Journal of the American Chemical Society
Communication
underwent smooth conversion to the required bicyclic product
11 (as a mixture of three CC position isomers) under the
influence of catalyst 1 (1.0 equiv) at −78 °C. The TIPS ether
mixture 11 was then transformed into a single product, the
conjugated aldehyde 12, in good yield by a four-step sequence:
(1) selective hydrogenation at the disubstituted olefenic linkage
using Brown’s P-2 nickel boride catalyst and H2 at 1 atm; (2)
desilyation; (3) Swern oxidation; and (4) base-catalyzed
isomerization to a single product, the conjugated aldehyde
12. Wittig methylenation of 12 afforded 13, which by
hydroboration and Suzuki coupling4 with the iodo ester 14
and basic hydrolysis provided (+)-dysideapalaunic acid 8.5
The enantioselectivity of the cyclization was determined to
the 10:1 by HPLC analysis of the pure conjugated α,β-enal 12.3
The absolute stereochemical course of the cyclization 10 → 11
follows from the comparison of the synthetic product 8 with
dysideapalaunic acid.4 This pathway of synthesis is much
simpler and shorter than the process that was employed in the
original synthesis of 8 (17 steps from a chiral octalin dione).2
We have also applied this methodology to a very short
synthesis of dehydroabietic acid (15)6 as outlined in Scheme 4
Scheme 5. Simple Route to 4-Epipodocarpic Acid (20)
Scheme 6. Enantioselective Route to Hydrophenylenes
Scheme 4. Enantioselective Synthesis of Dehydroabietic
Acid (15)
This type of double annulation has considerable generality as
is indicated by the five examples shown in Table 1. These
tricyclic structures are versatile intermediates for the synthesis
of many more complex structures by further elaboration. For
example, the product of Table 1, entry 1, tricyclic olefin 30 has
been transformed into a wide variety of tri- and tetracyclic
products, as is illustrated by the transformations in Scheme 7.
Several of the transformations of 30 shown in Scheme 7
deserve comment. The addition of dichloroketene10 to 30 is
both regio- and diastereoselective to form 31. The Bayer−
Villiger oxidation of 31 gave 32 regioselectively, but the RuO4
oxidation of 31 to give 3311 occurred with the opposite O-
insertion regiochemistry. The allylic oxidation of 30 can be
directed to either allylic terminus to form 34 or 35,12
depending on reagent. The hydroboration−Dess−Martin
oxidation sequence 30 → 36 was diastereoselective.
A third way of utilizing the chiral catalyst 1 for the initiation
of cationic cyclization at an internal π-bond is demonstrated by
the process depicted in Scheme 8. In this approach bromine
substituents at the terminal double bond are employed to
enforce selective proton transfer from catalyst 1 to the internal
double bond, as takes place in the enantioselective conversion
of the dibromodiene 39 to the bicyclic product 40 (Scheme 8).
The two bromine substituents on the terminal carbon of 38
decrease the proton affinity of the terminal π-bond sufficiently
so that cyclization occurs solely by protonation of the internal
double bond. The standby dibromovinyl group 40 also serves a
useful purpose as a reactive center for further synthetic
and of the C(4)-diasteroisomer of podocarpic acid (16)7 as
shown in Scheme 5. The brevity and enantioselectivity of these
routes to 15 and 16 underscore the utility of the key
enantioselective cationic polycyclization steps. The correspond-
ence of optical rotation of synthetic 15 and dehydroabietic acid
established the absolute stereochemical course of the cationic
cyclization step, which clearly applies to the synthesis of 20 as
well.
A second tactic for achieving enantioselective cationic
cyclization originating in an internal π-bond is illustrated in
Scheme 6, which shows a simple route to the acetylenic olefin
28 and its cyclization by the action of the chiral catalyst 1 in a
single step to the tricyclic product 29 in 75% yield and 87% ee.
This process is clearly initiated by protonation of the internal
olefinic π-bond to from a bicyclic acetylene which then
undergoes a second (and slower) cyclization to generate the
tricycle 29, which is of interest as a close analogue of the
pseudopterosin core.8,9 This second tactic succeeds because of
the lower proton affinity of CC relative to CC.
B
dx.doi.org/10.1021/ja4125093 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX