Sequential acyl halide-aldehyde cyclocondensation and enzymatic resolution as a route to enantiomerically enriched β-lactones

Full text of DOI:10.1021/jo9913412

J . Org. Chem. 2000, 65, 1227-1230
1227
products 1 in high yields (eq 2).5 Under the optimized
AAC reaction conditions, substoichiometric quantities of
Al(SbF6)3 (5-20 mol %) catalyze the amine-mediated
cyclocondensation of acetyl bromide and aliphatic alde-
hydes to afford the corresponding â-lactones as the
exclusive reaction products (g81% yield). To extend the
utility of this reaction technology in synthesis activities,
the preparation of optically active â-lactones by the
enzymatic resolution of the racemic 4-substituted-2-
oxetanones derived from the AAC reactions was explored.
Sequ en tia l Acyl Ha lid e-Ald eh yd e
Cyclocon d en sa tion a n d En zym a tic
Resolu tion a s a Rou te to En a n tiom er ica lly
En r ich ed â-La cton es
Scott G. Nelson* and Keith L. Spencer
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received August 24, 1999
Substituted â-lactones constitute versatile intermedi-
ates for organic synthesis and are integral architectural
features of a number of pharmacologically active natural
products.1,2 The utility of â-lactones as intermediates for
asymmetric organic synthesis, however, has been im-
peded by the relatively limited number of methods for
their preparation in enantiomerically pure form.3,4 Re-
cently, we have reported catalyzed acyl halide-aldehyde
cyclocondensation (AAC) reactions as an efficient and
operationally simple method for the synthesis of a variety
of 4-substituted â-lactones.5 The facile access to â-lactones
afforded by the AAC reaction technology has led us to
examine enzymatic resolution as a general means for
obtaining enantiomerically enriched â-lactones (eq 1).
Sequential application of the catalyzed AAC methodology
and the enzymatic lactone resolution described herein
represents an economical and easily executed synthesis
of optically active â-lactones.
Enantioselective cleavage of reactive ester linkages is
among the transformations that have proven most ame-
nable to enzymatic mediation.6 The ring strain-induced
lability of the C-O linkage in â-lactones, therefore,
implicates racemic 2-oxetanones as candidates for enzyme-
mediated resolution.7 Indeed, Yamamoto has reported the
successful enzymatic resolution of two 4-substituted-2-
oxetanone substrates.8 The routine preparation of 4-sub-
stituted â-propiolactones provided by the AAC reactions
has allowed a detailed investigation of enzyme-mediated
resolution as a general route to enantiomerically enriched
â-lactones. Attempted resolution of the cyclohexanecar-
boxaldehyde-derived lactone 1 (R ) c-C6H11) under the
reported conditions using Lipase PS Amano, benzyl
alcohol, and acetone solvent afforded poor conversion and
resolution efficiency. Substituting isopropyl ether as the
reaction solvent, however, resulted in dramatically im-
proved reaction efficiency under otherwise identical
resolution conditions (eq 3). Thus, commercially available
Lipase PS Amano in conjunction with benzyl alcohol
i
(BnOH) as the requisite nucleophile in Pr2O affords both
the resolved lactone 2a and the â-hydroxy ester 3a
reaction product with high enantioselectivity and chemi-
cal yield.
Catalyzed acyl halide-aldehyde cyclocondensation re-
actions involve the Al(III)-catalyzed reaction of acyl
halides with enolizable aldehydes to deliver â-lactone
(6) For reviews of enzyme-mediated asymmetric reactions, see: (a)
Poppe, L.; Novak, L. Selective Biocatalysis; VCH: Weinheim, Germany,
1992. (b) Halgas, J . Biocatalysis in Organic Synthesis; Elsevier: New
York, 1992. (c) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi,
A. Chem. Rev. 1992, 92, 1071-1140. (d) Wong, C.-H., Whitesides, G.
M. Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
(e) Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic Synthesis;
VCH: Weinheim, Germany, 1995. (f) Schoffers, E.; Golebiowski, A.;
J ohnson, C. R. Tetrahdron 1996, 52, 3796-3826. (g) Faber, K.
Biotransformations in Organic Chemistry, 3rd ed.; Springer-Verlag:
Heidelberg, Germany, 1997. (h) Roberts, S. M.; Williamson, N. M. Curr.
Org. Chem. 1997, 1, 1-20.
(7) For some examples of asymmetric enzyme-mediated lactone ring-
opening, see: (a) Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.;
Poli, S.; Gardini, F.; Guerzoni, M. E. Tetrahedron: Asymmetry 1992,
3, 107-114. (b) Gelo, M.; Sunjic, V. Tetrahedron 1992, 48, 6511-6520.
