Reduction of sugar lactones to hemiacetals with lithium triethylborohydride

Article abstract of DOI:10.1016/j.carres.2016.06.002

Reduction of ribono-1,4-lactones and gulono-1,4-lactone as well as ribono-1,5-lactone and glucono-1,5-lactones with LTBH (1.2 equiv.) in CH₂Cl₂at 0 °C for 30 min provided the corresponding pentose or hexose hemiacetals in high yields. Commonly used in carbohydrate chemistry protecting groups such as trityl, benzyl, silyl, acetals and to some extent acyls are compatible with this reduction.

Full text of DOI:10.1016/j.carres.2016.06.002

Carbohydrate Research 432 (2016) 17e22
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Carbohydrate Research
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Note
Reduction of sugar lactones to hemiacetals with lithium
triethylborohydride
Cesar Gonzalez, Sam Kavoosi, Andersson Sanchez, Stanislaw F. Wnuk*
Department of Chemistry & Biochemistry, Florida International University, Miami, FL 33199, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reduction of ribono-1,4-lactones and gulono-1,4-lactone as well as ribono-1,5-lactone and glucono-1,5-
lactones with LTBH (1.2 equiv.) in CH2Cl2 at 0 ꢀC for 30 min provided the corresponding pentose or
hexose hemiacetals in high yields. Commonly used in carbohydrate chemistry protecting groups such as
trityl, benzyl, silyl, acetals and to some extent acyls are compatible with this reduction.
© 2016 Elsevier Ltd. All rights reserved.
Received 6 May 2016
Received in revised form
7 June 2016
Accepted 9 June 2016
Available online 11 June 2016
Keywords:
Reduction
Lithium triethylborohydride
Super-hydride
Sugar lactones
Sugar lactols
Hemiacetals
The reduction of sugar lactones to hemiacetals (lactols) plays an
important role in the synthesis of modified carbohydrates and
nucleosides [1,2]. The commonly used reagents for this trans-
formation include NaBH4, [3,4] and organic-soluble metal hydrides
[2,5,6]. LiAlH4 under controlled reaction conditions has also been
used for this purpose [7]. NaBH4 is effective in the reduction of
sugar lactones to aldoses. However, it requires aqueous acid con-
ditions to prevent over reduction, which is problematic for
nonpolar and/or acid labile compounds [7,8]. Although DIBAL-H is
an efficient reagent for this reduction, it often requires low tem-
perature and large excess of the reagent, which is a disadvantage
for large scale work [9]. Catalytic reduction of lactones to lactols
with generated in situ titanocene(III) hydride, in the presence of
silanes as a hydride source, has also been developed [10,11]. This
approach was utilized for the large scale preparation of sugar
hemiacetals [12].
corresponding arabinofuranose [14], and Selectride was employed
for the partial reduction of acetyl protected D-galactono-1,4-
lactone [15].
Reduction of the pre-constructed sugar lactones to their corre-
sponding hemiacetals and their further coupling with nucleobases
are often key steps in the synthesis of important drugs (e.g., anti-
cancer gemcitabine [2], anti-HIV 3 TC and dideoxynucleosides
[5,16] and others). In our program on developing novel inhibitors of
S-ribosylhomocysteine (SRH) hydrolase (LuxS; EC 4.4.1.21), which
mediates the interspecies quorum sensing among bacteria [17,18],
we recently applied lithium triethylborohydride (LTBH, Super-Hy-
dride®) [19,20] for the reduction of lactam and lactone analogues of
SRH to the corresponding azahemiacetals (N,O-acetals) [21] or
lactols (O,O-acetals) [22]. Although application of LTBH for the
reduction of lactams to cyclic hemiaminals (azahemiacetals) is
documented [23,24], the reduction of lactones to the hemiacetals
with LTBH is underdeveloped. In his landmark paper from 1980
[25], Brown reported that LTBH, when used in excess (2 equiv.),
efficiently reduced esters to alcohols and lactones to diols and this
protocol has been used in organic synthesis [19,26]. Herein, we
report application of lithium triethylborohydride for the efficient
reduction of sugar lactones to hemiacetals.
Although borane-based reagents have been used for the
reduction of lactones to lactols and diols [13], reports of reductions
of sugar lactones to hemiacetals using borane reagents are sparse.
For example, disiamylborane was used for the conversion of 2,3-di-
O-acetyl-5-S-acetyl-5-thio-D-arabinono-1,4-lactone
to
the
Initially, we tested reduction of lactones to hemiacetals with
LTBH with readily available 5-O-benzyl-2,3-O-isopropylidene-D-
ribono-1,4-lactone [12] 1 (Scheme 1). Thus, treatment of 1 with
* Corresponding author.
E-mail address: wnuk@fiu.edu (S.F. Wnuk).
http://dx.doi.org/10.1016/j.carres.2016.06.002
0008-6215/© 2016 Elsevier Ltd. All rights reserved.

18
C. Gonzalez et al. / Carbohydrate Research 432 (2016) 17e22
Scheme 1. Reduction of the protected ribono-1,4-lactone 1 with LTBH.
1.0 equiv. or 1.1 equiv. of LTBH (CH2Cl2/0 ꢀC/30 min) showed about
90e95% conversion to the ribofuranose 2 with ~5e10% of substrate
1 remaining unchanged (1H NMR; Table 1, entries 1 and 2). How-
ever, treatment of 1 with 1.2 equiv. of LTBH gave a complete con-
shorter reaction time (10 min) provided hemiacetals 9 in 70% yield
(entry 4). Reduction of 2,3,5-tri-O-acetyl lactone 10 gave hemi-
acetals 11 but in low yield (30%, entry 5). Conversion of 2,3-O-iso-
propylideneribono-1,4-lactone 12 to ribose 13 required an
increased amount of LTBH (1.6 equiv.; entry 6). Reduction of the
3,5-O-TBDMS-2-deoxy-D-ribono-1,4-lactone 14 also proceeded
efficiently to give the 2-deoxyribose product 15 when 1.5 equiv. of
LTBH was used (entry 7). However, reduction of 5-O-TBDMS-2,3-
dideoxy-D-ribono-1,4-lactone 16 yielded both the 2,3-
dideoxyribose 17 and the corresponding diol byproduct (entry 8).
Moreover, reduction of D-ribono-1,5-lactone 18 efficiently pro-
duced the corresponding ribopyranose derivative 19 in 88% yield
(entry 9).
version to hemiacetals 2 (a/b, 1:4) without noticeable detection of
the peaks for the lactone 1 and diol 3 on the 1H NMR spectra of the
crude reaction mixture (entry 3, see SI Section). Effect of different
ratios of LTBH to lactone 1 as well as temperature, reaction time and
solvent are summarized in Table 1. Briefly, increasing the ratio of
LTBH to 1.5 equiv. still gives 2 as a sole product (entry 4). However,
reduction with 2.5 equiv. of LTBH led to the substantial formation of
diol 3 (entry 5). Yet, even when the reduction was carried out for
longer time (up to 22 h) hemiacetals 2 was still isolated although in
lower yields. Interestingly, temperature did not have a significant
effect on the reduction of lactone 1 to hemiacetals 2 and similar
results were obtained at ꢁ78 ꢀC, 0 ꢀC, or r.t. (entries 4, 6 and 7).
Additionally, reduction of 1 in other solvents (toluene or chloro-
form) did not affect the reduction (entries 8 and 9) with the
exception of THF which gave substantially lower yield (entry 10).
In order to investigate the reaction profile for the conversion of
lactone 1 to lactol 2 and diol 3, reduction of 1 was performed using
1.2 equiv (see Fig. S1 in SI section) and 2.5 equiv. of LTBH (see Fig. S2
in SI section). In both cases complete conversion of lactone 1 to
lactol 2 was observed in less than 5 min. In the reaction with
1.2 equiv. of LTBH no diol 3 was detected even after 1 h. Reduction
of 1 with 2.5 equiv. of LTBH was completed within 1 min showing
exclusive formation of lactol 2. Longer reaction time showed a slow
The lactones derived from hexoses were also efficiently reduced
with LTBH to the corresponding hemiacetals. Thus, reduction of
2,3:5,6-di-O-isopropylidene-D-gulono-1,4-lactone 20 gave gulo-
nofuranose 21 (91%, entry 10). Treatment of trimethylsilyl protected
glucono-1,5-lactones 22 with LTBH yielded glucopyranose 23 (a/b,
2:1; entry 11). Analogous reduction of the fully acetylated D-glu-
cono-1,5-lactone 24 provided glucose 25 in low yield due to
concomitant reduction of the ester protecting group (entry 12).
Attempted reduction of the fully benzoylated glucono-1,5-lactone
gave similar results (entry 12, footnote f). However, reduction of
glucono-1,5-lactone 26 bearing benzylidene and tert-butyldime-
thylsilyl protection groups proceeded efficiently to give hemi-
acetals 27 in 80% yield (entry 13). Hence, reduction of sugar
lactones with LTBH to lactols appears to have a general character
and is clearly compatible with acid-, base- and fluoride-labile
protecting groups commonly used in carbohydrate chemistry.
