Synthesis of the carbobicyclic substructure of CP-225,917 and CP-263,114

Article abstract of DOI:10.1039/a706075k

The bridgehead alkenic ketones 22a and 22b, representing the carbobicyclic substructure of the squalene synthase and farnesyl transferase inhibitors CP-225,917 (1) and CP-263,114 (23), have been synthesized from the 7-norbornenone acetal 8, using an anion

Full text of DOI:10.1039/a706075k

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Synthesis of the carbobicyclic substructure of CP-225,917 and CP-263,114
Paulo W. M. Sgarbi and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
The bridgehead alkenic ketones 22a and 22b, representing
the carbobicyclic substructure of the squalene synthase and
farnesyl transferase inhibitors CP-225,917 (1) and CP-
263,114 (23), have been synthesized from the 7-norbornen-
one acetal 8, using an anionic oxy-Cope rearrangement of
21a and 21b in the key step; the synthesis serves as a test of
a potential route to both natural products.
Our model study (Scheme 2) began with the readily available
norbornene 8.12 The double bond was first saturated (8?9; Pd–
C, H2; 92%), and the resulting alcohol was then benzoylated
(BzCl, pyridine; 98%) and treated with aqueous acetic acid to
hydrolyse the acetal (9?10?11). When esterification was
omitted, extensive decomposition occurred during attempts at
deacetalization, presumably by a retroaldol process. Ketone 11
is quite sensitive, and so it was used without purification. While
we had originally planned to introduce a vinyl group at C(11)
(cf. 11?12) by an intramolecular Barbier reaction, we
wondered if adequate facial selectivity would be observed for a
simple intermolecular process13 and, in the event, treatment of
crude 11 with vinylmagnesium bromide in Et2O gave a !5:1
mixture of tertiary alcohols, with the desired isomer 12 being
the major product. In the present study, carbons C(9) and C(17)
of 11 are unsubstituted; in a more advanced model those
carbons would carry alkyl groups, and steric factors may
improve the already satisfactory product ratio. Separation of the
C(11) isomers could be performed chromatographically after
hydrolysis of the benzoyl group (12?13; LiOH, 9:1 THF–
water, 60 °C; 44% overall from 10; 9% of C(11) isomer of 13).
Oxidation of the major diol (13) was initially problematic, until
we tried the Dess–Martin reagent,14 which smoothly converts
13 into keto alcohol 14 (93%).
The structurally complex anhydride 1 was isolated from the
fermentation broth of an unidentified fungus, and described
recently by chemists at Pfizer Central Research.1,2 The
substance is related to the nonadrides3—at least on the basis of
its proposed2 biosynthetic origin. It was given the designation
CP-225,917, and was found1 to inhibit squalene synthase4 (from
rat liver) and Ras farnesyl transferase5 (from rat brain).
Inhibition of these enzymes represents an opportunity for
controlling serum cholesterol levels6 as well as certain types of
abnormal cell growth,5 and so 1 may serve as a lead in the
design of cholesterol-lowering and anticancer drugs.
2
1
O
3
O
7
O31
30
8
9
10 OH
11
OH
O
12
The next task was to protect the tertiary hydroxy group
(14?15) in order to avoid retroaldol fragmentation.15 Et3-
SiOTf in the presence of 2,6-lutidine proved to be a satisfactory
combination of reagents (84%); attempts to introduce tert-
butyldimethylsilyl or p-methoxybenzyl groups were unsuccess-
ful. The remainder of the hexa-1,5-diene subunit required for
the anionic oxy-Cope rearrangement was assembled by a short
sequence, beginning with aldol condensation (15?16; LDA,
THF, 278 °C; excess of MeCHO; > 76%), so as to form the
b-hydroxy ketones 16 as an isomer mixture. Without separation,
these alcohols were converted into the corresponding mesylates
17 (MsCl, Et3N, CH2Cl2, 0 °C) and, again without isomer
separation, the mesylates were treated with DBU (THF, room
temperature), affording the desired enones 18, which were
easily separable (E-isomer, 60% overall from 15; Z-isomer,
11% overall from 15).§ As a matter of convenience, only the
major ketone was taken further. Reduction (18?19; NaBH4,
18
O
26
O
27
17
24
13
23
15 16
14
28
25
CO2H
29
1
CP-225,917 is the hemiacetal of a bicyclo[4.3.1]decadienone
substructure 2,† and one of its notable features is the bridgehead
double bond. Although the related olefinic ketone 3 (which was
obtained in admixture with the isomer 4) has been prepared,7 the
method used to make that particular compound does not seem
well-suited to the task of synthesizing the natural product. We
report a model study8,9 that establishes a route to 22a and 22b
(see Scheme 2), both of which we take to represent the
[4.3.1]-carbobicyclic substructure of CP-225,917.
O
O
O
26
10
9
17
11
OH
O–
12
R2
R2
15
R3
R3
16
14
13
R4
R4
2
3
4
R5O
R1
R5O
R1
Our approach is based on the idea that anionic oxy-Cope
rearrangement‡ of compounds such as 5 (Scheme 1) should lead
to enolates 6, which have a number of features that are
appropriate for further elaboration in the desired manner
(6?7/7A). In particular, the C(26) oxygen function of 7/7A could
provide the corresponding acetal unit of 1, and the enolate 6
would offer several opportunities for constructing the anhy-
dride, perhaps by initial capture with an electrophile, such as
Mander’s reagent.11 The route summarized in Scheme 1 should
also be able to accommodate introduction of two substituents at
C(14) (see 7/7A), which is a quaternary centre in the natural
product.
5
6
E+
E
OR5
26
O
R1
R2
R3
O
R2
14
R4
R4
E
26
14
R3
R5O
R1
7′
7
Scheme 1
Chem. Commun., 1997
2157

