STEREOSELECTIVE SYNTHESIS TRISUBSTITUTED OLEFINS

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

STEREOSELECTIVE SYNTHESIS OF TRISUBSTITUTED OLEFINS ETHYL 4-METHYL-E-4,8-NONADIENOATE... 

The use of the Claisen rearrangement and several other methods for the stereoselective synthesis of trisubstituted olefins has been reviewed.6 In allyl vinyl ethers of type A, the stereochemistry of the rearrangement is determined largely... 

Faulkner, D. J. Stereoselective synthesis of trisubstituted olefins. Synthesis 1971, 175-189. 

Still, W. C., Mitra, A. A highly stereoselective synthesis of Z-trisubstituted olefins via [2,3]-sigmatropic rearrangement. Preference for a pseudoaxially substituted transition state. J. Am. Chem. Soc. 1978,100,1927-1928. 

Denmark, S.E., and Amburgey, J.S., Stereoselective synthesis of trisubstituted olefins. Phosphorus, Sulfur Silicon Relat. Elem., Ill, 196, 1996. 

A -Acyl-oxazolidin-2-ones, as 203, are widely used in aldol reactions, however an unprecedented use of the aldol adducts for a stereoselective synthesis of trisubstituted a, 3-unsaturated amides and acids was reported. The yy -aldol adduct 204 underwent clean elimination upon treatment with KHMDS and afforded the E -olefin 205 with a 97% ds. The reaction was wide in scope but with a loss in selectivity using a,P-unsaturated or chiral aldehydes <05OBC2976>. This synthetic approach found immediate application in the synthesis of semiplenamide C 206 <05TL5547>. Oxazolidin-2,4-diones 207, obtained from cyanohydrins, can be easily converted into the corresponding a-hydroxyamides 208 in a reaction that can be accelerated by microwaves <05T7247>. 

Several variants of [3,3] sigmatropic Claisen-type rearrangements have been used for the stereoselective synthesis of di- and trisubstituted olefinic systems 11,28,279,28°. 

The stereospecific olefination method involving synthesis, separation, and base-catalysed, decomposition of diastereomeric P-hydroxyalkylphosphine oxides has been used for the preparation of pure isomers of y,S-unsaturated acetals (Scheme 11). The same principle has been extended to trisubstituted alkenes. The yields are generally still good, but the diastereomeric hydroxyphosphine oxides involved are less stable in some cases and the routes to them are less stereoselective. However, the method works reasonably well for the synthesis of ( )-and (Z)-allylic amines (Scheme 12). Unfortunately, (2-substituted-2-amino)-... 

The reaction of allyl acetates, halides and sulfides derived from the MBH adducts with carbon nucleophiles has been well investigated. In fact, Drewes and co-workers first reported the utilization of the nucelophilic addition of a MBH adduct in the stereoselective synthesis of (2 )-integerrinecic acid, a natural product with a trisubstituted olefinic moiety." Subsequently, Drewes et a/ 34,40d,ii9 carried out stereo- and regioselective addition of carbon nucleophiles derived from ethyl acetoacetate, malonate and phenylacetylide derivatives to various MBH halides and MBH acetates. 

Helquist and his co-workers have now given more useful experimental details of the stereoselective synthesis of trisubstituted olefins by addition of alkyl-copper complexes, especially methylcopper, to acetylenes (Scheme 8). Clean results are obtained consistently only if the copper(i) bromide-dimethylsulphide complex (22) is white in appearance and its solutions are colourless. If either the solid or solution develops a pink colour (indicative of Cu" salts) then larger amounts of dienes formed from coupling of the alkenyl-copper intermediates (23), are obtained. Complex (22) is best stored under nitrogen, although manipu-... 

Scheme 24 depicts a synthesis of functionalized trisubstituted olefins from [(trimethylsilyl)acetyl] trimethylsilane " this intermediate and other related acylsilanes can be prepared from silylacetylenes via a hydroboration-oxidation sequence. A stereoselective synthesis of /8-nitro- (and subsequently /3-amino-) alcohols reported this year proceeds as shown in Scheme 25, although the same O-silylated nitroalcohol intermediates can be obtained by the addition of aldehydes R CHO to silyl nitronates R CH=N02SiR3. These latter com-... 

Vinyl silanes continue to attract attention as intermediates for the stereoselective synthesis of olefins. Zweifel and Lewis now describe the stereoselective synthesis of both -and Z-(l-halogenoalk-l-enyl)silanes (15) from alk-l-ynyl-silanes, and show how they may then be processed to dialkyl-substituted vinyl-silanes, alkenyl halides, and trisubstituted olefins (Scheme 12). The E-l-halogenoalkenyltrimethylsilanes are readily prepared in high isomeric purity by treatment of the dialkylhydroalumination adduct (14) with N-chlorosuccinimide,... 

The stereoselective synthesis of vinyl ethers is accomplished by N -(arylidene (or alkylidene) amino) - 2-azetidinones reaction with ozone and NaBH treatment resulting in di- and trisubstituted olefins derivatives [78],... 

Although the introduction of a substituent at both C-a and C-P may be expected to destabilize the transoid state of rearrangement due to additional 1,2-allylic interactions, the tendency to form an -double bond exclusively is retained in the synthesis of trisubstituted olefins as well. The first such report, shortly following the initial Evans report , was made by Grieco who achieved a completely stereospecific general synthesis of ( )-y-substituted methallyl alcohols, including the synthesis of racemic ( )-nuciferol (45, equation 24) . Subsequently, other examples of nearly or completely stereospecific syntheses of ( )-) , y-substituted allylic alcohols have also been pub-lished - " . On the other hand, in the synthesis of y,y-disubstituted allylic alcohols a diminished stereoselectivity has been observed. In this case, the /Z ratio depends on the... 

Stereoselectivity in the synthesis of trisubstituted olefins is necessary for the study of biosynthetic routes to polyisoprenoids, the nonenzymatic cyclization of polyolefinic substrates, and the study of insect hormones. 

Although the trisubstituted olefinic linkage of the pheromone could be fashioned readily in a less selective manner followed by HPLC purification, we sought a stereoselective route in addition. Still and Mitra completed a synthesis of the... 

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). 

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