On the lipase-catalyzed resolution of functionalized biaryls

Tetrahedron: Asymmetry 24 (2013) 1052–1056

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On the lipase-catalyzed resolution of functionalized biaryls Benedikt Skrobo, Jan Deska ⇑ Department für Chemie, Universität zu Köln, 50939 Cologne, Germany

a r t i c l e

i n f o

Article history: Received 20 June 2013 Accepted 9 July 2013

a b s t r a c t The implementation of lipase catalysis as a tool for the preparation of optically active biaryls is discussed. While attempts toward dynamic kinetic resolution based on the catalytic ring opening of configurationally unstable biaryl lactones were fruitless, kinetic resolution via transesterification of hydroxymethyldecorated substrates was successfully employed in the generation of optically enriched, axially chiral biaryls. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Atropisomeric biaryls are among the most prominent representatives of non-central chirality and their unique architecture has attracted much interest among chemists with different research areas over the years. Almost ubiquitous, biaryl subunits are nowadays found as a key element in a wide range of catalyst systems. Binaphthyl-based ligand families such as BINAPs or MonoPhos phosphoramidites represent benchmark systems with regard to the development of metal-catalyzed asymmetric transformations.1 Likewise, atropisomeric binaphthyl backbones are one of the privileged structural elements in modern organocatalysis,2 as reflected by the evolution of TRIP-type phosphoric acids and related Brønsted-acid catalysts.3 Moreover, Nature itself utilizes axially chiral biaryl building blocks for the construction of structurally interesting secondary metabolites that not uncommonly exhibit remarkable biological activities.4,5 Powerful methods for the stereoselective preparation of rotationally hindered biaryls have been the focus of many research groups and various fundamentally different strategies have been successfully designed.5 Both with regard to the conceptual foundation as well as its broad applicability, Bringmann’s lactone concept stands out as an interesting synthetic principle for the atroposelective synthesis of non-C2-symmetric highly functionalized biaryls.6–8 Based on the observation that the helically-twisted structure of lactone-bridged biaryls often exhibit remarkably lower isomerization barriers when compared to their corresponding non-bridged axially chiral derivatives, various methods for stereoselective lactone cleavage have been developed. Thanks to the fast helimerization of those twisted substrates, for example, (M)-1 to (P)-1 (Scheme 1), dynamic kinetic ring opening can be achieved by nucleophiles as simple as non-racemic chiral alkoxides9 or amides10 to give axially ⇑ Corresponding author. Tel.: +49 (221)4707991; fax: +49 (221)4705102. E-mail address: [email protected] (J. Deska). 0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.07.014

KHN

H N HO

Ph

O

THF 0 °C to r.t. O

(P,S)-2 85%, 90% de

O

(M)-1

(–)-Me-CBS (10 mol%) BH3·THF

OH HO

THF 30 °C (M)-3 94%, 88% ee

O O

(P)-1 spontaneous helimerization (t1/2 < 1 min at r.t.)

(+)-H8-BINAP (24 mol%) AgBF4 (20 mol%)

OMe HO

O

THF/MeOH –20 °C (M)-4 92%, 82% ee

Scheme 1. Dynamic kinetic lactone cleavage.

chiral products in high yield and with excellent enantiomeric purity [see (P,S)-2, Scheme 1]. Apart from stoichiometric reagents, catalytic protocols have also found application such as Corey– Bakshi–Shibata-type reductions to give rotationally hindered, primary alcohols (P)-3,5,11 or silver-mediated alcoholysis for access toward non-racemic biaryl esters ((M)-4).12