We also performed reduction of several sugar lactones with
NaBH4 and DIBAL-H, in order to compare LTBH protocol with these
commonly used reducing agents. Thus, reduction of 4 or 14 with
NaBH4 (1.1 equiv.) in EtOH (0 ꢀC) after 30 min showed only a small
conversion to the lactol products 5 and 15 (~10%) with the un-
changed lactones (~80%) and the corresponding diols (~10%) pre-
sent (TLC, 1H NMR). Increasing the amount of NaBH4 (5 equiv.)
resulted in the formation of the corresponding diols as the major
product (~70%). Reduction of 14 with DIBAL-H in CH2Cl2 (ꢁ78 ꢀC,
30 min) yielded lactol 15 (90%). However, analogous treatment of 5-
disappearance of lactol
2 with increasing formation of diol
byproduct 3 [0.5 h, 2 (72%)/3 (28%); 2 h, 2 (65%)/3 (35%)].
To probe the generality of the reduction of sugar lactones to the
corresponding hemiacetals with LTBH, several
g- and d-lactones
were tested (Table 2). Thus, reduction of 2,3-O-isopropylidene-
ribono-1,4-lactones with trityl (4), benzoyl (6) or acetyl (8) pro-
tection at 5-hydroxyl provided the corresponding hemiacetals 5, 7,
and 9 (entries 2e4). The trityl and benzoyl protection groups were
found to be stable under these reducing conditions. Reduction of
the 5-O-acetyl lactone 8 yielded also substantial amount of 2,3-O-
isopropylidene-a/b-D-ribofuranose as a result of the reduction of
an acetyl ester. However, reduction with 1.1 equiv. of LTBH and
Table 1
Effect of various reaction parameters on reduction of 1 with LTBHa.
Entry
Solvent
LTBH (equiv.)
Temperature (ꢀC)
Yieldb 2 (%)
Yieldb 3 (%)
Ratiob 1:2:3
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CHCl3
1.0
1.1
1.2
1.5
2.5
1.5
1.5
1.5
1.5
1.5
0
0
0
0
0
20
ꢁ78
0
0
0
90
95
e
1:9:0
1:19:0
0:1:0
0:1:0
0:4:6
0:1:0
0:1:0
0:1:0
1:19:0
7:3:0
e
99 (95)c
99
e
e
40 (34)c
94
60 (55)c
e
e
e
e
e
95
93
95
30
THF
a
Reduction was performed on 0.15 mmol scale of 1 with 1 M solution of LTBH in THF.
Determined by 1H NMR of the crude reaction mixture.
Isolated yield.
b
c

C. Gonzalez et al. / Carbohydrate Research 432 (2016) 17e22
19
Table 2
Reduction of various sugar lactones with LTBH to hemiacetals.a
Entry
1
Substrate
Product
LTBH (equiv.)
1.2
Yieldb (%)
90c
2
3
4
1.2
1.2
1.1
89
85
70d
5
6
1.1
1.6
30
90
7
8
1.5
1.2
72
37e
(continued on next page)

20
C. Gonzalez et al. / Carbohydrate Research 432 (2016) 17e22
Table 2 (continued )
Entry
9
Substrate
Product
LTBH (equiv.)
1.2
Yieldb (%)
88
10
1.2
91
11
1.2
84
12
1.1
20f
13
1.2
80
a
Reduction was performed on 0.1e1.0 mmol scale of lactones with 1 M solution of LTBH/THF.
b
c
d
e
f
Isolated yield as a mixture of
Reduction on 1.0 mmol scale.
a/b anomers.
With 1.2 equiv. of LTBH the 2,3-O-isopropylidene-
(R)-5-(benzyloxy)pentane-1,4-diol (42%) and the residual amount of unchanged 16 (~5%) was also isolated.
Analogous reduction of 2,3,4,6-tetra-O-benzoylglucono-1,5-lactone [27] yielded 2,3,4,6-tetra-O-benzoylglucopyranose (~15e20%; TLC, 1H NMR).
a/b-D-ribofuranose was isolated in 37% yield.
O-acetyl lactone 8 with DIBAL-H yielded mixture (~2:3) of desired
lactol 9 and the lactol 13 as a result of the concomitant reduction of
the acetyl ester.
