2 Further members of this family were isolated subsequently, see:
J. I. Jimenez, U. Huber, R. E. Moore and G. M. L. Patterson,
J. Nat. Prod., 1999, 62, 569.
3 C. D. Smith, J. T. Zilfou, K. Stratmann, G. M. Patterson and
R. E. Moore, Mol. Pharmacol., 1995, 47, 241. For a relevant
review, see: I. D. Kerr and N. S. Simpkins, Lett. Drug
Des. Discovery, 2006, 3, 607.
4 For reviews, see: (a) C. Avendano and J. C. Menendez, Curr. Org.
Synth., 2004, 1, 65; (b) J. C. Menendez, Top. Heterocyl. Chem.,
2007, 11, 63.
Scheme 4 Alkene transposition.
5 (a) J. L. Wood, A. A. Holubec, B. M. Stoltz, M. M. Weiss,
J. A. Dixon, B. D. Doan, M. F. Shamji, J. M. Chen and
T. P. Heffron, J. Am. Chem. Soc., 1999, 121, 6326;
(b) G. I. Elliot, J. P. Konopelski and M. M. Olmstead, Org. Lett.,
1999, 1, 1867; (c) M. E. Jung and F. Slowinski, Tetrahedron Lett.,
distortions from ideal trigonal planar geometry. In 16 the
angles subtended at C12 range from 114.43(11) to 128.59(13)1
and sum to 358.101; C12 lies 0.113 A out of the C11–C13–C17
plane. The geometry at C14 in 18 is even more distorted, with
angles ranging from 111.96(15) to 130.99(17)1 and summing to
357.871; C14 lies 0.120 A out of the C6–C13–C15 plane.
We also found that these enones could not be coerced into
Michael addition chemistry, either using soft heteroatom nucleo-
philes, such as thiolate (PhSH, Et3N, CH2Cl2 at reflux) or
organocuprate reagents. Our disappointment at the reluctance
of these bridgehead alkenes to react with nucleophiles might be
compensated if they could instead be reacted with electrophilic
reagents. However, the co-existence of a much more reactive
nucleophilic indole in these systems dictates that conversion into
oxindoles should be carried out prior to attempting electrophilic
additions to the bridgehead alkenes. Such studies are ongoing.
Finally, we were interested to attempt isomerisation of the
bridgehead enones. Treatment of 16 with mild bases such as
DBU or NaOMe did not result in isomerisation of the bridge-
head a,b-unsaturated ketone into a less strained b,g-unsaturated
isomer. However, treatment of 16 with RhCl3 in EtOH at reflux
for 24 h resulted in quite clean isomerisation to give the
transposed enone 20, Scheme 4.12
2001, 42, 6835; (d) H. Deng and J. P. Konopelski, Org. Lett., 2001,
3, 3001; (e) P. Lo
´
´
pez-Alvarado, S. Garcia-Granda, C. Alvarez-Ru
´
a
and C. Avendano, Eur. J. Org. Chem., 2002, 1703; J. A. MacKay,
R. L. Bishop and V. H. Rawal, Org. Lett., 2005, 7, 3421;
(f) T. J. Greshock and R. L. Funk, Org. Lett., 2006, 8, 2643;
(g) R. Lauchli and K. J. Shea, Org. Lett., 2006, 8, 5287; (h) J. Xia,
L. E. Brown and J. P. Konopelski, J. Org. Chem., 2007, 72,
6885.
6 J. Baudoux, A. J. Blake and N. S. Simpkins, Org. Lett., 2005, 7,
4087.
7 For our previous bridgehead enolate studies, see: G. M. P. Giblin,
D. T. Kirk, L. Mitchell and N. S. Simpkins, Org. Lett., 2003, 5,
1673. For recent use of bridgehead enolates in synthesis, see:
(a) C. Tsukano, D. R. Siegel and S. J. Danishefsky, Angew. Chem.,
Int. Ed., 2007, 46, 8840; (b) N. M. Ahmad, V. Rodeschini,
N. S. Simpkins, S. E. Ward and A. J. Blake, J. Org. Chem.,
2007, 72, 4803.
8 We are not aware of direct precedent for this type of structure. This
structure was subsequently confirmed by X-ray crystallography;
further details will be published elsewhere. The undesired excursion
via the azide 13 could be avoided by removal of excess azide salts
from the intermediate acyl azide prior to thermolysis in toluene,
providing easy access to 15.
9 S. Kim and K. Y. Yi, J. Org. Chem., 1986, 51, 2613.
10 S. M. Sheehan, G. Lalic, J. S. Chen and M. D. Shair, Angew,
Chem., Int. Ed., 2000, 39, 2714.
11 For both structures displacement ellipsoids are drawn at the 50%
probability level. Crystal data for enone 16. C16H15NO, FW =
This isomerisation moves the ring alkene into the position
required for welwistatin, making the sequence of bridgehead
selenylation, elimination and isomerisation a new possibility for
installation of the vinyl chloride found in the natural product.
We expect that the alkene function in 20 could serve as a
very useful handle for preparing more advanced welwistatin
models and synthetic intermediates, and we will report on
further progress in due course.
237.29, monoclinic, space group P21/c,
14.083(2), 10.0083(14) A,
a
b
=
=
9.7651(14),
117.807(2)1,
b
=
c
=
U = 1217.4(3) A3, Z = 4, Dc = 1.295 Mg mꢁ3, m(Mo-Ka) =
0.081 mmꢁ1
,
T
=
150(2) K. 2788 unique reflections
(Rint = 0.106). Final R1 [2263 I 4 2s(I)] = 0.0492, wR2
(all data) = 0.134. Enone 18: C19H23NOSi, FW = 309.47,
orthorhombic, space group Pna21,
a = 23.565(2), b =
10.8079(10), c = 6.5185(6) A, U = 1660.2(4) A3, Z = 4,
Dc = 1.238Mg mꢁ3, m(Mo-Ka) = 0.143 mmꢁ1, T = 150(2) K.
3751 unique reflections (Rint = 0.039). Final R1 [2929 I 4 2s(I)] =
0.0349, wR2 (all data) = 0.0741.
Notes and references
1 K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter, G. M.
L. Patterson, S. Shaffer, C. D. Smith and T. A. Smitka, J. Am.
Chem. Soc., 1994, 116, 9935.
12 P. A. Grieco, M. Nishizawa and N. Marisovic, J. Am. Chem. Soc.,
1976, 98, 7102.
ꢀc
This journal is The Royal Society of Chemistry 2009
1400 | Chem. Commun., 2009, 1398–1400