The conversion of racemic terminal epoxides into either (+)- or (-)-diol γ- and δ-lactones

Article abstract of DOI:10.1039/b003793l

The conversion of racemic terminal epoxides into either (+)- or (-)-diol γ-and δ-lactones was described with hydrolytic kinetic resolution (HKR). The optically active epoxide and diol were isolated together from the reaction mixture by bulb-to-bulb distillation. The HKR of racemic terminal epoxides gave active epoxides and diols which were converted into the corresponding lactones.

Full text of DOI:10.1039/b003793l

View Article Online / Journal Homepage / Table of Contents for this issue
The conversion of racemic terminal epoxides into either
(؉)- or (؊)-diol ꢀ- and ꢁ-lactones
Zhi-Yu Liu,*a Jian-Xin Jib and Bo-Gang Lib
1
a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China. E-mail: zhiyuliu@pub.sioc.ac.cn
b Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
Received (in Cambridge, UK) 11th May 2000, Accepted 17th August 2000
First published as an Advance Article on the web 2nd October 2000
The conversion of racemic terminal epoxides into either (ϩ)- or (Ϫ)-diol γ- and δ-lactones is described with
hydrolytic kinetic resolution (HKR) as the key step.
Hydrolytic kinetic resolution (HKR) as developed by Jacob-
sen’s group1 provided practical access to both terminal
epoxides and 1,2-diols in excellent ee using (R,R)-(salen)-
Co(OAc) complex A as the catalyst and water as the only
reagent. However, HKR afforded two kinds of compounds,
epoxides and diols, with the opposite configuration and the two
products have to be separated for further use in most cases.2–5
Considering the advantages of configuration inversion of ter-
minal epoxides in the reaction of intramolecular ring opening
of the epoxide, we are interested in designing a proper pro-
cedure to convert the two products of HKR into the same diol
γ- or δ-lactones (Scheme 1) in the theoretical maximum yield
of 100% from racemic terminal epoxides.
Optically active diol γ- and δ-lactones are important inter-
mediates in the synthesis of natural products and biologically
active compounds.6–11 Until now, (R)-(Ϫ)-diol γ-lactone could
be obtained starting from its (S)-(ϩ)-enantiomer,12 which was
prepared from (S)-(ϩ)-glutamic acid.13 (S)-(ϩ)-δ-Lactone
could be obtained starting from the expensive commercially
available tri-O-acetyl--glucal10 or from -mannitol14 by a
relative long route. In the present work, either (ϩ)- or (Ϫ)-diol
γ- and δ-lactones were prepared from racemic terminal
epoxides in high yields and excellent ee with HKR as the key
step.
50% yield and 94% ee, not the diol 4a, was separated from the
mixture of products as well as the epoxide 3a in 45% yield.
Evidently, the lactonization of diol 4a occurred spontaneously.
Subsequent treatment12 of 3a with TFA gave the same lactone
5a in 87% yield and 96% ee.
Terminal epoxide 2b was prepared by the epoxidation of 1b
with MCPBA. Similarly, treatment of 2b under the general pro-
cedure of HKR afforded epoxide 3b in 46% yield and diol 4b in
49% yield. Unfortunately, the conversion of 3b to 5b with TFA
using the same procedure as for 5a gave an unsatisfactory yield.
The successful lactonization of 3b by a two-step procedure
(Scheme 3), hydrolysis with LiOH and lactonization with CSA
gave lactone 5b in 86% overall yield and 98% ee. The same
lactone was obtained by lactonization of diol 4b in the presence
of Hϩ-exchange resin in 89% yield and 95% ee.
It is more convenient that 5a and 5b could also be obtained
directly by a one-pot procedure from the mixture of the prod-
ucts of HKR reaction. Treatment of the mixture of 3a and 4a
with TFA gave 5a in 88% yield and 95% ee. Hydrolysis of the
mixture of 3b and 4b gave a mixture of crude products, sub-
sequent treatment of which with CAS gave 5b in 83% yield and
96% ee. The enantiomers of 4a and 4b were obtained when the
(S,S)-(salen)Co(OAc) complex was used for HKR.
Thus, we have developed a practical and efficient method to
convert racemic terminal epoxides into either (ϩ)- or (Ϫ)-diol
γ- and δ-lactones in high chemical yield and excellent ee via
HKR and simple transformations.
Results and discussion
At first, the HKR of racemic terminal epoxides gave optically
active epoxides and diols, which were separated from the reac-
tion mixture and converted into the corresponding lactones.