2,3-dideoxyribonolactone). The fact that reduction of 2,3-
dideoxyribonolactone with LTBH can be controlled to give the
hemiacetals product, while under similar conditions
g-
Reduction of
g-butyrolactone 28 with LTBH (1.8 equiv./CH2Cl2/
0
ꢀC; Method A, Scheme 2] gave 1,4-butanediol 29 as the sole
product. Various modifications of the reduction protocol [LTBH
(0.5e1.2 equiv.)/CH2Cl2/ꢁ78 ꢀC or 0 ꢀC or r.t./30 min to 2 h] pro-
duced diol 29 in addition to different quantities of the unchanged
lactone 28, but the corresponding lactol was not observed. This is in
agreement with the results reported by Brown that reduction of 28
with LTBH (2.0 equiv.; THF/ꢁ78 ꢀC; Method B) gave 29 in 94% [25].
Typically, the reduction of the sugar lactones with LTBH in
CH2Cl2 is higher yielding when the lactone has a larger number of
hydroxyl groups (e.g., ribonolactone > 2-deoxyribonolactone >>
Scheme 2. Reduction of g-butyrolactone with LTBH to 1,4-butanediol.

C. Gonzalez et al. / Carbohydrate Research 432 (2016) 17e22
21
butyrolactone is converted to the diol provides support for the
assumption that chelation of the borane reagent to the exocyclic
sugar hydroxyl group (oxygen) is critical in this reduction process.
Buchwald invoked coordination of the titanium center to the lac-
tone's oxygen atoms during reduction of lactones to lactols with
titanocene(III) hydrides [10]. The fact that reduction with LTBH gave
better yields in CH2Cl2 than in THF (Table 1) may be attributed to
the additional coordination of LTBH reagent to the more polar THF
solvent which can result in weakening of the LTBH chelation to the
lactone oxygens. Our studies also showed that lactones containing
an ester protection group (acetyl or benzoyl) can be chemo-
selectively reduced to the hemiacetals under certain reduction
conditions with LTBH/CH2Cl2 combination while the ester moiety
remains intact.
1H, Bn), 4.65 (d, J ¼ 11.7 Hz, 1H, Bn), 4.74 (d, J ¼ 5.9 Hz, 1H, H3), 5.28
(d, J ¼ 6.0 Hz, 1H, H1), 7.29e7.30 (m, 5H, Ph); 13C NMR
d 24.9 (CH3),
26.5 (CH3), 71.2 (C5), 74.1 (Bn), 82.0 (C3), 85.6 (C2), 87.5 (C4), 103.8
(C1), 112.1 (CMe2), 127.5 (Ar), 128.5 (Ar), 136.2 (Ar); HRMS (TOF-ESI)
m/z calcd for C15H20O5Naþ [MþNa]þ 303.1197; found 303.1188.
Minor anomer had: 1H NMR
d
1.38 and 1.55 (2 ꢂ s, 2 ꢂ 3H,
2 ꢂ CH3), 3.54 (dd, J ¼ 2.5, 10.2 Hz, 1H, H5), 3.61 (dd, J ¼ 2.5, 10.2 Hz,
1H, H50), 4.22 (t, J ¼ 2.2 Hz,1H, H4), 4.41 (d, J ¼ 11.7 Hz, 1H, Bn), 4.48
(d, J ¼ 11.7 Hz, 1H, Bn), 4.57 (dd, J ¼ 4.4, 6.5 Hz, 1H, H2), 4.71 (dd,
J ¼ 4.4, 6.5 Hz, 1H, H3), 5.47 (dd, J ¼ 3.8, 11.9 Hz, 1H, H1), 7.29e7.30
(m, 5H, Ph). 13C NMR peaks for the ribose moiety:
73.7(Bn), 79.4 (C3), 79.7 (C2), 81.8 (C4), 97.8 (C1).
d 72.0 (C5),
1.2.2. 5-O-Benzyl-2,3-O-isopropylidene-D-ribitol (3) [28]
In summary, we have developed an efficient protocol for the
Treatment of 1 (55 mg, 0.20 mmol) with 2.5 equiv. of LTBH ac-
cording to the general procedure gave 2 (19 mg, 34%) followed by 3
reduction of sugar
g- and d-lactones with LTBH (1.2 equiv.) in
(31 mg, 55%). Diol 3 had: 1H NMR
d
1.33 and 1.38 (2 ꢂ s, 2 ꢂ 3H,
CH2Cl2 (0 ꢀC, 30 min) to the corresponding hemiacetals. Several
ribono- and gulono-1,4-lactone as well as glucono-1,5-lactones
were reduced to the corresponding pentose or hexose hemi-
acetals in high yields. The reduction with LTBH can be carried out in
the presence of protecting groups such as trityl, benzyl, silyl (TMS
or TBDMS), isopropylidene/benzylidene and to some extent acyl
(Bz, or Ac) that are commonly used in the synthetic carbohydrate
chemistry.
