Anti substrate-controlled

In the hydrogenation of diketones by Ru-binap-type catalysts, the degree of anti-selectivity is different between a-diketones and / -diketones [Eqs (13) and (14)]. A variety of /1-diketones are reduced by Ru-atropisomeric diphosphine catalysts to indicate admirable anti-selectivity, and the enantiopurity of the obtained anti-diol is almost 100% (Table 21.17) [105, 106, 110-112]. In this two-step consecutive hydrogenation of diketones, the overall stereochemical outcome is determined by both the efficiency of the chirality transfer by the catalyst (catalyst-control) and the structure of the initially formed hydroxyketones having a stereogenic center (substrate-control). The hydrogenation of monohydrogenated product ((R)-hydroxy ketone) with the antipode catalyst ((S)-binap catalyst) (mis-... 

Addition of the indium reagent derived from the foregoing (P)-allenylstannane to /8-benzyloxy-a-methylpropanal as the aldehyde substrate at low temperature afforded a 70 30 mixture of anti,anti and anti,syn adducts (Eq. 9.141). The improved dia-stereoselectivity in this case can be attributed to substrate control, reflecting the chelating ability of an OBn versus an ODPS group. The lower temperature may also account for the improved diasteroselectivity. 

As can be seen from Table 2, very high stereoselectivities could be observed for both syn and anti substrates, depending on the 2-alkyl substituent (R). In the absence of ZnCl2, a nonchelated chairlike transition state was anticipated, following the Solladie model, with intramolecular hydride transfer. This process was expected to lead to an opposite sense of selectivity to that observed for the chelation-controlled model (with DIBAL/ZnCl2). This reversal in stereoselectivity was indeed observed... 

From Table 4 it is apparent that a major controlling factor in governing the levels of product diastereoselection is the relative size of the 2-alkyl substituent (R). For syn substrates, the highest levels of diastereoselectivity are observed with a methyl group as the 2-substituent, whereas for anti substrates, ethyl gives the highest levels. 

To identify the stereochemical course of the protonation of the vinyl carbon, cis and trans silyl enol ethers derived from menthone were isomerized by use of a deuter-ated achiral proton source. Surprisingly, only the identical syn isomer was obtained from both the silyl enol ethers. Thus reaction of the cis isomer occurs via an anti Se mechanism whereas reaction of the trans isomer occurs via a syn Se mechanism. Interestingly, this cis silyl enol ether was isomerized more rapidly than the trans isomer. In the cis silyl enol ether, deuterium was located at a psewdo-axial position in the isomerized product. Therefore, the anti-S pathway can be explained by the product developing control via the product-like transition state assembly. The syn-S pathway for the trans silyl enol ether can be explained by substrate control via the favored intermediate. The relative contributions of the two pathways depend on the relationship between the free energies of their transition state assemblies (Sch. 8). 

Further evidence for the racemization premise was obtained from experiments employing (R)-a-methyl-/3-ODPS propanal (Eq, 85) [93]. Addition of the allenylin-dium chloride derived from an enantioenriched (P)-allenyl stannane yielded a 60 40 mixture of anti, anti and anti, syn adducts, not unlike that obtained when racemic alle-nylstannane was used to generate the transient allenylindium chloride. When the (5) aldehyde was employed for this addition a 40 60 mixture of anti, anti and anti, syn adducts was formed. Thus it can be concluded that substrate control (Felkin-Ahn or chelation) is, at best, only modest in these reactions, and that the rate of racemization is only slightly less than the rate of addition. The use of -benzyloxy-a-methyl propa-... 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

In their synthesis of the cA-octahydronaphthalene nucleus 471 of superstolide A (Fig. 11 -39), Roush and co-workers demonstrated the use of Keck s original catalytic allylation procedure to effect the diastereoselective conversion of aldehyde 472 to the 1,3-vyn diol 473 (79% yield, selectivity=94 6) (Scheme 11-37) [313]. This transformation constitutes a mismatched reaction since the 3-anti diol is favored under substrate-controlled allylation (see Section 11.3 for a discussion of 1,3-stereo-induction) [93]. 

