Aldol reagent-controlled

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The chiral borane 3f-mediated aldol reaction proceeds with a-chiral aldehydes in a reagent-controlled manner. Both enantiomers are obtained almost optically pure from one racemic aldehyde (Eqs 53 and 54) [43d]. 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

Important limitations were observed with regard to reagent control in reactions with highly sterically hindered aldehydes involving a chiral hydroxy function at the p position (Eq. 58) [43g]. When (S)-3f was used for 32, diastereo- and enantioselectivity were less satisfactory. When (l )-3f was used, however, the reaction proceeded more smoothly to give the corresponding aldols with moderate syn selectivity in 87 % yield. Each of the isomers obtained was almost enantiomericaUy pure. The spatial orienta-... 

The smallest member of such homologous series are the 2,3-dihydroxy succinic (tartaric) dialdehydes. Three stereoisomeric forms are possible, i. e. one meso (erythro) and two enantiomeric (d- and L-threo) compounds (i. e. 3). Because of the enantiotopic nature of the termini of a meso chain, any twofold aldol addition under reagent control imposed by the same chiral biocatalyst would eliminate the element of cj-symmetry and thus effect a terminus differentiation (cf. Scheme 4). For the same reason, enzymes that cannot easily differentiate the two enantiotopic aldehyde groups would lead to the formation of two different. 

The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiomer of 50 that was used in the previous aldol reaction. The stereochemistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome of the reaction ... 

The linear synthesis of the title compound started from an enantiopure building block with one stereogenic center. The other six stereogenic centers were introduced by two reagent-controlled Evans aldol reactions, an unselective 1,3-dipolar cycloaddition with subsequent separation of the diastereomers, and a substrate-controlled epoxidation step. 

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. 

Kiyooka et al. have reported that stoichiometric use of chiral oxazaborolidines (e.g. (S)-47), derived from sulfonamides of a-amino acids and borane, is highly effective in enantioselective aldol reactions of ketene TMS acetals such as 48 and 49 (Scheme 10.39) [117]. The use of TMS enolate 49 achieves highly enantioselective synthesis of dithiolane aldols, which can be readily converted into acetate aldols without epimerization. The chiral borane 47-promoted aldol reaction proceeds with high levels of reagent-control (Scheme 10.40) [118] - the absolute configuration of a newly formed stereogenic center depends on that of the promoter used and not that of the substrate. 

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Our final highlight in the discodermolide synthesis is the use of reagent control to get what we want and not what the molecules want. The combination of enol borinate 276 and an aldehyde 277 featuring a cis double bond, led to the formation of aldols anti- and syn-278. A model study had shown that the inherent selectivity with these enals could be improved by the use of ( )-Ipc groups on boron instead of cyclohexyl but it is not the selectivity that was wanted. (+)-Ipc groups were able to turn around the selectivity and improve the yield of the reaction while they were at it.50... 

This complex aldol coupling requires the use of reagent control to reverse the intrinsic substrate selectivity, i.e., it is a mismatched reaction. ... 

Under either the catalytic (eq 1) or the stoichiometric conditions (eq 2), the reagent undergoes addition to chiral aldehydes with complete reagent control , i.e. the stereochemistry of the aldol reaction is totally controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the chiral aldehydes (eq 4). Titanium(IV) chloride and tm(TV) chloride mediate the addition of the title reagent to chiral a-alkoxy aldehydes and -alkoxy aldehydes with complete chelation control (eq 5), whereas the corresponding silyl ketene acetal is unselective. 4... 

Scheme 3.48 Reagent-controlled enantioselective homo-aldol reaction with chiral 1-oxyallyllithium derivatives.

As disclosed already by Reetz and coworkers, the inherent diastereofacial selectivity of the a-aminoaldehydes Hke 288 can be overridden in reagent-controlled aldol additions mediated by diphenylborolane 282b [143b]. In an analogous... 

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... 

Whereas the examples above used substrate control for stereoselective transannular aldol or related reactions, reagent control has also been reported for the transannular aldol reactions. One example is synthesis of the musk ordorants (R)-muscone and (R,Z)-5-muscenone by Knopff and co-workers. It involved enantioselective formation of 73 by the transannular aldol condensation of the symmetrical macrocyclic 1,5-diketone 72 using sodium ephedrate for desymmetrization (Scheme 20.19). The reaction was assumed to proceed by a reversible transannular aldol reaction followed by an enantioselective dehydration reaction. 

---