The synthesis of (S)-( + )-pantolactone and its analogues from an ephedrine-derived morpholinone

Article abstract of DOI:10.1016/j.tetasy.2004.02.022

An efficient general route for the enantioselective synthesis of (S)-(+)-pantolactone and its analogues has been developed from an ephedrine-derived chiral morpholin-3-one. Selective dialkylation of an ephedrine-derived chiral template without epimerization is the key step in this synthesis.

Full text of DOI:10.1016/j.tetasy.2004.02.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1081–1084
The synthesis of (S)-(þ)-pantolactone and its analogues from an
ephedrine-derived morpholinone
Bidhan A. Shinkre and Abdul Rakeeb A. S. Deshmukh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Received 7 February 2004; accepted 24 February 2004
Dedicated toDr. S. Rajappa on his 70th birthday
Abstract—An efficient general route for the enantioselective synthesis of (S)-(þ)-pantolactone and its analogues has been developed
from an ephedrine-derived chiral morpholin-3-one. Selective dialkylation of an ephedrine-derived chiral template without epi-
merization is the key step in this synthesis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The asymmetric synthesis of pantolactone and its ana-
logues continues to be an area of active interest to
organic chemists as a consequence of their biological
activity, utility as a secondary alcohol derived chiral
auxiliary1 and as a building block in the synthesis of
natural products.2 The taurine derivative of pantothenic
acid (pantoyl taurine) has been shown3 toinhibit the
growth of streptococci, pneumococci, plasmodium
relictum4 and certain strains of diptheria bacilli.5 Fur-
thermore, pantolactone is an important starting com-
pound for pantothenic acid6 (a member of B complex
vitamins), calcium pantothenate7 (enzyme cofactor
vitamin), (R)-panthenol8 (bactericide) and (R)-pante-
theine9 (growth factor). Enantiomerically pure panto-
lactone and its analogues have been obtained by
chemical10 and enzymatic resolution of the racemate,11
enantioselective reduction of 3,3-dimethyl-2-oxo-
butyrolactone,12 Sharpless asymmetric dihydroxylation
of the corresponding cyclic silylketene acetal, a panto-
lactone precursor,13 asymmetric functionalization of
linear or cyclic precursors14 and asymmetric aldol reac-
tion of silyl enolate with ethyl glyoxylate.15
report the efficient use of ephedrine for the enantio-
selective synthesis of pantolactone and its analogues.
Recently, the synthesis of pantolactone has been
achieved in our laboratory by a stereoselective Prins
reaction on an ephedrine-derived chiral alkylidine
morpholinone.17 However, this synthesis not only gives
a low overall yield of pantolactone but also has limita-
tions in it being utilized as a general route for the syn-
thesis of analogues. We envisaged, a,a-dialkylation of
ephedrine-derived chiral morpholin-3-one ester 4 as a
key strategy, which on further functional group trans-
formations would give us pantolactone and its vari-
ous analogues. While there have been numerous reports
on the asymmetric synthesis of pantolactone deriva-
tives, to the best of our knowledge, there has been no
report on a dialkylation strategy for the introduction
of the gem-dialkyl moiety in pantolactone or its ana-
logues.
The starting morpholin-3-one ester 4 was easily acces-
sible in its enantiomerically pure form commercially
available ephedrine in three steps following our previ-
ously reported procedure16b in good overall yield
(Scheme 1). Introduction of the gem-dialkyl moiety, a
key step in the synthesis, via selective dialkylation on the
a-carbon to the ester carbonyl was then investigated.
