Deracemization of <i>sec</i>-Alcohols through Sequential Application of <i>C. albicans</i> and Ketoreductases

Nasário, Fábio D.; Moran, Paulo J. S.; Rodrigues, José Augusto R.

doi:10.21577/0103-5053.20180205

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Article • J. Braz. Chem. Soc. 30 (4) • Apr 2019 • https://doi.org/10.21577/0103-5053.20180205 copy

Deracemization of sec-Alcohols through Sequential Application of C. albicans and Ketoreductases

Authorship SCIMAGO INSTITUTIONS RANKINGS

A biocatalytic cascade process was developed using immobilized cells of the wild type yeast Candida albicans CCT 0776 in calcium alginate beads and a commercially available ketoreductase. The aim was to promote deracemization by stereoinversion of (±)-1-arylethanols in high substrate concentration (above 100 mmol L^-1) to prepare the (R)-enantiomers of the alcohols (90-99%), with a high enantiomeric excess (83-99%) after 2 to 19 h. The (R)-1-(3-methoxyphenyl)ethanol, with 70% yield and 91% ee, obtained after 5 h was used to prepare (S)-1-(3-methoxyphenyl)-ethylamine with 60% yield and 91% ee after two steps, a key intermediate in the synthesis of (S)-rivastigmine.

Keywords:
oxidative kinetic resolution; deracemization; stereoinversion; ketoreductase; alcohol dehydrogenase


entry	KRED	Cofactor	Recycling system	time / h	1a
entry	KRED	Cofactor	Recycling system	time / h	Conversion^d d conversion measured by gas chromatography-mass spectrometry (GC-MS); / %	ee^e e enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID). KRED: ketoreductase; NADH: nicotinamide adenine dinucleotide; ADH-PL: alcohol dehydrogenases from Parvibaculum lavamentivorans; NADPH: nicotinamide adenine dinucleotide phosphate; GDH: glucose dehydrogenase. / %
1^a a 10 mg of KRED, 1 mL of KRED Recycle Mix N with 50 mmol L-1 of 2a;	KRED-101	NADPH	GDH/glucose	19	93	4 (S)
2^a a 10 mg of KRED, 1 mL of KRED Recycle Mix N with 50 mmol L-1 of 2a;	KRED-119	NADPH	GDH/glucose	19	93	98 (S)
3^a a 10 mg of KRED, 1 mL of KRED Recycle Mix N with 50 mmol L-1 of 2a;	KRED-130	NADPH	GDH/glucose	19	98	> 99 (S)
4^a a 10 mg of KRED, 1 mL of KRED Recycle Mix N with 50 mmol L-1 of 2a;	KRED-NADH-101	NADH	GDH/glucose	19	96	> 99 (S)
5^a a 10 mg of KRED, 1 mL of KRED Recycle Mix N with 50 mmol L-1 of 2a;	KRED-NADH-110	NADH	GDH/glucose	19	96	87 (R)
6^b b 10 mg of KRED or	KRED-P1-A04	NADPH	2-propanol	4	96	> 99 (R)
7^b b 10 mg of KRED or	KRED-P1-B02	NADPH	2-propanol	4	98	3 (S)
8^b b 10 mg of KRED or	KRED-P1-B05	NADPH	2-propanol	4	96	28 (S)
9^b b 10 mg of KRED or	KRED-P1-B10	NADPH	2-propanol	4	98	4 (S)
10^b b 10 mg of KRED or	KRED-P1-B12	NADPH	2-propanol	4	98	1 (R)
11^b b 10 mg of KRED or	KRED-P1-C01	NADPH	2-propanol	4	98	4 (S)
12^b b 10 mg of KRED or	KRED-P1-H08	NADPH	2-propanol	4	97	9 (S)
13^b b 10 mg of KRED or	KRED-P1-H10	NADPH	2-propanol	4	96	93 (R)
14^b b 10 mg of KRED or	KRED-P2-B02	NADPH	2-propanol	4	98	5 (S)
15^b b 10 mg of KRED or	KRED-P2-C02	NADPH	2-propanol	4	98	7 (S)
16^b b 10 mg of KRED or	KRED-P2-B02	NADPH	2-propanol	4	96	90 (R)
17^b b 10 mg of KRED or	KRED-P2-DO3	NADPH	2-propanol	4	98	4 (S)
18^b b 10 mg of KRED or	KRED-P2-D11	NADPH	2-propanol	4	97	53 (S)
19^b b 10 mg of KRED or	KRED-P2-D12	NADPH	2-propanol	4	97	8 (R)
20^b b 10 mg of KRED or	KRED-P2-G03	NADPH	2-propanol	4	96	89 (R)
21^b b 10 mg of KRED or	KRED-P2-H07	NADPH	2-propanol	4	96	> 99 (R)
22^b b 10 mg of KRED or	KRED-P3-B03	NADPH	2-propanol	4	95	> 99 (S)
23^b b 10 mg of KRED or	KRED-P3-G09	NADPH	2-propanol	4	94	46 (S)
24^b b 10 mg of KRED or	KRED-P3-H12	NADPH	2-propanol	4	96	96 (S)
25^c c 15 µL of enzyme suspension, 0.9 mL of KRED Recycle Mix P, 0.1 mL of 2-propanol, 25 mmol L-1 of 2a;	ADH-PL	NADPH	2-propanol	24	90	> 99 (R)


