Asymmetric synthesis first-generation, examples

Two classes of intramolecular reactions, types I and II, were established using this methodology (Figure 3). The type I reaction provides access to fused bicycles, whereas the type II reaction generates bridged bicycles. For example, the first asymmetric synthesis of a... 

This was the first unexpected example of the combined acids system for asymmetric synthesis (Scheme 10) [20]. It is known that coordinatively unsaturated monomers are far more Lewis acidic than doubly bridged coordinatively saturated dimers [21]. A mono-coordinated complex, however, can be generated in some cases and is even more Lewis acidic than the monomer through the formation of a singly bridged dimer. This species is the combined acid catalyst. 

The concept of high-resolution reaction time control using a flow microreactor system can also be effectively applied to asymmetric synthesis. In some cases, enantiomerically enriched intermediates can easily be isomerized (racemized) reducing the enantioselectivity of the reaction. Batch reaction would often give products with low enantiomeric purity because of such isomerization. Flow microreactor system, however, could allow the formation of products with high enantiomeric purity by first generating the intermediates and then promptly using it in subsequent reactions before isomerization. An example of such synthesis will now be described. 

Significant improvement in the catalytic activity of ALB was realized without any loss of enantioselectivity by using the second-generation ALB [27] generated by the self-assembled complex formation of ALB with alkali metal-malonate or alkoxide. This protocol allowed the catalyst loading to be reduced to 0.3 mol %, for example, the Michael addition of methyl malonate to cyclohexenone catalyzed by the self-assembled complex of (ff)-ALB (0.3 mol %) and KO Bu (0.27 mol %) in the presence of MS 4A gave the adduct in 94% yield and 99% ee [28]. This reaction has been successfully carried out on a 100-g scale wherein the product was purified by recrystallization. The kinetic studies of the reactions catalyzed by ALB and ALB/Na-malonate have revealed that the reactions are second-order to these catalysts (the rate constant ALB = 0.273 M 1h 1 ALB/Na-maionate = 1-66 M 1h 1) [27]. This reaction was used as the first key step for the catalytic asymmetric total synthesis of tubifolidine (Scheme 8D. 11) [28]. 

Two principal approaches to the synthesis of an optically pure chiral secondary or tertiary alcohol from the reaction of an organometallic reagent with an aldehyde or ketone respectively are of current interest. In the first approach an alkyllithium or dialkylmagnesium is initially complexed with a chiral reagent which then reacts with the carbonyl compound. In this way two diastereo-isomeric transition states are generated, the more stable of which leads to an enantiometic excess of the optically active alcohol. This approach is similar in principle to the asymmetric reductions discussed in Section 5.4.1 (see also p. 15). Two chiral catalysts may be noted as successful examples, (10) derived... 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

The synthesis of HBT (73), which contains three [5]helicene units, illustrates the power of the cyclotrimerization of polycyclic arynes for the synthesis of he-licenes. More examples are shown in Table 2. Again, Pd2(dba)3 is the catalyst of choice for trimerization of the asymmetric arynes 77-79, which are generated from the corresponding o-(trimethylsilyl)aryl triflates 74-76. In the reactions of 1,2-didehydronaphthalene (77) and 1,2-didehydrophenanthrene (78), mixtures of regioisomers are obtained, whereas 84 is the only isomer isolated from the cyclotrimerization of 79. Compounds 80 and 82 contain a [5]helicene unit, while compound 84 is the first example of a double helicene formed by a pen-tahelicene and a heptahelicene with two rings in common. 

Kanai and colleagues developed an enantioselective synthesis of various 2-(2-hydroxyethyl)indole scaffolds via the amido-cupration of allenes followed by the asymmetric addition of carbonyl compounds. Treatment of allene 88 with a copper catalyst forms a stable and highly nucleophilic allyl-copper species, which then adds into benzaldehyde (89) to furnish indole 90. A range of carbonyl compounds are competent in the sequence, including aryl- and heteroaryl aldehydes, alkyl aldehydes, and aryl ketones. This is reported to be the first example of a combined catalytic indole generation and subsequent enantioselective addition of carbonyl compormds (14CS1585). 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

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