Different bases such as LDA, NaH, KOtBu and KH
were employed for the dialkylation of ester 4 using
methyl iodide as an alkylating agent. The reaction did
not work with NaH and gave back the starting material,
while LDA gave an inseparable complex mixture of
products. However, dimethylated product 5a could be
As a part of our ongoing research programme on the
application of commercially available ephedrine as a
chiral template for asymmetric synthesis,16 we herein
* Corresponding author. Tel./fax: +91-20-25893153; e-mail: arasd@
dalton.ncl.res.in
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.022

1082
B. A. Shinkre, A. R. A. S. Deshmukh / Tetrahedron: Asymmetry 15 (2004) 1081–1084
Me
Me
Me
Me
Me
(COCl)2, Et3N,
DMAP, CH2Cl2
Me
O
Ph
Me
O
Ph
Me
O
Ph
Me
O
Ph
N
N
N
Me
Ph
N
a
90%
b
N
H
O
O
O
HCl
O
97%
OH
O
2
1
OMe
OMe
OMe
Ph3PCHCO2Et
CH2Cl2
7
6c
8
Scheme 3. Reagents and conditions: (a) Grubb’s catalyst, CH2Cl2, rt;
(b) H2, Pd/C, EtOAc.
Me
Me
Me
Ph
Me
Ph
H2, Pd/C, EtOAc
N
N
O
O
O
O
and 11 (Scheme 4). Conversion of the hydroxy butyr-
amides to the target lactones was achieved by a one-pot
reaction sequence. The primary hydroxyl group in
butyramides was liberated by demethylation with BBr3
in methylene chloride at À78 ꢁC. Subsequent acid cata-
lyzed lactonization at À15 ꢁC, which presumably
involves a very facile intramolecular acyl transfer from
N toO, furnished ( S)-(þ)-pantolactone 10a21 and its
analogues 10b–c and 12 in 70–97% yields (Table 1) with
high enantiomeric excesses.22
CO2Et
CO2Et
4
3
Scheme 1.
obtained for the first time in moderate yield (65%) using
KOtBu and methyl iodide using THF as a solvent.
Further studies on dimethylation showed that the base
of choice was KH, which gave the dimethylated product
5a in 96% yield.18 No epimerization of the product was
observed (1H NMR) under these reaction conditions.
Other dialkylated products 5b–c were alsoobtained in
excellent yields (92–93%) using the corresponding alkyl
halides and KH (Scheme 2).
Me
O
NH
OH
OH
O
O
a
b
6a-c
R
R
R
R
OMe
10
9
a, R = Me, 63%
a, (S)-(+)-pantolactone,
Me
R = Me, 70%
b, R = Et, 65%
Me
Me
O
Ph
c, R = Allyl, 56%
b, R = Et, 97%
Me
O
Ph
N
R
a
b
c)
N
R
d, R = n-propyl, 99% c, R = n-propyl, 88%
4
O
O
R
Me
CO2Et
R
NH
OMe
O
5
6
OH
b
a
O
O
8
a, R = Me, 96%
b, R = Et, 93%
a, R = Me, 78%
b, R = Et, 74%
c, R = Allyl, 71%
63%
92%
OH
c, R = Allyl, 92%
OMe
11
12
Spirolactone
Scheme 2. Reagents and conditions: (a) KH, R–X, THF, 0 ꢁC tort; (b)
(i) DIBAL-H, THF, À78 ꢁC tort, (ii) NaH, MeI, THF.
Scheme 4. Reagents and conditions: (a) (i) Na/liq. NH3, THF, À78 ꢁC,
(ii) MeOH; (b) (i) BBr3, CH2Cl2, À78 to À15 ꢁC, (ii) H2O, À15 ꢁC, (iii)
H2SO4, À15 ꢁC tort; (c) H 2, Pd/C, EtOAc.
Further selective reduction of the dialkylated esters 5a–c
was achieved by excess DIBAL-H togive the corre-
sponding alcohols, which were protected as methyl
ethers 6a–c (Scheme 2) in 71–78% overall yields.19 Other
protecting groups, such as acetate, caused complications
during the removal of the chiral auxiliary, while eth-
oxyethyl and methoxymethyl gave poor yields. Diallyl
compound 6c offers an added advantage, as manipula-
tion of the double bonds is possible. One such conver-
sion of 6c tofive-membered cyclic alkene 7 was achieved
by ring closing metathesis (RCM) using Grubb’s cata-
lyst. The RCM product 7 was hydrogenated using a Pd/
C catalyst to give cyclopentyl compound 8 (Scheme 3).
