Tetrahedron: Asymmetry 24 (2013) 1369–1381

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry

journal homepage: www.elsevier .com/locate / tetasy

Preparative access to medicinal chemistry related chiral alcoholsusing carbonyl reductase technology

0957-4166/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetasy.2013.09.015

⇑ Corresponding author.E-mail address: andrew.rowan@almacgroup.com (A.S. Rowan).

S

O

2

NH

N

OH OH

O- 0.5Ca2+

OO

F1

FN

O

OH

F

OH

3

Figure 1. A selection of drugs derived from chiral alcohol precurso

Andrew S. Rowan a,⇑, Thomas S. Moody a, Roger M. Howard b, Toby J. Underwood c, Iain R. Miskelly a,Yanan He d, Bo Wang d

a Biocatalysis & Isotope Chemistry Group, Almac, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, Northern Ireland, UKb Chemical Research & Development, Pfizer Ltd, Sandwich Laboratories, Ramsgate Road, Kent, UKc Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, UKd Biotools, Inc., 17546 Bee Line Highway, Jupiter, FL 33458, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 10 June 2013Accepted 18 September 2013Available online 29 October 2013

Libraries of highly enantioenriched secondary alcohols in both enantiomeric forms were synthesised byenzymatic reduction of their parent ketones using selectAZyme™ carbonyl reductase (CRED) technology.Commercially available CREDs were able to reduce a range of substrate classes efficiently and with veryhigh enantioselectivity. Matching substrate classes to small subsets of CREDs enabled the fast develop-ment of preparative bioreductions and the rapid generation of 100–1500 mg samples of chiral alcoholsin typically >95% ee and the majority in P99.0% ee. The conditions for small scale synthesis were thenscaled up to 0.5 kg to deliver one of the chiral alcohols, (S)-1-(4-bromophenyl)-2-chloroethanol, in99.8% ee and 91% isolated yield.

� 2013 Elsevier Ltd. All rights reserved.

NH

rs.

1. Introduction

Chiral secondary alcohols are an important building block inmedicinal chemistry. Indeed at least 17 of the top 100 brand-nameprescription drugs by total US prescriptions in 2010 couldbe derived from these structural precursors.1 Drugs such asLipitor� (Atorvastatin) 1, Cymbalta� (Duloxetine) 2 and Zetia�

(Ezetimibe) 3 have all been highly successful for their respectivepharmaceutical companies (Fig. 1).

Having an efficient and environmentally sound method of syn-thesising these enantioselective alcohols for library protocols andsingleton synthesis is highly desirable. Often the initial medicinalchemistry synthesis of a candidate pharmaceutical involves thepreparation of a racemate followed by separation of the enantio-mers by chiral preparative HPLC. In many cases, this method isnot favoured for larger scale follow-up work, thus necessitatingthe development of chemical asymmetric ketone reductionprocesses.2

Biocatalytic processes continue to dominate the press due tothe success stories that follow their applications.3 The need for eco-nomic, robust, scalable and reliable processes for the synthesis ofchiral APIs and intermediates has resulted in process chemiststuning their skills at the interface of chemistry and biology and in-deed embracing biocatalysts and biocatalytic processes in organic

synthesis.4 Enzymatic asymmetric reduction of prochiral ketonesusing carbonyl reductase (CRED) enzymes is now a well-established tool for the efficient generation of chiral alcohols inhigh enantiomeric excess with glucose or iso-propanol commonlyused as a stoichiometric reductant (Fig. 2).5,6

Although CRED technology has seen many applications in pro-cess chemistry, scale-up and delivery of chiral product, it has seenless uptake in medicinal chemistry labs. The research presentedherein is aimed at showing medicinal chemists the ease withwhich commercially available CREDs can be used to bolster

NAD(P)H

NAD(P) *

CRED

glucose

gluconate

GDH

iso-propyl alcohol

acetone

CRED

or

(pH stat)

ReductionCofactorRecycle

R1 R2

O

R1 R2

OH

Figure 2. CRED catalysed bioreduction of prochiral ketones with cofactor recycling.

1370 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

compound libraries with scaffolds of enantiopure chiral alcoholbuilding blocks, as well as providing a means to quickly generatefurther amounts of these and similar alcohols when required. Theresearch has demonstrated that early access to enantiopure alco-hols using CRED technology would obviate the need for chromato-graphic or chemical resolution of racemic API, thus speedingmedicinal chemistry timelines from conception to reality.

Typically, a prochiral ketone substrate is screened against alarge number of CRED enzymes for a potential asymmetric biore-duction and the reaction conditions for the best candidate(s) opti-mised prior to running preparative reactions. Herein it was hopedthat the initial screening efforts could be reduced by narrowing thenumber of CREDs to those most likely to provide the best (R)- and(S)-selectivity for substrates belonging to particular structural clas-ses. After subsequent microscale validation to confirm enzymeactivity and selectivity, these biocatalysts could be employeddirectly in preparative reactions. In this manner it would bepossible to generate gram-scale libraries of enantiopure alcoholsquickly and efficiently, with the potential to up-scale withoutfurther development.

2. Results and discussion

2.1. Carbonyl reductase screening

Structurally similar ketones, falling into seven structural clas-ses, were selected based on their potential as precursors to(R)- and (S)-chiral alcohol building blocks useful for target synthe-sis and structure–activity relationship work within a medicinalchemistry lab. A library of commercially available selectAZyme™

Set 1(methyl aryl-

ketones)

Set 2(alpha-halo aryl-

ketones)

Set 3(fused bicyclics)

Ar Me

O

Ar

OX

X = Cl or Br

O

R nR

Set 4(beta-cyanaryl-ketone

Ar

O

A131 (Prelog)A161 (Anti-Prelog)A601 (Anti-Prelog)

A131A161A231 (Anti-Prelog)A601

A131A161A231A281 (Prelog)

A131A161A231A281

Figure 3. Structural motifs of the substrate classes involved herein. High-performing carbselectivity given in parentheses.7

CREDs was screened against lead members of each substrate classand the consistently high-performing enzymes identified as candi-date CREDs for that class. The candidate CREDs for each substrateclass are shown in Figure 3 (selectAZyme™ CRED number).

Rapid microscale screens of the candidate CREDs against theremaining members of each substrate class were then carried outin order to identify those enzymes hitting the minimum perfor-mance criteria desired for scale-up (P5% conversion to alcohol inP95% ee). Excellent results were observed, with candidate enzymesubsets taken from only six CREDs (A131, A161, A201, A231, A281and A601) providing both Prelog and anti-Prelog hits for thirty-three out of forty-one (80%) of the substrate ketones tested.Considering that both enantiomers of each alcohol were targetedindividually, hits were found for an impressive sixty-nine of theeighty-two target alcohols, an 84% hit rate. It was also observedthat the product was generated with exceptionally high enantio-meric excess (P99% ee) for the majority of target alcohols (68%),as illustrated in Figure 4.

2.2. Preparative bioreductions

Preparative bioreductions were carried out on thirty-five of theketones and gave excellent results, especially when taking intoconsideration that these were one-time, un-optimised, reactions(Table 1). Only four (6%) of the sixty-nine preparative reactionsattempted resulted in a product of less than 95.0% ee, with themajority of the reactions (forty-six of sixty-nine, 66%) deliveringP99.0% ee and the remaining nineteen reactions (28%) generatingsecondary alcohols in 95.0–99.0% ee. The yields were respectablewith an average of 68%. In cases where low yields were observed,optimisation of the work-up procedure would likely improve theyield considerably.

The absolute configurations of organic compounds can be deter-mined by several methods including X-ray crystallography and themodified Mosher’s NMR procedure.25 Herein, in cases where thespecific rotation of either enantiomer of alcohol product was notknown in the literature, the determination of enantiomeric config-uration was conducted using vibrational circular dichroism26 (videinfra) or, tentatively, by analogy to the selectivity observed for theCRED employed against other members of the substrate class.

The vibrational circular dichroism (VCD) technique has playedan important role in the field of absolute structure determination,particularly over the past decade. It is routinely used in the phar-maceutical industry and research institutions mainly due to thecommercial availability of VCD instruments and the maturity ofthe theoretical calculations used to support structure determina-tions. Herein the absolute stereochemistries of eighteen secondaryalcohols were determined by this method, which compared the IRand VCD spectra of enantioenriched samples with the correspond-ing theoretically calculated spectra.27

Set 5(pyrrolidinoneanalogues)

N

os)

CN n

R

Set 6(alpha-branched

alkyl aryl-ketones)

Ar

OR1

R2

Set 7(alpha-trifluoromethyl

aryl-ketones)

Ar

O

CF3

A131A161A201 (Anti-Prelog)

A131A161A231A601

A131A161A231A601

O

onyl reductases associated with each class are given below in blue with their typical

Figure 4. Screening results of the best Prelog and anti-Prelog selective CREDs for each of the substrates screened. Screening was carried out with subsets of CREDs A131,A161, A201, A231, A281 and A601, determined by substrate class (as given in Fig. 3). Prelog selectivity is denoted by positive ee values on the x-axis and anti-Prelog selectivityby negative ee values.

