Endo-Stereoselectivity

Catalyst H and the corresponding N-(l-naphthylmethyl) derivative I give high e.e. and good endo stereoselectivity for several typical dienophiles with cyclopentadiene. 

Goldstein, E., Beno, B., Houk, K. N., 1999, Transition Structures and Exo/Endo Stereoselectivities of Concerted [6+4] Cycloadditions with Density Functional Theory, Theor. Chem. Acc., 103, 81. 

The [4+2] cycloaddition of 2-amino-l-thia-3-azabutadienes, for example, 652, formed in situ from W-(trimethylsilyl)-imines and PhNCS, and PTAD leads to the regioselective formation of cycloadducts 653 with complete endo-stereoselectivity (Equation 96) <1995S985>. 

Reaction of adduct 167 with excess cyclopentadiene 131 occurred with high exo,endo-stereoselectivity to furnish isomeric 2 l-adducts 168 (sy/i-isomer) and 169 (anti-isomer) (ratio 1 5), which could be separated by chromatography. These isomers contained the same ring structure and differed only by the relative geometry of the N-Z groups. Each N-Z bridge was... 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

Overman, L.E., Petty, C.B., Doedens, R.J. Synthetic application of N-(acylamino)-1,3-dienes. Control of endo stereoselectivity by the acyl substituent, stereospecific synthesis of the analgesic tilidine, J. Org. Chem. 1979, 44, 4183-4185. 

Intermolecular meta photocycloaddition of cycloalkenes to benzene rings occurs with marked endo stereoselectivity, although the exo process would be favored on purely steric grounds. Because of intramolecular anomalous stereoselectivity, the exo process is often feasible [55] (Scheme 55). 

Griesbeck, A.G. and Stadtmuller, S. (1990) Photocycloaddition of benzaldehyde to cyclic olefins electronic control of endo stereoselectivity. Journal of the American Chemical Society, 112, 1281-1283. 

Quadrelli, P Romano, S. Toma, L. Caramella, P. A bispericyclic transition structure allows for efficient relief of antiaromaticity enhancing reactivity and endo stereoselectivity in the dimerization of the fleeting cyclopentadienone, 7. Org. Chem. 2003, 68, 6035-6038. 

However, the cyclodimerization of 1,3-cyclohexadiene and also the addition of the cis,cis isomer of 2,4-hexadiene to 1,3-cyclohexadiene are only modestly stereoselective. The addition of cis,rra i-2,4-hexadiene to 1,3-cyclohexadiene is highly stereoselective for the addition to the lra s-propenyl group, but only modestly stereoselective for the addition to the cw-propenyl group. Further, the addition of a dienophile having a pendant, unsubstituted vinyl double bond to this diene is also highly endo stereoselective. The installation of a cis group at the terminus of the dienophilic moiety consistently appears to reduce the endo stereoselectivity to a more modest level. It has been proposed that the cis substituent attenuates the secondary interaction involving the endo double bond in the transition state for cycloaddition [47, 48]. The effect has been termed the cfs-propenyl effect . The addition of the ira j-anethole cation radical to both 1,3-cyclohexadiene and 1,3-cyclopentadiene is, however, only moderately diastereospecific (ca 3 1) [49]. 

Several groups have examined the exo/endo stereoselectivity of thioaldehyde cycloadditions. f- > Scheme 23 outlines some of the methods used for in situ generation of thioaldehydes and selected stereochemical results with cyclopentadiene. As can be seen, these reactions generally give a predominance of endo products kinetically. Vedejs has rationalized this outcome as arising from steric factors. 

More impressively, azadienes, such as 59, that could tautomerise to enamines 58 also give good yields of adducts 60 with high regioselectivity and endo stereoselectivity. 1-Azadienes are still not easy to use but enough methods are now available to make heterocycle synthesis by this route a practical proposition. 

