An enantiospecific approach to 8,9-seco-C-aromatic taxanes

Article abstract of DOI:10.1055/s-2002-34902

An enantiospecific approach to functionalised C-aromatic-8,9-seco-taxanes starting from the readily available monoterpene (R)-carvone is described.

Full text of DOI:10.1055/s-2002-34902

LETTER
1907
An Enantiospecific Approach to 8,9-seco-C-Aromatic Taxanes
An
E
nantiospecific
.
A
pproachto
S
8,9-seco
-
C
-A
r
romatic
i
Taxan
k
es rishna,* P. Ravi Kumar, V. Padmavathi1
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
Fax +91(80)3600683; E-mail: ask@orgchem.iisc.ernet.in)
Received 11 September 2002
2C side chain
Me
Abstract: An enantiospecific approach to functionalised C-aromat-
ic-8,9-seco-taxanes starting from the readily available monoterpene
(R)-carvone is described.
Me
RO
A
C
Key words: C-aromatic-8,9-seco-taxanes, Paclitaxel, antitumor ac-
tivity, carvone
H
CH2-(C-ring)
(R)-carvone 2
O
8,9-seco-taxane 3
Scheme 1
Paclitaxel (1, Taxol),2 by virtue of its complex and dense-
ly functionalised structure, coupled with its novel mecha-
nism of action, potent antitumor activity and its clinical
use as a powerful anti-cancer drug has attracted the atten-
tion of many synthetic chemists. Indeed, only very few
molecules in the last two decades have stirred as much
imagination and activity among synthetic chemists as tax-
anes.3 While a few paid attentions to the total synthesis of
1, a large number of research groups confined themselves
to the development of methodologies towards various
segments of 1 as well as analogues of taxanes.4 In this
context, earlier we have developed5 an approach to A-ring
of taxanes and 2,3-seco-nortaxoids starting from the
cheap and abundantly available monoterpene (R)-carvone
2 (Figure 1), wherein the C-5 and C-3 carbons of carvone
were transformed in to C-1 and C-13 carbons of taxanes,
respectively. We have now developed an alternate strate-
gy, wherein the carbons C-1 and C-5 of carvone are equat-
ed to C-1 and C-13 carbons of taxanes, respectively, and
applied in the synthesis of 8,9-seco-C-aromatic taxanes
belonging to natural series, which is the subject of this
communication.
After identifying the C-1 and C-5 carbons of carvone (2)
as C-1 and C-13 carbons of taxanes, as displayed in
Scheme 1, it requires five tasks to be carried out for the
conversion of carvone into a 8,9-seco-taxane 3, viz i) in-
troduction of a carbon along with C-ring of taxane at C-1
of carvone; ii) and iii) introduction of methyl groups at C-
2 and 4 positions; iv) introduction of a two carbon side
chain at C-3 position; and v) conversion of the isoprope-
nyl group into an hydroxy (or equivalent) group.
To test the feasibility of the strategy, synthesis of B-seco-
C-aromatic taxanes was investigated (Scheme 2). The
first task was accomplished employing a 1,3-enone-trans-
position methodology.6 Thus, sonochemically accelerated
Barbier reaction of (R)-carvone 2 with lithium and benzyl
bromides 4a–c, followed by oxidation of the resultant al-
lylic tertiary alcohols with pyridinium chlorochromate
(PCC) and silica gel in methylene chloride efficiently fur-
nished the enones 5a–c. It was contemplated that reduc-
tive methylation followed by methylation at -position of
the ketone and degradation of the isopropenyl group will
lead to suitable precursor for B-seco-taxanes. Thus, reduc-
tive alkylation of the enones 5a–c using lithium in liquid
ammonia and methyl iodide furnished the ketones 6a–c.
