Enantiomerically pure bases

Organoboranes are modest Lewis acids that react easily with a variety of neutral or negatively charged bases to form thermally stable adducts, because of the formal p-vacancy on boron. Hence, the addition to alkenes may be considered to be driven by initial association of the alkene with the vacant p-orbital on boron, followed by a hydride transfer within the ensuing complex. This mechanism has been the subject of computational studies, and provides a working model for the reaction mechanism in accord with the observed selectivities [5]. This cannot be the complete picture, since the employment of a borane co-ordinated to an enantiomerically pure base leads to a discemable e.e. in the product [6],... 

Crystalline adduct 25 (2.4 mmol) obtained from DCC (1 mmol) and HOPfp (3 mol) was added to a soln or suspension of R OCO-Xaa -Xaa -OH (2 mmol) in EtOAc (4-5 mL) while stirring. After 10 min, the temperature was brought to 0°C and stirring was continued for 10 min. The mixture was filtered, the solvent was removed, the residue was triturated in hexane, and the crystals were collected. The products were recrystallized (hexane or EtOAc/hexane). The products were enantiomerically pure based on analysis for isoleucine/alloisoleucine after hydrolysis and comparison of the specific rotation of a model peptide prepared by the acyl azide method. 

The use of enantiomerically pure bases to catalyse asymmetric deprotonations is an exciting idea that has been shown to be technically feasible. The major difficulty is that the catalytic base must be continuously deprotonated under the reaction conditions. In order to be effective, whatever achiral base provides the continuous deprotonation must not directly deprotonate the substrate. This is conceptually similar to catalytic protonation reactions, which are described in more detail in the next section. 

A very diflferent application is the enantioselective protonation of the cyclic allyl enol carbonate of Scheme 61. Liberation of the enolate is followed by protonation in the presence of an enantiomerically pure base.t ° ... 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Asymmetric induction by sulfoxide is a very attractive feature. Enantiomerically pure cyclic a-sulfonimidoyl carbanions have been prepared (98S919) through base-catalyzed cyclization of the corresponding tosyloxyalkylsulfoximine 87 to 88 followed by deprotonation with BuLi. The alkylation with Mel or BuBr affords the diastereomerically pure sulfoximine 89, showing that the attack of the electrophile at the anionic C-atom occurs, preferentially, from the side of the sulfoximine O-atom independently from the substituent at Ca-carbon. The reaction of cuprates 90 with cyclic a,p-unsaturated ketones 91 was studied but very low asymmetric induction was observed in 92. 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

Addition of enantiomerically pure cnamines derived from (.Y -jmethoxymethyfipyrrolidine (SMP) and ketones (cyclohexanone, cycloheptanone, propiophenone) to AGY-dimethylmethylene-iminium tetrachloroaluminate11,42 give the corresponding Mannich bases in moderate to good yields (56 -79%) and low to moderate enantioselectivities (30-66% ce)12, l3. The (-)-isomer is the major enantiomer in each case. The absolute configuration of the major enantiomer has not been determined. The auxiliary can be recovered. 

The (S )-valine based bislacdm ether adds regioselectively in a 1,6-fashion to a,/ -y,<5-unsat-urated -substituted esters with both simple and induced diastereoselectivity exceeding 99 1. This provides, after hydrolysis, virtually enantiomerically pure dimethyl ( )-2-amino-3-hep-tene-l,7-dioates 206. 

For a chiral molybdenum-based catalyst available in situ from commercial components, see (a) Aeilts SL, Cefalo DR, Bonitatebus PJ, Houser JH, Hoveyda AH, Schrock RR (2001) Angew Chem Int Ed 40 1452 (b) For the first enantiomerically pure solid-sup-ported Mo catalyst, see Hultzsch KC, Jernelius JA, Hoveyda AH, Schrock RR (2002) Angew Chem Int Ed 41 589 (c) For a chiral Mo catalyst, allowing RCM to small- and medium-ring cyclic amines, see Dolman SJ, Sattely ES, Hoveyda AH, Schrock RR (2002) J Am Chem Soc 124 6991 (d) For a novel adamantyl imido-molybdenum complex with advanced selectivity profiles, see Tsang WCP, Jernelius JA, Cortez GA, Weatherhead GS, Schrock RR, Hoveyda AH (2003) J Am Chem Soc 125 2591... 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

Addition of such a-lithiosulfinyl carbanions to aldehydes could proceed with asymmetric induction at the newly formed carbinol functionality. One study of this process, including variation of solvent, reaction temperature, base used for deprotonation, structure of aldehyde, and various metal salts additives (e.g., MgBrj, AlMej, ZnClj, Cul), has shown only about 20-25% asymmetric induction (equation 22) . Another study, however, has been much more successful Solladie and Moine obtain the highly diastereocontrolled aldol-type condensation as shown in equation 23, in which dias-tereomer 24 is the only observed product, isolated in 75% yield This intermediate is then transformed stereospecifically via a sulfoxide-assisted intramolecular 8, 2 process into formylchromene 25, which is a valuable chiron precursor to enantiomerically pure a-Tocopherol (Vitamin E, 26). 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

Reaction of allylic silanes with enantiomerically pure 1,3-dioxanes has been found to proceed with moderate enantioselectivity.104 The homoallylic alcohol can be liberated by oxidation followed by base-catalyzed (3-elimination. The alcohols obtained in this way are formed in 70 5% e.e. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

Another synthesis of P-D lactone that is based on an enantiomerically pure starting material is shown in Scheme 13.35. The stereocenter in the starting material is destined to become C(4) in the final product. Steps A and B served to extend the chain to provide a seven-carbon 1,5-diene. The configuration of two of the three remaining stereocenters is controlled by the hydroboration step, which is a stereospecific syn addition (Section 4.5.1). In 1,5-dienes of this type, an intramolecular hydroboration occurs and establishes the configuration of the two newly formed C—B and C—H bonds. 

One approach to the synthesis of enantiomerically pure compounds is to start with an available enantiomerically pure substance and effect the synthesis by a series of enantiospecific reactions. Devise a sequence of reactions that would be appropriate for the following syntheses based on enantiomerically pure starting materials. 

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

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