Wittig Reaction - Schlosser Modification

The asymmetric total synthesis of ISP-I (myriocin, thermozymocidin) was accomplished by utilizing the Schlosser modified Wittig reaction as one of the key steps in the laboratory of Y. Nagao. The phosphonium bromide fragment was treated with PhLi at 0 °C to generate the phosphorous ylide which was reacted with the aldehyde at -78 °C. The resulting mixture of lithiobetaines was treated with PhLi at 0 °C to afford the desired ( j-alkene with excellent stereoselectivity. 

During the stereospecific total synthesis of (7S,15S) and (7R, 15S)-dolatrienoic acid by G.R. Pettit et al., the C7-C10 and C11-C16 subunits were coupled using the highly ( )-selective Wittig-Schlosser reaction The traditional Wittig conditions resulted in a mixture of alkenes in which the (Z)-stereoisomer was predominant. When the Schlosser conditions were applied, the stereoselectivity was reversed in favor of the ( )-alkene. 

A simple and efficient method was developed by E.A. Couladouros and co-workers for the synthesis of optically pure five- or six-membered hydroxylactones. The method begins from y-butyrolactone and uses the following key transformations reduction, Wittig-Schiosser reaction. Sharpless asymmetric dihydroxylatlon, oxidation, and lactoniza-tion. The preparation of antitumor agent (-)-muricatacin was achieved in 6 steps and in 43% overall yield. 

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Wittig reaction-Schlosser modification One-pot multistep preparation of (E)-alkenes from "nonstabilized" phosphorous ylides and carbonyl compounds by the equilibration of the intermediate lithiobetaines. 488... 

Peterson olefination, Takai-Utimoto olefination, Tebbe olefination, Wittig reaction, Wittig reaction - Schlosser modification ... 

This Is a variation of the Schlosser modification of the WIttIg reaction [Schlosser, M, Coffinet, . Synthesis 1971, 380 and Synthesis 1972, 575], Vedejs has published Interesting work that provides a rational for the stereochemical and regloohemical course of the key reaction Vedejs, E. Snoble, K. A. J. "Direct Observation of Oxaphosphatanes from Typical Wittig Reactions" J. Am. Chem. Soc. 1973, 95, 5778,... 

Retrosynthetic cleavage of the trans A8,9 disubstituted double bond in intermediate 11, the projected precursor of diketone 10, provides phosphorus ylide 12 and aldehyde 13 as potential precursors. In the forward sense, a Wittig reaction could conceivably achieve a convergent coupling of intermediates 12 and 13 with concomitant formation of the requisite trans C8-C9 olefin. Ordinarily, the union of a nonstabilized ylide, such as 12, with an aldehyde would be expected to afford an alkene with a cis geometry.8 Fortunately, however, the Schlosser modification of the Wittig reaction permits the construction of trans olefins from aldehydes and nonstabilized phosphorus ylides.9... 

The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefms. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes f-olefins instead. 

By adding a strong base to the cold solution of the oxaphosphetane before it eliminates, die oxaphosphetane equilibrates to die more stable anti isomer and die E olefin is produced upon elimination. This so-called Schlosser modification in conjunction with the normal Wittig reaction enables either the Z or E isomer of the olefin to be prepared selectively. 

The Schlosser Modification of the Wittig Reaction allows the selective formation of -alkenes through the use of excess lithium salts during the addition step of the ylide and subsequent deprotonation/protonation steps. 

Addition of the ylide to the carbonyl is postulated to lead first to the zwitterionic intermediate betaine, which would then close to form a four-membered cyclic intermediate, an oxaphosphetane. The existence of the betaine hasn t been fully established, although its intermediacy plays an important role in the Schlosser Modification. Betaines may be stabilized by lithium salts leading to side products therefore, suitable bases in the Wittig Reaction are for example NaH, NaOMe, NEt3). 

The normal preference for (Z) alkenes in reactions of non-stabilized phos-phoranes can be reversed by employing the Schlosser modification of the Wittig reaction (Scheme 6).19 Here, equilibration of the initially formed erythro and threo betaine intermediates is achieved by reaction with additional strong base, usually an alkyl lithium. The resulting betaine ylide then gives the (E) alkene on treatment with a proton source followed by potassium tert-butoxide. 

Although the Schlosser modification of the Wittig reaction provides access to trans-olefins from non-stabilized ylides, the Julia-Lythgoe olefination has proven to be the method of choice for solving this synthetic problem today, a) M. Schlosser, K.-F. Christmann, Justus Liebigs Ann. Chem. 1967, 708, 1-35 b) M. Schlosser, K.-F. Christmann, A, Piskala, Chem. Ber. 1970, 103, 2814-2820. 

Schlosser modification of Wittig reaction The presence of soluble metal salts such as lithium salts decreases the aVfrans-selectivity. The normal Wittig reaction of non-stabilized ylides with aldehydes gives Z-alkenes. The Schlosser modification of the Wittig reaction of non-stabilized ylides furnishes -alkenes. In the presence of lithium halides oxaphosphetanes can often be observed, but betaine-lithium halide adducts are also formed. If lithium salts are added to the equilibrium, oxaphosphetane formation and elimination of... 

Application of the Wittig reaction of a nonstabilized ylide to the synthesis of an ( )-alkene is practically and effectively carried out by the Schlosser modification. Alternatively, the use of a trialkylphos-phonium ylide can produce high ratios of ( )-alkene." Recently, Vedejs has developed a reagent using dibenzophosphole ylides (110) to synthesize ( )-disubstituted alkenes (111) fixnn rddehydes (equation 24). The initial addition of ylide occurs at -78 C, but the intermediate oxaphosphetane must be heated to induce alkene formation. The stereoselectivity in the process is excellent, particularly for aldehydes with branched substitution a to the reacting center. Both the ethyl and butyl yli s have b n utilized. 

Schlosser Modification. Almost pure tran -olefins are obtained from nonstabilized ylides by the Schlosser modification of the Wittig reaction (Wittig-Schlosser reaction). For example, treatment of the (cij )-oxaphosphetane intermediate A with n-BuLi or PhLi at -78 °C results in lithiation of the acidic proton adjacent to phosphoras to produce the P"Oxido phosphonium ylide B. Protonation of B with f-BuOH leads to the trans-1,2-disubstituted alkene C. 

As pointed out in this woric, the mild conditions of the Cr reaction resulted in no observed epimeriza-tion, and offered an excellent alternative to the Schlosser modification of the Wittig reaction. Both the C1CI2 chemistry and the TiCU/Zn method discussed in Section 3.1.12.1.2 have the advantage of preparing the metallocarbene complex in situ. 

Schlosser s modification" of the Wittig reaction produced the phosphonium salts 1137 in excellent yield. 

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