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Br
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N
OTBS
a
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(c) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.;
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5
27
b
N
OTBS
H
3
O
Scheme 8. Reagents and conditions: (a) 10 mol % Pd2(dba)3, 30 mol %
Xantphos, KOtBu/PhOH, THF, reflux, 7 h (43%); (b) Li, NH3, then 27
added in THF, ꢀ78 °C, 4 h (67%).
Dissolving metal reduction (Li, NH3/THF) of 22 then
provided the desired bridged cyclohexanone 25 in good
yield (75%), thus completing our model study (Scheme
7).
5. For a general discussion of 6-endo-trig radical cyclisations
see: Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev.
1991, 91, 1237–1286, and references cited therein.
6. Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett 2004,
1443–1445.
Having successfully developed a synthesis of 25, we were
keen to examine the synthesis of 3, which is the stereo-
isomer required for our planned synthesis of (ꢀ)-
FR901483. Thus, diastereoisomeric vinyl bromide 5
was subjected to the previously optimised Pd-catalysed
intramolecular enolate alkenylation conditions, and we
were pleased to observe that the required tricycle 27
was produced in 43% yield. Dissolving metal reduction
of this tricyclic enone finally afforded the desired target
3 as a single stereo- and regioisomer (Scheme 8).
7. An independent synthesis of a TBDPS-protected version
of 8 via an enolate alkylation route has also been reported:
Nagumo, S.; Matoba, A.; Ishii, Y.; Yamaguchi, S.;
Akutsu, N.; Nishijima, H.; Nishida, A.; Kawahara, N.
Tetrahedron 2002, 58, 9871–9877.
8. (a) Hayes, C. J.; Bradley, D. M.; Thomson, N. M. J. Org.
Chem. 2006, 71, 2661–2665; (b) Hayes, C. J.; Sherlock, A.
E.; Selby, M. D. Org. Biomol. Chem. 2006, 4, 193–195; (c)
Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C.
J. J. Org. Chem. 2002, 67, 7613–7617; (d) Green, M. P.;
Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43,
6609–6611; (e) Worden, S. M.; Mapitse, R.; Hayes, C. J.
Tetrahedron Lett. 2002, 43, 6011–6014; (f) Mapitse, R.;
Hayes, C. J. Tetrahedron Lett. 2002, 43, 3541–3542; (g)
Green, M. P.; Prodger, J. C.; Sherlock, A. E.; Hayes, C. J.
Org. Lett. 2001, 3, 3377–3379; (h) Gabaitsekgosi, R.;
Hayes, C. J. Tetrahedron Lett. 1999, 40, 7713–7716.
Work in our laboratory is now focussed upon further
optimisation of the synthesis of 3, and on the utilisation
of this key intermediate for a total synthesis of (ꢀ)-
FR901483. These studies will be reported in due course.
9. Neophyl rearrangements of this type are fast (k ꢁ 107 sꢀ1
)
Acknowledgements
in comparison to hydrogen atom abstraction from
nBu3SnH (k ꢁ 106 Mꢀ1 sꢀ1) see: (a) Ingold, K. U. Pure
Appl. Chem. 1984, 56, 1767–1779; (b) Chatgilialoglu, C.;
Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1981, 103,
7739–7742.
We thank the EU (Marie Curie HPMT-CT-2001-00334
(DIAMeCTS)), KUSTEM, Malaysia, EPSRC and
Merck, Sharp and Dohme for the financial support of
this work.
10. Cyclohexenone 19 is the direct precursor to cyclohexenol
6, whose preparation is shown in Scheme 2.
11. The use of enantiomerically pure (+)- and (ꢀ)-BINAP was
also examined for this alkenylation reaction, but no
improvement in yield or product distribution was
observed over rac-BINAP.
References and notes
1. Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M.
J. Antibiot. 1996, 49, 37.
12. The relative stereochemistry of 24 was unambiguously
1
determined using H NMR NOE experiments.
2. FR901483: (a) Brummond, K. M.; Hong, S. P. J. Org.
Chem. 2005, 70, 907–916; (b) Kan, T.; Fujimoto, T.; Ieda,
S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett. 2004,
6, 2729–2731; (c) Ousmer, M.; Braun, N. A.; Bavoux, C.;
Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123,
7534–7538; (d) Maeng, J. H.; Funk, R. L. Org. Lett. 2001,
3, 1125–1128; (e) Ousmer, M.; Braun, N. A.; Ciufolini, M.
A. Org. Lett. 2001, 3, 765–767; (f) Scheffler, G.; Seike, H.;
Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593–
3.63%
1.38%
H
H
2.4%
H
H
4.24%
N
H
H
O
OTBS
H
24