Reductive aldol cyclization

Chiu et al. developed a catalytic reductive aldol cyclization of alkyne-diones such as 115 and 117 using [Ph3PCuH]6 (10mol%) as catalyst and polymethylhydrosiloxane PMHS (200 mol %) as terminal reductant. The... 

Reductive Cyclization of Activated Olefinic Carbonyl Compounds 10.10.3.2.1 Reductive aldol cyclization... 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

Most recently, reductive aldol cyclization catalyzed by In(OAc)3 in the presence of PhSiH3 was reported.50 This catalytic system is applicable to both aldehyde and ketone acceptors. As demonstrated by the reductive cyclization of 65a and 68a, cycloaldol products are produced in good yields and excellent ry -diastereoselectivity (Scheme 48). 

Table 22.2 Catalytic hydrogen-mediated reductive aldol cyclization of keto-enones.

Apart from this work, Krische has also developed Co- and Rh-catalyzed 1,4-reduction-aldol cyclizations where a hydrido-metal species adds to an enone moiety before aldol cyclization [85,86]. 

Scheme 29 Reductive aldol cyclization of alkyne-diones catalyzed by Stryker s reagent...

In the early 2000s, Krische and co-workers reported a series of reductive aldol cyclization using molecular hydrogen as the reductant (Scheme 2-86). This method represents a novel approach to reductive aldol cyclization, which differs from traditional literature methods that use hydrosilane and diethylzinc as terminal reductants.f ... 

Scheme 2-86. Reductive aldol cyclizations using molecular hydrogen as reductant.

Scheme 2-87. Rh-catalyzed reductive aldol cyclization imder hydrogenation conditions.

Scheme 2-88. Rh-catalyzed reductive aldol cyclizations of enone-aldehyde.

The reductive aldol cyclization of enone-ketone substrate 550c, wherein the aromatic enone moiety is tethered to a ketone moiety, afforded five- and six-membered ring products 551c in good yields and excellent diastereoselectivities (dr > 95 5) (Scheme 2-89). In the reaction, however, considerable amounts of the reduced products 554c were formed. ... 

While the reductive aldol cyclization products of keto-enones were accompanied by significant amounts of 1,4-reduction products, use of a 1,3-dione as the coupling partner proved to be efficient in attenuating the conjugate reduction pathway. The dione moiety is a more reactive electrophile than are simple ketone moieties because of its inductive effects and relief of dipole-dipole interactions of the two carbonyls. The reaction of dione-containing substrates 552 under the standard reaction conditions led to the formation of bicyclic aldol products 553 with excellent diastereoselectivity (>95 5) without formation of the 1,4-reduction product in most cases (Scheme 2-90). Reactions of enal-ketones 552 were also studied. Under optimal reaction conditions, five- and six-membered ring products 553 were formed accompanied by a moderate quantity of the conjugate reduction products. Representative results are summarized in Table 2-12. 

Scheme 2-90. Rh-catalyzed reduction aldol cyclization of enone-dione.

A proposed mechanism for the Rh-catalyzed reductive aldol cyclization of enone/enal-ketone/aldehyde 550A ( = 1) is illustrated in Figure 2-25. Oxidative addition of hydrogen is followed by deprotonation to generate Rh-monohydride... 

Figure 2-25. Proposed mechanism for the Rh-catalyzed reductive aldol cyclization.

Scheme 11.31 Domino reductive aldol cyclization of functionalized a,P-unsaturated ester [50].

Scheme 11.33 Desymmetrical reductive aldol cyclization of enethioate of 1,3-dione [52].

Lipshutz and co-workers have developed an enantioselective version of the silane-mediated intramolecular reductive aldol cyclization catalyzed by Cu complexes (Scheme 112) (182). The reaction of enones 251 with Cu-Josiphos complexes L3 or L4 in the presence of diethoxymethylsilane (DBMS) gave a single diastereomers of the products 252 in high enantiomeric excess (up to 98% ee). 

Villanueva Margalef, L, Rupnicki, L., and Lam, H.W. (2008) Formal synthesis of salinosporamide A using a nickel-catalyzed reductive aldol cyclization-lactonization as a key step. Tetrahedron, 64, 7896-7901. 

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