Letter
Syntheses of the Carotane-type Terpenoids (+)-Schisanwilsonene A
and (+)-Tormesol via a Two-Stage Approach
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ABSTRACT: Stereoselective syntheses of terpenoids in a more
efficient manner have been a long-term pursuit for synthetic chemists.
Herein we describe the two-step, enantiospecific and protecting-group-
free synthesis of (+)-schisanwilsonene A from a carotane compound,
which was produced in E. coli. We also completed the first
enantiomeric synthesis of (+)-tormesol in five steps. The two-stage
strategy offers a step- and redox-economical approach to prepare
terpene natural products and their analogues.
reconstruct the biosynthetic pathways of terpenoids in
erpenoids have a variety of important biological functions
Tin plants, including essential roles in growth, develop- microorganisms. For example, two groups reported the
ment, defense, communication, and environmental sensing.1
heterologous production of guaian-6,10(14)-diene in E. coli
and S. cerevisiae and the synthesis of (−)-englerin A, a potent
and selective inhibitor toward renal cancer cell lines.10
Additionally, Smanski and coworkers reported the production
of ent-atiserenoic acid in an engineered Streptomyces strain and
the synthesis of serofendic acid, a natural neuroprotective
compound found in fetal calf serum.11 Herein we describe the
concise syntheses of plant terpenoids (+)-schisanwilsonene A
(1) and (+)-tormesol (2) (Figure 1A) from a carotane-type
precursor produced in E. coli (Figure 1C).
(+)-Schisanwilsonene A (Figure 1A) is a carotane-type
sesquiterpenoid that is isolated from the fruits of Schisandra
wilsoniana and exhibits antiviral activity.12 Studies show that it
inhibits HBsAg and HBeAg secretion by 76.5 and 28.9% at 50
μg/mL. (+)-Schisanwilsonene A features a trans-fused
bicyclo[5.3.0]carotane scaffold and a syn relationship between
the angular methyl group and the side chain, which makes it a
challenging synthetic target. In 2013, Echavarren and cow-
orkers reported the only total synthesis of (+)-schisanwilso-
nene A in 13 steps (ca. 4% overall yields from a known
synthetic intermediate 4, Figure 1B).13 The synthesis
comprises the gold-catalyzed tandem cyclization, 1,5-migra-
tion, and cyclopropanation as key steps to construct the
carotane skeleton. To develop an efficient synthetic approach
of (+)-schisanwilsonene A, we searched for a sesquiterpene
synthase, which could convert farnesyl pyrophosphate (FPP)
They are also the sources of many commercially valuable
chemicals, such as pharmaceuticals, fragrances, flavors, and
insecticides.2 Traditionally, plant terpenoids can be obtained
by extraction from their natural sources or by total synthesis
and semisynthesis.2,3 In the past two decades, the heterologous
production of high-value terpenoids or their precursors in
genetically engineered microorganisms has attracted much
attention.4 For example, Keasling and coworkers have
developed strains of Saccharomyces cerevisiae for the high-
yielding production of artemisinic acid and converted them
into artemisinin through chemical transformations.5 However,
the applications of this strategy to produce medicinal plant
terpenoids are limited thus far owing to a few reasons. First,
only a small percentage of plant terpenoids has been
biosynthetically characterized, largely due to the difficulties
in the identification of the biosynthetic pathways for plant
natural products. Unlike bacteria and fungi, the genes for the
secondary metabolites in plant are scattered throughout the
entire genome, which makes the identification of a complete
biosynthetic pathway tedious and time-consuming.6 Second,
the functional characterization of the plant terpene synthases in
an engineered host can be problematic due to low activity,
incorrect localization, or limited solubility.5c,7 Third, orches-
trating a series of enzymatic reactions to maximize the
production in a microbe without influencing the primary
metabolism is a formidable task.4c Recently, genome
sequencing of bacteria and fungi has revealed many terpene
synthases, and biochemical studies demonstrated that their
products share the same or similar scaffolds as many known
plant terpenoids.8 Although some terpenes from bacteria have
the opposite absolute configurations of plant terpenoids,9 these
findings have enriched the toolbox for synthetic biologists to
Received: November 24, 2020
Published: December 29, 2020
© 2020 American Chemical Society
Org. Lett. 2021, 23, 400−404
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