The stereochemistry of the benzyl group was assigned on
the basis of the thermodynamic considerations and in
analogy with the well established9 reductive alkylation of
3-methylcarvone. Kinetic alkylation with LDA and meth-
yl iodide in THF–HMPA transformed the ketones 6a–c
into the alkylated compounds 7a–c. Ozonolysis and Crie-
gee rearrangement7 was explored for the conversion of the
isopropenyl group in 7a–c in to an acetoxy group. How-
ever, as it is ideally suited (at the -position of a ketone)
for an elimination reaction,8 ozonolysis in methanol–
dichloromethane followed by treatment of the intermedi-
ate methoxyhydroperoxide with acetic anhydride, triethy-
lamine and 4-N,N-dimethylaminopyridine (DMAP) in re-
fluxing benzene transformed 7a–c into the enones 8a–c
via Criegee fragmentation. Allyl group was chosen as the
functionalised two carbon equivalent (C-9 and C-10 of
O
AcO
OH
O
Ph
O
H
O
H
Ph
N
H
O
OAc
OH
OH
O
Ph
Paclitaxel (1)
O
19
9
7
O
18
11
1
8
15
C
3
5
A
B
5
1
3
13
20
H
2,3-Secotaxane
Carvone (2)
Figure 1
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1907,1909,ftx,en;D17302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1908
A. Srikrishna et al.
LETTER
taxane) for the conversion of the enones 8a–c into func- noting that the absolute stereochemistry at the C-1 and C-
tionalised B-seco-nortaxoids. Thus, reaction of the enones 13 positions in the 8,9-seco-taxane 13 is identical to those
8a–c with allylmagnesium chloride followed by oxidation present in natural taxanes.
of the resultant tert-alcohols with PCC and silica gel fur-
nished the 8,9-seco-bisnor and nortaxanes 9a–c.
OMe
OMe
OMe
a
b,c
O
Br
82%
50%
O
X
Y
X
Y
Br
+
a,b
OH
10
11
12
4d
d
73%
O
2
4a-c
5a-c
c
OMe
Br
e
OMe
O
O
X
X
Y
Y
d
5d
f
6a-c
9a-c
7a-c
OMe
OMe
a. X = Y = H
b. X = Me; Y = H
c. X = H; Y = OMe
e
O
HO
g
O
80%
Y
H
H
X
X
Y
9d
13
O
f,b
Scheme 3 Reagents and conditions: (a) Br2, CH2Cl2, 0° C, 15 min;
(b) Li, THF, DMF, 1 h; (c) NaBH4, MeOH, 0° C; (d) PPh3, CBr4,
H
8a-c
CH2Cl2, 0° C
r.t., 0.5 h; (e) i. 2, Li, THF, 1 h; ii. PCC, silica gel,
CH2Cl2, 6 h; (f) as in Scheme 2; (g) LiAlH4, Et2O, –70° C, 1 h.
Scheme 2 Reagents and conditions: (a) Li, THF, 1 h; (b) PCC, silica
gel, CH2Cl2, 6 h; (c) i. Li, liquid NH3, THF, 15 min; ii. MeI, 1 h;
(d) LDA, THF, HMPA, MeI, 0° C r.t., 24 h; (e) i. O3/O2, CH2Cl2–
MeOH, –70° C; ii. Ac2O, Et3N, DMAP, C6H6, reflux, 4 h; (f)
CH2=CHCH2MgCl, THF, 0° C, 1 h.
In conclusion, a convenient approach was developed for
the generation of a series of 8,9-seco-C-aromatic taxanes
starting from the readily available monoterpene (R)-car-
vone employing a simple and straightforward approach.
Currently, we are investigating the extension of this meth-
odology for the enantiospecific construction of the tricy-
clic ring system of taxanes.
