Cycloadditions with chiral templates

Stereoselective inverse-demand hetero (4 + 2) cycloadditions. A Chiral Template for C-Aryl Glycoside Synthesis. Chiral allenamides2 4 had been used in highly stereoselective inverse-demand hetero (4 + 2) cycloaddition reactions with heterodienes.5 These reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. Further elaboration of these cycloadducts provides a unique entry to C-aryl-glycosides and pyranyl structures that are common in other natural products (Scheme 1). 

There have been two main approaches to the development of dipolarophile facial selectivity (1) the use of chiral substrates, templates, and auxiharies and (2) the use of chiral rhodium catalysts [35]. In one of the earhest examples of chiral substrate selectivity, Pirmng and Lee reported a selective hydroxy-directed cycloaddition with chiral hydroxy-substituted vinyl ethers [95]. This effort was followed by a number of chiral template approaches to diastereocontrol, including the use of (R)- or (S)-phenylglycinol to form a cycHc phenyloxazinone for the facially selective cycloaddition of isomtinchnones [96, 97]. Padwa and Prein demonstrated acycHc diastereofacial control in the cycloaddi-... 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

A similar approach to enantiomericaUy pure norbornene derivatives was developed by Nouguier et al. who employed l,3 2,4-di-0-methylene acetals of pentitols as chiral templates [62]. Hence, the 5-(5-acryloyl-D-arabinatol derivative 82 underwent highly stereoselective Lewis acid catalyzed cycloaddition with cyclopentadiene, giving 83 (Scheme 10.28). The stereochemical outcome of the reaction was explained in terms of the chelate complex 84, in which the chair-like dioxane ring and the acrylic moiety are fixed in two parallel planes, forcing the diene to approach the cisoid acrylate from the ii-face. The synthesis and utihty of various methylene protected glycosides have also been reported by this group [63-66]. 

Independently, Harwood also demonstrated the role of chiral-templated isomunchnones in 1,3-dipolar cycloaddition reactions. Thus using the rhodium(II)-catalyzed decomposition of diazo carbonyl compounds, Harwood and co-workers explored cycloadditions of isomunchnone derivatives of (5R)- and (55)-phenyloxazin-2,3-dione. Along with the work of Padwa (vide supra), these reactions appear to represent the first examples of chiraUy templated isomunctmone 1,3-dipolar cycloadditions. For example, reaction of 471 under standard rhodium acetate conditions in the presence of NPM affords a mixture of endo-472 and exo-473 adducts (Fig. 4.146). A-Methylmaleimide and DMAD react with 471 similarly. 

Organopalladium complexes containing the (S)-form of ort/jo-palladated (l-(dimeth-ylamino)ethyl)-naphthalene have been used successfully as chiral templates to promote asymmetric cycloaddition reactions between coordinated 3,4-dimethyl-1 -phenylphosphole 8.34 and two dienophiles (A, A-dimethy lacrylamide and styrene) via two pathways, endo (compounds 8.35) with X=C1 and exo (com-ponnds 8.36) with X=0C103, which proceed as shown in Scheme 8.3 [23]. 

In conclusion, these studies further demonstrate that the carbohydrates are plentiful sources of inexpensive chiral auxiliaries. On one molecular unit they carry a high density of functional and chiral information which can be amplitied by complexation with Lewis acidic centers. Taking advantage of these properties the carbohydrates can efficiently be used as the chiral templates in [4+2] cycloaddition reactions and also in other types of chemical transformations. 

Harwood and co-workers (105) utihzed a phenyloxazine-3-one as a chiral derived template for cycloaddition (Scheme 4.50). An oxazinone template can be formed from phenylglycinol as the template precursor. The diazoamide needed for cycloaddition was generated by addition of diazomalonyl chloride, trimethyl-dioxane-4-one, or succinimidyl diazoacetate, providing the ester, acetyl, or hydrogen R group of the diazoamide 198. After addition of rhodium acetate, A-methylmaleimide was used as the dipolarophile to provide a product that predominantly adds from the less hindered a-face of the template in an endo fashion. The cycloaddition also provided some of the adduct that approaches from the p-face as well. p-Face addition also occurred with complete exo-selectivity. Mono- and disubstituted acetylenic compounds were added as well, providing similar cycloadducts. 

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>. 

On the methodological front of these broadly based endeavors, we have exploited pericyclic processes such as the dipolar cycloadditions of nitrile oxides together with the aldol reaction and related constructions as tactical devices for the formation of new carbon-carbon bonds with high levels of stereochemical control Another important focus of these explorations has been upon the development of techniques for the manipulation and refunctionalization of hydropyrans, since this structural subunit is not only common to a variety of natural substances, but it may also be effectively exploited as a conformationally-biased template for the stereoselective construction of various skeletal arrays present in numerous natural products. In this context, we have devised a novel and highly effective strategy for the asymmetric syntheses of oxygenated natural products. The fundamental approach features the intermediacy of the hydro-3-pyranones 12, which may be accessed from the chiral furfuryl carbinols 10 via the hydroxy enediones 11 by well-established oxidative techniques (Scheme 1). A critical element of this overall planll is that the hydro-3-pyranones 12 are admirably endowed with differentiated functionality that is suitable for further elaboration by reaction with selected nucleophiles... 

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]. 

The reaction of ortto-palladated (l-(dimethylantino)ethyl)-naphthalene with a perchlorate complex proceeds by the exo-pathway and produces (+)-exo-syn-methylthio-substituted phosphanorbomene P-S bidentate chelate 8.42, as shown in Eq. (8.7). Generation of the chelating cycloadduct involved an intramolecular cycloaddition mechanism, in which both the cychc diene and the hetero dienophile were coordinated simultaneonsly to the chiral palladium template during the course of the cycloaddition reaction [25]. 

The first iron-catalysed 2-I-2-cycloaddition of enimides with alkylidene mal-onates yielded -amino acid cyclobutane derivatives with excellent yields and diastereoselectivities. The enantioselective intermolecular 2-i-2-photocycloaddition of isoquinolone with alkenes, in the presence of a chiral hydrogen-bonding template (11), produced functionalized cyclobutane cycloadducts in high yields (86-98%) and excellent regio-, diastereo-, and enantio-selectivity. ... 

A suggestion has been made that asymmetric induction is possible in cycloaddition reactions leading to azetidinones. The reaction of dimethylketene methyl-trimethylsilylacetal with the Schifl s bases of chiral a-aminoesters in the presence of titanium tetrachloride gave rise to the corresponding /3-lactams with extremely high stereoselectivity. The authors propose the formation of a template (183) between titanium and the Schiff s base leading to stereocontrol (Scheme 24). 

Sibi et al. reported that substoichiometric chiral Mg(II) complexes catalyzed regio- and enantioselective nitrile oxide cycloadditions to electron-deficient alkenes (Scheme 4.8) [6]. For an achiral template, bulky pyrazolidinone (20) was essential for high regio- and enantioselectivity in (22) and (23), while oxazolidinone crotonate and 3,5-dimethylpyrazole gave the adducts, but with poor results. In particular, mesityl nitrile oxide (21), a stable dipole, was chosen as the reagent due to steric interactions of that group with either a bulky achiral template and/or a bulky Lewis acid center. Aliphatic (t-Bu and i-Bu) nitrile oxides also provided cycloaddition... 

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