Diastereoselectivity fused bicyclic

Iodoetherification (vide supra) of ( )-aIlyl alcohols 99 followed by transannular radical cyclization in a 5-exo-trig mode was reported to provide ci s-fused bicyclic acetals with high diastereoselectivities. To illustrate, an example is given below <00SL1193>. 

Addition of Bu3Sn-GeBu3 to bis(allene)s occurs diastereoselectively in the presence of Pd(PPh3)4 to give cis-germastannative cyclization products along with m-fused bicyclic dienes (Equation (128)).297... 

Wender et al. s [5 + 2] metal-catalyzed annulation strategy has also been applied to the total synthesis of (+)-aphanamol I (154) [34]. The scope of this method was expanded by using a tetrasubstituted allene that resulted in the stereoselective formation of an angular methyl group. The reaction of allene 149 with 0.5 mol% of rhodium biscarbonyl choride dimer afforded the fused bicyclic product 152 in 93% yield with complete exo/endo and diastereoselectivity (Scheme 19.28). The stereoselectivity of this process was attributed to a preference for formation of the cis-fused metallo-... 

The scope of the reaction was subsequently expanded to the 1,3-dipolar cycloaddition of nitrones to cyclic a,/ -unsaturated aldehydes, allowing for the formation of fused bicyclic isoxazolidines (Scheme 3.7). Here, the use of catalyst 1 resulted in almost no reaction, whereas a proline-based diamine (9) afforded high levels of enantio-and diastereoselectivity [59, 60]. 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

The diastereoselectivity of the cycloadditions of 4-substituted 3//-l,2,4-triazole-3,5(4//)-diones to cis-fused bicyclic compounds A-I has been examined. 

Fused bicyclic morpholones 145 and 146 have been synthesized in good yields but with modest diastereoselectivity from 1,3-oxazolidines 144 via reaction of the nitrogen of the oxazolidine with a metallocarbene intermediate followed by a benzyl migration (Scheme 37) <2003TA917>. 

A plausible intermediate for the enantio- and diastereoselective addition of diethylzinc to a-thioaldehyde catalyzed by 20o is shown in Fig. 3-4. When 20o ((—)-DFPE) is used in the ethylation of the racemic aldehyde 41, the (li)-enantiomer reacts faster than the (5)-enantiomer and the newly produced stereogenic center from (P)-41 has the S-configuration. This stereochemical property can be reasonably explained by considering the 7/6-fused bicyclic intermediate depicted. Compound (P)-41 has lower steric hindrance than (S)-41 in the reaction complex and ethylzinc preferentially attacks from the Si face of (7 )-41 to afford the S-configuration. Therefore, (i )-41 reacts faster than (S)-41 to afford (3S,4R)-42. 

Equally successful stereocontrol has been achieved with secondary cycloalkyl diazoacetates where diastereoselectivity is associated with the formation of cis-and trans-fused bicyclic lactones. With cyclohexyl diazoacetate, Eq. (44) and Rh2(OAc)4 racemic lactones with only a small preference for the trans-isomer are formed (60 40). Use of chiral Rh2(5S-MEPY)4 led to diastereocontrol of only 3 1, but enantiocontrol was nearly complete (97% ee) in the cis-lactone. However, both high enantio control and nearly full diastereocontrol were realized with Rh2(4S-MACIM)4. Rh2(4S-MEOX)4, the oxazolinidinone analog of Rh2(5S-MEPY)4, catalyzed high enantio control, but little diastereocontrol [63]. Similarly high enantio- and diastereoselectivities have been observed with cyclopentyl, cycloheptyl, and cyclooctyl diazoacetates, with cis- or fra s-4-methylcyclohexyl diazoacetate (where preferential insertion into equatorial bonds leads to lactones (36) and (37) in Fig. 14) has been demonstrated [63,64] and with 2-ada-mantyl diazoacetate (Fig. 14, (38)) [21]. With these substrates Rh2(MEOX)4 catalysts achieved the highest levels of enantio control. 

In the case of the cyclic substrate 51, the intervention of a C-H insertion pathway reveals itself in terms of the diastereoselectivity, not regioselectivity. Thus, exposure of enyne 51 to the standard Ru catalyst at ambient temperature produced the transfused bicyclo[5.4.0]undecene 52 (Equation 1.60, path a) [55]. If a metallacycle mechanism was operative, coordination of the metal with both the alkene and alkyne must occur to form the cis-fused product. On the other hand, coordination of the Ru with the Lewis basic bridgehead substituent directs it to abstract an allylic C-H on the same face as the substituent, which then leads to the trans-fused product as observed. On the other hand, cycloisomerization using a Pd(0) precatalyst does indeed lead to the Z-fused bicycle (Equation 1.60, path b). 

Intramolecular hetero-Diels-Alder cycloaddition of A-acylimines 173 and 178, prepared in situ from an isomeric mixture of methylol acetates (172) by heating (81JA7573 84JA3240) or from chloroformate (177) and iv-trimethylsilylimines (176) derived from aldehydes 175 (91TL4371), respectively, diastereoselectively afforded only one type of the cycloaddition products 174 and 179, containing trans-fused bicycles. 

Annulation of five- and six-membered rings proceeds with excellent diastereoselectivity via an intramolecular Barbier-type process (eq 16). The Barbier-type coupling scheme provides a reliable and convenient alternative to other such methods for preparing fused bicyclic systems. 

The intramolecular reaction of vinyl-cyclopropanes tethered to alkenes 206 yielding fused bicyclic products 207 has also been applied to the [5-f2-l-l] cycloaddition (Scheme 92) (164). However, in this case, a low partial pressure of CO was found to be effective. Substrates with sulfonamides, ethers, and germinal diesters tethers were effective in the cycloaddition. In addition, substitutions on either the olefin component or the VCP component were also tolerated yielding 5-8 fused ring products with high diastereoselectivity. The ElZ olefin geometry... 

The diastereoselectivity in the Pd(II)-LiX-CuX2-catalyzed cyclization of 2 -alkenyl 2-alkynoates is similar to that in the Pd(II)-LiX-catalyzed cyclization of 4 -het-eroatom-2 -alkenyl 2-alkynoates. The similar diastereoselectivity was observed in the synthesis of a-alkylidene-y-butyrolactams. The diastereoselectivity is further supported by the cascade cyclization reaction. A monocyclic product was obtained in the reaction of l, 5 -hexadien-3 -yl propynoate. The failure of the second cyclization might be due to the trans-configuration of the /S.y-disubstituents in the product. The reaction of r,5 -hexadien-3 -yl 3-substituted 2-aIkynoates under the same conditions yielded the cw-fused bicyclic a-(Z)-chloroalkylidene- y-butyrolactone derivatives implying the cw-diastereochemistry of the /3,y-disubstituents in the first cyclization (Scheme 16). 

In the course of examining the chemistry of oxazolidines, Meyers developed diastereoselective alkylation reactions of fused, bicyclic lactams such as 91 (Scheme 3.15). The approach is particularly useful for the construction of a large array of molecules containing quaternary stereogenic centers [68]. The starting bicyclic lactams are readily prepared by condensation of chiral /3-amino alcohols such as 89 with keto acids 90 to give 91, which subsequently participates in diastereoselective alkylation reactions. Hydrolysis... 

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