Angewandte
Chemie
enabled the stereoselective introduction
of an allyl group at the C4 position with
the potential for further manipulation
to a diverse range of functional groups.
Blepharocalyxin D is assembled on
a
trans-2,8-dioxabicyclo[4.4.0]decane
scaffold that has equatorial side-chains
at the C3, C5, C7, and C9 positions
(Scheme 1).[1] Having established that
this bicyclic framework with equatorial
groups at the C3 and C7 positions may
be assembled efficiently from g,d-unsa-
turated alcohols, we turned our atten-
tion to the incorporation of a further
substituent at the C9 position to give Scheme 9. Preparation of trisubstituted 2,8-dioxabicyclodecanes.
analogues of blepharocalyxin D. The
acid-mediated reaction of racemic unsa-
turated alcohol 8 with (R)-3-benzyloxybutanal (27) gave two
bicyclic products 28 and 29 from the reaction of the
enantiopure aldehyde with each enantiomer of alcohol 8
(Scheme 8). The reactions are likely to proceed via tetrahy-
dropyrans I and II, which each have three equatorial sub-
stituents that are generated from the cyclization of the
initially formed oxocarbenium ions. In the case of (3R)-
diastereomer I, the second ring closure leads to an equatorial
group at the C9 position to give 28, whereas the (3S)-isomer II
gave the bicyclic product 29, which has an axial methyl group
(H9 in 28, d = 3.75 (dqd, J = 11, 6, and 2 Hz); H9 in 29 d = 4.5
(apparent quin, J = 7 Hz)). The two products were readily
separated by chromatography and the structures were con-
firmed by extensive NMR spectroscopic studies.
All of the studies described above involve racemic (E)-2-
hydroxy-6-arylhex-5-en-2-ols as substrates, which lead to 2,8-
Scheme 10. Enantioselective synthesis of 40. DMSO=dimethylsulfox-
ide; TBS=tert-butyldimethylsilyl.
dioxabicycles with an equatorial methyl group at the C3 posi-
tion. In contrast, blepharocalyxin D has a 2-arylethyl group at
the C3 position. Hence, for the synthesis of further analogues
of blepharocalyxin D, racemic alcohol 30, which has a p-
methoxyarylethyl group (Scheme 9), was prepared by the
addition of the requisite Grignard reagent to aldehyde 7. The
reaction of 30 with (S)-3-benzyloxyaldehyde 31 under the
standard conditions gave (À)-2,8-dioxabicycle 32 in 35%
yield (from cyclization with the R enantiomer of 30) and
diastereomer 33 in 35% yield (from cyclization with the
S enantiomer of 30).
34 was prepared by a Keck allylation of dihydrocinnamalde-
hyde,[15] and was then protected as silyl ether 35. After
hydroboration of the alkene with 9-borabicyclo[3.3.1]nonane
(9-BBN)/H2O2, the resultant primary alcohol 36 was oxidized
under Swern conditions to give aldehyde 37 in 68% yield over
the 2 steps. Treatment of 37 with diethyl benzylphosphonate
in the presence of nBuLi gave 38 with the required
E geometry at the double bond. Subsequent deprotection of
the silyl ether of 38 gave alcohol 39.[16] Treatment of 39 with 3-
benzyoxylpropanal in the presence of TMSOTf gave (À)-2,8-
dioxa[4.4.0]bicyclodecane (40) in 86% yield.
To extend the utility of this method, a route for the
enantioselective synthesis of (+)-g,d-unsaturated alcohol 39
was developed (Scheme 10). The known[14] (S)-allylic alcohol
In conclusion, an efficient approach
for the rapid stereocontrolled assembly of
2,8-dioxa[4.4.0]bicyclodecanes from g,d-
unsaturated alcohols has been reported.
The substrates for the key cyclizations are
readily prepared in high yield by using
either a Johnson–Claisen rearrangement
or Horner–Wadsworth–Emmons reaction
to establish the E configuration at the
double bond. The cascade process gener-
ates the two heterocyclic rings and creates
Scheme 8. Preparation of trisubstituted 2,8-dioxabicyclodecanes.
up to three new stereogenic centers in
Angew. Chem. Int. Ed. 2012, 51, 3901 –3904
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3903