From receptors in the nose to supramolecular biopolymers, nature shows a remarkable degree of specificity in the recognition of chiral molecules, resulting in the mirror image arrangements of the two forms eliciting quite different biological responses. It is thus critically important that during a chemical synthesis of chiral molecules only one of the two three-dimensional arrangements is created. Although certain classes of chiral molecules (for example secondary alcohols) are now easy to make selectively in the single mirror image form, one class-those containing quaternary stereogenic centres (a carbon atom with four different non-hydrogen substituents)-remains a great challenge. Here we present a general solution to this problem which takes easily obtainable secondary alcohols in their single mirror image form and in a two-step sequence converts them into tertiary alcohols (quaternary stereogenic centres). The overall process involves removing the hydrogen atom (attached to carbon) of the secondary alcohol and effectively replacing it with an alkyl, alkenyl or aryl group. Furthermore, starting from a single mirror image form of the secondary alcohol, either mirror image form of the tertiary alcohol can be made with high levels of stereocontrol. Thus, a broad range of tertiary alcohols can now be easily made by this method with very high levels of selectivity. We expect that this methodology could find widespread application, as the intermediate tertiary boronic esters can potentially be converted into a range of functional groups with retention of configuration.

Organoboranes and boronic esters readily undergo nucleophilic addition, and if the nucleophile also bears an alpha-leaving group, 1,2-metallate rearrangement of the ate complex results. Through such a process a carbon chain can be extended, usually with high stereocontrol and this is the focus of this review. A chiral boronic ester (substrate control) can be used for stereocontrolled homologations with (dichloromethyl)lithium in the presence of ZnCl(2). Subsequent alkylation by an organometallic reagent also occurs with high levels of stereocontrol. Chiral lithiated carbanions (reagent control) can also be used for the reaction sequence with achiral boronic esters and boranes. Aryl-stabilized sulfur ylide derived chiral carbanions can be homologated with a range of boranes including vinyl boranes in good yield and high diastereo- and enantioselectivity. Lithiated alkyl chlorides react with boronic esters, again with high stereocontrol, but both sets of reactions are limited in scope. Chiral lithiated carbamates show the greatest substrate scope and react with both boronic esters and boranes with excellent enantioselectivity. Furthermore, iterative homologation with chiral lithiated carbamates allows carbon chains to be "grown" with control over relative and absolute stereochemistry. The factors responsible for stereocontrol are discussed.

Dedicated to Professor Saverio Florio on the occasion of his 70th birthdayA general method for the preparation of fully substituted carbon atoms (e.g. quaternary stereogenic centers [1] or tertiary alcohols [2] ) that routinely gives high enantioselectivities (> 96 % ee) with broad substrate scope is one of the most challenging goals in organic synthesis.[3] Our research group has recently described a conceptually new method that comes close to meeting such a challenge (Scheme 1).[4] In this process, readily available enantioenriched secondary alcohols were first converted into carbamate compounds. Lithiation and subsequent reaction with boron reagents gave, after oxidative workup, tertiary alcohols with high ee values. Perhaps the most intriguing facet of this novel methodology was that in all cases the reactions occurred with essentially complete inversion of configuration when boranes were employed but almost complete retention of configuration when boronic esters were used. Although the reaction worked well for simple substrates (> 90 % ee), we have found that the introduction of sterically more demanding groups in the carbamate or boronic ester or the introduction of electronwithdrawing aromatic groups in the carbamate resulted in a considerable erosion of enantioselectivity. Herein, we provide a rationale for the observed decrease in enantioselectivity and through understanding the intricacies of the process, we also present a solution to the problem that now results in > 98 % ee for all the substrates tested, even the most demanding.The problem we encountered is illustrated in Scheme 2 (and expanded in the Supporting Information). Thus, reaction of the para-chlorophenyl-substituted carbamate 1 c with EtBpin 2 b (1.1 equiv) gave the tertiary boronic ester with only 40 % ee. Furthermore, we observed an unusual dependence of the ee value on the stoichiometry: increasing the stoichiometry of 2 b from 1.1 equivalents to 3 equivalents led to an increase in the ee value of the product 4 cb from 40 % to 96 % ee.Although a number of possible explanations can be advanced for this observation, we focused on the possible scenario shown in Scheme 3. We suspected that the critical issue was not the selectivity in the formation of the atecomplex, for which it would be difficult to rationalize the dependence of the ee value on stoichiometry, but instead the fate of the ate-complex upon warming. Even though the desired stereospecific 1,2-migration occurred upon warming, it was also possible that competing dissociation of the atecomplex (k À1 ) back to the starting lithiated carbamate and boronic ester species might also take place.[5] This dissociation could be followed by racemization of the lithiated carbamate and subsequent erosion of the ee value. The dependence of the ee value on the stoichiometry can therefore be understood. At low stoichiometry, reversion to starting materials results in a low concentration of the boronic ester, and so the subsequent recombination of the lithiated carbamate with RBpin is inevitably ...

