Bromination diastereoselective

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

NMR-spectroscopic studies and a single crystal X-ray structure determination of the reduced Co / form of 100 revealed the presence of a bridging 2,3-dibromo-3-phenyl-propionato ligand (threo dl pair). The complex bearing the erythro form of 2,3-dibromo-3-phenyl-propionate is only produced in minor yields <3%. Therefore, the bromination of the encapsulated alkene is a highly diastereoselective syu-addition. This is rather... 

Buynak et al. reported the synthesis of representative 7-vinylidenecephalosporine derivatives bearing an axial allene chirality (Scheme 4.5) [9]. A chiral allene 24 was prepared stereoselectively utilizing the reaction of an organocopper reagent with propargyl triflate 23, obtained by a diastereoselective ethynylation of the ketone 22 with ethynylmagnesium bromide. Terminally unsubstituted allene 26 was synthesized via bromination of the triflate 23 followed by reduction of the bromide 25 with a zinc-copper couple. 

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

In the latter reaction, remarkable examples of diastereoselectivity have been reported. Thus, the treatment of 7,7-dibromonorcarane 22 with n-butyllithium leads to exo-7-bromo-ewdo-7-lithiobicyclo[4.1.0]heptane23 exclusively, as shown by carboxylation (Scheme 8). It turns out that a slight excess of dibromonorcarane 22 relative to butyllithium is prerequisite to that high degree of stereoselectivity. The result is explained as follows the exo-bromine atom in 22 is exchanged first in a kinetically controlled reaction so that the ewrfo-bromo-exo-lithio-isomer 24 is formed. In a second step, an equilibration occurs by means of another bromine-lithium exchange, which takes place between 24 and the dibromonorcarane 22 (still present because used in excess). Thus, the thermodynamically... 

SCHEME 8. Diastereoselective bromine-hthium exchange reaction in dibromonorcarane 22... 

Chelation is another driving force that provides diastereoselective bromine-lithium exchange reactions to give cyclopropyl carbenoids. Thus, the exo-bromine atom in dibro-mocyclopropane 25 is exchanged exclusively due to the methoxy substituent, which encourages the lithium to occupy the cis orientation (equation 16) ° Several representative examples of cyclopropyl bromo lithium carbenoids obtained by bromine-lithium exchange reactions are given in Table 1. 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

An intramolecular substitution of trimethylamine fix>m 17 gave a bicyclic oxetane 18 in a diastereoselective process <98MI2185>. A [2+2]cycloaddition of 2,2,4,5-tetrasubstituted 2,3-dihydrofuran to aryl aldehydes gave the bicyclic oxetane 19 <98JCS(P1)3261>. 2,2-Disubstituted-3-bromooxetane was obtained by a 4-endo-tcig cyclization process of 3,3 -disubstituted allyl alcohol in the presence of bis(collidine)bromine hexafluorophosphate <99JOC81>. 

The mixed 1,2-bimetallic Zn/Si-reagent 47 is a versatile species which reacts with aldehydes in high diastereoselectivity . It is prepared by a bromine/lithium exchange reaction starting from 48 followed by a transmetalation with ZnCl2 (Scheme 21). The... 

Asymmetric hromination of ketals of alkyl aryl ketones,l a-Bromination of the ketals of alkyl aryl ketones obtained with the dimethyl esters of (2R,3R)- or (2S,3S)-tartaric acid is highly diastereoselective. Hydrolysis of the products provides optically active 2-bromo ketones. 

In the above discussion of stereoselectivity the mechanisms of various reactions have been used to rationalize why some are stereoselective and some are not. Thus the bromination of olefins proceeds via a bridged bromonium ion intermediate and gives only trails addition across the double bond [reactions (6.2) and (6.3)]. In contrast, the addition of HBr across a double bond gives a carboca-tion intermediate that does not maintain the facial integrity of the olefin and is thus much less stereoselective [reaction (6.1)]. In these examples the mechanism of the reaction is used to explain and understand the diastereoselectivity that is observed. There are many other examples (usually in textbooks) where the mechanism of a reaction is used to rationalize the stereoselectivity of the process. To do this requires that the mechanism be known with certainty. 

Reaction of 4-isopropenylazetidin-2-ones with bromine results in diastereoselective (g) electrophile-induced ring expansions (Scheme 22).39... 

The diastereoselective alkylation of /V-acyloxazolidinones enolates was examined first. Lithium enolates of 107 were reacted with a variety of alkyl halides, and alkylation products were formed with excellent diastereoselectivities (94-99% de). Hydrolysis gave optically pure carboxylic acids, and the chiral auxiliary was recovered for reuse almost quantitatively.105-106 Highly diastereoselective bromination was also achieved by reaction of the boron enolate of 107 with /V-bromosuccinimide (NBS) (98% de). Optically pure amino acids could be accessed by simple synthetic transformations (Scheme 24.26).106... 

The stereochemical quality of diastereoselective reactions is expressed as a numeric ratio ds = x y ( z ...) (from diastereoselectivity). It is the ratio of the yields of the two (or more) diastereomers formed normalized to 100. Normalized to 100 means that we must have x+y (+z +... ) = 100. Figures 3.5 and 3.6 illustrate the use of the measure ds as applied to a moderately diastereoselective bromination. The complete description of the stereochemical result is shown in Figure 3.5, and the common short form is shown in Figure 3.6. 

The halogen-metal exchange of one of a geminal pair of bromine atoms is readily achieved -a carbenoid is formed which may have sufficient stability to react as an organolithium before decomposing to a carbene by a-elimination.. m in cyclic systems, diastereoselectivity in this process has long been known,114116 though the outcome of reactions such as that of 137 is under a mixture of kinetic and thermodynamic control.117... 

Hoffmann has shown that diastereoselective bromine-lithium exchange may be achieved even in acyclic systems.118 Treatment of 138 with BuLi in the Trapp solvent mixture at -120 °C in the presence of acetone generates the epoxides 139 and 140 in a 94 6 ratio of diastereoisomers.119 120 The selectivity was found to depend on the organolithium used for the bromine-lithium exchange, and it must therefore be under kinetic control. 

Changing the protecting group at O altered the ratio of products, particularly when a powerful Li-coordinating group (such as a carbamate) was introduced.121 Reasonable levels of diastereoselectivity could also be obtained from 141, with the alkoxy substituent in the 2-position.122 Diastereoselective bromine-lithium exchange of this sort has been employed in the synthesis of a segment of the bryostatins (section 9.7).123... 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

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