The epoxidation of 1a with MCPBA gave 2a (Scheme 2),
which was proposed to undergo HKR by the general procedure
to afford epoxide 3a and diol 4a. In fact, the lactone 5a in
Experimental
General details
IR spectra were recorded as neat films on a Bio-Rad FTS-185
Scheme 1
DOI: 10.1039/b003793l
J. Chem. Soc., Perkin Trans. 1, 2000, 3519–3521
This journal is © The Royal Society of Chemistry 2000
3519

View Article Online
2.95 (m, 1H), 2.72 (m, 1H), 2.45 (m,1H), 2.44–2.38 (t, J = 7.4,
2H), 2.0–1.85 (m, 1H), 1.80–1.65 (m, 1H), 1.25 (t, J = 7.2, 3H);
m/z 145 (Mϩ ϩ 1, 2%), 115 (14), 99 (56), 85 (57), 71 (99), 55
(100).
General procedure of HKR
To a mixture of terminal epoxide (10 mmol) and (R,R) or (S,S)-
(salen)Co(OAc) complex (34 mg, 0.05 mmol), water (100 mg,
0.55 mmol) was slowly added and the reaction mixture was
stirred at rt for 30 h after the addition. The optically active
epoxide and diol were isolated together from the reaction mix-
ture by bulb-to-bulb distillation and subsequent flash chrom-
atography of the distillate gave epoxide (hexane–EtOAc, 9:1)
and diol (hexane–EtOAc, 2:8).
Ethyl (R)-(؉)-4,5-epoxypentanoate (3a)
Treatment of 2a (1.44 g, 10 mmol) under the general procedure
of HKR using (R,R)-(salen)Co(OAc) complex as the catalyst
gave 3a (0.65 g, 45% yield). [α]D20 = ϩ16.9 (c 0.9, CHCl3). The
other spectra data were identical in all respects to those of 2a.
Scheme 2 Reagents and conditions: i, MCPBA, 6 h, 91%; ii, 1% mol
(R,R)-(salen)Co(OAc), 0.55 equiv. H2O, rt, 30 h, 45% of 3a, 50% of 5a;
iii, TFA, Ϫ10 ЊC, 15 min, 87%.
Method A for (S)-(؉)-ꢀ-hydroxymethyl-ꢀ-butyrolactone (5a)
Treatment of 2a (2.56 g, 20 mmol) under the general procedure
of HKR using (R,R)-(salen)Co(OAc) complex as the catalyst
gave 5a (580 mg, 50% yield, 94% ee). The ee value of 5a was
determined by chiral HPLC using a Chiralpak AS column with
UV detection (201 nm) and an eluant of propan-2-ol–heptane
(4:6). Peaks were observed at 10.81 and 12.41 min. [α]D20 = ϩ50.7
(c 1.2, CHCl3) [lit.12 [α]D = ϩ53.5 (c 5.7, CHCl3)]; νmax/cmϪ1
1192, 1767, 3400; δH 4.63 (m, 1H), 3.95–3.82 (dd, J1 = 12.5,
J2 = 2.7, 1H), 3.70–3.60 (dd, J1 = 12.5, J2 = 4.6, 1H), 2.70–2.35
(m, 1H), 2.34–2.10 (m, 1H); m/z 117 (Mϩ ϩ 1, 1%), 85 (100), 57
(17), 42 (11).
Method B for 5a
A mixture of 3a (287 mg, 2 mmol) and TFA (1 mL) was stirred
at Ϫ10 ЊC for 15 min. Then benzene (10 mL) was added and
most of the solvent was removed under vacuum. Purification of
the residue by flash chromatography (EtOAC) gave 5a (202 mg,
87% yield, 96% ee). [α]D20 = ϩ51.5 (c 0.6, CHCl3).
Scheme 3 Reagents and conditions: i, MCPBA, 6 h, 93%; ii, 1% mol
(R,R)-(salen)Co(OAc), 0.55 equiv. H2O, rt, 30 h, 46% of 3b, 49% of 4b;
iii, LiOH, H2O, THF; iv, CSA, CH2Cl2, 0 ЊC, 15 min, 86%; v,
Amberlyst-15, a few 4 Å molecular sieves, CH3CN, 30 ЊC, 3 h, 89%.
