Key words
fucoxanthin - total synthesis - commercialization
1
Introduction
Fucoxanthin is the most abundant xanthophyll carotenoid, and it plays a pivotal role
in photosynthesis and photoprotection in various types of algae. It has anti-cancer,
anti-oxidant, anti-obesity, anti-diabetic and anti-inflammatory activity and it has
received FDA approval as a nutritional supplement.[1]
[2] Furthermore, it has shown promising results in phase-II clinical trials to treat
metabolic syndrome (MetS).[3] Besides its primary use as a medicinal agent, it holds a prominent space in cosmetics
formulations such as anti-aging, skin brightening, and sunscreen products. The market
for fucoxanthin in 2024 is valued at 31 million US dollars and is projected to grow
with a compound annual growth rate (CAGR) of 3.9% from 2024–2032, ultimately reaching
41 million USD.[4]
The chemical synthesis of fucoxanthin assumes significance commercially because the
yield from natural sources has not crossed 7%. Additionally, there are patent infringement
issues with producing fucoxanthin from high-yielding species. Moreover, there are
several other bottlenecks in the fucoxanthin extraction process such as limited evaluation
of scale-up cultivation and extraction, a few unclear steps in its biosynthetic pathway,
and conflict between biomass and fucoxanthin accumulation under high-light conditions.[5]
[6]
The present review summarizes the various total synthesis methodologies available
for fucoxanthin. We also provide in-depth analyses of the methodologies that exhibit
promising potential for commercial success and discuss their intricacies in detail.
Types of Synthetic Strategies
2
Types of Synthetic Strategies
There are two synthetic procedures reported for producing fucoxanthin to date. The
major challenge in its chemical synthesis is the extremely alkali-labile β,γ-epoxy
keto moiety. This structural feature prevented the stereochemical control of both
the epoxidation and polyene chain formation from being efficiently achieved in the
first reported synthetic procedure, which involved 30 synthetic steps. Additionally,
the synthetic yield of the method was 8% fucoxanthin in the final step.[7]
[8] The most promising method described to date was reported by Takayuki Kajikawa et
al. in 2012,[9] wherein the stereochemical control of both the epoxidation and polyene chain formation
was achieved successfully with a modest yield of 40% in the final step of the synthesis.
The primary distinction between this method and the first approach lies in the formation
of the epoxide ring as an intermediate rather than in the final step of the synthesis
(Scheme [1]).
Scheme 1 Comparison of the reported synthetic methodologies to access fucoxanthin
A Promising Synthetic Method: Takayuki Kajikawa’s Total Synthesis
3
A Promising Synthetic Method: Takayuki Kajikawa’s Total Synthesis
The most successful synthetic method for fucoxanthin involves the fusion of an allenic
segment (I) and a hydroxy sulfone fragment (II) by the modified Julia olefination method to obtain an isomeric mixture III. It was not possible to estimate the ratio of isomers because of the mixture with
the C8-epimer (of hydroxy sulfone part) on HPLC analysis. Hence, the mixture of isomers
III was used in the next oxidation step with Dess–Martin periodinane (DMP), wherein the
C8 hydroxy group is converted into a ketone (IV). This was followed by deprotection of the TES group to obtain cis/trans fucoxanthin isomers. Thereafter, the all-trans isomer V was obtained by keeping the mixture in benzene under fluorescent light in an argon
atmosphere for three days (Scheme [2]).[9]
Scheme 2 Synthesis of fucoxanthin. NaHMDS = sodium bis(trimethylsilyl)amide. DMP = Dess–Martin
periodinane, PPTS = pyridinium p-toluenesulfonate.
3.1
Synthesis of Allenic Segment I
The allenic segment I was synthesized starting from 4-hydroxy-2,2,6-trimethylcyclohexane-1-one (Scheme
[3]). First, the hydroxy group was protected with TBS, followed by OTf conversion of
the ketone group to afford the methyl ester under a carbon monoxide atmosphere using
tetrakis(triphenylphosphine)palladium catalyst.[10]
[11] The ester was then reduced to the alcohol with lithium aluminum hydride and submitted
to Sharpless epoxidation using t-butyl hydroperoxide. The diastereomeric mixture 5 was subjected to Swern oxidation using oxalyl chloride to obtain the required 5S,6R aldehyde 6.[11] This stereocontrolled epoxide formation in good yield is crucial for this synthetic
procedure. The epoxide was converted into the corresponding acetylene derivative 7 by utilizing chloromethyl triphenylphosphonium chloride and n-BuLi. The intermediate crude vinyl chloride formed was subjected to elimination using
potassium t-butoxide to obtain 7.[11] The Pd- and Cu-catalyzed Sonogashira reaction between acetylene 7 and trienyl iodide proceeded smoothly to furnish the desired coupling product 8 in 81% yield with complete retention of stereochemistry.[12] The reduction of 8 with DIBAL for the construction of the allenic moiety 9 afforded the C20-allenic triol, which was oxidized to the corresponding aldehyde
10 with manganese dioxide.[9] The synthesis of the allenic segment I is depicted in Scheme [3]. The crude aldehyde was used in the next acetylation step without further purification
to obtain 10 (allenic segment I).
