place the requisite functional
groups and appendages onto the tricyclic synthon for
further elaboration to the pyridone ring, a new pyridone
approach, as shown in our retrosynthetic analysis in
Scheme 1.
R
O
O
O
N
N
N
N
N
N
O
O
OH
The allylic alcohol 7 was synthesized from readily
available starting materials as shown in Scheme 2.
1
OH O
R = OMe,Nothapodytine A1
R = H, Nothapodytine B 2
Mappicine3
Camptothecin 4
Accordingly, allylation of O’Donnell’s Schiff’s base 8
with chlorocompound 9, prepared from propargyl
alcohol according to modification of the reported pro-
cedure,9 under phase transfer conditions in the presence
of TBABr afforded the allylglycine 10 after the usual
workup followed by hydrolysis of the alkylated Schiff’s
Both 1 and 2 exhibit significant cytotoxicity against the
human KB cell line and antiviral activity against the
herpes viruses HSV-1, HSV-2 and human cytomegalo-
virus including those resistant to acyclovir.4 The
impressive biological activity of these alkaloids and low
abundance coupled with the possibility of obtaining
better antiviral leads by preparing substituted analogues
has attracted considerable attention towards their syn-
thesis. As a result, recent efforts have been directed to
improve the degradation chemistry of camptothecin5
and towards the development of novel synthetic routes
O
3
N
NR
COOR
N
N
2
5
6
NHCbz
EtOOC
NR
N
OH
OR
Keywords: Total synthesis; Nothapodytine B; Mappicine; Johnson
orthoester rearrangement; Pyridone.
7
* Corresponding author. Tel.: +91-20-589-3300-2289; fax: +91-20-589-
3614; e-mail: spchavan@dalton.ncl.res.in
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.089

3942
S. P. Chavan, R. Sivappa / Tetrahedron Letters 45 (2004) 3941–3943
Ph
Ph
EtOOC
H3COOC
NH2
H3COOC
NHCbz
H3COOC
N
NCbz
ii
i
v
iv
O
8
+
OR
OR
OR
OR
11
12
R=Ac
Cl
iii
13 R=PMB
9
R=Ac
R=Ac
10
R=PMB
viii
OH
ix
vi
vii
NCbz
NCbz
NCbz
NCbz
O
N
N
N
COOEt
N
OR
OR
NH2
15
R=PMB
N
14
16
17
R=PMB
7
O
O
O
O
N
xi
x
N
x
N
N
N
N
N
O
OH
2
18
19
3
Scheme 2. Reagents and conditions: (i) (a) TBABr, KI, K2CO3, CH3CN, reflux; (b) 10% HCl, 0.5 h, 86%; (ii) CbzCl, K2CO3, DCM, 96%; (iii) (a)
K2CO3, CH3OH, 95%; (b) p-MeOC6H4CH2O–C(@NH)CCl3, BF3ÆOEt2 (cat.), rt, 3 h, 81%; (iv) NaH, ethyl acrylate, reflux, 2.5 h, 66%; (v) NaCl,
DMSO; (vi) p-TSA, toluene, reflux 3 h, 69% (over two steps); (vii) DDQ, DCM, 90%; (viii) triethyl orthopropionate, CH3CH2COOH (cat.), 130 °C,
2 h, 92%; (ix) (a) TMSI, pyridine, rt, 1 h, 81%; (b) EtOH, NaOAc, reflux, 85%; (x) DDQ, dioxane, reflux, 80%; (xi) O3, DMS, CH2Cl2, 76%, (x)
NaBH4, MeOH, 69%.
base. Amine 10 thus obtained was protected as its benz-
yloxy carbamate 11 employing potassium carbonate as
the base in anhydrous dichloromethane. Next, the acet-
ate protecting group was replaced with a PMB group.
Hydrolysis of the acetate in the presence of K2CO3 in
methanol and treatment of the resulting allylic alcohol
with PMB trichloroacetimidate furnished carbamate 12.
accomplished and suggests straightforward extensions
to the synthesis of camptothecin and related analogues.
The total synthesis of camptothecin and homocampto-
thecin is underway employing this strategy.
Acknowledgements
The Michael induced ring closure,10 originally employed
for the pyrrolidinone construction with ethyl acrylate
afforded b-ketoester 13, which was decarboxylated
under Krapcho’s conditions to give pyrrolidinone 14.
Friedlander condensation of pyrrolidone 14 with Schiff’s
base 15 furnished quinoline 16. The deprotection of the
PMB ether with DDQ afforded the allylic alcohol 7.
R.S. thanks CSIR, New Delhi for financial support.
Funding from DST (SP/S1/G-28/2001) and CSIR, New
Delhi to S.P.C. under the YSA scheme is gratefully
acknowledged.