The morpholinones 6a–c and 8 are protected versions of
the required a,c-dihydroxy butyric acid, a precursor to
pantolactone and its analogues. The ephedrine portion
in 6a–c and 8 was removed by reduction with Na/NH3,20
which gave the a-hydroxy-c-methoxy butyramides 9a–c
The simplicity of the above synthetic sequence makes it
viable for the synthesis of pantolactone and its ana-
logues on a preparative scale. In this regard it is note-
worthy that several grams of the key intermediate 6a–c
and 8 can be prepared readily.
In conclusion, a general route for the enantioselective
synthesis of (S)-(þ)-pantolactone and its analogues has
been developed from an ephedrine-derived chiral mor-
pholinone. The above method should provide access to
a variety of enantiomerically enriched b,b-dialkyl-a-
hydroxy-c-butyrolactones in either enantiomeric forms,
since both enantiomers of ephedrine are commercially
available.

B. A. Shinkre, A. R. A. S. Deshmukh / Tetrahedron: Asymmetry 15 (2004) 1081–1084
Table 1. Synthesis of pantolactone and its analogues 10a–c and 12
25
1083
Substrate
Product
Yielda (%)
½aŠ (Solvent)
Eeb (%)
D
Me
NH
O
OH
O
Me
Me
OH
Me
9a
9b
9d
10a
10b
10c
70
þ51.8 (H2O)
þ14.9 (MeOH)
þ8.4 (CHCl3)
91
O
OMe
Me
Me
O
O
NH
OH
OH
Et
97
88
91
92
O
O
Et
Et
Et
O
OMe
Me
O
NH
OH
OH
OMe
Me
O
O
O
NH
OH
11
12
92
þ18.6 (CHCl3)
94
OH
OMe
a Isolated yields.
b Enantiomeric excess of the lactones was determined by chiral GC analysis on a CP-Chiracel-Dex CB column.
M.; Williamson, M. Adv. Enzymol. Relat. Areas Mol. Biol.
1982, 53, 345.
7. Lipmann, F. Science 1954, 120, 855.
8. Shimizu, S.; Tani, Y.; Ogata, K. Agric. Biol. Chem. 1974,
38, 1989.
Acknowledgements
B.A.S. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for a Research Fellow-
ship. We also thank Mr. Yogesh Borole for determining
the enantiomeric excesses of the lactones.
9. King, T. E.; Stewart, C. J.; Cheldelin, V. H. J. Am. Chem.
Soc. 1953, 75, 1290.
10. (a) Stiller, E. T.; Harris, S. A.; Finkelstein, J.; Keresztesy,
J. C.; Folkers, K. J. Am. Chem. Soc. 1940, 62, 1785; (b)
Fuji, K.; Node, M.; Murata, M.; Terada, S.; Hashimoto,
K. Tetrahedron Lett. 1986, 27, 5381; (c) Bevinakatti, H. S.;
Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989, 54,
2453; (d) Kagan, F.; Heinzelman, R. V.; Weisblat, D. I.;
Greiner, W. J. Am. Chem. Soc. 1957, 79, 3545.
11. Baumann, M.; Hauer, B. H.; Bornscheuer, U. T. Tetra-
hedron: Asymmetry 2000, 11, 4781.
12. (a) Ojima, I.; Kogure, T.; Terasaki, T.; Achiwa, K. J. Org.
Chem. 1978, 43, 3444; (b) Kagan, H. B.; Tahar, M.; Fiaud,
J.-C. Tetrahedron Lett. 1991, 32, 5959; (c) Genet, J.-P.;
Pinel, C.; Mallart, S.; Juge, S.; Cailhol, H.; Laffittee, J. A.