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1371

2.3. 0.5 kg Scale up

In order to demonstrate the scalability of the developed meth-odology, a 0.5 kg scale reduction of ketone 15 was carried out usingCRED A161 in order to access chiral alcohol (S)-50 (Scheme 1). ThisCRED was found to be able to utilise iso-propanol (IPA) for cofactorregeneration, precluding the requirement for glucose dehydroge-nase (GDH) and therefore the need for pH control. The reactionprofile is shown in Figure 5. The reduction was complete after6 h and simple extraction with methyl tert-butyl ether (MTBE)afforded (S)-50 in >99.0% ee and 91% isolated yield.

Process mass intensity (PMI) is a common green chemistry met-ric, widely applied to enable the benchmarking of processes.28 It isa measure of the mass of raw materials, reagents, solvents and soon used to provide the mass of chemical synthesised, that is, kginput/kg output. The calculation of the PMI for the bioreductionof 15 to (S)-50 gave a value of 35, with the aqueous solventcontributing 22 kg per kg product and organic solvent contributing11 kg per kg product. These values compare favourably withsimilar asymmetric reduction protocols.29

3. Conclusion

Biocatalysis has proved to be a fast and efficient tool for thegeneration of libraries of enantioenriched chiral alcohols with min-imal screening and optimisation effort required to transform gramamounts of their ketone precursors. VCD has been shown to be anexcellent tool for the determination of the absolute stereochemis-try for small organic molecules in the solution state. Furthermore,the successful asymmetric bioreduction of 0.5 kg of ketone 15 sup-ports our belief that if larger quantities of the enantioenrichedalcohols presented or analogues from the same structural classesare required in the future, the procedures described herein willpresent an excellent basis for scale-up.

4. Experimental

4.1. Chemicals and enzymes

Chemicals were purchased from Sigma Aldrich and Alfa Aesaror, if not commercially available, synthesised using conventionalmethodology. SelectAZyme™ CRED enzymes were purchased fromAlmac.

4.2. Analytical methods

1H NMR spectra were recorded at 400 MHz on a Bruker AV-400spectrometer; shifts are relative to internal TMS; J values are givenin Hz. [a]D values are given in 10�1 deg cm2 g�1. Conversions andenantiomeric excesses were measured by chiral stationary phaseHPLC using a Shimadzu system equipped with LC-10AS pumps, aSIL-10AD VP auto injector and SPD-10A UV-VIS detector (seeSection 4.4 for method details).

4.3. General screening procedure

A typical screening procedure: Into a set of glass vials contain-ing a selection of Almac CREDs (5–10 mg) were added potassiumphosphate buffer (pH 7.0, 1.7 mL), NADP or NAD (1–2 mg)(depending on enzyme preference), glucose dehydrogenase (GDH,2 mg), a solution of glucose (75 mg) in buffer (300 lL) and finallya solution of substrate ketone (20 mg) in DMSO (50–100 lL,depending on solubility). For CREDs that had previously shown tol-erance to iso-propanol, an additional reaction was run using thiscofactor recycle system, replacing GDH and glucose with iso-propanol (300 lL). Reactions were shaken overnight at 30 �C andthen extracted with MTBE (2 mL). This was passed through a glasspipette containing a cotton wool plug and anhydrous MgSO4

directly into an HPLC vial. The MTBE was evaporated in an oven

Table 1Results from preparative reactions

Substrate class Ketone Alcohol product CRED Experimental method Yield (%) ee (%) ½a�20D

Ref.

Set 1

F

O

4

(R)-39c A601 A 88 99.5 +42.5 (c 1.0, CHCl3) —

(S)-39c A131 A 52 98.3 �38.0 (c 1.0, CHCl3) —

N

NN

O

5

(R)-40b A601 B 55 100 +43.5 (c 1.0, CHCl3) 8

(S)-40b A131 B 79 99.9 �44.0 (c 1.0, CHCl3) —

N

N

O

6

(R)-41c A601 B 45 99.8 +30.3 (c 1.0, CHCl3) —

(S)-41c A131 B 59 99.8 �29.4 (c 1.0, CHCl3) 9

NCl

O

7

(R)-42c A601 A 71 95.4 +65.7 (c 1.0, CHCl3) —

(S)-42c A131 A 54 99.9 �66.5 (c 1.0, CHCl3) —

SO O

NH2

O

8

(R)-43d A161 A 89 98.3 +29.4 (c 1.0, MeOH) —

(S)-43d A131 A 90 99.8 �29.5 (c 1.0, MeOH) —

N

N

O

9

(R)-44c A161 A 68 99.5 +89.0 (c 1.0, CHCl3) —

(S)-44c A131 A 25 99.7 �86.9 (c 1.0, CHCl3) —

S

N

O

10

(R)-45c A161 B then C 47 99.6 +36.4 (c 1.0, CHCl3) —

(S)-45c A131 B 72 99.8 �35.3 (c 1.0, CHCl3) —

Set 2O

Br

F3CO 11

(R)-46d A131 B then C 54 98.8 �34.8 (c 1.0, CHCl3) —

(S)-46d A601 B then C 49 96.9 +33.2 (c 1.0, CHCl3) —

O

Br

F

MeO

12

(R)-47d A131 A then B 26 99.6 Decomposed —

(S)-47d A161 A then B 24 99.2 Decomposed —

O

BrNC

13

(R)-48c A131 A 25 99.9 �43.0 (c 1.0, CHCl3) —

(S)-48c A601 B 42 97.6 +43.5 (c 1.0, CHCl3) —

O

Cl

F

F 14

(R)-49a A131 B 78 100 �38.6 (c 1.0, CHCl3) 10

(S)-49a A601 B then C 81 99.5 +38.0 (c 1.0, CHCl3) 11

1372 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

Table 1 (continued)

Substrate class Ketone Alcohol product CRED Experimental method Yield (%) ee (%) ½a�20D

Ref.

Br

O

Cl

15

(R)-50d A131 B 93 99.6 �39.4 (c 1.0, CHCl3) 12

(S)-50d A161 B 91 99.9 +40.2 (c 1.0, CHCl3) 13

F

O

Cl

16

(R)-51a A131 B 96 99.1 �54.6 (c 1.0, CHCl3) 12

(S)-51a A161 B 96 98.4 +52.8 (c 1.0, CHCl3) 13

O

Cl

17

(R)-52a A131 B 91 99.9 �60.3 (c 1.0, CHCl3) 14

(S)-52a A231 B 76 96.6 +57.8 (c 1.0, CHCl3) 14

Set 3

N

O

18

(R)-53a A161 B 78 99.8 �53.9 (c 1.0, CHCl3) 15

(S)-53a A131 A 76 98.3 +51.7 (c 1.0, CHCl3) —

O

O

19

(R)-54a A161 B 57 99.1 +66.9 (c 1.0, CHCl3) 16

(S)-54a A131 A 44 93.5 �65.1(c 1.0, CHCl3) 16

O

Br 20

(R)-55c A161 B 32 99.3 +4.0 (c 1.0, CHCl3) —

(S)-55c A131 A 80 90.9 �4.0 (c 1.0, CHCl3) —

N

O

Cl

S OO21

(R)-56d A231 A 91 99.0 +4.9 (c 1.0, CHCl3) —

(S)-56d A281 A 62 99.3 �5.7 (c 1.0, CHCl3) —

O

O

22

(R)-57c A131 A 78 95.9 �18.8 (c 1.0, CHCl3) —

(S)-57c A231 A 93 96.0 +17.6 (c 1.0, CHCl3) —

NClO

23

(R)-58a A231 A 70 96.3 �3.6 (c 1.0, CHCl3) 17

(S)-58a A131 B 79 99.5 +2.4 (c 1.0, CHCl3) 18

SO O

O

24

(R)-59d A131 B 99 99.8 +56.8 (c 1.0, CHCl3) —

(S)-59d A231 A 92 98.4 �55.4 (c 1.0, CHCl3) —

Set 4

Br

ON

25

(R)-60a A161 B then C 93 97.7 +44.6 (c 1.0, CHCl3) 19

(S)-60a A131 B then C 93 99.4 �46.3 (c 1.0, CHCl3) 20

ON

26

(R)-61a A161 B 92 99.6 +64.8 (c 1.0, CHCl3) 19

(S)-61a A131 A 80 100 �61.3 (c 1.0, CHCl3) 20

(continued on next page)

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1373

Table 1 (continued)

Substrate class Ketone Alcohol product CRED Experimental method Yield (%) ee (%) ½a�20D

Ref.

