Carvone based approaches to chiral functionalised B-seco-taxanes

Article abstract of DOI:10.1039/a805862h

Starting from (R)-carvone, the synthesis of chiral, functionalised C-aromatic-B-seco-taxanes and an extension to the synthesis of a B-seco-20-nortaxane derivative have been described.

Full text of DOI:10.1039/a805862h

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Carvone based approaches to chiral functionalised B-seco-taxanes†
Adusumilli Srikrishna,* T. Jagadeeswar Reddy and P. Praveen Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received (in Cambridge) 27th July 1998, Accepted 24th August 1998
Starting from (R)-carvone, the synthesis of chiral,
OH
O
functionalised C-aromatic-B-seco-taxanes and an exten-
Br
sion to the synthesis of a B-seco-20-nortaxane derivative
have been described.
a
+
Paclitaxel 1 (Taxol),1 by virtue of its complex and densely func-
tionalised structure, coupled with potent antitumor activity and
4
5
novel mechanism of action, has attracted the attention of many
synthetic chemists. During the last two decades, more than
thirty five research groups have been actively involved in the
development of convenient approaches to taxane diterpenoids2
and so far four groups have reported the total synthesis of
b
c, d
Taxol 1.3 Recently, we have initiated a new approach4 to taxanes
MeO
O
starting from the readily available monoterpene, carvone 2, and
developed an efficient route for the construction of functional-
ised chiral A-ring derivatives of taxanes, e.g. 3 (Scheme 1).4 It
7
6
AcO
O
OH
e
10
9
C
O
Ph
O
H
A
f
O
H
Ph
N
H
O
MeO
MeO
13
5
OH O
AcO
OH
Ph
1
COOH
O
O
Paclitaxel (TaxolR ) 1
8
9
Scheme 2 Reagents and conditions: (a) Li, THF, sonication, 1 h; (b)
PCC–silica gel, CH2Cl2, 36 h, 92% (2 steps); (c) LAH, Et2O, Ϫ78 ЊC,
2 h, 99%; (d) NaH, THF, DMF, Bu4NI, MeI, 8 h, 99%; (e) O3–O2,
MeOH–CH2Cl2 (1:4), Ϫ70 ЊC; Me2S, 8 h, 76%; (f) NaOH, Br2,
dioxane, 3 h, 0 ЊC–RT, 50%.
F
O
PO
A
This methodology was extended to incorporate the desired
oxygen functionality at the C-9 and C-10 positions present in
the taxane skeleton. Thus the sequence was carried out as in
Scheme 3 using the illustrated phenylacetylene compound as a
1,2-dioxygenated ethyl group equivalent. Reaction of dimethyl-
carvone 4 with the lithium anion of phenylacetylene followed
by oxidation of the resulting allyl alcohol furnished the
enynone 11, [α]D25 ϩ36 (c 2.39, CHCl3). Analogous to the earlier
series, reduction followed by protection of the resulting allyl
alcohol with benzoyl chloride, pyridine and DMAP trans-
formed the enynone 11 into the benzoate 12, [α]D25 ϩ33.3 (c 2.40,
CHCl3) which on ozonolysis furnished the acetyl compound 13
[α]D25 ϩ22.7 (c 2.07, CHCl3). In another reaction, controlled
hydrogenation of the acetylene moiety in the enynone 11 using
Lindlar catalyst furnished the cis-olefin 14,‡ suitable for further
elaboration to taxanes. In continuation, the sequence was also
carried out with p-methoxyphenylacetylene to incorporate the
oxygen functionality at the C-5 carbon of taxanes as well. Thus,
employing the same sequence of reactions, dimethylcarvone 4
was converted into the oxobenzoate 15 {[α]D26 ϩ3.27 (c 2.75,
CHCl3)}, via the enynone 16 {[α]D26 ϩ35.5 (c 2.25, CHCl3)} and
the benzoate 17 {[α]D26 Ϫ200 (c 0.2, CHCl3)}.
F
Carvone 2
(A-Ring) 3
Scheme 1
was anticipated that incorporation of a suitable C-ring com-
ponent would result in the generation of B-seco-taxane deriv-
atives5 en route to taxanes. As a model study in this direction,
herein we describe the synthesis of various chiral functionalised
B-seco-nortaxane derivatives.
We first contemplated an intramolecular Friedel–Crafts
acylation or equivalent for the closure of the B-ring, and thus
focused our attention on the synthesis of C-aromatic B-seco
derivatives of taxanes employing phenethyl bromide as the
starting material, Scheme 2. Thus, reaction of dimethyl-
carvone4 4 with phenethyl bromide in the presence of lithium,
activated by ultrasonic irradiation, followed by oxidation of the
resulting tert-allyl alcohol 5 furnished the enone 6.‡ For the
conversion of the enone 6 into a B-seco-taxane derivative, prior
to the degradation of the isopropenyl group, the carbonyl
group was masked. Consequently, stereoselective6 reduction of
the enone 6 followed by protection of the resulting allyl alcohol
(mp 106–108 ЊC) as its methyl ether generated the ether 7, [α]D24
ϩ58 (c 2.1, CHCl3). A two step protocol was chosen for the
degradation of the isopropenyl moiety into the corresponding
acid. First, regioselective ozonolysis followed by reductive
work-up transformed the isopropenyl compound 7 into the
acetyl compound 8.‡ Haloform reaction of compound 8 using
freshly prepared sodium hypobromide furnished the B-seco-
taxane derivative, the acid 9.
After successfully accomplishing the synthesis of C-aromatic
bis-nortaxane derivatives, attention was turned towards the
synthesis of a C-20 nortaxane derivative employing an appro-
priate aliphatic C-ring precursor containing the C-19 carbon
(tert-methyl at C-8) of taxanes, Scheme 4. Bromide 18 was
identified as a potential precursor, and was prepared in four
steps starting from 3-methylcyclohex-2-enol. Coupling of the
bromide 18 with dimethylcarvone 4 in the presence of lithium
J. Chem. Soc., Perkin Trans. 1, 1998, 3143–3144
3143

