Lactonization diastereoselective

Several contributions have appeared in which intermolecular reductive couplings between ketones or aldehydes and electron-deficient alkenes have been described [30h, 53]. Reactions of aldehydes and ketones with unsaturated esters result in the formation of lactones. Diastereoselectivities are normally modest in these cases, but can be quite high for certain substitution patterns (Eq. 45). 

The abiUty of enals to react as homoenolates [84] in the presence of NHC catalysts was first noted in 2004 independently by the groups of Glorius and Bode [85]. In both cases, the use of stericaUy-hindered catalyst 99 and a strong base (DBU or Bu OK) allowed a -d umpolung through the extended Breslow intermediate (101), thereby attacking an aldehyde electrophile and ultimately forming a y-lactone diastereoselectively (105, = H) (Scheme 18.18). Whereas two aldehydes can... 

Asymmetric Photodeconjugation Principle Enantioselective Photodeconjugation of a,P-Unsaturated Esters and Lactones Diastereoselective Photodeconjugations. .. 70-7... 

The (partial) description of the synthesis and coupling of the five fragments starts with the cyclohexyl moiety C —C. The first step involved the enantio- and diastereoselective harpless epoxidation of l,4-pentadien-3-ol described on p. 126f. The epoxide was converted in four steps to a d-vinyl d-lactone which gave a 3-cyclohexenecarboxylate via Ireland-CIaisen rearrangement (cf. p. 87). Uncatalysed hydroboration and oxidation (cf. p. 131) yielded the desired trans-2-methoxycyclohexanol which was protected as a silyl ether. The methyl car-... 

Many examples of stereospecific allylation consistent with the above mechanism have been reported. As one example, the regioselective and highly diastereoselective allylation of the lactone 17 with the optically active allylic phosphate 16 proceeded with no appreciable racemization of the allylic part to give the lactones l8 and 19, and the reaction has been used for the synthesis of a polypropionate chain[26]. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

CotLespondingly, tlie catalytic 1,4-addition of dialkylzinc reagents to 3-nitro-iimarin 89 iSdieme 7.24), witli a fixed irans orientation of tlie aiyl and nitro oiips, proceeds witli excellent yidds 190-99 96), bigli diastereoselectivity Id.r. up to ), and enantiosdectivities of up to 9296. Hydrolysis of tlie lactone moiety in 90 IS accompanied by decarboxylation, providing an asymmetric syntliesis of /J-aiyl-troalkane 91. 

Removal of the unsaturated side-chain appendage from C-8 in 22 provides diol lactone 23 and allylic bromide 24 as potential precursors. In the synthetic direction, a diastereoselective alkylation of a hydroxyl-protected lactone enolate derived from 23 with allylic bromide 24 could accomplish the assembly of 22, an intermediate that possesses all of the carbon atoms of PGF2o- It was anticipated that preexisting asymmetry in the lactone enolate would induce the... 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

When a solution of 25 in a 1 1 mixture of methanol and methylene chloride is exposed to periodic acid, the dithiane group is cleaved oxidatively to give, after treatment of the crude product with camphorsulfonic acid (CSA) in methanol, bisacetal 12 as a 2 1 mixture of C-12 anomers in a yield of 80% (Scheme 3). Although the conversion of 12 into 10 could be carried out on the mixture of anomers, it was found to be more convenient to carry each isomer forward separately. When 12 is treated with lithium diethylamide, the methine hydrogen adjacent to the lactone carbonyl is removed as a proton to give an enolate which is then oxidized in a completely diastereoselective fashion with Davis s oxaziridine18 to afford 11. 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Methylmagnesium chloride has been added to various d-(4-substituted-phenyl) <5-oxo esters 15 (X = H, Cl 13, F, Cl, Br, OC11,) which provides the diastereomeric -lactones 1642. The electronic properties of the phenyl 4-substituent have no significant influence on the diastereoselectivity. Except for the 4-methoxyphenyl compound, which is unreactive even at 60 °C, a ratio of ca. 40 60 in favor of the anti-Cram product is observed at 60 "C in tetrahydrofuran as reaction solvent. Lowering the reaction temperature to 0 °C slightly increases the anti-Cram selectivity in the case of the 4-fluoro-, 4-chloro-, and 4-bromo-substituted compounds. On the other hand, a complete loss of reactivity is observed with the <5-phenyl- and <5-(4-methylphenyl)-substituted h-oxo esters. 

Due to the /( -elimination of thiolate, the enolate of (2/ ,5/ )-2-/enolate formed in situ delivers the adducts in >90% diastereoselectivity and about 50% chemical yield115. 

The addition of the dianion of /j-sulfmylcarboxylic acids to carbonyl compounds leads to the formation of the corresponding hydroxy derivatives which undergo spontaneous eyclization to give y-lactones. It was found that when optically active ( + )-(/ )-3-(4-methylphenylsulfinyl)pro-panoic acid is used for the reaction, the corresponding diastereomeric /i-sulfinyl-y-lactones are formed in a ratio which is dependent on the substituents of the carbonyl component. However, the diastereoselectivity was always moderate. 

Lactones have been ultilized as donors, as well as acceptors, in Michael additions giving products with excellent diastereoselectivity. Once the 7>faces of the enolate or the oi,/ -unsatu-rated lactone are effectively shielded by an appropriate substituent at a stereogenic center a to the olefin moiety, this results in the exclusive formation of the Irons-adduct. 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

Photolysis of chromium alkoxycarbene complexes with aldehydes in the presence of Lewis acids produced /J-lactones [83]. Intermolecular reactions were slow, low-yielding, and nonstereoselective, while intramolecular reactions were more efficient (Eqs. 19 and 20). Subsequent studies showed that amines, particularly DMAP, could also catalyze this process (Table 13) [84], resulting in reasonable yields and diastereoselectivity in intermolecular cases. 

The cycloaddition of glyoxylic acid with cyclopentadiene in water at pH 6 and 60 °C is slow and occurs with low yield and low diastereoselectivity [18] (Scheme 6.17). Proton (pH = 0.9) [18], copper salts [27] and Bi(OTf)3 [28] accelerate the reaction and increase the diastereoselectivity. The lactones 28 and 29 originate from endo and exo cycloadducts 27, respectively. The proposed rearrangement is depicted in Scheme 6.17 for the major endo adduct 30. A competitive ene reaction that originates 28 and 29 cannot be excluded [28]. 

The intermolecular C-C bond formation mediated by (TMSlsSiH has been the subject of several synthetically useful investigations. The effect of the bulky (TMSfsSiH can be appreciated in the example of jS- or -substituted a-methylenebutyrolactones with -BuI (Reaction 65). The formation of a,P- or a,y-disubstituted lactones was obtained in good yields and diastereoselectivity, when one of the substituents is a phenyl ring. 

You and co-workers have demonstrated enantioselective y-lactone formations nsing glyoxalate 163, achieving up to 78% ee with the NHC derived from chiral triazohum salt 164, although with low levels of diastereoselectivity (Scheme 12.35) [70],... 

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],... 

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