Enantioselective reduction of 2-substituted tetrahydropyran-4-ones using Daucus carota plant cells

Article abstract of DOI:10.1016/j.tetlet.2008.02.131

Enzymatic reduction of 2-substituted tetrahydropyran-4-ones with Daucus carota, plant cells as biocatalyst occurred in water under extremely mild and environmentally benign conditions giving a 1:1 mixture of diastereoselectively (2R,4S)- and (2S,4S)-2-aryl- or 2-alkyl-tetrahydropyranols in high yields.

Full text of DOI:10.1016/j.tetlet.2008.02.131

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2768–2771
Enantioselective reduction of 2-substituted
tetrahydropyran-4-ones using Daucus carota plant cells
J. S. Yadav *, B. V. Subba Reddy, Ch. Sreelakshmi, G. G. K. S. Narayana Kumar,
A. Bhaskar Rao
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 January 2008; revised 22 February 2008; accepted 25 February 2008
Available online 29 February 2008
Abstract
Enzymatic reduction of 2-substituted tetrahydropyran-4-ones with Daucus carota, plant cells as biocatalyst occurred in water under
extremely mild and environmentally benign conditions giving a 1:1 mixture of diastereoselectively (2R,4S)- and (2S,4S)-2-aryl- or
2-alkyl-tetrahydropyranols in high yields.
Ó 2008 Published by Elsevier Ltd.
Keywords: Biocatalytic transformation; Carrot root; Enantioselective reduction; Chiral tetrahydropyranols
Tetrahydropyranols are present as structural units in a
number of natural products such as avermectins, aplysia-
toxin, oscillatoxins, latrunculins, talaromycins and acuti-
phycins.1 Optically pure tetrahydropyranols are potential
chiral building blocks for the synthesis of anti-1,3-diols.2
The Prins-cyclization is one of the most simple and
straightforward approaches for the construction of a tetra-
hydropyran ring system.3–6 However, there is no report on
an asymmetric Prins-cyclization for the direct preparation
of enantiomerically pure hydroxy tetrahydropyrans. There-
fore, we have developed an enzymatic approach for the
preparation of optically active tetrahydropyranols by
means of kinetic resolution of racemic tetrahydropyranols
via lipase mediated transesterification.7 Recently, plants
have been considered as suitable biochemical systems for
the biotransformation of exogenous substrates.8,9 Among
plants, carrots (Daucus carota) are effective biocatalysts
for the stereoselective reduction of ketones, both as immo-
bilized plant cell cultures10 and whole plant tissues.11
D. carota root has been used previously for the enantio-
selective reduction of prochiral ketones to produce chiral
secondary alcohols.12
In this Letter, we describe an enzymatic approach for
the preparation of chiral tetrahydropyranols by means of
enantioselective reduction of 2-substituted tetrahydropy-
ran-4-ones using D. carota roots in water (Scheme 1).
The 2-susbtituted tetrahydropyran-4-ones were easily
prepared by the oxidation of ( )-tetrahydropyranols
obtained via the condensation of an aldehyde with
3-buten-1-ol via the Prins-cyclization.13 Subsequently,
these tetrahydropyran-4-ones were subjected to D. carota
reduction. The bioreduction of the keto group was per-
formed using fresh carrot roots obtained from a local mar-
ket. Initially, the reduction was carried out using a solution
O
O
OH
O
OH
O
Daucus carota
H2O, r.t.
+
R
R
R
+
1a
( )
(-)-(2S
,4S
)-2a
(+)-(2R,4S)-3a
-
−
R = aryl or alkyl
*
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
Scheme 1. Reduction of tetrahydropyran-4-ones with Daucus carota
E-mail addresses: yadavpub@iict.res.in, yadav@iict.res.in (J. S.
roots.
Yadav).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.131

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2768–2771
2769
of the ketone (1 mmol) in ethanol (1 mL) with fresh carrot
(10 g) in water (70 mL) followed by incubation in an orbi-
tal shaker at 30 °C. The progress of the reaction was mon-
itored by TLC analysis. The results are summarized in
Table 1.
son with authentic samples.14 The reductions in water gave
the best results. The effects of ring substituents on the
reduction of aryl-substituted tetrahydropyran-4-ones by
D. carota are quite general. First, the corresponding (S)-
alcohols were obtained in all cases, with enantiomeric
excesses ranging from 83% to 94%. With aryl-substituted
tetrahydropyran-4-ones, it was observed that electron-
donating substituents slowed the reaction, highlighting
the sensitivity of bioreduction kinetics to electronic effects,
which is in accordance with results reported in the litera-
ture.12 As with aryl-substituted tetrahydropyran-4-ones,
2-hexyl-tetrahydropyran-4-one underwent smooth reduc-
tion with D. carota roots to give optically active 2-hexyl-
4-hydroxy tetrahydropyrans in good yields and with high
degrees of enantioselectivity (Scheme 2).
