Absolute stereochemical outcome

Diels-Alder reaction of 2-bromoacrolein and cyclopentadiene using 10 mol% of titanium catalyst 74 gave the synthetically versatile (R)-bromoaldehyde adduct 75 in 94% yield, 67 1 exo. endo diastereoselectivity, and 93% ee. The absolute stereochemical outcome of the reaction is consistent with the proposed transition state assembly 76 in which the dienophile coordinates at the axial site of the metal, proximal to the indane moiety through Ji-attractive interactions. In this complex, the 7t-basic indole and the Ji-acidic dienophile can assume a parallel orientation facilitated by the octahedral geometry of the transition metal. The aldehyde would then react through a preferential s-cis conformation (Scheme 17.27).54... 

The optimized structure of a BIPOL-SnCl4 complex was determined at the B3LYP/LANL2DZ level to enable understanding of the absolute stereochemical outcome of the cyclizations (Fig. 3). It is noteworthy that two acidic protons are likely to be located at pseudo-axial sites parallel to an apical axis of the tin atom, and electrostatic interaction between the acidic protons and the apical chlorines is expected. 

The use of well-designed chemical processes, aided hy chiral molecular catalysts, can provide truly practical and efficient synthetic methods for the production of hioactive substances and functional materials. In particular, the growing awareness of the importance of chirality to the function of chemical substances has led to the development of many new chiral molecular catalysts for use in large-scale production. Chiral molecular catalysts consisting of a metal atom or ion and a chiral organic ligand(s), under the appropriate conditions, can not only repeatedly accelerate organic reactions, but also simultaneously control the absolute stereochemical outcome [1]. 

A series of innovative investigations by Kiyooka and co-workers have introduced the use of tandem reaction processes that commence with a stereoselective aldol addition reaction and are followed by C=0 reduction [13]. A chiral oxazaboroli-dine complex prepared from BH3-THF and A-/ -toluenesulfonyl (L)-valine controls the absolute stereochemical outcome of the aldol reaction. In a subsequent reaction, the /i-alkoxyboronate effects intramolecular reduction of the ester to furnish the corresponding /i-hydroxy aldehyde. 

It is possible to predict both the relative and the absolute stereochemical outcome of diyl trapping reactions [27] (Scheme 9). The preferred stereochemical outcome... 

The key feature in this IMDA approach was the incorporation of a stereogenic center into the tether, allowing the possibility to control the absolute stereochemical outcome of the cyclization. The use of (5)-l,3-butanediol in the tether gave the best results - cyclization proceeded with excellent asymmetric induction affording only two exo and endo products) out of the possible four 4,5-cis diastereoisomers. It is also noteworthy that this cyclization must proceed in a stepwise fashion since the starting dienophile has a tran.s geometry while the products possess a cis substitution pattern at C (4) and C (5). 

The diene precursor 78 is readily accessed in a few steps from the Wieland-Miescher ketone 79, which also provides the A- and B-rings of the steroid skeleton. Furthermore, the presence of an axial methyl group at C(19) (steroid numbering) allows the possibility of controlling the absolute stereochemical outcome of the key cycloaddition used to... 

The absolute stereochemical outcome of the Diels-Alder reactions via these catalysts can be successfully predicted on the basis of the pretransition state assemblies shown in Figure 1.1. 

Considering the unique features that the Nozaki-Hiyama-Kishi reaction possesses and its undoubted potential in the synthesis of complex natural products, the development of an efficient enantioselective version to control the absolute stereochemical outcome for a range of processes was highly desirable. However, because of the difficulties such as ligand coordination and specificity combined with the tendency of chromium(II) to form dimers or clusters with polydentate ligands, considerable effort has been devoted to the development of enantioselective variants. These studies have resulted in the expansion of the NHK to now include an impressive array of carbon-carbon, bond-forming processes (Scheme 12.6). 

However, the configuration of the major isomer obtained in the conjugate addition to methyl ( )-3-[(35,)-3-tot-butoxycarbonyl-2,2-dimcthyl-4-oxazolidinyl]-2-propenoate (entry 3) did not depend on the cuprate type alkyl-, vinyl-, 2-methylpropenyl-, phenyl-, and benzvl-cuprates induced the same sense of asymmetry, although the absolute configuration was not determined5. Here also, the stereochemical outcome was not dependent upon the geometry of the double bond. 