Dedicated to Professor Saverio Florio on the occasion of his 70th birthdayA general method for the preparation of fully substituted carbon atoms (e.g. quaternary stereogenic centers [1] or tertiary alcohols [2] ) that routinely gives high enantioselectivities (> 96 % ee) with broad substrate scope is one of the most challenging goals in organic synthesis.[3] Our research group has recently described a conceptually new method that comes close to meeting such a challenge (Scheme 1).[4] In this process, readily available enantioenriched secondary alcohols were first converted into carbamate compounds. Lithiation and subsequent reaction with boron reagents gave, after oxidative workup, tertiary alcohols with high ee values. Perhaps the most intriguing facet of this novel methodology was that in all cases the reactions occurred with essentially complete inversion of configuration when boranes were employed but almost complete retention of configuration when boronic esters were used. Although the reaction worked well for simple substrates (> 90 % ee), we have found that the introduction of sterically more demanding groups in the carbamate or boronic ester or the introduction of electronwithdrawing aromatic groups in the carbamate resulted in a considerable erosion of enantioselectivity. Herein, we provide a rationale for the observed decrease in enantioselectivity and through understanding the intricacies of the process, we also present a solution to the problem that now results in > 98 % ee for all the substrates tested, even the most demanding.The problem we encountered is illustrated in Scheme 2 (and expanded in the Supporting Information). Thus, reaction of the para-chlorophenyl-substituted carbamate 1 c with EtBpin 2 b (1.1 equiv) gave the tertiary boronic ester with only 40 % ee. Furthermore, we observed an unusual dependence of the ee value on the stoichiometry: increasing the stoichiometry of 2 b from 1.1 equivalents to 3 equivalents led to an increase in the ee value of the product 4 cb from 40 % to 96 % ee.Although a number of possible explanations can be advanced for this observation, we focused on the possible scenario shown in Scheme 3. We suspected that the critical issue was not the selectivity in the formation of the atecomplex, for which it would be difficult to rationalize the dependence of the ee value on stoichiometry, but instead the fate of the ate-complex upon warming. Even though the desired stereospecific 1,2-migration occurred upon warming, it was also possible that competing dissociation of the atecomplex (k À1 ) back to the starting lithiated carbamate and boronic ester species might also take place.[5] This dissociation could be followed by racemization of the lithiated carbamate and subsequent erosion of the ee value. The dependence of the ee value on the stoichiometry can therefore be understood. At low stoichiometry, reversion to starting materials results in a low concentration of the boronic ester, and so the subsequent recombination of the lithiated carbamate with RBpin is inevitably ...

Significance: The enantioselective synthesis of chiral tertiary alcohols remains a challenge in organic synthesis. The authors have previously developed an approach based on the lithiation of chiral secondary carbamates and their subsequent reaction with organoboron reagents (V. K. Aggarwal and co-workers Nature 2008, 456, 778). In the present report the authors address factors which are important to the enantioselectivity of the process and provide solutions to overcome the poor selectivity observed with challenging substrates. Comment:The authors had identified that certain substrates gave poor selectivity. They rationalized that the erosion of selectivity could be explained by the inversion of the lithiated carbamate, which in turn is dependent upon the stability of the atecomplex (see Scheme). Through elegant reaction design the authors were able to determine the efficiency of the individual steps in the overall process. The results of this study demonstrated that bulky or electron-withdrawing groups on the substrate tend to cause reversion of the ate-complex to the lithiated carbamate, similarly a sterically hindered boronic ester or migrating group will favor reversion. To address these issues, the authors added MgBr 2 and methanol. The Lewis acid effectively increased the rate of migration (k 2 ) and the added methanol destroyed any of the lithiated carbamate which may have reverted. Alternatively, neopentyl boronic esters could be used. When these changes were made essentially perfect stereoretention was observed. R 2 OCb R 1 R 1 = H, Me, Cl, F, OMe R 2 = Alk 99% ee R 2 Bpin/Bneop R 1 R 3 1. s-BuLi, Et 2 O, -78 °C 2. R 3 Bpin (1.5 equiv), -78 °C, 1 h 3. 1 M MgBr 2 /MeOH, -78 °C to r.t., 16 h 1. s-BuLi, Et 2 O, -78 °C 2. R 3 Bneop (1.2 equiv), -78 °C, 0.5 h, then r.t., 16 h R 3 = Alk, alkenyl, Ar 63-93% yield 96-99% ee R a t i o n a l i z a t i o n f o r e r o s i o n o f e e :