Evaluation of asymmetric Diels-Alder approaches for the synthesis of the cyclohexene subunit of CP-225,917 and CP-263,114

Article abstract of DOI:10.1016/S0040-4039(03)00835-9

Asymmetric synthesis of a functionalised cyclohexenone required for total synthesis of CP-225,917 and CP-263,114 is reported, using a Lewis acid-promoted Diels-Alder reaction between a 2-silyloxy-1,3-diene and a dienophile bearing an oxazolidinone auxilia

Full text of DOI:10.1016/S0040-4039(03)00835-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3915–3918
Evaluation of asymmetric Diels–Alder approaches for the
synthesis of the cyclohexene subunit of CP-225,917 and
CP-263,114ꢀ
Alan Armstrong,* Nicholas G. M. Davies, Nathaniel G. Martin and Alistair P. Rutherford
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 27 February 2003; revised 20 March 2003; accepted 28 March 2003
Abstract—Asymmetric synthesis of a functionalised cyclohexenone required for total synthesis of CP-225,917 and CP-263,114 is
reported, using a Lewis acid-promoted Diels–Alder reaction between a 2-silyloxy-1,3-diene and a dienophile bearing an
oxazolidinone auxiliary. A novel method for appendage of the exocyclic malonate unit, via cyclopropane ring opening, is also
described. © 2003 Elsevier Science Ltd. All rights reserved.
Challenging structures along with important biological
activity (inhibition of ras-farnesyl protein transferase
and squalene synthase) have made the natural products
CP-225,917 11 and the closely related CP-263,114
highly popular targets for total synthesis.2–4 We have
previously reported a concise synthesis of a model
bicyclo[4.3.1]octenone core 2 involving reaction of the
cyclohexenone 3a (R1=R2=H) with a bis-electrophile
equivalent,5a,b as well as methodology for the construc-
tion of the g-lactone acetal unit.5c Another important
requirement for extension of our strategy to a total
synthesis is a route to enantiomerically pure cyclo-
hexenone 3 bearing the C-9 and C-17 side-chains.†
Diels–Alder chemistry was an obvious possibility, and
we envisaged preparation of a silyl enol ether derivative
4 using this approach, by reaction of a dienophile 5
bearing a chiral auxiliary (e.g. Oppolzer sultam or
Evans oxazolidinone) with suitable oxygenated dienes.
Scheme 1.
Keywords: CP-compounds; Diels–Alder; oxazolidinone; cyclopropanation.
ꢀ Supplementary data associated with this article can be found at doi:10.1016/S0040-4039(03)00835-9
* Corresponding author. Fax: +44-(0)20-7594-5804; e-mail: a.armstrong@imperial.ac.uk
† Natural product numbering as depicted in Scheme 1 is used throughout this paper.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00835-9

