Chiral control element

Diels-Alder disconnection will have been eliminated, and the rctrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

In ketone 26, the chiral control elements are close to the reacting carbonyl, thus enhancing the stereochemical communications between the catalyst and the substrate. The fused ring or quaternary centers are placed at the a-position to the carbonyl group, which minimizes potential epimerization of the stereogenic centers. Electron-withdrawing oxygen substituents inductively activate the carbonyl. 

The reaction protocol was further developed by alterations to the chiral controlling element of the reaction (49). Use of the precursor 183 under the standard ylide generation and cycloaddition conditions gave a greatly improved diastereomeric excess of >95%, an endo/exo ratio 1 15 and an isolated yield of 62%, with A-phenylmaleimide as the dipolarophile. The improvement in the reaction was rationalized by both endo and exo attack of the dipolarophile to the same diastereomerically favored face of the conformationally restricted U-shaped ylide 184 (Scheme 3.52). 

Early work from the McIntosh group [1 lh,85] and extensive research from the Dehmlow group [24e-i,48b] concerning chiral catalyst design is noted. Recently, Lygo and co-workers have reported short enantio- and diastereoselective syntheses of the four stereoisomers of 2-(phenylhydroxymethyl)quinuclidine. The authors report that these compounds, which contain the basic core structure of the cinchona alkaloids, will be examined as possible chiral control elements in a variety of asymmetric transformations [86]. 

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). 

Preparation. A number of methods have been reported for both the racemic and asymmetric preparations of l-amino-2,3-dihydro-lH-inden-2-ol (1), most commonly starting from inexpensive and readily available indene. These methods have been described in detail in recent reviews. The valuable properties of 1 as both a component of a medicinally active compound and as a chirality control element, derive primarily from its rigid and well-defined stereochemical structure. As a result, the compound is most desirable in enantiomerically pure form. One of the most efficient asymmetric syntheses of 1, which may be employed for the synthesis of either enantiomer of the target molecule, involves an asymmetric epoxidation (89% yield, 88% ee) of indene to give epoxide 2 using the well-established Jacobsen catalyst. This is followed by a Ritter reaction using oleum in acetonitrile resulting in conversion to the oxazoline (3) which is subsequently hydrolysed to the amino alcohol. Fractional crystallization with a homochiral diacid permits purification to >99% ee (eq 1). ... 

Staudinger Reactions. Chiral oxazolidinones have been employed as the chiral control element in the Staudinger reaction as well as the ultimate source of the a-amino group in the formation of p-lactams." Cycloaddition of ketene derived from 4-(S)-phenyloxazolidylacetyl chloride with conjugated imines affords the corresponding p-lactams in 80-90% yields with excellent diastereoselectivity (eq 54). The auxiliary can then be reduced under Birch conditions to reveal the a-amino group. 

Tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands synthesized from tartaric acid have been extensively employed by Narasaka as the chiral control element in selective Diels-Alder reactions. Initial experiments were conducted with simple dienes and a,P-unsaturated imides using complex 44 (Scheme 36) [104,105]. Several rather subtle features have contributed to the success of these endeavors 1) the use of the acetophenone-derived dioxolane rather than the ac-etonide resulted in an increase of 20% ee 2) the use of alkyl-substituted benzenes as solvent augmented enantioselectivities relative to more common organic solvents e.g., CH2CI2, THF) [106] 3) use of 4 A molecular sieves was typically required to achieve maximum enantioselectivity. 

A rather different titanium(IV) Diels-Alder catalyst employed a cfs-amino in-danol, prepared in five steps from indene, as the chiral control element [125]. The amino indanol is regioisomeric to the one incorporated into a bisoxazolinyl... 

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). 

In 1996, Yang and co-workers reported on a C2-symmetric chiral binaphthyl ketone 54 as an efficient catalyst for the asymmetric epoxidation of unfunctionalized olefins. In ketone 54, a remote binaphthalene unit was used as the chiral control element to make the catalytic center less hindered, and the electron-withdrawing esters at the a-carbon made ketone 54 very reactive (Figure 35.7). High conversion and moderate-to-good enantioselectivity for the epoxidation of tra i-disubstituted olefins and trisubstituted olefins can be obtained with as low as 5 mol% of catalyst 54... 

In 1999, Armstrong and coworkers reported trifluoromethyl ketone 78, using the chiral oxazolidinone as the chiral control element. Up to 34% ee was obtained (Scheme 3.58) [85]. Carnell and coworkers found that N,N-diaLkylaUoxans such as 79... 

Discovering highly enantioselective ketone catalysts for asymmetric epoxidation has proven to be a challenging process. As shown in Scheme 3.62, quite a few processes are competing with the catalytic cycle of the ketone mediated epoxidation, including racemization of chiral control elements, excessive hydration of the carbonyl, facile... 

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