N

ON

27

(R)-62c A161 A 54 99.8 +11.5 (c 0.2, CHCl3) —

(S)-62c A131 C 44 99.6 �10.6 (c 0.2, CHCl3) —

Set 5

N

N N

O

28

(R)-63c A201 A 39 94.8 �44.5 (c 1.0, CHCl3) —

(S)-63c A131 B 31 99.2 +44.4 (c 1.0, CHCl3) —

N N

O

29

(R)-64c A161 A 56 95.6 �29.3 (c 1.0, CHCl3) —

(S)-64c A131 B 56 99.9 +34.1 (c 1.0, CHCl3) —

N

N N

O

30

(R)-65 No hit — — — — —

(S)-65c A131 B 40 99.9 +68.5 (c 1.0, CHCl3) —

Set 6

Br

O

31

(R)-66c A231 A 60 99.4 �36.3 (c 1.0, CHCl3) —

(S)-66c A131 A 58 99.0 +32.1 (c 1.0, CHCl3) —

N

O

32

(R)-67c A601 A 52 99.7 �36.2 (c 1.0, CHCl3) —

(S)-67c A131 B 54 99.9 +32.7 (c 1.0, CHCl3) —

N

O

33

(R)-68c A161 B 93 99.7 +52.2 (c 1.0, CHCl3) —

(S)-68c A131 B 94 98.7 �52.0 (c 1.0, CHCl3) —

O

Cl

34

(R)-69c A161 A 58 99.5 +30.6 (c 1.0, CHCl3) —

(S)-69c A131 B 76 97.7 �31.6 (c 1.0, CHCl3) —

Set 7

N

F

CF3

O

Me 35

(R)-70c A131 C 71 99.9 �14.8 (c 1.0, CHCl3) —

(S)-70c A231 A 89 99.9 +12.9 (c 1.0, CHCl3) —

Cl

O

CF3

36

(R)-71a,c A131 B 68 99.8 �28.7 (c 1.0, CHCl3) 21

(S)-71a,c A161 B 65 98.7 +26.1 (c 1.0, CHCl3) 22

O

CF3Cl

37

(R)-72a A131 B 89 95.3 �24.5 (c 1.0, CHCl3) 23

(S)-72a A161 C 81 99.6 +23.1 (c 1.0, CHCl3) —

1374 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

O

Cl

Br

OH

Cl

Br

CRED A161

NADIPA

0.1 M KH2PO4 (pH 7)15 (S)-50

Scheme 1. Enzymatic reduction of ketone 15 by CRED A161 to afford chiral alcohol(S)-50.

Table 1 (continued)

Substrate class Ketone Alcohol product CRED Experimental method Yield (%) ee (%) ½a�20D

Ref.

O

CF3

HO2C 38

(R)-73a A131 C 90 99.7 �34.6 (c 1.0, MeOH) 24

(S)-73a A161 C 78 93.4 +24.5 (c 1.0, MeOH) —

a Assigned by comparison to literature ½a�20D .

b Assigned by comparison to ½a�20D of the commercially available compound.

c Assigned (or assignment corroborated) by VCD analysis.d Assigned by comparison to selectivities achieved for other members of this compound set.

Figure 5. Reaction profile for the CRED A161-catalysed asymmetric reduction ofpara-bromophenacyl chloride 15.

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1375

and the residue analysed by chiral HPLC after re-dissolving inmobile phase.

4.4. Small scale preparative scale-ups

Preparative experimental method A: Almac CRED (200 mg),NADP or NAD (10 mg), GDH (20 mg) and glucose (1.5 equiv) weremeasured into a 100 mL round bottomed flask then dissolved in0.1 M potassium phosphate buffer (pH 7, ca. 50 mL) and stirredat 30 �C. Next, a solution of ketone (900–1700 mg) in DMSO(2.5–5 mL, depending on solubility) was added to the reactionand this was allowed to stir overnight under pH-stat control (pH7.0, adjusted with 1 M NaOH solution). The following day, reactionprogress was checked by 1H NMR. If not complete, additional CRED(100–200 mg), NADP or NAD (10 mg) and GDH (10 mg) wereadded and stirring was continued. This was repeated until the reac-tion reached completion or had stalled and would not go any fur-ther. Method B: Almac CRED (200 mg) and NADP or NAD (10 mg)were charged into a 100 mL round bottomed flask and dissolvedin 0.1 M potassium phosphate buffer (pH 7, ca. 50 mL). Next, IPA(7 mL) was added, followed by a solution of ketone (900–1700 mg) in DMSO (2.5–5 mL, depending on solubility). This was

shaken at room temperature overnight and the reaction progresswas checked by 1H NMR. If not complete, additional CRED (100–200 mg) and NADP or NAD (10 mg) were added and shaking wascontinued. This was repeated until the reaction reached comple-tion. If the reaction appeared to stall or proceed very slowly, exper-imental method C was used. Method C: Almac CRED (200 mg) andNADP or NAD (10 mg) were measured into a 250 mL round-bottomed flask then dissolved in 0.1 M potassium phosphate buf-fer (pH 7, ca. 50 mL). IPA (7 mL) was added, followed by a solutionof ketone (900–1700 mg) in DMSO (2.5–5 mL, depending on solu-bility). This was stirred at 35 �C under 500 mbar reduced pressureto aid removal of acetone formed by IPA oxidation. Standardwork-up procedure: The pH of the reaction mixture was adjustedif necessary (basic or acidic depending on estimated pKa of alcoholproduct) with either 1 M NaOH or 1 M HCl. The reaction mixturewas then extracted with MTBE (3 � 100 mL). The organic solventwas washed with brine (ca. 100 mL), dried over anhydrous magne-sium sulfate, filtered and concentrated in vacuo to afford thedesired alcohol. If recovery of the alcohol was low, the aqueousphase was re-extracted with EtOAc (3 � 100 mL), washed withbrine (ca. 100 mL), dried (MgSO4), filtered and concentrated invacuo, then combined with the alcohol recovered from the MTBEextraction. If the reaction did not go to >95% completion, or thepurity of the isolated alcohol was <95% by NMR, flashmaster silicapurification was carried out to afford a clean alcohol. Analysis ofthe enantiomeric excess was carried out by chiral HPLC.

4.4.1. 1-(3-Fluoro-4-methylphenyl)ethanol 39Analysis of the enantiomeric excess was performed on a Chiral-

cel OB-H column with eluent 98:2 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 22 min; retentiontimes for (S)-39 and (R)-39 were 14.3 and 17.4 min, respectively.(S)-39. Pale yellow oil (523 mg, 52%). ½a�20

D ¼ �38:0 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.06 (1H, m, Ar-H), 6.94 (2H, m,2 � Ar-H), 4.76 (1H, m, CH-OH), 2.17 (3H, s, Ar-CH3), 1.38 (3H, d,J = 6.5 Hz, CH-CH3); ee = 98.3%. (R)-39. Pale yellow oil (892 mg,88%). ½a�20

D ¼ þ42:5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d7.06 (1H, m, Ar-H), 6.94 (2H, m, 2 � Ar-H), 4.77 (1H, m, CH-OH),2.18 (3H, s, Ar-CH3), 1.39 (3H, d, J = 6.4 Hz, CH-CH3); ee = 99.5%.

4.4.2. 1-(4-(1H-1,2,4-Triazol-1-yl)phenyl)ethanol 40Analysis of the enantiomeric excess was performed on a Chiral-

cel OJ column with eluent 6:4 hexane/IPA + 0.1% DEA, flow rate1 mL min�1, detection 254 nm and run time 10 min; retentiontimes for (S)-40 and (R)-40 were 7.0 and 8.7 min, respectively.(S)-40. White solid (916 mg, 79%). ½a�20

D ¼ �44:0 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 8.54 (1H, s, triazole-H), 8.10 (1H, s, tria-zole-H), 7.66 (2H, m, 2 � Ar-H), 7.52 (2H, m, 2 � Ar-H), 4.99 (1H, m,CH-OH), 1.53 (3H, d, J = 6.5 Hz, CH3); ee = 99.9%. (R)-40. White solid(640 mg, 55%). ½a�20

D ¼ þ43:5 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 8.54 (1H, s, triazole-H), 8.10 (1H, s, triazole-H), 7.66

1376 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

(2H, m, 2 � Ar-H), 7.53 (2H, m, 2 � Ar-H), 4.99 (1H, m, CH-OH),1.53 (3H, d, J = 6.4 Hz, CH3); ee = 100%.

4.4.3. 1-(Pyrazin-2-yl)ethanol 41Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 9:1 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 7 min; retentiontimes for (S)-41 and (R)-41 were 5.6 and 5.0 min, respectively.(S)-41. Pale yellow oil (656 mg, 59%). ½a�20

D ¼ �29:4 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 8.68 (1H, s, Ar-H), 8.52 (2H, m,2 � Ar-H), 5.00 (1H, m, CH-OH), 1.57 (3H, d, J = 6.6 Hz, CH3);ee = 99.8%. (R)-41. Pale yellow oil (502 mg, 45%). ½a�20

D ¼ þ30:3 (c1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.68 (1H, s, Ar-H), 8.52(2H, m, 2 � Ar-H), 5.00 (1H, m, CH-OH), 1.57 (3H, d, J = 6.6 Hz,CH3); ee = 99.8%.

4.4.4. 1-(3-Chloropyridin-4-yl)ethanol 42Analysis of the enantiomeric excess was performed on a Chir-

alpak IA column with eluent 95:5 hexane/IPA + 0.1% DEA, flow rate1 mL min�1, detection 254 nm and run time 14 min; retentiontimes for (S)-42 and (R)-42 were 11.9 and 10.3 min, respectively.(S)-42. Yellow oil (926 mg, 54%). ½a�20

D ¼ �66:5 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 8.27 (2H, m, 2 � Ar-H), 7.50 (1H, d,J = 5.0 Hz, Ar-H), 5.11 (1H, m, CH-OH), 1.38 (3H, d, J = 6.5 Hz,CH3); ee = 99.9%. (R)-42. Yellow oil (800 mg, 71%). ½a�20

D ¼ þ65:7(c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.47 (2H, m, 2 �Ar-H), 7.56 (1H, d, J = 5.0 Hz, Ar-H), 5.23 (1H, m, CH-OH), 1.50(3H, d, J = 6.5 Hz, CH3); ee = 95.4%.