Tetrahedron Lett. 1992, 33, 5343; (d) Takahashi, H.;
Hattori, M.; Chiba, M.; Morimoto, T.; Achiwa, K.
Tetrahedron Lett. 1986, 27, 4477; (e) Roucoux, A.;
Agbossou, F.; Mortreux, A.; Petit, F. Tetrahedron:
Asymmetry 1993, 4, 2279; (f) Chiba, M.; Takahashi, H.;
Takahashi, H.; Morimoto, T.; Achiwa, K. Tetrahedron
Lett. 1987, 28, 3675.
References and notes
1. (a) O’Meara, J. A.; Gardee, N.; Jung, M.; Ben, R. N.;
Durst, T. J. J. Org. Chem. 1998, 63, 3117; (b) Davies, H.
M. L.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.;
Churchill, D. G. J. Org. Chem. 1998, 63, 2641, and
references cited therein; (c) Hansen, M. M.; Bertsch, C. F.;
Harkness, A. R.; Huff, B. E.; Hutchison, D. R.; Khau, V.
V.; LeTourneau, M. E.; Martinelli, M. J.; Misner, J. W.;
Peterson, B. C.; Rieck, J. A.; Sullivan, K. A.; Wright, I. G.
J. Org. Chem. 1998, 63, 775.
2. (a) Kagan, F.; Heinzelman, R. V.; Weisblat, D. I.;
Greiner, W. J. Am. Chem. Soc. 1957, 79, 3545; (b)
Neidlein, R.; Greulich, P. Helv. Chim. Acta 1992, 75, 2545;
(c) Fischer, G. C.; Turakhia, R. H.; Morrow, C. J. J. Org.
Chem. 1985, 50, 2011; (d) Dolle, R. E.; Nicolou, K. C. J.
Am. Chem. Soc. 1985, 107, 1691; (e) Lavallee, P.; Ruel, R.;
Greiner, L.; Bissonnette, M. Tetrahedron Lett. 1986, 27,
679; (f) Sone, H.; Suenaga, K.; Bessho, Y.; Kondo, T.;
Kigoshi, H.; Yamada, K. Chem. Lett. 1998, 85.
13. Upadhya, T. T.; Gurunath, S.; Sudalai, A. Tetrahedron:
Asymmetry 1999, 10, 2899.
14. (a) Rao, A. V. R.; Rao, S. M.; Sharma, G. V. M.
Tetrahedron Lett. 1994, 35, 5735; (b) Effenberger, F.;
Eichhorn, J.; Roos, J. Tetrahedron: Asymmetry 1995, 6,
271.
3. Kuhn, R.; Wieland, T.; Moller, E. F. Ber. 1941, 74, 1605.
4. Winterbottom, R.; Clapp, J. W.; Miller, W. H.; English,
J. P.; Roblin, R. O., Jr. J. Am. Chem. Soc. 1947, 69, 1393.
5. Roblin, R. O., Jr. Chem. Rev. 1946, 38, 255.
15. Evans, D. A.; Wu, J.; Masse, C. E.; MacMillan, D. W. C.
Org. Lett. 2002, 4, 3379.
6. (a) Lehninger, A. L. Principles of Biochemistry; Worth
Publishers: New York, 1987, pp 256–257; (b) Brown, G.
16. (a) Shinkre, B. A.; Puranik, V. G.; Bhawal, B. M.;
Deshmukh, A. R. A. S. Tetrahedron: Asymmetry 2003, 14,

1084
B. A. Shinkre, A. R. A. S. Deshmukh / Tetrahedron: Asymmetry 15 (2004) 1081–1084
453; (b) Pansare, S. V.; Shinkre, B. A.; Bhattacharyya, A.