References and notes
To our delight, allylic alcohol 7 underwent facile rear-
rangement with triethyl orthopropionate in the presence
of propionic acid (cat.) to furnish the a,b-unsaturated
ester 17 as a mixture of diastereoisomers. The carbamate
functionality of 17 was removed with TMSI/pyridine to
yield a secondary amine, which readily underwent lac-
tamization in refluxing ethanol in the presence of KOAc
to give the tetrahydropyridone 18. Oxidation of the
tetrahydropyridone 18 with DDQ afforded pyridone 19.
Controlled ozonolysis of the olefin 19 completed the
synthesis of nothapodytine B 2.
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Reduction of the ketone group of 2 with NaBH4 affor-
ded (ꢀ)-mappicine 3. The spectral data of compounds 2
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data.11;12
In conclusion, a novel and efficient total synthesis of
nothapodytine B and (ꢀ)-mappicine based on the
implementation of a new pyridone approach was

S. P. Chavan, R. Sivappa / Tetrahedron Letters 45 (2004) 3941–3943
3943
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12. Selected spectroscopic data for compound 17 (mixture of
diastereomers): 1H NMR (200 MHz, CDCl3): d 8.09 (m,
2H), 7.95–7.75 (m, 2H), 7.47 (t, J ¼ 8:3 Hz, 1H), 7.34 (m,
5H), 5.29–5.25 (m, 4H), 4.95–4.27 (m, 2H), 3.89 (m, 2H),
2.5–2.2.5 (m, 3H), 2.24–1.75 (m, 4H), 1.25–0.71 (m, 9H).
13C NMR (50 MHz, CDCl3) d: 175.07 (C), 173.08 (C),
161.91 (C), 154.63 (C), 149.78 (C), 148.16 (CH), 147.8 (C),
136.51 (C), 136.17 (C), 128.97 (2CH), 128.72 (CH), 128.28
(2CH), 127.87 (CH), 127.47 (CH), 127.32 (CH), 110.62
(CH2), 67.86 (CH2), 60.26 (CH), 59.97 (CH), 59.61 (CH2),
50.31 (CH2), 44.39 (CH), 42.74 (CH), 32.78 (CH2), 27.08
(CH2), 13.99 (CH3), 11.98 (CH3), 8.70 (CH3). Mass: m=z
(%): 486(M þ, 5), 424 (5), 385 (5), 351 (10), 306(18), 277
(8), 249 (23), 224 (16), 197 (8), 169 (95), 91 (100), 67 (10).
1
Compound 18: H NMR (200 MHz, CDCl3): d: 8.24–8.14
(m, 2H), 7.87 (d, J ¼ 8:3 Hz, 1H), 7.53 (t, J ¼ 5:8 Hz, 1H),
7.63 (t, J ¼ 8:3 Hz, 1H), 5.5–4.5 (m, 5H), 2.90–2.5 (m,
2H), 2.47 (m, 1H), 2.25–1.83 (m, 3H), 1.4–1.1 (m, 6H). 13
C
NMR (50 MHz, CDCl3): d: 178.41 (C), 168.63 (C), 148.52
(C), 132.91 (C), 129.09 (2CH), 126.78 (C), 127.69 (CH),
127.43 (C), 125.96(2CH), 101.78 (CH ), 58.01 (CH), 49.1
2
7. Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett.
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(CH2), 47.28 (CH), 41.2 (CH), 32.93 (CH2), 27.08 (CH),
13.98 (CH3) 12.17 (CH3). Mass: m=z (%): 306(M þ, 5), 289
(15), 277 (4), 249 (50), 224 (74), 196 (25), 182 (65), 169
(100), 140 (60), 128 (30), 115 (35), 81 (40), 67 (60).
Compound 19: 1H NMR (200 MHz, CDCl3): d: 8.31 (s,
1H), 8.17 (d, J ¼ 8:3 Hz, 1H), 7.89 (d, J ¼ 8:3 Hz, 1H),
7.81 (t, J ¼ 7:3 Hz, 1H), 7.59 (t, J ¼ 7:3 Hz, 1H), 7.18 (s,
1H), 5.28 (s, 1H), 5.27 (s, 2H), 4.98 (s, 1H), 2.44 (q,
J ¼ 7:9 Hz, 2H), 2.24 (s, 3H), 1.1 (t, J ¼ 7:9 Hz, 3H). 13C
NMR (50 MHz, CDCl3) d: 161.87 (C), 153.42 (C), 152.61
(C), 149.45 (C), 148.82 (C), 141.88 (C), 130.70 (CH),
130.15 (CH), 129.59 (CH), 128.79 (CH), 128.02 (C), 127.32
(CH), 127.02 (C), 126.40 (C), 113.50 (CH2) 102.62 (CH),
50.01 (CH2), 29.62 (CH2), 14.03 (CH3), 12.23 (CH3).
Mass: m=z (%): 302 (Mþ, 50), 287 (100), 273 (14), 243 (25),
218 (24), 128 (25), 77 (35).
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