Trisubstituted olefins

Stereospecific Synthesis of Trisubstituted Olefins from Acetylenes or Aldehydes Applications to the Total Synthesis of Cecropia Juvenile Hormones (JH) and Farnesol... 

Synthesis of trisubstituted olefins via LAH reduction of the propargylic alcohols and iodination as the key step (Ref. 1). 

The reaction was adapted to the stereospecific synthesis of trisubstituted olefins in two ways as shown in the following scheme. 

The first synthesis of trisubstituted olefins from acetylenes was applied to the total synthesis of several natural products as outlined on the next page. 

Reaction of an alkyltriphenylphosphorane in tetrahydrofuran with an aldehyde produces the oxaphosphetane B, which can be further treated with 1 eq. of 3-butyllithium to form the P-oxidophosphonium ylide C. This ylide can in turn react with another aldehyde, for instance, paraformaldehyde to give, after work-up, the trisubstituted olefin D. 

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. 

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

The low rate of reaction for trisubstituted olefins was shown to be a result of slow hydrolysis of the osmium glycolate 29. However, this hydrolysis can be accelerated by a factor of up to 50 simply by the addition of methanesulfonamide.26 This modification permits the AD to be performed at lower temperature, which nearly always results in an increase in the stereoselectivity of the reaction.27... 

For trisubstituted olefins, the nucleophile attacks predominantly at the less substituted end of the allyl moiety, e.g. to afford a 78 22 mixture of 13 and 14 (equation 7). Both the oxidative addition of palladium(O) and the subsequent nucleophilic attack occur with inversion of configuration to give the product of net retention7. The synthesis of the sex pheromone 15 of the Monarch butterfly has been accomplished by using bis[bis(l,2-diphenylphosphinoethane)]palladium as a catalyst as outlined in equation 87. A substitution of an allyl sulfone 16 by a stabilized carbon nucleophile, such as an alkynyl or vinyl system, proceeds regioselectively in the presence of a Lewis acid (equation 9)8. The... 

Scheme 58 Allyl to prenyl interconversion by the use of a trisubstituted olefin in CM, in garsubellin A (302)-directed work [137]...

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. 

The argument of the directing effect of lone pairs on the substiment [92] easily extends to the alkyl cases. The orbital interaction (Scheme 20) [103] in the pere-poxide quasi-intermediate suggests the stabilization occurs by the simultaneous interaction of O with two allylic hydrogens on the same side of the alkene. Photooxygenation of trisubstituted olefins revealed a strong preference for H-abstraction from disubstituted side of the double bond [104, 105],... 

However, high conversions (82-91%) and high enantioselectivities (up to 90% ee) could be obtained in the cycUzation of the ( )-trisubstitued olefin 64 catalyzed by complex 61d (Scheme 41). hi this reaction neither solvent nor temperature has a significant effect on the enantioselectivity. In the case of the corresponding (Z)-trisubstituted olefins, conversions are high, but enantioselectivities are lower (ee < 36%). 

Cyclisation has occurred to the tertiary carbonium ions as kinetic preference for a five-membered ring cannot overcome thermodynamic preference for a six-membered ring in this cyclisation of trisubstituted olefin. 

II, while 9 failed. For substrates with H, both catalysts were found to be effective providing preferentially the rrawi-configured products 15a. Enynes carrying trisubstituted olefin moieties failed to react. 

The C-19 methylene protons appeared as a broad singlet at 8 2.72 and showed weak allylic interactions with the vinylic C-11 proton that appeared at 8 5.45 as a multiplet and itself showed vicinal coupling with the C-12 methylene protons. This trisubstituted olefinic bond when tailored into ring C of the skeleton gives rise to fragment II. 

B. Reactions.—This year has seen the publication of a number of papers on the reactions of olefins and acetylenes with phosphorus pentachloride, to produce new phosphorus-carbon bonds. An investigation into the structural requirements of trisubstituted olefins (40) undergoing the above reaction has shown that both steric and electronic factors are important, e.g. an adduct forms with (40 X = CH3) but no reaction occurs for (40 X = Ph). Further examples of the reactions of unsaturated ethers include the formation and decomposition of adducts from a-methoxystyrene... 

The jS-oxido-ylides synthesis of trisubstituted olefins has also been applied to the synthesis of farnesol (127). The phosphonium salt (123) with the aldehyde (124) and formaldehyde gave the hydroxy farnesol derivative (125) which was transformed into farnesol (127) and into (126), a position isomer of Cj juvenile hormone. 

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... 

The regiochemistry of the hydrozirconation of disubstituted stannyl- [24, 167-170] and silyl- [171] acetylenes and boron- [118, 172-175] and zinc- [34, 126] alkynyl derivatives result in the formation of 1,1-dimetallo compounds. Hydrozirconation of alkynyliodonium salts affords alkenylchlorozirconocenes with the Zr-C bond geminal to the iodonium moiety [176]. These zirconocene complexes allowed the preparation of ( )-trisubstituted olefins (Scheme 8-20). 

Mono-, di-, and trisubstituted olefins undergo osmium-catalyzed enantioselective dihydroxylation in the presence of the (R)-proline-substituted hydroquinidine 3.9 to give diols in 67-95% yields and in 78-99% ee.75 Using potassium osmate(VI) as the catalyst and potassium carbonate as the base in a tm-butanol/water mixture as the solvent, olefins are dihydroxylated stereo- and enantioselectively in the presence of 3.9 and potassium ferricyanide with sodium chlorite as the stoichiometric oxidant the yields and enantiomeric excesses of the... 

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