Exploiting sequential lipase-catalyzed reactions to achieve enantiomerically pure chiral primary alcohols

Abstract

The lipase-catalyzed enantioselective acetylation of benzofused cycloalkane-containing primary alcohols with vinyl acetate was performed and allowed the isolation of enantiopure alcohols. Lipases from P. cepacia, C. rugosa, C. antarctica, P. fluorescens, C. cylindracea and M. miehei exhibited remarkable activity towards acetylation of these alcohols, affording the corresponding acetates with high conversion. Due to the high lipase activity toward primary alcohols, the enantioselectivity was low. To circumvent this problem, sequential kinetic resolution was employed with enantiocomplementary lipases leading to enantiomerically pure primary alcohols. This method represents a new approach to obtain chiral building blocks bearing ring systems, such as indanes, chromanes and tetralins.

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Introduction

Chiral primary alcohols are important building blocks for the asymmetric synthesis of several biologically active molecules, e.g. pheromones^1,2 and other natural products.^3,4 Benzofused cycloalkanes, such as chromanes,^5–7 tetralins^8–10 and indanes^11,12 are important ring systems found in many biologically active compounds, such as Ramelteon,^13–15 Rasagiline^16–19 and compound I;²⁰ Fig. 1).

Fig. 1 Examples of biologically active compounds.

Several approaches to synthesize those molecules, including enantioenriched benzofused cycloalkane derivatives have been studied, mainly by metallic catalysis with Pd,^21,22 In,²³ Ru²⁴ and Cu.²⁵ Silva and coworkers^26,27 have synthesized a series of racemic primary alcohols bearing different ring systems in their structure employing hypervalent iodine(III). Aiming enantiopure primary alcohols, we considered the application of kinetic resolution (KR) using lipases as biocatalysts. While optically pure secondary alcohols can be successfully obtained by lipase-catalyzed enantioselective acetylation, primary alcohols are still very hard to achieve by kinetic enzymatic resolution, mainly due to their lower enantio-differentiation by lipases.²⁸

Despite of the moderate selectivity of lipases, different strategies have been developed to circumvent these limitations, such as, the use of bulky acyl donors,²⁹ modifying reaction solvent,³⁰ or applying sequential KR.^31,32 In the sequential KR, when the first KR step leads to the product with only a moderate ee, the obtained product can be then submitted to a second KR step to achieve a highly enantioenriched product. A literature survey revealed that lipases from P. cepacia and C. rugosa are efficient biocatalysts for transesterification of primary alcohols.^29–32 Despite of all efforts, kinetic resolution of primary alcohols by lipases remains a challenge.

To obtain both enantiomers of benzofused cycloalkanes-containing primary alcohols, which can be further used as chiral building blocks for the synthesis of more complex molecules (Fig. 2), we decided to explore the selectivity of enantiocomplementary lipases for sequential kinetic resolutions.

Fig. 2 Benzofused cycloalkanes-containing primary alcohols selected as targets for sequential kinetic resolution.

Experimental section

Methods

All enzymes were purchased from Sigma-Aldrich chemical company and stored at 4 °C. All solvents used were HPLC or ACS grade. Nuclear magnetic resonance (NMR) spectra were recorded on Varian Gemini or Bruker DPX spectrometer at operating frequencies of 200 and 300 MHz (¹H NMR). The ¹H NMR chemical shifts are reported in ppm relative to TMS peak. Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J) in Hertz and integrated intensity. Low-resolution mass spectra were obtained on a GC/MS Shimadzu spectrometer, operating at 70 eV. Gas chromatography (GC) analysis for measurement of enantiomeric excess was obtained using a Shimadzu 17 A Gas Chromatograph, Flame Ionization Detector (FID), and chiral column α-DEX 120 (Supelco) (25 m × 0.32 mm × 0.25 μm).

GC conditions (carrier gas: H₂ = 80 kPa): detector 250 °C, injector: 220 °C. Oven: 100 °C, 2 °C min⁻¹ to 180 °C.

General procedure for screening of lipases for transesterification of 2a–c

To a solution of racemic alcohol 2a–c (0.05 mmol) and vinyl acetate (10 μL; 0.1 mmol) in 1 mL of hexanes (for alcohol 2a and 2b) or toluene (for alcohol 2c), 2 mg of lipase was added. The reaction mixture was shaken at 32 °C in 700 rpm in a Thermomixer (Eppendorf®) for the appropriate time. The reaction was filtered and concentrated under reduced pressure for GC chiral analysis.

