Preparation of the diastereomerically pure 2S-hydroxy derivative of dihydrolevoglucosenone (cyrene)

Article abstract of DOI:10.1016/j.mencom.2019.03.029

Diastereomerically pure levoglucosenone alcohol, synthesized from levoglucosenone, upon hydrogenation on Raney Ni or Pd/BaSO₄ undergoes epimerization at C² atom caused by formation of cyrene by-product and its subsequent non-specific

Full text of DOI:10.1016/j.mencom.2019.03.029

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 200–202
Preparation of the diastereomerically pure 2S-hydroxy
derivative of dihydrolevoglucosenone (cyrene)
Bulat T. Sharipov,* Anna N. Davydova, Liliya Kh. Faizullina and Farid A. Valeev
Ufa Institute of Chemistry, Russian Academy of Sciences, 450054 Ufa, Russian Federation.
E-mail: sharipovbt@anrb.ru
DOI: 10.1016/j.mencom.2019.03.029
Diastereomerically pure levoglucosenone alcohol, synthesized
O
O
H2, Pd/C
from levoglucosenone, upon hydrogenation on Raney Ni or
O
O
2
O
O
OH
OH
O
Pd/BaSO undergoes epimerization at C atom caused by
4
O
formation of cyrene by-product and its subsequent non-specific
reduction. A microbiological stereospecific technique using
baker’s yeast (Saccharomyces cerevisiae) has been developed
for cyrene reduction into cyrene alcohol and also applied to
reduce 4-alkoxy and 4-benzyloxy derivatives of cyrene.
O
baker’s yeast
O
O
OH
levoglucosenone
R
O
R
R = H (cyrene), OMe, OEt, OBn
Pure optically active substances are highly demanded in organic
ones.6,7 The addition of CeCl to the reaction mixture during
3
borohydride reduction improves the diastereomeric purity. In
13
synthesis. Levoglucosenone (1,6-anhydro-3,4-dideoxy-b-d-glycero
-
hex-3-enopyranos-2-ulose) and its derivatives are of growing
interest as precursors for stereospecific synthesis of natural
our hands, repeating the process in the presence of CeCl resulted
3
in increased diastereomeric ratio in favor of 2S-epimer 2.
1
1–3
i
compounds, chiral auxiliary reagents, and also as bio-based
In the reduction of cyrene 1 with Bu AlH in dichloromethane,
2
4
alternatives for dipolar aprotic solvents. For example, some chiral
the temperature had more significant effect on the total yield than
alcohols can be derived directly from levoglucosenone or through
its derivative, dihydrolevoglucosenone (cyrene, 1,6-anhydro-
on the ratio of alcohols. The use of LiAlH in diethyl ether afforded
product mixture with even better cyrene alcohol 2 content.
4
3
,4-dideoxy-b-d-glycero-hexopyranos-2-ulose). These chiral
Taking into account the fact that the reduction of levo-
alcohols demonstrate good regio- and stereoselectivity when used
glucosenone 3 with NaBH in water proceeds stereoselectively
4
2
,3
as auxiliary reagents in asymmetric Diels–Alder reactions. In
addition, they deserve attention as substrates for the reduction of
unsymmetrical ketones by hydride reagents and as precursors for
the synthesis of chiral solvents.
O
O
O
i
O
O
+
O
4
2
OH
OH
R
S
O
OH
2'
The known reduction techniques for cyrene 1 and levo-
glucosenone 3 result predominantly in the formation of a diastereo-
meric mixture of alcohols enriched in 2S-epimers (Scheme 1).
The pure 2S-epimer of cyrene alcohol 2 is typically prepared by
indirect approach from other carbohydrates.5 Available data on
the reduction of cyrene to cyrene alcohol with various reagents
1
2
O
O
O
ii
iii
O
O
2 + 2'
,6
3
4
show that the use of NaBH in methanol results in an inseparable
mixture of compounds 2 and 2' (89:11), with [a]D –117.3°
4
Scheme 1 Reagents and conditions: i, see Tables 1 and 2; ii, NaBH , H O,
4 2
6,7
25
0°C; iii, H , see Table 1.
2
8
(
c 2.00 in CHCl ). The use of LiAlH for the reduction of
3
4
9
–11
9
cyrene has been extensively investigated.
In the early work,
Table 1 Preparation of alcohols 2 and 2' from cyrene 1 or levoglucosenone
alcohol 4.
2
the configuration of the alcohol reduction product at C was
determined incorrectly, and later it was clarified.7 After that,
the content of cyrene alcohol 2 in the resulting diastereomeric
mixture was established to be 91%. The use of hydrogen under
pressureonvariouspalladiumcatalystsaffordsthediastereomeric
ratio of 4.7 in favor of compound 2. The hydrogenation of
pure 2S-epimer of unsaturated levoglucosenone alcohol 4 on
Pd/C leads to alcohol 2 containing 11 to 29% of cyrene, in
,10
Starting
compound
Yield of
2 + 2' (%)
Reaction conditions
dr 2:2' a
1
1
1
1
1
3
4
4
4
4
NaBH , MeOH, 0°C
99
86
75
68
86
90
99
85:15b
90:10
79:21c
69:31
67:33
59:41
91:9
4
1
2
NaBH4, CeCl3·7H2O, MeOH, 0°C
LiAlH , Et O, 0°C
4
2
i
2
Bu2AlH, CH2Cl2, 0°C
i
9
Bu AlH, CH Cl , –78°C
contrast to the hydrogenation on Pd/BaSO , although these latter
2
2
2
4
H , Raney Ni, EtOAc, ~20°C
results do not specify the diastereomeric purity of alcohol 2.
