High endo/exo selectivity

A titanium complex derived from chiral /V-arencsulfonyl-2-amino-1 -indanol [20], a cationic chiral iron complex [21], and a chiral oxo(salen)manganese(V) complex [22] have been developed for the asymmetric Diels-Alder reaction of oc,P-unsaturated aldehydes with high asymmetric induction (Eq. 8A.11). In addition, a stable, chiral diaquo titanocene complex is utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and a series of a.P Unsaturated aldehydes at low temperature, where catalysis occurs at the metal center rather than through activation of the dienophile by protonation. The high endo/exo selectivity is observed for a-substituted aldehydes, but the asymmetric induction is only moderate [23] (Eq. 8A. 12). 

The use of a chiral auxiliary or group on the dienophile can provide for face selectivity. High endo-exo selectivities have been achieved with bicyclic adducts, together with high asymmetric induction. Chiral dienophiles can be classified as either type I or type II reagents (Figure 26.1).4... 

As shown in Fig. (7), the relative configurations for the diastereo-meric adducts were determined by NOESY correlations and coupling constants for ring protons. All the IMDA reactions proceeded with high endo/exo selectivity (A+B/C+D), while the n-facial selectivity of the endo-adducts (A/B) depended on the protecting group at C-l. The C-l alkyl- and acyl-protected substrates (88, 95, or 96) and non-protected substrate 89 provided the undesired cycloadduct B preferentially... 

Alternative catalysts are titanium systems chirally modified with binaphthols27,29,36,9 92. These are either introduced as dilithio diolates27 or prepared in situ by azeotropic removal of 2-propanol from titanium isopropoxides29 and have been successfully used in the presence of molecular sieves36. Thus, high endo/exo selectivities (98 2) with medium enantioselectivities (50%) are obtained29. 

Additional work by the Harwood team " with diazo imides 474, and related ones, revealed that the resulting isomunchnones react with methyl propiolate to form adducts 475 (Fig. 4.147). Diazo imides 474 (R = C02Et, Ac, H) also react with maleimides and DMAD to afford adducts with high endo, exo selectivities and moderate diastereofacial selectivities. 

In reactions of chiral vinylsulfoxides, " absolute exo selectivity and high diastereoselectivities were obtained using cyclic nitrones. The cycloaddition of nitrones to chiral vinylphosphine oxides was found to proceed with high endo/exo selectivities and moderate diastereoselectivities. ... 

By using unactivated K-10 montmorillonite in the absence of solvent, the endo-exo selectivity of the cycloadditions of acrolein and methyl vinyl ketone with cyclopentadiene and cyclohexadiene is low [8] (Table 4.2, entry 3), while highly reactive dienophiles such as 1,4-benzoquinone and N-phenyl... 

While widespread investigations on rate accelerations in Diels-Alder reactions by additives were highly successful, the effect of these additives on the selectivities of [4 + 2]-cycloadditions in water has not received much attention. Scattered reports on this aspect point to an increase in endo/exo selectivity by additives, due to an increase in the hydrophobic interactions209. 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

In subsequent studies, methyl vinyl ketone (2.0 mmole) was chosen as the dienophile so as to determine the combined effect of the ionic liquid (2 mL) and the Lewis acids (0.2 and 0.5 wt%) upon the yield and selectivity. Without the Lewis acid catalyst, this system demonstrated a 52% conversion of the cyclopentadiene (2.2 mmol) in 1 h with the endojexo selectivity being 85/15. The cerium triflate-catalyzed reaction was quantitative in 5 min and the endo. exo selectivity was very good for this experiment as well (94 6, endo. exo). Also with the scandium or yttrium salts tested, reactions came to completion in a short time with high stereo-selection. Cerium, scandium and yttrium triflates are strong Lewis acids known to be quite effective catalysts in the cycloadditions of cyclopentadiene with acyclic aldehydes, ketones, quinones and cycloalkenones. These compounds are expected to act as strong Lewis acids because of their hard character and the electron-withdrawing triflate group. On the other hand, reaction times of 1 hour were required for... 

