Scheme 1
Scheme 2a
the nature of R, it is envisioned that the single stereogenic
center in 4 would have an influence on the cycloaddition,
either by steric repulsion or hydrogen bonding, and thus
allow an asymmetric synthesis toward (-)-cephalotaxine to
be realized.
a Reaction conditions: (a) DEAD, Ph3P, THF, rt; (b) hν, MeCN,
Pyrex, 29 h.
Initial model studies were carried out using dimethyl
maleimide 6, as our previous studies showed that photocy-
cloaddition of simple maleimide derivatives leads to side
products resulting from dimerization.6 Mitsunobu coupling
of 6 with the known9 cyclopentenone-alcohol 7 gave the
photocycloaddition precursor 8 in 66% yield. Irradiation of
this in acetonitrile for 29 h gave a 16% yield of the tricyclic
azepine 9 along with 30% recovered starting material.
Confirmation of the structure and proof that the relative
stereochemistry of 9 was the same as 1 was confirmed by
X-ray crystallographic analysis (Scheme 2).10 The low yield
and uncharacteristically long irradiation time for this system
was attributed to the presence of the cyclopentenone unit. It
was postulated that the enone unit was effectively quenching
the excited state of the maleimide by intersystem crossing,
thus preventing efficient turnover of the substrate. Attempts
to avoid this problem by reduction of the enone carbonyl,
and thus removal of the competing chromaphore, were
fruitless. It was found that whatever the reducing agent
employed, we were unable to reduce 8 effectively, as
reduction of the maleimide carbonyls was always an at-
tendant problem.
using standard protocols gave the ethers 11a-c in moderate
to excellent yields. Metal halogen exchange with t-BuLi and
reaction of the resulting vinyllithiums with oxetane under
BF3‚Et2O catalysis12 gave the alkenols 12a-c. Mitsunobu
coupling of these with dimethyl maleimide as before gave
the photocycloaddition precursors 13a-c in good yield.
Irradiation of these gave the [5 + 2] products 14a-c as
mixtures of diastereoisomers. The fact that the yields were
higher and irradiation times much shorter confirmed that the
cyclopentenone chromophore in 8 was indeed responsible
for the very limited lack of success with this system.
However, it was disappointing to note the poor levels of
diastereoselection obtained with the three alkoxy groups
studied. Even with very bulky silyl groups such as TIPS
(14b) the highest de observed was only 17%. This would
clearly suggest that any alkoxy group has a very minor
influence over which face of the cyclopentene the photoex-
cited maleimide unit adds to (Scheme 3).
In light of this we then elected to study if a free hydroxy
group could influence the stereochemical outcome of the
photocycloaddition by formation of a hydrogen-bonded
intermediate. Initial attempts to desilylate 13c were frustrated
by the apparent instability of the alcohol 15 to the standard
TBAF reaction conditions. It was found, however, that 15
could be isolated in high yield if the TBAF-mediated
desilylation was effected in the presence of AcOH.13 Irradia-
To overcome these problems an alternative synthesis of
cyclopentenol-substituted ethers was developed. 3-Bromo-
2-cyclopentene-1-ol 10 was readily available, in multigram
quantities, from cyclopentane-1,3-dione.11 Protection of 10
(8) In reality a protected maleimide will be used to avoid potential
problems with photodimerization (ref 6).
(9) Molander, G. A.; Hiersemann, M. Tetrahedron Lett. 1997, 38, 4347.
(10) Data deposited at Cambridge Crystallographic Data Centre (CCDC
158520).
(11) (a) Ito, S. I.; Kasai, M.; Ziffer, H. Silverton, J. V. Can. J. Chem.
1987, 65, 574-582. (b) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I.
Can. J. Chem. 1982, 60, 210-223.
(12) (a) Eis, M. J.; Wrobel, J. E.; Ganem, B.; Bach, T.; Bergmann, H. J.
Am. Chem. Soc. 1984, 106, 3693-3694. (b) Yamaguchi, M.; Shibato, K.;
Hirao, I. Tetrahedron Lett. 1984, 25, 1159-1162. (c) Overman, L. E.;
Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248-2256.
3006
Org. Lett., Vol. 3, No. 19, 2001