Organic Letters
Letter
structures of six PPAPs (garcimultiflorones D−F, 18-
hydroxygarcimultiflorone D, isogarcimultiflorone F, and
garcimultiflorone J, 23−28), which were previously deter-
mined by NMR analysis and comparing NMR with the
proposed guttiferone F, are now structurally corrected to be
30S (Scheme 4C).26 Specifically, we now know that the
cyclization of the natural product previously identified as
guttiferone F (but now known to be garcinol) led to cambogin,
not 30-epi-cambogin as reported.16 After these revisions, all
(30R)-endo-type B PPAPs with a lavandulyl group at C-5 are
corrected to be (30S)-endo-type B PPAPs.27 Despite the fact
that there is still a number of PPAPs with unknown C-30
the natural PPAPs are most likely to have an (S)-lavandulyl
group at C-5. This bias can be used as a valuable reference for
determining the structure of unknown PPAPs and as an
inspiration for preferred biosynthetic pathways.
Scheme 4. Structural Determination of PPAPs with
Exocyclic Chiral Centers
With the synthetic 4, the originally assigned structure of
guttiferone F, in hand, we then attempted O-cyclization to
afford 5. Surprisingly, none of the desired 5 was observed when
we treated 4 with acidic conditions such as HCl/MeOH,
HCl(aq)/toluene, and p-TsOH/toluene (Scheme 3). The
unexpected results prompted us to conduct additional
experiments to determine the difference in cyclization between
4 and 1 with respect to the C-30 configuration. As we know, a
large number of PPAPs bearing a C-30 stereocenter similar to
2 have been assigned structures without determination of the
C-30 configuration. Further study of the O-cyclization of these
compounds may provide evidence that allows us to determine
the configurations of their C-30 stereocenters.
First, with Me2AlSEt as the promoter, we envisioned that the
O-cyclization might happen after the domino Dieckmann
cyclization of 17 to afford the tricyclic products 29 and 29′.
However, only the cyclized product 29 from 18 was isolated
after an extended reaction time, along with the unreacted 18/
18′ in a total yield of 43% (Scheme 5A). The purified
compounds 18 and 18′ were then subjected to O-cyclization in
the presence of HCl/MeOH, respectively. The reaction with
18 proceeded smoothly to give the desired product 29 in 86%
yield, whereas the reaction with 18′ gave a mixture of MeOH
adducts of the alkenes. These results suggested that PPAPs
such as 4 and 18′ were more reluctant to undergo the O-
cyclization under acidic conditions (Scheme 5B). In contrast
with the possible transition state of 18 (I), the prenyl group in
the transition state of 18′ (II) was in an axial position, which
prevented the reaction from proceeding due to steric hindrance
(Scheme 5B).
To get more insight into the cyclization, we conducted a
conformational analysis of 18/18′, which also supported the
hypothesis on the reaction differentiation. For 18, the lowest
energy conformation has the propenyl group in close proximity
to the enol group for cyclization. We speculate that the
activation energy of the reaction is mostly from enolization of
the diketone. Subsequent cationic cyclization is facile because
it has no energy barrier. For 18′, in addition to enolization,
there is a conformational energy cost to bring the propenyl
group and the enol close enough for cyclization. This increases
the activation energy of the desired cyclization, reduces the
“effective concentration” of the enol, and enables the
competitive formation of MeOH adducts (Scheme 5C).
Interestingly, when we collected all of the natural PPAPs
found the biogenetic O-cyclization of PPAPs, including types A
the natural product whose structure was originally proposed to
be 13,14-DDHIG had been misidentified and that it was
actually 7-epi-13,14-DDHIG (20) (Scheme 4A). It should be
noted that the relative/absolute configuration of natural 20 was
determined by nuclear Overhauser effect (NOE) spectroscopy
and ECD, which were shown in this study to be unreliable
methods for determining the configuration of PPAP side
chains. With the synthesis of 6 completed, the difficulties in
accessing all of the epimers of 20 were overcome by combining
the work of the Porco group.14
Next, the acylation of 18′ with 19 in the presence of SmCl3
resulted in the asymmetric synthesis of 4 in 42% yield. The
NMR spectra and specific rotation of 4 differed significantly
from those reported for the natural guttiferone F, confirming
the misassignment of its original structure.16,18 The chemical
shifts in 13C NMR with major deviations (Δδ > 0.3) between
the proposed guttiferone F and 4 were calculated. As shown in
Scheme 4B, these carbons are mostly around the C-30
stereocenter (see Table S3′ for details), which implied that the
stereochemistry of C-30 in the proposed guttiferone F was
incorrect. Inspired by the Grossman−Jacobs rule for
determining the exo/endo configuration,4 a significant chemical
shift variance of 13C NMR at C-9 between 4 and 1 (Δδ = 1.6)
indicated that a correlative rule to determine the configuration
of C30 (R/S) based on the chemical shift of the bridged
carbonyl carbon could be inferred after further study (Scheme
4B).
Consequently, a large number of misled studies over the last
two decades should be clarified with the revision of the
proposed guttiferone F to 1 via asymmetric synthesis. These
studies include the alleged isolation of 4, structural
determination based on 4, and biological studies.25 The
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Org. Lett. 2021, 23, 4203−4208