Stereoselective control elements

In Heading 1.4 we have already seen that three different kinds of control elements [3] may be considered 1) chemoselective control elements (controlling chemical reactivity), 2) regioselective control elements (controlling the orientation of reactants) and 3) stereoselective control elements (controlling the spatial arrangement of atoms within the molecule), which may control either the relative (diastereoselective) or the absolute spatial arrangement (enantioselective control elements). 

Regarding stereoselective control elements, some of the most important and updated methods and strategies, have been already discussed in Chapters 8 and 9 (see also the Summary given below). 

Level 1 The different control elements -whether they are chemo-, regio- or stereoselective- are introduced ad hoc (expressly) and they are then eliminated once the control has been exerted. This requires at least two extra steps in the synthetic sequence with the concomitant lowering of overall yields. 

The alkylation of cyclopentanoid enolate groups, which are part of polycyclic systems, is a common step in natural product syntheses, particularly in the synthesis of terpenoids and steroids. A high degree of stereoselectivity is usually encountered in such reactions, for example, in the preparation of the bicyclic compounds 17-2054 59. Steric, rather than electronic, control elements determine the diastereoselectivity. 

Substrates A3 (Q = O) have been employed not only as starting materials for fragmentation reactions but also to probe novel stereoselectivity concepts. The photochemical transformation of axial chirality into central chirality was achieved by Carreira et al., who employed chiral, enantiomerically pure allenes in intramolecular [2 + 2]-photocycloaddition reactions (Scheme 6.27) [79]. The reaction of enantiomerically pure (99% ee) cyclohexenone 71, for example, yielded the two diastereomeric products 72a and 72b, which differed only in the double bond configuration. Apparently, the chiral control element directs the attack at the allene to its re face. The double bond isomerization is due to the known configurational liability of the vinyl radical formed as intermediate after the first C—Cbond formation step (see Scheme 6.2, intermediate C). 

Reactions with substituted ylides give rise to questions of relative stereochemistry in the product epoxides. ( )/(Z)-Selectivity is usually low in the absence of other stereochemical control elements. An exception is diphenylsiilfonium benzylide, which reacts stereoselectively with aldehydes to give... 

Cram discussed a cyclic model for nucleophilic additions to chiral carbonyl compounds containing an a-alkoxy, a-hydroxy, and a-amino group capable of forming a chelate with the organometallic reagent. Incorporation of chelate organization into the design of stereoselective processes is an important control element in diastereo-selective " and enantioselective carbonyl additions. 

A similar approach was used for the asymmetric synthesis of yohimbone, a process that uses the stereocenter created by asymmetric alkylation as the control element for the stereoselective formation of two more stereocenters, as shown in Scheme 32. 

In this Chapter, we provide an overview of the various aldol control elements available for achieving synthetically useful stereoselectivity and then analyze some representative syntheses of polyketide natural products (particularly macro-lide targets) which are based primarily on the strategic use of aldol chemistry. These examples are chosen to illustrate the variety of aldol processes that have been applied to structurally complex targets and are taken largely from the recent literature (1989-1999). This selection covers some of our own research along with important contributions from other groups. 

Aromatic interactions, particularly, those between Ph and furan ring, as control elements in stereoselective organic reactions 13ACR979. Aromatic—proline interactions Electronically tunable CH/tt interactions 13ACR1039. 

Hoveyda AH, Lombardi PJ, O Brien RV, Zhugralin AR, H-Bonding as a Control Element in Stereoselective Ru-Catalyzed Olefin Metathesis. J Am Chem Soc. 2009 131(24) 8378-8379. 

Krenske, E. H. Houk, K. N. Aromatic Interactions as Control Elements in Stereoselective Organic Reactions. Acc. Chem. Res. 2013,46,979-989. 

A similar reaction mechanism could be assumed for the aza-Henry reaction catalyzed by urea 38 [46], In this particular case, the sulfinyl group acts both as an acidifying agent and a chiral controlling element, and allows the stereoselective addition of nitroethane to aromatic and, in two instances, aliphatic N-Boc imines (Scheme 29.21). 

Kishi has cleverly employed chelation control in the second-generation synthesis of ketone 49 [62], a key intermediate in the synthesis of the polyether antibiotic lasalocid A (50, Scheme 2.5) [63]. The stereoselective addition of ethylmagnesium bromide to ketone 46 can be understood as proceeding through chelate 47. This example demonstrates the synthetic utility of chelation as a stereochemical control element in a complex molecular setting. Application of this method along with other modern synthetic improvements allowed Kishi to synthesize ketone 49 in only 10 steps, starting exclusively from acyclic precursors [62], compared to his first reported 19-step synthesis [63]. 

There are also reactions which show stereoselectivity primarily because of mechanism rather than spatial bias of substrate. For instance, the conversion of an olefin to a 1,2-diol by osmium tetroxide mechanistically is a cycloaddition process which is strictly suprafacial. The hydroxylation transform has elements of both substrate and mechanism control, as illustrated by the retrosynthetic conversion of 146 to 147. The validity of the retrosynthetic removal of both... 

Recently, silicon-tethered diastereoselective ISOC reactions have been reported, in which effective control of remote acyclic asymmetry can be achieved (Eq. 8.91).144 Whereas ISOC occur stereoselectively, INOC proceeds with significantly lower levels of diastereoselection. The reaction pathways presented in Scheme 8.28 suggest a plausible hypo thesis for the observed difference of stereocontrol. The enhanced selectivity in reactions of silyl nitronates may he due to 1,3-allylie strain. The near-linear geometry of nitrile oxides precludes such differentiating elements (Scheme 8.28). 

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