Organic Letters
Letter
gives 2,8-dioxabicyclo[4.4.0]decanes 3 in good yields (75−
selectively manipulating the cyclization product. The latter
approach was investigated using 15 as the substrate (Scheme
3). Treatment of 15 with N-bromosuccinimide and NaHCO3
6
,7
83%).
To begin, an efficient and versatile approach for the synthesis
of a series of γ,δ-unsaturated alcohols was required. Primary
alcohol 10 was prepared in two steps and 76% overall yield
from the known o-hydroxycinnamaldehyde 8. A 1,4-addition
Scheme 3. Introduction of the Cinnamoyl Side Chain
8
of phenylvinylboronic acid to 8 in the presence of Et NH gave
2
lactol 9 which was reduced with NaBH (Scheme 2).
4
Scheme 2. Synthesis and Cyclization of γ,δ-Unsaturated
Alcohol 10
gave bromide 16 in 73% yield; the regiochemical outcome of
the reaction was confirmed by NOE studies. Bromide 16 was
converted to cinnamoyl derivative 18 via lithiation with nBuLi
followed by reaction with Weinreb amide 17.
With optimized conditions in hand for the key cyclization to
generate the tricyclic framework with two equatorial sub-
stituents, the next challenge was stereoselective synthesis of the
secondary alcohol 4 required for cyclization to 5 (Scheme 1).
Thus, lactol 9 was reacted with phenethylmagnesium bromide
to give a ca. 5:1 mixture of diastereomers 19 and 20 in 96%
yield, which were separated by column chromatography. The
major alcohol 19 was recrystallized from ethyl acetate/hexane,
and X-ray crystallography confirmed that the hydroxyl group
and styryl side chain were syn (see Supporting Information).
The selectivity in this addition was unexpected, and we propose
that it may arise through chelation of the phenol−OH to the
Grignard reagent. Indeed following selective protection of
phenol of 10 as a benzyl ether, using benzyl bromide and
K CO , a sequential oxidation to aldehyde 21 and reaction with
The key cyclization of γ,δ-unsaturated alcohol 10 with
benzaldehyde was investigated, and following optimization, it
was found that use of TMSOTf, in CH Cl at −50 °C, gave the
2
2
required product 12 in 95% yield as a single diastereomer while
generating two rings and three new stereocenters in one pot
2
3
phenethylmagnesium bromide gave a 1:1 mixture of diaster-
eomers 22 and 23 in 85% yield; these coeluted on column
chromatography. Each secondary alcohol 19 and 20 was
separately converted to their corresponding benzyl ether 22
and 23, and comparison of the spectral data confirmed the
(
Scheme 2). NMR studies (500 MHz, CDCl ) revealed that 12
3
has the required trans ring junction (1-H: δ 3.09, td, J 11.5, 4.0
Hz: 6-H: δ 2.48, dt, J 11.5, 9.5 Hz) with both side chains
equatorial (5-H: δ 4.27, d, J 9.5 Hz; 7-H: δ 4.90, J 9.5 Hz).
Various electrophiles could be used in the cyclization including
benzaldehydes with electron-deficient or electron-rich aromatic
rings; the 4-phenylsulfonyl and 3,4-dimethoxy derivatives 13
and 14 were isolated in 86% and 80% yield, respectively. When
propanal was used as the electrophile, a 9:1 mixture of epimers
11
results from the Grignard reaction.
Scheme 4. Synthesis of Cyclization Substrates 19 and 20
1
5 at C-5 was formed in 95% yield. Reddy and co-workers have
very recently published their investigations on a similar
cyclization. However, they reported the reaction of either 10
9
with 2,3,4-trifluorobenzaldehyde or the corresponding PMB
protected phenol with a series of aldehydes, in the presence of
TMSOTf at −40 °C, gave a mixture of products in varying
9
yields.
Our strategy has the added benefit that an enantioselective
10
conjugate addition may be achieved using a chiral base.
Indeed we found that, by using imidazolidinone 11 and
CHCl CO H in place of Et NH in the 1,4-addition step, the
2
2
2
resultant lactol 9 was isolated with 90:10 er (established by
chiral SFC) thus enabling the enantioselective synthesis of our
targets. The enantiopurity of primary alcohol 10 was improved
to 99.8:0.2 er following recrystallization from chloroform/
pentane. Following conversion of 10 to the pyranochromene
derivative 12, it was confirmed that there was no loss of
stereochemical integrity during the cascade reaction.
To prepare analogues more closely related to calyxin J and
epicalyxin J further, functionality was required on the fused
aromatic ring. This could be achieved either by starting with a
more complex phenol in γ,δ-unsaturated alcohol 10 or by
The TMSOTf-mediated reaction of diastereomer 19 with
benzaldehyde gave cyclized product 24 as a single diastereomer
in 85% yield (Scheme 5). H NMR coupling constants
combined with NOE studies established the structure 24 with
the trans ring junction and all three side chains as equatorial. In
this case both the phenol and phenethyl side chains can occupy
pseudoequatorial positions in the oxycarbenium transition state,
thus generating the three new stereocenters via the cascade
process proposed in Scheme 1.
1
B
Org. Lett. XXXX, XXX, XXX−XXX