In contrast, other reactions are endo selective, as in the cycloaddition 6.354 of an azomethine ylid to dimethyl maleate giving largely (80 20) the endo adduct endo-6.355.869,870 Thus the stereoselectivity depends in a not always predictable way upon the dipole, the dipolarophile and their substituents, in contrast to Diels-Alder reactions, which more often than not obey the endo rule. It is advisable, when planning a synthesis, to look up close analogies before relying upon the exo or endo stereoselectivity of a 1,3-dipolar cycloaddition. 

The high endo selectivity of aromatic aldehydes is also a result of their capability to participate in secondary orbital interactions. The mixing of the LUMO of benzaldehyde with the HOMO of the diene can form secondary orbital overlap which lowers the energy of the endo transition state. The electron-withdrawing effect of the catalyst [e.g. Eu(fod)3] on the aldehyde further enhances secondary orbital overlap with aromatic aldehydes by an additional reduction of the LUMO energy (Figure 2). Similar arguments have been made to rationalize the increase in endo selectivity of homo Diels-Alder reactions when Lewis acids are used as catalysts.Secondary orbital interactions are, however, absent when the dienophile is an aliphatic aldehyde in such reactions the cis (endo) stereoselectivity is based solely on steric interactions. 

These intramolecular C-4-alkenyl nitrone cycloaddition reactions afford m-fused products with complete endo stereoselection. The induced stereoselection is also high and may be rationalized by the assumption that the transition structures with the bulkier substituent(s) at the stereocentcr(s) in a pseudo-equatorial position are favored over those with these groups in the pseudo-axial position. In conformationally mobile acyclic systems this generally results in a trans arrangement between the preexisting stereocenter and the newly formed stereocenter. This tendency seems compelling for x-substituted nitrones. In cyclic systems steric factors dictate the stereochemical outcome of the reaction. 

The endo stereoselectivity ( > 95%), the preservation of dienophile olefin geometry, and the enhanced reactivity of ( )-l-ethoxypropene versus (2)-1-ethoxypropene [k(E) k(Z) = 35] in the [4 + 2] cycloadditions of 2-ace-tylcyclohex-2-enone with electron-rich olefins have been interpreted as being consistent and characteristic of a concerted inverse electron demand Diels-Alder reaction [Eq. (19)].104... 

A highly diastereoselective 1,3-dipolar cycloaddition of a nitrone employing the sultam auxiliary has been used in the synthesis of 215, a major metabolite of nicotine <04T9997>. i-gulose-derived nitrone 212, upon treatment with a, P-unsaturated sultam (25)-213, undergoes 1,3-dipolar cyeloaddition to afford the isoxazolidine 214 with high endo stereoselectivity, which is further elaborated to hydroxycotinine (-i-)-215. 

An appreciation of the ability of 48 to attain appreciable levels of double diastereoselection when reacted with chiral (racemic) vinyl organocerium reagents had earlier been gained in this laboratory [32]. Consequently, it occasioned no surprise to observe that 49 [33] adds to this bicyclic ketone with customary endo stereoselectivity to deliver 50 and 51 in a relative ratio of 92 8. The major product, easily purified by chromatographic means, was smoothly isomerized to 52 under anionic conditions at room temperature. For structural reasons, this sigmatropic change is required to proceed via a boat-like transition state. The all-... 

Fig. 10.6. Effect of the polarity of the medium on endo stereoselectivity in the cycloaddition of methyl vinyl ketone to furan at 300 MPa.

This complexation accentuates both the energy and orbital distortion effects of the substituent and enhances both the reactivity and selectivity of the dienophile relative to the uncomplexed compound. Usually, both regioselectivity and exo,endo stereoselectivity increase. Part of this may be due to the lower reaction temperature. However, the catalysts also shift the reaction toward a higher degree of charge transfer by making the EWG substituent more electrophilic. 

