One-pot sequential 1,4- and 1,2-reductions of α,β-unsaturated δ-lactones to the corresponding δ-lactols with CuCl and NaBH 4 in methanol

Article abstract of DOI:10.1055/s-0033-1340195

An efficient, one-pot method for the highly chemoselective synthesis of δ-lactols from α,β-unsaturated δ-lactones using CuCl and NaBH₄ in methanol was developed. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340195

1764▌
LETTER
letter
One-Pot Sequential 1,4- and 1,2-Reductions of α,β-Unsaturated δ-Lactones to
the Corresponding δ-Lactols with CuCl and NaBH4 in Methanol
1,4- and 1,2-Reductions of α,β-Unsaturated δ-Lactones
Yasunobu Matsumoto,*a,b Masahiro Yonagaa,b
a
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b
Discovery Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan
Fax +81(0)298472037; E-mail: y7-matsumoto@hhc.eisai.co.jp
Received: 27.03.2014; Accepted after revision 01.05.2014
that reduction of 4 with three molar equivalents of NaBH4
Abstract: An efficient, one-pot method for the highly chemoselec-
alone in MeOH at room temperature for three hours gave
tive synthesis of δ-lactols from α,β-unsaturated δ-lactones using
five products, along with recovered starting material; the
main product was diol 5e, which was produced by overre-
duction (Table 1, entry 1). The use of ten equivalents of
CuCl and NaBH4 in methanol was developed.
Key words: copper, hydrides, lactones, lactols, reduction
NaBH4 at a lower temperature (–50 °C) resulted in the re-
covery of most of the starting material (70%, Table 1, en-
try 2). Surprisingly, the use of 0.5 equivalents of CuCl
along with three equivalents of NaBH4 gave the desired
lactol 5b in moderate yield (Table 1, entry 3). This com-
δ-Lactols, which are the cyclic equivalents of δ-hydroxy
aldehydes, are useful synthons for a broad range of inter-
mediates for the synthesis of natural products and biolog-
ically active compounds.1 δ-Lactols 3 can be generally
bination of reagents is known to effectively reduce α,β-
prepared by a two-step reduction of α,β-unsaturated lac-
unsaturated esters to saturated esters via 1,4-reduction by
tones 1 (Scheme 1), which will be easily prepared by ring-
CuH generated in situ,3 but the application of this combi-
closing metathesis.2
nation to sequential reductions of α,β-unsaturated lac-
tones has not previously been reported. Further
O
O
OH
optimization experiments revealed that 0.5 equivalents of
CuCl and ten equivalents of NaBH4 in MeOH provided
lactol 5b in high yield almost without overreduction (Ta-
ble 1, entry 4). Under these reaction conditions, we ob-
served that upon addition of the CuCl, the reaction
temperature briefly rose from –50 to ca. –20 °C, owing to
the exothermic nature of the reaction. When the amount of
CuCl was decreased to 0.2 equivalents, some amount of
5a remained (Table 1, entry 5). Interestingly, the combi-
nation of 0.5 equivalents of CuCl and one equivalent of
NaBH4 gave mostly saturated lactone 5a (Table 1, entry
6). When ten equivalents of NaBH4 were used with
NiCl2·6H2O instead of CuCl, a good yield of 5b was ob-
tained (Table 1, entry 7),1a whereas CoCl2 gave only a
moderate yield (Table 1, entry 8).1a,4 The order of the ad-
dition of CuCl and NaBH4 was important: In the opti-
mized protocol, NaBH4 was added to the solution of α,β-
unsaturated lactone in MeOH at –50 °C, and the solution
was stirred at this temperature for 15 minutes; then CuCl
was added to the reaction mixture, at which point the re-
action began immediately, as indicated by the evolution of
H2 gas.