General procedure for enzymatic hydrolysis of 3a catalyzed by lipases

To a solution of ester 3a (0.05 mmol) in 1 mL of phosphate buffer (0.01 M; pH 7), 2 mg of lipase was added. The reaction mixture was shaken at 32 °C in 700 rpm in a Thermomixer (Eppendorf®) for the appropriate time. The reaction was filtered and lipase beads were washed with AcOEt. The organic layer was dried over anhydrous MgSO₄, filtered and solvent evaporated under reduced pressure for GC chiral analysis.

General procedure for sequential kinetic resolution of alcohol 2a–c catalyzed by lipases

In a vial (2 mL) containing a solution of racemic alcohol 2a–c (0.05 mmol) and vinyl acetate (10 μL; 0.1 mmol) in 1 mL of hexane (for alcohol 2a and 2b) or toluene (for alcohol 2c), 2 mg of lipase was added. The reaction mixture was shaken at 32 °C in 700 rpm in a Thermomixer (Eppendorf®) for the appropriate time. The reaction was filtered and lipase beads were washed with AcOEt. The esters 3a–c and alcohols 2a–c were purified by flash column chromatograph (EtOAc/hexane 1/5).

The isolated alcohols 2a–c were applied in a new reaction (kinetic resolution) to enhance optical purity. The esters 3a–c were hydrolyzed with K₂CO₃ in MeOH, and then a new kinetic resolution was performed to enhance optical purity.

(2,3-Dihydro-1H-inden-1-yl)methanol (2a). MS: m/z (%) 148 [M⁺] (19), 128 (4), 117 (100), 115 (36), 102 (1), 91 (10), 77 (2).

¹H NMR (200 MHz, CDCl₃): δ 7.32–7.11 (m, 4H), 3.80 (dd, J = 6.1 and 1.3 Hz, 2H), 3.36 (quint, J = 6.1 Hz, 1H), 3.11–2.77 (m, 2H), 2.39–2.14 (m, 1H), 2.07–1.83 (m, 1H), 1.56 (s, 1H).

Enantiomers separation by GC analysis equipped with α-DEX chiral column. Retention time: 20.4 min and 20.7 min.

(R)-(2,3-Dihydro-1H-inden-1-yl)methanol (2a). (R)-2a was obtained with 19% overall yield and with >99% ee. Spectral data were similar to the racemic compound. [α]_D = +6.0 (c 0.6 CHCl₃) or [α]_D = +25.0 (c 0.6, iso-octane) (lit. +27.0; c 0.6, iso-octane).³³

(S)-(2,3-Dihydro-1H-inden-1-yl)methanol (2a). (S)-2a was obtained with 12% overall yield and with 91% ee. Spectral data were similar to the racemic compound. [α]_D = −6.0 (c 0.6 CHCl₃).

(1,2,3,4-Tetrahydronaphthalen-1-yl)methanol (2b). MS: m/z (%) 162 [M⁺] (13), 144 (4), 131 (100), 116 (11), 115 (12), 103 (3), 91 (25), 77 (4).

¹H NMR (200 MHz, CDCl₃): δ 7.27–7.07 (m, 4H), 3.80 (d, J = 6.4 Hz, 2H), 3.06–2.88 (m, 1H), 2.79–2.73 (m, 2H), 1.95–1.54 (m, 4H), 1.54 (s, 1H).

Enantiomers separation by GC analysis equipped with α-DEX chiral column.

Retention time: 27.79 min and 28.10 min.

(R)-(1,2,3,4-Tetrahydronaphthalen-1-yl)methanol (2b). (R)-2b was obtained with 6% overall yield and with 99% ee. Spectral data were similar to the racemic compound. [α]_D = +3.0 (c 0.6 CHCl₃) (lit. +3.8; c 0.6, CHCl₃).³⁴

(S)-(1,2,3,4-Tetrahydronaphthalen-1-yl)methanol (2b). (S)-2b was obtained with 5% overall yield and with 90% ee. Spectral data were similar to the racemic compound. [α]_D = −3.4 (c 0.6 CHCl₃).

(3,4-Dihydro-2H-chromen-4-yl)methanol (2c). MS: m/z (%) 164 [M⁺], 133 (100), 115 (4), 105 (48), 91 (4), 79 (11), 77 (17).

¹H NMR: (300 MHz, CDCl₃) δ 7.21–7.08 (m, 2H), 6.90–6.80 (m, 2H), 4.27–4.16 (m, 2H), 3.91 (dd, J = 10.9 and 5.0 Hz, 1H), 3.81 (dd, J = 10.9 and 7.9 Hz, 1H), 3.04–2.97 (m, 1H), 2.14–2.02 (m, 2H), 1.61 (s, 1H).