Computations have also been applied to the analysis of exo endo ratios. The computed differences in energies of the exo and endo TS are often small and are subject to adjustments when solution models are used. Cyclopentadiene has been a common subject, since there is more experimental data for this compound than for any other. MP3/6-31G -level computations were used to compare the exo and endo TS for the reactions with acrylonitrile and but-2-en-3-one (methyl vinyl ketone), and ZPE and thermal corrections were included in the calculations. Good qualitative agreement was achieved with the experimental results, which is little stereoselectivity for acrylonitrile and endo stereoselectivity for but-3-en-2-one. 

The extent of this interaction is different in the endo and exo TSs and contributes to the enhanced endo stereoselectivity that is observed in catalyzed reactions. This structural feature is consistent with the catalyzed reaction having more extensive charge transfer, owing to the more electrophilic character of the complexed dienophile. In the limiting case, the reaction can become a stepwise ionic process. 

Ujaque, G. Lee. P.S. Houk, K.N. Henteniann. M.F. Danishefsky. S.J. The origin of endo stereoselectivity in the hetero-Diels-Alder reactions of aldehydes with ortho-xylylenes CH-tc, tc-tc, and steric effects on stereoselectivity. Chern. Eur, J. 2002. 8. 3423-3430. 

Cycloaddition between the electron-rich, 2-substituted NBD 20 and acrylonitrile (AN) or N-phenylmaleimide (NPM) exclusively forms [2 + 2] adducts (Scheme 23). Unlike the cycloadditions with electron-deficient norbomadienes (19 and 41), which give the major adduct with an exo-(cis-anti-cis)-geomctry (exo-39 and 42), cycloaddition with electron-deficient NBD 20 affords the endo-(cis-anti-cis)-zddacts (43 and 44) as the major product. As shown in Scheme 23, improvement in the endo stereoselectivity to 12 1 is achieved by changing the phosphine from PPhj to P(OPh)3, but unfortunately, this increase occurs at the expense of the yield. 

Cycloadditions of the Parent Dienes 2a and 2p. The results are summarized in Table I. First, it must be noted the considerable rate enhancements of the aqueous cycloadditions using the unprotected dienes 2 (3.5 hrs at room temperature with methacrolein) were observed when compared with the corresponding cycloadditions conducted in toluene with the peracetylated dienes 8 (168 hrs at 80°C with the same dienophile). Second, a virtually complete endo stereoselectivity was obtained in water... 

It reacts with traws-piperylene with high regioselectivity and endo stereoselectivity no exo product is observed (Table 30.6) [23]. However, the major isomer is reversed from that observed with vinyl-9-BBN, which has afforded only meta substituted products [5]. 

In the Diels-Alder reactions of some 1,4-disubstituted cyclopentadienes with a variety of terminal olefin dienophiles a linear relationship between log(fc,ei) og endo/exo) is found. The substantial deviation from the linear correlation in the cases of maleic anhydride and N-phenylmaleimide, where a higher endo-stereoselectivity is observed than is expected from the k,ei values, is ascribed to the double secondary orbital interactions that can occur with these two cyclic dienophiles. It is difficult, however, to see how one can ignore the appreciable differences in steric effects between dienophiles of different types. 

However, these aUcenylboronic esters can be considered as poor dienophiles compared to the corresponding dialkylboranes since hi temperatures were generally required to afford cydoadducts with low regio- and stereoselectivities. The great reactivity of vinyldialkylboranes in Diels-Alder reactions cannot be rationalized by means of FMO theory and the high endo stereoselectivity suggests the presence of an important [4+3] interaction in the transition state. This hypothesis has been confirmed by ab initio calculations [47a]. 

Similarly, 3-nitrocoumarin (9) behaves as An component in the cycloaddition reactions with electron-rich dienophiles such as ethyl vinyl ether (61), 2,3-dihydrofuran, and 3,4-dihydro-2H-pyran. Under solvent-free conditions and in organic solvent (DCM, CH3COCH3, PhH), the reactions are totally regio- and endo-stereoselective. For example, the cycloaddition of 9 with 61 gives only the adduct 67 with 90% yield (Scheme 5.18). 

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