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Notes and references
O
† Chiral synthons from carvone, Part 35. For part 34 see reference 7.
‡ All the compounds exhibited spectral data (IR, 1H and 13C NMR,
LRMS and HRMS) consistent with the proposed structures. Spectral
data for selected compounds are as follows: For the enone 6: mp
52–53 ЊC [α]D26 ϩ36.4 (c 3.3, CHCl3); νmax (neat)/cmϪ1 1665, 1605, 895,
750, 700; δH (200 MHz, CDCl3) 7.15–7.40 (5 H, m), 4.95 (1 H, s), 4.8
(1 H, s), 2.40–2.85 (7 H, m), 1.90 (3 H, s), 1.74 (3 H, s), 1.29 (3 H, s),
1.15 (3 H, s); δC (22.5 MHz, CDCl3) 198.1 (s), 162.9 (s), 145.4 (s), 141.3
(s), 130.9 (s, C-2), 128.4 (2 C, d), 127.9 (2 C, d), 126.1 (d), 114.9 (t), 51.8
(d), 39.6 (2 C, t and s), 34.5 (t), 33.1 (t), 27.1 (q), 22.9 (q), 22.0 (q), 11.4
(q); m/z 282 (Mϩ, 13%), 267 (39), 191 (49), 105 (37), 91 (100) (Found: C,
85.38; H, 9.5; C20H26O requires C, 85.06; H, 9.28%). For the keto ether
8: [α]D24 ϩ45.0 (c 2.0, CHCl3); νmax (neat)/cmϪ1 1700, 1600, 750, 695; δH (90
MHz, CDCl3) 7.00–7.40 (5 H, m), 3.73 (1 H, dd, J 8.0 and 6.5 Hz), 3.38
(3 H, s), 2.22 (3 H, s), 1.85–2.35 (7 H, m), 1.78 (3 H, s), 1.2 (3 H, s), 1.09
(3 H, s); δC (22.5 MHz, CDCl3) 209.6 (s), 141.7 (s), 140.1 (s), 128.5 (s),
127.7 (2 C, d), 127.3 (2 C, d), 125.2 (d), 78.0 (d), 55.1 (q), 54.8 (d), 37.6
(s), 35.3 (t), 30.7 (2 C, t), 26.6 (q), 26.2 (q), 22.0 (q), 14.5 (q); m/z 300
(Mϩ, 10%), 202 (52), 195 (17), 187 (23), 111 (35), 105 (47), 91 (100). For
the dienone 14: [α]D27 ϩ9.0 (c 1.33, CHCl3); νmax (neat)/cmϪ1 1660, 1590,
895, 770, 690; δH (200 MHz, CDCl3) 7.35–7.20 (5 H, m), 6.60 (1 H, d,
J 13.0 Hz), 6.16 (1 H, d, J 13.0 Hz), 5.00 (1 H, s), 4.80 (1 H, s), 2.70–2.50
(3 H, m), 1.8 (3 H, s), 1.6 (3 H, s), 1.23 (3 H, s), 1.18 (3 H, s).
For 2-methyl-2-methylene-(20)-nor-(2,3)-secotax-11-en-13-one 19: [α]D25
+
a
R
4
O
PhCOO
b
R
R
11 R = H
16 R = OMe
12 R = H
17 R = OMe
d
c
PhCOO
O
R
O
ϩ38.5 (c 3.9, CHCl3); νmax (neat)/cmϪ1 1660 (C᎐O), 1600, 890; δH (200
᎐
13 R = H
15 R = OMe
MHz, CDCl3) 4.9 (1 H, s) and 4.74 (1 H, s) [C᎐CH2], 2.54 (3 H, s, H-1
14
᎐
and 14), 2.19 (2 H, dd, J 11.7 and 8.3 Hz, H-10), 1.78 (3 H, s) and 1.69
(3 H, s) [2 × olefinic CH3], 1.1–1.6 (12 H, m), 1.2 (3 H, s), 1.08 (3 H, s)
Scheme 3 Reagents and conditions: (a) i, n-BuLi, THF, 8 h, 0 ЊC–RT;
ii, PCC–silica gel, CH2Cl2, 92 and 80% (2 steps); (b) i, LAH, Et2O,
Ϫ78 ЊC, 2 h, 99 and 90%; ii, PhCOCl, Py, DMAP, CH2Cl2, 95 and
85%; (c) O3–O2, Ϫ70 ЊC, MeOH–CH2Cl2 (1:4), Me2S, 8 h, 80 and 72%;
(d) Lindlar catalyst, H2 (balloon), MeOH, 35 h, 90%.
and 0.94 (3 H, s) [3 × tert-CH3]; δC (22.5 MHz, CDCl3) 196.8 (C᎐O),
᎐
163.8 (C-11), 145.1 (C᎐CH2), 129.9 (C-12), 114.1 (C᎐CH2), 51.6 (C-1),
᎐
᎐
39.4 (C-15), 39.1 (2 C, C-14 and 10), 37.0 (2 C, C-3 and 7), 32.5, 26.8,
