Alder Chiral Templates

The last approach to chiral synthesis begins with a chiral precursor whose components will be integrated into the final product, which is the chiral template approach (sec. 10.9). The examples of asymmetric syntheses involving Diels-Alder templates are as varied as the targets. One typical example is by Oppolzer, who reported an asymmetric synthesis of pumiliotoxin C via Diels-Alder cyclization of 303, prepared from (/ )-norvaline, to give 304.248 

Carbohydrates are efficient chiral templates and have been used in the Diels-Alder reaction. Sherbum used L-ascorbic acid as a template to synthesize 305.249 Heating this compound in refluxing toluene led to a 96 4 mixture of 306 and 307 (68% yield). The chirality inherent in the carbohydrate precursor provides the needed facial selectivity that is transferred to the cycloadduct product. The use of chiral templates for preparing Diels-Alder precursors will undoubtedly increase in importance. As the need for enantiomerically pure material increases, the chiral template approach coupled with the power of the Diels-Alder reaction will be an effective combination. 

The Diels-Alder reaction occupies a prominent place in organic synthesis, as we have seen, but there are other pericyclic reactions that are also quite useful. One of them is the [2-1-2]-cycloaddition that occurs between two alkenes or between an alkene and a carbonyl or imine.250 Cyclobutanes and oxetanes are 

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In 1990, Choudary [139] reported that titanium-pillared montmorillonites modified with tartrates are very selective solid catalysts for the Sharpless epoxidation, as well as for the oxidation of aromatic sulfides [140], Unfortunately, this research has not been reproduced by other authors. Therefore, a more classical strategy to modify different metal oxides with histidine was used by Moriguchi et al. [141], The catalyst showed a modest e.s. for the solvolysis of activated amino acid esters. Starting from these discoveries, Morihara et al. [142] created in 1993 the so-called molecular footprints on the surface of an Al-doped silica gel using an amino acid derivative as chiral template molecule. After removal of the template, the catalyst showed low but significant e.s. for the hydrolysis of a structurally related anhydride. On the same fines, Cativiela and coworkers [143] treated silica or alumina with diethylaluminum chloride and menthol. The resulting modified material catalyzed Diels-Alder reaction between cyclopentadiene and methacrolein with modest e.s. (30% e.e.). As mentioned in the Introduction, all these catalysts are not yet practically important but rather they demonstrate that amorphous metal oxides can be modified successfully. 

Microwave-assisted Diels-Alder reactions of 9-substituted anthracenes with 2-acetamidoacrylate in DMF generate conformationally constrained bicyclic bisaryl a-amino acid derivatives with high regioselectivity.138 The Sc(OTf)3-catalysed Diels-Alder reaction of anthracenes with methyl vinyl ketone does not proceed via an electron-transfer process from anthracenes to the MVK-Sc(OTf)3 complex.139 (-)-(/ )-9-(l,2-Dimethoxyethyl)anthracene has been used as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the synthesis of a,j3-unsaturated lactams.140... 

Staehle, W, Kunz, H, Carbohydrates as chiral templates stereoselective Diels-Alder synthesis with dienes of differing reactivity, Synlett, 260-262, 1991. 

Nouguier, R, Gras, J L, Giraud, B, Virgili, A, Methyl 3,4-p-D-arabinoside as a new chiral template for the asymmetric Diels-Alder reaction. Tetrahedron Lett., 32, 5529-5530, 1991. 

Chiral (helical) Lewis acids for asymmetric Diels-Alder catalysis are prepared from titanium tetraisopropoxide 5 and a chiral binaphthol ligand 4 [13]. The titanium reagent 6 plays an important role as chiral template for the fixation of a,fi-unsaturated aldehydes and thereby for the enantioface recognition of substrates. The asymmetric Diels-Alder reaction, e. g., of cyclopentadiene 7 and acrolein 8, is effected in the presence of catalytic (P)-6 (10 mol%), producing the endo adduct 9 (R =R2=H) in 88% ee (Scheme 1). 

Scheme 1. In the presence of the asymmetric titanium catalyst (f)-6, which acts as chiral template for the fixation of a,y9-unsaturated aldehydes, the Diels-Alder reaction of cyclopentadiene 7 and acrolein 8 leads to the enr/o-adduct 9 (Ri=R2=H) in...

