Cycloaddition facial selectivity

The cycloaddition of chiral, racemic and non-racemic alkoxybutadienes 109 with phenyltriazolinedione led to aza compounds [110] in high yield, with good facial selectivity (diastereomeric excess 87-92%) (Equation 2.31). The cycloadditions of the same dienes with N-phenylmaleimide require Lewis acid catalysis. 

The sterically unbiased dienes, 5,5-diarylcyclopentadienes 90, wherein one of the aryl groups is substituted with NO, Cl and NCCHj), were designed and synthesized by Halterman et al. [163] Diels-Alder cycloaddition with dimethyl acetylenedicarbo-xylate at reflux (81 °C) was studied syn addition (with respect to the substituted benzene) was favored in the case of the nitro group (90a, X = NO ) (syrr.anti = 68 32), whereas anti addition (with respect to the substituted benzene) is favored in the case of dimethylamino group (90b, X = N(CH3)2) (syn anti = 38 62). The facial preference is consistent with those observed in the hydride reduction of the relevant 2,2-diaryl-cyclopentanones 8 with sodium borohydride, and in dihydroxylation of 3,3-diarylcy-clopentenes 43 with osmium trioxide. In the present system, the interaction of the diene n orbital with the o bonds at the (3 positions (at the 5 position) is symmetry-forbidden. Thus, the major product results from approach of the dienophile from the face opposite the better n electron donor at the (3 positions, in a similar manner to spiro conjugation. Unsymmetrization of the diene % orbitals is inherent in 90, and this is consistent with the observed facial selectivities (91 for 90a 92 for 90b). 

Facial selectivities of cycloaddition reactions of 5,5-disnbstitnted cyclopentadienes have been stndied by Inagaki and Ishida [32, 44, 45] and other groups [40],... 

This reviews contends that, throughout the known examples of facial selections, from classical to recently discovered ones, a key role is played by the unsymmetri-zation of the orbital phase environments of n reaction centers arising from first-order perturbation, that is, the unsymmetrization of the orbital phase environment of the relevant n orbitals. This asymmetry of the n orbitals, if it occurs along the trajectory of addition, is proposed to be generally involved in facial selection in sterically unbiased systems. Experimentally, carbonyl and related olefin compounds, which bear a similar structural motif, exhibit the same facial preference in most cases, particularly in the cases of adamantanes. This feature seems to be compatible with the Cieplak model. However, this is not always the case for other types of molecules, or in reactions such as Diels-Alder cycloaddition. In contrast, unsymmetrization of orbital phase environment, including SOI in Diels-Alder reactions, is a general concept as a contributor to facial selectivity. Other interpretations of facial selectivities have also been reviewed [174-180]. 

Kahn and Hehre straightforwardly extended this idea to the description of Jt-facial selectivity in Diels Alder reactions. They simply stated cycloaddition involving electron-rich dienes and electron-poor dienophiles should occur preferentially onto the diene face which is the more nucleophilic and onto the diene face which exhibits the greater electrophihcity (Scheme 40) [49],... 

Dienes 581 and 583 undergo smooth Diels-Alder cycloaddition with a wide range of dienophiles affording the corresponding products. Their reaction with PTAD gives the respective products 582 and 584 with complete Jt-facial selectivity (Equations 82 and 83) <2005CEJ5136>. 

The readily available enantiopure acyclic hydroxy 2-sulfinyl butadiene 585 undergoes a highly face-selective Diels-Alder cycloaddition with PTAD to generate the densely functionalized cycloadduct 586 (Equation 84). The complete reversal of facial selectivity is observed when sulfonyl derivative 587 is treated with PTAD under identical conditions (Equation 85). These results demonstrate that the sulfinyl functionality is not just synthetically useful but also an extremely powerful element of stereocontrol for intermolecular Diels-Alder cycloadditions. On the other hand, the corresponding ( , )-hydroxy-2-sulfinyldienes treated with PTAD affords the cycloadducts in high yield but with moderate 7i-facial selectivity <1998CC409, 2005CEJ5136>. 