entry^a a 0.5 mmol of 1a-i, 0.150 mL of acetone, 11 g of C. albicans immobilized in calcium alginate beads, 10 mL of H2O. The reactions were mixed at 30 ºC and 180 rpm;	Substrate	R	time / h	Alcohol
	Substrate	R	time / h	Conversion^b b conversion monitored by gas chromatography-mass spectrometry (GC-MS); / %	ee^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID); / %
1	(±)-1a	H	0.67	49	94 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
2	(±)-1b	4-Cl	4	73	79 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
3	(±)-1c	4-F	1	57	90 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
4	(±)-1d	4-Br	6	79	75 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
5	(±)-1e	4-Me	1	55	93 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
6	(±)-1f	4-OMe	2	49	> 99 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
7	(±)-1g	4-OH	16	49	> 99 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
8	(±)-1h	3-OMe	2	57	93 (R)^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
9	(±)-1i	3-OH	16	53	96 (R)^d d ee was determined by HPLC.

entry^a a 1st step: 0.5 mmol of 1a-i, 0.150 mL of acetone, 11 g of immobilized C. albicans, 10 mL of H2O; 2nd step: 1 mL of the reaction, 25 mg of dry Recycle Mix P, 0.100 mL of 2-propanol;	Substrate	R	Reduction catalyst	time / h	1a-i
	Substrate	R	Reduction catalyst	time / h	Conversion^e e conversion monitored by gas chromatography-mass spectrometry (GC-MS); / %	ee / %
1^b b 4 mg of KRED or	1a	H	KRED-P1-A04	2	90	97 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
2^b b 4 mg of KRED or			KRED-P1-H10	2	98	92 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
3^d d 10 mL of oxidative kinetic resolution (OKR) (first step), 0.100 mL of ADH‑PL, 1 mL of 2-propanol and 250 mg of dry Recycle Mix P;			ADH-PL	9	92	95 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
4^b b 4 mg of KRED or	1b	4-Cl	KRED-P2-C11	5	> 99	82 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
5^b b 4 mg of KRED or			KRED-P2-H07	5	> 99	83 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
6^c c 15 µL of ADH-PL;			ADH-PL	12	> 99	84 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
7^b b 4 mg of KRED or	1c	4-F	KRED-P1-A04	3	90	94 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
8^b b 4 mg of KRED or			KRED-P2-C11	3	92	95 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
9^c c 15 µL of ADH-PL;			ADH-PL	7	91	95 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
10^b b 4 mg of KRED or	1d	4-Br	KRED-P1-A04	19	> 99	89 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
11^b b 4 mg of KRED or			KRED-P2-C11	7	> 99	84 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
12^c c 15 µL of ADH-PL;			ADH-PL	14	> 99	79 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
13^b b 4 mg of KRED or	1e	4-CH₃	KRED-P2-C11	2	96	96 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
14^b b 4 mg of KRED or			KRED-P2-H07	2	97	95 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
15^b b 4 mg of KRED or	1f	4-OCH₃	KRED-P1-A04	24	50	> 99 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
16^c c 15 µL of ADH-PL;	1g	4-OH	ADH-PL	40	52	87 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
17^b b 4 mg of KRED or	1h	3-OMe	KRED-P1-A04	19	95	93 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
18^b b 4 mg of KRED or			KRED-P2-H07	3	99	93 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
19^d d 10 mL of oxidative kinetic resolution (OKR) (first step), 0.100 mL of ADH‑PL, 1 mL of 2-propanol and 250 mg of dry Recycle Mix P;			ADH-PL	10	96	91 (R)^f f enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID);
20^b b 4 mg of KRED or	1i	3-OH	KRED-P1-A04	17	94	96 (R)^g g ee determined by HPLC. KRED: ketoreductase; ADH-PL: alcohol dehydrogenases from Parvibaculum lavamentivorans.
21^b b 4 mg of KRED or			KRED-P2-H07	17	94	96 (R)^g g ee determined by HPLC. KRED: ketoreductase; ADH-PL: alcohol dehydrogenases from Parvibaculum lavamentivorans.

entry^a a 1st step: (±)-1a 35-200 mmol L-1, 4 equiv. of acetone, 11 g of immobilized C. albicans, 10 mL of H2O, 1 h; 2nd step: 1 mL of the reaction, 25 mg of dry Recycle Mix P, 37 equiv. of 2-propanol, 4 mg of KRED-P1-A04, 1 h;	Substrate concentration ((±)-1a) / (mmol L^-1)	1a
	Substrate concentration ((±)-1a) / (mmol L^-1)	Conversion^b b conversion monitored by gas chromatography-mass spectrometry (GC‑MS); / %	ee^c c enantiomeric excess (ee) determined by gas chromatography-flame ionization detector (GC-FID). / %
1	35	94	93 (R)
2	55	92	94 (R)
3	82	92	93 (R)
4	110	91	90 (R)
5	150	92	79 (R)
6	200	75	40 (R)

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