Julia condensation

Vinyl esters are silylated at the trigonal a-carbon, making available the enol esters of silyl ketones. The regioselective deprotonation of )3-alkoxyacrylic esters and the ability of the lithio derivative to undergo a tandem Michael-Julia condensation with suitable acceptors are exploitable in the synthesis of highly functionalized cyclopentenones. ... 

Julia condensation. LHMDS is also an effective base for the generation of sulfonyl carbanions, which may undergo condensation with esters. 

Julia condensation. Application of the method to form a benzooxacyclooctenone is crucial to a synthesis of heliannuol A. 

Nucleophilic additions to carbonyl groups lead to alcohols which on dehydration, furnish alkenes70,71. This two-step protocol has been extremely useful for diene and polyene synthesis with wide variation in the carbonyl substrate and the nucleophilic addendum. Diene synthesis using aldol-type condensation as well as phenyl sulphonyl carbanion (the Julia reaction) are also discussed in this section. 

A stereoselective synthesis of all E retinal, via a condensation of a Cio chloroacetal with (3-eyelogerany 1 sulfone was described by Julia et al. [29]. The chloroacetal was reacted with the silylenol ether, using TiCl4/Ti(OMe)4, to give in 63% yield, the chloromethoxyacetal derivative as a mixture of E Z isomers (80/20). The aldehyde was converted in 97% yield into the corresponding acetal with HC(OMe)3 and camphorsulfonic acid in methanol, Fig. (6). 

These French chemists described a synthesis of ethyl 9-methylene-13E and 13Z-retinoates via the Julia strategy [74]. The required new C15 sulfone was prepared by O-silylation of P-ionone, followed by catalytic condensation (ZnBr2) of the enol with PI1SCH2CI. 

Another sulfone-based elimination of large applicability was proposed by Julia [418,419], Condensation of a metalled phenyl alkyl sulfone with a carbonyl compound, functionalization of the alkoxide and reductive elimination leads to an olefin. 

Cyclopropane compounds containing the olefin isostere replacement for the amide bond were prepared using Julia olefination chemistry. Aldehydes 39 and 40 were obtained by LAAIH4 reduction of the chiral w-butyl esters of 32 and 33, respectively, followed by swera oxidation of the corresponding alcohols (Figure 22). Condensation of the (S)-N-BOC-cyclohexylalanine sulfone 41 with aldehyde 39 gave after treatment with 2% Na(Hg) and deprotection, the trans and cis olefin-amines... 

P. R. Blakemore, The Modified Julia Olefination Alkene Synthesis via the Condensation of Metallated Heteroarylalkylsulfones with Carbonyl Compounds, J. Chem. Soc. Perkin Trans. 12002, 2563—2585. 

Fig. 11.23. Julia-Kocienski olefination to obtain tmns-alkenes from aldehydes in a single step their condensation reaction with the sulfonyl anion B, followed by an Ar-SN reaction (- E) and a fragmentation.

Auto condensation of sulfones in the anion formation step was recorded by the Julia group [9]. The reaction consists of nucleophilic substitution of the sulfonyl moiety by a sulfonyl anion, as indicated in Scheme 70. 

Keck attempted to apply the Julia coupling to the synthesis of pseudomonic acid Despite the success of the sulfone (393) in reactions with simple aldehydes, only modest yields of the desired coupling were observed. This problem was solved by reversing the aldehyde (395) and sulfone components (394), as shown in Scheme 55. The anion was formed with LDA in THF and condensed with the aldehyde. The P-hydroxysulfone was converted to the mesylate, and the reduction and simultaneous deprotection of the benzylglycoside was carried out with lithium and ammonia to produce the ( )-alkene (396), in 37% overall yield with excellent selectivity. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

The Julia olefination reaction is highly regioselective and ( )-stereoselective, providing a valuable alternative to the Schlosser reaction for making rrans -disubstituted olefins. The reaction involves condensation of a metalated alkyl phenyl sulfone with an aldehyde to yield a P-hydroxysulfone, which is then subjected to a reductive elimination to produce the alkene. There are limitations to the preparation of tri- and tetra-substituted alkenes via the sulfone route because the P-alkoxy sulfones derived from addition of the sulfone anion to ketones may be difficult to trap and isolate or they may revert back to their ketone and sulfone precursors. 

By comparison with the Homer-Wittig reaction, the Julia alkenation has two principal assets. First, as the nucleophilic partner in the connective step (stage 2), sulfones are used, which are often more readily available and more easily purified than the corresponding phosphonium salts. Secondly, the 1,2-disub-stituted alkenes produced in the key reductive elimination step have predominantly ( )-stereochemistry. One detraction of the Julia alkenation is its length — it can be foiled at any one of the four stages. In practice, stage 2, the condensation of the metalated sulfone with the carbonyl, is usually the most problematic but in certain circumstances all of the stages have their pitfalls. These will be examined individually below. 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

Blakemore, P. R. The modified Julia olefination alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585. 

Among the different methods for the formation of C-C double bonds, the reductive elimination of (3-functionalized (mainly P-hydroxy or (3-carboxy) sulfones, is one of the most widely used ones in organic synthesis. The reductive elimination of (3-hydroxy sulfones and derivatives is the so-called Julia,94 or Julia-Lythgoe olefination reaction (Eq. 2). It usually involves a condensation between the anion of an alkyl sulfone and a carbonyl compound to afford a (3-hydroxy sulfone (Eq. 47). The metal alkoxide intermediate is typically transformed in situ into a carboxylic or sulfonic ester derivative, which is then reduced... 

Majima et al. prepared ethyl y-(3-indolyl)-y-oxobutyrate (250) in a similar manner by the condensation of the indole Grignard reagent with /3-ellioxycarbonylpropionyl chloride.107 Methyl y-(3-indolyl)-y-oxobutyrate (251) has been obtained by the action of /3-mcthoxycarbonylpropionyl chloride on indole magnesium iodide in ether.118 119 Ballantine et al. prepared methyl y-(5-methoxy-3-indolyl)-y-oxobutyrate 252118 and Julia et al. obtained methyl y-(5-bromo-3-indolyl)-y-oxobutyrate (253)120 by analogous procedures. 

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