Cyclopentanol 1-benzyl

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

Despite the many simple methods for preparation of carboxylic esters and thioesters, in some instances, use of 1-acylbenzotriazoles 915 as O and S acylating agents may be advantageous. For example, easy to prepare salicylic acid derivative 941 reacts with cyclopentanol under microwave irradiation to give 92% yield of cyclopentyl salicylate in 10 min <2006JOC3364>. In another example, L-phenylalanine derivative 942 reacts with benzyl mercaptan... 

Substrates include benzyl (2 g) and cinnamyl (2.7 g) alcohols to acids cyclopentanol (1 g), benzhydrol (3.9 g), benzoin (4 g), pantolactone (2.6 g) to ketones (RuCy TCCA/( Bu N)Br/aq. Kj(C03)/CH3CN) (Fig. 2.14) [25] [[2-[2-hydroxypropyl) amino]-l,2-dioxoethyl]amino]acetic acid ethyl ester (6.21 kg) to [(l,2-dioxo-2-oxopropyl)amino]ethyl)amino] acetic acid ethyl ester, part of the industrial-scale synthesis of thrombin inhibitor (RuCyaq. Na(BrOj)/CH3CN) [166] (H-)-dihydroc-holesterol (8 g) to cholest-3-one (RuO /aq. K(10 )/(BTEAC)/CHCl3) [308] ... 

Benzyl chloride is an acceptable starting material, because the problem has specified that we must start with alkyl halides. However, we must still prepare the alkoxide anion. This is the conjugate base of cyclopentanol and can be made by the reaction of the alcohol with sodium metal ... 

Further studies indicate that this method of oxidation is efficient only with easily oxidized alcohols, especially arylalkylmethanols. Reasonable yields can be obtained in the case of propane-2-ol (68%), cyclopentanol (607o)> and benzyl alcohol (80%). Simple primary aliphatic alcohols are converted mainly into N-phenylcarbamates formed from two molecules of the dione and one of the iilcohol (equation I). Pyridine catalyzes this reaction and suppresses oxidations of the alcohol. 

Alcohols butanol 1, tert-amyl alcohol 6, isopropylmethylcarbinol 1—6, isoamyl alcohol 6, benzyl alcohol 6, cyclopentanol 6... 

Figure 27.7 Structure -reactivity trend observed in the photoxidation of alcohols in water by heterogeneous PDMS-Wio, PVDF-Wio, and homogeneous Na4Wio032 (Wio). In aU reactions substrate (0.04 mmol), H2O (2 mL, pH = 7), p02=l atm, > 345 nm, T=25°C. Wio (0.6 p,mol), PDMS-Wio (6.3% loading, 0.6 p,mol) PVDF-Wio (25% loading, 0.6 xmol). Substrate cis-1,2-cyclohexandiol (CyD) cycloheptanol (c-Cy) cyclohexanol (c-Cg) cyclopentanol (C-C5) n-pentanol (n-Cg) benzyl alcohol (Bz). (Adapted from Bonchio et al., 2003.)...

An application of this approach is the synthesis of chiral primary alcohols labeled with tritium at one of the enantiotopic a-hydrogens. Liver alcohol dehydrogenase, for example, reduces benzaldehyde to (7 )-[methylene- H]benzyl alcohol (27) in the presence of NAD/NAD H, which is regenerated by oxidation of (/ ,5)-[l- Hi]ethanol to acetaldehyde. Because the enzyme transfers exclusively the Re-positioned isotope of (R,5)-[ 1 - Hj Jethanol, the theoretical radiochemical yield is only 50% (the other 50% remains in acetaldehyde), and the specific activity of the product is only half that of this isotope source. One way to overcome this drawback is to use achiral, secondary alcohols such as [1- H]-cyclohexanol or [l- H]cyclopentanol (2S) as isotope sources. The corresponding (5)-antipode of 27 would be accessible by analogous reduction of benz[ H]aldehyde using nonisotopic cofactors. 

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