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O
O
MeO
HO
OMe
MeO
RO
OMe
11
O
O
17
O
i
iii
O
9
O
BzO
O
11
8
9 R = H
10 R = Bz
CO2H
ii
23
iv
OSiEt3
OH
11
OR
A closely related natural product (CP-263,114, 23) was
isolated along with CP-225,917, and found to have similar
biological properties, although of a lower potency with respect
to squalene synthase inhibition. The present work is, of course,
equally relevant to the synthesis of the congener.
All new compounds, except 11, one epimer of 16, 17 and the
C(11) epimer of 12, were satisfactorily characterized by
spectroscopic methods, including high resolution mass spec-
troscopic measurements.
Acknowledgment is made to the Natural Sciences and
Engineering Research Council of Canada for financial support,
and we thank Dr Yunxin Bo for advice. P. W. M. S. held a
Graduate Scholarship from CNPq (Brazil).
vi
viii
O
ix
O
OR
RO
14 R = H
15 R = SiEt3
16 R = H
17 R = Ms
x
12 R = Bz
13 R = H
vii
v
OSiEt3
OSiEt3
14
xi
O
HO
18
19
OR
OR
xii
Footnotes and References
+
BnO
* E-mail: derrick.clive@ualberta.ca
† We use the non-systematic numbering given in ref. 2.
‡ For recent examples of the preparation of bicyclic systems by anionic oxy-
Cope rearrangement, see ref. 10.
§ We have not yet explored the possibility of conjugate addition for
introducing what will eventually be the second substituent at the quaternary
centre [C(14)].
BnO
20a R = SiEt3
21a R = H
20b R = SiEt3
21b R = H
xiii
xiii
xiv
xiv
OBn
BnO
O
O
1 T. T. Dabrah, H. J. Harwood, L. H. Huang, N. D. Jankovich, T. Kaneko,
J.-C. Li, S. Lindsey, P. M. Moshier, T. A. Subashi, M. Therrien and
P. C. Watts, J. Antibiot., 1997, 50, 1.
H
H
2 T. T. Dabrah, T. Kaneko, W. Massefski, Jr. and E. B. Whipple, J. Am.
Chem. Soc., 1997, 119, 1594.
Me
Me
22a
22b
3 E.g. J. E. Baldwin, D. H. R. Barton and J. K. Sutherland, J. Chem. Soc.,
1965, 1787 and earlier papers in the series; J. K. Sutherland, Fortschr.
Chem. Org. Naturst., 1967, 25, 131.
Scheme 2 Reagents and conditions: i, H2, 10% Pd–C, MeOH, room temp.,
ca. 5 h, 92%; ii, BzCl, pyridine, room temp., 10 h, 98%; iii, 6:1 AcOH–
H2O, 150 °C, 40 min; iv, H2CNCHMgBr, Et2O, 0 °C, 40 min; v, LiOH·H2O,
9:1 THF–H2O, 80 °C, 12 h, 53% over 3 steps [44% for 13, 9% for C(11)
isomer of 13]; vi, Dess–Martin periodinane, 33:1 CH2Cl2–DMSO, room
temp., 12 h, 93%; vii, Et3SiOSO2CF3, 2,6-lutidine, CH2Cl2, room temp.,
1 h, 84%; viii, LDA, THF, 278 °C, 1 h, then MeCHO, 278 °C, 1 h; ix,
MeSO2Cl, Et3N, CH2Cl2, 0 °C; x, DBU, THF, room temp., 1 h, 71% over