The cycloaddition of ketone 54 could be effected in a sealed glass tube in a modified microwave oven to afford the tricyclic system stereoselectively. This major adduct arose via the preferred transition state, in which the nonbonded interactions were minimized, because of the alignment of the dienophile beneath the triene unit furthest from the MOM substituent. This pattern of n-facial selectivity implies that, with the natural C2 stereoselectivity, the preferred geometry should provide the relative stereochemistry required for taxol itself. 

Facial selectivity in 1,3-dipolar cycloadditions to cis-3,4-dimethylcyclobutene (73) (Scheme 1.21) was studied. Only phenylglyoxylo- and pyruvonitrile oxides lacked facial selectivities (anti syn = 1 1). All other nitrile oxides formed preferably anti-74. The anti/syn ratio increased from 60 40 (R = P-O2NC6K4) and 65 35 (R = Ph) to 87 13 and 92 8 for bulky ten-Bu and mesityl substituents, respectively. The transition-state structure of the cycloaddition of formonitrile oxide was determined using both HF/6-31G and B3LYP/6-31G methods. The... 

Cycloaddition of a-aryl-A-phenylnitrones to the C16-C17 n-bond in 16-dehydropregnenolone-3P-acetate (545) involves only the minor rotamer (A-form) of the nitrones. It proceeds regio-, stereo- and Jt-facial-selectively to give steroido[16,17-d]isoxazolidines (546) in high yield (Scheme 2.257), (Table 2.24) (760). Similarly the cycloaddition of a,N -diphenylnitrones proceeds with five-membered heterocyclic enones (761). 

The Lewis acid-promoted [4+ 2]-cycloaddition reaction of the allenic ester 103 having a camphor-derived chiral auxiliary with cydopentadiene provided the adduct with excellent Jt-facial selection, leading to an enantioselective synthesis of (-)-/l-san-talene [92]. 

This modification is based on the consideration that such bidentate dienophiles would form rigid complexes with a chiral Lewis acid, resulting in high reactivity and a good level of TT-facial selectivity during the cycloaddition reaction. 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

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-... 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

As observed in other dipolar cycloadditions, there are three stereochemical issues that must be addressed (Scheme 2.3). These issues include the regioselec-tivity, the stereoselectivity, and the facial selectivity of the cycloaddition. The first two will be discussed in this section, while the latter will be discussed in Sections 2.3 and 2.4 as it relates to specihc examples. 

This section shall consider the effects of substitution on both the nitronate as well as the dipolarophile, as they relate to both the inter- and intramolecular versions of the dipolar cycloaddition. Also included will be a discussion of facial selectivity in the reaction of a chiral dipolarophile. 

In a second report on the use of chiral dipolarophiles, the cycloadditions of silyl nitronates with 123 and 124 provide modest facial selectivity (Table 2.37) (35). Unfortunately, the yields of the cycloadducts are only moderate because of the steric bulk of the dipolarophile. 

A second strategy to control facial selectivity involves the use of chiral sultams and lactams as auxiliaries for the dipolarophile (120-123). Cycloaddition of 132 with a variety of substituted nitronates provides up to 9 1 selectivity of the major diastereomer (Table 2.38). However, substitution at the a-position of the dipolarophile leads to a reduction in stereoselectivity (entry 5). Assuming an s-cis conformation of the dipolarophile, it is proposed that the major isomer arises from an endo approach of the nitronate to the Re face of the dipolarophile (Fig. 2.13). This is supported by X-ray crystallographic analysis of one of the cycloadducts, which resides in a conformation similar to the proposed transition state. However, this analysis assumes that the silyl nitronate is only reacting through the... 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

In both bridged cases, chiral vinyl ethers have been utilized to prepare diastereomerically enriched nitronates (86,253). Since only a single atom tether has been investigated for two bridged modes, the facial selectivity of the dipolar cycloaddition is completely controlled by the configuration of the nitronate at the point of attachment. 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

Koizumi and co-workers (38) reported the first asymmetric synthesis of (15)-(—)-a-tropanol (149) via a 1,3-dipolar cycloaddition protocol. Treatment of the chiral dipolarophile 150 with 151 in tetrahydrofuron (THF) delivered cycloadducts exo-152 and endo-153. Although the reaction proceeded with low facial selectivity,... 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

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