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Based on our recent studies on the use of enzyme catalysts for the enantioselective synthesis of axially chiral allenic building blocks,13–15 we were interested in investigating the potential application of biocatalysts for the atroposelective transformation of helically-twisted biaryl lactones. We envisioned lipase-mediated transesterification as being a valuable supplement to the field of catalytic biaryl synthesis. Moreover, with only a few successful examples given in the literature,16–21 more fundamental studies on enzymatic transformations of biaryl substrates would be desirable. 2. Results and discussion Without a reported precedent for the enzymatic ring opening of biaryl lactones, we started our studies with a thorough investigation of potential catalysts for the alcoholysis of model lactone 5. Thus, racemic 5 was incubated in a solution of toluene and n-butanol (10% v/v) in the presence of 17 different lipases and pig liver esterase (100 wt.-%) at 40 °C. Unfortunately, the majority of proteins tested did not show any activity and 5 could be recovered quantitatively. However for some of the enzymes, after an extended reaction time of 7 days, a slight conversion could be detected reaching up to 11% of the desired butyl ester 6 (Table 1).

compete with the examples of atroposelective dynamic kinetic ring opening presented by Bringmann and others, we were still eager to take a closer look at the axially chiral biaryl architecture itself. We argued that the obvious lack of reactivity might be attributed to the large bulk around the carboxylate, making it problematic to achieve productive interaction with the active site’s catalytic triade. However, thanks to our recent successful studies on the kinetic resolution of N-stereogenic functionalized Tröger’s bases using hydroxymethyl-groups as enzyme-binding entities, we knew that very bulky substrates could be used as nucleophiles in lipasecatalyzed transesterifications.23 With the biaryl lactones in hand, the preparation of the corresponding primary alcohols was straightforward. Thus, after treatment of lactones 1 and 5 with lithium aluminiumhydride, racemic biaryl methanols 3 and 7 were isolated in 87% and 92% yield, respectively (Scheme 2).

O

OH LiAlH4

O

OH THF 0 °C, 90 min

R

R

R' Table 1 Alcoholysis of biaryl lactone 5a

O

toluene 40 °C, 7 days

R=H, R'=CH3: rac-3, 87% R=CH3, R'=H: rac-7, 92%

R=H, R'=CH3: rac-1 R=CH3, R'=H: rac-5

Scheme 2. Lactone reduction give biaryl methanols.

lipase n-butanol

O

R'

O HO

*

O

6

rac-5 Entry

Lipase from

Conv. (%)

ee (6) (%)

1 2 3 4 5 6 7 8

Aspergillus niger Candida antarctica type A Candida antarctica type B Chromobacterium viscosum Mucor miehei Pseudomonas cepacia Pig liver (esterase) Rhizopus niveus

4 6 11 1 6 8 6 2

10 1 0 7 5 5 13 8

Subsequently, another enzyme screening was conducted, this time incubating alcohol rac-7 together with isopropenyl acetate as acyl donor and different lipases in toluene at 40 °C for three days. Out of 23 commercially available protein preparations four lipases exhibited substantial reactivity. Both lipases from Candida antarctica gave relatively fast conversion, although the low enantiomeric purity of both alcohol 7 and acetate 8 indicated a very low enantioselectivity (Table 2, entries 1 and 2). Candida rugosa

Table 2 Kinetic resolution of alcohol 7a

a Reaction conditions: rac-5 (1.0 mg), enzyme (1.0 mg), toluene (180 ll), n-butanol (20 ll), 40 °C, 168 h. Conversion and enantiomeric excess were determined by HPLC on a chiral stationary phase from the crude mixture.

Hardly any conversion rates exceeded the 10% threshold nor did any enantiomeric purities with only Aspergillus niger lipase and pig liver esterase catalyzing the formation of 6 and giving rise to two-digit enantiomeric excesses (10% ee and 13% ee,22 respectively; Table 1, entries 1 and 7). Further attempts to achieve atroposelective ring opening by other means failed entirely. Conversely, all of the proteins that were evaluated positively in the alcoholysis were also tested under various hydrolytic reaction conditions. Regardless of whether the solvent systems were biphasic (toluene/phosphate buffer) or aqueous (DMSO-solution), not even trace amounts of the naphthoic acid derivative could be detected. On the other hand, replacement of the O-nucleophiles by benzylamine led to the faster appearance of the ring opened biaryl, although the product formation was entirely based on the non-catalyzed attack of the nitrogen nucleophile leading to a completely racemic amide. At this point, we concluded that the originally envisioned lactone cleavage employing lipase catalysts was not applicable without major optimization or fundamental alteration of the system. Despite the fact that this protocol would by no means be able to