25.9, 24.1, 23.8, 22.4, 21.8, 21.5 (2 C), 10.7; m/z 302 (Mϩ, 43%), 287
(69), 245 (29), 234 (25), 177 (42), 137 (20), 135 (22), 123 (23), 109 (22),
97 (100) (Found: m/z 302.2599. C21H34O requires 302.2610).
O
a
+
1 M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon and A. T. McPhail,
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O
Br
2 C. S. Swindell, Org. Prep. Proced. Int., 1991, 23, 465; Tetrahedron
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18
19
b
19
10
7
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c
MeO
13
15
MeO
3
5
1
O
2
21
20
Scheme 4 Reagents and conditions: (a) i, Li, THF, sonication; ii, PCC–
silica gel, CH2Cl2, 81% (2 steps); (b) i, LAH, Et2O, Ϫ78 ЊC, 2 h, 90%;
ii, NaH, THF, Bu4NI, MeI, 6 h, 91%; (c) i, O3–O2, MeOH–CH2Cl2
(1:4), Ϫ70 ЊC; ii, Me2S, 8 h, 55%.
followed by oxidation of the resulting allyl alcohol furnished
the enone6 19 [2-methyl-2-methylene-(20)-nor-(2,3)-secotax-11-
en-13-one]. Regioselective reduction of the enone 19 and pro-
tection of the allyl alcohol generated the methyl ether 20, [α]D24
ϩ58.0 (c 2.12, CHCl3), which on ozonolysis followed by
reductive work-up generated 13-methoxy-2-methyl-(2,3)-seco-
20-nortax-11-en-2-one 21.
In conclusion, we have achieved the synthesis of various
functionalised B-seco-analogues of taxanes starting from the
readily available monoterpene (R)-carvone, and currently we
are investigating the extension of this methodology with
functionalised chiral C-ring derivatives for the construction of
B-seco analogues suitable for further elaboration to taxanes.
4 A Srikrishna, T. J. Reddy and P. P. Kumar, Chem. Commun., 1996,
1369.
5 For recent reports on the synthesis of B-seco-taxanes, see: (a)
C. Montalbetti, M. Savignac, F. Bonnefis and J. P. Genet, Tetrahedron
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J.-P. Ferezou, A Pancrazi, J. Prunet and J.-Y. Lallemand, Tetrahedron
Lett., 1996, 37, 3313; (c) F. Delaloge, J. Prunet, A. Pancrazi and
J.-Y. Lallermand, Tetrahedron Lett., 1997, 38, 237; (d) G. Stork,
T. Doi and L. Liu, Tetrahedron Lett., 1997, 38, 7471; (e) K. Yamada,
H. Iwadare and T. Mukaiyama, Chem. Pharm. Bull., 1997, 45, 1898.
6 L. Garver, P. van Eikeren and J. E. Byrd, J. Org. Chem., 1976, 41,
2773.
Acknowledgements
We thank the Department of Science and Technology, New
Delhi, for financial support, the University Grants Commission
and Council of Scientific and Industrial Research for the award
of research fellowships to TJR and PPK, respectively, and the
Sophisticated Instrumentation Facility and Department of
Inorganic and Physical Chemistry for recording the high field
NMR spectra.
7 A. Srikrishna and T. J. Reddy, Tetrahedron, 1998, 54, 11 517.
Communication 8/05862H
3144
J. Chem. Soc., Perkin Trans. 1, 1998, 3143–3144