Stereospecific Ring Closure Approach

The majority of the syntheses discussed up to this point have involved the C-C coupling of side chain components to an enantiomerically enriched chromane.

Another important approach to vitamin E synthesis is by a stereospecific ring closure, where the desired stereochemistry is defined beforehand.

Due to their high selectivity, asymmetric epoxidation and dihydroxylation reactions have seen considerable use in natural product synthesis.190 _{Inoue et al. used a}

sulfoxide-mediated phenol alkylation and an asymmetric epoxidation in the total

synthesis of α-tocopherol.191_{Phenoxy- and azasulfonium ylids such as96are known}

to undergo [2,3] sigmatropic rearrangements to yieldo-alkylated products97(Scheme 24).192-194

Scheme 24.o-Alkylation of phenols with dialkyl sulphides.

Scheme 25 shows the synthesis carried out by Inoueet al. Epoxide98was obtained in enantiomerically pure form by the Sharpless epoxidation195 _{of the corresponding}

allylic alcohol, with the sulfide 100 generated over a further four transformations. Treatment of sulfide 100 with sulfuryl chloride, triethylamine and phenol 101 at -40 °C yielded the alkylated compound 102. The synthesis was completed by desulfurisation, reduction of the acetyl groups and acid-catalysed cyclisation as described by Cohenet al.196 _{The reported yield of α-tocopherol was 81% from sulfide}

Scheme 25. Total synthesis of α-tocopherol 1.

Takanoet al. reported the synthesis of α-tocopherol viaan enantiomerically enriched 3-hydroxyacetylene (Scheme 26).197

Scheme 26. Synthesis of known benzoquinone intermediate108.

The epoxide98was obtained from the Sharpless epoxidation of natural phytol. Takano

et al. had previously shown that enantiomerically enriched chloroepoxides such as104

could be converted into the corresponding 3-hydroxyacetylenes without racemisation.198 _{Thus, treatment of epoxide 104 with n-butyllithium furnished the}

hydrogenation yielded alcohol 106, which was converted into the known p- benzoquinone108. Completion of the synthesis from this compound was previously reported,191 _{and α-tocopherol was obtained in nine steps and 24% overall yield from}

natural phytol.

Hübscher and Barner reported the synthesis of α-tocopherol using several epoxide

ring-opening reactions (Scheme 27).199_{Diol109was obtained by the initial Sharpless}

epoxidation of 2-methylprop-2-en-1-ol, in 81% overall yield over two steps and 98%

e.e.Treatment with NaH and alkyllithium111yielded the diol112.

Scheme 27. Synthesis of α-tocopherol 1by Hübscher and Barner.

Activation of the primary alcohol by tosylation allowed the formation of epoxide113, which was subsequently ring-opened by an enantiomerically enriched Grignard reagent. Completion of the synthesis from alcohol 107 was carried out using the method of Takano et al.,197 _{to yield α-tocopherol 1 in an overall yield of 17% over}

Scheme 28. Synthesis of α-tocopherol using a stereoselective Shi epoxidation.

Alkene114was synthesised from trimethylhydroquinone and phytyl bromide using a four step sequence. Shi epoxidation gave the epoxide 115in a d.e. of 97%, where the bulky TBDPS (tert-butyldiphenylsilyl) protecting group was required to give good selectivity. Subsequent deprotection and cyclisation in 2M HCl/Et2O gave the

chromane117in 93%d.e. Note that the 6-exo-tet cyclisation is formally disfavoured according to Baldwin’s rules, and the authors found that the 5-exo-tet benzofuran product was formed as a by-product in 19% yield. The slight decrease ind.e. is due to the extent of carbenium ion formation during the reaction. The chromane117was then

converted into α-tocopherol, with an overall yield of 20% over 11 steps.

Reinet al. reported a synthesis where the key steps were construction of a chromane ring by stereospecific ring closure, and ano-DPPB (o-diphenylphosphanyl benzoate) -directedsynsubstitution (Scheme 29).201_{Synthesis of the chromane ring began with}

the coupling of aryl iodide 118 with alcohol 119, derived from an enzymatic hydrolysis. Subsequent hydrogenation yielded the acetonide 120 from which the conversion into chromane 61had been described by Cohenet al.171, 196_{A further six}

steps furnished the iodide precursor122.o-DPPB has been shown to act as a directing group in the addition of organic cuprates with excellent selectivity; furthermore, a single equivalent of organometallic reagent can be used in contrast to the two or more

equivalents commonly required.202 _{Thus, the Grignard reagent 123 was coupled to}

alkene 124insyn fashion. Hydrogenation furnished α-tocopherol in an overall yield

of 30% over 13 steps. The coupling fragment124was synthesised in ten steps with an overall yield of 18%, where the stereochemistry was introduced by a rhodium- catalysed hydroformylation reaction, with ad.e.of 91%.

Scheme 29. α-Tocopherol synthesis using a directed cuprate addition.

Woggon et al. used the Mitsunobu reaction with an α-hydroxy ester to obtain the

between monoprotected hydroquinone 130 and α-hydroxy ester 129 was achieved with 94%d.e.and complete inversion of configuration. Alcohol133was then obtained following olefination and rhodium-catalysed hydroboration. Oxidation to the aldehyde followed by acid-catalysed cyclisation yielded the chromene 135, which after

hydrogenation and demethylation yielded α-tocopherol 1 in a yield of 18% over 13

steps. Thed.e.of the Mitsunobu reaction (94%) was retained throughout the synthesis.

R O ClMgO HO R1 R = OH 35 R = Br 56 R = MgBr 126 O OH O O R2 HO _O O R2 O O R2 OH O O R2 O O O R2 HO O R2 131 132 133 134 135 _-tocopherol1 127 R1= CH2OH R1= CO2CH3 128 129 130 2 R2₌

Scheme 30. α-Tocopherol synthesis using a Mitsunobu reaction.