(c) Fellous, R.; Lizzanicuvelier, L.; Loiseau, M. A.; Sassy, E. Tetrahe-
dron: Asymmetry 1994, 5, 343-346. (d) Ha, H.-J .; Yi, D.-G.; Yoon, K.-
N.; Song, C.-W. Bull. Kor. Chem. Soc. 1996, 17, 544-547. (e) Viazzo,
P.; Alphand, V.; Furstoss, R. Tetrahedron Lett. 1996, 37, 4519-4522.
(f) Onakunle, O. A.; Knowles, C. J .; Bunch, A. W. Enzyme Microb.
Technol. 1997, 21, 245-251. (g) Enzelberger, M. M.; Bornscheuer, U.
T.; Gatfield, I.; Schmid, R. D. J . Biotechnol. 1997, 56, 129-133. (h)
Ha, H.-J .; Yoon, K.-N.; Lee, S.-Y.; Park, Y.-S.; Lim, M.-S.; Yim, Y.-G.
J . Org. Chem. 1998, 63, 8062-8066.
(1) For a review of transformations involving â-lactones, see: Pom-
mier, A.; Pons, J .-M. Synthesis 1993, 441-459.
(2) (a) Yang, H. W.; Romo, D. J . Org. Chem. 1997, 62, 4-5. (b)
Calter, M. A.; Guo, X. J . Org. Chem. 1998, 63, 5308-5309. (c) Rzasa,
R. M.; Shea, H. A.; Romo, D. J . Am. Chem. Soc. 1998, 120, 591-592.
(d) Dymock, B. W.; Kocienski, P. J .; Pons, J .-M. Synthesis 1998, 1655-
1661. (e) Yang, H. W.; Romo, D. J . Org. Chem. 1999, 64, 7657-7660.
(3) (a) Wynberg, H.; Staring, E. G. J . J . Am. Chem. Soc. 1982, 104,
166-168. (b) Wynberg, H.; Staring, E. G. J . J . Org. Chem. 1985, 50,
1977-1979. (c) Tamai, Y.; Someya, M.; Fukumoto, J .; Miyano, S. J .
Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshi-
wara, H.; Someya, M.; Fukumoto, J .; Miyano, S. J . Chem. Soc. Chem.
Commun. 1994, 2281-2282. (e) Dymock, B. W.; Kocienski, P. J .; Pons,
J .-M. J . Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Calter, M.
A. J . Org. Chem. 1996, 61, 8006-8007. (g) Romo, D.; Harrison, P. H.
M.; J enkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.;
Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references
therein. (h) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-
2880. (i) Nelson, S. G.; Peelen, T. J .; Wan, Z. J . Am. Chem. Soc. 1999,
121, 9742-9743.
(4) For a comprehensive review of asymmetric â-lactone syntheses,
see: H. W. Yang, D. Romo, Tetrahedron 1999, 55, 6403-6434.
(5) Nelson, S. G.; Wan, Z.; Peelen, T. J .; Spencer, K. L. Tetrahedron
Lett. 1999, 40, 6535-6540.
(8) (a) Koichi, Y.; Suginaka, K.; Yamamoto, Y. J . Chem. Soc., Perkin
Trans. 1 1995, 1645-1646. See also: (b) Adam, W.; Groer, P.; Saha-
Moller, C. R. Tetrahedron: Asymmetry 1997, 8, 833-836. (c) Ito, T.;
Shimizu, M.; Fujisawa, T. Tetrahedron 1998, 54, 5523-5530.
10.1021/jo9913412 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/25/2000

1228 J . Org. Chem., Vol. 65, No. 4, 2000
Notes
Ta ble 1. En zym a tic Resolu tion of Ra cem ic â-La cton es
Usin g Bn OH
% ee 2
% ee 3
entry
â-lactone 1 (R)
(% yield, config)a,b
(% yield)b,d
a
b
c
d
e
f
c-C6H11
Me2CH
99 (44, S)
99 (5.4, S)c
93 (38, R)d
97 (42, R)
98 (26, R)
90 (40, R)
99 (32, R)
84 (44, S)d
92 (48)
62 (53)
32 (61)
74 (51)
27 (62)
88 (52)
50 (60)
96 (48)
PhCH2CH2
CH3(CH2)3
CH3CH2CH2
Me2CHCH2
CH2CH(CH2)8
BnOCH2
g
h
Under these resolution conditions, the lipase enzyme
is relatively insensitive to the structure of the lactone
â-substituent (Table 1). Lactones incorporating R-branched
(entries a and b), straight chain (entries c-e), â-branched
(entry f), and functionalized (entries g and h) alkyl side
chains all represent effective substrates for the enzyme.