2 ꢂ CH3), 2.86 (m, 2H, 2 ꢂ OH), 3.55 (dd, J ¼ 6.7, 9.6 Hz, 1H, H5), 3.74
(dd, J ¼ 9.6, 3.0 Hz, 1H, H50), 3.78 (m, 1H, H1), 3.86 (dd, J ¼ 7.8,
11.6 Hz, 1H, H10), 3.96 (m, 1H, H4), 4.10 (dd, J ¼ 5.8, 9.6 Hz, 1H, H3),
4.35 (dt, J ¼ 5.2, 8.1 Hz, 1H, H2), 4.59 (s, 2H, Bn), 7.34 (m, 5H, Ph).
1.2.3. 4,6-O-Benzylidene-2,3-bis-O-(tert-butyldimethylsilyl)-
glucopyranose (27)
a/b-D-
Reduction of 26 (50 mg, 0.1 mmol; prepared by standard sily-
lation 4,6-O-benzylidene-D-glucopyranose [29] with TBDMS/
1. Experimental section
imidazole/DMF) according to the general procedure gave 27 (
a/b,
1:1, 39 mg, 80%): 1H NMR
d
0.010e0.17 (6 ꢂ s, 12H, MeSi),
1.1. General procedure
0.75e0.98 (2 ꢂ s, 18H, t-BuSi), 3.92e4.00 (m, 1.5H), 4.13e4.20 (m,
2H), 4.25 (m, 1H), 4.35 (m, 0.5H), 4.44 (m, 1H), 5.07 (m, 0.5H, H1),
5.65 (m, 0.5H, H1), 6.12 (s, 0.5H, CHPh), 6.16 (s, 0.5H, CHPh),
The 1H (400 MHz) and 13C (100 MHz) NMR spectra were
determined with solutions in CDCl3 unless otherwise noted. TLC
was performed with Merck Kieselgel 60-F254 sheets and products
were detected with 254 nm light or by visualization with Ce(SO4)2/
(NH4)6Mo7O24$4H2O/H2SO4/H2O reagent. Merck kieselgel 60
(230e400 mesh) was used for column chromatography. The ratio of
the products for reduction of 28 to 29 were determined using a
Hewlett-Packard (HP) GC/MS (EI) system with a HP 5973 mass
7.35e7.48 (m, 5H, Ph); 13C NMR
d
ꢁ5.49, ꢁ5.46, ꢁ5.44, ꢁ5.17
, ꢁ4.84, ꢁ4.77, ꢁ4.74, ꢁ4.71 (MeSi), 18.1 (CMe3), 18.2 (CMe3), 18.3
(CMe3), 25.7 (Me), 25.8 (Me), 26.0 (Me), 26.1 (Me), 66.3 (C6), 66.4
(C6), 72.6 (C5), 74.7 (C5), 75.2 (C4), 75.3 (C4), 76.2 (C3), 79.8 (C3),
80.0 (C2), 80.7 (C2), 96.0 (CH-Ph), 97.5 (CH-Ph), 100.1 (C1), 103.8
(C1), 126.1 (Ar), 126.4 (Ar), 128.5 (Ar), 128.6 (Ar), 129.3 (Ar), 129.9
(Ar), 138.2 (Ar), 138.5 (Ar); HRMS (TOF-ESI) m/z calcd for
selective
detector
[capillary
column
HP-5MS
25H44O6Si2Naþ [MþNa]þ 519.2569; found 519.2587.
(30 m ꢂ 0.25 mm ꢂ 25
mm)] using calibrated standards. All glass-
ware used was dried thoroughly in an oven, and cooled under ni-
trogen prior to use. Reagent grade chemicals were used.
C
Acknowledgement
1.2. Typical procedure for reduction of the sugar lactones to
hemiacetals with LTBH
This work was partially supported by NIGMS/NCI
(1SC1CA138176).
LTBH (1 M/THF; 0.24 mL, 0.24 mmol) was added to a solution of
the appropriate sugar lactone (0.2 mmol) in anhydrous CH2Cl2
(3 mL) at 0 ꢀC. After 30 min, the reaction mixture was quenched
with MeOH and the volatiles were evaporated. The resulting res-
idue was dissolved in CH2Cl2 (10 mL) and washed with NaHCO3/
H2O. The organic layer was then dried (Mg2SO4), evaporated and
the residue was column chromatographed (7:3 / 1:1, hexane/
EtOAc, unless stated otherwise) to afford the corresponding sugar
hemiacetals 2, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 (see SI Section
for synthetic details and spectral characterization for all com-
pounds). Yields and different reaction conditions are described in
Table 2.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.carres.2016.06.002.
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