Endo approach

The effect of ligands on the endo-exo selectivity of Lewis-acid catalysed Diels-Alder reactions has received little attention. Interestingly, Yamamoto et al." reported an aluminium catalyst that produces mainly exo Diels-Alder adduct. The endo-approach of the diene, which is normally preferred, is blocked by a bulky group in the ligand. 

The preference for endo attack in 7,7-dimethylnorbomene is certainly steric in origin, with the 7-methyl substituent shielding the exo direction of approach. The origin of the preferred exo-attack in norbomene is more subject to discussion. A purely steric explanation views the endo hydrogens at C—5 and C—6 as sterically shieldihg the endo approach. There probably is also a major torsional effect Comparison of the exo and endo modes of reproach shows that greater torsional strain develops in the endo mode of... 

The exo addition mode is expected to be preferred because it suffers fewer steric repulsive interactions than the endo approach however, the endo adduct is usually the major product because of stabilizing secondary orbital interactions in the transition state (Scheme 1.10). The endo preference is known as Alder s rule. A typical example is the reaction of cyclopentadiene with maleic anhydride which, at room temperature, gives the endo adduct which is then converted at... 

The chiral catalyst 142 achieves selectivities through a double effect of intramolecular hydrogen binding interaction and attractive tt-tt donor-acceptor interactions in the transition state by a hydroxy aromatic group [88]. The exceptional results of some Diels-Alder reactions of cyclopentadiene with substituted acroleins catalyzed by (R)-142 are reported in Table 4.21. High enantio- and exo selectivity were always obtained. The coordination of a proton to the 2-hydroxyphenyl group with an oxygen of the adjacent B-0 bond in the nonhelical transition state should play an important role both in the exo-endo approach and in the si-re face differentiation of dienophile. 

Enantiomers (M)- and (P)-helicenebisquinones [32] 93 have been synthesized by high pressure Diels-Alder reaction of homochiral (+)-(2-p-tolylsulfo-nyl)-l,4-benzoquinone (94) in excess with dienes 95 and 96 prepared from the common precursor 97 (Scheme 5.9). The approach is based on the tandem [4 + 2] cycloaddition/pyrolitic sulfoxide elimination as a general one-pot strategy to enantiomerically enriched polycyclic dihydroquinones. Whereas the formation of (M)-helicene is explained by the endo approach of the arylethene toward the less encumbered face of the quinone, the formation of its enantiomeric (P)-form can be the result of an unfavourable interaction between the OMe group of approaching arylethene and the sulfinyl oxygen of 94. 

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

The cyclohexene is easy to see so that the Diels-Alder disconnection follows. The stereochemistry of the double bonds comes from two separate arguments the dienophile (a in 5) must be trarjs as the two substituents it produces in (4) are also trans. The diene must be all ain or all trann since the two substituents it produces in (4) are ois (both down). The all tvan, is needed because endo approach (6) is preferred. 

The stereospecificity is of course correct all trans diene producing ais substituents and ais dienophile producing [Pg.424]

There have been ab initio studies of the transition structure using several model catalysts and calculations attheHF/3-21G, HF/6-31G(4), and MP2/6-31G(4) levels.155 The enantioselectivity is attributed to the preference for an exo rather than an endo approach of the ketone, as shown in Figure 5.8. 

To summarize the key points, D-A reactions are usually concerted processes. The regio- and stereoselectivity can be predicted by applying FMO analysis. The reaction between electron donor dienes and electron acceptor dienophiles is facilitated by Lewis acids, polar solvents, and favorable hydrogen-bonding interactions. The D-A reaction is quite sensitive to steric factors, which can retard the reaction and also influence the stereoselectivity with respect to exo or endo approach. 

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Ethoxy)-allylidenecyclopropane (136a) readily underwent Diels-Alder reaction with activated dienophiles under mild conditions (Table 14) [33]. Only one regioisomer was formed with unsymmetrically substituted dienophiles such as methyl maleic anhydride (137), and quinones 138-141 (entries 2 and 3-6). AH the cycloadducts 143-147 derive from an endo approach between the two reagents. Two site-isomers were obtained in 96 4 ratio with 3-isopropyl-6-methyl-p-quinone (141) (entry 6) and the high site-selectivity observed in this... 

The nitrone and the substituted methylenecyclopropane approach, in each of the two possible regioisomeric arrays, away from the nitrone substituent and away from the methylenecyclopropane substituent. The most favoured anti-anti Transition State produces the observed major diastereoisomers [81,65c]. The only two isomers formed, for each regioisomeric mode, must derive from anti-anti exo and anti-anti endo approaches. No exo-endo selectivity is generally observed, as a consequence of the strong preference for the anti approach towards the substituent on the cyclopropyl ring. 

