Asymmetric 3-lactone formation

The acid chloride precursor for the multicomponent reaction was accessed (Scheme 11) through the method that was developed in the theopederin D synthesis. The sequence largely followed the excellent route that was reported by Nakata." Our variation on this route was the incorporation of a catalytic asymmetric (3-lactone formation" " from acetaldehyde and propionyl chloride in the presence of 44 to yield, after opening with the lithium enolate of t-butyl... 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and -lactones, respectively (equations 137 and 138) The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of -alkenes in bicyclic y-lactone formation . Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enantioselectivity in intramolecular cyclopropanation (equation 139) ". On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140). ... 

Recent developments extend the asymmetric P-lactone formation to dichloroaldehydes 183 with formation of the ketene 163 by elimination on acetyl chloride rather than from a ketene generator. A mixture of the aldehyde 183, Hunig s base and 2 mol % quinidine 169 is treated with acetyl chloride to give the p-lactones 184 in good yield (40-85%) and excellent ee. Reduction with DIBAL gives the diol 185 with the two chlorine atoms intact.42... 

The second key step is lactone formation from the carboethoxy substituted cyclohexanone unit in 44. The third key step is construction of the tricyclic ring system by asymmetric radical cyclization of 43, and construction of 43 from 2-isopropylphenol (42) using alcohol chiral auxiliaries (R OH) was designated as the fourth key step. This disconnection scheme represents Yang s specific approach using key chemical transformations such as radical cyclization (see sec. 13.7). Clearly, other disconnections are possible, and at each stage other disconnections could lead to alternate synthetic trees. 

RCM was used to form the seven-membered ring of sundiversifolide 8.232 (Scheme 8.63). The substrate 8.229 was assembled by an asymmetric aldol reaction and cyclized using the Grubbs second-generation catalyst. Reduction of the enone 8.230 formed allowed lactone formation by Claisen rearrangement, iodocy-clization and deiodination. Further steps lead to the natural product 8.232. 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

A combination of axially chiral C2-symmetric binaphthol 85 with Zr(OBu-f)4 and TBHP represented a novel access to asymmetric BV oxidation. The system works under stoichiometric conditions and leads to the formation of the zirconium species 113, responsible for the activation of ketone and, likely, of the peroxide . As an example, the BV oxidation of 114 afforded the lactones 115 and 116 in a ratio 1 5 with 84% and 14% ee, respectively (equation 80). Asymmetric inductions are preserved also if one of the two chiral diols coordinated to zirconium is replaced with conformationally flexible biphenols . 

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

Halicholactone 214, a marine metabolite with lipoxygenase inhibitory activity, belongs to the family of oxylipins which all contain a lactone moiety substituted by a /ra r-disubstituted cyclopropane subunit. Stereoselective RCM for the formation of the nine-membered lactone core in 214 was the penultimate step (212 —> 213) in a asymmetric... 

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