Stereocontrol in cyclic systems

An important and differentiating feature of cyclic systems is the relatively rigid conformations assumed by these molecules (sec. 1.5.B). In both Chapters 3 and 4, conformational bias had a profound effect on reaction pathways and also on the trajectory of attack. These effects provide the tools to control selectivity. 

Alkene positional isomerism is a problem that arises from time to time. It is conceptually related to regiochemistry and is presented here. Careful synthetic planning is usually required to solve this problem, as illustrated by the Burk-Soffer synthesis of e-cadinene (53) and V2-cadinene (54). 9 Conversion of 52 first to the ketone, then to the tertiary alcohol, and finally to the tertiary chloride allows E2 elimination to give 53. Conversely, Wittig olefination (sec. 8.8.A) of the ketone gave the exo methylene derivative, 54. It is important to note that formation of the C2-C3 C=C unit is favored for trans decalin derivatives over the C3-C4 unit. 

As we have just seen in the formation of 53 or 54, regioselectivity is important is the formation of double bonds in elimination reactions. In Chapter 2 both E2 (anti) elimination (sec. 2.9.A) and syn elimination (sec. 2.9.C) processes were discussed. Regiocontrol in the elimination was achieved by binding the base to the 

A unique regiochemical problem arises in small bicyclic compounds. Elimination of the bromine and H in 2-bromonorbornane (62) gave exclusively the A -norbornene (63) and none of the A -norbornene (64). To form an alkene such as 64 would require that bridgehead carbon atoms be compressed toward planarity, but the Jt overlap required for a planar C=C unit would be diminished due to structure-imposed twisting. The 

How large must ring systems be before they fail to comply with Bredt s rule For [2.2.1], [2.1.1], and [1.1.1] bicyclic systems, Bredt s rule is applied. Prelog established that cyclization of 67 gave 68 when n 5 32,30e When n = 5, both 68 and 69 were formed, but 68 was not formed when n 5. 

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Aside from the well-documented ability of the Luche reduction to provide stereocontrol in cyclic systems, acyclic stereocontrol is also viable through this process.39-41 A notable example of this was demonstrated in the synthesis of (+)-cannabisativine, a unique natural product found in the common marijuana plant.42 This synthesis necessitated a stereoselective Luche reduction to produce the diol 36 as a single diastereomer. The reaction proceeded in 96% yield and with 95% de. The pronounced diastereoselectivity can be attributed to Cram s rule, in which the hydride ion is delivered from the least sterically hindered side of the intermediate 34. Reduction via the chelated intermediate 35 would also account for the observed stereochemical outcome. 

It is apparent from preceding sections that stereocontrol in cyclic systems is much easier than in acyclic systems, which is due, of course, to the conformational bias inherent in cyclic systems. Synthetic chemists have exploited this fact for many years. A cyclic system can be used to position functional groups, often with control of regio- and stereochemistry. The ring is then opened to give an acyclic system and the regiochemistry and stereochemistry of the substituents has been fixed. There are many examples. 

Six-membered Rings Five-membered Rings Stereocontrol in Cyclic Systems Acyclic Diastereoselection Biomimetic Synthesis... 

A significant advance13 towards the synthesis of aminosugars uses halocyclocarbamation in cyclic systems which proceeds under high regio- and stereocontrol. 

Blackburn, B. K., Sharpless, K. B. Rhodium(l) catalyzed hydroboration of olefins. The documentation of regio- and stereocontrol in cyclic and acyclic systems. Chemtracts Org. Chem. 1989, 2, 33-35. 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

Some sort of cyclic aspect is usually a feature of good stereocontrol. This aspect might be in the form of a cyclic transition state or perhaps in the generation of a genuinely cyclic compound but in any case a cyclic aspect is associated with fewer degrees of freedom - or less Soppiness - in whatever system we are considering which usually means better control. Without trying to be exact, the cyclic aspect of reactions broadly decreases down the series -... 

Acyclic Substrates. The situation in acyclic systems is much more complicated than in cyclic ones as high stereocontrol for additions to prostereogenic double bonds [reactions (47a,b), Scheme 16] or carbonyl groups [reaction (48), Scheme 16] can only be achieved if the molecule adopts a definite reactive conformation in which one of the two diastereofaces is efficiently shielded by the steric effects of the substituents (Scheme 16) [41]. This means that these substituents have to be of different sizes and may be classified as small (S), medium... 

In the absence of a preexisting cyclic system, achieving similar levels of stereocontrol with chiral diols can be difficult. An instructive example along these lines derives from the Pettit... 

An alternate strategy is to use asymmetric induction by a preexisting chiral center in the substrate to direct the fluorination step. This approach has not been widely employed and the best results are those of Enders who reported Aat scalemic a-silyl ketones can be stereoselectively fluorinated at the a -position.(7) After desilylation, a-fluoro ketones can be obtained in high ee s for cyclic systems. Unfortunately, open chain systems give poorer results. In this symposium Davis has reported recent results using a chiral auxiliary as a stereocontrol element for the synthesis of a-fluoro esters in high enantiomeric purity.(8)... 

Some representative examples of the [3+2] annulatlon are listed in Table 1. Both cyclic and acyclic allenophiles participate in the reaction, a-Alkylidene ketones undergo annulation to provide access to spiro-fused systems, and acetylenic allenophiles react to form cyclopentadiene derivatives. The reactions of (E)- and (Z)-3-methy1-3-penten-2-one illustrate the stereochemical course of the annulation, which proceeds with a strong preference for the suprafacial addition of the allene to the two-carbon allenophile. The high stereoselectivity displayed by the reaction permits the stereocontrol led synthesis of a variety of mono- and polycyclic systems. 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Iodolactonization has become a useful reaction for the stereocontrol led introduction of chiral centers in both cyclic and acyclic3" systems. Depending upon the reaction conditions, the cyclizatlon can be carried out... 

To exploit the whole capacity of the Claisen rearrangement, appropriate methods for the preparation of the allyl vinyl ethers starting from allyl alcohols are necessary. The classical approach involves vinyl-ation with simple vinyl ethers or acetals. Unfortunately these methods fail with more complex systems and do not allow, except in the case of cyclic enol ethers, control of the stereochemistry of the substituted enol ether double bond. Until recently it was only possible to generate such substituted systems with appreciable stereocontrol via ketene N.O-acetals. Their preparation by addition of lyl alcohols to substituted ynamines can lead to adducts of either ( )- or (Z)-geometry, depending upon the conditions used (Scheme 60). 

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