After successfully demonstrating the suitability of the
methodology for the generation of 8,9-seco-nortaxanes
9a–c, it has been extended to the synthesis of 6-methoxy-
9-methylene-8,9-seco-taxa-3,5,7,11-tetraen-13-one 9d
starting from 4-methoxy-2,6-dimethylbenzyl bromide 4d,
obtained from 3,5-dimethylanisole 10, as depicted in
Scheme 3 via the enone 5d. The results are summarised in
Table 1. Reduction of the enone 9d with lithium alumini-
um hydride in ether at –70°C furnished 6-methoxy-9-me-
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
Mass) consistent with their structures. Selected spectral data for the
representative compounds are as follows: For the compound 6a: IR
(neat): max = 1699, 893, 751, 701 cm–1. 1H NMR (300 MHz, CDCl3
+ CCl4): = 7.25 (2 H, t, J = 7.2 Hz), 7.16 (1 H, t, J = 7.2 Hz), 7.10
(2 H, d, J = 7.2 Hz), 4.68 (1 H, s), 4.65 (1 H, s), 2.94 (1 H, d, J =
13.2 Hz), 2.53 (1 H, t, J = 13.5 Hz), 2.32–2.20 (2 H, m), 2.10 (1 H,
thylene-8,9-seco-taxa-3,5,7,11-tetraen-13-ol 13 in
a
highly stereo- and regioselective manner.5,10 It is worth
Table 1a,b
Entry
Compound 5
Compound 6
Compound 7
Compoundc 8
Compound 9
Yieldd
75%
70%
64%
44%
[ ]D
Yield
55%
55%
52%
45%
[ ]D
Yield
75%
70%
80%
70%
[ ]D
Yield
62%
70%
60%
57%
[ ]D
Yieldd
80%
82%
65%
61%
[ ]D
a
b
c
d
+65.3
+28.9
+67.4
+32.7
–68.5
–64.1
–71.1
–27.5
–11.7
+5.84
–11.4
+21.4
+18.6
+15.3
+15.0
+60.9
+60.4
+85.6
+57.7
+85.0
a Yields refer to isolated and chromatographically pure compounds. Optical rotations were recorded in CHCl3 (c 1.2–5.5) at 22–25° C.
b Melting points: 6a, 86–87° C; 6b, 61–62° C; 6d, 76–78° C; 7a, 70–71° C; 7b, 96–97° C; 7c, 69–70° C.
c In addition, varying amounts (10–20%) of normal ozonolysis product was also obtained.
d Yield for two steps.
Synlett 2002, No. 11, 1907–1909 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Enantiospecific Approach to 8,9-seco-C-Aromatic Taxanes
1909
m of t, J = 12.9 Hz), 1.75–1.60 (2 H, m), 1.65 (3 H, s), 1.43 (1 H, q,
J = 12.9 Hz), 1.24 (3 H, s), 1.13 (3 H, s). 13C NMR (75 MHz, CDCl3
+ CCl4): = 214.1 (C), 147.3 (C), 140.7 (C), 129.0 (2 C, CH), 128.5
(2 C, CH), 126.2 (CH), 109.9 (CH2), 49.0 (CH), 48.2 (C), 44.4
(CH), 42.8 (CH2), 36.9 (CH2), 31.5 (CH2), 22.3 (CH3), 20.5 (CH3),
Acknowledgement
We thank the D. S. T., New Delhi for the financial support, and the
C. S. I. R., New Delhi for the award of a research fellowship to
PRK. VP thanks the Indian National Science Academy, New Delhi
for the award of an INSA visiting fellowship, and S.V. University
for permitting to avail the fellowship.
19.7 (CH3). Mass: 256 (M+). For the enone 8a: IR (neat):
=
max
1669, 1603, 703 cm–1. 1H NMR (300 MHz, CDCl3 + CCl4): = 7.24
(2 H, t, J = 7.5 Hz), 7.15 (1 H, d, J = 7.5 Hz), 7.09 (2 H, d, J = 7.5
Hz), 6.47 (1 H, s), 2.96 (1 H, d, J = 11.7 Hz), 2.30 (1 H, m), 2.20–
1.90 (3 H, m), 1.74 (3 H, s), 1.28 (3 H, s), 1.07 (3 H, s). 13C NMR
(75 MHz, CDCl3 + CCl4): = 203.5 (C), 141.6 (CH), 140.3 (C),
133.8 (C), 129.0 (2 C, CH), 128.5 (2 C, CH), 126.2 (CH), 46.0
(CH), 45.3 (C), 36.1 (CH2), 28.0 (CH2), 23.1 (CH3), 19.2 (CH3),
References
(1) INSA Visiting Scientist. Present address: Department of
Chemistry, Sri Venkateswara University, Tirupathi 517502,
India.
16.7 (CH3). Mass: 228 (M+). For the enone 9a: IR (neat):
=
max
(2) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
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(d) Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Acc.
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Int. Ed. Engl. 1994, 33, 15. (g) Taxane Anticancer Agents:
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therein.