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A. Armstrong et al. / Tetrahedron Letters 44 (2003) 3915–3918
Use of a 2-silyloxydiene 6 would lead to 4 directly,
whilst use of Danishefsky’s diene 8 would also afford 4
after conjugate reduction of the resulting enone 7.
Surprisingly, there appeared to be little literature prece-
dent for the reaction of oxygenated dienes with chiral
dienophiles of this type.6,7 Here we report an evaluation
of several such Diels–Alder reactions and their applica-
tion to the successful synthesis of 3.8
crystallography11 was used to assign the stereochemistry
of the major isomer 11a unambiguously (Scheme 2).
This stereochemical outcome is in accord with the
model proposed by Pindur in the Diels–Alder reaction
of similar dienophiles with vinyl indoles.12 Adduct 11a
has the opposite absolute configuration to that required
for synthesis of 1, but the other enantiomer of the
chiral auxiliary is available. In order to incorporate
functionality that could be used for conversion to the
full natural product side-chain, a similar Diels–Alder
sequence was carried out using the dienophile 9b. This
reaction afforded a 22:1 mixture of diastereomers
according to LCMS analysis, with 11b assumed to be
the major by analogy to the formation of 11a.
Results and discussion
Our initial studies focused on Diels–Alder reactions of
the more reactive bis-oxygenated diene 8 with chiral
dienophiles9 9a and 10a bearing the well-established
Evans oxazolidinone and Oppolzer sultam auxiliaries.
Perhaps not surprisingly, attempts to catalyze this reac-
tion with Lewis acids were not productive, leading to
polymerisation of electron-rich diene 8. Turning to
thermal conditions, reaction between Evans dienophile
10a and diene 8 under sealed tube conditions followed
by treatment with TMSOTf10 provided a mixture of
four inseparable enones in a 50:30:18:7 ratio, suggesting
poor cycloaddition regioselectivity and/or stereospecifi-
city as well as stereoselectivity. However, reaction of
diene 8 with Oppolzer dienophile 9a under similar
conditions gave a 9:1 mixture of enones. X-Ray
While the levels of stereocontrol achieved in the synthe-
sis of 11b were encouraging, attempts to effect conju-
gate reduction of the enone were not. Use of
Wilkinson’s catalyst in the presence of silanes did
afford the desired products (cf. 4), but the reactions
were unreliable, with varying amounts of ketone side-
products obtained due to silyl enol ether hydrolysis.
This led us to refocus our efforts on Diels–Alder reac-
tions of monoxygenated dienes, which would provide a
more direct route. Thermal reaction of 6 with 9b or 10b
was slow, and appeared to proceed with poor levels of
stereocontrol. Attempts to accelerate the reaction
between 9b and 6 with Lewis acids (TiCl4, Et2AlCl or
EtAlCl2) led to decomposition of the diene. However,
far more encouraging results were obtained with the
oxazolidinone dienophiles 10b and 10c, which cleanly
underwent the desired cycloaddition with 6 in the pres-
ence of 1.4 equiv. Et2AlCl (Scheme 3). While the use of
oxazolidinone dienophiles of this type in Diels–Alder
reactions mediated by Et2AlCl is well precedented for
simple dienes,13 to the best of our knowledge this is the
first example of the use of 2-silyloxydienes in this
process. Careful control of reaction pH was necessary
during work-up to prevent hydrolysis of the product
1
silyl enol ether 12. H NMR analysis indicated that the
products 12 were obtained in good diastereoselectivity
(89% de for 12a; 85% de for 12b); the diastereomers
could be separated by flash chromatography, affording
diastereomerically pure 12a (77% yield) or 12b (81%).14
Reductive removal of the auxiliary from 12b and benzyl
protection led to 13. An efficient asymmetric route to a
cyclohexene derivative with differential protection on
the two side-chains had therefore been achieved.
Scheme 2. Reagents and conditions: (a) (i) heat, toluene,
sealed tube. For 11a: 150°C, 68 h; for 11b, 140°C, 21 h. (ii)
TMSOTf, acetone, collidine, CH2Cl2, −78°C; 75% for 11a,
59% for 11b.
Scheme 3. Reagents and conditions: (a) Et2AlCl (1.4 equiv.), CH2Cl2, −78 to −20°C, quenched with 9:1 NH3 (aq):NH4Cl (aq), 77%
n
for 12a, 81% for 12b. (b) LiBH4 (1.05 equiv.), EtOH (1 equiv.), THF, 0°C to rt, 51%. (c) NaH, THF, then BnBr, Bu4NBr (cat.),
60% (73% based on recovered starting material).

A. Armstrong et al. / Tetrahedron Letters 44 (2003) 3915–3918
3917
Scheme 4. Reagents and conditions: (a) TiCl4, diethyl ketomalonate, −78°C, 30 min, then add 13, THF, 51%. (b) 2 mol%
Cu(acac)2, 1.1 equiv. EtO2CCHN2, EtOAc, 110°C, 96%. (c) (i) LDA, THF, −78°C, 30 min; (ii) add EtO2CCl, warm to rt, 12 h;
(iii) 0.5 equiv. 1 M TBAF, THF, 73%. (d) NaHMDS, NBS, 92%. (e) DABCO®, C6H6, 92%.
Acknowledgements
Reaction of 13 with diethyl ketomalonate in the pres-
ence of TiCl4 allowed installation of the diester unit in
14 (Scheme 4). In our model synthesis lacking the
side-chains,5a,b we were able to effect elimination of the
tertiary hydroxyl and olefin migration by conversion to
the acetate with TMSOTf/Ac2O followed by reaction
with DABCO. However, attempts to functionalise the
tertiary hydroxyl in 14 were thwarted by competing
deprotection of the PMB-ether and cyclisation of the
resulting hydroxyl onto the ketone group. Similar
difficulties were encountered with TBDMS-protection
in place of PMB. These problems required us to
develop a new method for incorporation of the mal-
onate carbon atoms, inspired by Reissig’s donor–accep-
tor-substituted cyclopropane chemistry.15 Thus,
Cu-catalysed cyclopropanation of 13 with ethyl diazo-
acetate led to 15. Deprotonation and reaction with
ethyl chloroformate followed by treatment with fluoride
resulted in opening of the cyclopropane ring, providing
16. The cyclohexenone double bond could then be
introduced by bromination/elimination accompanied by
spontaneous alkene migration, affording the desired
cyclohexene 3b16 with differentially protected side-
chains.
We thank the EPSRC (GR/M25438) for funding this
work. We are also grateful to Pfizer, AstraZeneca,
Merck Sharp and Dohme and Bristol-Myers Squibb for
generous unrestricted funding of our research
programme.
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In conclusion, we have examined the Diels–Alder reac-
tions of monooxygenated diene 6 and bisoxygenated
diene 8 with dienophiles 9 and 10. Bisoxygenated diene
8 reacts under thermal (sealed tube) conditions with
sultam dienophiles 9 with good diastereoselectivity. For
monooxygenated diene 6, best results were obtained in
an Et2AlCl-mediated cycloaddition with the oxazolidi-
nones 10. We have also demonstrated a novel method
for the appendage of a malonate unit to a silyl enol
ether, via cyclopropanation/ring opening. In addition
to the application to our ongoing synthetic studies on
the CP-compounds, these results may have more gen-
eral application to the asymmetric synthesis of func-
tionalised cyclohexene derivatives.

