Ene cyclization

Conceptually, intramolecular ene reactions [79] (ene cyclizations) can be classified into six different groups (Sch. 25) [45b,80]. In the ene cyclizations, the carbon numbers where the tether connects the [l,5]-hydrogen shift system are shown by the notation (m,n). A numerical prefix stands for the size of the ring being formed. 

Asymmetric catalysis of ene reactions was initially investigated for the intramolecular examples, because intramolecular versions are much more facile than their inter-molecular counterparts. The first reported example of an enantioselective 6-(3,4) car-bonyl-ene cyclization employed a BINOL-derived zinc reagent [81]. This, however, was successful only when excess zinc reagent (at least 3 equiv.) was used. An enantioselective 6-(3,4) olefin-ene cyclization has also been developed which uses a stoichiometric amount of a TADDOL-derived chiral titanimn complex (Sch. 26) [82]. In this ene reaction, a hetero Diels-Alder product was also obtained, the periselectivity depending critically on the solvent system employed. In both cases, geminal disubstitution is required of high ee are to be obtained. Neither reaction, however, constitutes an example of a truly catalytic asymmetric ene cyclization. 

We reported the first examples of asymmetric catalysis of intramolecular carbonyl-ene reactions of types (3,4) and (2,4) using the BINOL-derived titanium complex (1) [80,83]. The catalytic 7-(2,4) carbonyl-ene cyclization gives the oxepane with high ee, and gem-dimethyl groups are not required (Sch. 27). In a similar catalytic 6-(3,4) ene cyclization, the fram-tetrahydropyran is preferentially produced, with high ee (Sch. 28). The sense of asymmetric induction is exactly the same as observed for the glyoxylate-ene reaction—the (f )-BINOL-Ti catalyst provides the (R)-cyclic alcohol. 

Thus the chiral BINOL-Ti catalyst effects efficient chiral recognition of the enantio-face of the aldehyde and discrimination between the diastereotopic protons of the ene component in a truly catalytic fashion. 

Basic research on the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxy vitamin D3 (la,25(OH)2D3) has led to the development of an important new field in medicinal chemistry [84]. We have also reported symmetry assisted enantiospecific synthesis of the A-ring of the vitamin D hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 (Sch. 29) [85], It should be noted here that extremely high 1,3-frans selectivity was achieved by combining the (f )-BINOL-Ti catalyst and the (i )-ene substrate without geminal disubstitution. 

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Scheme 12. Trost s palladium(n)-catalyzed Alder ene cyclization process.

Alkenes can add to double bonds in a reaction different from those discussed in 15-19, which, however, is still formally the addition of RH to a double bond. This is called the ene reaction or the ene synthesis For the reaction to proceed without a catalyst, one of the components must be a reactive dienophile (see 15-58 for a definition of this word) such as maleic anhydride, but the other (which supplies the hydrogen) may be a simple alkene such as propene. Cyclopropene has also been used. ° The reaction is compatible with a variety of functional groups that can be appended to the ene and dienophile. N,N-Diallyl amides give an ene cyclization. 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acid-catalyzed) and a closely related Prins cyclization (B, Brpnsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460 06OBC51>. Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = f-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. 

The Alder-ene cyclization of allylic silyl ethers represents a clever use of cycloisomerization chemistry, as the enol ether products can be easily unmasked to yield aldehydes. Palladium-catalyzed cycloisomerization of 1,6- and 1,7-enynes containing an allylic oxygen most often gives rise to 1,3-dienes (see Section 10.12.4.1). However, enynes of type 63 underwent facile Alder-ene cyclization to the corresponding five- or six-membered rings (Equation (40)) using both [CpRu(MeCN)3]PF6 41 and the Cp analog ([Cp Ru(MeCN)3]PF6, 64).53... 

While palladium, ruthenium, and rhodium are the most common metal catalysts used to facilitate Alder-ene cyclization, a few successful examples of catalysis using different metals have been published. Both of the references reviewed in this section demonstrate chemistry that is novel and complimentary to the patterns of reactivity exhibited by late transition metals in the Alder-ene cyclization. 

