Anti stereoselectivity

Fluorine and sulfur (in the form of a methylthio group) are added to nucleophilic olefins with Markovnikov regwselectivity and anti stereoselectivity by di-methyl(niethylthio)sulfoninni fluoroborate and triethylamine tris(hydrogen fluoride) [777] (equation 21)... 

Fluorine and selenium, in the form of a phenylselenenyl group, add to nucleophilic olefins with Markovnikov regioselectivity and anti stereoselectivity on reaction with several reagents that may form phenylselenenyl fluoride in situ [792, 193, 194] (equation 30)... 

With Sulfur Nucleophiles N-Carboxy-protected aziridine-2-carboxylates react with thiols to give P-mercapto-ot-amino acid derivatives. The reaction is usually catalyzed by BF3 and the yields range from fair to excellent [15, 16, 108-111]. With N-unprotected 3-substituted aziridine-2-carboxylates, the ring-opening with thiols usually takes place with anti stereoselectivity, especially in the case of the C-3 aliphatic substituted substrates. In cases in which C-3 is aromatic, however, the stereoselectivity has been found to be a function of the substitution pattern on the aromatic ring 3-p-methoxy ph eri yl-su bs li In led aziridines 143a (Scheme 3.51) and... 

Cyclic and open transition state models have been used to explain syn/anti stereoselectivity in these reactions1. The possible transition states (including boat B and chair C transition states) can be deduced from the E/Z geometry of the crotyl reagent and the imine. The postulated cyclic transition states for the preferred E geometry of the imine arc shown below. 

The reaction of 3-substituted 3-haloallenes with various cuprates, the converse reaction of propargyl derivatives, proceeds in an SN2 manner to form alkynes 69b. Very high anti stereoselectivity is achieved693. 

Extensive studies (/ /) of such SE- reactions of allylsilanes have demonstrated a high degree of anti stereoselectivity with the majority of electrophiles, except in cases where steric effects play a dominant role. 

Which isomer is predominantly formed depends on R, R, and on the method by which the carbene or carbenoid is generated. Most studies have been carried out on monosubstituted species (R = H), and in these studies it is found that aryl groups generally prefer the more substituted side (syn addition) while carbethoxy groups usually show anti stereoselectivity. When R = halogen, free halocarbenes show little or no stereochemical preference, while halocarbenoids exhibit a preference for syn addition. Beyond this, it is difficult to make simple generalizations. 

Trialkylstannyl enolates can be prepared from enol acetates by reaction with trialkyltin alkoxides and are sufficiently reactive to add to aldehydes. Uncatalyzed addition of trialkylstannyl enolates to benzaldehyde shows anti stereoselectivity.31... 

Several enolates of 4,4-dimethyl-3-(trimethylsiloxy)-2-pentanone have been investigated.106 The lithium enolate reacts through a chelated TS with high 2,2 -anti stereoselectivity, based on the steric differentiation by the f-butyl group. 

Camphor-derived sulfonamide can also permit control of enantioselectivity by use of additional Lewis acid. These chiral auxiliaries can be used under conditions in which either cyclic or noncyclic TSs are involved. This frequently allows control of the syn or anti stereoselectivity.143 The boron enolates give syn products, but inclusion of SnCl4 or TiCl4 gave excellent selectivity for anti products and high enantioselectivity for a range of aldehydes.145... 

Alkynes react with electrophilic selenium reagents such as phenylselenenyl tosylate.155 The reaction occurs with anti stereoselectivity. Aryl-substituted alkynes are regioselective, but alkyl-substituted alkynes are not. 

Chelation effects also come into play in the reduction of a,[3-epoxyketones. Both CaCl2 and LaCl3 lead to enhanced anti stereoselectivity.139 The same stereoselectivity is observed with CeCl3 and with Zn(BH4)2.140... 

The homoallylation is applicable to multigram-scale experiments (Scheme 15) [36]. In the presence of 3mol% of Ni(acac)2, a mixture of 25 mmol of benzaldehyde, 50 mmol of Et3B, and 50 mmol of isoprene provides anti-3-methyl-l-phenyl-4-pentenol in 92% yield (4.1 g) with excellent 1,3-anti stereoselectivity. The product is purified by means of a single Kugelrohr distillation of the reaction mixture after an appropriate aqueous workup. 

The possible formation of a delocalised benzyl type carbocation (16) results in much lower (70%) ANTI stereoselectivity than with trans 2-butene (5 =100% ANTI stereoselectivity, p. 180), where no such delocalisation is possible. It is also found that increasing the polarity, and ion-solvating ability, of the solvent also stabilises the carbocation, relative to the bromium ion, intermediate with consequent decrease in ANTI stereoselectivity. Thus addition of bromine to 1,2-diphenylethene (stilbene) was found to proceed 90-100% ANTI in solvents of low dielectric constant, but =50% ANTI only in a solvent with e = 35. 

The formation of the carbocationic intermediate (37), either directly or via an initial it complex, appears to be rate-limiting, and the overall orientation of addition is Markownikov. There is evidence of some ANTI stereoselectivity, but this is not very marked and is dependent on the alkene and on the reaction conditions. 

The marked ANTI stereoselectivity observed with cyclohexyl systems (see above) reflects the ability to achieve, and the very marked preference to eliminate from, the so-called trans-diaxial conformation (34) ... 

This is borne out by the high degree of ANTI stereoselectivity that is observed in acyclic examples (cf. p. 254), when either or both the bromine atoms are attached to secondary or tertiary carbon atoms, e.g.(64) ... 

Moreover, the reaction with aldehydes occurs with good to excellent anti stereoselectivity, typically 100 0 to 9 1 for R = alkyl or alkenyl, and 9 1 to 7 3 for R - phenyl [10,12]. The diastereoselectivity even increases when using Cp-substituted crotyltitanocenes... 

Scheme 2.5 Mechanistic model for the anti-stereoselective SN2 substitution...

Scheme 2.6 Anti-stereoselective SN2 substitution of propargylic mesylate 18.

The beneficial effect of added phosphine on the chemo- and stereoselectivity of the Sn2 substitution of propargyl oxiranes is demonstrated in the reaction of substrate 27 with lithium dimethylcyanocuprate in diethyl ether (Scheme 2.9). In the absence of the phosphine ligand, reduction of the substrate prevailed and attempts to shift the product ratio in favor of 29 by addition of methyl iodide (which should alkylate the presumable intermediate 24 [8k]) had almost no effect. In contrast, the desired substitution product 29 was formed with good chemo- and anti-stereoselectivity when tri-n-butylphosphine was present in the reaction mixture [25, 31]. Interestingly, this effect is strongly solvent dependent, since a complex product mixture was formed when THF was used instead of diethyl ether. With sulfur-containing copper sources such as copper bromide-dimethyl sulfide complex or copper 2-thiophenecarboxylate, however, addition of the phosphine caused the opposite effect, i.e. exclusive formation of the reduced allene 28. Hence the course and outcome of the SN2 substitution show a rather complex dependence on the reaction partners and conditions, which needs to be further elucidated. 

Scheme 4.31 Palladium(0)-catalyzed synthesis of allenes with anti stereoselectivity.

A cuprate prepared in situ from tBuPh2SiLi and Cul has been found to react with alkynyl epoxides to afford allenylsilanes (Eq. 9.43) [50]. Enantioenriched alkynyl epoxides, which are readily prepared in high yield through Sharpless asymmetric epoxidation [51], afford chiral allenylsilanes with anti stereoselectivity. 

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