OH OH OAc OH OH

(P)-7 lipase + toluene 40 °C, 66 h OAc

rac-7

HO (M)-8

Entry

Lipase from

Conv. (%)

ee (7) (%)

ee (8) (%)

E

1 2 3 4

C. antarctica type A C. antarctica type B C. rugosa M. miehei

83 86 60 63

7 9 72 86

3 5 48 50

1.1 1.2 5.9 7.8

a Reaction conditions: rac-7 (1.0 mg), isopropenyl acetate (2.0 ll), lipase (1.0 mg), toluene (0.1 ml), 40 °C, 66 h. Conversion and enantiomeric excess determined by HPLC on chiral stationary phase from the crude mixture.

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lipase showed a considerably enhanced selectivity (E = 5.9) giving rise to compounds 7 and 8 in moderate to good enantiopurity (Table 2, entry 3). The lipase from Mucor miehei gave the most promising results with enantiomeric excess of 86% for alcohol 7 after slight over acylation with 63% overall conversion (Table 2, entry 4). Attempts to further improve the moderate enantioselectivity by means of other solvents or temperature adaption were unsuccessful. Accordingly, both alcohols rac-3 and rac-7 were resolved preparatively under similar conditions using one weight equivalent of Lipozyme IM (immobilized M. miehei lipase) and five equivalents of isopropenyl acetate. After three days, the remaining optically enriched alcohols 3 and 7 were isolated in yields of 27% and 33%, respectively (Scheme 3). Alcohol 3 was obtained with a slightly lower enantiomeric excess of 79% as compared to 7, which was obtained in 87% ee. The absolute configuration of the remaining enantiomer of alcohol 3 was confirmed as the (P)-isomer by comparison of its specific rotation with the literature data 20 {½a20 D ¼ þ21:9 (c 0.80, CHCl3) 79% ee; lit: ½aD ¼ 26:9 (c 0.61, 24 CHCl3) 89% ee, M-isomer }. With regard to the structural similarity and conformity of the chiroptical properties of 3 and 7, both in the sense and magnitude of the rotation, axially chiral 7 was also assigned to have a (P)-configuration.

OAc OH OH

OH

lipase from Mucor miehei

OH

4.2. Synthesis of the racemic samples

R

4.2.1. (±)-1,3-Dimethyl-6H-benzo[b]naphtho[1,2-d]pyranone 125 Under an argon atmosphere, 1-bromo-2-naphthoic acid (3,5-dimethyl phenyl)ester (354 mg, 1.0 mmol) was dissolved in anhydrous N,N-dimethylacetamide (7.5 ml), after which were added Pd(OAc)2 (90 mg, 0.4 mmol), triphenyl phosphine (157 mg, 0.6 mmol), and sodium acetate (328 mg, 4.0 mmol) and the reaction mixture was stirred at 145 °C for 16 h. The mixture was cooled to room temperature, filtered through cotton and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate (20 ml), washed with aq HCl (0.5 M, 10 ml) and sat aq NaHCO3 (10 ml), and dried over MgSO4. After removal of the solvent under reduced pressure, the lactone was purified by column chromatography (SiO2, cyclohexane/ethyl acetate 97/3 to 93/7) and 1 was obtained as a colorless solid (129 mg, 0.47 mmol, 47%). Mp (CH2Cl2/MTBE): 154 °C. Rf: 0.43 (cyclohexane/ethyl acetate 9/1). 1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 8.5 Hz, 1H), 7.76–7.34 (m, 3H), 7.47 (dd, J = 8.5 Hz, J = 7.3 Hz, 1H), 7.36 (dd, J = 8.7 Hz, J = 7.6 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 2.47 (s, 3H), 2.27 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 161.7, 151.8, 140.1, 136.3, 136.2, 135.4, 128.9, 128.8, 128.8, 128.6, 128.2, 128.0, 125.9, 123.9, 121.1, 115.9, 114.6, 23.7, 21.9. FT-IR (ATR): m [cm1] = 3061 (w), 2922 (m), 2853 (w), 1715 (s, br), 1614 (m), 756 (s).

