Houk conformation

The reactive conformation of the alkene is probably the Houk conformation (Chapter 34) with the hydrogen atom on the stereogenic centre eclipsing the alkene. Attack occurs syn to the OH group... 

The Houk conformation for reactions ofalkenes with electrophiles Allyl silanes... 

The Houk conformation depends upon allylic 1,3 strain so we will look at this first.52 The strain we are concerned with is between substituents on the double bond with substituents at the allylic position. They will be in the same plane for the strain to be present 218. When the substituent on the double bond is merely a proton, the allylic 1,3 strain is not too bad between the proton and a larger group. About 25% of the conformations will have the proton and the substituent in the same plane 218b but the rest will have two hydrogens in the plane 218a. 

Epoxidation of the cis allyl sulfone Z-224 gives the stereochemical outcome we would expect from a Houk conformation.53 The selectivity with the trans compound -224 is less good - also as we would expect. Things are rarely quite so simple as this of course and dihydroxylation of the same substrates gives rise not only to reduced selectivity but a reversal in stereoselectivity 226. 

The lithium enolate is expected to have the (enolate) configuration 147. Chelation is impossible and it adopts the Houk conformation 147a with the H atom on the inside eclipsing the ir-bond. The enormous protected amine forces the allyl bromide to the opposite face. The potassium enolate prefers the chelated structure 148 and the same group directs the allyl iodide to the bottom face. 

In these examples the sheer size of one of the groups controlled the transmission of stereochemical information. If the directing group is a silicon atom, electronic factors are important too.23 Alkylation of the enolate from 149 was used in a synthesis of tetrahydrolipstatin.24 There is no question of chelation here as no chelating group is present. The Houk conformation 151 of the lithium enolate has H inside and the Me3Si group directs the alkylation to the bottom face. 

We shall see in this section that allyl silanes can direct the transfer of chirality through Houk conformations without the need to form an enolate. The typical reaction of an allyl silane with an electrophile (chapter 12) is at the remote atom of the alkene with loss of the silyl group. This transfers, but does not create, chirality. So the allyl silane 152 reacts with formaldehyde and a Lewis acid to give the homoallylic alcohol 153 with no loss of ee. The silyl group has gone, the alkene is transposed, and the sense of the SE2 reaction is anti. All this is explained by the Houk conformation 154 with the C-Si bond able to interact with the alkene to raise the energy of the p-orbital and direct both the regio- and the stereoselectivity.25... 

If 259 is first treated with BuLi and then turned into the lithium enolate and reacted with MoOPH, a good yield of the other diastereoisomer, anti-261 is formed. The first result is probably hydroxylation opposite the very large NHR group in a Houk conformation of the enolate (chapter 21) while anti-selective hydroxylation probably results from chelation control. 

FIGURE 2.18. Reactive conformations of imidazolidinone iminium cations, (a) MacMiUan conformation, (b) Houk conformation. 

Theoretical work by the groups directed by Sustmann and, very recently, Mattay attributes the preference for the formation of endo cycloadduct in solution to the polarity of the solvent Their calculations indicate that in the gas phase the exo transition state has a lower energy than the endo counterpart and it is only upon introduction of the solvent that this situation reverses, due to the difference in polarity of both transition states (Figure 1.2). Mattay" stresses the importance of the dienophile transoid-dsoid conformational equilibrium in determining the endo-exo selectivity. The transoid conformation is favoured in solution and is shown to lead to endo product, whereas the cisoid conformation, that is favoured in the gas phase, produces the exo adduct This view is in conflict with ab initio calculations by Houk, indicating an enhanced secondary orbital interaction in the cisoid endo transition state . 

The stereochemical outcomes of the above reactions can be explained by the proposed transition states A and B (Fig. 2.25). Model A, derived from the Houk model for nucleophilic addition to olefins, explains the formation of, v y -adducts. Model B, involving a different nitrone conformation, due to the chelation of diethylaluminum chloride, accounts for the formation of anti -adducts (581). 

Houk, K.N., Williams Jr., J.C., Mitchell, P.A. and Yamaguchi, K. (1981). Conformational control of reactivity and regioselectivity in singlet oxygen ene reactions Relationship to the rotational barriers of acyclic alkylethylenes. J. Am. Chem. Soc. 103, 949-951... 

The transition-state model for these cyclizations (Scheme 34) differs fundamentally from the well-established Beckwith-Houk transition model for radical cyclizations [130,146-148]. Thus, while both models invoke chairlike transition states, without excluding the possibility of twist boatlike systems in some instances, the Beckwith-Houk model involves full conformational... 

Using this information in conjunction with a study into the preferred conformations of iminium ions generated from catalysts 12 and 21, Houk suggests that the additional steric bulk of the ferf-butyl group causes the benzyl arm of the catalyst to shield better the Si face of the C=C double bond - a requirement for high ees in an open transition state. For both the Diels-Alder and pyrrole/indole alkylation... 

High diastereofacial selectivities are observed in cycloadditions and Michael additions with ot,(3-unsaturated esters having chiral heterocyclic auxiliary at the p-position, as shown in Schemes 11.20, 11.21, and 11.25, and cannot be well-explained using Kozikowski s awfi-periplanar model (124,125) or Houk s inside alkoxy model (126,127). Both the anti-periplanar conformation and the syn-periplanar conformation of the acceptors participate in the transition structures, depending on nonbonding interactions in the dipole-chiral auxiliary pair (121). 

Normally, additions depicted by model C lead to the highest asymmetric induction. The antiperiplanar effect of OR substituents can be very efficient in the Houk model B ( , , , , ) however it plays no role in model C. Furthermore, the Houk model B must be considered in all cycloaddition-like reactions. The Felkin-Anh model A is operative for nucleophilic additions other than cuprate additions ( ). The epoxidation reactions are unique as they demonstrate the activation of one diastereoface by a hydroxy group which forms a hydrogen bridge to the reagent ( Henbest phenomenon ). The stereochemical outcome may thus be interpreted in terms of the reactive conformations 1 and 2 where the hydroxy function is perpendicular to the olefinic plane and has an optimal activating effect. 

Saunders M, Houk KN, Wu YD, Still WC, Lipton M, Chang G, Guida WC. Conformations of cycloheptadecane. A comparison of methods for conformational searching. J Am Chem Soc 1990 112 1419-1427. 

---