For example, reduction of ( )-2-phenyl-tetrahydro-2H-
pyran-4-one with D. carota in water afforded (2S,4S)-2-
phenyl-tetrahydropyranol and (2R,4S)-2-phenyl-tetra-
hydropyranol in a 1:1 ratio. These stereoisomers could
be easily separated by column chromatography. The
enantiomeric excesses of both the cis- and trans-tetrahydro-
pyranols were determined by HPLC using chiral columns
and were higher than 92%. The structures of the products
1
were established by H NMR, IR and mass spectrometry
and also by comparison with authentic samples.14 The
absolute stereochemistry of (2R,4S)- and (2S,4S)-2-aryl-
or 2-alkyl-tetrahydropyranols was established by compari-
The use of cut carrot roots in water offers several advan-
tages compared to Baker’s yeast, such as low cost, ease of
Table 1
Enantioselective reduction of tetrahydropyranones using Daucus Carota
25
25
b
b
Entry
Substrate
Alcohol 2a
½aꢀD
ee (%)c
Alcohol 3
½aꢀD
ee (%)c
92
Time (h)
24
Yield (%)d
92
O
OH
OH
a
ꢁ18.8
94
+15.6
O
O
O
OH
O
O
OH
O
b
c
ꢁ14.7
ꢁ16.0
90
87
+25.3
+17.8
86
85
26
30
94
90
O
Cl
Cl
Cl
OH
O
O
O
OH
O
MeO
MeO
MeO
OH
O
OH
d
e
ꢁ27.9
ꢁ18.6
94
90
+25.6
+16.6
89
83
29
24
90
92
O
O
O
O
O
OH
OH
O
O
Br
Br
Br
OH
O
O
OH
f
ꢁ9.9
ꢁ8.6
88
92
+9.6
+6.6
86
87
32
38
88
85
O
O
OH
O
O
O
OH
O
g
OH
O
OH
h
ꢁ11.2
ꢁ28.2
90
92
+9.5
87
88
24
24
91
92
O
O
O
F
F
F
OH
O
O
OH
O
i
+21.7
O
Me
Me
Me
a
All products were characterized by IR, NMR and mass spectroscopy.
Optical rotations were recorded in CHCl3 (c = 1.0).
Enantiomeric excesses of alcohols were determined using chiral HPLC.
Yield refers to pure products after chromatography.
b
c
d

2770
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2768–2771
2. (a) Yadav, J. S.; Reddy, M. S.; Raso, P. P.; Prasad, A. R. Tetrahedron
OH
OH
O
Lett. 2006, 47, 4397; (b) Yadav, J. S.; Reddy, M. S.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4937.
Daucus carota
H2O, r.t.
+
O
O
O
3. Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661.
4. (a) Wei, Z. Y.; Li, J. S.; Wang, D.; Chan, T. H. Tetrahedron Lett.
1987, 28, 3441; (b) Perron, F.; Albizati, K. F. J. Org. Chem. 1987, 52,
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1989, 54, 5768; (d) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem.
1988, 53, 913.
(+)-(2R,4S)-2g
(-)-(2S,4S)-3g
+
( )
-
1g
−
Scheme 2. Reduction of 2-hexyl-tetrahydropyran-4-one with Daucus
carota roots.
5. (a) Yang, J.; Viswanathan, G. S.; Li, C. J. Tetrahedron Lett. 1999, 40,
1627; (b) Yang, J.; Li, C. J. Synlett 1999, 717; (c) Chan, K.-P.; Loh,
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70, 57.
HO
O
H
L
S
L
S
6. (a) Viswanathan, G. S.; Yang, J.; Li, C. J. Org. Lett. 1999, 1, 993; (b)
Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, C. V. S. R.
Tetrahedron Lett. 2001, 42, 89.