O
O
O
R
R
R
1
2
3
Scheme 1 Reduction of α,β-unsaturated lactones 1 to lactols 3
Typically, the conjugated double bond of lactones 1 is hy-
drogenated, and then the carbonyl group of α,β-saturated
lactones 2 is reduced with diisobutylaluminum hydride
(DIBAL-H).1b,e,f,i,p However, both of these reduction reac-
tions suffer from poor functional-group tolerance. In the
hydrogenation reaction, other double bonds, as well as tri-
ple bonds and benzyl ether groups, can also be reduced. In
addition, DIBAL-H has the potential to reduce ester, ace-
tate, and cyano groups. To our knowledge, no effective
methods leading to lactols 3 from α,β-unsaturated lac-
tones 1 with high functional-group tolerance have previ-
ously been reported. Furthermore, obtaining lactols 3
directly from α,β-unsaturated lactones 1 in one pot is chal-
lenging. In this letter, we report that CuCl and NaBH4 in
MeOH is a simple, effective reagent system for highly
chemoselective sequential 1,4- and 1,2-reductions of α,β-
unsaturated lactones 1 to lactols 3 in one pot.
Using the optimized reaction conditions, we explored the
substrate scope and generality of the CuCl–
NaBH4/MeOH reagent system by carrying out sequential
reductions of various substituted α,β-unsaturated lactones
(Table 2). Substitution at the α-, β-, or γ-position had no
deleterious effects; the desired lactols 7a–c were obtained
in high yields. Experiments with δ-lactones with a substi-
tuted phenyl group at the δ position indicated that elec-
tron-donating and electron-withdrawing substituents on
the benzene ring had little effect on the yields of the de-
We chose α,β-unsaturated benzyl-substituted lactone 4 as
a representative substrate to optimize the reaction condi-
tions for the sequential reductions (Table 1). We found
SYNLETT 2014, 25, 1764–1768
Advanced online publication: 03.06.2014
DOI: 10.1055/s-0033-1340195; Art ID: St-2014-u0263-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
1,4- and 1,2-Reductions of α,β-Unsaturated δ-Lactones
1765
Table 1 Optimization of the Reaction Conditionsa
O
O
OH
OH
O
O
O
Ph
Ph
Ph
Ph
Ph
O
4
5a
5b
reagents
O
O
OH
Ph
MeOH
OH
OMe
OH
OH
4
Ph
5c
5d
5e
Entry Reagents
(equiv)
Bath temp
(°C)
Time
(h)
Yield of 4 Yield of 5a Yieldof5bYield of 5c Yield of 5d Yield of 5e
(%)b
(%)b
(%)b
(%)b
(%)b
(%)b
1
2
3
4
5
6
7
8
NaBH4 (3)
r.t.
3
1
1
1
1
1
1
1
6
<1
4
7
3
1
71
13
16
<1
<1
c
c
NaBH4 (10)
–50
70
–
–
<1
c
c
CuCl (0.5), NaBH4 (3)
CuCl (0.5), NaBH4 (10)
CuCl (0.2), NaBH4 (10)
CuCl (0.5), NaBH4 (1)
0
–
5
68
90
79
<1
86
58
<1
<1
–
c
c
–50 to –20
–50 to –20
–50 to –20
–
<1
7
–
c
c
<1
<1
–
–
c
c
c
90
<1
35
–
–
–
c
c
c
NiCl2·6H2O (0.5), NaBH4 (10) –50 to –20
CoCl2 (0.5), NaBH4 (10) –50 to –20
–
–
–
<1
c
c
c
–
<1
–
–
a General conditions: α,β-unsaturated lactone 4 (0.5 mmol), MeOH (5 mL).
b Because 4, 5a, and 5c were inseparable, their yields were determined by NMR spectroscopy; the other yields are isolated yields.
c Not detected.
(I)
sired lactols 7d–g. Furthermore, the carboxylate ester
group of 6f and the cyano group of 6g were unaffected un-
der these reduction conditions. An ethyl ester and an ace-
tate functional group, which are sensitive to DIBAL-H
reduction, were tolerated well, as were an isolated double
bond and triple bonds, including a terminal triple bond;
the desired lactols 7h–l were obtained without hydrobora-
tion.5 However, we found that α,β-unsaturated γ-lactone
6m and ε-lactone 6n gave the corresponding saturated lac-
tones in 90% and 85% yields, respectively. That is, the
five- and seven-membered ring lactones underwent only
1,4-reduction without subsequent 1,2-reduction.