Enantiomers separation by CG analysis equipped with α-DEX chiral column.

Retention time: 31.36 min and 31.63 min.

(R)-(3,4-Dihydro-2H-chromen-4-yl)methanol (2c). (R)-2c was obtained with 18% overall yield and with 78% ee. Spectral data were similar to the racemic compound. [α]_D = +10.0 (c 1.2 CHCl₃).

(S)-(3,4-Dihydro-2H-chromen-4-yl)methanol (2c). (S)-2c was obtained with 13% overall yield and with 90% ee. Spectral data were similar to the racemic compound. [α]_D = −10.1 (c 0.8 CHCl₃).

(2,3-Dihydro-1H-inden-1-yl)methylacetate (3a). MS: m/z (%): 130 (100), 117 (57), 115 (36), 91 (9), 77 (2), 65 (3), 43 (17).

¹H NMR (300 MHz, CDCl₃): δ 7.42–7.05 (m, 4H), 4.27 (dd, J = 10.8 and 6.5 Hz, 1H), 4.16 (dd, J = 10.8 and 7.3 Hz, 1H), 3.49 (quint, J = 6.9 Hz, 1H), 3.09–2.72 (m, 2H), 2.34–2.22 (m, 1H), 2.06 (s, 3H), 1.98–1.76 (m, 1H).

(1,2,3,4-Tetrahydronaphthalen-1-yl)methyl acetate (3b). MS: m/z (%) 144 (100), 131 (62), 129 (46), 116 (13), 115 (13), 103 (3), 91 (21), 77 (3).

¹H NMR (200 MHz, CDCl₃): δ 7.24–7.07 (m, 4H), 4.31 (dd, J = 11.0 and 5.2 Hz, 1H), 4.14 (dd, J = 11.0 and 9.0 Hz, 1H), 3.13 (dd, J = 9.0 and 4.8 Hz, 1H), 2.79 (d, J = 5.6 Hz, 2H), 2.09 (s, 3H), 1.84 (dd, J = 6.5 and 3.4 Hz, 4H).

(3,4-Dihydro-2H-chromen-4-yl)methyl acetate (3c). MS: m/z (%) 206 [M⁺] (2), 146 (100), 133 (31), 131 (23), 115 (5), 105 (36), 91 (6), 79 (6), 77 (11).

¹H NMR (300 MHz, CDCl₃) δ 7.25–7.08 (m, 2H), 7.01–6.74 (m, 2H), 6.85 (dd, J = 8.0 and 1.5 Hz, 1H), 4.39 (dd, J = 11.2 and 5.1 Hz, 1H), 4.32–4.10 (m, 3H), 3.18 (hex, J = 3.2 Hz, 1H), 2.11 (s, 3H), 2.04–1.86 (m, 1H), 0.99–0.77 (m, 1H).

Results and discussion

The primary alcohols 2a–c were prepared from benzofused alkenes by iodine(III)-mediated ring contraction reaction.^26,27 Aiming enantiomeric pure alcohols, the kinetic resolution of racemic 2a–c via a lipase-catalyzed transesterification was proposed (Scheme 1). In this approach, the screening protocol involved several lipases and primary alcohols 2a–c, vinyl acetate (VyAc) as acyl donor in an organic solvent (hexanes or toluene), at 32 °C for 4 hours (Table 1).

Scheme 1 Kinetic resolution of primary alcohols by lipases.