High enantioselectivity, and good chemical yields in all
but one trial, are obtained for all of the recovered lactones
2a -h (84-99% ee).9 The isolated yield of the isobutyral-
dehyde-derived lactone 2b is uncharacteristically low
(5.4%) due to the volatility of this lactone; the yield of
the â-hydroxy ester reaction product 3b (52%) would
suggest that this resolution reaction is relatively efficient
and is compromised only by lactone volatility. In some
instances, highly enantiomerically enriched â-hydroxy
ester products are also obtained (3a , f, and h ; 88-96%
ee) although ester enantiomeric purity is considerably
more variable than that obtained for the unreacted
lactones.
The lipase is equally insensitive to the structure of the
alcohol reagent employed in the resolutions. In fact,
resolutions employing ethanol afford enantioselectivities
superior to those reactions using benzyl alcohol (eq 4).
Resolutions using ethanol rather than benzyl alcohol offer
the additional advantage of allowing the excess alcohol
reagent to be removed by evaporation prior to purifica-
tion. For each lactone substrate, the enantiomerically
enriched lactone is separated from the corresponding
â-hydroxy ester product by routine column chromatog-
raphy.
a
Enantiomer ratios determined by chiral capillary GC (Chiral-
dex G-TA column) unless otherwise specified. b Reported yields are
for chromatographically purified materials. c Yield reflects lactone
d
volatility. Enantiomer ratio determined by chiral HPLC (Chiral-
cel OD-H column).
Exp er im en ta l Section
Proton NMR chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal
standard (chloroform: δ 7.26 ppm); proton-decoupled 13C NMR
chemical shifts are reported in ppm from tetramethylsilane with
the solvent as the internal standard (deuteriochloroform: δ 77.0
ppm). Analytical gas-liquid chromatography (GLC) was per-
formed using a flame ionization detector and a Chiraldex G-TA
column (20 m × 0.25 mm) (Advanced Separation Technologies
Inc.). Analytical high performance liquid chromatograph (HPLC)
was performed using a Daicel Chiralcel OD-H column (250 ×
4.6 mm) (Daicel Inc.).
All experiments were carried out under a nitrogen atmosphere
in oven- or flame-dried glassware using standard inert atmo-
sphere techniques for introducing reagents and solvents. Diiso-
propyl ether (iPr2O), benzyl alcohol, and ethanol were distilled
from CaH2 under N2. Lipase PS Amano ()30000 u/g) was
purchased from Amano Enzyme USA Co. All other commercially
obtained reagents were used as received. The racemic â-lactone
substrates 1a -h were prepared according to the procedure in
ref 5.
Complete or partial spectroscopic data for the following
compounds has been reported previously:
(S)-4-cyclohexyloxetan-2-one (2a ),3g (S)-4-(1-Methylethyl)ox-
etan-2-one (2b),8a (()-4-(2-phenylethyl)oxetan-2-one (2c),2a (R)-
4-butyloxetan-2-one (2d ),3g (R)-4-propyloxetan-2-one (2e),8a (()-
4-(benyloxymethyl)oxetan-2-one (2h ),2a and (R)-3-cyclohexyl-3-
hydroxypropionic acid, benzyl ester (3a ).10
Gen er a l P r oced u r e for th e Lip a se P S-Med ia ted Resolu -
tion of â-La cton es. To a mixture of Lipase PS Amano [∼30
u/mg of 1; 1:1 mass ratio lipase:lactone 1] and â-lactone 1 in
iPr2O (6 mL/g of substrate) was added BnOH or EtOH (0.8 equiv
to â-lactone), and the resulting heterogeneous mixture was
heated at 35 °C for 30-72 h. Progress of the resolution was
monitored by removing reaction aliquots and assaying the
enantiomeric purity of the unreacted lactone by chiral HPLC
(Chiracel OD-H, 90:10 hexanes:iPrOH, 1 mL/min) or chiral GC
(Chiraldex G-TA column, flow rate 0.5 mL/min, method: 100
°C for 10.00 min, ramp @ 10.00 °C/min to 130 °C for 8.00 min,
ramp @ 10.00 °C/min to 160 °C for 5.00 min). Upon cooling to
ambient temperature, the reaction mixture was eluted through
a silica gel pad with EtOAc, and the eluent was concentrated in
vacuo. The products were isolated by flash chromatography
(hexanes:ethyl acetate).