4.4.5. 3-(1-Hydroxyethyl)benzenesulfonamide 43Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 93:7 hexane/EtOH, flow rate1 mL min�1, detection 210 nm and run time 110 min; retentiontimes for (S)-43 and (R)-43 were 91.5 and 83.6 min, respectively.(S)-43. Yellow oil (1275 mg, 90%). ½a�20

D ¼ �29:5 (c 1.0, MeOH); 1HNMR (DMSO-d6, 400 MHz): d 7.91 (1H, s, Ar-H), 7.74 (1H, m,Ar-H), 7.61–7.54 (2H, m, 2 � Ar-H), 4.86 (1H, m, CH-OH), 1.40(3H, d, J = 6.4 Hz, CH3); ee = 99.8%. (R)-43. Yellow oil (1182 mg,89%). ½a�20

D ¼ þ29:4 (c 1.0, MeOH); 1H NMR (DMSO-d6, 400 MHz):d 7.85 (1H, s, Ar-H), 7.68 (1H, m, Ar-H), 7.55–7.48 (2H, m, 2 �Ar-H), 4.81 (1H, m, CH-OH), 1.35 (3H, d, J = 6.4 Hz, CH3); ee = 98.3%.

4.4.6. 1-(3-Methylpyrazin-2-yl)ethanol 44Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 9:1 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 11 min; retentiontimes for (S)-44 and (R)-44 were 8.0 and 7.3 min, respectively.(S)-44. Pale yellow oil (349 mg, 25%). ½a�20

D ¼ �86:9 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 8.41 (1H, d, J = 2.6 Hz, Ar-H), 8.37(1H, d, J = 2.4 Hz, Ar-H), 5.03 (1H, m, CH-OH), 2.58 (3H, s, Ar-CH3), 1.45 (3H, d, J = 6.4 Hz, CH-CH3); ee = 99.7%. (R)-44. Brownoil (907 mg, 68%). ½a�20

D ¼ þ89:0 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 8.41 (1H, d, J = 2.5 Hz, Ar-H), 8.37 (1H, d, J = 2.4 Hz,Ar-H), 5.04 (1H, m, CH-OH), 2.58 (3H, s, Ar-CH3), 1.45 (3H, d,J = 6.4 Hz, CH-CH3); ee = 99.5%.

4.4.7. 1-(4-Methylthiazol-5-yl)ethanol 45Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 98:2 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 24 min; retentiontimes for (S)-45 and (R)-45 were 21.4 and 18.4 min, respectively.(S)-45. Pale yellow oil (762 mg, 72%). ½a�20

D ¼ �35:3 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 8.59 (1H, s, thiazole-H), 5.21 (1H,m, CH-OH), 2.41 (3H, s, thiazole-CH3), 1.56 (3H, d, J = 6.4 Hz,CH-CH3); ee = 99.8%. (R)-45. Pale yellow oil (505 mg, 47%).½a�20

D ¼ þ36:4 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.61

(1H, s, thiazole-H), 5.22 (1H, m, CH-OH), 2.44 (3H, s, thiazole-CH3), 1.56 (3H, d, J = 6.4 Hz, CH-CH3); ee = 99.6%.

4.4.8. 2-Bromo-1-(4-(trifluoromethoxy)phenyl)ethanol 46Analysis of the enantiomeric excess was performed on a Chir-

alpak IA column with eluent 9:1 hexane/IPA, flow rate 1 mL min�1,detection 254 nm and run time 20 min; retention times for (S)-46and (R)-46 were 6.5 and 6.0 min, respectively. (S)-46. Pale yellowoil (652 mg, 49%). ½a�20

D ¼ þ33:2 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 7.43 (2H, m, 2 � Ar-H), 7.24 (2H, m, 2 � Ar-H), 4.95(1H, m, CH-OH), 3.64 (1H, dd, J = 10.5, 3.4 Hz, CHAHB), 3.52 (1H,dd, J = 10.5, 8.9 Hz, CHAHB); ee = 96.9%. (R)-46. Pale yellow oil(707 mg, 54%). ½a�20

D ¼ �34:8 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 7.43 (2H, m, 2 � Ar-H), 7.24 (2H, m, 2 � Ar-H), 4.95(1H, m, CH-OH), 3.64 (1H, dd, J = 10.5, 3.3 Hz, CHAHB), 3.52 (1H,dd, J = 10.5, 8.9 Hz, CHAHB); ee = 98.8%.

4.4.9. 2-Bromo-1-(3-fluoro-4-methoxyphenyl)ethanol 47Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 25 min; retentiontimes for (S)-47 and (R)-47 were 18.2 and 21.1 min, respectively.Optical rotation measurements were not made due to product deg-radation. (S)-47. Pale yellow oil (360 mg, 24%). 1H NMR (CDCl3,400 MHz): d 7.12 (2H, m, 2 � Ar-H), 6.95 (1H, t, J = 8.4 Hz, Ar-H),4.87 (1H, m, CH-OH), 3.89 (3H, s, OCH3), 3.60 (1H, dd, J = 10.4,3.4 Hz, CHAHB), 3.50 (1H, dd, J = 10.5, 8.8 Hz, CHAHB); ee = 99.2%.(R)-47. Colourless oil (340 mg, 26%). 1H NMR (CDCl3, 400 MHz): d7.12 (2H, m, 2 � Ar-H), 6.95 (1H, t, J = 8.5 Hz, Ar-H), 4.87 (1H, m,CH-OH), 3.89 (3H, s, OCH3), 3.60 (1H, dd, J = 10.4, 3.4 Hz, CHAHB),3.50 (1H, dd, J = 10.5, 8.8 Hz, CHAHB); ee = 99.6%.

4.4.10. 3-(2-Bromo-1-hydroxyethyl)benzonitrile 48Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 8:2 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 8 min; retention timesfor (S)-48 and (R)-48 were 4.5 and 5.3 min, respectively. (S)-48.Colourless oil (609 mg, 42%). ½a�20

D ¼ þ43:5 (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz): d 7.73 (1H, s, Ar-H), 7.63 (2H, m, 2 � Ar-H),7.50 (1H, m, Ar-H), 4.98 (1H, m, CH-OH), 3.65 (1H, dd, J = 10.6,3.5 Hz, CHAHB), 3.51 (1H, dd, J = 10.6, 8.4 Hz, CHAHB); ee = 97.6%.(R)-48. Pale yellow oil (253 mg, 25%). ½a�20

D ¼ �43:0 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.73 (1H, s, Ar-H), 7.63 (2H, m,2 � Ar-H), 7.51 (1H, m, Ar-H), 4.98 (1H, m, CH-OH), 3.65 (1H, dd,J = 10.6, 3.5 Hz, CHAHB), 3.51 (1H, dd, J = 10.6, 8.5 Hz, CHAHB);ee = 99.9%.

4.4.11. 2-Chloro-1-(2,4-difluorophenyl)ethanol 49Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 15 min; retentiontimes for (S)-49 and (R)-49 were 10.2 and 9.0 min, respectively.(S)-49. Colourless oil (1140 mg, 81%). ½a�20

D ¼ þ38:0 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.53 (1H, m, Ar-H), 6.92 (1H, m,Ar-H), 6.81 (1H, m, Ar-H), 5.18 (1H, m, CH-OH), 3.81 (1H, dd,J = 11.3, 3.3 Hz, CHAHB), 3.62 (1H, dd, J = 11.2, 8.4 Hz, CHAHB);ee = 99.5. (R)-49. Pale yellow oil (1070 mg, 78%). ½a�20

D ¼ �38:6 (c1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.53 (1H, m, Ar-H), 6.94(1H, m, Ar-H), 6.81 (1H, m, Ar-H), 5.18 (1H, m, CH-OH), 3.81 (1H,dd, J = 11.2, 3.3 Hz, CHAHB), 3.62 (1H, dd, J = 11.1, 8.3 Hz, CHAHB);ee = 100.

4.4.12. 1-(4-Bromophenyl)-2-chloroethanol 50Analysis of the enantiomeric excess was performed on a Chiral-

cel OJ column with eluent 9:1 hexane/IPA, flow rate 1 mL min�1,detection 254 nm and run time 16 min; retention times for

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1377

(S)-50 and (R)-50 were 13.6 and 12.3 min, respectively. (S)-50.White solid (1105 mg, 91%). ½a�20

D ¼ þ40:2 (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz): d 7.51 (2H, m, 2 � Ar-H), 7.27 (2H, m, 2 �Ar-H), 4.88 (1H, m, CH-OH), 3.72 (1H, dd, J = 11.3, 3.5 Hz, CHAHB),3.60 (1H, dd, J = 11.2, 8.6 Hz, CHAHB); ee = 99.9%. (R)-50. Whitesolid (1131 mg, 93%). ½a�20

D ¼ �39:4 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 7.51 (2H, m, 2 � Ar-H), 7.27 (2H, m, 2 � Ar-H), 4.87(1H, m, CH-OH), 3.72 (1H, dd, J = 11.2, 3.4 Hz, CHAHB), 3.60 (1H,dd, J = 11.2, 8.6 Hz, CHAHB); ee = 99.6%.