3 steps [60% isolated yield of (E)-alkene and 11% isolated yield of
(Z)-alkene]; xi, NaBH4, CeCl3·7H2O, MeOH, room temp., 1.5 h, 86%
(endo-19, 42%; exo-19, 44%); xii, BnBr, NaH, THF, 70 °C, 24 h, 94% for
20a, 70% for 20b; xiii, Bu4NF, THF, room temp., 2 min, 89% for 21a, 89%
for 21b; xiv, (Me3Si)2NK, PhMe, 100 °C, 20 h, 95% for 22a, 82% for
22b
4 N. S. Watson and P. A. Procopiou, Prog. Med. Chem., 1996, 33, 331.
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6 J. D. Bergstrom, M. M. Kurtz, D. J. Rew, A. M. Amend, J. D. Karkas,
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O. D. Hensens, J. M. Liesch, D. L. Zink, K. E. Wilson, J. Onishi,
J. A. Milligan, G. Bills, L. Kaplan, M. Nallin Omstead, R. G. Jenkins,
L. Huang, M. S. Meinz, L. Quinn, R. W. Burg, Y. L. Kong, S. Mochales,
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2285; cf. H. O. House and T. V. Lee, J. Org. Chem., 1979, 44, 2819.
8 Cf. K. C. Nicolaou, M. W. Ha¨rter, L. Boulton and B. Jandeleit, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1194.
9 Cf. H. M. L. Davies, R. Calvo and G. Ahmed, Tetrahedron Lett., 1997,
38, 1737.
10 S. F. Martin, J.-M. Assercq, R. E. Austin, A. P. Dantanarayana,
J. R. Fishpaugh, C. Gluchowski, D. E. Guinn, M. Hartmann, T. Tanaka,
R. Wagner and J. B. White, Tetrahedron, 1995, 51, 3455; L. A.
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G. Mehta, F. Ahmad Khan, B. Ganguly and J. Chandrasekhar, J. Chem.
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14 R. E. Ireland and L. Liu, J. Org. Chem., 1993, 58, 2899.
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MeOH, CeCl3·7H2O; 86%) gave a 1:1 mixture of endo- (42%
isolated yield) and exo-alcohols (44%), which were easily
separated and individually protected by benzylation (endo-
19?20a, 94%; exo-19?20b, 70%). At this point, desilylation
of both 20a and 20b was accomplished under standard
conditions (Bu4NF, THF, room temperature; 89% for each
compound) and finally, the resulting alcohols were subjected to
anionic oxy-Cope rearrangement [(Me3Si)2NK, PhMe, 100 °C,
ca. 20 h]. endo-Benzyl ether 21a gave the bridgehead keto
alkene 22a (95%) and the exo isomer (21b) gave 22b (82%),
1
whose structures were confirmed by extensive H–1H COSY
and ROESY NMR measurements. In neither case was the rate of
oxy-Cope rearrangement noticeably increased by addition of
18-crown-6.
Formation of 22a and 22b (which is crystalline) serves as an
initial test of the plan summarized in Scheme 1.
Received in Corvallis, OR, USA, 18th August 1997; 7/06075K
2158
Chem. Commun., 1997