To obtain the data in addition to the published ones and to
arrange the resulting information, we have investigated and when
necessary reproduced various approaches to the preparation of
alcohols 2 and 2' (Scheme 1, Table 1).
2
H , Raney Ni, EtOAc, ~20°C
2
H , Raney Ni, EtOAc, AcOH, ~20°C 98
94:6
2
H , Pd/BaSO , EtOAc, ~20°C
87d
71e
98:2
2
4
H , Pd/C, EtOAc, ~20°C
>99
2
According to the data in Table 1, our results on borohydride
reduction of cyrene 1 in methanol are close to the published
a
b
6,7
c
11
9
dr is diastereomeric ratio. Lit., 89:11. Lit., 6:1 and lit., content of 2
d
e
91%. Yield of cyrene was 12%. Yield of cyrene was 28%.
©
2019 Mendeleev Communications. Published by ELSEVIER B.V.
–
200 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2019, 29, 200–202
to form alcohol 4 with only 2% impurity of its 2R-epimer,14 and
that alcohol 4 is further readily isolated in a diastereomerically
pure form by recrystallization from light petroleum–CH Cl , the
O
O
i
O
i
O
O
+ 2, 10%
OH
2
2
OH
O
OH
O
attractive direct way to the pure alcohol 2 may be the hydro-
genation of the double bond in the pure unsaturated alcohol 4.
In our hands, the hydrogenation of alcohol 4 on Raney Ni
resulted in a mixture of alcohols 2 and 2' in a ratio of 91:9. Most
probably, similar to the known evidence of ketone production on
5a
6a, 39%
O
O
O
O
+
OH
OR
O
OR
OR
OH
1
5
Raney Ni, such an outcome may be rationalized by formation
of small amount of cyrene 1, which is further hydrogenated to
afford mixture of 2 and 2'. The addition of acetic acid to inhibit
the Raney Ni activity slightly reduced the yield of undesired
diastereomer 2'. The use of levoglucosenone 3 as starting com-
pound in the hydrogenation on Raney Ni did not improve the
specificity and yielded a mixture of 2 and 2' in a ratio of 59:41.
The most effective method to prepare the diastereomerically
pure alcohol 2 turned out to be the hydrogenation of unsaturated
5b R = Me
5c R = Et
d R = Bn
6b R = Me, 89% 6'b R = Me, 3%
6c R = Et, 81%
6d R = Bn, 81%
6'c R = Et, 4%
6'd R = Bn, 5%
5
Scheme 2 Reagents and conditions: i, baker’s yeast, H O, d-glucose, 30°C.
2
It is known that the reduction of hydroxy ketone 5a with NaBH4
gives a mixture of alcohol 6a and its 2R-epimer in a ratio of
71:14 determined from the mass yields of the corresponding
14
diacetate derivatives. The reduction of methoxy ketone 5b yields
2
17
alcohol 4 on Pd/C in ethyl acetate; it was accomplished in less
a mixture of alcohols 6b and 6'b in a ratio of 10:11; while
than an hour and was only slightly complicated by the forma-
tion of cyrene 1 as by-product. Hydrogenation of alcohol 4 on
alcohols 6d and 6'd in the borohydride reduction of benzyloxy
derivative 5d are formed in almost equal amounts.
1
8
Pd/BaSO in ethyl acetate proceeded with complete conversion
in 24 h with the formation of alcohol 2 in 87% yield and cyrene
In our hands, the reduction of hydroxy ketone 5a with baker’s
yeast proceeded for 5d to form pure alcohol 6a in a yield of 39%
together with small amount of alcohol 2. The reduction of ketones
5b–d took less than 24 h; the reaction was characterized by high
stereoselectivity, good yields of alcohols 6b–d, and the forma-
tion of small amount of diastereomeric alcohols 6'b–d, which
could be easily separated from the main products. It was noted
that the selectivity of the reduction of levoglucosenone keto
derivatives with baker’s yeast decreased for compounds bearing
4
1
in 12% yield. The formation of cyrene under these condi-
9
tions has not been previously reported. The hydrogenation with
Pd/BaSO4 afforded alcohol 2 with lower purity, which was
associated with a longer reaction time when non-specific reduc-
tion of cyrene 1 occurred.
Given the fact that microbiological syntheses are widely used
for preparation of chiral products, we investigated the reduction
of cyrene 1 in the presence of baker’s yeast (Saccharomyces
cerevisiae), which is known to turn the stereoselectivity of ketone
reduction in favor of (S)-alcohol for simple arylmethyketones,
4
bulky substituents at C ; however, this microbial technique is still
more effective than all those described above.