4.4.13. 2-Chloro-1-(4-fluorophenyl)ethanol 51Analysis of the enantiomeric excess was performed on a Chiral-

cel OB-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 210 nm and run time 17 min; retentiontimes for (S)-51 and (R)-51 were 13.7 and 12.0 min, respectively.(S)-51. Dark yellow oil (1175 mg, 96%). ½a�20

D ¼ þ52:8 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.37 (2H, m, 2 � Ar-H), 7.07 (2H, m,2 � Ar-H), 4.89 (1H, m, CH-OH), 3.72 (1H, dd, J = 11.3, 3.5 Hz,CHAHB), 3.62 (1H, dd, J = 11.2, 8.7 Hz, CHAHB); ee = 98.4%. (R)-51.Dark yellow oil (1185 mg, 96%). ½a�20

D ¼ �54:6 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 7.37 (2H, m, 2 � Ar-H), 7.07 (2H, m,2 � Ar-H), 4.89 (1H, m, CH-OH), 3.72 (1H, dd, J = 11.2, 3.5 Hz,CHAHB), 3.62 (1H, dd, J = 11.2, 8.7 Hz, CHAHB); ee = 99.1%.

4.4.14. 2-Chloro-1-phenylethanol 52Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 13 min; retentiontimes for (S)-52 and (R)-52 were 10.3 and 11.2 min, respectively.(S)-52. Pale yellow oil (925 mg, 76%). ½a�20

D ¼ þ57:8 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.40–7.30 (5H, m, 5 � Ar-H), 4.91(1H, m, CH-OH), 3.75 (1H, dd, J = 11.2, 3.4 Hz, CHAHB), 3.65 (1H,dd, J = 11.2, 8.8 Hz, CHAHB); ee = 96.6%. (R)-52. Pale yellow oil(1111 mg, 91%). ½a�20

D ¼ �60:3 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz): d 7.41-7.30 (5H, m, 5 � Ar-H), 4.91 (1H, m, CH-OH),3.75 (1H, dd, J = 11.2, 3.4 Hz, CHAHB), 3.65 (1H, dd, J = 11.2,8.8 Hz, CHAHB); ee = 99.9%.

4.4.15. 5,6,7,8-Tetrahydroisoquinolin-5-ol 53Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 28 min; retentiontimes for (S)-53 and (R)-53 were 21.9 and 23.9 min, respectively.(S)-53. Pale orange solid (951 mg, 76%). ½a�20

D ¼ þ51:7 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.39 (1H, d, J = 5.1, Ar-H),8.34 (1H, s, Ar-H), 7.39 (1H, d, J = 5.0 Hz, Ar-H), 4.74 (1H, m, CH-OH), 2.76 (2H, m, CH2), 2.15–1.76 (4H, m, 2 � CH2); ee = 98.3%.(R)-53. Pale orange solid (921 mg, 78%). ½a�20

D ¼ �53:9 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz): d 8.38 (1H, d, J = 5.1, Ar-H),8.33 (1H, s, Ar-H), 7.39 (1H, d, J = 5.1 Hz, Ar-H), 4.74 (1H, m, CH-OH), 2.76 (2H, m, CH2), 2.12 (1H, m, CHAHB), 2.00 (1H, m, CHAHB),1.81 (2H, m, CH2); ee = 99.8%.

4.4.16. Chroman-4-ol 54Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 85:15 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 8 min; retention timesfor (S)-54 and (R)-54 were 3.6 and 4.3 min, respectively. (S)-54.White solid (594 mg, 44%). ½a�20

D ¼ �65:1 (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz): d 7.32 (1H, m, Ar-H), 7.21 (1H, m, Ar-H), 6.93(1H, m, Ar-H), 6.85 (1H, m, Ar-H), 4.80 (1H, m, CH-OH), 4.28 (2H,m, CH2), 2.13 (1H, m, CHAHB), 2.04 (1H, m, CHAHB); ee = 93.5%.(R)-54. White solid (758 mg, 57%). ½a�20

D ¼ þ66:9 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 7.31 (1H, m, Ar-H), 7.21 (1H, m, Ar-H),6.93 (1H, m, Ar-H), 6.85 (1H, m, Ar-H), 4.80 (1H, m, CH-OH), 4.28(2H, m, CH2), 2.13 (1H, m, CHAHB), 2.04 (1H, m, CHAHB); ee = 99.1%.

4.4.17. 5-Bromo-1,2,3,4-tetrahydronaphthalen-1-ol 55Analysis of the enantiomeric excess was performed on a Chir-

alpak IB column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 10 min; retentiontimes for (S)-55 and (R)-55 were 7.6 and 8.3 min, respectively.(S)-55. White solid (806 mg, 80%). ½a�20

D ¼ �4:0 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 7.48 (1H, m, Ar-H), 7.41 (1H, m, Ar-H),7.08 (1H, t, J = 7.8 Hz, Ar-H), 4.77 (1H, m, CH-OH), 2.85 (1H, m,CHAHB), 2.67 (1H, m, CHAHB), 2.04-1.79 (4H, m, 2 � CH2);ee = 90.9%. (R)-55. White solid (397 mg, 32%). ½a�20

D ¼ þ4:0 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.48 (1H, m, Ar-H), 7.42(1H, d, J = 7.7 Hz, Ar-H), 7.09 (1H, t, J = 7.8 Hz, Ar-H), 4.78 (1H, m,CH-OH), 2.84 (1H, m, CHAHB), 2.68 (1H, m, CHAHB), 2.04–1.80(4H, m, 2 � CH2); ee = 99.3%.

4.4.18. 6-Chloro-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-ol 56

Analysis of the enantiomeric excess was performed on a Chir-alpak AD-H column with eluent 9:1 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 27 min; retentiontimes for (S)-56 and (R)-56 were 19.1 and 16.8 min, respectively.(S)-56. White solid (766 mg, 62%). ½a�20

D ¼ �5:7 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz): d 7.73 (1H, d, J = 9.0 Hz, Ar-H), 7.40 (1H,m, Ar-H), 7.26 (1H, m, Ar-H), 4.80 (1H, m, CH-OH), 4.02 (1H, m,CHAHB), 3.77 (1H, m, CHAHB), 2.92 (3H, s, CH3), 2.10 (2H, m, CH2);ee = 99.3%. (R)-56. White solid (1257 mg, 91%). ½a�20

D ¼ þ4:9 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz): d 7.73 (1H, d, J = 8.9 Hz,Ar-H), 7.40 (1H, m, Ar-H), 7.26 (1H, m, Ar-H), 4.79 (1H, m,CH-OH), 4.02 (1H, m, CHAHB), 3.77 (1H, m, CHAHB), 2.92 (3H,s, CH3), 2.10 (2H, m, CH2); ee = 99.0%.

4.4.19. Isochroman-4-ol 57Analysis of the enantiomeric excess was performed on a Chir-

alpak IA column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 18 min; retentiontimes for (S)-57 and (R)-57 were 14.0 and 15.1 min, respectively.(S)-57. Yellow oil (1023 mg, 93%). ½a�20

D ¼ þ17:6 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz) d 7.45 (1H, m, Ar-H), 7.28 (2H, m, 2 �Ar-H), 6.99 (1H, m, Ar-H), 4.75–4.63 (2H, m, CH2), 4.54 (1H, m,CH-OH), 4.10 (1H, dd, J = 11.9, 2.7 Hz, CHAHB), 3.87 (1H, dd,J = 11.8, 2.7 Hz, CHAHB); ee = 96.0%. (R)-57. Yellow oil (994 mg,78%). ½a�20

D ¼ �18:8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d7.45 (1H, m, Ar-H), 7.28 (2H, m, 2� Ar-H), 7.00 (1H, m, Ar-H), 4.81–4.65 (2H, m, CH2), 4.55 (1H, m, CH-OH), 4.11 (1H, dd, J =12.0, 2.8 Hz, CHAHB), 3.87 (1H, dd, J = 11.9, 2.7 Hz, CHAHB);ee = 95.9%.

4.4.20. 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol 58Analysis of the enantiomeric excess was performed on a Chiral-

cel OB-H column with eluent 3:2 hexane/IPA + 0.1% DEA, flow rate1 mL min�1, detection 254 nm and run time 9 min; retention timesfor (S)-58 and (R)-58 were 6.4 and 5.0 min, respectively. (S)-58.Pale yellow oil (991 mg, 79%). ½a�20

D ¼ þ2:4 (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.53 (1H, d, J = 8.0 Hz, Ar-H), 7.19 (1H, d,J = 8.0 Hz, Ar-H), 5.20 (1H, m, CH-OH), 3.02 (1H, m, CHAHB), 2.81(1H, m, CHAHB), 2.57 (1H, m, CHCHD), 2.08 (1H, m, CHCHD);ee = 99.5%. (R)-58. Pale yellow oil (948 mg, 70%). ½a�20

D ¼ �3:6 (c1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.53 (1H, d, J = 8.0 Hz,Ar-H), 7.18 (1H, d, J = 8.0 Hz, Ar-H), 5.20 (1H, m, CH-OH), 3.02(1H, m, CHAHB), 2.81 (1H, m, CHAHB), 2.57 (1H, m, CHCHD), 2.09(1H, m, CHCHD); ee = 96.3%.

