Angewandte
Chemie
in 85% yield as a mixture of diastereoisomers (1.7:1 d.r.). The
structures of these isomers were unambiguously confirmed
using X-ray crystallography and confirm that the reaction
proceeded with exclusive endo selectivity.
The scope of this type II intramolecular [5+2] cyclo-
addition was then explored (Scheme 2). The reaction pro-
ceeded well with various acetoxypyranones with an alkene
tethered at the C3 position, giving bicyclo[4.4.1]undecanes
(
7b–e) as the sole products, even with the challenging gem-
dimethyl group (7d). The reaction of 5 f at 1008C for 3 h gave
f in 98% yield (1.0 gram scale) as a mixture of diastereo-
7
isomers (1.8:1 d.r.). Introduction of an OTBS or OTIPS group
at the allylic position of the dienophile improved the
diastereoselectivity (3.4:1 and 5.6:1 d.r., respectively), giving
bicyclo[4.4.1]undecanes 7g and 7h, respectively, in high yield.
The presence of a methyl group at the internal carbon center
on the alkene, as in 5e and 5i, gave high yields of the bridged
cycloheptane bicycles 7e and 7i, respectively, which have
a bridgehead quaternary carbon center. This result is partic-
ularly significant because the introduction of a quaternary
stereogenic bridgehead carbon center within a bridged bicycle
is very challenging. This result offers the possibility to further
modify this position (C* in Figure 1) in natural products, such
as ingenol, welwitindolinone alkaloids, and ajmaline. Product
7
j was also isolated in 90% yield, showing that an ester at the
terminal position of the alkene is also tolerated, and four new
stereogenic centers can be introduced diastereoselectively in
a single step. Furthermore, these conditions worked well with
methyl or ethyl substituents at the C6 position of the
acetoxypyranone, providing 7k and 7l with a quaternary
carbon center, respectively. It is noteworthy that an acetoxy
group at the allylic position of the dienophile alkene group
can also be tolerated, giving 7m with high diastereoselectivity
Scheme 3. Substrate scope using substrates with tethers of various
lengths. [a] For X-ray structure, see bottom of the graphic.
(
d.r. > 20:1) in 92% yield. This finding will be very important
for diastereoselective total synthesis of natural product and
potentially useful for the asymmetric synthesis through the
chirality transfer of the substrates.
This methodology was then investigated for the gener-
ation of other bridged cycloheptane bicycles from substrates
with tethers of various lengths (Scheme 3). Under similar
conditions, bicyclo[4.3.1]decanes 7n and 7o and bicyclo-
molecular [5+2] cycloaddition reactions in Schemes 2 and 3
proceeded with exclusive endo selectivity.
In the total synthesis of natural products, it is particularly
important that optically active molecules can be readily and
reliably generated for the investigation of their biological
activities. With this in mind, we evaluated the ability of
optically active 5v to undergo a stereospecific [5+2] reaction
without effecting the existing stereochemisty. Under the
optimized conditions (Scheme 3B), bicycle (+)-7v with
a bridgehead all-carbon quaternary center was obtained
with high diastereoselectivity (d.r. > 20:1) in 89% yield and
92% ee (see the Supporting Information). These results
indicate that this [5+2] cycloaddition reaction is stereospe-
cific, and that the chirality of the substrates effectively
transfers to the products.
To demonstrate such a concept, the methodology was then
applied to the highly strained tricyclic cores of ingenol and
cyclocitrinol (Scheme 4). Readily available iodide 9 was
converted to the corresponding alkyl lithium species and
reacted with cyclopent-1-enecarbaldehyde 10 to give 11. TBS
protection of the resultant alcohol then gave 12. Formylation
of the furan in 12 and reduction of the aldehyde afforded
[
5.4.1]dodecane 7p were formed. The more challenging
bridged 7/9-bicycle bicyclo[6.4.1]tridecane 7q was also
obtained in good yield. Oxygen-tethered substrates were
also tolerated, generating useful bridged cycloheptane bicy-
cles (7r–u) in high yield. Upon treatment of 5t with TMP at
1
008C, the terminal double bond migrated prior to the
cycloaddition to give 7t in 89% yield and with good
diastereoselectivity (6:1 d.r.). Bicycle 7u was isolated as the
sole product from 5u, indicating that the allenic ester forms
before the cycloaddition under basic conditions and with heat.
This product is difficult to access using other strategies.
Additionally, after deprotection–oxidation, compounds 8a,
8
f, 8j–l, and 8p were formed as single diastereomers (see the
Supporting Information). The structure of one separable
diastereoisomer of 7n, with exclusive endo selectivity, was
determined unambiguously using X-ray crystallography
(
Scheme 3B). These results showed that the type II intra-
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!
Mei, Guangjian
