Inhoffen-Lythgoe diol synthesis

Similar reactions were applied to the syntheses of rf/-ep/-pyroangolen-solide, i/-pyroangoensolide (Eq. 12.29)88 and the formal synthesis of the Inhoffen-Lythgoe diol (Eq. 12.30).89 The key step in the formal synthesis of the Inhoffen-Lythgoe diol is the aqueous Diels-Alder reaction between the sodium salt of the diene and methacrolein to form the cycloadduct, which then undergoes subsequent reactions to form the known hydrin-dan. Sodium (E)-4, 6, 7-octatrienoate reacted smoothly with a variety of dienophiles to give conjugated diene products.90... 

A synthesis of the Inhoffen-Lythgoe diol (46.7, Scheme 2.46), a useful intermediate in the synthesis of Vitamin D derivatives, demonstrates the use of a chiral acetal in an asymmetric tandem cyclisation reaction.102 Once again, Lewis acid co-ordination to the less hindered oxygen of the acetal 46.1 initiated a Prins-like cyclisation that terminated by attack of the propargylsilane on an incipient tertiary carbocation. After removal of the chiral auxiliary, the allene function in the alcohol 46.4 was transformed into the side chain of 46.7 with the creation of two new stereogenic centres. 

This reaction was eventually used to effect an efficient formal synthesis of the Inhoffen-Lythgoe diol. The /-selectivity of this aqueous Diels-Alder reaction is consistent with a transition state that has the dienophile approaching the most stable allylic rotamer of the diene from the face opposite that of the hydrophilic carboxylate group. 

Brandes, E. Grieco, P.A. Gamer P., Diastereoselection in an aqueous Diels-Alder reaction A formal total synthesis of the Inhoffen-Lythgoe diol, / Chem. Soc., Chem. Commun., 1988,500-2. 

This aldehyde is a key intermediate in the synthesis of the Inhoffen-Lythgoe diol, which is one possible precursor to vitamin D and its derivatives [21], The aldehyde could not be formed by pyrolysis of the corresponding ester in decalin at 95 C. Other procedures that accomplished the rearrangement required heating in excess of 220°C [22]. 

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