Katsuki Sharpless Asymmetric Epoxidation and its Synthetic Applications

1. PRESENTED BY :
KESHAV KUMAR SINGH
Reg. No.:- Y19266023
Deptt. of Chemistry
DHSGU Sagar (M.P.)

2.  The Sharpless Epoxidation (or Katsuki–Sharpless
epoxidation) reaction is an enantioselective chemical
reaction to prepare 2,3-epoxyalcohols from primary and
secondary allylic alcohols.
 It is the first method for asymmetric epoxidation of allylic
alcohols, published on 1st August 1980.
 Epoxidation of Allylic alcohols, with tert-butyl
hydroperoxide [t-(BuOOH)], a titanium (IV) metal catalyst,
and a tartrate ester ligand, is called Sharpless Asymmetric
Epoxidation.

3.  Oxidizing agent: Tert-butyl hydroperoxide [t-(BuOOH)]
 Catalyst: Titanium tetra isopropoxide [Ti(O-i-Pr)4] &
diethyl tartrate [DET].
 Chirality by: ±DET; it provides enantioselectivity
 Substrate: Allylic alcohol

4. Limitation:- The major limitation of
this reaction is that, it is reliable but it is
only used for allylic alcohols (However
there is an alternative method which
works with simple alkenes and and
involves mangnese catalyst with a chiral
ligand built from a simple diamine;
Jacobsen Katsuki epoxidation).
Sharpless Asymmetric epoxidation
reaction is normally carried out with 5-
10% titanium catalyst and in the
presence of activated molecular seive.

5. Epoxidation of allylic alcohols with tert-butyl
hydroperoxide, catalyzed by tetraisopropoxy titanium(IV)
[Ti(O-i-Pr)4], gave the epoxy alcohol with high
enantioselectivity when (+)- or (-)-diethyl tartrate was
added to the reaction medium.

6. The natural isomer of DET [L-(+)-] is readily
available as is the unnatural tartrate [(D-(-)-],
although the latter is significantly more
expensive.
When the epoxy alcohol product was water
soluble, both the optical activity and the yield
were diminished.

7. It is believed to take place by coordination of tartrate ligand to the
metal catalyst, where tartrate ligand displaces two isopropoxide
ligands, hence the activated complex formed from two titanium
atoms bridged by two tartrate ligands, each of them retaining two of
their isopropoxide ligands, forming a dimeric species.
activated complex
i.e. (Ti-o-i-Pr)4 + [L+(DET)] -2 isopropoxide Dimeric Activated Complex

8. Now when the oxidizing agent (t-BuOOH) is added to
the mixture it displaces one isopropoxide and one of the
tartret carbonyl group, bonded at one of the two titanium
in dimeric complex.
i.e. Dimeric Complex + (t-BuOOH) – isopropoxide Oxidising Complex

9.  Now for this oxidizing complex to react with allylic acohol, the
alcohol must become coordinated to the titanium too, displacing
further isopropoxide on the same titanium at which (t-BuOOH)
is coordinated, and because of the shape of complex, reactive
oxygen of the bound hydroperoxide has to be delivered from
bottom face of alkene and epoxide formed, in high enantiomeric
excess, is displaced by another molecule of hydroperoxide and
cycle starts again.
i.e. Oxidizing Complex + allylic alcohol - isopropoxide Epoxide

10.  Each enantiomer of chiral tartrate ligand delivers oxygen to one
face of double bond, but enantiomeric face of alkene to be
attacked depends upon the chiral ligand, and since D(-)DET is
just invert configuration of L(+)DET hence it would deliver
oxygen from top face of alkene.

11. Facial selectivity on allylic alcohols for (+) and (-)-diethyl tartrate

12. (1). Allylic alcohols Containing Stereogenic center gives
two diastereoisomer. It is found that sharpless
Asymmetric epoxidation is a powerful reagent
controlled reaction that Commonly overides any
substrate control.

13. (2). The epoxidation of dienol discussed is highly
chemoselective that it gave only 48 epoxide as shown in
example. This reaction is even tolerant of different
functional groups like ester, epoxides, acetals, enones
etc.