toluene 40 °C, 3 days R R' rac-3 or rac-7

and toluene were freshly distilled from sodium and benzophenone. Commercially available reagents were used without further purification. The biocatalysts used were obtained from: ANL: Lipase AN from Aspergillus niger, Jülich Fine Chemicals; CALA: Lipase A, Candida antarctica, CLEA, Sigma; CALB: Lipase acrylic resin from Candida antarctica, Novozym 435, Novo Nordisk A/S; CRL: Lipase from Candida rugosa, Amano AYS, Amano Enzyme; CVL: Lipoprotein lipase from Chromobacterium viscosum, Fluka Biochemika; MML: lipase from Mucor miehei, Lipozyme IM, Novo Nordisk A/S; PCL: Lipase from Pseudomonas cepacia, immobilized on Immobead 150, Sigma; PLE: Esterase, immobilized on Eupergit C from hog liver; RNL: lipase from Rhizopus niveus, Fluka Biochemika. All products were purified by column chromatography over silica gel (Macherey-Nagel MN-Kieselgel 60 (40–60 lm, 240–400 mesh)). Analytical thin-layer chromatography was performed on Macherey-Nagel precoated silica gel plates (ALUGRAMM Sil G/UV254), visualization of the compounds was achieved by UV light (254 nm), KMnO4-solution or iodine. 1H and 13C NMR spectra were recorded on a Bruker Avance 300 spectrometer at room temperature at 300 and 75 MHz, respectively. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane, using residual CHCl3 (7.26 and 77.1 ppm, respectively) as the internal standard. Infrared-spectra were recorded on a Shimadzu IRAffinity-1 FT-IR-spectrometer, absorption bands are reported in wave numbers [cm1]. High resolution mass spectrometry was performed on a Finnigan MAT 900 S. High performance liquid chromatography was performed on a Merck D-7000 with a Merck L-4500 PDA-detector using analytical Daicel columns (250 mm  4.6 mm). Specific optical rotations were measured on a Perkin–Elmer 343plus.

R' (P)-3, 27%, 79% ee (P)-7, 33%, 87% ee

Scheme 3. Kinetic resolution of biaryl methanols.

3. Conclusion In conclusion, our initial attempts to develop a biocatalytic dynamic kinetic resolution of biaryl lactones based on the lactone concept were unsuccessful due to low selectivity and almost negligible reactivity of all of the proteins tested in this study. However, reduction of the racemic lactones gave rise to primary alcohols, which turned out to be suitable for a lipase-catalyzed kinetic resolution. Thus, axially chiral alcohols can be obtained in good enantiomerc purity using the lipase from Mucor miehei. The kinetic resolution of these substrates by means of Lipozyme IM does not necessarily keep up with some of the other protocols such as dynamic kinetic CBS-reduction with regard to the enantiomeric purity of the alcohols. However, as part of our future studies enantioselectivity might be greatly enhanced by carefully designing related substrate structures offering improved atroposelective discrimination.