Thus, methods for the reduction of cyrene and the hydrogena-
tion of unsaturated alcohol, prepared from borohydride reduction
of levoglucosenone, have been tested to synthesize a diastereo-
merically pure cyrene 2S-alcohol. The data obtained demonstrate
that the most efficient chemical method to gain this purpose
is hydrogenation on Pd/C. The reduction of cyrene by micro-
biological method using baker’s yeast (S. cerevisiae) proceeds
stereospecifically. This latter technique also turned out well in
the reduction of oxa-Michael adducts of levoglucosenone with
methanol, ethanol or benzyl alcohol. The microbial reduction
technique for levoglucosenone derivatives is a promising way
to synthesize chiral functionalized alcohols, including large scale
processes.
1
6
ethyl acetoacetate or substituted bicyclo[3.3.0]octane-2,8-diones.
Although the laboratory strains of baker’s yeast are used in
these biotransformations, organic chemists typically employ the
commercial ones, so we utilized baker’s yeast purchased from
Pakmaya Company (Turkey). The results of our experiments are
presented in Table 2.
The reaction was carried out in water at 30°C with constant
stirring, both in the absence of carbohydrates and in the presence
of d-glucose or sucrose as a growth medium. In the presence of
†
sucrose the reaction proceeded slowly, and with d-glucose its
rate increased significantly. Thus, the most effective run proceeds
2
0
stereospecifically with d-glucose to give alcohol 2 with [a]
D
20
‡
–
134.2° (c 1.0 in CHCl ) and [a] –132.8° (c 1.0 in H O).
3 D 2
In addition, we investigated the reduction of hydroxy-func-
This study was performed in the framework of the State contract
(AAAA-A17-117011910022-5) and supported by the Russian
Foundation for Basic Research (grant no. 17-43-020166 r_a).
tionalized cyrene derivatives 5a–d (Scheme 2) that were easily
14,17
prepared from levoglucosenone 3 by the oxa-Michael reaction.
Table 2 Microbiological reduction of cyrene 1.a
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.029.
Baker’s yeast/g
Carbohydrate
t/h
Yield of 2 (%)
2
2
4
a
.0
.0
.0
sucrose
d-glucose
–
50
24
7
65
99
78
‡
1
,6-Anhydro-3,4-dideoxy-b-d-threo-hexopyranose 2. Alcohol 2 was
prepared from cyrene 1 (200 mg, 1.56 mmol) according to the general
procedure as a clear oil that partially crystallized; 201 mg (99%); [a]
2
0
D
Conditions: cyrene 1 (200 mg, 1.56 mmol), 30°C.
2
0
5
–
(
134.2° (c 1.0, CHCl ); [a] –132.8° (c 1.0, H O) {lit., mp ~28°C
3 D 2
unsharp), [a]2 –133° (c 0.6 in H O)}. IR (n/cm ): 3418 (OH), 2954
5
–1
D
2
†
1
General procedure for the reduction of ketones with baker’s yeast.
(C–H), 1131 and 1070 (C–O–C), 985 and 900 (O–C–O). H NMR
A suspension of baker’s yeast (1.3 g) and d-glucose (1 g) in water (10 ml)
was stirred at ca. 30°C for 1 h, then a solution of ketone (1 mmol) in
water (3 ml) was added. The reaction mixture was stirred at ca. 30°C.
The reaction was monitored by silica-gel TLC until the disappearance
of the starting ketone (ca. 24 h). Then ethanol (10 ml) was added, the
precipitate was filtered off, washed with ethanol and the solution obtained
was combined with filtrate. The filtrate was evaporated in vacuo and the
residue was purified by column chromatography.
(500 MHz, CDCl ) d: 1.49 (dtd, 1H, H-3, J 12.9, 10.0, 6.1 Hz), 1.57 (dd,
3
1H, H-4, J 13.9, 6.1 Hz), 1.82–1.91 (m, 1H, H-4), 1.98–2.04 (m, 1H,
H-3), 2.18 (br.s, 1H, OH), 3.58 (dd, 1H, H-2, J 10.0, 6.2 Hz), 3.79 (dd,
1H, H-6, J 7.1, 5.4 Hz), 3.83 (d, 1H, H-6, J 7.1 Hz), 4.46–4.49 (m, 1H,
1
3
3
H-5), 5.30 (s, 1H, H-1). C NMR (125 MHz, CDCl ) d: 26.02 (C ),
3
4
6
2
5
1
27.82 (C ), 68.17 (C ), 69.98 (C ), 72.80 (C ), 102.92 (C ). MS (APCI),
m/z: 130.1 [M] . Found (%): C, 55.45; H, 7.79. Calc. for C H O (%):
+
6
10
3
C, 55.37; H, 7.74.
–
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Mendeleev Commun., 2019, 29, 200–202
ˇ
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1
Received: 15th October 2018; Com. 18/5719
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