Aminoindanol auxiliary

Saigo et al. reported a related approach to absolute asymmetric induction by use of an aminoindanol auxiliary (Scheme 4.43) [45]. Treatment of the allyl glycinate with NaHMDS and the unusual silylating agent HSiMejCl gave 92 8 ratio of C2 stereoisomers. The authors proposed that an -silyl ketene acetal was formed and adopted the conformation shown to minimize dipolar interactions. Approach of the allylic alkene from the more sterically accessible face of the oxazolidine would then yield the observed product. The authors did not indicate how the auxiliary would be removed. 

The phosphodiesterase (PDE) IV inhibitor (109, Scheme 2.17) has been identified by Merck Research Laboratories as a potential lead for the treatment of asthma. Although an early synthesis of 109 relied on the use of Oppolzer s chiral sultam auxiliary, a more economic approach was subsequently developed that exploited an aminoindanol auxiliary. In the revised synthesis, the car-boxyhc acid 103 (available in two steps from isovanillin) is coupled with (15,2/ )-cis -aminoindanol 12 and subsequently converted into the amide 104. After protection of the amino alcohol, reaction of the resulting Michael acceptor 106 with phenyllithium 107 and subsequent... 

Chiral carboxyamides derived from acid chlorides and A-chiral cA-aminoindanol can be protonated and Li Cu transmetallated to generate copper enolates which react with A-lithium derivative of A-Boc-O-tosylhydroxylamine (LiBTOC) 31 to give a-A-Boc amino carboxamides in high yields and enantiomeric excess (Scheme 38) . The chiral auxiliary can be removed by acidic hydrolysis to obtain the a-aminocarboxylic acid. 

A wide variety of chiral auxiliaries are available to prepare amino acids (Chapter 23). The most popular are oxazolidinones, a-amino acids, aminoindanol (Chapter 24), imidazolidones, and pseu-doephedrine.7 Oxazolidinones 5 have found widespread usage as chiral auxiliaries. A wide range of reactions is available and well documented7 and includes the following aldol alkylations ... 

Enantiomerically pure d.v-1 -amino-2-indanol and its derivatives have been used as ligands in numerous catalytic asymmetric carbon-hydrogen, carbon-carbon, and carbon-heteroatom bond formation reactions. The conformationally constrained indanyl platform has emerged as a particularly valuable backbone in a variety of catalytic processes leading to high levels of asymmetric induction. The aminoindanol 1 has also been used as a resolution agent (Chapter 8) as well as a chiral auxiliary (Chapter 24). For the synthesis of 1 see Chapter 24. 

Merck and Banyu process research and development teams have demonstrated the use of chiral auxiliaries for the production of an endothelin receptor antagonist.57 In one step, (1R, 2S)-cis-aminoindanol is used as the chiral auxiliary in the alkylation of the enolate derived from the propionyl amide 35 with benzyl chloride 36 (Scheme 23.10) (cf. Chapter 24). 

The physical properties of 2 were modified by introduction of polar substituents to improve both antiviral potency and hydrophilicity. These studies led to the discovery of L-689,502 (3) and L-693,549 (4), each bearing a polar, hydrophilic substituent at the para position of the P/ phenyl ring.7-9 Both compounds indeed displayed improved solubilities and antiviral potencies (Table 24.1). An inhibitor with pseudo-C2-symmetry, L-700,417 (5) was designed by rotation of the C-terminal half of 1 around the central hydroxyl-bearing carbon (Figure 24.2).10 Askin and co-workers reported a concise and practical synthesis of compounds 2-5 by diastereoselective alkylation of a chiral amide enolate derived from (I.S, 2/f)-aminoindanol.n This strategy, which efficiently used the cis-aminoindanol platform as chiral auxiliary, is fully detailed later in this chapter. 

Conformationally constrained m-aminoindanols and its derivatives have been used as chiral auxiliaries in a number of asymmetric reactions. The availability of both cis enantiomers, the high levels of asymmetric induction attained, and the ease of recovery are all assets to the development of efficient and practical processes with those auxiliaries. 

Ghosh also took advantage of the C—2 hydroxyl moiety of aminoindanols as a handle in the aldol reaction. Chiral sulfonamide 41 was O-acylated to give ester 42. The titanium enolate of ester 42 was formed as a single isomer and added to a solution of aldehyde, precomplexed with titanium tetrachloride, to yield the anft -aldol product 43 in excellent diastereoselectivities.63 One additional advantage of the ester-derived chiral auxiliaries was their ease of removal under mild conditions. Thus, hydrolysis of 43 afforded a ft -a-methyl- 3-hydroxy acid 44 as a pure enantiomer and cis-1-/ -1 o I y I s u I f on a m i do- 2 - i n da n ol was recovered without loss of optical purity (Scheme 24.7).63... 

The alternative strategy of using d,v-aminoindanol as a chiral auxiliary on the Michael donor has also been explored.81 Chiral amide enolates were reacted with a,P-unsaturated ester 70, and the resultant adducts were reduced and cyclized to 8-lactones 73 to determine the facial selectivity on the Michael acceptor. It is interesting that protected amino alcohol 71 did not lead to significant diastereofacial discrimination, whereas 72 afforded lactone 73 with high 4-(,S )-selectivity (Scheme 24.15). 

The versatility of d,v-aminoindanol as chiral auxiliary has been considered in various Claisen9293 rearrangements and was found to be particularly efficient in the 6-azaelectrocyclization reaction.93 Indeed, the reaction of ( >3-carbonyl-2,4,6-trienal 98 with enantiopure m-aminoindanol 1 proceeded under remarkably mild conditions to produce pentacyclic piperidine 99 as a single isomer. The reaction was thought to proceed via isomerization of dihydropyridine intermediate 100 toward the thermodynamically more stable aminoacetal 99 (Scheme 24.22). 

Aminoindanol and Amino Acid-derived Chiral Auxiliaries... 

Silks and co vorkers reported anti-selective aldol reactions in conjunction vith their investigations on chiral selenium compounds [39]. They discovered that bidentate oxyaldehydes precomplexed vith TiCl4 led to anti aldol products in good yield and vith excellent stereoselectivity, as sho vn in Table 2.35, entries 1 and 2. Presumably, this chelation-controlled reversal of syn/anti selectivity is a phenomenon similar to that vhich Ghosh and co vorkers exploited to produce syn aldols from aminoindanol chiral auxiliaries. Both benzyl and isopropyl oxazolidineselone chiral auxiliaries have comparable anti diastereoselectivity. 

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