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A. B. Tetrahedron Lett. 2007, 48, 4613.
L= Large group; S = Small group
Fig. 1. Prelog’s rule for the bioreduction of ketones.
8. Ishihara, K.; Hamada, H.; Hirata, T.; Nakajima, N. J. Mol. Catal. B:
Enzym. 2003, 23, 145–170.
9. Cordell, G. A.; Lemos, T. L. G.; Monte, F. J. Q.; de Mattos, M. C. J.
Nat. Prod. 2007, 70, 478–492.
availability of the biocatalyst, simple work-up and product
recovery. No specific match/mismatch effect from the adja-
cent stereocentre was observed, as can be seen from the
reduction of 2-phenyl-tetrahydropyran-4-one ( )-1a
(Table 1).15 At 100% conversion, an equal amount of enan-
tiopure tetrahydropyranols 2a and 3a were isolated in 92%
yield. Reduction occurs from the re-face only of the prochi-
ral ketone, independently of the configuration of the 2-aryl-
or alkyl-substituted stereocentre. The stereochemical
course of many bioreductions of ketones may be predicted
from a simple model which is generally referred to as Pre-
log’s rule.16 This empirical model, originally designed for
the reduction of ketones by the fungus Curvularia falcata
implies that the outcome is mainly dependent on the steric
requirements of the substrate (Fig. 1).
The observed enantioselectivity is in accordance with
Prelog’s rule. The presence of several competing oxidore-
ductases with opposite stereoselectivities in the plant tissues
may be the origin of the stereochemical outcome with these
substrates. Hence, this biocatalytic approach is found to be
suitable for the preparation of a wide range of tetrahydro-
pyranols. Finally, the recovered carrot could be used for
composting.
10. (a) Akakabe, Y.; Takahashi, M.; Kamezawa, M.; Kikuchi, K.;
Tachibana, H.; Ohtani, T.; Naoshima, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 1295–1298; (b) Baskar, B.; Ganesh, S.; Lokeswari, T.
S.; Chadka, A. J. Mol. Catal. B: Enzym. 2004, 27, 13–17.
11. (a) Baldassarre, F.; Bertoni, G.; Chiappe, C.; Marioni, F. J. Mol.
Catal. B: Enzym. 2000, 11, 55–58; (b) Yadav, J. S.; Nanda, S.;
Thirupathi Reddy, P.; Rao, A. B. J. Org. Chem. 2002, 67, 3900–3903.
12. (a) Blanchard, N.; Weghe, P. V. D. Org. Biomol. Chem. 2006, 4, 2348–
2353; (b) Caron, D.; Coughlan, A. P.; Simard, M.; Bernier, J.; Piche,
Y.; Chenevert, R. Biotechnol. Lett. 2005, 27, 713–716; (c) Scarpi, D.;
Occhiato, E. G.; Guarna, A. Tetrahedron: Asymmetry 2005, 16, 1479–
1483; (d) Mazczka, W. K.; Mironowicz, A. Tetrahedron: Asymmetry
2004, 15, 1965–1967; (e) Comasseto, J. V.; Omori, A. T.; Porto, A. L.
M.; Andrade, L. H. Tetrahedron Lett. 2004, 45, 473–476; (f) Maczka,
W. K.; Mironowicz, A. Tetrahedron: Asymmetry 2002, 13, 2299–2302;
(g) Yadav, J. S.; Reddy, G. S. K. K.; Sabitha, G.; Krishna, A. D.;
Prasad, A. R.; Rahaman, H. U. R.; Rao, K. V.; Rao, A. B.
Tetrahedron: Asymmetry 2007, 18, 717–723.
13. (a) Zhang, W. C.; Viswanathan, G. S.; Li, C. J. Chem. Commun. 1999,
291–292; (b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.; Reddy, M.
S.; Nirangan, N. J. Mol. Catal. A: Chem. 2004, 210, 99; (c) Zhang, W.
C.; Li, C. J. Tetrahedron 2000, 56, 2403–2411.
14. (a) Haslegrave, J. A.; Jones, J. B. J. Am. Chem. Soc. 1982, 104, 4667–
4671; (b) Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.;
Inoue, A.; Oku, A. J. Org. Chem. 1992, 57, 1412; (c) Nunez, M. T.;
Martin, V. S. J. Org. Chem. 1990, 55, 1928.