Table 1 Screening of lipases for kinetic resolution of primary alcohols 2a–c^a

Entry	Compound	Lipases	Alcohol^b (%) [ee^c %]	Ester^b (%)
a Reagents and conditions: alcohol 2a–c (0.05 mmol), vinyl acetate (0.1 mmol), hexane (200 μL), 4 h, 32 °C, 700 rpm.b Determined by chromatographic concentration using GC-MS.c Determined by GC analysis.
1	2a	Mucor javanicus (Amano M)	96 [2]	4
2	2a	C. cylindracea (Fluka 62316)	22 [81] (S)	78
3	2a	C. antarctica (CAL-b, Nov. 435)	—	>99
4	2a	P. cepacia (Amano PS)	10 [>99] (R)	90
5	2a	Aspergillus niger (Amano A)	3	14
6	2a	P. cepacia (Amano PSD-I)	—	>99
7	2a	C. rugosa (Sigma type VII)	10 [>99] (S)	90
8	2a	P. cepacia (Amano PSC-II)	—	>99
9	2a	Mucor miehei (Sigma)	—	>99
10	2a	P. fluorescens (Amano AK)	—	>99
11	2a	Porcine pancreas (Sigma tipo II)	88 [<1]	12
12	2b	Mucor javanicus (Amano M)	99 [-]	1
13	2b	C. cylindracea (Fluka 62316)	12 [92]	88
14	2b	C. antarctica (CAL-b, Nov. 435)	8 [>99] (R)	92
15	2b	P. cepacia (Amano PS)	80 [1]	20
16	2b	Aspergillus niger (Amano A)	91 [2]	9
17	2b	P. cepacia (Amano PSD-I)	2 [>99]	98
18	2b	C. rugosa (Sigma type VII)	11 [92] (S)	89
19	2b	P. cepacia (Amano PSC-II)	—	>99
20	2b	Mucor miehei (Sigma)	98 [6]	2
21	2b	P. fluorescens (Amano AK)	55 [18]	45
22	2b	Porcine pancreas (Sigma tipo II)	98 [5]	2
23	2c	Mucor javanicus (Amano M)	96 [6]	4
24	2c	C. cylindracea (Fluka 62316)	25 [76] (−)	75
25	2c	C. antarctica (CAL-b, Nov. 435)	7 [84] (+)	93
26	2c	P. cepacia (Amano PS)	58 [14]	42
27	2c	Aspergillus niger (Amano A)	95 [6]	5
28	2c	P. cepacia (Amano PSD-I)	10 [40]	90
29	2c	C. rugosa (Sigma Tipo VII)	25 [76]	75
30	2c	P. cepacia (Amano PSC-II)	—	>99
31	2c	Mucor miehei (Sigma)	98 [8]	2
32	2c	P. fluorescens (Amano AK)	20 [94]	80
33	2c	Porcine pancreas (Sigma tipo II)	95 [6]	5

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Lipases from P. cepacia, C. rugosa, C. antarctica, P. fluorescens, C. cylindracea and M. miehei exhibited remarkable activities toward the primary alcohols 2a–c (>80% conversion) (Table 1). However, in contrast to secondary alcohols, these lipases were very active for both enantiomers of the primary alcohols 2a–c, meaning they are better substrates for transesterification reaction, but with poor enantioselectivities. P. cepacia and C. rugosa lipases were efficient for kinetic resolution of compound 2a, C. antarctica and C. rugosa lipases for compound 2b and C. antarctica and C. cylindracea lipases for compound 2c. Furthermore, it was possible to identify different enantiospecificity for these enzymes, as shown in Table 2.

Table 2 Lipases selected for optimization study in the kinetic resolution of 2a–c

	Substrate
	2a	2b	2c
Lipase (isomer)	P. cepacia (S)	C. antarctica (S)	C. antarctica (S)
	C. rugosa (R)	C. rugosa (R)	C. cylindracea (R)

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Considering that bulky acyl donors may enhance the enantioselectivity of lipases due to the sterical effects,^35,36 a study involving heptanoic acid as the acyl donor was conducted with P. cepacia and C. rugosa lipases (Table 3).

Table 3 Comparison of lipase-catalyzed reaction of 2a with vinyl acetate and heptanoic acid as acyl donors^a

Lipase	Acyl donor	[Ester (3a)]^b	[Alcohol (2a)]^b (ee)^c
a Reagents and conditions: alcohol 2a (0.05 mmol), acyl donor (0.1 mmol), hexane (200 μL), 4 h, 32 °C, 700 rpm.b Determined by chromatographic concentration using GC-MS.c Determined by GC analysis.
P. cepacia		90%	10% (>99%)
C. rugosa		90%	10% (>99%)
P. cepacia		80%	20% (25%)
C. rugosa		60%	40% (55%)

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In the enantioselective acylation of 2a with a long carbon chain acyl donor (heptanoic acid) no enhancement of enantioselectivity was observed. Once again, lipases have shown great activity towards these primary alcohols, since the produced ester was obtained in >60% concentration. Also, modifying lipases source and acyl donors, almost no significant change in enantio-differentiation was observed.

To circumvent this issue, sequential kinetic resolution would be a reasonable process to achieve enantiomeric pure alcohols. Based on this concept, a kinetic resolution by lipase-catalyzed transesterification could be performed until the complete transformation of one alcohol enantiomer 2 to the corresponding ester 3, or as an alternative, until the reaction reaches 50% conversion. Using this strategy, the enantioenriched alcohol 2 and ester 3 could be separated by chromatography. Then, the ester 3 could be submitted to another kinetic resolution with enantiocomplementary lipase by enzymatic hydrolysis (Scheme 2a) or chemical hydrolysis with K₂CO₃ and lipase-catalyzed transesterification (Scheme 2b, step 1 and step 2, respectively). On the other hand, the remaining enantioenriched alcohol could be applied as substrate in a second kinetic resolution via lipase-catalyzed transesterification (Scheme 2c).

