Shikimic acid is
a natural product of industrial importance utilized
as a precursor of the antiviral Tamiflu. It is nowadays produced in
multihundred ton amounts from the extraction of star anise (Illicium verum) or by fermentation processes. Apart from
the production of Tamiflu, shikimic acid has gathered particular notoriety
as its useful carbon backbone and inherent chirality provide extensive
use as a versatile chiral precursor in organic synthesis. This review
provides an overview of the main synthetic and microbial methods for
production of shikimic acid and highlights selected methods for isolation
from available plant sources. Furthermore, we have attempted to demonstrate
the synthetic utility of shikimic acid by covering the most important
synthetic modifications and related applications, namely, synthesis
of Tamiflu and derivatives, synthetic manipulations of the main functional
groups, and its use as biorenewable material and in total synthesis.
Given its rich chemistry and availability, shikimic acid is undoubtedly
a promising platform molecule for further exploration. Therefore,
in the end, we outline some challenges and promising future directions.
A newly developed stable chlorohydrosilane derived from pinacol is herein described. This was successfully used in the reduction of salicylaldehydes in reasonable to excellent yields (51–97 %). The ability of the hydrosilane to react as a reducing agent is increased upon the in situ formation of a trialkoxyhydrosilane and activation with a Lewis base, as further indicated by density functional theory studies. 1,3‐Dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone (DMPU) was identified to be a suitable catalyst for this metal‐free reduction, promoting the regio‐ and chemoselective reduction of aldehydes in ortho‐position to phenols, despite the presence of vicinal ketones. The performance of pinacol‐derived chlorohydrosilane in the reduction of salicylaldehydes was further observed to be superior to that of well‐established commercially available chlorohydrosilanes.
A biomass‐based route to the preparation of hydroquinone starting from the renewable starting material quinic acid is described. Amberlyst‐15 in the dry form promoted the one‐step formation of hydroquinone from quinic acid in toluene without any oxidants or metal catalysts in 72 % yield. Several acidic polymer‐based resins and organic acids as promoters as well as a variety of reaction conditions were screened including temperature, concentration and low‐ and high‐boiling‐point solvents. A 1:4 (w/w) ratio of quinic acid/Amberlyst‐15 was determined to be optimal to promote hydroquinone formation with only traces of a dimeric side‐product. A mechanism has been proposed based on the decarbonylation of protonated quino‐1,5‐lactone that is supported by experimental and computational calculation data.
A new metal-free
reductive amination protocol using a pinacol-derived
chlorohydrosilane/pyridine system for the preparation of aminoalkylphenols
is described. This method is selective toward iminiums derived from
alkylphenol ketones under an in situ formation of a trialkoxyhydrosilane
and activation with a Lewis base, as further indicated by computational
studies. This method demonstrated high functional group tolerance
affording an array of novel aminoalkylphenols in moderate to high
yields with equimolar amounts of reactants and a wide substrate scope.
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