Synthons conjugate additions

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Cyclohexadienones 61 and 64 are readily available from monoprotected hydro-quinones or para-substituted phenols, respectively. Conjugate additions to these symmetrical dienones result in desymmetrization of the prochiral dienone moieties, providing access to multifunctional chiral synthons in two steps from the aromatic precursors (Scheme 7.17) [72]. 

C synthons, synthetic equivalents of which being the amino-acetaldehyde-derived metallated aminonitrile D bearing the chiral auxiliary (S,S)-53 and an a,P-unsaturated ester E, respectively. This should make it possible to open up a pathway to an enantioselective conjugate addition of an a-aminoacyl carbanion equivalent D to enoates in order to access the target 3-substituted 5-ainino-4-oxo esters. 

While there are few examples of conjugate additions of either a-oxygen- or a-silyl-stabilized carbanions, Tamao and Posner have reported two hydroxymethyl synthons ["ClfcOH] (246 and 247) which show synthetic promise. Additions with the silicon-based synthon (246) is restricted to 2-cyclohexen-l-ones and work-up requires a successive acid and base procedure that is incompatible with sensitive molecules,188a-b while the tin-based synthon (247) is more versatile and the hydroxyl group is obtained under neutral conditions (Scheme 83).,88c... 

Aside from the nitronates, cyanide anion and acyl anion equivalents, e.g. (219), examples of conjugate additions of a-aza-stabilized carbanions are rare. The aminomethyl synthon [ CHRNH2] is typically introduced with either nitronates or cyanide however, a-metallomethyl isocyanides (248) also show synthetic promise in conjugate additions. In addition, depending on hydrolytic conditions employed, they also serve as equivalents for the N-formamidomethyl anion ["CHRNHCHO] or the isocyanatomethyl anion ["CHRN=C ] (Scheme 84).189... 

To start with you may like to draw the synthons and, by inspecting the carbon synthon, decide which electrophilic reagent to use. But as this chapter develops, you will see that there is a particular chemistry used to make each different relationship (e.g. a 1,3-relationship suggests conjugate addition) and you may soon not bother with the synthons but write the reagents directly. This is a matter for personal choice. 

We have met the acyl anion or d1 synthon in chapter 23 but for the disconnection 8 on 1,4-diketones we need a d1 reagent that will do conjugate additions on enones such as 36. Sadly that eliminates dithians from consideration as they are too basic (hard) and tend to add direct to carbonyl groups. 

A better strategy emerges from disconnection of the six-membered ring 44a. Aldol disconnection reveals a triketone with two 1,4-dicarbonyl relationships 49. An ideal disconnection would correspond to a reagent for the d1 synthon 51 that can do conjugate additions to both 50 and 52. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

And we know what the reagent was (A). This is a d synthon. Aldehydes are naturally electrophilic at C3 (by conjugate addition) so to make a reagent with unnatural polarity umpolung , p. 798), the aldehyde must be protected. 

Orthoesters of acrylic acid are converted to y.y-dialkoxyallylzirconocene ethoxides with CpjZr. These latter species serve as 2,2-dialkoxycyclopropyl anion synthon, showing y-addition reactivity toward carbonyl compounds to afford homoallylic alcohols. In the presence of MejSiOTf cyclopropyl carbinols are formed, due to a switch to the -addition mode conjugate addition to enones leads to P-cyclopropyl ketones (e.g., from 2-cyclopen tenone)... 

Although these microbial reactions may substitute for chemical resolution methods, they likewise have the inherent disadvantage that only one half of the material is theoretically utilizable, for the substrate is already chiral. It is therefore preferable to design substrates with pro-chiral centers suitable for microbial asymmetric inductions. Examples that have been applied in the prostaglandin area follow. Reduction of triketone 40 with Dipodascus uninucleatus and Mucor rommanianus furnished the (R) and (S) alcohols (41 and 42) respectively. 6 The (R) alcohol (41) was then chemically converted into 43, a key synthon for prostaglandin synthesis via conjugate addition. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Secondary amines, immobilized on mesoporous FSM-16 silica by the same methodology, were utilized to obtain substituted 5-ketoaldehydes, which are important synthons for the preparation of natural products such as terpenoids, by direct 1,4-conjugate addition of unmodified aldehydes to vinyl ketones (Scheme 3.15). ... 

Another disconnection outside the enone system is 4e which looks at first sight like a conventional conjugate addition to an a3 Michael acceptor. However we need to get the alkene back again after the Michael addition has occurred. The a3 synthon 14 is unsaturated. 

Amino nitriles are useful for conjugate addition Acyl anion equivalents of the ester d1 synthon - C02R Methods Based on Vinyl (Enol) Ethers and Enamines Lithium derivatives of cyclic vinyl ethers The synthesis of pederin and related anti-tumour agents Lithium derivatives ofallenyl ethers Oxidative Cleavage of Allenes... 

The reaction of yne-ones (also synthons for 1,3-dicarbonyl compounds) with 3-amino-enones or 3-amino-acrylates (the Bohlmann-Rahtz reaction) is regioselective, since conjugate addition of the ketone enamine is the first step the intermediates thus produced can be isolated from reactions in ethanol and converted on to the aromatic pyridine Acetic acid or ytterbium triflate give good results. 

M. (1997) Propargyl alcohols as synthons for allenols in conjugate addition. Journal of the American Chemical Society, 119, 11319-11320. 

Branch at C-5 - The nonulosonic acid derivative 44 has been prepared by aldolase-catalysed reaction of pyruvate with 2-deoxy-2-C-hydroxymethyl-D-mannose as a possible synthon for the C-12 to C-20 sequence of amphotericin B. The latter compound was made in several steps from ethyl 2,3-dideoxy-4,5 6,7-di-0-isopropylidene-D-ara6/>io-hept-2-enoate by conjugate addition of vinylmagne-sium bromide followed by transformation of the vinyl group into a hydroxymethyl group in the key steps. ... 

Pyrolytic prod, from cellulose, in low yield. Important chiral synthon. The most important carbohydrate used in conjugate additions. 

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