4. Experimental 4.1. General All moisture or air sensitive reactions were performed under an argon atmosphere in oven-dried glassware. Dry tetrahydrofuran

4.2.2. (±)-1,4-Dimethyl-6H-benzo[b]naphtho[1,2-d]pyranone 5 1-Bromo-2-naphthoic acid (2,5-dimethyl phenyl)ester (354 mg, 1.0 mmol) was reacted in analogy to the preparation of 1. After column chromatography (SiO2, cyclohexane/ethyl acetate 97/3 to 93/ 7) 5 was obtained as colorless solid (191 mg, 0.71 mmol, 71%). Mp (heptane/MTBE): 154 °C. Rf: 0.43 (cyclohexane/ethyl acetate 9/1). 1 H NMR (300 MHz, CDCl3): d = 8.31 (d, J = 8.5 Hz, 1H), 8.00–7.96 (m, 3H), 7.70–7.55 (m, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 2.54 (s, 3H), 2.24 (s, 3H). 13C NMR (75 MHz, CDCl3):

B. Skrobo, J. Deska / Tetrahedron: Asymmetry 24 (2013) 1052–1056

d = 161.1, 150.1, 136.4, 135.8, 128.7, 134.1, 131.2, 129.1, 129.0, 128.9, 128.3, 127.2, 126.2, 124.1, 123.4, 121.8, 118.3, 23.8, 16.0. FT-IR (ATR): m [cm1] = 2926 (w, br), 1717 (s, br), 1093 (m), 828 (s), 770 (s). Anal. Calcd for C19H14O2: C, 83.19; H, 5.14. Found: C, 82.87; H, 5.30. HRMS (EI): m/z [M]+ calcd for C19H14O2: 274.0994; found: 274.1000. 4.2.3. (±)-Butyl 1-(2-hydroxy-3,6-dimethylphenyl)naphthalene2-carboxylate 6 To a solution of n-butanol (53.3 mg, 0.72 mmol) in abs THF (2 ml) was added NaH (60%, 18.0 mg, 0.72 mmol) and the mixture was stirred for 10 min at room temperature. Next, the alkoxide solution was treated with lactone 5 (65.8 mg, 0.24 mmol, in 2 ml abs THF) and the reaction mixture was stirred at room temperature for 3 h. Next, sat aq NH4Cl (5 ml) was added, the solution was extracted with ethyl acetate (3  10 ml) and the combined organic layers were dried over MgSO4. After removal of the solvent in vacuo, column chromatography (SiO2, cyclohexane/ethyl acetate 95/5) yielded 6 (15.0 mg, 0.04 mmol; 17%) as a pale yellow oil. Rf: 0.34 (cyclohexane/ethyl acetate 9/1). 1H NMR (300 MHz, CDCl3): d = 8.02–7.44 (m, 6H), 7.12 (d, 3J = 7.5 Hz, 1H), 6.81 (d, 3J = 7.5 Hz, 1H), 4.41 (s, 1H), 4.07 (t, 3J = 6.4 Hz, 2H), 2.28 (s, 3H), 1.76 (s, 3H), 1.42–1.32 (m, 2H), 1.27–1.14 (m, 2H), 0.85 (t, 3J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): d = 168.3, 151.3, 135.3, 135.2, 134.8, 132.4, 130.4, 130.2, 128.9, 128.3, 128.1, 127.6, 126.8, 126.1, 124.7, 121.6, 121.5, 65.4, 