Tetrahedron 2002, 58, 8985.
room temperature until ammonia was completely
removed. The solvent was removed under reduced
pressure and the residue partitioned with ethyl acetate
(10 mL) and water (2 mL). The ethyl acetate layer was
separated and the aqueous layer extracted three times with
ethyl acetate. The combined extracts were washed with
brine solution (5 mL), dried over Na2SO4 and concen-
trated to obtain a crude product, which upon purification
by flash column chromatography (2:3 EtOAc/Pet-ether)
furnished 9a as a colourless gum (95 mg, 63%). IR
17. (a) Pansare, S. V.; Bhattacharyya, A. Tetrahedron 2003, 59,
3275; (b) Pansare, S. V.; Jain, R. P. Org. Lett. 2000, 2, 175.
18. Typical procedure for dialkylation of morpholinone ester
4: To a stirred suspension of KH (712 mg, 17.7 mmol) in
anhydrous THF (10 mL) at 0 ꢁC was added a solution of
morpholinone ester 4 (1.475 g, 5.07 mmol) in anhydrous
THF (20 mL) dropwise over a period of 45 min. After
stirring for 1 h at 0 ꢁC, methyl iodide (1.42 mL, 22.8 mmol)
was added dropwise and the reaction mixture allowed to
warm up to room temperature and stirred for 12 h.
Saturated NH4Cl solution (ꢀ2 mL) was then added and
the solvent removed under reduced pressure. The precip-
itated solid was dissolved in the minimum amount of
water (ꢀ3 mL) and extracted with ethyl acetate
(3 · 15 mL). The combined extracts were washed with
brine solution (10 mL), dried over Na2SO4 and concen-
trated tofurnish a crude product, which was purified by
flash column chromatography on silica gel using ethyl
1
(CHCl3): 1666, 3431 cmÀ1; H NMR (200 MHz, CDCl3):
d 1.0 (s, 6H, C(CH3)2), 2.85 (d, 3H, J ¼ 5:1 Hz, NCH3),
3.25 (d, 1H, J ¼ 9:2 Hz, CH2), 3.35 (d, 1H, J ¼ 9:2 Hz,
CH2), 3.35 (s, 3H, OCH3), 4.00 (d, 1H, J ¼ 3:6 Hz, CH),
4.45 (d, 1H, J ¼ 3:6 Hz, OH), 6.80 (br s, 1H, NH); 13C
NMR (50 MHz, CDCl3): d 20.2, 21.6, 25.3, 38.4, 59.1,
77.9, 81.7, 172.9; MS (m=z): 175 (Mþ); Anal. Calcd for
C8H17NO3: C 54.84, H 9.78, N 7.99, obtained: C 54.99, H
9.97, N 8.23.
21. Typical procedure for lactonization: To a stirred solution
of 9a (120 mg, 0.92 mmol) in anhydrous dichloromethane
(7 mL) was added at À78 ꢁC boron tribromide (1 M
solution in dichloromethane 9.2 mL, 9.2 mmol) with the
resulting reaction mixture gradually warmed to À15 ꢁC
with continuous stirring. The reaction was kept at À15 ꢁC
for 2 h with water (3.5 mL) then added over a period of
5 min. The mixture was stirred for a further 15 min after
which 6 M H2SO4 (3.5 mL) was added. The mixture was
stirred overnight, during which time it was warmed to
ambient temperature. The mixture was then cooled in an
ice bath and neutralized via the addition of small portions
of solid sodium bicarbonate. The resulting semi-solid
residue was then extracted with dichloromethane
(3 · 15 mL). The combined dichloromethane extracts were
dried over Na2SO4 and concentrated to obtain crude
lactone, which was purified by flash column chroma-
acetate/petroleum ether (1:1) to give 5a as a clear
25
D
colourless gum (1.55 g, 96%). ½aŠ ¼ À131:5 (c 1.17,
CHCl3); IR (CHCl3): 1649, 1728 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 0.96 (d, 3H, J ¼ 6:8 Hz, CH3CH),
1.28 (t, 3H, J ¼ 7:1 Hz, CH3CH2), 1.32 (s, 3H, CH3C),
1.41 (s, 3H, CH3C), 3.01 (s, 3H, NCH3), 3.49–3.55 (dq,
1H, J ¼ 2:8, 6.8 Hz, CHCH3), 4.15–4.28 (m, 2H, OCH2),
4.68 (s, 1H, CHCO), 5.04 (d, 1H, J ¼ 2:8 Hz, PhCH),
7.22–7.42 (m, 5H, ArH); 13C NMR (125.76 MHz, CDCl3):
d 13.0, 13.9, 19.1, 23.2, 33.1, 45.9, 58.3, 60.4, 76.3, 81.8,
125.1, 127.4, 128.2, 137.6, 167.4, 175.4; MS (m=z): 319
(Mþ); Anal. Calcd for C18H25NO4: C 67.69, H 7.89, N
4.39, obtained: C 67.80, H 8.17, N 4.22.