In conclusion, the enantioselective reduction of a series
of 2-substituted tetrahydropyran-4-ones was achieved
using D. carota roots in water, which afforded the corres-
ponding (S)-alcohols with ee ranging from 83% to 94%.
The low cost and the easy availability of the biocatalyst
besides the experimental simplicity suggest the possible
use of the present method for large scale preparations of
important chiral tetrahydropyranols.
OH
O
OH
O
OH
10% Pd/C
EtOH, r.t.
or
HO
Ph
Ph
Ph
(S)
25
[α]D -7.2 (c 1.5, EtOH)
15. Reduction of ketones with D. carota roots: Twelve carrots were
obtained from a local market. The external layer was removed and the
remainder was cut into small thin pieces (1 cm long slices). Ketone
(100 mg) was added to a suspension of the freshly cut carrot root
(10 g) in 70 mL of water and the reaction mixture was incubated in an
orbital shaker at room temperature. The suspension was then filtered
off and the carrot root was washed three times with water. The
filtrates were extracted with ethyl acetate and the combined organic
layers were dried over sodium sulfate, filtered and evaporated. The
crude products were purified by flash chromatography to furnish the
corresponding diastereomerically pure cis- and trans-tetrahydropyr-
Acknowledgement
ChSL and GGKSNK thank CSIR New Delhi for the
award of fellowships.
References and notes
1. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
Weinhein, 1996.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 2768–2771
2771
anols in approximately 1:1 ratios. All the compounds were charac-
terized by 1H NMR, IR, and mass spectroscopy and HPLC. The
enantiomeric excess of the product was determined using a Shimadzu
high-performance liquid-chromatography (HPLC) system equipped
with a chiral HPLC column (Chiralcel OD) and a UV detector at an
absorbance of 225 nm. A solvent system of n-hexane and isopropanol
(8:2) at a flow rate of 1.0 ml/min was used. Spectroscopic data for
selected products: Compound 2b: (2S,4S)-2-(4-chlorophenyl)tetrahy-
(m, 5H), 1.34–0.83 (m, 10H). 13C NMR (75 MHz, CDCl3): d 73.6,
64.4, 58.8, 44.7, 39.5, 35.7, 31.0, 29.8, 25.6; LCMS: (M+H+): 185.
HRMS calcd for C11H21O2: 185.1541. Found: 185.1546. Compound
25
3f: (2R,4S)-2-cyclohexyl-tetrahydro-2H-4-pyranol: Liquid, ½aꢀD +9.6
(c 1.0, CHCl3, ee = 86%); IR (KBr): mmax 3275, 2927, 2851, 1448,
1364, 1320, 1123, 1071, 1040, 996 cmꢁ1; 1H NMR (CDCl3, 300 MHz):
d 3.90 (dd, 1H, J = 4.7, 11.5 Hz), 3.61 (m, 1H), 3.24 (m, 1H), 2.89 (dd,
1H, J = 6.0, 11.1 Hz), 1.89–1.51 (m, 5H), 1.44–0.77 (m, 10H). 13C
NMR (75 MHz, CDCl3): d 73.6, 64.4, 58.8, 44.7, 39.5, 35.7, 31.0, 29.8,
25.6; LCMS: (M+H+): 185. HRMS calcd for C11H21O2: 185.1541.