In turn, bis(2-hydroxyethyl)phenylphosphine P-borane 90 underwent acetylation only in the presence of the lipase from Pseudomonas fluorescens, but its stereochemical outcome depended on the solvent used (Equation 43). The absolute configuration of 91 was not determined. 

In addition to the enhanced rate of hydroalumination reactions in the presence of metal catalysts, tuning of the metal catalyst by the choice of appropriate ligands offers the possibility to influence the regio- and stereochemical outcome of the overall reaction. In particular, the use of chiral ligands has the potential to control the absolute stereochemistry of newly formed stereogenic centers. While asymmetric versions of other hydrometaUation reactions, in particular hydroboration and hydrosi-lylation, are already weU established in organic synthesis, the scope and synthetic utiHty of enantioselective hydroalumination reactions are only just emerging [72]. 

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

The above-mentioned facts have important consequences on the stereochemical outcome of the kinetic resolution of asymmetrically substituted epoxides. In the majority of kinetic resolutions of esters (e.g. by ester hydrolysis and synthesis using lipases, esterases and proteases) the absolute configuration at the stereogenic centre(s) always remains the same throughout the reaction. In contrast, the enzymatic hydrolysis of epoxides may take place via attack on either carbon of the oxirane ring (Scheme 7) and it is the structure of the substrate and of the enzyme involved which determine the regioselec-tivity of the attack [53, 58-611. As a consequence, the absolute configuration of both the product and substrate from a kinetic resolution of a racemic... 

The most efficient catalyst system for the Morita-Baylis-Hillman reaction of methyl vinyl ketone has been reported by Miller [183, 184], Use of L-proline (58) (10 mol%) in conjunction with the A-methyl imidazole containing hexapeptide 131 (10 mol%) provided an efficient platform for the reaction of 125 with a series of aromatic aldehydes 127 (52-95% yield 45-81% ee) (Scheme 52). Importantly, it was shown that the absolute configuration of the proline catalyst was the major factor in directing the stereochemical outcome of the reaction and not the complex peptide backbone. 

In this section an approach is discussed whereby absolute configurational assignment is based on auxiliary- or reagent-controlled stereoselective key reactions. The stereochemical outcome of the reaction used for the assignment must be predictable, from either the absolute configuration of the auxiliary or the reagent, by a rule or (better) a well-defined model of the transition state220. 

In the cases where auxiliary- or reagent-controlled stereoselectivity is employed for the assignment of absolute configurations, it must always be considered that the normal stereochemical outcome of the particular reaction may be reversed depending on both the structure of the starting material and/or the reaction conditions. Some examples are discussed ... 

The stereochemical outcome of these electrophilic additions is consistent with a transition state in which the metal chelates the oxazolidinone carbonyl and the enolate oxygen. Reaction with an electrophile would, therefore, occur at the less hindered diastereotopic face of the (Z)-enolate, away from the shielding methyl groups of the auxiliary (Figure 24.6). Because both enantiomers of oxazolidinone 108 are equally available, the direction of the asymmetric induction can be controlled by proper choice of the absolute stereochemistry of the chiral auxiliary.106... 

The absolute configuration of the quaternary stereocenter of the acy-loin 107 (R = Me) produced was determined to be S by comparison of the measured optical rotation value with the corresponding literature data (Davis and Weismiller 1990). This stereochemical outcome might be explained by the transition state shown in Scheme 33, which is an adaptation of the transition state proposed by Dudding and Houk on the basis of computational calculations (Dudding and Houk 2004). The Si... 

This overriding effect of 1,3-chirality transfer as compared to induced diastereoselectivity was also observed in chiral, nonracemic, secondary allylic sulfides bearing a remote chiral dioxolanyl moiety (Scheme 91) [215]. The reactions of E-(S)-570 and Z- R)-571 with ethyl diazoacetate under the influence of various Rh catalysts delivered ylides which rearranged to products 372 and 2 -epi-372. From the analysis of the products it was deduced that 1,3-chirality was almost complete, whereas the stereochemical outcome at C2 differed somewhat with the catalysts used and was only modest in all cases. Obviously the reaction of 370 to the major diastereomer epz-372 involves TS-I or TS-II (Scheme 88) (R = dioxolanyl moiety, R = Me, G = C02Et) with the absolute topicity of attack being Re (C2 )ISi (C3). After desulfanylation only... 

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