Because of the particular structural features of compound 4, pointed out in Section I, the D-glucofuranosyluronic halide anomers not only have inverse thermodynamic stabilities with respect to those of D-glucopyranosyl halides but also show a different behavior towards alcohols. For instance, 2,5-di-O-acyl-a-D-gluco-furanosylurono-6,3-lactone halides, which are difficult to prepare, do not react with alcohols, inasmuch as an endo approach of the reagent is inhibited.14 The /3-bromides and -chlorides, however, just like /3-D-glucopyranosyl chlorides, are subject to alcoholysis, with formation of /3-D-glucofuranosidurono-6,3-lactones.16... 

Cycloaddition of 3-methylenephthalide with ot./V-diphenylnitrone gave two diastereoisomers of 2,3-diphenyl-2,3-dihydrospiro 1,3-oxazole-5(47/ )l (3 H)-2-benzoluran]-3 -one (805). The 1,3-dipolar cycloaddition reaction of /V-benzyl-C-(2-furyl)nitrones with electron-rich alkenes gave preferentially trans-3,5-disubstituted isoxazolidines (endo approach). These experimental results are in good qualitative agreement with those predicted from semiempirical (AMI and PM3) and ab initio (HF/3-21G) calculations (806). 

If the tether consists of three atoms (-RCH—X-( ) - (n= 1)), the stereoselectivity of the process is very high, and trans isomer 188a prevails among the reaction products, regardless of the composition of the tether, due to the endo approach of the tether to the Z isomer of the nitronate. An increase in the length of the tether to four atoms (n = 2) leads to a sharp decrease in selectivity of cycloaddition, and cis isomer (188b) prevails among the reaction products. Evidently, the latter isomer is formed as a result of the exo approach of the tether to the nitronate. 

It was demonstrated that the transition state of these processes exhibits a weak zwitterionic character and that secondary orbital interactions facilitate the endo approach. 

This approach did not provide a complete explanation for the observed degree of stereoselectivity. On the whole, the endo approach of olefin to nitronate is stabilized by secondary orbital interactions but, at the same time, is destabilized due to steric hindrance. 

The authors (162) attempted to explain the stereochemical outcome of the reactions (Schemes 3.169 and 3.170) in the terms used earlier (337), that is, by steric factors, which destabilize the endo approach of a dipolarophile, and the electronic effect (secondary orbital interactions), which is most typical for electron-rich dipolarophiles and can slightly stabilize the endo approach of these olefins. 

Cycloaddition reactions using tropone or another cyclic triene as the 6ji partner have been abundantly described in the literature. It has been found that virtually all metal-free [6 + 4] cycloadditions of cyclic trienes afford predominantly exo adducts. This has been rationalized by consideration of the HOMO-LUMO interactions between the diene and triene partners. An unfavorable repulsive secondary orbital interaction between the remaining lobes of the diene HOMO and those of the triene LUMO develops during an endo approach. The exo transition state is devoid of this interaction (Figure 9). 

Subsequent monosilylation and Wittig reaction furnished unsymmetrical double diene 170. The synthesis of the other Diels-Alder partner started from bromophenol 173 (prepared in three steps from dimethoxytoluene), which was doubly metalated and reacted with (S,S)-menthylp-toluenesulfinate 173. CAN oxidation delivered quinone 171, which underwent a Diels-Alder reaction with double diene 170 to give compound 175 possessing the correct regio- and stereochemistry. Upon heating in toluene the desired elimination occurred followed by IMDA reaction to adduct 176, which was obtained in an excellent yield and enantioselectivity. Both Diels-Alder reactions proceeded through an endo transition state the enantioselectivity of the first cyclization is due to the chiral auxiliary, which favors an endo approach of 170 to the sterically less congested face (top face) (Scheme 27). 

Notice that the substituents present in the precursor play a crucial role in the choice of the transition state (exo or endo approach) and, ultimately, in determining the stereochemistry of the resulting cyclisation product, either 14a or 14b. 

To rationalize the enantioselectivity of the TADDOL-catalyzed HDA reaction between Danishefsky s diene and benzaldehyde, eight possible diastereomeric transition states of different regio- and stereochemistry should in principle be considered for comprehensive analysis. The cycloaddition between the model diene and benzaldehyde can take place along two regio-isomeric meta (C1-06, C4-C5 bond formation) and ortho (C1-C5, C4-06 bond formation) reaction channels. For both of these pathways, an exo- and an endo-approach can be formulated (Scheme 11) [64]. 

The energy of the localized transition state for the ortho route (uncatalyzed reaction) is 14kcal/mol higher than that of the meta channel. Therefore, the ortho channel can be excluded. Unlike the uncatalyzed transformation, the TADDOL-catalyzed HDA reaction exhibited a clear energetic preference for the endo- over the exo-approach. Thus, only endo transition states were considered. The number of possible reaction paths/transition states is thus reduced from eight to two, namely endo-approach with re- or si-face attack of the model diene to the activated benzaldehyde. 

I 5 Br0nsted Acids, H-Bond Donors, and Combined Acid Systems in Asymmetric Catalysis TS A endo approach)... 

The combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

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... 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

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