One-pot procedure for 5a
HKR of 2a (721 mg, 5 mmol) under the general procedure
using (R,R)-(salen)Co(OAc) complex as the catalyst gave a
mixture of epoxide and diol by bulb-to-bulb distillation. To the
mixture was added TFA (2 mL) at Ϫ15 ЊC. After the solution
was stirred at Ϫ10 ЊC for 15 min, benzene (25 mL) was added.
Most of the solvent was removed in vacuo and purification of
the residue by flash chromatography (hexane–EtOAc, 2:8) gave
5a (510 mg, 88% yield, 95% ee). [α]D20 = ϩ51.1 (c 0.9, CHCl3).
spectrometer. 1H NMR spectra were determined with TMS
as an internal standard in CDCl3 at 300 MHz on a Bruker
AM-300 spectrometer; J values are given in Hz. Mass spectra
were obtained on a HP-5989A spectrometer using the electron
impact technique. Microanalysis was performed using an
Elementar Vario EL. Optical rotations were measured on a
Perkin-Elmer 341 polarimeter. Enantiomeric excesses were
determined by HPLC analysis with an Chiralpak AS column.
Solvents were dried and distilled prior to use. Flash column
chromatography was conducted silica gel H (100–400 mesh)
from Qingdao Haiyang Chemical Works.
Ethyl 5,6-epoxyhexanoate (2b)
The same procedure as described for the preparation of 2a was
used. The epoxidation of 1b (2.84 g, 20 mmol) with MCPBA
(5.10 g, 22 mmol) gave 2b (2.94 g, 93% yield). Bp 93 ЊC/5 Torr
(Found: C, 60.49; H, 9.00. C8H14O3 requires C, 60.74; H,
8.92%); νmax/cmϪ1 1176, 1735; δH 4.16–4.08 (q, J = 7.1, 2H), 2.90
(m, 1H), 2.72 (m, 1H), 2.43 (m, 1H), 2.35 (t, J = 7.0, 2H), 1.87–
1.70 (m, 2H), 1.68–1.40 (m, 2H), 1.23 (t, J = 7.5, 3H); m/z 159
(Mϩ ϩ 1, 1%), 113 (28), 84 (52), 71 (64), 55 (100).
Compounds 1a15 and 1b16 were prepared by literature
methods.
Ethyl 4,5-epoxypentanoate (2a)
To a solution of 1a (2.56 g, 20 mmol) in CH2Cl2 (100 mL) was
added MCPBA (5.05 g, 22 mmol). After stirring for 6 h, the
reaction mixture was diluted with ether, washed with sat.
Na2S2O3 (20 mL), sat. Na2CO3 (20 mL), brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was subjected to distillation to afford 2a (2.6 g, 93% yield). Bp
76 ЊC/5 Torr (Found: C, 58.11; H, 8.41. C7H12O3 requires: C,
58.32; H, 8.39%); νmax/cmϪ1 1182, 1736; δH 4.10 (q, J = 7.6, 2H),
Ethyl (R)-(؉)-5,6-epoxyhexanoate (3b)
Treatment of 2b (1.58 g, 10 mmol) under the general procedure
of HKR using (R,R)-(salen)Co(OAc) complex as the catalyst
gave 3b (727 mg, 46% yield). [α]D20 = ϩ14.9 (c 0.2, CHCl3). The
other spectra data were identical in all respects to those of 2b.
3520
J. Chem. Soc., Perkin Trans. 1, 2000, 3519–3521

View Article Online
Ethyl (S)-(؊)-5,6-dihydroxyhexanoate (4b)
CHCl3) [lit.13 [α]D Ϫ53.5 (c 3.17, CHCl3)]. The other spectra
data were identical in all respects to those of 5a.
Treatment of 2b (1.58 g, 10 mmol) under the general procedure
of HKR using (R,R)-(salen)Co(OAc) complex as the catalyst
gave 4b (862 mg, 49% yield). [α]D20 = Ϫ14.1 (c 2.0, EtOH) (Found:
Method B for 5aЈ
C, 54.47; H, 9.17. C8H16O4 requires: C, 54.53; H, 9.15%); νmax
/
Treatment of 3aЈ (285 mg, 2 mmol) by method B for 5a gave 5aЈ
(207 mg, 89% yield, 96% ee). [α]D20 = Ϫ51.9 (c 2.1, CHCl3).
cmϪ1 1035, 1193, 1734, 3399; δH 4.12 (q, J = 7.1, 2H), 3.70–3.56
(m, 2H), 3.46–3.30 (m, 2H), 3.28–3.15 (m, 1H), 2.22 (t, J = 7.3,
2H), 1.48–1.38 (m, 2H), 1.25 (t, J = 6.4, 3H); m/z 177 (Mϩ ϩ 1,
6%), 113 (98), 99 (91), 71 (100), 55 (79).
