Configuration Double inversion

A consequence of the Fischer projection rules is that such formulae must not be rotated 90°, because this would mean an inversion of the configuration of the stereogenic center, but they can be rotated 180° without altering the configuration (double inversion = retention) (see Figure 2.4). 

Overall retention of configuration (double inversion) is the rule with stabilized carbon nucleophiles. 

Retention of configuration is expected for conversion of 3 to 59a. It is curious, however, for the rearrangement of 59a to 60a, since the most obvious pathway—opening of the O—O bond followed by rotation and reclosing—should lead to inversion of configuration. Double isotopic labeling with, 80 was used to show that the rearrangement of 59a to 61a, as well as the initial oxidation of 3 to 59a, is fully intramolecular. 

Treatment of the enantiomerically enriched acyclic allylic carbonate (S)-l (97% ee) under the standard reaction conditions furnished the allylic alkylation product (S)-14 (95% ee) in 86% yield, with net retention of absolute configuration (Eq. 3). This result implies that the displacement occurs via a classical double inversion process, albeit through a configurationally stable distorted u-allyl or enyl ff+n) organorhodium intermediate. This is supported by the fact that the achiral ff-spedes iii would undoubtedly have afforded the racemate of 14 (Scheme 10.3). Additionally, the enyl (a+n) organo-metallic intermediate provides a model for the regio- and enantiospedfidty observed in the reaction. 

The fluorinase enzyme mediates a substitution reaction whereby fluoride ion displaces L-methionine with formation of a C-F bond and cleavage of a C-S bond. In order to explore the mechanism in detail, the process has been explored both experimentally and theoretically. The stereochemical course of the reaction was of immediate interest, particularly to delineate between direct inversion or double inversion during the substitution process. A direct substitution will proceed with inversion of configuration at the C5 carbon, whereas a double inversion process will proceed with an overall retention of configuration at the C-5 carbon. To explore this, it was important to prepare SAM 8 carrying a stereospecifically... 

Epoxides also undergo the Ritter reaction in good yields with retention of configuration via a episulfonium intermediate 190a (double-inversion process). For monosubstituted epoxides, the yields of oxazolines are lower due to nondis-criminatory attack of the nitrile on both the primary and the secondary carbon atom of the episulfonium intermediate. Complete retention of configuration is still observed despite the lower yield (Scheme 8.54). 

The double inversion sequence provides unequivocal evidence that the nucleophilic displacements assisted by neighboring boron proceed with inversion of configuration at carbon. 

The mechanism proposed by Foster49 for this deamination postulates the formation of an unstable, intermediate a-lactone (22a), which subsequently undergoes attack by the hydroxyl group on C-5 this process would explain, by a double inversion, the net retention of configuration that is observed. 

Distal C-C bond formation can also be used to construct cyclic ethers, but this demands that methods be developed for the enantioselective assembly of complex acyclic ethers. P. Andrew Evans of Indiana University has demonstrated (Angew. Chem. Jnt. Ed. 2004, 43,4788) that Rh-mediated coupling of secondary allylic carbonates such as 7 with secondary alcohols such as 8, both enantiomerically pure, proceeds with clean retention (double inversion) of absolute configuration. Alkene metathesis then delivers the cyclic ether 9 in high diastereomeric and enantiomeric purity. 

A systematic study of the alkylation of benzene with optically active 1,2-, 1,3-, 1,4-, and 1,5-dihaloalkanes showed that the stereochemical outcome depends on the halogens and the chain length.142 Retention of configuration in alkylation with (S)-1,2-dichloropropane was explained by invoking double inversion and the involvement of a bridged cation such as 27. (S)-l-Bromo-2-chloropropane, in contrast,... 

The vinylogous elimination to give alkenylcyclopropanes may also be effected via rt-allyl palladium complexes34,35. The palladium(0)-catalyzed substitution of allylic esters with stabilized carbon nucleophiles via 7i-allyl palladium derivatives stereospecifically proceeds with net retention (double inversion) of configuration. Thus, the chirality of an allylic substrate is transferred to resultant alkenylcyclopropanes in the intramolecular S J/ reaction via 7i-allyl palladiums (equation 21)36,3. ... 

In combination with the inversion step in the oxidative addition, allyl—X ir-allyl precursors show overall retention of configuration relative to the C—X bond via a double inversion process (equation 152). 

In this reaction sequence, allylic alcohol 6 is converted into 7 with a double inversion of configuration, and thus retention. 

Studies of the stereochemical course of the transglycylation reactions catalysed by lysozyme show retention of configuration at Cl in the product. This can be attributed most economically to the intervention of an acylal intermediate in the mechanism (see Scheme 11.21). A similar result is found in the alkaline phosphatase-catalysed solvolysis of isotopomeric phospho-esters which indicates a double inversion via a phospho-enzyme intermediate (Scheme 11.22). 

An improved method for the conversion of lycorine to hippamine (5) has been developed that commenced with the conversion of 2 to the chloride 175 by the action of phosphorus oxychloride and hydrochloric acid (Scheme 18) (729). The retention of configuration at C-2 was presumably the result of a double inversion sequence involving the participation of the acetate group at C-l. Brief treatment of 175 with sodium methoxide in methanol at 0°C proceeded readily to provide lycorene a-oxide (176), which furnished hippamine (5) when heated with so-... 

A Sharpless asymmetric epoxidation features in a synthesis of (S)-chromanethanol (15). In the key cyclisation step, the absolute configuration of the diol is retained by a double inversion (95SL1255). trans-6-Cyano-2,2-dimethylchroman-3,4-diol is obtained from the racemic diol with excellent optical purity by the stereoselective acylation using Candida cylindraceae lipase (95TA123). 

Configurationally stable sulfur-substituted organolithiums probably also react with retention. Hoffmann showed that the retro-anionic cyclisation of 17 and electrophilic substitution with Mel of 18 proceeded with overall retention, indicating either double inversion or double retention.16 A tin electrophile behaved similarly. 

It is known that valine is incorporated into the penicillins with overall retention of configuration at C-3. It has been shown that l- l-14C,3-3H]valine is incorporated into the disulphide dimer of (100), in cultures of a mutant of C. acremonium, with complete retention of tritium at C-3 of the valine moiety.96 This indicates that valine is built into (100) with retention of configuration and that therefore no double inversion occurs during the biotransformation of valine into the penicillins. 

The reaction usually proceeds with retention of configuration at the reacting centre. As in SN2 reactions going with retention (Chapter 37), this can mean only a double inversion. Coordination of Pd to the double bond of the allylic acetate occurs on the less hindered face opposite the leaving group and the nucleophile adds to the face of the 7t-allyl Pd cation complex opposite the Pd. The net result is displacement of the leaving group by the nucleophile with retention. Thereafter, the... 

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