30.5, 19.8, 19.2, 16.0, 13.8. FT-IR (ATR): m [cm1] = 3474 (w, br), 2959 (m), 2930 (w), 2872 (w), 1701 (s), 1279 (s), 1209 (s), 1134 (s), 1119 (s), 768 (s). HRMS (EI): m/z [M+Na]+ calcd for C23H24O3Na: 371.1624; found: 371.1620. HPLC (Chiracel AD-H, n-hexane/i-PrOH 97/3, 1.0 ml/min, 269 nm): tR = 14.13 min; tR = 18.03 min. 4.2.4. (±)-1-(2-Hydroxy-4,6-dimethylphenyl)-2-(hydroxymethyl) naphthalene 326 A solution of LiAlH4 (15.2 mg, 0.40 mmol) in abs THF (1.0 ml) was cooled to 0 °C. Lactone 1 (100 mg, 0.36 mmol), dissolved in abs THF (1.8 ml), was then added dropwise and the reaction mixture was stirred at 0 °C for 90 min. After careful addition of ethyl acetate (5 ml) and aq HCl (0.5 M, 2 ml) the layers were separated, the organic layer was washed with sat aq NaHCO3 (2 ml) and brine (2 ml), dried over MgSO4, and concentrated under reduced pressure. After column chromatography (SiO2, cyclohexane/ethyl acetate 8/2) alcohol rac-3 (87.3 mg, 0.31 mmol, 87%) was obtained as a colorless solid. Mp: 126 °C. Rf: 0.48 (cyclohexane/ethyl acetate 6/4). 1H NMR (300 MHz, CDCl3): d = 7.90–7.25 (m, 6H), 6.77 (s, 1H), 6.70 (s, 1H), 4.99 (s, 1H), 4.47 (s, 2H), 2.36 (s, 3H), 2.24 (s, 1H), 1.77 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 153.2, 139.3, 138.2, 137.6, 133.6, 132.7, 131.3, 129.1, 128.3, 127.0, 126.6, 126.4, 125.6, 123.5, 121.1, 114.2, 63.9, 21.4, 19.9. FT-IR (ATR): m [cm1] = 3264 (w, br), 3945 (w), 2858 (w), 1616 (m), 1570 (m), 1449 (m), 1301 (m), 1045 (s, br), 817 (s, br), 750 (s). HPLC (Chiracel AD-H, n-hexane/i-PrOH 95/5, 1.0 ml/min, 240–260 nm): tR ((M)3) = 27.79 min; tR ((P)-3) = 39.25 min. 4.2.5. (±)-1-(2-Hydroxy-3,6-dimethylphenyl)-2-(hydroxymethyl) naphthalene 7 Similar to the reduction of lactone 3, compound 5 (100 mg, 0.36 mmol), dissolved in abs THF (1.8 ml), was added dropwise and the reaction mixture was stirred at 0 °C for 90 min. After careful addition of ethyl acetate (5 ml) and aq HCl (0.5 M, 2 ml), the layers were separated, the organic layer was washed with sat aq NaHCO3 (2 ml) and brine (2 ml), dried over MgSO4, and concentrated under reduced pressure. After column chromatography (SiO2, cyclohexane/ethyl acetate 8/2) alcohol rac-7 (92.4 mg, 0.33 mmol, 92%) was obtained as a colorless solid. Rf: 0.46 (cyclohexane/ethyl acetate 6/4). 1H NMR (300 MHz,