Scheme 3 Synthesis of allenic segment for preparing fucoxanthin
3.2
Synthesis of Hydroxy Sulfone Segment II
The synthesis of the hydroxy sulfone segment II started from 3-epi-actinol. First, the alcohol group was TES-protected for the introduction of the aldehyde
group at C-5 (13) via the formation of acetylene derivative 12.[8]
[13] The carbon chain of aldehyde 13 was extended with the introduction of the C8 hydroxyl group by reacting 13 with vinyl iodide and t-BuLi to produce the desired alcohol 14 in high yield. Acetylation of the resulting alcohol 15 and subsequent chemoselective removal of the TES group led to the R-homoallylic alcohol 16. Thereafter, the reaction of organoaluminum peroxide, prepared in situ from TBHP
and (t-BuO)3Al with 16, exhibited complete stereocontrol and formed the desired compound 17 in 74% yield as a single diastereomer. Inversion of the resulting secondary hydroxyl
group under Mitsunobu reaction conditions using 4-nitrobenzoic acid afforded diester
18 in 70% yield in a completely stereocontrolled manner. This was followed by TBAF treatment
to deprotect the terminal OH group to obtain 19. Thereafter, the alcohol group was oxidized with manganese dioxide and the crude
aldehyde was used in the next subsequent Horner–Emmons reaction to obtain the E-isomer of triene ester 20 in excellent yield. Selective hydrolysis of the p-nitrobenzoyl group (to obtain 21) and then TES protection of the resulting alcohol afforded the triene ester 22 in excellent yield (Scheme [4] and Scheme [5]). The ester group of 22 was transformed into the sulfide 23 by DIBAL reduction followed by the Mitsunobu reaction with 2-mercapto benzothiazole.
The C8 of compound 23 was oxidized to the keto group with Dess–Martin periodinane to obtain 24 in 70% yield. The oxidation of the sulfide to sulfone 25 was carried out with aluminum heptamolybdate and 30% aqueous hydrogen peroxide. Reprotection
of the C3 hydroxyl group with TES followed by the Luche reduction afforded the desired
hydroxyl sulfone 27 (Scheme [5]).[9]
4
Future Perspectives
There are immense opportunities in the total synthesis of fucoxanthin because only
two methods have been reported to date. One of them has the potential for commercialization
and is discussed in detail in this review. However, researchers need to find novel
ways to improve the total synthesis of fucoxanthin. One such example is the procedure
reported by Satoshi Okumura and co-workers for the synthesis of C37 and C32 fucoxanthin.[14] The method employs a fusion of the allenic sulfone segment and aldehydic epoxy fragment
by the Julia olefination method. It is the reverse of the promising method described
in this review, wherein allenic aldehyde segment is fused with an epoxy sulfone fragment
(Scheme [6]). The yield for all the steps is 50–100% with a final step yield of 64%. The tedious
step for the introduction of C-8 carbonyl group is reduced by two steps and overall
there are 29 steps leading to the final product. It is 10 years since the modified
synthetic procedure for C37 fucoxanthin was reported and it is yet to be reported
for C42 fucoxanthin (marketed as fucoxanthin). Therefore, we are a little skeptical
about this procedure. Nevertheless, this synthetic methodology provides another approach
to fucoxanthin. Additionally, it can generate ideas for exploring structure-activity
relationship studies of fucoxanthin derivatives.
Scheme 4 Synthesis of hydroxy sulfone segment for preparing fucoxanthin, Part I.
5
Conclusions
The most promising synthesis of fucoxanthin reported to date comprises 32 steps, including
the preparation of two intermediates. The advantage of this method is that the yield
for the synthetic steps can be rated as moderate (50%) to excellent (99%). The final
step in fucoxanthin production demonstrates a five-fold improvement in yield (40%)
compared to the previous method. Furthermore, to our knowledge, this method does not
pose any patent infringement issues. Hence, this synthetic method has the potential
for commercial manufacture of fucoxanthin. The 32 synthetic steps give ample scope
for process patents in the future, which can act as a good revenue source for companies
engaged in the commercial manufacture of fucoxanthin. An initial assessment of the
synthesis costs indicates that it is economically feasible to substitute traditional
extraction methods, which are still not widely favored commercially. The primary drawback
lies in the multitude of synthetic steps required, posing a potential challenge during
scale-up operations. Nonetheless, we are confident that advancements in technology
will enable us to gradually surmount these challenges.
Scheme 5 Synthesis of hydroxy sulfone segment for preparing fucoxanthin, Part II. HSBT = 2-mercaptobenzothiazole.
Scheme 6 Synthesis of C37 fucoxanthin derivatives