CuCl + NaBH4
CuH + BH3 + NaCl
MeOH
BH3–n(OMe)n + H2
O
(II)
BH2–n(OMe)n+1
O
CuH
R
A
BH3–n(OMe)n
O
CuOMe
O
We propose that our one-pot sequential reductions of α,β-
unsaturated δ-lactones with CuCl and NaBH4 in MeOH
proceeds via successive CuH-catalyzed reduction reac-
tions. CuH-catalyzed 1,4-reduction of α,β-unsaturated
carbonyl compounds by CuCl and NaBH4 is known to oc-
cur,3,6 and the first step of our reaction can be expected to
proceed by a similar mechanism. Specifically, reducing
species CuH and BH3–n(OMe)n are generated by reaction
of CuCl, NaBH4, and MeOH (Scheme 2, I). CuH (A) then
reacts with the α,β-unsaturated lactone, a Michael accep-
tor, to form π-complex B, which reacts with MeOH to
form lactone E via copper enolate C (Scheme 2, II). Re-
duction of generated copper alkoxide D by BH3–n(OMe)n
regenerates CuH.
D
CuH
R
B
O
O
O
Cu
O
R
MeOH
E
R
C
Scheme 2 Mechanism of 1,4-reduction of α,β-unsaturated lactones
by CuCl–NaBH4 in MeOH
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1764–1768

1766
Y. Matsumoto, M. Yonaga
LETTER
Table 2 Sequential 1,4- and 1,2-Reductions of α,β-Unsaturated Lac-
Table 2 Sequential 1,4- and 1,2-Reductions of α,β-Unsaturated Lac-
tones with CuCl and NaBH4 in MeOHa
tones with CuCl and NaBH4 in MeOHa
O
OH
O
OH
CuCl
NaBH4
CuCl
NaBH4
O
O
O
O
R
MeOH
R
R
MeOH
R
n
n
n
n
6a–n
7a–n
6a–n
7a–n
Entry
Product 7
Yield of 7 (%)
Entry
1
Product 7
Yield of 7 (%)
OH
OH
OH
OH
O
O
Ph
92
8
91
TIPS
7a
7k
OH
O
2
3
83
79
Ph
O
9
78
7b
7l
OH
O
O
10
0b
Ph
Ph
7m
7c
OH
OH
O
O
11
0b
90
91
85
80
Ph
4
R
7n
a General conditions: α,β-unsaturated lactones 6a–n (1.0 mmol),
CuCl (0.5 mmol), NaBH4 (10 mmol), MeOH (10 mL), –50 to –20 °C,
1 h. Yields are isolated yields.
7d R = H
7e R = OMe
7f R = CO2Me
7g R = CN
b The corresponding saturated lactones were isolated in 90% and 85%
yields, respectively (data not shown).
OH
O
5
88
We propose that the second step of the reaction sequence
involves 1,2-reduction of saturated lactone E by the same
reducing species, as indicated by the fact that saturated
lactone 5a can be reduced to lactol 5b under the optimized
reaction conditions (Table 3, entry 1).7 This result indi-
cates that BH3–n(OMe)n and CuH generated in situ were
the reducing species that provided the lactol. In addition,
in the absence of CuCl, reduction with ten equivalents of
NaBH4 gave only overreduction product diol 5e. Under
these conditions, unreacted excess NaBH4 overreduced
the hydroxyl aldehyde that was in equilibrium with the
lactol during the workup with aqueous NH4Cl (Table 3,
entry 2). We speculate that in the presence of CuCl, excess
NaBH4 is rapidly transformed to B(OMe)3, which pre-
vents overreduction after the successive 1,4- and 1,2-
reductions by CuH and BH3–n(OMe)n. Additionally, we
propose that activation of the carbonyl group by CuH (F)
facilitates conversion of saturated lactone E into lactol G
(Scheme 3).