Found: 185.1549. Compound 2i: (2R,4S )-2-(4-methylphenyl)tetra-
25
dro-2H-4-pyranol: Solid, mp 92–94 °C, ½aꢀD ꢁ14.7 (c 1.0, CHCl3,
ee = 90%); IR (KBr): mmax 3380, 2952, 2921, 2858, 1515, 1448, 1371,
1284, 1125, 1068, 1044, 985, 813 cmꢁ1; 1H NMR (CDCl3, 200 MHz):
d 7.17 (d, 2H, J = 8.3 Hz), 7.08 (d, 2H, J = 8.3 Hz), 4.72 (m, 1H), 4.27
(m, 1H), 4.06 (dt, 1H, J = 2.2, 12.0 Hz), 3.90 (ddd, 1H, J = 1.5, 5.2,
12.0 Hz), 2.01 (br s, 1H), 1.90 (m, 1H), 1.81 (m, 1H), 1.63 (m, 1H),
1.57 (m, 1H); 13C NMR (75 MHz, CDCl3): d 142.6, 128.3, 127.3,
125.8, 73.8, 64.2, 62.8, 40.6, 32.8; LCMS: (M+H+): 213. HRMS calcd
for C11H14O2Cl: 213.0682. Found: 213.0686. Compound 3b: (2R,4S)-
25
hydro-2H-4-pyranol: Liquid, ½aꢀD ꢁ28.2 (c 1.0, CHCl3, ee = 92%); IR
(KBr): mmax 3386, 2932, 2856, 1447, 1366, 1256, 1175, 1073, 970,
807 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 7.17 (d, 2H, J = 8.3 Hz),
;
7.08 (d, 2H, J = 8.3 Hz), 4.80–4.66 (m, 1H ), 4.40–4.24 (m, 1H), 4.01
(dt, 1H, J = 2.2, 12.0 Hz), 3.88 (ddd, 1H, J = 1.5, 5.3, 12.0 Hz), 2.32
(s, 3H), 1.99–1.87 (m, 1H), 1.85–1.77 (m, 1H), 1.66–1.59 (m, 1H),
1.59–1.54 (m, 1H); 13C NMR (75 MHz, CDCl3): d 138.9, 137.4,
129.1, 125.9, 78.3, 68.4, 66.4, 43.2, 35.4, 21.2; LCMS: (M+H+): 193.
HRMS calcd for C12H17O2: 193.1228. Found: 193.1236. Compound
25
2-(4-chlorophenyl)tetrahydro-2H-4-pyranol: Solid, mp 69–71 °C, ½aꢀD
+25.3 (c 1.0, CHCl3, ee = 86%); IR (KBr): mmax 3382, 2940, 2842,
1489, 1448, 1409, 1364, 1301, 1249, 1163, 1142, 1085, 1015, 987, 691,
885, 823, 717, 689, 594 cmꢁ1; 1H NMR (CDCl3, 300 MHz): d 7.28 (d,
2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.3 Hz), 4.24 (dd, 1H, J = 2.2,
11.3 Hz), 4.14 (ddd, 1H, J = 2.2, 4.5, 12.0 Hz), 3.87 (m, 1H), 3.52 (dt,
1H, J = 2.2, 12.0 Hz), 2.15 (m, 1H), 2.01 (br s, 1H), 1.93 (m, 1H),
1.68–1.30 (m, 2H). 13C NMR (75 MHz, CDCl3): d 142.6, 128.3, 127.3,
125.8, 73.8, 64.2, 62.8,40.6, 32.8; LCMS: (M+H+): 213. HRMS calcd
for C11H14O2Cl: 213.0682. Found: 213.0688. Compound 2f: (2S,4S)-
25
3i: (2R,4S)-2-(4-methylphenyl)tetrahydro-2H-4-pyranol: Liquid, ½aꢀD
+21.7 (c 1.0, CHCl3, ee = 88%); IR (KBr): mmax 3387, 2923,2851,
1493, 1365, 1250, 1139, 1083, 1014, 987, 825 cmꢁ1; 1H NMR (CDCl3,
300 MHz): d 7.16 (d, 2H, J = 8.3 Hz), 7.08 (d, 2H, J = 8.3 Hz), 4.21
(dd, 1H, J = 1.5, 12.0 Hz), 4.11 (ddd, 1H, J = 1.5, 4.5, 12.0 Hz), 3.83
(m, 1H), 3.51 (dt, 1H, J = 1.5, 12.0 Hz), 2.32 (s, 3H), 2.09 (m, 1H),
1.89 (m, 1H), 1.66–1.39 (m, 2H); 13C NMR (75 MHz, CDCl3): d
138.9, 137.4, 129.1, 125.9, 78.3, 68.4, 66.4, 43.2, 35.4, 21.2; LCMS:
(M+H+): 193. HRMS calcd for C12H17O2: 193.1228. Found:
193.1230.
25
2-cyclohexyl-tetrahydro-2H-4-pyranol: Liquid, ½aꢀD ꢁ9.9 (c 1.0,
CHCl3, ee = 88%); IR (KBr): mmax 3388, 2938, 2848, 1458, 1372,
1251, 1147, 1083, 1045, 980, 874 cmꢁ1; 1H NMR (CDCl3, 200 MHz):
d 4.19 (m, 1H), 3.78 (m, 1H), 3.68 (m, 1H), 3.40 (m, 1H), 1.92–1.42
16. Prelog, V. Pure Appl. Chem. 1964, 9, 119.