Linckia
laevigata (also known as the Okinawan blue sea starfish) is a bright blue species
of starfish that inhabits the tropical waters of the Indian and Pacific oceans.
It has five cylindrical arms with a bright blue body color and yellow tube feet
(See Image above). The distinctive color comes from a blue pigment called
linckiacyanin as well as some accessory yellow carotenoids. The intense blue coloring
of L. laevigata likely warns
potential predators of toxicity, although there are no known adverse effects of
the starfish on humans. Interestingly, these animals possess remarkable
regenerative capabilities. For example, the blue seastar can use autotomy, or
self-severance of a limb, to escape predation. Moreover, body parts lost to
predators can also be regenerated by the starfish. Due to the aesthetic quality
derived from their brilliant blue color, L.
laevigata is popular with marine aquarium hobbyists for incorporation in
personal reef aquariums, in spite of requiring slow acclimatization and being
extremely sensitive to changes in temperature, oxygen level and pH.
In light of the regenerative
capacities mentioned above, natural products obtained from L. laevigata were screened in the early 2000s for much sought-after
neuritogenic pharmacological properties. Neuritogenic compounds or neurotrophic
factors, exemplified by nerve growth factor (NGF), induce neuronal
differentiation, wherein the neurons generate and extend neurites to form a
functional network. For a previously reported example of a neuritogenic
steroid, see. Neuritogenic activity is a vital component in the search for preventative and
therapeutic agents for neurodegenerative diseases such as Alzheimer’s disease.
Linckosides A and B, along with 20 minor congeners, were identified during the
course of the screening campaign. Linckosides share a pentahydroxy-cholestane structural
framework with variable glycosylation patterns. Polyhydroxylated steroid
glycosides are commonly encountered as metabolites in starfishes. However,
across bioactive and naturally occurring steroids, the hydroxylation pattern of
the linckosides is relatively uncommon and hydroxyl groups located at the steroidal
carbogenic position 8 (C8) are particularly rare. Very recently, Biao Yu’s
group at the Shanghai Institute of Organic Chemistry completed the first semisynthetic
preparation of linckosides A and B. In this post, we will outline their
synthetic approach for oxidative functionalization of the steroid nucleus,
paying particular attention to the strategy for introduction of the C8-hydroxyl
group, an undertaking that is not well-precedented in the synthetic literature.
As depicted above, the partial
synthesis of linckosides A and B begins from the well-known plant-derived
sterol diosgenin, which was converted into the side-chain degradant vespertilin
acetate by a high yielding four-step sequence that was conducted by Yu’s group
on 33-gram scale. The steroidal C7 position was then modified under standard allylic
bromination conditions to provide a functional handle that facilitated eventual
access to the elusive C8 position. In brief, exposure of a C7 b-thioarylether intermediate to an
oxaziridine reagent furnished the corresponding sulfoxide as an epimeric
mixture. Subsequent treatment with a mild base at 80 oC promoted cis-elimination of the sulfoxide to
yield a 5,7-diene. The D7,8
unit of unsaturation within the diene system is crucial to the overall strategy
to ultimately hydroxylate the embedded C8 position. However, the more
accessible D5,6 olefin was
first selectively epoxidized using methyltrioxorhenium and urea-hydrogen
peroxide and hydrolysis of the resultant oxirane generated the advanced 5a,6b-diol
intermediate shown above.
The Mukaiyama hydration reaction was
used to install the C8-hydroxyl group onto the steroidal skeleton of the critical
polyhydroxylated D7,8 olefin
intermediate. A similarly impressive cobalt-catalyzed Mukaiyama hydration
reaction was previously employed by Baran’s group for the stereocontrolled
functionalization of a trisubstituted D4,5
double bond within a complex steroid system (See Scheme above, top panel). The
formamido-diol product thus obtained was then condensed with trimethyl
orthoformate, furnishing a protected intermediate that was suitable for
eventual conversion into the natural product cortistatin A. In the current case
of the linckoside synthetic campaign, Mukaiyama hydration of the aforementioned
key substrate provided the desired C8 b-hydroxy
product in a yield that can be considered acceptable in view of the novelty and
exquisite stereoselectivity of the transformation. This critical reaction
likely proceeds through the intermediacy of a cobalt(III)-peroxy intermediate
as the active species, which adds to the least hindered p-face of the olefin with Markovnikov selectivity. The reaction
was demonstrated on 330-milligram scale.
Yu’s group appended the final
monosaccharide unit to the western C3-hydroxyl using an o-alkynylbenzoate building block as the glycosyl donor. This type
of donor, which was developed in Biao Yu’s laboratory, is activated in the
presence of a gold(I) cationic catalyst and, in this example, the 2-deoxy-b-glycosidic linkage was constructed with a
high level of stereocontrol, even in the absence of a participatory
C2-neighboring group within the glycosyl donor. A final global deprotection
operation (methanolysis) effectively cleaved the acyl linkages of penultimate synthetic
precursor to yield about 7 milligrams of the neuritogenic natural product
linckoside A, for the first time in a laboratory setting. The chemical
synthesis of linckosides A and B proceeds by a longest linear sequence 32 steps
(44 total) and in 0.5% overall yield. The work is particularly notable as it
provides a good blueprint for oxidative functionalization of the steroid C8
position in the context of a highly complex and biologically relevant synthetic
target molecule.
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