(S)-4-Cycloh exyloxeta n -2-on e (2a ).3g The general procedure
was followed employing 250 mg of 4-cyclohexyloxetan-2-one (1a )
and 140 mg of benzyl alcohol (72 h reaction time). Column
chromatography (90% hexane, 10% ethyl acetate) of the crude
reaction mixture afforded 110 mg of the title compound (44%).
Separation of the enantiomers by chiral GC (Chiraldex G-TA
column, flow rate 0.5 mL/min, method: 100 °C for 10.00 min,
ramp @ 10.00 °C/min to 130 °C for 8.00 min, ramp @ 10.00 °C/
min to 160 °C for 5.00 min, Tr 22.1 (S) and 24.3 (R) min)
Catalyzed AAC reactions and the accompanying lac-
tone resolution provide a general and easily executed
synthesis of optically active 4-substituted â-propiolac-
tones. The facile access to enantiomerically enriched
â-lactones provided by this methodology is expected to
facilitate the integration of â-lactones as intermediates
in asymmetric organic synthesis.
(9) See Experimental Section for stereochemical assignment of
resolved â-lactones.
(10) Mukaiyama, T.; Kobayashi, S.; Sano, T. Tetrahedron 1990, 46,
4653-4662.

Notes
J . Org. Chem., Vol. 65, No. 4, 2000 1229
determined the enantiomeric excess to be greater than 99%
(other enantiomer not observed). [R]D +14.7° (c 4.0, CH2Cl2).
(R)-3-Cycloh exyl-3-h yd r oxyp en ta n oic Acid , Ben zyl Es-
ter (3a ).10 From the resolution of 1a described above, column
chromatography (90% hexane, 10% ethyl acetate) of the crude
reaction mixture afforded 204 mg of the title compound (48%).
Separation of the enantiomers by chiral HPLC (Daicel Chiracel
OD-H column, flow rate 1.0 mL/min, 10% PrOH, 90% hexane
Tr 25.5 (S) and 26.7 (R) min) determined the enantiomer ratio
to be 24:1 (92% ee). [R]D +20.4° (c 6.0, CH2Cl2).
°C for 10.00 min, ramp @ 10.00 °C/min to 130 °C for 8.00 min,
ramp @ 10.00 °C/min to 160 °C for 5.00 min, Tr 12.4 (R) and
13.2 (S) min) determined the enantiomer ratio to be 20:1 (90%
ee). [R]D +37.2° (c 5.8, CH2Cl2). IR (NaCl): 1828 cm-1; 1H NMR
(300 MHz, CDCl3): δ 4.54-4.59 (m, 1H), 3.54 (dd, J ) 16.3, 5.9
Hz, 1H), 3.04 (dd, J ) 16.3, 4.3 Hz, 1H), 1.75-1.86 (m, 2H),
1.56-1.73 (m, 1H), 0.96 (d, J ) 6.50, 6H); 13C NMR (75 MHz,
CDCl3): δ 168.6, 70.4, 43.7, 43.6, 25.5, 22.9, 22.3; MS (EI, 70
eV): m/z 128 (M+), 113, 109, 104, 95, 91, 85, 71, 56. HRMS (FAB)
m/z cacld for C7H12O2: 128.0837. Found: 128.0835.
i
(S)-4-(1-Meth yleth yl)oxeta n -2-on e (2b).8a The general pro-
cedure with the following modifications was followed employing
1.0 g of 4-(1-methylethyl)oxetan-2-one (1b) and 759 mg of benzyl
alcohol (72 h reaction time). After the resolution was complete,
the reaction mixture was eluted through a silica gel pad with
ethyl ether. The filtrate was concentrated in vacuo and the
products separated by column chromatography (90% pentane,
10% ether) to afford 54 mg of the title compound (5.4%).
Separation of the enantiomers by chiral GC (Chiraldex G-TA
column, flow rate 0.5 mL/min, method: 100 °C for 10.00 min,
ramp @ 10.00 °C/min to 130 °C for 8.00 min, ramp @ 10.00 °C/
min to 160 °C for 5.00 min, Tr 9.9 (S) and 10.6 (R) min)
determined the enantiomeric excess to be 99%. [R]D +20.1° (c
(S)-3-Hyd r oxy-5-m eth ylh exa n oic Acid , Ben zyl Ester (3f).
