Squalene, stereoselective synthesis

In the particular case in which the carbonyl group belongs to a carboxylic acid derivative, such as an ester (17) or an amide (18) (or other functional groups which may be converted into it by a FGI), then they may be disconnected according to the "orthoacetate-modification" of the retro-Claisen rearrangement (Schemes 7.7 and 7.8) developed mainly by Eschenmoser [7] and Ziegler [8], independently, in the synthesis of alkaloids, and Johnson in a very simple and yet highly stereoselective synthesis of squalene [9]. 

Tetrabromocyclohexadienone has been shown to be an efficient alternative to A -bromosuccinimide for the preparation of terminal bromohydrins of polyenes like squalene/° A stereoselective synthesis of mokupalide (4), an unusual head-to-tail linked hexaprenoid from a marine sponge, is summarized in the Scheme. ... 

This reaction was first reported by Johnson et al. in 1970. It is a highly stereoselective synthesis of y,5-unsaturated esters from the reaction between allylic alcohols and an orthoester in the presence of a trace amount of weak acid, such as propionic acid. Because this reaction is the modification or variant of the Claisen Rearrangement, it is often referred to as the Johnson orthoester Claisen rearrangement. Occasionally, this reaction is also known as the Claisen-Johnson orthoester rearrangement, " or Johnson orthoester protocol. This reaction involves the formation of mixed orthoester from allyl alcohol and the added orthoester, which loses an alcoholic component to form a ketene acetal then migrates to unsaturated carbonyl compounds via the Claisen Rearmagement with high syn selectivity. Posner further extended this reaction to use sulfonyl orthoester. Overall, this reaction has been applied to the synthesis of a variety of complicated natural products, such as squalenes. ... 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Scheme 7.6 Stereoselective acetylation of the hydroxyl diethyl ester (9) to the (S)-acetate as an intermediate for the synthesis of a squalene synthase inhibitor ( ) of cholesterol synthesis.

Figure 17 Enzymatic synthesis of chiral synthon for BMS-188494, a squalene synthase inhibitor stereoselective acetylation of racemic (52).

Johnson et al. used their newly developed orthoester Claisen reaction to achieve a highly stereoselective total synthesis of aM-trans squalene (5)1 (Scheme 1.20. The diene diol 6 underwent Johnson-Claisen rearrangement when it was heated with ethyl orthoacetate in the presence of propionic acid for 3 h at 138 C. The diene dialdehyde 7, obtained by treatment of the resulting ester with lithium aluminum hydride followed by oxidation with Collins reagent, reacted with 2-propenyllithium to give the tetraene diol 8. The tetraene dialdehyde 9, which... 

Faulkner and Petersen also used the Claisen rearrangement for a synthesis of the optically active forms of Cecropm juvenile hormone (8). The stereoselectivity in this case was not so high as in the synthesis of squalene. 

The reaction of the analogous aliphatic allyl ethers is stereoselective, an observation first applied to the synthesis of trans-trisubstituted olefins, in particular squalene (see Scheme 19.2). 

As observed by Johnson in the original publication that described the first utilization of this reaction in a very elegant synthesis of squalene 50 with double chain extension [7], the orthoester rearrangement of 1,1-disubstituted allylic alcohols is highly stereoselective and gave rise to -trisubstituted double bonds. Thus, successive rearrangements afforded efficiently a tetraene ester 49 as illustrated in Scheme 6.5. 

Following his impressive illustration of the usefulness of the orthoester Claisen rearrangement in the synthesis of squalene [7], Johnson [66] used this reaction thoroughly in several biomimetic syntheses of steroids. Some examples of these reactions are depicted in Scheme 6.47. Esters were generally obtained in high yield with complete stereoselectivity. 

Johnson WS, Werthemann L, Bartlett WR, Brocksom TJ, Li T-T, Faulkner DJ, Petersen MR. Simple stereoselective version of the Claisen rearrangement leading to trans-tri-suhstituted olefinic bonds. Synthesis of squalene. J. Am. Chem. Soc. 1970 92(3) 741-743. 

Squalene 2,3-oxide has been proposed to account for a vast array of polycyclic triterpenes in natureJ The synthesis of 6-amyrin by van Tamelen and his associates mimics the biological cyclization process, featuring the stereoselective generation of five asymmetric centres during a polyolefinic cyclization of the terminal epoxide Preparation of DIE Component ... 

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