Reactions of enantiomeric allenylstannanes (P)-286 and (M)-286 with (5)-2-benzyloxypropion-aldehyde, in the presence of MgBr2 OEt2, are highly substrate-controlled processes, giving the syn,syn-297 and anti,syn-298 diastereomers, respectively (Scheme 5.2.65). 

Catalyst-controlled stereoselectivity is observed for fhe 59-catalyzed aldol reaction of (S)-2-benzyloxypropanal the sense of diastereoselectivity depends on the absolute configuration of the catalyst (Scheme 10.53) [149]. The level of stereoselectivity with (R)-59 is, however, lower than fhat wifh (,S)-59. Thus, a slight influence of substrate control is observed. The stereochemical outcome can be rationalized in terms of steric repulsion between the methyl and TMS groups in fhe cyclic transition structure leading to anti adducts. 

The use of ( S)-HYTRA (645) produces the mixture of 647 and 648 in an 87 13 ratio, whereas (R)-HYTRA (646) reverses the selectivity to favor the anti isomer 648 syn anti ratio = 8 92). At first glance, predominant formation of the anti isomer appears to violate the Cram cyclic model for chelation controlled conditions. However, the stereochemical outcome of this reaction is determined by reagent control rather than substrate control, which means that the diastereoselectivity is governed by the chirality of the HYTRA rather than 632. 

Tumambac GE, Mei X, Wolf C (2004) Stereoselective sensing by substrate-controlled syn/ anti intCTc[Pg.216]

Substrate-controlled diastereoselective hydroboration of protected chiral allylic alcohols [25-27] or amines [28, 29] with 9-BBN gives almost always anti selective products. On the other hand, catalyzed hydroboration in most of the cases using catecholborane as hydroborating agent tends to be syn selective [28-30] (Eq. 5.9). 

The reaction led to two products. The major one had an E-configurated double bond from which we conclude that it must be the anti-Cram isomer 35. Therefore reagent control of diastereoselectivity dominated the reaction. The minor product of the reaction contained a Z-double bond. It must arise via transition state 36 and should therefore be the product of substrate control of diastereoselectivity. 

As shown in Scheme 14.9a,b, an efficient protocol for the stereoselective synthesis of 1,3-syn and -anti tetrahydropyrimidinones (syn- and anti- 2) could be developed [13]. The modular procedure is based on a stereodivergent cycliza-tion of readily available urea-type substrates 41 by intramolecular allylic substitution. The cychzation proceeds with excellent yield (up to 99%) and selectivity (up to dr > 20 1), purely based on substrate control. The product pyrimidines 42 can be readily transformed into the corresponding free syn- and anti-amines 43. Furthermore, also a novel domino sequence for the rapid assembly of 1,3-syn-substituted oxazines 46 could be realized [14]. Mechanistically, the one-pot procedure is based on a three-step sequential process involving a hemi-aminalization... 

Roush and coworkers expanded the scope of this reagent 18 for the double aUylation of carbonyl compounds. As expected, the first allylation (170) showed reagent-controUed anti-diastereoselec-tion and the second allylation (172) proceeded via substrate-controlled stereoselection to produce optically active ( )-pent-2-ene-l,5-diols (E)-173 in high yields (Schane 25.24). They further noted that the increase of bulk on boronate ring led to the formation of the corresponding (Z)-173 Z-diols as single isomers upon oxidative woikup (Scheme 25.25). 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

The final C—C bond forming step turned out to be a mismatched boron enolate aldol reaction. Nevertheless, the use of (-l-)-DIPCl as a stereochemical inducer guaranteed the disposition for reagent control versus substrate control. Required product 324a was isolated in approximately 60% yield after chromatography on reverse-phase silica gel. The Evans group anti-reduction of the newly obtained aldol product gave substance 325, which was totally deprotected... 

Substrate-controlled conjugate additions of oxy-anionic nucleophiles have been reported to proceed with high levels of acyclic stereocontrol [31]. A notable case was disclosed by Mulzer, who studied conjugate additions of alkoxides to the j -substituted acceptor 51 (Equation 8) [71], Addition of methoxide afforded the anti diastereomer 52 in dr =95 5 and 85% yield. 

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