25
19. Data for 6a: A clear colourless gum. ½aŠ ¼ À191:7 (c 3.6,
D
CHCl3); IR (CHCl3): 1649 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d 0.86 (d, 3H, J ¼ 6:4 Hz, CH3CH), 1.06 (s, 6H,
(CH3C)2), 2.91 (s, 3H, NCH3), 3.25 (s, 3H, OCH3), 3.34
(d, 1H, J ¼ 8:7 Hz, OCH2), 3.36–3.42 (dq, 1H, J ¼ 2:8,
6.4 Hz, CHCH3), 3.46 (d, 1H, J ¼ 8:7 Hz, CH2O), 4.13 (s,
1H, CHCO), 4.83 (d, 1H, J ¼ 2:8 Hz, PhCH), 7.15–7.30
(m, 5H, ArH); 13C NMR (50 MHz, CDCl3): d 12.7, 21.7,
33.0, 39.8, 58.4, 58.7, 76.0, 79.4, 81.3, 125.1, 127.1, 127.9,
138.0, 168.3; MS (m=z): 291 (Mþ); Anal. Calcd for
C17H25NO3: C 70.07, H 8.65, N 4.81, obtained: C 70.30,
H 8.85, N 5.05.
tography to furnish 10a as
a white solid (62 mg,
25
D
70%). ½aŠ ¼ þ51:8 (c 2, H2O); IR (H2O): 1782,
3446 cmÀ1
;
1H NMR (500 MHz CDCl3): d 1.11 (s, 3H,
CH3C), 1.26 (s, 3H, CH3C), 2.34 (bs, 1H, OH), 3.97 (d,
1H, J ¼ 9:1 Hz, OCH2), 4.05 (d, 1H, J ¼ 9:1 Hz, CH2O),
4.14 (s, 1H, CHCO); 13C NMR (125.76 MHz, CDCl3): d
18.8, 22.9, 40.9, 75.8, 76.3, 177.3; MS (m=z): 130 (Mþ);
Anal. Calcd for C6H10O3: C 55.37, H 7.74, Found: C
55.65, H 7.96. Enantiomeric excess of 10a was 91% by GC
analysis.
20. Typical procedure for the removal of ephedrine portion:
To anhydrous liquid ammonia (10 mL), was added Na
(329 mg, 14.3 mmol) at À78 ꢁC and the mixture stirred for
15 min. To the resulting blue solution was added a solution
of morpholinone 6a (250 mg, 1.43 mmol) in THF (1.5 mL).
The mixture was stirred at À78 ꢁC (3 min), methanol
(5 mL) was then added and the mixture stirred further at
22. Enantiomeric excess of the lactones 10a–c and 12 was
determined by GC analysis on a CP-Chiracel-Dex CB
capillary column (25.0 m · 250 lm · 0.25 lm). Tempera-
ture gradient: 60 ꢁC (2 min); 3 ꢁC minÀ1 to120 ꢁC (3 min);
20 ꢁC minÀ1 to180 ꢁC (10 min); carrier gas: nitrogen; flow
rate: 2 mL minÀ1
.