4.4.21. 3-Hydroxy-2,3-dihydrobenzo[b]thiophene 1,1-dioxide 59Analysis of the enantiomeric excess was performed on a

Chiralpak AS-H column with eluent 3:2 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 18 min; retention

1378 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

times for (S)-59 and (R)-59 were 10.8 and 6.7 min, respectively.(S)-59. Pale yellow solid (1110 mg, 92%). ½a�20

D ¼ �55:4 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.76–7.64 (3H, m, 3 � Ar-H),7.59 (1H, m, Ar-H), 5.52 (1H, br, CH-OH), 3.81 (1H, dd, J = 13.5,6.7 Hz, CHAHB), 3.47 (1H, dd, J = 13.5, 4.3 Hz, CHAHB); ee = 98.4%.(R)-59. Pale yellow solid (1120 mg, 99%). ½a�20

D ¼ þ56:8 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.77–7.65 (3H, m, 3 � Ar-H),7.60 (1H, m, Ar-H), 5.53 (1H, br, CH-OH), 3.82 (1H, dd, J = 13.5,6.8 Hz, CHAHB), 3.48 (1H, dd, J = 13.5, 4.3 Hz, CHAHB); ee = 99.8%.

4.4.22. 3-(4-Bromophenyl)-3-hydroxypropanenitrile 60Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 25 min; retentiontimes for (S)-60 and (R)-60 were 18.9 and 21.1 min, respectively.(S)-60. Yellow oil (1245 mg, 93%). ½a�20

D ¼ �46:3 (c 1.0, CHCl3); 1HNMR (DMSO-d6, 400 MHz) d 7.56 (2H, m, 2 � Ar-H), 7.38 (2H, m,2 � Ar-H), 4.90 (1H, m, CH-OH), 2.90 (1H, dd, J = 16.7, 5.0 Hz,CHAHB), 2.82 (1H, dd, J = 16.7, 6.4 Hz, CHAHB); ee = 99.4%. (R)-60.Yellow oil (1136 mg, 93%). ½a�20

D ¼ þ44:6 (c 1.0, CHCl3); 1H NMR(DMSO-d6, 400 MHz) d 7.56 (2H, m, 2 � Ar-H), 7.38 (2H, m,2 � Ar-H), 4.90 (1H, m, CH-OH), 2.90 (1H, dd, J = 16.7, 5.0 Hz,CHAHB), 2.82 (1H, dd, J = 16.7, 6.4 Hz, CHAHB); ee = 97.7%.

4.4.23. 3-Hydroxy-3-phenylpropanenitrile 61Analysis of the enantiomeric excess was performed on a Chiralcel

OJ column with eluent 7:3 hexane/IPA, flow rate 1 mL min�1, detec-tion 254 nm and run time 12 min; retention times for (S)-61 and(R)-61 were 8.2 and 9.2 min, respectively. (S)-61. Brown oil(903 mg, 80%). ½a�20

D ¼ �61:3 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz) d 7.42–7.32 (5H, m, 5 � Ar-H), 5.03 (1H, m, CH-OH), 2.75(2H, m, CH2); ee = 100%. (R)-61. Brown oil (1160 mg, 92%).½a�20

D ¼ þ64:8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.43–7.32(5H, m, 5� Ar-H), 5.04 (1H, m, CH-OH), 2.77 (2H, m, CH2); ee = 99.6%.

4.4.24. 3-Hydroxy-3-(pyridin-4-yl)propanenitrile 62Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 4:1 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 12 min; retentiontimes for (S)-62 and (R)-62 were 10.2 and 8.3 min, respectively.(S)-62. Orange solid (486 mg, 44%). ½a�20

D ¼ �10:6 (c 0.2, CHCl3); 1HNMR (DMSO-d6, 400 MHz) d 8.56 (2H, m, 2 � Ar-H), 7.42 (2H, m,2� Ar-H), 4.94 (1H, m, CH-OH), 3.02–2.83 (2H, m, CH2); ee = 99.6%.(R)-62. Orange solid (620 mg, 54%). ½a�20

D ¼ þ11:5 (c 0.2, CHCl3); 1HNMR (DMSO-d6, 400 MHz) d 8.56 (2H, m, 2 � Ar-H), 7.42 (2H, m,2� Ar-H), 4.94 (1H, m, CH-OH), 3.02–2.83 (2H, m, CH2); ee = 99.8%.

4.4.25. 1-(Pyrimidin-2-yl)piperidin-3-ol 63Analysis of the enantiomeric excess was performed on a Chiral-

cel OJ column with eluent 4:1 hexane/IPA + 0.1% DEA, flow rate1 mL min�1, detection 254 nm and run time 18 min; retentiontimes for (S)-63 and (R)-63 were 7.5 and 6.7 min, respectively.(S)-63. Colourless oil (341 mg, 31%). ½a�20

D ¼ þ44:4 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz) d 8.29 (2H, m, 2 � Ar-H), 6.46 (1H, t,J = 4.7 Hz, Ar-H), 4.11 (1H, m, N-CHAHB), 3.95–3.83 (2H, m, N-CHCHD,CH-OH), 3.66–3.58 (2H, m, N-CHAHB, N-CHCHD), 1.98–1.50 (4H, m,2� CH2); ee = 99.2%. (R)-63. Colourless oil (369 mg, 39%).½a�20

D ¼ �44:5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 8.29 (2H,m, 2 � Ar-H), 6.46 (1H, t, J = 4.7 Hz, Ar-H), 4.12 (1H, dd, J = 13.1,3.4 Hz, N-CHAHB), 3.96–3.83 (2H, m, N-CHCHD, CH-OH), 3.66–3.57(2H, m, N-CHAHB, N-CHCHD), 1.98–1.50 (4H, m, 2 � CH2); ee = 94.8%.

4.4.26. 1-(Pyridin-2-yl)pyrrolidin-3-ol 64Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 30 min; retention

times for (S)-64 and (R)-64 were 19.3 and 21.9 min, respectively.(S)-64. Yellow oil (622 mg, 56%). ½a�20

D ¼ þ34:1 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz) d 8.15 (1H, m, Ar-H), 7.44 (1H, m, Ar-H),6.54 (1H, m, Ar-H), 6.37 (1H, d, J = 8.5 Hz, Ar-H), 4.61 (1H, m, CH-OH), 3.67–3.50 (4H, m, 2 � CH2), 2.21–2.04 (2H, m, CH2);ee = 99.9%. (R)-64. Yellow oil (573 mg, 56%). ½a�20

D ¼ �29:3 (c 1.0,CHCl3); 1H NMR (CDCl3, 400 MHz) d 8.15 (1H, m, Ar-H), 7.44 (1H,m, Ar-H), 6.54 (1H, m, Ar-H), 6.37 (1H, d, J = 8.5 Hz, Ar-H), 4.61(1H, m, CH-OH), 3.67–3.50 (4H, m, 2 � CH2), 2.19–2.06 (2H, m,CH2); ee = 95.6%.

4.4.27. 1-(Pyrimidin-2-yl)pyrrolidin-3-ol 65Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 28 min; retentiontimes for (S)-65 and (R)-65 were 23.3 and 21.0 min, respectively.(S)-65. Off-white solid (421 mg, 40%). ½a�20

D ¼ þ68:5 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz) d 8.32 (2H, m, 2 � Ar-H), 6.49 (1H, t,J = 4.8 Hz, Ar-H), 4.62 (1H, br, CH-OH), 3.79–3.63 (4H, m,2 � CH2), 2.20–2.04 (2H, m, CH2); ee = 99.9%.

4.4.28. (4-Bromophenyl)(cyclopropyl)methanol 66Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 14 min; retentiontimes for (S)-66 and (R)-66 were 11.2 and 10.0 min, respectively.(S)-66. Pale yellow oil (616 mg, 58%). ½a�20

D ¼ þ32:1 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz) d 7.50 (2H, m, 2 � Ar-H), 7.33 (2H, m,2 � Ar-H), 4.00 (1H, d, J = 8.2 Hz, CH-OH), 1.19 (1H, m, CH), 0.71–0.60 (4H, m, 2 � CH2); ee = 99.0%. (R)-66. Pale yellow oil (611 mg,60%). ½a�20

D ¼ �36:3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d7.50 (2H, m, 2 � Ar-H), 7.33 (2H, m, 2 � Ar-H), 4.00 (1H, m, CH-OH), 1.19 (1H, m, CH), 0.70–0.61 (4H, m, 2 � CH2); ee = 99.4%.

