Reduction substrate-controlled

Most recently new applications for substrate-controlled branched-selective hydroformylation of alkenes substituted with inductively electron-with drawing substituents have emerged. A recent example is the hydroformylation of acrylamide with a standard rhodium/triphenylphosphine catalyst, which yields the branched aldehyde exclusively (Scheme 4) [40]. Reduction of the aldehyde function furnishes 3-hydroxy-2-methylpropionamide, which is an intermediate en route to methyl methacrylate. 

Hydrogenation of diacetyl (5) catalyzed by (S)-l-Ru gives a 74 26 mixture of meso-6 and S,S-6. Evidently in this reduction catalyst control favoring formation of meso-diols dominates over substrate control favoring formation of / or d-diols. 

This is a LiAlH4 reduction of the a,(3-unsaturated ketone of the seven-membered ring. The low temperature and the use of only 0.25 eq. of LiAlH4 ensures that only the fastest reaction takes place and no reduction of the ketone in the five-membered ring or of the double bonds is observed. This reduction proceeds with substrate control of the diastereoselectivity, because the hydride attacks the molecule mainly from its convex and not from its concave face. This becomes clear when looking at 44 which is a three-dimensional representation of 31. Whether the diastereomeric ratio of 10 1 is important, will become clear in the further synthesis. 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

An alternative strategy has been used by ourselves in the synthesis of the aply-ronine macrocycle 166, whereby chiral ketones 167 and 168 were used in two substrate-controlled aldol reactions (Scheme 9-49) [67]. Following reduction, this... 

Our synthesis of the C1-C7 fragment 227 of oleandolide started with a substrate-controlled tin-mediated aldol reaction of a-chiral ketone (5)-18 which afforded syn adduct 52 with 93% ds. This same transformation could also be achieved using reagent control with (Ipc)2BOTf, albeit with lower selectivity (90% ds). In a key step, treatment of the aldol adduct 52 with (-i-)-(Ipc)2BH led to controlled reduction of the C3 carbonyl together with stereoselective hydrobora-tion of the C -Cv olefin, affording the desired triol 228 with 90% ds. 

Paterson reported a total synthesis of (+)-leucascandrolide A (199) in which essentially complete control over all of the stereochemistry is achieved. As outlined in Scheme 61, two Mitsunobu reactions were employed for macro-cyclization and installation of the side chain. The two ds-alkenes in the side chain were introduced by double Lindlar hydrogenation in the final stage. The oxygenated stereogenic centers on seco-acid 286 were constructed by reduction at C17 and C9, C-glycosidation at C15, and l,5-a ti-aldol reaction at Cll, all of which were by using substrate control. The 2,6-cis-tetrahydropyran in 287 was synthesized by the asymmetric hetero Diels-Alder reaction. 

The synthetic plan for leucascandrolide A by Paterson and co-workers in 2003 involved the incorporation of all oxygenated stereocenters in a substrate controlled manner. The synthesis began with the construction of the 2,6-cw-tetrahydropyran. An asymmetric hetero-Diels-Alder reaction of silyloxy diene 2.122 with aldehyde 2.121, catalyzed by the Jacobsen chromium Schiff base complex [116], afforded 2,6-cw-tetrahydropyranone 2.123 (80 %, dr >20 1, ee >98 %). Reduction of the... 

The final C—C bond forming step turned out to be a mismatched boron enolate aldol reaction. Nevertheless, the use of (-l-)-DIPCl as a stereochemical inducer guaranteed the disposition for reagent control versus substrate control. Required product 324a was isolated in approximately 60% yield after chromatography on reverse-phase silica gel. The Evans group anti-reduction of the newly obtained aldol product gave substance 325, which was totally deprotected... 

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