One-pot procedure for 5aЈ
Treatment of 2a (720 mg 5 mmol) under the one-pot procedure
as described for the preparation of 5a except using (S,S)-
(salen)Co(OAc) complex as the catalyst for HKR reaction gave
5aЈ (522 mg, 90% yield, 95% ee). [α]D20 = Ϫ51.6 (c 2.2, CHCl3).
Method A for (S)-(؉)-ꢁ-hydroxymethyl-ꢁ-valerolactone (5b)
A solution of 3b (316 mg, 2 mmol) and LiOH (120 mg, 3 mmol)
in THF–H2O (1:1, 10 mL) was stirred at rt for 1.5 h, acidified
to a pH 4 and extracted with EtOAc. The combined extracts
were dried over Na2SO4 and the solvent was removed in vacuo.
To the resulting crude product in dry CH2Cl2 (10 mL) was
added CSA (46 mg, 0.2 mmol). After stirring at Ϫ5 ЊC for 20
min, the reaction was quenched with Et3N and the solvent was
evaporated. Purification of the residue by flash chromatography
(hexane–EtOAc, 2:8) gave 5b (224 mg, 86% overall yield from
4b, 98% ee). The ee value of 5b was determined by chiral HPLC
using a Chiralpak AS column with UV (201 nm) and an eluant
of propan-2-ol–heptane (2:8). Peaks were observed at 11.57
and 12.30. [α]D20 = ϩ34.5 (c 0.6, CHCl3) [lit.10 [α]D20 = ϩ34.68 (c 1.3,
CHCl3)]; νmax/cmϪ1 1055, 1248, 1725, 3403; δH 4.46–4.36 (m,
1H), 3.86–3.72 (m, 1H), 3.70–3.60 (m, 1H), 2.75 (m, 1H), 2.65–
2.55 (m, 1H), 2.50–2.40 (m, 1H), 2.0–1.80 (m, 3H), 1.78–1.60
(m, 1H); m/z 131 (Mϩ ϩ 1, 8%), 113 (15), 99 (100), 71 (75), 55
(45), 43(47).
Ethyl (S)-(؊)-5,6-epoxyhexanoate (3bЈ)
Treatment of 2b (1.58 g, 10 mmol) under the general procedure
of HKR using (S,S)-(salen)Co(OAc) complex as the catalyst
gave 3bЈ (711 mg, 45% yield). [α]D20 = Ϫ15.0 (c 1.1, CHCl3). The
other spectra data were identical in all respects to those of 3b.
Ethyl (R)-(؉)-5,6-dihydroxyhexanoate (4bЈ)
Treatment of 2b (1.58 g, 10 mmol) under the general procedure
of HKR using (S,S)-(salen)Co(OAc) complex as the catalyst
gave 4bЈ (862 mg, 49% yield). [α]D20 = Ϫ14.2 (c 2.0, EtOH). The
other spectra data were identical in all respects to those of 4b.
Method A for (R)-(؊)-ꢁ-hydroxymethyl-ꢁ-valerolactone (5bЈ)
Treatment of 3bЈ (318 mg, 2 mmol) by method A for 5b gave 5bЈ
(231 mg, 89% yield, 98% ee). [α]D20 = Ϫ34.3 (c 1.3, CHCl3) [lit.10
[α]D20 = ϩ34.68 (c 1.3, CHCl3) for its enantiomer]. The other
spectra data were identical in all respects to those of 5b.
Method B for 5b
To a solution of 4b (352 mg, 2 mmol) in CH3CN (10 mL)
was added a catalytic amount of Hϩ-ion-exchange resin
(Amberlyst-15) and a few 4 Å molecular sieves. The reaction
mixture was stirred at rt for 3.5 h, and then filtered. The solvent
was removed in vacuo. Purification of the residue by flash
chromatography (hexane–EtOAc, 2:8) gave 5b (231 mg, 89%
yield, 95% ee). [α]D20 = ϩ33.2 (c 2.1, CHCl3).
Method B for 5bЈ
Treatment of 4bЈ (350 mg, 2 mmol) by method B for 5b gave 5bЈ
(234 mg, 90% yield, 96% ee). [α]D20 = Ϫ33.5 (c 1.0, CHCl3).
