Lactone stereochemistry

The 1,10 and 4,5 double bonds are trans (or assumed to be). Unassigned lactone stereochemistry. Probably cw-fused lactone, i.e., 8a-H. Also 11,13-dihydro-derivatives. cf. vernomygdin. Table 2 (i) these two compounds are related via their identical tetrahydro-derivatives. 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

Neomethymycin (12, R = H, R = OH), an isomer co-produced with methymycin, is the product of hydroxylation at C-12 rather than C-10 of the lactone (34,35). The corresponding aglycone, neomethynoHde (13, R = H, R = OH), was isolated with methynolide from broths of S. vene elae (36). The stereochemistry of 12(R)- for neomethynoHde was estabHshed by total synthesis (37). YC-17 (12, R = R = H), also found in broths of S. vene elae is a possible precursor of methymycin and neomethymycin. The hydroxyl groups at C-12 and C-10 are probably added as late steps in the biosynthesis (38). 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

The stereochemistry of the vinyl ether is retained during its reaction with the a-peroxy lactone (41) which leads to a l,4-dioxan-2-one <96JOC8432>. 

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

Entry 10 was used in conjunction with dihydroxylation in the enantiospecific synthesis of polyols. Entry 11 illustrates the use of SnCl2 with a protected polypropionate. Entries 12 and 13 result in the formation of lactones, after MgBr2-catalyzed additions to heterocyclic aldehyde having ester substituents. The stereochemistry of both of these reactions is consistent with approach to a chelate involving the aldehyde oxygen and oxazoline oxygen. 

Entry 23 was part of a synthesis of the pancratistatin structure. The lactone ring was used to control the stereochemistry at the cyclization center. Noncyclic analogs gave a mixture of stereoisomers at this center. In this reaction, triphenylstannane gave much better yields than tri-n-butylstannane. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 12.5.2), so the correct stereochemistry is established for the C—O bond. The final stereocenter for which configuration must be established is the methyl group at C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not very stereoselective. However, since this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate was formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C(6). 

There have been several syntheses of P-D lactone that were based on carbohydrate-derived starting materials. The starting material used in Scheme 13.42 was prepared from a carbohydrate produced in earlier work.27 The relative stereochemistry at C(4)... 

The synthesis in Scheme 13.47 was also based on use of a chiral auxiliary and provided the TBDMS-protected derivative of P-D lactone in the course of synthesis of the macrolide portion of the antibiotic 10-deoxymethymycin. The relative stereochemistry at C(2)-C(3) was obtained by addition of the dibutylboron enolate of an A-propanoyl oxazolidinone. The addition occurs with syn anti-Felkin stereochemistry. 

The synthesis in Scheme 13.49 features use of an enantioselective allylic boronate reagent derived from diisopropyl tartrate to establish the C(4) and C(5) stereochemistry. The ring is closed by an olefin metathesis reaction. The C(2) methyl group was introduced by alkylation of the lactone enolate. The alkylation is not stereoselective, but base-catalyzed epimerization favors the desired stereoisomer by 4 1. 

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