.
Angewandte
Communications
our group became interested in developing an enantioselec-
tive synthesis to enable further exploration of their biosyn-
thetic relationships and biological activity.
The structurally complex presilphiperfolanols are distin-
guished by their rare, compact tricyclic terpenoid core, which
bears five contiguous stereocenters, two all-carbon quater-
nary centers, and a tertiary alcohol (Figure 1A). In addition
to these readily apparent structural features, considerable
ring strain is built into the tricyclic system,[4c,19] allowing these
compounds to undergo thermodynamically favorable skeletal
rearrangements leading to numerous terpenes (Fig-
ure 1C).[1–4] Our goal was to develop an efficient and general
asymmetric route to access various members of the presilphi-
perfolanol family. Here, we describe the first asymmetric total
syntheses of the reported structures of presilphiperfolanols
1 and 2. Our investigation has confirmed the structure of 2
and prompted us to reassign the structure of 1. Finally, in the
context of this reassignment, we propose a new biosynthetic
route to account for our observations.
Scheme 1. Gram-scale synthesis of acylcyclopentene 11 and IMDA.
HMDS=hexamethyldisilazane, pmdba=4,4’-methoxydibenzylidene-
acetone, TFE=2,2,2-trifluoroethanol, TBS=tert-butyl dimethylsilyl,
NOE=nuclear Overhauser effect.
Retrosynthetic analysis suggested that tricycle 9 could
serve as an intermediate for the divergent synthesis of several
members of the family (Figure 2). Two of the three rings could
be forged simultaneously in an intramolecular [4+2] cyclo-
mediated two-carbon ring contraction to provide multigram
quantities of acylcyclopentene 11 in 92% yield over two
steps.[20] After straightforward silyl dienol ether formation, we
were able to examine our bicyclization strategy (via 10a: R =
OTBS, R’ = CH2). The intramolecular Diels–Alder (IMDA)
reaction[29] proceeded efficiently with microwave irradiation
despite the lack of an activated dienophile,[30] affording
tricycle 16 in 80% yield over two steps as a single diastereo-
mer. The cis relationship of the C(7) and C(8) hydrogens was
determined by NOESY experiments on cycloadduct 16.
Unfortunately, in order to proceed toward targets 1 and 2,
a trans relationship was required.
With a general and concise strategy to the tricyclic core,
we next pursued the installation of the naturally occurring
substituents and stereochemistry present in the strained
presilphiperfolanols. Our revised strategy aimed to introduce
the gem-dimethyl group at an earlier stage to potentially
improve IMDA diastereoselectivity toward the desired trans
product (via acylcyclopentene 17, Scheme 2). Inspection of
the possible IMDA transition states of the silyl dienol ether
10b suggested that nonbonding interactions from the C(6)
steric bulk could help favor the desired C(7) stereochemistry
(Scheme 2B).[31] In TS-A, the steric elements would be
oriented away from the bond-forming centers while cyclo-
addition through TS-B could only proceed with severe steric
clash between the cyclopentene ring and the gem-dimethyl
functionality. Additionally, the new gem-dimethyl groups
should decrease the C(5)-C(6)-C(7) bond angle while also
providing greater conformational bias[32] for the desired
cyclization with this uncommon IMDA substrate type.[33]
Our efforts toward this end commenced with a regio-
selective 1,4-hydroboration/oxidation of the sterically hin-
dered 2-substituted 1,3-diene 18 after carbonyl protection of
11 (Scheme 2A). While Pd,[34a] Fe,[34b] and Ni[34c,d] catalysts are
known to effect this transformation, literature precedent
suggested that the regioselective formation of linear product
19a would be most favorable with iron catalysis. To our
surprise, the Ritter FeCl2(py-imine) catalyst system provided
a disappointing 1.1:1 ratio of linear:branched products.[34b,35]
Figure 2. Synthetic strategy toward the presilphiperfolane core.
addition (via 10), thereby avoiding a more conventional
sequential annulation strategy. Monocyclic precursor 11 could
be prepared from an a-quaternary vinylogous ester 12 by
a two-carbon ring contraction. The strategic application of
our recently reported methodology for the synthesis of g-
quaternary acylcyclopentenes and a-quaternary vinylogous
esters would provide a solid starting point for our synthesis.[20]
Our synthetic efforts began with acylation/alkylation of
commercial 3-isobutoxycycloheptenone 14 using isoprenol-
derived carbamate 15[21,22] and methyl iodide under basic
conditions (Scheme 1). This improved protocol enabled
efficient access to b-ketoester 13 in a single synthetic
operation and avoided employing the corresponding cyano-
formate.[23] With our desired functionality installed, we were
poised to evaluate our asymmetric Pd-catalyzed decarbox-
ylative alkylation[20,24] on this novel substrate type containing
a 2-vinyl allyl fragment. To our delight, treatment of b-
ketoester 13 with catalytic Pd2(pmdba)3 and (S)-tBu-
PHOX[25,26] in toluene proceeded smoothly on 10 g scale,
affording isoprenylated vinylogous ester 12 in 91% yield and
95% ee.[27,28] Subsequent LiAlH4 reduction afforded an
intermediate b-hydroxyketone, which underwent a base-
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!