EtO2C
7h
OH
O
6
7
83
70
AcO
7i
OH
O
7j
Synlett 2014, 25, 1764–1768
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,4- and 1,2-Reductions of α,β-Unsaturated δ-Lactones
1767
Table 3 1,2-Reduction of Saturated Lactone 5a
OH
OH
OH
O
O
O
+
Ph
Ph
Ph
5e
5a
5b
Entry
Conditions
Yield of 5b (%)a Yield of 5e (%)a
1
2
CuCl (0.5 equiv), NaBH4 (10 equiv), MeOH, –50 to –20 °C, 1 h
NaBH4 (10 equiv), MeOH, –50 to –20 °C, 1 h
88
<1
<1
90
a Yields are isolated yields.
HCu
lifetime of BH3–n(OMe)n were not enough to complete the
second-step 1,2-reduction.
O
OH
O
BH3–n(OMe)n
MeOH
Comparison of the reactivities of the five-, six-, and
seven-membered ring lactones shown in Table 2 revealed
that unlike the six-membered ring lactones, the five- and
seven-membered ring lactones gave only 1,4-reduction
products; that is, the 1,2-reduction to the corresponding
lactols did not occur. To explore the origin of these reac-
tivity differences, we performed density functional theory
calculations. Previously, Wiberg et al. reported that the
calculated proton affinity of a δ-lactone is 8 kcal/mol
greater than that of a γ-lactone.8 Although CuH is a soft
Lewis acid in comparison to a proton, in a similar concept,
we thought the reactivity of these lactones might be ex-
plained by their coordinating affinity to CuH. However,
our density functional theory calculations of the energies
of complexes between CuH and model γ-, δ-, and ε-lac-
tones did not provide any clear evidence to support the in-
volvement of CuH affinity in the observed reactivity
differences between these lactones (see Supporting Infor-
mation).
O
O
CuH
O
R
R
R
E
F
G
Scheme 3 1,2-Reduction of saturated lactones E by CuCl and
NaBH4 in MeOH
To confirm the participation of CuH in the 1,2-reduction,
we conducted an experiment using BH3·THF as a reduc-
ing agent in the absence of CuH (Scheme 4). Specifically,
saturated lactone 5a was treated with ten equivalents of
BH3·THF in MeOH at –50 °C, and then the reaction tem-
perature was raised to –20 °C. That no reaction occurred
under these conditions supports the idea that CuH is in-
volved in the 1,2-reduction.
O
BH3⋅THF(10 equiv)
O
no reaction
MeOH
In summary, we have described a new highly chemoselec-
tive one-pot method to prepare δ-lactols in high yields
from α,β-unsaturated δ-lactones using CuCl and NaBH4 in
methanol.9 This simple and convenient protocol consti-
tutes a new method for the preparation of useful synthons
for synthetic chemistry.
–50 to –20 °C, 1 h
Ph
5a
Scheme 4 Treatment of saturated lactone 5a with BH3·THF in
MeOH
Next, we scaled the reaction up to 1.0 g (5.2 mmol) of α,β-
unsaturated lactone 4 as a substrate (Scheme 5). At this
scale, we could decrease the amount of CuCl from 0.5
equivalents to 0.2 equivalents, and we obtained the de-
sired lactol 5b in excellent yield (91%). However, as
shown in entry 5 of Table 1, it turned out that at least 0.5
equivalents of CuCl were required in a 0.5 mmol scale
reaction, and we suppose the regeneration of CuH and
Acknowledgment
We acknowledge Satoko Sasaki and Yumi Asai (Eisai Co.) for
assistance with high-resolution mass spectrometry, Masaki Kato
(Eisai Co.) for assistance with NMR analysis and Atsushi Inoue
(Eisai Co.) for assistance with DFT calculations
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
O
OH
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
CuCl (0.2 equiv)
NaBH4 (10 equiv)
O
O
Ph
Ph
MeOH
–55 to –20 °C, 3 h
References and Notes
4
5b
91%
(1) For example, see: (a) Bhattacharjee, A.; Soltani, O.; De
Brabander, J. K. Org. Lett. 2002, 4, 481. (b) Statsuk, A. V.;
Liu, D.; Kozmin, S. K. J. Am. Chem. Soc. 2004, 126, 9546.
