Anti-selective reactions

Scheme 25). The anti selective reactions require somewhat more elaborate catalysts but the enantioselectivities and diastereoselectivities are excellent in both cases. 

With ketone donors, both syn and anti selective reactions are possible. Typically, a,p-unsaturated nitro compounds are used as acceptors. The majority of these reactions are syn selective (Scheme 28) [94, 269, 271, 278, 279, 288-309]. This is a result of favored formation of the (fj-configured enamine and favorable electrostatic interactions between the nitro group and the enamine (Scheme 29) [290, 291, 310]. Of the known anti selective reactions, primary amine-thiourea catalysts such as 158 appear to perform best (Scheme 28) [271, 299, 301]. 

Diastereoselective carbonyl allylation.1 Pd(II)-catalyzed allylation of aldehydes when carried out with SnCl2 (3 equiv.) can result in a- and/or y-addition. In addition, y-addition can be syn- and/or anti-selective. The regio- and diastereoselec-tivity can be controlled by the solvent. All three products are obtained from reaction of (E)-2-butenol-l with C CHO in THF. Addition of H20 permits reactions at -20° and results only in y-addition with anti-selectivity. Reactions of DMS0/H20 can be controlled by the amount of water to provide either syn- or anti-y-addition. 

Non-Evans Aldol Reactions. Either the syn- or onri-aldol adducts may be obtained from this family of imide-derived eno-lates, depending upon the specific conditions employed for the reaction. Although the illustrated boron enolate affords the illustrated jyn-aldol adduct in high diastereoselectivity, the addition reactions between this enolate and Lewis acid-coordinated aldehydes afford different stereochemical outcomes depending on the Lewis acid employed (eq 35). Open transition states have been proposed for the Diethylaluminum Chloride mediated, anti-selective reaction. These anfi-aldol reactions have been used in kinetic resolutions of 2-phenylthio aldehydes. ... 

The second important group of configuralionally stable bis-protected a-amino aldehydes are the V-dibenzvl derivatives 5, easily prepared from amino acids in a three-step procedure65. These aldehydes react with various nucleophiles to normally provide the nonchelation-con-trolled adducts in high diastereoselectivity. This anti selectivity is observed when diethyl ether or telrahydrofuran is used as reaction solvent. Certain Lewis acidic nucleophiles or additives, such as tin(IV) chloride, in dichloromethane as solvent force chelation and therefore provide the. syn-adducts, once again with a high diastereoselectivity. 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

The addition of ( )-(3-trimcthylsilylallyl)boronate (10) to the racemic oxime 9 has been used in connection with a total synthesis of cannabisativine n. The results are congruent with the application of ( )-crotylboronatc as organometallic reagent9,, 0. The reaction is anti selective and generates the diastereomeric hydroxylamines 11 and 12, where 11 is converted to a tetrahydropyridine 13, a useful intermediate for the synthesis of cannabisativine11. 

Bulky amides show, however, anti selectivity, i.e., trawi-2,5-bis(methoxymethoxymethyl)-1-(1-oxopropyl)pyrrolidine gives a synjanti ratio of 9 91 in the same reaction. 

When 2,2-dimethylpropanal is used to prepare the azomethine moiety, the corresponding azaallyl anion may be obtained when l,8-diazabicyclo[5.4.0]undec-7-ene/lithium bromide is used as base. The subsequent addition to various enones or methyl ( )-2-butenoate proceeds with anti selectivity, presumably via a chelated enolate. However, no reaction occurs when triethylamine is used as the base, whereas lithium diisopropylamide as the base leads to the formation of a cycloadduct, e.g., dimethyl 5-isopropyl-3-methyl-2,4-pyrrolidinedicarboxylate using methyl ( )-2-butenoate as the enone84 89,384. 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

Of perhaps greater use for organic synthesis was the observation that photo-driven reactions of alkoxycarbenes with unsubstituted optically active ene carbamates [65] produced aminocyclobutanones in fair yield with high dia-stereoselectivity (Table 12) [66]. In contrast, with a gem-disubstituted ene carbamate, the syn-anti selectivity was low but high asymmetric induction a to nitrogen was observed (Eq. 16). Trans-monosubstituted ene carbamates failed to react, as did a,/J-unsaturated chromium carbene complexes. 

Ginsburg and coworkers found that the sulfoxide 94 and sulfone 95 reacted with iV-phenyltriazolinedione at the syn side of sulfoxide and sulfone moiety respectively [52] (Scheme 44). These results strongly contradict the anti selectivity observed in the reaction of the sulfide 39 (see Scheme 25). 

