Organic Letters
Letter
with 1,3-dihydroxyacetone (DHA) under basic conditions,
which made us decide to treat the mixture of 13 and 8 in situ
with acidic methanol to bring about the oxa-Michael reaction.
Thus, a reaction mixture prepared by the addition of PhLi (1.1
equiv) to (±)-7 in THF at −78 °C followed by 30 min of
stirring was treated, without extraction, with CSA (1.6 equiv)
and MeOH (1 equiv) successively, and the resulting mixture
was stirred at −30 °C for 1.5 h. This one-pot process afforded,
as expected, the desired cyclic enol ether 14 in an exclusively
gave tricyclic product 5 diastereoselectively in an excellent
5
,6
yield of 88% (Scheme 1a). This transformation can be
rationalized by assuming the following three consecutive
reactions: (1) oxa-Michael addition of DHA to enone 4,
which proceeds trans to the C5 methyl group; (2) intra-
molecular aldol reaction of the resulting adduct 6; and finally
(
3) intramolecular hemiacetalization to furnish the tricycle 5.
9
Inspired by this precedent, in which the cyclohexenone
derivative 4 served as the Michael acceptor, we envisaged a
cascade sequence involving the 2,3-dihydropyrylium ion 9 as
the pivotal intermediate. The cyclic oxocarbenium ion 9 would
possibly undergo the oxa-Michael addition of DHA to give
keto enol ether 10, which would then lead to bicyclic oxonium
ion 11 via an intramolecular aldol-type reaction under acidic
conditions. Finally, acetal formation from the hydroxy
oxonium ion 11 should afford 1. The generation of the key
transient intermediate 9 would be possible by treating cyclic
hemiacetal 8 with an appropriate acid, and the hemiacetal 8, in
turn, would readily be obtained by the addition of a phenyl
anion species to known chiral lactone 7. Since the reactions
from 8 to 9 and from 10 to 11 were both considered to be
promoted by acid, we expected that the conversion of 8 into 1
could be realized in a cascade manner.
trans-selective manner in 71% yield. The relative stereo-
1
chemistry of 14 was assigned on the basis of the H NMR
coupling constants depicted in Scheme 2.
Having established the desirable trans-selective formation of
14, we applied the protocol to the one-pot synthesis of 1 from
7 using DHA instead of methanol (Scheme 3). The optically
Scheme 3. One-Pot Synthesis of 1 from 7 via an Oxa-
Michael−Aldol−Acetalization Cascade
To preliminarily assess the diastereoselectivity of the oxa-
Michael addition reaction between 9 and DHA, we first
conducted a model experiment using (±)-7, prepared from 12
7
by a known three-step sequence, and methanol as the
active form of 7 (96% ee) was prepared from 12 in ca. 70%
nucleophile (Scheme 2). Addition of PhLi to (±)-7 and
yield by a three-step sequence comprising an asymmetric
10
allylation, esterification of the resulting homoallylic alcohol
Scheme 2. Addition of Phenyllithium to (± )-7 Followed by
with acryloyl chloride, and ring-closing metathesis using
11
Treatment with Wet SiO or CSA/MeOH
Grubbs first-generation catalyst. After exposing the α,β-
unsaturated lactone 7 to PhLi in THF, the resulting mixture
was successively treated with CSA, DHA (dimer), and DMF,
providing 1 as a single diastereomer in an excellent yield of
2
9
0%; the addition of DMF was necessary to dissolve the
1
13
crystalline DHA dimer. The H and C NMR spectra of 1
obtained as a colorless crystalline solid (mp 127.3−128.8 °C)
were in good agreement with those of natural diocollettines A.
2
0
The specific rotation of 1 ([α]
−130 (c 0.19, toluene);
D
2
0
D
[
α] −150 (c 0.10, MeOH)) also matched the value reported
20
for the natural product ([α]
−126.82 (c 0.104,
D
1a,12
MeOH)).
In conclusion, the enantio- and diastereoselective total
synthesis of diocollettines A (1) was accomplished in a
surprisingly excellent yield of 90% from the known α,β-
unsaturated lactone 7 by a one-pot transformation consisting
of the addition of PhLi to 7 (7 → 8), acid-promoted
dehydration of 8 to give the 2,3-dihydropyrylium ion 9, and
the oxa-Michael−intramolecular aldol−intramolecular acetali-
zation cascade (9 → 10 → 11 → 1). The overall yield of 1
obtained in 4 steps from the commercially available aldehyde
quenching of the resulting mixture with sat. aq NH Cl to
4
obtain 8 (the precursor of 9) gave unexpectedly a considerably
complex mixture, probably due to the acidic nature of the
reaction medium after quenching, which might have induced
some additional reactions. Fortunately, when the reaction was
quenched with wet silica gel, the clean and nearly quantitative
formation of an equilibrium mixture consisting of the cyclic
hemiacetal 8 (produced as a single diastereomer) and its ring-
1
2 amounted to 63%. Our efforts toward the total synthesis of
the related natural products streptoglycerides A and B (2 and
3
) are now underway and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
1
opened form 13 (Z-form) was observed by H NMR analysis
of the crude reaction product, which showed the latter to be
8
significantly predominant (13/8 = ca. 12:1). Upon exposure
to prolonged silica gel column chromatography, the mixture
gradually changed into a more complicated product mixture,
Experimental procedures, characterization data, and
NMR spectra for new compounds (PDF)
B
Org. Lett. XXXX, XXX, XXX−XXX
Kawamoto, Misaki
