Stereoselectivity benzylation

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

Stereoselective benzylic alkylation.6 Benzylic acetates of arenechromium tricarbonyls react with R3A1 or (QHs Zn-TiCU to form exo-alkyl chromium complexes. 

Stereoselective benzylation of a methyl dithionate (l).3 Benzylation of 1 is effected with the highest (Z)-stereoselectivity with KF absorbed on alumina as base, either under dry conditions or in CH3CN (equation I). 

A highly stereoselective benzylation has been developed oscr-di branched /3-phenyl -propylamines and -ethanolamines can be synthesized in any desired configuration... 

A variety of common electrophiles can be used in conjunction with deprotonation of the benzylic position of complexed aUcylbenzenes. This includes alkyl iodides, aldehydes, ketones, and epoxides. Mitosanes can be prepared by deprotonation of the tricyclic complex (52) followed by addition of oxirane (Scheme 92). Depending on the substituent on the complexed aromatic ring, both regio-and stereoselective benzylic alkylations are observed. For example, deprotonation and alkylation of the benzylic position meta to the dimethylamino group of (53) is exclusively observed (Scheme 93). 

Figure 16.1-15. Examples of regio- and stereoselective benzylic hydroxylation.

Figure 21 Stereoselective benzylic hydroxylations of benzocycloalkenes by P. putida.

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Both methyltriethylphosphonium fluoride and methyltributylphospho-nium fluoride have been prepared The latter generates benzyl fluoride from benzyl chloride in 80% yield and ethyl fluoroacetate from ethyl bromoacetate in 53% yield Methyltnbutylphosphonium fluoride converts 1-bromododecane to a 50 50 mixture of 1-fluorododecane and 1-dodecene Methyltnbutylphosphonium fluoride also quantitatively forms styrene from 1-bromo-1-phenylethane [26] Methyl-tnbutylphosphonium fluonde is the reagent of choice for the conversion of N,N dimethylchloroacetamide to its fluoride, but it is not able to convert chloro-acetonitnle to fluoroacetomtrile Methyltnbutylphosphonium fluoride changes chloromethyl octyl ether to the crude fluoromethyl ether in 66% yield The stereoselectivity of methyltnbutylphosphonium fluoride is illustrated by the reac tions of the 2-tert-butyl-3-chlorooxiranes [27] (Table 2)... 

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

Florio et al. demonstrated that the lithiation/electrophile trapping of enantio-pure styrene oxide, as well as the (3-substituted styrene oxides 180 and 182, is totally stereoselective (Scheme 5.42) [66]. These results demonstrate that the intermediate benzylic anions are configurationally stable within the timescale of depro-tonation/electrophile trapping. 

On the other hand, addition of methylmagnesium bromide, as well as (triisopropoxy)methyl-titanium, to the O-benzyl-protected analog 4 proceeds with the facial stereoselection predicted by Cram s open-chain model, although the selectivities are very low72. 

On the contrary, in the latter case, a total loss of stereoselectivity occurs68. TV-Bis-benzyl-a-amino aldehydes 1 (R = R3 = Bn) under the assistance of boron trifluoride, zinc bromide or tin(lV) chloride lead to the nonchclation-controlled adducts preferentially, whereas titanium(IV) chloride or magnesium bromide result in chelation control70. In some cases, the O-trimcthylsilyl cyanohydrins arc the primary products, but the workup procedure usually provides the desily-lated products. 

The carbonyl addition reactions of benzylmetals, compared to the allylic counterparts, have found few applications in stereoselective synthesis, apparently for the following reasons The carbonyl addition of alkali metal salts (M = Li, Na, K, Cs) of benzyl anions, with few exceptions, usually proceeds with low levels of simple diastereoselectivity affording mixtures of syn- or <7 / -diastereomers (see Section 1.3.2.3.1.). 

In most cases, the addition of prostereogenic benzyl anion reagents with prostereogenic aldehydes (or ketones) proceeds with low stereoselectivity. Some notable exceptions are reviewed later. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

The relative ease of H/D exchange of the methylene protons of benzyl methyl sulfoxide is markedly influenced by the nature of the base and the solvent used, as shown in Table 12. The data reveal that rather high stereoselectivities can be observed when alkyllithium-THF is used. 

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