Vicinal stereochemistry

More recently the introduction of low-valent transition metal and lanthanoid based reducing systems, especially those based on titanium, has provided dramatic advances in efficiency and selectivity. It is now possible to select appropriate conditions for efficient coupling of all types of carbonyl compounds, often with high chemo-, regio- and stereo-selectivity. Moreover, imino- and thio-carbonyl derivatives are also coupled via pinacolic methodology. The coupling of imines to 1,2-diamines is particularly effective, with excellent control of vicinal stereochemistry. 

The next total synthesis relied on setting the vicinal stereochemistry of the morpholine ring by a stereoselective hydrogenation. The goal was to use the acetal stereocenter to control the stereochemical induction at the adjacent carbon. A proof of concept was needed to validate this route. 

Stork has continued his monumental work on the use of the intramolecular Michael addition to control vicinal stereochemistry in the construction of /ran -fused hydrindanes, and this year he has extended the study to a short stereoselective synthesis of adrenosterone (66) (Scheme 6). ... 

Control of Vicinal Stereochemistry Through Control of Olefin Geometry... 

In this chapter we will take a look at several syntheses of a sesquiterpene ester called juvabione. We will see that it became a target for synthesis because of structural and biological issues, and became a test molecule for the evaluating methodology for controlling vicinal stereochemistry in acyclic systems. But first let s once again examine the steroid sidechain problem. 

This synthesis did not address the vicinal stereochemistry problem in a selective manner. The synthesis did provide an impressive amount of 27, largely because it involved simple and reliable chemistry. The stereochemistry problem was solved using separation science. 

Two additional syntheses that did not address the vicinal stereochemistry problem are outlined here. They differ from the Mori synthesis in regard to the chemistry used to introduce the sidechain, but are similar in that they rely on reactions of a 4-substituted cyclohexanone to introduce the vicinal stereochemical relationship. 

The first clear attempt to address the stereochemical problem presented by the juvabiones was reported by Birch. The plan was to use enone 33 to desymmetrize the 4-substituted cyclohexanone intermediates encountered thus far. The vicinal stereocenters in enone 33 were to be derived from 34 via a retro-aldol condensation. As we will see, 34 was to be prepared via a Diels-Alder reaction, a reaction that frequently has been used to establish vicinal stereochemistry with a high degree of selectivity. 

Overall the Birch strategy is creative and directly addresses the vicinal stereochemistry problem that is the focus of this chapter. The execution of the plan, however, is problematic. I imagine that with more time, and tools... 

Let s begin with 59 (R=Me). Treatment of this rearrangement substrate with KH provided a 96 4 ratio of 67 + 68. These diastereomers differ in terms of vicinal stereochemistry and enol ether geometry. The major product (67) presumably was formed via rearrangement of the intermediate alkoxide via a chairlike transition state as anticipated. The minor product (68) was presumed to arise from rearrangement via a competing boat-like transition state. This nicely explains the differences in stereochemistry between the observed products (vicinal stereochemistry and olefin geometry). 

This study provided insight into mechanistic aspects of the anion accelerated oxy-Cope rearrangment. It also illustrates how control of terminal olefin stereochemistry in [3.3]-sigmatropic rearrangements can be used to establish vicinal stereochemistry. Note that both 59 (R=Me) and 71 give superb control. Only when there are overriding steric factors (70 and 72) does erosion of stereocontrol begin to occur. 

Both of these approaches use the now-familiar set stereochemistry in a ring, then open the ring strategy. They are effective in establishing vicinal stereochemistry, but are long because of the choice of starting material. 

A conceptually different approach to the juvabiones would be to develop reactions of cyclohexenone (127) with nucleophiles of type 128 that afford conjugate adducts of type 129 with good control over relative (vicinal) stereochemistry and absolute stereochemistry. This plan is conceptually related to the Pearson approach (Juvabione-12) but uses the electrophile needed to directly connect with the now familiar 3-substituted cyclohexanone endgame for juvabione synthesis. We will look at three different approaches that adapt this general strategy. 

This paper presents a nice "overview" of other approaches (13 key intermediates). The "plan" involves an interesting disconnection that is related to the Evans solution to the vicinal stereochemistry problem. The plan is great, but lack of selectivity in the orbital symmetry... 

---