Stereochemical control in six-membered rings

something about thermodynamic control. Because of the strong preference for substituents to adopt the equatorial position, diastereoisomers may equilibrate by processes such an enolization. For example, this fine perfumery material is made worthless by enolization. 

The situation is bad because the worthless compound is preferred in the equilibrium mixture (92 8). This is because the two substituents are both equatorial in the tram-isomer. 

Although a disadvantage here, in other cases equilibration to the more stable all-equatorial conformation can be a useful source of stereochemical control. You will very shortly see an example of this. 

We discussed the reduction of cyclohexanones in Chapter 18 and established that reducing agents prefer the equatorial approach while small reagents may prefer to put the OH group in the more stable equatorial position. If the nucleophile is not H but something larger than OH then we can expect equatorial attack to dominate both because of ease of approach and because of product stability. 

A simple example is the addition of PhLi to the heterocyclic ketone below which has one methyl group next to the carbonyl group. This methyl group occupies an equatorial position and the incoming phenyl group also prefers the equatorial approach so that good stereoselectivity is observed. 

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Stereochemical control in six-membered rings 826 Further reading 930... 

Anti stereochemistry in six-membered rings Conformational control from a chiral centre in the cyclohexenone Remote stereochemical control in five-membered rings prostaglandins Regio- and stereochemical control in open chain compounds Asymmetric induction by a chiral auxiliary on the enolate Tandem Michael-Michael Reactions One Conjugate Addition Follows Another Double Michael or Diels-Alder reaction ... 

To show how ring-closing reactions, particularly those on the side of an already existing ring, can give excellent stereochemical control. And again - the importance of conformation in six-membered rings. 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

The most successful examples of stereochemical control in electrophilic heteroatom cyclizations are those in which the substitution pattern constrains the substrate so that the two diastereofaces of the tt-system are significantly different. The most straightforward prediction of stereochemistry involves incorporating both the ir-system and the directing chiral center into a ring such that rotation about the vinylic bond that attaches the nucleophile to the double bond is highly restricted. Comparison of equations (1) and (2) illustrates this difference. For this reason, in the sections on cyclizations to form five- and six-membered rings, examples with constrained C=C—C bonds will be discussed separately. 

The lack of significant ring strain and favorable entropic factors results in facile cyclofunctionalization to form five- or six-membered rings. Emphasis in this review is placed on examples which illustrate general principles of regiochemical and stereochemical control. 

The major use of cyclofunctionalization in stereochemical control has been in the area of relative asymmetric induction that is, control of stereochemistry in the introduction of a new stereogenic center by stereogenic center(s) present in the substrate. Several types of structural features have been found to provide high levels of stereocontrol in cyclofunctionalizations to five- and six-membered rings. 

Intramolecular six-membered ring formation is also efficient. Treatment of bisdiene 62a with 0.05 equiv of a [Pd(OAc)2/3 PhjP] mixture in THF (65 °C, 24 h) affords the cyclized and intramolecularly trapped diene 63a in good chemical yield (82%) and with good diastereoselectivity (9 1 mixture of two diastereomers) (Scheme 20). The conversion of 62a to 63a is a unique cascade cyclization in that it constructs two new six-membered rings via the net 1,4-addition of the elements carbon and oxygen across a diene subunit. Three stereochemical elements are controlled in the cyclization of 62a to 63a. Two of these elements, the ( )-configuration of the double bond and the trans... 

Once again, the intramolecular version of the reaction can result in excellent regio- and stereochemical control, with a strong preference for either five- or six-membered ring formation, as well as a catalyst-dependent preference for insertion into tertiary C-H bonds, over secondary C-H bonds and even benzylic secondary bonds (Scheme 8.150). A sulfonyl linker showed a significant tendency towards six-membered ring... 

Anionic ring-opening polymerization of l,2,3,4-tetramethyl-l,2,3,4-tetraphenylcyclo-tetrasilane is quite effectively initiated by butyllithium or silyl potassium initiators. The process resembles the anionic polymerization of other monomers where solvent effects play an important role. In THF, the reaction takes place very rapidly but mainly cyclic live- and six-membered oligomers are formed. Polymerization is very slow in nonpolar media (toluene, benzene) however, reactions are accelerated by the addition of small amounts of THF or crown ethers. The stereochemical control leading to the formation of syndiotactic, heterotactic or isotactic polymers is poor in all cases. In order to improve the stereoselectivity of the polymerization reaction, more sluggish initiators like silyl cuprates are very effective. A possible reaction mechanism is discussed elsewhere49,52. 

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