One-pot procedure for 5bЈ
Treatment of 2b (791 mg 5 mmol) under the one-pot procedure
as described for the preparation of 5b except using (S,S)-
(salen)Co(OAc) complex as the catalyst for HKR gave 5bЈ (527
mg, 81% yield, 96% ee). [α]D20 = Ϫ33.8 (c 0.8, CHCl3).
One pot procedure for 5b
HKR of 2b (791 mg, 5 mmol) under the general procedure
using (R,R)-(salen)Co(OAc) complex as the catalyst gave a mix-
ture of epoxide 3b and diol 4b by bulb-to-bulb distillation. The
mixture was diluted with THF–H2O (1:1, 50 mL) and
LiOHؒH2O (314 mg, 7.5 mmol) was added. The solution was
stirred at rt for 1.5 h, acidified with KHSO4 to pH 4 and
extracted with EtOAc (3 × 25 ml). The combined extracts were
dried over Na2SO4, and the solvent was removed in vacuo. To
the resulting crude product in CH2Cl2 (45 mL), was added CSA
(115 mg, 0.5 mmol) at Ϫ10 ЊC. After stirring at Ϫ10–ϩ20 ЊC for
2 h, the reaction was quenched with Et3N, and the solvent was
evaporated. Purification of the residue by flash chromatography
(hexane–EtOAc, 2:8) gave 5b (540 mg, 83% yield, 96% ee).
[α]D20 = ϩ34.0 (c 1.5, CHCl3).
References
1 (a) M. Tokunaga, J. F. Larrow, F. Kakiuchi and E. N. Jacobsen,
Science, 1997, 277, 936; (b) S. E. Schaus, J. Branalt and E. N.
Jacobsen, J. Org. Chem., 1998, 63, 4876; (c) D. A. Annis and
E. N. Jacobsen, J. Am. Chem. Soc., 1999, 121, 4147.
2 M. K. Gurjar, B. V. N. B. S. Sarma, K. Sadalapure and S. Adhikari,
Synthesis, 1998, 1424.
3 P. S. Savle, M. J. Lamoreaux, J. F. Berry and R. D. Gaudour,
Tetrahedron: Asymmetry, 1998, 9, 1843.
4 Q. Yu, Y. K. Wu, L. J. Xia, M. H. Tang and Y. L. Wu, Chem.
Commun., 1999, 129.
5 P. B. Wyatt and P. Blakskjær, Tetrahedron Lett., 1999, 40, 6481.
6 J. W. Scott, in Asymmetric Synthesis, Academic Press, 1984, vol. 4,
pp. 1–226.
7 K. Mori, Tetrahedron, 1975, 31, 3011.
8 J. P. Robin, O. Gringore and E. Brown, Tetrahedron Lett., 1980, 21,
2709.
9 S. Takano, M. Yonaga, K. Chiba and K. Ogasawara, Tetrahedron
Lett., 1980, 21, 3697.
10 E. J. Corey, S. G. Pyne and W.-G. Su, Tetrahedron Lett., 1983, 24,
4883.
Ethyl (S)-(؊)-4,5-epoxypentanoate (3aЈ)
Treatment of 2a (1.44 g, 10 mmol) under the general procedure
of HKR using (S,S)-(salen)Co(OAc) complex as the catalyst
gave 3aЈ (620 mg, 43% yield). [α]D20 = Ϫ17.1 (c 0.8, CHCl3). The
other spectra data were identical in all respects to those of 2a.
11 R. M. Ortuño, J. Bigorra and J. Font, Tetrahedron, 1987, 43, 2199.
12 P.-T. Ho and N. Daviles, Synthesis, 1983, 462.
13 M. Taniguchi, K. Koga and S. Yamada, Tetrahedron, 1974, 30, 3547.
14 P. Pianetti and J.-R. Pougny, J. Carbohydr. Chem., 1988, 811.
15 M. Gaudemar, Tetrahedron Lett., 1983, 24, 2749.
16 G. Cardinale, J. A. M. Leen and J. P. Ward, Tetrahedron, 1985, 41,
2899.
Method A for (R)-(؊)-ꢀ-hydroxymethyl-ꢀ-butyrolactone (5aЈ)
Treatment of 2a (1.44 g, 10 mmol) under the general procedure
of HKR using (S,S)-(salen)Co(OAc) complex as the catalyst
gave 5aЈ (580 mg, 50% yield, 95% ee). [α]D20 = Ϫ51.5 (c 1.5,
J. Chem. Soc., Perkin Trans. 1, 2000, 3519–3521
3521