Dipole-dipole interactions may also be important in determining the stereoselectivity of Mukaiyama aldol reactions proceeding through an open TS. A BF3-catalyzed reaction was found to be 3,5-anti selective for several (3-substituted 5-phenylpentanals. This result can be rationalized by a TS that avoids an unfavorable alignment of the C=0 and C-X dipoles.97... 

These reactions have been applied to a-benzyloxy and a-(r-butyldimethylsiloxy)-thioacetate esters.164 The benzyloxy derivatives are anti selective, whereas the siloxy derivatives are syn selective. These differences are attributed to a chelated structure in the case of the benzyloxy derivative and an open TS for the siloxy system. 

Isayama described the coupling reaction of N-methylimine 157 and ethyl crotonate catalyzed by Co(acac)2 and mediated by PhSiH3 to produce Mannich product 158 in 82% with syn-selectivity (Scheme 41) [71]. The (i-laclam 159 was readily synthesized by heating 158. In 2002, Matsuda et al. reported cationic Rh complex [Rh(COD) P(OPh)3 2]OTf (1 mol%) as an active catalyst for the reductive Mannich reaction [72]. N-Tosylaldiminc 160 was coupled with methyl acrylate and Et2MeSiH (200 mol%) at 45 °C to give the b-amino ester 161 in 96% with moderate anti-selectivity 68%. 

Table 5 summarizes the reactions of isoprene with aromatic aldehydes and unsaturated aldehydes. Salicylaldehyde provides the expected product as a cyclic boric ester derivative and shows apparently lower stereoselectivity, giving a mixture of 1,3-anti and 1,3-syn isomers in a ratio of 6 1 (run 1, Table 5). 2-Furfural reacts as usual and provides a 1,3-anti isomer as a single diastereomer in good yield (run 2). Unsaturated aldehydes, irrespective of their substitution patterns, undergo homoallylation selectively with excellent 1,3-anti selectivity, the geometry of the double bond of the starting aldehydes remaining intact (runs 3-5). 1,2-Addition to unsaturated aldehyde takes place selectively and no 1,4-addition is observed.

The complex -Tol-BINAP-AgF (/>-Tol-BINAP - 2,2 -bis(di-/)-tolylphosphanyl)-l,l -binapthyl) catalyzes the asymmetric addition of allylic trimethoxysilanes to aldehydes (Equation (7)).7 3 The process can provide various optically active homoallylic alcohols with high enantioselectivity (up to 96% ee) and a remarkable 7 and anti- selectivities are observed for the reaction with crotylsilanes, irrespective of the configuration of the double bond ... 

Samarium(II) iodide also allows the reductive coupling of sulfur-substituted aromatic lactams such as 7-166 with carbonyl compounds to afford a-hydroxyalkylated lactams 7-167 with a high anti-selectivity [74]. The substituted lactams can easily be prepared from imides 7-165. The reaction is initiated by a reductive desulfuration with samarium(ll) iodide to give a radical, which can be intercepted by the added aldehyde to give the desired products 7-167. Ketones can be used as the carbonyl moiety instead of aldehydes, with good - albeit slightly lower - yields. 

They react with a wide range of aliphatic and aromatic aldehydes in the presence of catalytic amounts of tetrabutylammonium fluoride (TBAF) to give the trialkylsilyl ethers of P-nitro alcohols with high anti-selectivity (98%). The diastereoselective Henry reaction is summarized in Table 3.2. The products are reduced to P-amino alcohols using Raney Ni-H2 with retention of the configuration of P-nitro alcohols (Scheme 3.12). 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

Another remarkable property of iodorhodium(III) porphyrins is their ability to decompose excess diazo compound, thereby initiating carbene transfer reactions 398). This observation led to the use of iodorhodium(III) me.vo-tetraarylporphyrins as cyclopropanation catalysts with enhanced syn anti selectivity (see Sect. 2.2.3) s7, i°o) as wep as catalysts for carbenoid insertion into aliphatic C—H bonds, whereby an unusually high affinity for primary C—H bonds was achieved (see Sect. 6.1)287). These selectivities, unapproached by any other transition metal catalyst,... 

In most cases, the stereochemical course of heterocyclic addition can be altered by pre-complexation of nitrones with Lewis acids. In the absence of complexation agents (Et2AlCl, TiCLi), addition of lithio-hetaryl derivatives to chiral 3-alkoxy nitrones (292a-d) gives P-alkoxy-a-hydroxylamino-2-alkylhetaryls (346a-d) in good yields with. vy/i-selectivity. In the presence of diethylaluminum chloride the reaction leads to the same adducts, but with anti-selectivity (Scheme 2.150) (Table 2.12) (581). 

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