1.0 g (5.2 mmol)
Scheme 5 Scale-up experiment
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1764–1768

1768
Y. Matsumoto, M. Yonaga
LETTER
(c) Taillier, C.; Gille, B.; Bellosta, V.; Cossy, J. J. Org.
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K.; Minnaard, A. J.; Feringa, B. L.; Govers, F. Proc. Natl.
Acad. Sci. U.S.A. 2008, 105, 8507. (g) Ilardi, E. A.;
Isaacman, M. J.; Qin, Y.; Shelly, S. A.; Zakarian, A.
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(9) General Procedure
NaBH4 (10 mmol, 10 equiv) was added in three roughly
equal portions to a stirred solution of an α,β-unsaturated δ-
lactone (1.0 mmol) in MeOH (10 mL; lactone concentration,
0.1 M) at –50 °C in a reaction flask connected to a drying
tube containing CaCO3. After the solution was stirred for 15
min at –50 °C, the drying tube was removed, and CuCl (0.5
mmol, 0.5 equiv) was added to the reaction mixture, which
immediately turned into a black suspension and evolved H2
gas (the flask was kept open to let out the gas). The reaction
temperature was warmed to –20 °C over the course of 1 h,
and the reaction was quenched at that temperature with sat.
aq NH4Cl. Then EtOAc and H2O were added to the mixture,
which was vigorously stirred for 30 min at r.t. The resulting
clear solution was extracted with EtOAc, and the combined
organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude mixture of products
was purified by silica gel flash column chromatography with
gradient of EtOAc and n-heptane as eluents to afford the
desired δ-lactol.
6-Benzyltetrahydro-2H-pyran-2-ol (5b)
White solid (90%, cis/trans = 1.4:1). 1H NMR (600 MHz,
CDCl3): δ = 7.30–7.27 (m, 4 H, cis trans), 7.22–7.20 (m, 6
H, cis trans), 5.28 (br s, 1 H, trans), 4.66 (m, 1 H, cis), 4.19
(m, 1 H, trans), 3.64 (m, 1 H, cis), 3.06 (d, J = 4.0 Hz, 1 H,
cis-OH), 2.95 (dd, J = 14.0, 7.0 Hz, 1 H, cis), 2.81 (dd, J =
14.0, 7.0 Hz, 1 H, trans), 2.73 (dd, J = 14.0, 7.0 Hz, 1 H, cis),
2.67 (dd, J = 14.0, 7.0 Hz, 1 H, trans), 2.55 (br s, 1 H, trans-
OH), 1.87–1.80 (m, 3 H, cis trans), 1.71–1.42 (m, 6 H, cis
trans), 1.35–1.28 (m, 2 H, cis trans), 1.25–1.18 (m, 1 H, cis).
13C NMR (150 MHz, CDCl3): δ = 138.7 (trans), 138.5 (cis),
129.4 (cis), 129.4 (trans), 128.2 (cis), 128.2 (trans), 126.2
(cis), 126.1 (trans), 96.5 (cis), 92.0 (trans), 77.3 (cis), 69.7
(trans), 42.8 (trans), 42.6 (cis), 32.5 (cis), 30.9 (trans), 30.0
(cis), 29.6 (trans), 21.9 (cis), 17.3 (trans). IR (ATR): ν =
3318, 2942, 2861, 1353, 1142, 1047, 1010, 903, 746, 700
cm–1. HRMS (ESI+): m/z calcd for: C12H20NO2 [M + NH4]+:
210.1489; found: 210.148.
(2) (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (b) Deiters,
A.; Martin, S. F. Chem. Rev. 2004, 2199. (c) D’Annibal, A.;
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(7) It is noteworthy to mention that the reduction of an saturated
lactone to a lactol with CuCl and NaBH4 in MeOH has not
been reported previously.
Synlett 2014, 25, 1764–1768
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