4.4.29. Cyclopropyl(pyridin-4-yl)methanol 67Analysis of the enantiomeric excess was performed on a Chir-

alpak AS-H column with eluent 9:1 hexane/IPA + 0.1% DEA, flowrate 1 mL min�1, detection 254 nm and run time 16 min; retentiontimes for (S)-67 and (R)-67 were 11.4 and 8.0 min, respectively.(S)-67. Brown oil (564 mg, 54%). ½a�20

D ¼ þ32:7 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz) d 8.55 (2H, m, 2� Ar-H), 7.36 (2H, m,2� Ar-H), 4.02 (1H, d, J = 8.4 Hz, CH-OH), 1.17 (1H, m, CH), 0.70-0.43 (4H, m, 2� CH2); ee = 99.9%. (R)-67. Brown oil (536 mg, 52%).½a�20

D ¼ þ36:2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 8.56 (2H,m, 2� Ar-H), 7.36 (2H, m, 2� Ar-H), 4.02 (1H, d, J = 8.4 Hz, CH-OH), 1.16 (1H, m, CH), 0.70–0.43 (4H, m, 2 � CH2); ee = 99.7%.

4.4.30. 2-Methyl-1-(pyridin-3-yl)propan-1-ol 68Analysis of the enantiomeric excess was performed on a Chiral-

cel OD-H column with eluent 9:1 hexane/IPA + 0.1% DEA, flow rate1 mL min�1, detection 254 nm and run time 15 min; retentiontimes for (S)-68 and (R)-68 were 10.7 and 12.2 min, respectively.(S)-68. Colourless oil (1046 mg, 94%). ½a�20

D ¼ �52:0 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz) d 8.50 (2H, m, 2 � Ar-H), 7.68 (1H, m,Ar-H), 7.27 (1H, m, Ar-H), 4.45 (1H, d, J = 6.5 Hz, CH-OH), 1.98(1H, m, CH(CH3)2), 0.99 (3H, d, J = 6.7 Hz, CH3), 0.83 (3H, d,J = 6.8 Hz, CH3); ee = 98.7%. (R)-68. Colourless oil (1018 mg, 93%).½a�20

D ¼ �52:0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 8.47(2H, m, 2 � Ar-H), 7.68 (1H, m, Ar-H), 7.27 (1H, m, Ar-H), 4.44(1H, d, J = 6.6 Hz, CH-OH), 1.97 (1H, m, CH(CH3)2), 0.99 (3H, m,CH3), 0.83 (3H, m, CH3); ee = 99.7%.

4.4.31. 1-(3-Chlorophenyl)-2-methylpropan-1-ol 69Analysis of the enantiomeric excess was performed on a

Chiralpak IB column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 8 min; retention times

Figure 6. Optimised geometries, relative energies and Boltzmann populations of the three calculated conformers of the (S)-configuration.

Figure 7. The IR and VCD spectra of each of the three lowest energy-conformerscompared with the observed spectra.

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1379

for (S)-69 and (R)-69 were 6.0 and 6.6 min, respectively. (S)-69. Col-ourless oil (812 mg, 76%). ½a�20

D ¼ �31:6 (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.33–7.16 (4H, m, 4 � Ar-H), 4.37 (1H, m, CH-OH), 1.94 (1H, m, CH(CH3)2), 1.85 (1H, d, J = 3.4 Hz, CH-OH), 0.98(3H, d, J = 6.7 Hz, CH3), 0.83 (3H, d, J = 6.8 Hz, CH3); ee = 97.7%. (R)-69. Colourless oil (673 mg, 58%). ½a�20

D ¼ þ30:6 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz) d 7.33–7.17 (4H, m, 4 � Ar-H), 4.37 (1H, m,CH-OH), 1.94 (1H, m, CH(CH3)2), 1.85 (1H, d, J = 3.4 Hz, CH-OH),0.98 (3H, d, J = 6.7 Hz, CH3), 0.83 (3H, d, J = 6.8 Hz, CH3); ee = 99.5%.

4.4.32. 2,2,2-Trifluoro-1-(6-fluoro-1-methyl-1H-indol-3-yl)ethanol70

Analysis of the enantiomeric excess was performed on a Chir-alpak AD-H column with eluent 9:1 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 17 min; retentiontimes for (S)-70 and (R)-70 were 10.9 and 13.3 min, respectively.(S)-70. White solid (911 mg, 89%). ½a�20

D ¼ þ12:9 (c 1.0, CHCl3); 1HNMR (CDCl3, 400 MHz) d 7.64 (1H, m, Ar-H), 7.20 (1H, s, Ar-H),7.01 (1H, m, Ar-H), 6.94 (1H, m, Ar-H), 5.30 (1H, m, CH-OH), 3.75(3H, s, CH3); ee = 99.9%. (R)-70. White solid (777 mg, 71%).½a�20

D ¼ �14:8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.64(1H, m, Ar-H), 7.20 (1H, s, Ar-H), 7.01 (1H, m, Ar-H), 6.95 (1H, m,Ar-H), 5.31 (1H, m, CH-OH), 3.76 (3H, s, CH3); ee = 99.9%.

4.4.33. 1-(4-Chlorophenyl)-2,2,2-trifluoroethanol 71Analysis of the enantiomeric excess was performed on a Chir-

alpak IB column with eluent 9:1 hexane/IPA, flow rate 1 mL min�1,detection 254 nm and run time 7 min; retention times for (S)-71and (R)-71 were 5.4 and 4.8 min, respectively. (S)-71. Pale yellowoil (716 mg, 65%). ½a�20

D ¼ þ26:1 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz) d 7.44–7.37 (4H, m, 4 � Ar-H), 5.02 (1H, m, CH-OH);ee = 98.7%. (R)-71. Pale yellow oil (758 mg, 68%). ½a�20

D ¼ �28:7 (c1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.44–7.37 (4H, m,4 � Ar-H), 5.02 (1H, m, CH-OH); ee = 99.8%.

4.4.34. 1-(3-Chlorophenyl)-2,2,2-trifluoroethanol 72Analysis of the enantiomeric excess was performed on a Chir-

alpak IB column with a Phenomenex Sphereclone 5l silica(150 � 4.6 mm) pre-column with eluent 95:5 hexane/IPA, flow rate1 mL min�1, detection 254 nm and run time 15 min; retentiontimes for (S)-72 and (R)-72 were 10.9 and 10.0 min, respectively.(S)-72. Pale yellow oil (853 mg, 81%). ½a�20

D ¼ þ23:1 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz) d 7.50 (1H, s, Ar-H), 7.41–7.32 (3H, m,3 � Ar-H), 5.02 (1H, m, CH-OH); ee = 99.6%. (R)-72. Colourless oil(1006 mg, 89%). ½a�20

D ¼ �24:5 (c 1.0, CHCl3); 1H NMR (CDCl3,400 MHz) d 7.50 (1H, s, Ar-H), 7.41–7.32 (3H, m, 3 � Ar-H), 5.02(1H, m, CH-OH); ee = 95.3%.

4.4.35. 4-(2,2,2-Trifluoro-1-hydroxyethyl)benzoic acid 73Analysis of the enantiomeric excess was performed on a Chir-

alpak AD-H column with eluent 9:1 hexane/IPA + 0.05% TFA, flow

rate 1 mL min�1, detection 254 nm and run time 18 min; retentiontimes for (S)-73 and (R)-73 were 10.0 and 14.0 min, respectively.(S)-73. White solid (823 mg, 78%). ½a�20

D ¼ þ24:5 (c 1.0, MeOH);1H NMR (DMSO-d6, 400 MHz) d 7.98 (2H, m, 2 � Ar-H), 7.62 (2H,m, 2 � Ar-H), 5.28 (1H, m, CH-OH); ee = 93.4%. (R)-73. White solid(965 mg, 90%). ½a�20

D ¼ �34:6 (c 1.0, MeOH); 1H NMR (DMSO-d6,400 MHz) d 7.98 (2H, m, 2 � Ar-H), 7.62 (2H, m, 2 � Ar-H), 5.29(1H, m, CH-OH); ee = 99.7%.

4.5. Large scale bioreduction

A161 cell free extract powder (5 g) was dissolved in 0.1 M phos-phate buffer (pH 7, 10 L) and stirred at 30 �C. Next, para-bromoph-enacyl chloride 15 (500 g, 2.14 mol) was dissolved in DMSO(200 mL) and added to the stirring solution, followed by NAD(1 g) and isopropyl alcohol (1 L). Reaction progress was monitored

1380 A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381

by HPLC analysis. After 6 h, the reaction was complete. The reac-tion mixture was extracted with MTBE (2 � 2 L), and the organicsolvent was dried (MgSO4, 300 g), filtered and concentrated invacuo to afford compound (S)-50 (458 g, 1.94 mol, 91% yield) as apale orange oil. Analysis of the ee was performed as described insection 4.4.12; ee of (S)-50 = 99.8%; ½a�20

D ¼ þ40:2 (c 1.0, CHCl3);1H NMR (CDCl3, 400 MHz): d 7.53 (2H, m, 2 � Ar-H), 7.30 (2H, m,2 � Ar-H), 4.89 (1H, m, CH-OH), 3.73 (1H, dd, J = 11.2, 3.7 Hz,CHAHB), 3.63 (1H, dd, J = 11.2, 8.4 Hz, CHAHB).