3918
A. Armstrong et al. / Tetrahedron Letters 44 (2003) 3915–3918
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7. An alternative approach, which we have not explored,
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dienes. To the best of our knowledge, however, these
have not been used with b-alkyl-substituted acrylates.
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9573.
8. For an alternative approach to chiral 4,5-disubstituted
cyclohex-2-enones, see: Quattropani, A.; Anderson, G.;
Bernardinelli, G.; Kundig, E. P. J. Am. Chem. Soc. 1997,
119, 4773–4774.
12. Pindur, U.; Lutz, G.; Fischer, G.; Schollmeyer, G.;
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13. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238–1256.
14. The stereochemical outcome of this reaction was assigned
based on the Evans chelation model for Diels–Alder
reactions of this type of dienophile with simple dienes
(Ref. 13). This was confirmed by correlation of sign of
optical rotation to compounds obtained by manipulation
of 11b. Details will be reported in a full account of this
work. The crystal structure of the Diels–Alder adduct
between 10a and 2-methoxy-1,3-butadiene has been
reported previously, without details of the conditions
used for the cycloaddition. The stereochemistry of this
compound is consistent with that in Scheme 3. See:
Marsh, R. E.; Schaefer, W. P.; Kukkola, P. J.; Myers, A.
G. Acta Crystallogr. 1992, C48, 1622–1644.
15. (a) Kahn, F. A.; Czerwonka, R.; Reissig, H.-U. Eur. J.
Org. Chem. 2000, 3607–3617; (b) Reissig, H.-U. Top.
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I.; Reissig, H.-U. Liebigs Ann. Chem. 1984, 512–530; (d)
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16. Data for 3b: colourless oil; [h]2D1=+69.0 (c 0.58 CHCl3);
wmax 2918, 2856, 1748, 1733, 1677, 1614, 1513, 1456, 1303,
1247, 1097, 1033 cm−1; lH (250 MHz, CDCl3): 7.38–7.25
(5H, m), 7.23 (2H, d, J=8.9 Hz), 6.98 (1H, dd, J=3.2,
0.8 Hz, CHꢀCCO), 6.85 (2H, d, J=8.9 Hz), 4.69 (1H, s,
CH(CO2Et)2), 4.51 (2H, s), 4.39 (2H, s), 4.12–4.25 (4H,
m, OCH2CH3), 3.79 (3H, s, OCH3), 3.66 (1H, dd, J=9.3,
5.0 Hz, CH2OBn), 3.38–3.57 (3H, m, CH2OBn,
CH2OPMB), 2.58–2.71 (2H, m), 2.21–2.38 (2H, m), 1.88
(1H, m, CHCH2OBn), 1.60 (1H, m, CH(CH2)2OPMB),
1.24 (3H, t, J=7.2 Hz, OCH2CH3), 1.22 (3H, t, J=7.2
Hz, OCH2CH3); lC (62.5 MHz, CDCl3): 196.5 (C), 167.9
(C), 167.8 (C), 159.2 (C), 149.7 (C), 138.0 (C), 132.6 (C),
130.3 (C), 129.2 (CH), 128.4 (CH), 127.7 (CH), 127.5
(CH), 113.8 (CH), 73.2 (CH2), 72.7 (CH2), 70.4 (CH2),
67.1 (CH2), 61.7 (CH2), 55.3 (CH3), 50.5 (CH), 42.4
(CH), 41.3 (CH2), 33.2 (CH), 32.9 (CH2), 14.0 (CH3). m/z
9. The dienophiles were prepared by reaction of the appro-
priate aldehyde RCHO with the auxiliary-bearing diethyl
phosphonate. For sultam dienophiles, see: (a) Oppolzer,
W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli,
G. Tetrahedron Lett. 1988, 29, 5885–5888. For oxazolidi-
nones, see: (b) Ishizaki, M.; Hara, Y.; Kojima, S.;
Hoshino, O. Heterocycles 1999, 50, 779–790; (c) Kat-
sumata, A.; Iwaki, T.; Fukumoto, K.; Ihara, M. Hetero-
cycles 1997, 46; 605–616.
10. Vorndam, P. E. J. Org. Chem. 1990, 55, 3693–3695.
11. We thank Dr. A. J. Blake, Dept. of Chemistry, Univer-
sity of Nottingham for this structure determination. Crys-
tallographic data (excluding structure factors) for 11a
(CI): 556 (M+NH4+, 2%), 538 (M+, 2%), 121 (100%).
+
Found: M+NH4
,
556.2912. C31H42NO8 requires:
556.2910.