4888
D. Rajagopal et al. / Tetrahedron Letters 42 (2001) 4887–4890
171.63
29.80
170.87
28.72
8.27
O-H
O-H
O
O
O
30.15
30.15
O
33.54
21.56
N
N
H
O
H
O
60.39
H
H
61.59
24.72
111.28
110.56
23.62
46.24
45.24
33.54
8
9
200 ml). The combined organic extract was washed
with brine, dried (anhyd. MgSO4) and concentrated in
vacuo to give the crude ketol SS-5a as a tan solid. This
was refluxed in dry benzene (25 ml) with a pinch of PTS
for 2 h to give a brown viscous liquid after washing
with H2O and removal of the solvent. Chromatography
on silica gel (200–400 mesh) with CHCl3 as eluant
furnished several fractions; using TLC, the appropriate
fractions were combined to give a viscous pale yellow
material (yield: 65–70%, ee: 76.6%). This material was
recrystallized from an ether–hexane (1:1) mixture after
cooling to give colorless crystals of S-1, mp 66–66.5°C
(60–65% chemical yield) and [h]2D5 +362.06 (c 1, C6H6),
ee 98.6%.
seen for trione 5, ketol SS-5a, the soluble proline
complex 8 and unreacted MVK. After 3 h the forma-
tion of ketol SS-5a is complete with no trace of MVK,
trione 5 or complex 8. Continued standing (up to 68 h)
showed mainly ketol SS-5a with a trace of enone S-1.
There was no evidence for the formation of any enam-
ine intermediate. Complex 8 showed the carbon signals
as indicated above. Evidently, the soluble proline com-
plex gives the Michael adduct 5 known6,8 to cyclize to
ketol SS-5a with S-proline. The one-step reaction with
the dione 4 was similarly monitored by taking the 13C
NMR spectra at regular intervals over a period of 22 h.
Again, there was no evidence for the formation of an
enamine; there was only evidence for the soluble com-
plex 9, which reacts with MVK to give the adduct 6,
known5a,8 to cyclize to S-2 in the presence of S-proline.
The same mechanism is probably followed in the one-
step processes carried out without solvent, though we
have no experimental evidence.
The above methodology was applied to dione 4, using
dry DMSO or dry DMF as solvent and an equivalent
amount of S-proline. After work-up, as above, a crude
brown liquid was obtained. Chromatographic purifica-
tion (silica gel, 25% EtOAc/hexane) furnished a less
colored liquid, which on distillation in vacuo (115–
120°C/0.05 mm) furnished S-2 as a liquid in 68%
chemical yield and 63% optical yield.
3. One-step syntheses of optically active spiroenediones
We have extended the one-step methodology to annula-
tion of a number of 2-formylcyclonones (Scheme 2),
and obtained the optically active spiroenediones S-14,
R-7 and S-15. The reaction conditions and results are
summarized in Table 1.
The same one-pot method in the presence of an equiva-
lent amount of pyrrolidine and acetic acid instead of
S-proline furnished a 70% yield of ( )-2, mp 48–9°C
after chromatography and distillation. The ‘neat’
methodology of asymmetric synthesis7 without solvent
was applied to the above one-pot annulation. Table 1
summarizes the results obtained with and without sol-
vent; both the optical and chemical yields were
improved using solvent.
The annulations were carried out ‘neat’ as well as in dry
DMSO. The chemical (48–52%) and optical yields (9–
34%) were approximately the same. The product
obtained from 2-formylcyclododecanone 13 turned out
to be ( )-16, identical in mp and spectral properties
with an authentic sample prepared according to the
literature.9 The spiroenediones were characterized by
1H NMR, 13NMR, CD and elemental analysis. Their
absolute configurations were deduced by comparison of
the ORD curves with that of the diketone S-2. The
2. Mechanism of the one-pot reaction
The above one-pot syntheses, particularly those carried
out in a solvent, may be expected to involve initial
formation of chiral enamines. With a view to getting
evidence for such intermediates, we carried out 13C
NMR studies to follow the course of the one-step
formation of ketol SS-5a.
O
CHO
1. S-proline
n
O
n
O
2. MVK
NEAT
Equivalent amounts of dione 3 and S-proline were
mixed together in DMSO-d6, allowed to stand for 6 h
and then distilled MVK (1 equiv.) was added. 13C
NMR (400 MHz) spectra taken at regular intervals
revealed that initially the insoluble proline forms the
soluble complex 8, which then reacts with MVK. Imme-
diately after the addition of MVK, carbon signals are
n = 1 , 10
n = 2 , 11
n = 3 , 12
n = 8 , 13
n = 1 , S-14
n = 2 , R-7
n = 3 , S-15
(±)
n = 8 , 16
Scheme 2.