14. (3). Allylic alcohols with E geometry or unhindered Z
geometry are excellent substrate, however Branched Z
allylic alcohols particularly those branched at C-4
carbon, exhibit decrease reactivity and selectivity as
discussed in example.

15. (4). In the absence of a chiral ligand, the chiral centre in
the substrate 49 directs the oxidation to only a small
degree (low diastereoselectivity in favour of epoxide 50).
This stereoselectivity is ‘matched’ with (−)-DIPT and
‘mismatched’ with (+)-DIPT, although both enantiomers of
the chiral ligand far outweigh the influence of the substrate
chirality, to provide either epoxide with high selectivity.

16. The rate of epoxidation of chiral allylic alcohol will be
different with either enantiomer of chiral ligand depending
upon the orientation of hindered group (say R).
Case a- If the hindered group R is present above the plane
of alkene of allylic alcohol then top attack with (-)D
tartrate becomes slower and selectivity with this chiral
ligand is reduced, bottom attack with (+)L tartrate
becomes faster and more selective comparatively.
Case b- If hindered group R is present below the plane
then bottom attack with (+)L tartrate becomes slower and
selectivity with this chiral ligand is reduced, top attack
with (-)D tartrate becomes faster and more selective
comparatively.

17. The epoxidation of racemic Secondary alcohols is one
such example where the rate is faster with either of two
chiral ligand depending upon the configuration of two
substrate in racemic mixture of secondary alcohol.

18.  The catalytic version of Asymmetric epoxidation is well
studied to Industrial exploitation, and American Company
J.T baker and employed it to synthetic disparlure,
phenomenon of the gypsy moth, by oxidation of epoxy
Alcohol to an aldehyde with pyredinium dichromate,
witting reaction and hydrogenation.

19. The chiral beta-blocker drug “Propranolol” and its
1,2,3-substitution pattern makes it a good candidate for
synthesis using asymmetric epoxidation.

20. Chemists at drug company Wyeth needed an amine,
which they obtained by sharpless asymmetric
epoxidation of fluorinated allylic alcohol using D(-)
DIPT (gives bettter selectivity than DET). The benzyllic
end of epoxide is more reactive towards nucleophilic
substitution, and in the presence of Ti(-o-i-Pr)4, this time
acting as simply a lewis acid, the lithiated heterocycle
opens the epoxide with inversion of configuration.

21.  The less hindered primary hydroxyl group of above
compound is then tosylated with TSCl base selectively,
which closes to an epoxide in base and then reopening the
epoxide at less hindered terminal position with
methylamine, gives desired amine.

22.  Epoxidation of racemic secondary allylic alcohol gives
an epoxide, which is a precursor for the synthesis of
Anticoccidial Antibiotic Diolmycin A1.

23. If the secondary allylic alcohol is enantiomerically pure
then high yields of desired epoxide is obtained upon
epoxidation. Selective Epoxidation of single enantiomer
of bis Allylic alcohol 56 with (+) DIPT gives the mono
epoxide anti- tumour agent; Laulimalide.

24. Sharpless Asymmetric Epoxidation can be used
to synthesise antibacterial agents, one of the
example is as follows;

25. The Sharpless group created synthetic intermediates of various
natural products: methymycin, erthromycin, leukotriene C-1, and
(+)-disparlure.
The Sharpless epoxidation has been used for the total synthesis of
various saccharides, terpenes, leukotrienes, pheromones,
and antibiotics.

26. (A). Use of molecular Sieves ; this reaction is
water sensitive as water can destroy the active
catalyst and hence leading to opening if
epoxide formed. Earlier this problem was
solved by using stoichiometric reagents but
now this is done by using molecular sieves
which not only reduces catalytic amount but
also increases yield of product.

27. (B). Use if supported catalyst ; Since heterogeneous
catalyst have many advantages like ease of work up,
recyclability etc hence to improve sharpless AE, either
titanium catalyst was made heterogeneous or chiral
ligand was mounted on polymer supports such as
Polystyrene.
(C). Use of higher temperatures ; Since reaction takes
place at lower temperatures, achieving lower
temperatures, makes this reaction costly hence to
overcome this, catalyst systems developed with which
reaction could take plate at room temperature.

28.  One such example is titanocene tartrate catalyst with
which reaction now takes place at room temperature,
however enantioselectivity is not so high.