Double aldol reaction strategy

The double aldol reaction strategy can also be used in conjunction with palladium-mediated reductive animation to produce tetrahydroxy pyrroli-zidine alkaloids, including 3-epiaustraline, australine, and 7-epialexine (Scheme 5.26(b)).47b These alkaloid natural products are active as glyco-sidase inhibitors. 

Strategy In the aldol reaction, H2O is eliminated and a double bond is formed by removing hvo hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner. The product is thus an a,/3-unsaturated aldehyde or ketone. 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

In addition to the consecutive aldol reactions of aldehydes, Barbas s group also reported enamine-activated Diels-Alder reactions (or double Michael reactions) between a,P-unsaturated ketones and nitroolefm (Scheme 1.15) for the first time in 2002 [17], hi contrast to MacMillan s iminium catalysis for Diels-Alder reactions, wherein a,P-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3], an alternative strategy involving the in situ generation of 2-amino-1,3-dienes from a,P-unsaturated ketones... 

In investigations of double diastereodifferentiating Mukaiyama aldol reactions, Evans demonstrated that the coupling of end silane 195 either to aldehyde 196 or to aldehyde 198 affords the Felkin products 197 and 199, respectively, with excellent diastereoselectivity (Scheme 4.21) [36]. Because of the involvement of open transition states in these aldol reactions, no direct correlation was found between the starting end silane geometry and the observed simply selectivity (syn versus anti). This contrasts with the simple diastereoselectivity typically observed for cis- and trans-metal enolates that react through cyclic Zimmerman-Traxler transition states. By this strategy, the addition of enol silane 201 to 200 provided an advanced intermediate 202 in the synthesis of 6-deoxyerythronolide B (187, Scheme 4.22) [97]. 

Masamune et al. have reviewed in detail the effects of double asymmetric induction not only for epoxidation, but also for the aldol, Diels-Alder, and catalytic hydrogenation reactions. The merits of this strategy are illustrated by an analysis of Woodward s synthesis" of erythromycin A (1), which has 10 chiral centers. 

The 1-methoxy-2-oxo-3.4-didehydro-1,2-dihydro-vi end group occurs in such carotenoids as spheroidenone and 2,2 -diketospirilloxanthin (199), which possesses a conjugated system of 15 double bonds. 2,2 -Diketospirilloxanthin (199) was synthesized via a C5 + (Cio + Cio + Cio) + C5 = C4o strategy [95]. The central Cao-building block 200 was obtained by a Wittig reaction between two moles of phosphonium salt 201 [96,97] and 15,15 -didehydro-12,12 -diapo-carotene-12,12 -dial (48). Aldol condensation of 200 with two moles of 3-methoxy-3-methylbutan-2-one (202) and NaOH, and then partial hydrogenation in the presence of Lindlar catalyst led to 2,2 -diketospirilloxanthin (199) in an overall yield of 38% referred to 202 Scheme 45). 

The unusual chiral (3-methoxy-y-amino acid dolaproine (Dap) is the most complex unit of dolastatin 52, which has a remarkable antineoplastic activity and is now in Phase II human cancer clinical trials. Many synthetic strategies such as aldol condensation and a cobalt-catalyzed Reformatsky reaction have been employed in its synthesis. Almeida and Coelho have demonstrated a stereoselective synthetic method for A-Boc-dolaproine (53) through a sequence of MBH reaction, a diastereoselective double bond hydrogenation and hydrolysis of the ester functional group (Scheme 5.8). ... 

---