4.6. Example of the procedure for the absolute structure determinationby VCD

VCD measurement: Chiral alcohol 39 from the reduction ofketone 4 by CRED A601 was dissolved in CDCl3 (17.9 mg/0.2 mL)and placed in a 100 lm path-length cell with BaF2 windows. Next,the IR and VCD spectra were recorded on a ChiralIRTM FT-VCD spec-trometer with Dual PEM (BioTools, Inc.), with 4 cm�1 resolutionand 10 h collection. The spectrum of CDCl3 was measured for 9 hfor VCD baseline correction and also used for subtraction of solventfor IR. The PEMs were optimised at 1400 cm�1.

Structure modelling and calculations of IR and VCD spectra: The(S)-configuration of chiral alcohol 39 was built with Hyperchem8(Hypercube, Gainesville, FL). A conformational search was carriedout with Hyperchem8 at the molecular mechanics level and resultedin nine low energy conformers. Geometry optimisation, frequencyand IR and VCD intensity calculations were then carried out at theDFT level with GAUSSIAN 09 (Gaussian Inc., Wallingford, CT) with theB3LYP hybrid functional and the 6-31G(d) basis set. The calculatedfrequencies were scaled by 0.97 and the IR and VCD intensities were

Figure 8. The observed VCD and IR spectra of the sample compared with those ofthe Boltzmann averaged VCD spectra of (S)- and (R)-configuration. The absoluteconfiguration of chiral alcohol 39 was assigned as (R).

converted to Lorentzian bands with 6 cm�1 half-width for compari-son to experiment. Three of the nine conformers had energies of lessthan 2 kcal/mol difference to that of the lowest-energy conformer(Fig. 6). By comparing the observed VCD and IR spectra of the sam-ples with those of the Boltzmann averaged VCD spectra of (S)- and(R)-configuration (Fig. 8; Boltzmann averaged from the predictedVCD spectra of the individual conformers shown in Fig. 7), the abso-lute configuration of chiral alcohol 39 was assigned as (R).

Acknowledgements

The authors wish to thank the UK Technology Strategy Board forits generous financial support of this project. Meredith Lloyd-Jones(BioBridge Ltd) and the Chemistry Innovation and BiosciencesKnowledge Transfer Networks are also thanked for co-ordinatingthe project and guidance in setting up this collaboration, respec-tively. Furthermore, Olivier Drap, Neal Sach and Andrew Cronin(Pfizer) are thanked for support and helpful discussions. This studywas part financed by the European Regional Development Fundunder the European Sustainable Competitiveness Program forNorthern Ireland.

References

1. Mack, D. J.; Weinrich, M. L.; Vitaku E.; Njarðarson, J. T. http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster.

2. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994;(b) Cho, B. T. Chem. Soc. Rev. 2009, 38, 443–452; (c) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2011, 50, 7329–7332.

3. (a) Moody, T. S.; Mix, S. Pharma Magn. 2011, 20; (b) Moody, T. S.; Geffroy, D. SP2Magn. 2011, 27.

4. Moody, T. S.; Mangan, D. Spec. Chem. 2011, 20.5. (a) Brown, G.; Mangan, D.; Miskelly, I.; Moody, T. S. Org. Process Res. Dev. 2011,

15, 1036–1039; (b) Calvin, S. J.; Mangan, D.; Moody, T. S.; Stevenson, P. J. Org.Process Res. Dev. 2012, 16, 82–86; (c) Matsuda, T.; Yamanaka, R.; Nakamura, K.Tetrahedron: Asymmetry 2009, 20, 513–557; (d) Borges, K. B.; de Souza Borges,W.; Durán-Patrón, R.; Pupo, M. T.; Bonato, P. S.; Collado, I. G. Tetrahedron:Asymmetry 2009, 20, 385–397; (e) Kaluzna, I. A.; Rozzell, J. D.; Kambourakis, S.Tetrahedron: Asymmetry 2005, 16, 3682–3689; (f) Weckbecker, A.; Hummel, W.Biocatal. Biotransform. 2006, 24, 380–389.

6. (a) Padhi, S. K.; Kaluzna, I. A.; Buisson, D.; Azerad, R.; Stewart, J. D. Tetrahedron:Asymmetry 2007, 18, 2133–2138; (b) Panizza, P.; Onetto, S.; Rodríguez, S.Biocatal. Biotransform. 2007, 25, 414–417; (c) Zhu, D.; Yang, Y.; Hua, L. J. Org.Chem. 2006, 71, 4202–4205; (d) Kosjek, B.; Nti-Gyabaah, J.; Telari, K.; Dunne, L.;Moore, J. C. Org. Process Res. Dev. 2008, 12, 584–588; (e) Kataoka, M.;Yamamoto, K.; Kawabata, H.; Wada, M.; Kita, K.; Yanase, H.; Shimizu, S. Appl.Microbiol. Biotechnol. 1999, 51, 486–490; (f) Matsuda, T.; Yamagishi, Y.;Koguchi, S.; Iwai, N.; Kitazume, T. Tetrahedron Lett. 2006, 47, 4619–4622.

7. For an explanation of Prelog’s rule for ketone bioreduction enantioselectivitysee (a) Pscheidt, B.; Glieder, A. Microb. Cell Fact. 2008, 7, 25; (b) Prelog, V. PureAppl. Chem. 1964, 9, 119–130.

8. Private communication from Enamine Ltd, Ukraine; ((1R)-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethan-1-ol) [a]D = +13.2 (c 0.75 M, MeOH).

9. Pal, M.; Srivastava, G.; Moon, L. S.; Jolly, R. S. Bioresour. Technol. 2012, 118, 306–314.

10. Zhu, D.; Hyatt, B. A.; Hua, L. J. Mol. Catal. B Enzym. 2009, 56, 272–276.11. Stepanenko, V.; Ortiz-Marciales, M.; Barnes, C. L.; Garcia, C. Tetrahedron Lett.

2009, 50, 995–998.12. Lin, H.; Chen, Y.-Z.; Xu, X.-Y.; Xia, S.-W.; Wang, L.-X. J. Mol. Catal. B Enzym. 2009,

57, 1–5.13. Wu, X.-F.; Min, C.; Nyamzundui, E.; Zhou, H.-B.; Dong, C. Tetrahedron:

Asymmetry 2011, 22, 1640–1643.14. Zhu, D.; Mukherjee, C.; Hua, L. Tetrahedron: Asymmetry 2005, 16, 3275–3278.15. Hsin, L.-W.; Chang, L.-T.; Liou, H.-L. Synlett 2008, 2299–2302.16. Ursini, C. V.; Dias, G. H. M.; Rodrigues, J. A. R. J. Organomet. Chem. 2005, 690,

3176–3186.17. Xie, Y.; Huang, H.; Mo, W.; Fan, X.; Shen, Z.; Shen, Z.; Sun, N.; Hu, B.; Hu, X.

Tetrahedron: Asymmetry 2009, 20, 1425–1432.18. Liu, K. K-C.; Cornelius, P.; Patterson, T. A.; Zeng, Y.; Santucci, S.; Tomlinson, E.;

Gibbons, C.; Maurer, T. S.; Marala, R.; Brown, J.; Kong, J. X.; Lee, E.; Werner, W.;Wenzel, Z.; Vage, C. Bioorg. Med. Chem. Lett. 2010, 20, 266–271.

19. Zhu, D.; Ankati, H.; Mukherjee, C.; Yang, Y.; Biehl, E. R.; Hua, L. Org. Lett. 2007, 9,2561–2563.

20. Vázquez-Villa, H.; Reber, S.; Ariger, M. A.; Carreira, E. M. Angew. Chem., Int. Ed.2011, 50, 8979–8981.

21. Xu, Q.; Zhou, H.; Geng, X.; Chen, P. Tetrahedron 2009, 65, 2232–2238.22. Matsuda, T.; Harada, T. J. Org. Chem. 2000, 65, 157–163.23. Zhao, H.; Qin, B.; Liu, X.; Feng, X. Tetrahedron 2007, 29, 6822–6826.

A. S. Rowan et al. / Tetrahedron: Asymmetry 24 (2013) 1369–1381 1381

24. Fujisawa, T.; Ichikawa, K.; Shimizu, M. Tetrahedron: Asymmetry 1993, 6, 1237–1240.

25. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.Chem. 1986, 51, 2370–2374.

26. Stephens, P. J.; Devlin, F. J.; Pan, J.-J. Chirality 2008, 20, 643–663.27. An example of the procedure for the assignment of the absolute

stereochemistry is given in the Experimental.

28. Henderson, R. K.; Kindervater, J.; Manley, J. Lessons Learned through MeasuringGreen Chemistry Performance—The Pharmaceutical Experience; AmericanChemical Society Green Chemistry Institute Pharmaceutical RoundtableBenchmarking: Washington, DC, 2006. http://portal.acs.org/portal/PublicWebSite/greenchemistry/industriainnovation/roundtable/CTP_005585.

29. For an example see Badland, M.; Burns, M. P.; Carroll, R. J.; Howard, R. M.; Laity,D.; Wymer, N. J. Green Chem. 2011, 13, 2888–2894.