The near perfect facial and endo/exo selectivities observed were reconciled by assuming that the reaction proceeded through the highly ordered endo transition state 173, in which both the azomethine ylide and the approaching dipolarophile are coordinated to the lithium cation (Fig. 3.10). Alternative endo transition state models that would allow for the observed stereochemical outcome of the cycloaddition do not permit an efficient and sterically less imposing environment for the relevant functionalities. 

In the case of the template 204, the endo/exo selectivity was only 1.8 1, but the material yield was high with a facial selectivity of 10 1. The ylides were also trapped with methyl acrylate, generating the expected cycloadducts with reasonable regio and diastereocontrol. Although the endo/exo selectivity was relatively poor, the facial selectivity and material yield were both reasonable and the removal of the template is nondestructive. 

Regiocontrol was also high with unsymmetrical dipolarophiles, as was the endo/exo selectivity. Simple destructive template removal followed by Boc protection gave a range of enantiomerically pure polycychc proline derivatives, as exemplified in... 

Mukai et al. (36,37) applied the chiral tricarbonyl(r -arene)chromium(0)-derived nitrone 24b in 1,3-dipolar cycloadditions with various alkenes, such as styrene 25 (Scheme 12.11). The analogous nonmetallic nitrone 24a was used in a reference reaction with 25, giving the isoxazohdine 26a with an endo/exo ratio of 82 18. By the apphcation of nitrone 24b in the 1,3-dipolar cycloaddition with 25, the endo/exo-selectivity changed significantly to give exo-26b as the only observable product. The tricarbonylchromium moiety effectively shielded one face of the nitrone, leading to high diastereofacial selectivity. The product exo- 26b was obtained with 96-98% de. 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

The use of chiral vinyl ethers in 1,3-dipolar cycloadditions with nitrones allows for the subsequent removal and recovery of the chiral group. Using the chiral vinyl ether 197 and the cyclic nitrone 77, the cycloaddition proceeded with high diastereoselectivity (Scheme 12.56). The endo/exo-selectivity was not given in this communication by Carmthers et al. (313), but this is of minor importance for the final outcome of this work, since one of the chiral centers was destroyed in the conversion of 198 into the final product 199. The chiral auxiliary can by recovered in this reaction sequence, and 199 was obtained with an optical purity of >95% ee. 

Recently, substantial progress in stereochemistry of the cycloaddition reaction has been reported [34], Cycloaddition between optically active oxadiene 13 and l-acetoxy-2-ethoxy-ethylene, promoted by dimethylaluminum chloride, leads to dihydropyran 14, with a very high endo-exo stereoselectivity (54 1) and in an almost quantitative yield (see Scheme 6). When trimethylsilyl triflate was used as the promoter in this reaction, the reverse endo-exo selectivity (1 5) has been noted. The dihydropyrans obtained served as substrates for the synthesis of (3-d- and 3-L-mannopyranosides [34]. 

The only paper concerning catalysis by Lewis acids of the Diels-Alder reactions of these simple sulfinyl ethylenes was due to Ronan and Kagan [20], who studied the influence of TMSOTf in the reaction of compound (S)-l with cyclo-pentadiene and furane. In the first case, the reaction occurs at 0°C in 3 h, giving an 89 11 mixture of endo and exo adducts (overall yield 60%) with very high n-facial selectivity (de> 92%). The high efficiency of the catalyst increasing the reactivity of 1 also made possible its reaction with furan, which evolved with low endo/exo selectivity (55 45) and lower 7r-facial selectivity (de 70%) than that observed with cyclopentadiene. These excellent results were nevertheless, eclipsed by those reported in the same paper [20] concerning the activation of... 

Pyridylsulfoxides 14a and 14b are able to react with furan, yielding a mixture of four adducts 18. In Scheme 9, only the major endo(t) and exo t)- adducts, derived from 14a, have been depicted. In the presence of Et2AlCl the reaction of 14a required 7 days at room temperature to reach completion [34], and its n-facial selectivity was very high (93 7 mixture of endo adducts and 96 4 mixture of exo-adducts), the results obtained from 14b being similar. In contrast, the endo/exo selectivity is only moderate for both dienophiles (<2 1). In the absence of the Lewis acid (50 °C, 6 days), the endo/exo selectivity of these reactions was slightly higher (almost 4 1 for 14a), but the 7r-facial selectivity for the endo-approach was clearly poorer (55 45). 

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