C. Asymmetric Diels-Alder Reactions Chiral Templates... 

Ort/ o-cyclometallated palladium complexes discussed in Section 2.2.2 have found another very important application as chiral templates that promote Diels-Alder and other reactions. This chemistry has been developed by Leung and co-workers and has allowed the synthesis of an impressing number of mono- and diphosphines bearing P-stereogenic atoms with peculiar scaffolds... 

Intramolecular reactions provided the best examples for requiring the proper conformation for a successful Alder-Ene reaction to occur. Oftentimes, a chiral template has been used to induce chirality into the Alder-Ene reaction. Retro-Diels-Alder reaction formed 71, which revealed the enophile, followed by cyclization to 72. Notably, reactions with the E-alkenes were very slow and poor yielding, while the Z-alkenes which underwent reaction via the exo-TS led to product the -alkene required the endo-TS. The authors suggested that due to the highly strained endo-TS, the Z-alkenes reacted more smoothly. ... 

The cyclopalladated complex (naphthyl)ethylamine-6, iV]-dipalladium has been used as a chiral template to promote the intramolecular [4 -h 2] Diels-Alder reaction between diphenyl-vinylphosphine and 1-phenyl-3,4-dimethylphosphole. Halide-bridged palladium(ii) dimers of orthopalladated (S)-(-h)-7V,7V-dimethyl-Q -methylbenzylamine and (naphthyl)ethyl]amine were reported by the same authors.Solution and solid-state structures were determined as well as reactions with 3,4-dimethyl-1-phenylphosphole and allyldiphenylphosphine carried out. 

The retro-Diels—Alder reaction of adduct 260 by FVP at 350 °C is the final step in the construction of the dioxolane product 261 using diene 11 as a chiral template (Scheme 51 2004ARK(ii)4). A retro-Diels—Alder reaction of adduct 262 was used to prepare the dioxolane 263 for use in total synthesis (2010T6331). 

Compared with the Diels-Alder reaction, the [2+2+2]-cycloaddition is potentially more powerful since the number of new bonds as well as chirality centers that are formed is higher. Unfortunately, the reaction seems to be entropically or kinetically unfavorable. This disadvantage can, however, be overcome by the use of transition metal catalysts (templates). Among the most successful examples of this reaction type, the nickel(II) catalyzed Reppe reactions 96), the cobalt(I) catalyzed cocyclizations of a,to-diynes with alkynes 97), the cobalt(I) catalyzed pyridine synthesis 985 and last but not least the palladium(0) catalyzed cyclotrimerizations of 3,3-dialkylcyclopropenes to frans-cr-tris-homobenzenes must be mentioned. The latter has been known for ten years 99>. 

Yeo W-C, Chen S, Tan G-K, Leung P-H (2007) Synthesis of P-chiral phosphines via chiral metal template promoted asymmetric furan Diels-Alder reaction. J Organomet Chem 692 2539-2547... 

Yeo WC, Vittal JJ, Koh LL, Tan GK, Leung PH (2(X)4) Chiral metal template promoted asymmetric pyrrole Diels-Alder reaction between N-(diphenylphosphino)pyrrole and diphenylvinylphosphine. Organometallics 23 3474—3482... 

The resulting chiral C—N axis could then be used as a good template to control the configuration of subsequent transformations as was shown for alkylation and Diels-Alder processes. 

A Diels-Alder reaction of 2-diphenylphosphinofuran with diphenylvinylphosphine in the presence of organoplatinum complex gives the chelating diphosphine exo-cycloadduct, 4(/ ), 5(if)-bis(diphenylphosphine)-7-oxabicyclo[2.2.1]hepta-2-ene 8.41 (M=Pt) in a 70 % isolated yield with many diastereoisomers, as shown in Eq. (8.6). The cycloaddition reaction proceeds at a significantly slower rate and exhibits a markedly lower stereoselectivity when the chiral platinum template is replaced with its organopalladium counterpart 8.41 (M=Pd) [24]. 

Ruthenium (II) polypyridyl complexes promote the photoredox reactions such as Diels-Alder reaction (see formulae 29 31) and azomethine ylide formation followed by [3 + 2] cycloaddition (32-34) by use of visible light. Yoon found 2,2 -bipyrazine ligand is better than 2,2 -bipyridine. Bach reported enantioselective intramolecular [2 + 2] and intermolecular [3 + 2] photocycloaddition by use of chiral hydrogen bond templates (37) and (41). ... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

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