Amino alcohol library

An Example Synthesis and Purification of a P-Amino Alcohol Library... 

Figure 8.25 Synthesis and purification of the solution-phase, discrete P-amino alcohol library L9 using SPE.

PSSEEs react with imines in the presence of a Lewis acid to afford /3-amino thioesters, which can be reduced to give amino alcohols (Table 6) [85a], In this reaction, although typical Lewis acids such as TiCU, SnCU, and BF3 OEt2 gave poor results, a catalytic amount of Sc(OTf)3 or Hf(OTf)4 gave better results. This process provides a convenient method for the construction of an amino alcohol library. 

Polymer-supported silyl enol ethers (PSSEEs) can be employed in Sc(OTf)3-catalyzed reactions with aldehydes and aromatic amines. This process provides a convenient method for the construction of a /8-amino alcohol library. 

Kob1996b Kobayashi, S., Moriwaki, M., Akiyama, R, Suzuki, S. and Hachiya, I., Parallel Synthesis Using Mannich-type Three-Component Reactions and Field Synthesis for the Construction of an Amino Alcohol Library, Tetrahedron Lett., 37 (1996) 7783-7786. 

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

In a soluble polymer strategy comparable to resin-capture [145], Janda reported a MeO-PEGsooo-supported dialkyl borane reagent (31) that was used in the purification of a solution-phase library of y9-amino alcohols [146]. Purification was achieved by simply adding (31) to the crude reaction mixture followed by subsequent precipitation of the polymer with diethyl ether to give polymer-supported 1,3,2-oxazaboroU-dine (32) (Scheme 5.2). The /9-amino alcohol product could then be released from the soluble support by treatment with acid. In a two-step synthetic strategy that is readily amendable to automation, the isolation of a small library of /9-amino alcohols was accomplished with all compounds obtained in >80% purity. 

This strategy using rapid automated synthesis of libraries of peptides and fluorescent screening of reactivity has allowed Miller to identify specific peptide-catalysts for specific applications such as the KR of an intermediate en route to an aziridomi-tosane [165,169], the KR of certain fert-alcohols [166], the regioselective acylation of carbohydrates [168], and finally the KR of AT-acylated fert-amino alcohols with s values from 19 to >50 (Scheme 21) [166],... 

Figure 6.11 Typical tridentate ligand structure incorporating a chiral amino alcohol and modified diamine-based tridentate ligand structure attached to the solid support for parallel catalyst library strategy.

The DMAP derivative 19a was tested for kinetic resolution of a variety of mono esters of cyclic cis diols (rac-20a-i) (Scheme 12.5) [15]. Catalyst 19a afforded selectivity factors up to 12.3 and highly enantioenriched mono esters 20 with conversions of 65-73%. For this type of reaction the selectivity of the Campbell catalyst 19b was similar (selectivity factor 13.2, Scheme 12.5) [16a], The latter catalyst was identified by screening of a 31-mer library prepared from the parent N-(4-pyridyl)-a-methylproline and a variety of amines [16a], The solid-phase-bound forms of N-(4-pyridyl)-a-methylproline, as reported by Anson et al. [16b], are easily recyclable acylation catalysts affording selectivity factors up to 11.9 in the kinetic resolution of the secondary alcohol rac-20b (Scheme 12.5). In the kinetic resolution of N-acylated amino alcohols, selectivity factors up to 21 were achieved by use of the Kawabata-Fuji catalyst 19a, and up to 18.8 by use of the Campbell system 19b (Scheme 12.5) [15, 16a]. 

Chng BL, Ganesan A, Solution-phase synthesis of a beta-amino alcohol combinatorial library, Bioorg. Med. Chem. Lett., 7 511-514, 1998. 

Walters and co-workers developed a synthesis of the library template 56 that was amenable to large-scale preparation (Scheme 40) <02JCO125>. Parallel synthesis employing this scaffold leads to a library of amino alcohols (major regioisomer shown). 

Multi-component couplings open up an economic and straightforward route to very different compound libraries. For example, 1,3-dipolar cycloaddition reactions of nitrones with alkenes furnish isoxazolines, which can be transformed reductively to hydroxyketones or )8-amino alcohols. In 1997, two groups reported on the synthesis of isoxazolines by rare earth metal-catalyzed [3 + 2] cycloadditions (Scheme 4) [13,14]. 

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported /3-amino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. /3-Amino acid and /3-lactam libraries are also constructed according by this method (Eq. 23). 

Zhang and coworkers elegantly demonstrated the use of F-isocyanates as well as F-isatoic anhydrides in the synthesis of a library of amino alcohols (via amine ring opening of glycidyl epoxide ethers) and a library of ureas and thioureas. Purities were reported to be in excess of 95%, while yields were slightly better when the anhydride was used (Scheme 8.19). 

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