While the transition metal-catalyzed Alder-ene reaction has been developed to offer excellent regio- and chemos-electivity, stereoselective variants have only recently begun to appear in the literature.58 The scope and limitations of many of these protocols have yet to be established. Nonetheless, several groups have published exciting examples of asymmetric Alder-ene cyclizations. 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

Weinreb86 has reported the Alder-ene cyclization of enallenes under thermal conditions (Equation (85)). Varying the substitution pattern of alkene and allene groups had little effect on the yield of cyclized product. One exception was a,/ -unsaturated ester 130(Equation (86)) cycloisomerization under thermal conditions led to the formation of the Alder-ene product 131 and the unexpected hetero-Diels-Alder product 132 in a 3 1 ratio. 

Ene catalyst.1 FeCl3 is superior to ZnBr2 or alkylaluminum halides as a catalyst for ene cyclization of the chiral 1,7-diene 1, the Knoevenagel adduct from citronellal and dimethyl malonate. Thermal cyclization provides the 1,2-trans-substituted... 

Allenyl ketones can undergo a Conia-ene cyclization, as shown in Eq. 13.56 [65]. Heating ketone 166 at 275 °C for 15 min leads to acetylcyclopentene 168 in 70% yield. Cyclization presumably takes place through a pericyclic mechanism involving enol 221. 

Enal (54) undergoes intramolecular carbonyl-ene cyclization to give cis- and trans-alcohols (55). Lewis acids such as boron trichloride and tin tetrachloride (and also dimethylaluminium chloride ) give predominantly the cis product, while the preference is reversed with the bulky MeALAr2(Ar = OC6H2 -Br-2, 6-di-Bu ). Open and closed chair-like transition states are considered and compared with previous... 

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

Xia, Q. Ganem, B. (2001) Asymmetric taal synthesis of (-)-o-kainic acid using an aiantioselective, metal-promoted ene cyclization. Org. Lett., 3, 485-7. 

Two papers describing the intramolecular ene cyclization for the preparation of C6 functionalized pteridines has appeared. Thus 4-amino-5-nitrosopyrimidines such as 249 reacted with a,/3-unsaturated acid chlorides acylating at the 6-amino group group to afford nitrosoamides 250 which on thermolysis in toluene underwent the pericyclic cyclization and subsequent loss of water to afford a mixture of the E- and Z-isomers of the 6-oxopteridine 251 in good yield <2006HCA1140, 2007HCA521>. 

Hydrolysis of the enamine 14 furnishes citronellal (15) in high optical purity (ca. 99% ee) which gives 17 via ene cyclization with zinc bromide as catalyst. The diastereoselectivity of this step is the result of simple diastereoselection in a trans-decalin-like transition state 16. Catalytic hydrogenation converts the olefin 17 into (—)-menthol (18). Despite its elegance this novel route has not been able to replace the older resolution-based procedure described earlier in this section. 

Additionally, some Pd-catalyzed type II zinc-ene cyclizations have been described. When the allylic acetate 181 was treated with EtiZn in the presence of a catalytic amount of Pd(PPh3)4, its slow conversion to a cyclic organozinc species by a type zinc-ene reaction was observed and iodinolysis afforded the six-membered ring 182 in relatively low yield. The regioselectivity was noteworthy as C-C bond formation occurred at the most substituted terminus of the allylmetal. By contrast, the type II palladium-ene cyclization of the allylic acetate 181, in conjunction with a /1-elimination process, proceeded with opposite regioselectivity and led to the six-membered ring 183 (equation 88)114. 

The 5-9-5 skeleton was assembled by the addition of the alkenyl cerate derived from 6 with the ketone 4, to give 7. -Cope rearrangement then gave the 5-9-5 enolate, which was quenched with methyl iodide to give 8. The ketone 8 underewent spontaneous intramolecular ene cyclization, to give 9. 

Ziegler et al. have reported the asymmetric desymmetrization approach to the synthesis of tricothecene, anguidine, via an ene cyclization (Scheme 8C.11) [31], The (2,4) ene cyclization (vide infra) of the prochiral aldehyde on silica gel gives a 1 1 diastereomeric mixture. Cyclization with purified Eu(fod)3 as Lewis acid catalyst gives an 8 1 mixture. The major isomer is a potential intermediate for the synthesis of anguidine. However, use of (+)-Eu(hfc)3, (+)-Eu(dppm)3, or (S)-BINOL-TiCl2 complex as chiral Lewis acid affords the major product with only 20-38% ee. 

Scheme 8C.17. Asymmetric ene cyclization catalyzed by TADDOL-Ti complex.

Scheme 8C.18. Asymmetric 7-(2,4) carbonyl-ene cyclization catalyzed by BINOL-Ti complex.

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