strates.7 We further found that by incorporating a chelation
element at the ortho-position of benzaldehydes, the syn-aldol
adduct 3 could be obtained as the major product through
transition state A (Scheme 1). In constrast, according to the
In this paper, we report our recent progress about the
asymmetric total synthesis and structure elucidation of NFAT-
68 (7 in Figure 1) via the chelation-controlled VMAR as a key
step.
Scheme 1. Vinylogous Mukaiyama Aldol Reaction
Figure 1. Retrosynthetic analysis.
NFAT-68 (7 in Figure 1), a polyketide from the fermenta-
tion broth and mycelia of two Streptomyces sp. was
discovered with NFAT-/lacZ ꢀ-galactosidase reporter gene
construct assay.8
The primary screening indicates that NFAT-68 is a potent
immunosuppressant with the IC50 concentrations less than 1
µg/mL, and that no apparent toxicity is observed at this
concentration. Therefore, NFAT-68 may become a useful
probe for studying signaling pathways of early T cell
activation.
report by Kobayashi and co-workers,3a when benzaldehyde
was employed as the substrate, the anti-aldol adduct 6 would
be formed predominantly through transition state B (Scheme
1).
The structure of NFAT-68 (7) was assigned based on
analyzing its NMR spectra. However, neither its stereochem-
istry nor optical rotation was reported in the original article.8
Hence in the meantime of pursuing the total synthesis of
NFAT-68 (7), our other mission is to validate its structure.
To resolve the structural issue of NFAT-68, we initially
assumed that the stereochemistry at C6 and C7 in NFAT-68
is a syn-relationship. We therefore expected that our recently
developed chelation-controlled VMAR could potentially be
applied to the synthesis of the δ-hydroxyl-R,γ-dimethyl-R,ꢀ-
unsaturated unite in natural product NFAT-68. Our retrosyn-
thetic analysis of NFAT-68 is outlined in Figure 1. We
envisaged that NFAT-68 could be derived from intermediate
8, which in turn could be generated from 1 and 9 via the
chelation-controlled VMAR (Figure 1).
Our synthesis began with investigating the chelation effect
of substrate on the diastereoselectivity of the aldol adducts
of VMARs. To this end, vinylketene silyl N,O-acetal 17 was
reacted with 2-methoxybenzaldehyde 2 under the conditions
listed in Scheme 2. Delightfully, adducts 10 and 11 were
obtained in 91% combined yield, and the ratio of 10/11 is
1/20 (Scheme 2).
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The stereochemistry for 11 was established by both NMR
and X-ray single crystal analysis. These studies demonstrate
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