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CDCl3): d = 7.98–7.33 (m, 6H), 7.16 (d, 3J = 7.5 Hz, 1H), 6.86 (d, 3 J = 7.5 Hz, 1H), 4.61 (s, 1H), 4.51 (s, 2H), 2.28 (s, 3H), 1.85 (s, 1H), 1.79 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 151.4, 137.7, 135.6, 133.7, 132.5, 131.1, 130.6, 129.3, 128.4, 127.1, 126.6, 126.5, 125.5, 123.5, 122.2, 122.0, 63.8, 19.8, 16.1. FT-IR (ATR): m [cm1] = 3489 (w, br), 2965 (w), 2920 (w), 1582 (m), 1458 (m), 1258 (m), 1204 (m), 1057 (s, br), 1204 (s, br), 820 (s), 800 (s). HRMS (ESI): m/z [M+Na]+ calcd for C19H18O2Na: 301.1205; found: 301.1200. HPLC (Chiracel AD-H, n-hexane/iPrOH 9/1, 1.0 ml/min, 269 nm): tR ((M)-7) = 11.87 min; tR ((P)7) = 26.83 min. 4.3. Kinetic resolution 4.3.1. (P)-1-(2-Hydroxy-4,6-dimethylphenyl)-2-(hydroxymethyl) naphthalene (P)-3 At first, rac-3 (55.7 mg, 0.20 mmol) and isopropenyl acetate (100 mg, 1.0 mmol) were dissolved in toluene (2.0 ml). Lipozyme IM (Mucor miehei lipase, 56 mg) was then added and the reaction mixture was incubated at 40 °C for three days. After filtration through cotton, the filtrate was concentrated in vacuo and the optically enriched alcohol was separated by column chromatography (SiO2, cyclohexane/ethyl acetate 8/2) to yield (P)-3 (15.0 mg, 0.054 mmol, 27%, 79% ee) as a colorless solid. ½a20 D ¼ þ21:9 (c 0.8, CHCl3); ee = 79%. Analytical data were in accordance with those reported for Section 4.2.4. 4.3.2. (P)-(2-Hydroxy-3,6-dimethylphenyl)-2-(hydroxymethyl) naphthalene (P)-7 In analogy to the resolution of alcohol 3, rac-7 (23.0 mg, 82.6 lmol) isopropenyl acetate (41.3 mg, 0.41 mmol) and Lipozyme IM (Mucor miehei lipase, 23 mg) were incubated in toluene at 40 °C for three days. Column chromatography (SiO2, cyclohexane/ethyl acetate 8/2) yielded (P)-7 (7.5 mg, 26.9 lmol, 33%, 87% ee) as a yellow oil. ½a20 D ¼ þ27:2 (c 0.4, CHCl3); ee = 87%. Analytical data were in accordance with those reported for Section 4.2.5. Acknowledgments We gratefully acknowledge the generous support by the Fonds der Chemischen Industrie. J.D. is grateful for a Liebig-fellowship, B.S. is grateful for a Chemiefonds-fellowship. References 1. Phosphorus Ligands in Asymmetric Catalysis; Börner, A., Ed., 1st ed.; Wiley-VCH: Weinheim, Germany, 2008. 2. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis, 1st ed.; Wiley-VCH: Weinheim, Germany, 2005. 3. Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539–4549. 4. Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193– 3207. 5. Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. 2005, 117, 5518–5563. Angew. Chem., Int. Ed. 2005, 44, 5384–5427. 6. Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525–558. 7. Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615–624. 8. Bringmann, G.; Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.; Kamikawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31–47. 9. Bringmann, G.; Breuning, M.; Walter, R.; Wuzik, A.; Peters, K.; Peters, E.-M. Eur. J. Org. Chem. 1999, 3047–3055. 10. Bringmann, G.; Breuning, M.; Tasler, S.; Endress, H.; Ewers, C. L. J.; Göbel, L.; Peters, K.; Peters, E.-M. Chem. Eur. J. 1999, 5, 3029–3038. 11. Bringmann, G.; Hartung, T. Angew. Chem. 1992, 104, 782–783. Angew. Chem., Int. Ed. Engl. 1992, 31, 761–762.. 12. Ashizawa, T.; Yamada, T. Chem. Lett. 2009, 38, 246–247. 13. Manzuna Sapu, C.; Bäckvall, J.-E.; Deska, J. Angew. Chem. 2011, 123, 9905–9908. Angew. Chem., Int. Ed. 2011, 50, 9731–9734.. 14. Hammel, M.; Deska, J. Synthesis 2012, 3789–3796. 15. Manzuna Sapu, C.; Deska, J. Org. Biomol. Chem. 2013, 11, 1376–1382.

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22. All enzymes showed a preference for the same enantiomer. However, as this method did not allow for the isolation of substantial amounts of optically enriched material we decided not to determine its absolute configuration. 23. Kamiyama, T.; Özer, M. S.; Otth, E.; Deska, J.; Cvengroš, J. unpublished results (manuscript submitted). 24. Ashizawa, T.; Tanaka, S.; Yamada, T. Org. Lett. 2008, 10, 2521–2524. 25. Bringmann, G.; Hartung, T.; Göbel, L.; Schupp, O.; Ewers, C. L. J.; Schöner, B.; Zagst, R.; Peters, K.; von Schnering, H. G.; Burschka, C. Liebigs Ann. Chem. 1992, 225–232. 26. Bringmann, G.; Hartung, T. Tetrahedron 1993, 49, 7891–7902.