Scheme 2 Possible approaches for kinetic resolution of primary alcohols by sequential KR.

In the first approach with alcohol (RS)-2a, a kinetic resolution by P. cepacia and vinyl acetate was performed until total consumption of one enantiomer of the alcohol 2a to the corresponding ester 3a. It was possible to obtain (R)-2a in high ee (>99%). After chromatographic separation, enantioenriched acetate 3a was employed in a kinetic resolution, now via hydrolysis reaction catalyzed by C. rugosa lipase (an enantiocomplementary lipase of P. cepacia, Table 2). Enzymatic hydrolysis afforded the alcohol 2a in maximum 52% ee (Scheme 3a). Another alternative involved the chemical hydrolysis of 3a, which after enzymatic acetylation of the enantioenriched 2a resulted in the enantiopure alcohol 2a (>99% ee, Scheme 3b). Thus, both enantiomers of alcohol 2a were successfully obtained, although in low yields (13–20%).

Scheme 3 Sequential kinetic resolution of alcohol 2a.

In the second approach with 2a, a kinetic resolution by P. cepacia and vinyl acetate was performed until around 50% conversion (Scheme 4). After chromatographic separation, alcohol 2a and ester 3a were obtained with 40% ee and 72% ee, respectively. The enantioenriched alcohol 2a (40% ee) was submitted to another KR with P. cepacia lipase and vinyl acetate, affording the enantiopure (R)-alcohol 2a (>99% ee) (Scheme 4a). The chemical hydrolysis of 3a (72% ee) yielded the respective alcohol 2a, which was then submitted to another KR with C. rugosa (enantiocomplementary to P. cepacia), affording the enantiopure (S)-alcohol 2a (91% ee) (Scheme 4b).

Scheme 4 Sequential kinetic resolution of alcohol 2a.

Despite the success of both routes (Schemes 3 and 4), considering the higher overall yields, the second strategy was chosen for alcohols 2b and 2c in combination with lipases previously selected in Table 2. Therefore, the KR of alcohol 2b with C. rugosa lipase and vinyl acetate afforded (S)-alcohol 2b with 70% ee and (R)-acetate 3b with 52% ee. A second KR with enantioenriched 2b and C. rugosa lipase as biocatalyst gave (S)-alcohol 2b with 90% ee (Scheme 5a). Enantioenriched acetate 3b from the first KR was hydrolyzed to the corresponding alcohol, which was subsequently submitted to KR with C. antarctica and vinyl acetate to afford (R)-alcohol 2b with >99% ee (Scheme 5b).

Scheme 5 Sequential kinetic resolution of alcohol 2b.

For the racemic alcohol 2c, a KR with C. cylindracea and vinyl acetate afforded enantioenriched alcohol 2c with 50% ee and enantioenriched acetate 3c with 34% ee (Scheme 6a). The second KR of the enantioenriched alcohol 2c (50% ee) increased the ee of (−)-2c to 90%. After hydrolysis of the ester 3c, KR of the enantioenriched alcohol with C. antarctica afforded (+)-2c with 78% ee (Scheme 6b).

Scheme 6 Sequential kinetic resolution of alcohol 2c.

In summary, the second approach was appropriate to give enantiopure alcohols 2a–c in high ee's.

For the assignment of absolute configuration of alcohol 2c, a comparison on the enantiopreference of C. antarctica lipase in the transesterification of (R)-2b was proposed. Based on this, we could assign (+)-2c as (R)-isomer (Scheme 7).³⁷

Scheme 7 Assignment of absolute configuration of alcohol 2c by analogy of the enantiopreference by C. antarctica lipase.

Conclusion

In summary, lipases from P. cepacia, C. rugosa, C. antarctica, P. fluorescens, C. cylindracea and M. miehei have shown remarkable activities in the transesterification of primary alcohols-containing benzofused cycloalkanes. The corresponding acetylated compounds were prepared in high conversion. Although showing high activities, the lipase enantioselectivity for these substrates was moderate. To overcome this difficulty, we have employed sequential KR using different lipases. Finally, both enantiomers of alcohols 2a–c were successfully obtained by means of sequential kinetic resolutions with enantiocomplementary lipases. A novel route toward chiral non-racemic indanes, chromanes and tetralins was herein presented. The synthesis of complex molecules can be envisioned from the enantiomerically pure alcohols 2a–c.

Acknowledgements

The authors are grateful for FAPESP, CAPES and CNPq for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra06469d

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