(5) (a) Srikrishna, A.; Reddy, T. J.; Kumar, P. P. Chem.
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1665, 1607, 912, 700 cm–1. 1H NMR (300 MHz, CDCl3 + CCl4):
= 7.22 (2 H, t, J = 7.2 Hz), 7.16 (1 H, d, J = 7.2 Hz), 7.07 (2 H, d,
J = 7.2 Hz), 5.90–5.70 (1 H, m), 5.09 (1 H, d, J = 12.9 Hz), 5.04
(1 H, d, J = 18.3 Hz), 3.10–2.90 (3 H, m), 2.40–1.95 (4 H, m), 1.74
(3 H, s), 1.31 (3 H, s), 1.15 (3 H, s). 13C NMR (75 MHz, CDCl3 +
CCl4): = 197.6 (C), 160.4 (C), 140.0 (C), 134.2 (CH), 132.6 (C),
129.1 (2 C, CH), 128.5 (2 C, CH), 126.2 (CH), 116.7 (CH2), 46.5
(CH), 40.1 (C), 38.0 (CH2), 36.6 (CH2), 34.7 (CH2), 26.2 (CH3),
21.1 (CH3), 11.7 (CH3). Mass: 268 (M+). For (+)-(1R)-6-methoxy-
9-methylene-8,9-seco-taxa-3,5,7,11-tetraen-13-one 9d: IR (neat):
max = 1665, 1605, 913 cm–1. 1H NMR (300 MHz, CDCl3 + CCl4):
= 6.51 (2 H, s), 5.77 (1 H, t of dd, J = 16.5,11.0 and 6.0 Hz), 5.10
(1 H, d, J = 11.0 Hz), 5.05 (1 H, d, J = 16.5 Hz), 3.74 (3 H, s), 3.07
(2 H, d, J = 6.0 Hz), 2.82 (1 H, dd, J = 13.5 and 3.0 Hz), 2.51 (1 H,
dd, J = 13.5 and 11.4 Hz), 2.25–2.00 (3 H, m), 2.25 (6 H, s), 1.74 (3
H, s), 1.34 (3 H, s), 1.19 (3 H, s). 13C NMR (75 MHz, CDCl3 +
CCl4): = 198.1 (C), 161.0 (C), 158.0 (C), 137.8 (2 C, C), 134.3
(CH), 132.6 (C), 128.4 (C), 116.8 (CH2), 114.1 (2 C, CH), 55.0
(CH3), 43.8 (CH), 40.7 (C), 37.7 (CH2), 34.7 (CH2), 28.7
(CH2), 25.9 (CH3), 21.0 (2 C, CH3), 20.1 (CH3), 11.8 (CH3).
Mass: 326 (M+). (+)-(1R,13S)-6-methoxy-9-methylene-8,9-seco-
taxa-3,5,7,11-tetraene-13-ol 13: IR (neat): max = 3363, 1604 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): = 6.58 (2 H, s), 5.85–5.70 (1
H, m), 5.10–4.95 (2 H, m), 3.90–3.80 (1 H, m), 3.77 (3 H, s), 2.95–
2.75 (2 H, m), 2.74 (1 H, d, J = 13.2 Hz), 2.44 (1 H, dd, J = 13.2 and
12.0 Hz), 2.29 (6 H, s), 1.66 (3 H, s), 1.80–1.50 (3 H, m), 1.40–1.19
(1 H, m), 1.20 (3 H, s), 1.02 (3 H, s). 13C NMR (75 MHz, CDCl3 +
CCl4): = 157.1 (C), 138.6 (C), 138.2 (2 C, C), 137.2 (CH), 131.9
(C), 130.0 (C), 114.9 (CH2), 113.7 (2 C, CH), 71.5 (CH), 55.1
(CH3), 42.7 (CH), 39.9 (C), 33.3 (CH2), 32.9 (CH2), 28.6 (CH2),
25.6 (CH3), 21.0 (2 C, CH3), 20.7 (CH3), 14.7 (CH3).
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Synlett 2002, No. 11, 1907–1909 ISSN 0936-5214 © Thieme Stuttgart · New York