From the resolution of 1f described above, column chromatog-
raphy (90% hexane, 10% ethyl acetate) of the crude reaction
mixture afforded 478 mg of the title compound (52%). Separation
of the enantiomers by chiral HPLC (Daicel Chiracel OD-H
i
column, flow rate 1.0 mL/min, 10% PrOH, 90% hexane Tr 5.9
(R) and 7.6 (S) min) determined the enantiomer ratio to be 16:1
1
(88% ee). [R]D +10.3° (c 6.5, CH2Cl2); IR (NaCl) 1730 cm-1; H
NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 5.17 (s, 2H), 4.12 (m,
1H), 2.75 (br s, 1H), 2.56 (dd, J ) 16.5 and 3.3 Hz, 1H), 2.45
(dd, J ) 16.5 and 8.7 Hz, 1H), 1.80 (m, 1H), 1.49 (ddd, J ) 14.0,
8.9, and 5.5 Hz, 1H), 1.18 (ddd, J ) 13.4, 8.7, and 4.4 Hz, 1H),
0.92 (d, J ) 6.6 Hz, 6H); 13C δ 172.5, 135.4, 128.4, 128.0 (2C),
66.2, 65.9, 45.4, 41.8, 24.4, 23.1, 21.7; TLC Rf 0.31 (20% ethyl
acetate, 80% hexane); MS (EI, 70 eV): m/z: 236 (M+). HRMS
(FAB) m/z cacld for C14H20O3: 236.1413. Found: 236.1418.
(R)-4-(9-Decylen yl)oxeta n -2-on e (2g). The general proce-
dure was followed employing 200 mg of 4-(9-decylenyl)oxetan-
2-one (1g) and 82 mg of benzyl alcohol (72 h reaction time).
Column chromatography (90% hexane, 10% ethyl acetate) of the
crude reaction mixture afforded 64 mg of the title compound
(32%). Separation of the enantiomers by chiral GC (Chiraldex
G-TA column, flow rate 0.5 mL/min, method: 100 °C for 10.00
min, ramp @ 5.00 °C/min to 130 °C for 12.00 min, ramp @ 10.00
°C/min to 160 °C for 15.00 min, Tr 38.5 (R) and 39.7 (S) min)
determined the enantiomeric excess to be greater than 99%
(other enantiomer not observed). [R]D +21.8° (c 4.7, CH2Cl2). IR
3.9, CH2Cl2). IR (NaCl): 1822 cm-1 1H NMR (300 MHz,
;
CDCl3): δ 4.20 (ddd, J ) 8.0, 5.7, 4.4 Hz, 1H), 3.44 (dd, J )
16.3, 5.6 Hz, 1H), 3.09 (dd, J ) 16.3, 4.4 Hz, 1H), 1.94 (m, 1H),
1.06 (d, J ) 6.6 Hz, 3H), 0.96 (d, J ) 6.8, 3H); 13C NMR (75
MHz, CDCl3): δ 168.7, 75.4, 40.4, 32.0, 17.1, 16.2; MS (CI,
isobutane): m/z 115 [M + H]+, 97, 71.
(R)-4-(2-P h en yleth yl)oxeta n -2-on e (2c).2a The general pro-
cedure was followed employing 500 mg of 4-(2-phenylethyl)-
oxetan-2-one (1c) and 246 mg of benzyl alcohol (30 h reaction
time). Column chromatography (90% hexane, 10% ethyl acetate)
of the crude reaction mixture afforded 189 mg of the title
compound (38%). Separation of the enantiomers by chiral HPLC
(Daicel Chiracel OD-H column, flow rate 1.0 mL/min, 10%
iPrOH, 90% hexane Tr16.2 (S) and 17.9 (R) min) determined the
enantiomeric excess to be 93%. [R]D +37.8° (c 2.4, CH2Cl2).
(R)-4-Bu tyloxeta n -2-on e (2d ).3g The general procedure was
followed employing 1.0 g of 4-isopropyloxetan-2-one (1d ) and 676
mg of benzyl alcohol (72 h reaction time). Column chromatog-
raphy (90% hexane, 10% ethyl acetate) of the crude reaction
mixture afforded 422 mg of the title compound (42%). Separation
of the enantiomers by chiral GC (Chiraldex G-TA column, flow
rate 0.5 mL/min, method: 100 °C for 10.00 min, ramp @ 10.00
°C/min to 130 °C for 8.00 min, ramp @ 10.00 °C/min to 160 °C
for 5.00 min, Tr 11.3 (R) and 11.9 (S) min) determined the
enantiomeric excess to be 97%. [R]D +21.5° (c 5.9, CH2Cl2). IR
1
(NaCl): 3075, 1828, 1125 cm-1; H NMR (300 MHz, CDCl3): δ
5.76-5.85 (m, 1H), 4.90-5.02 (m, 2H), 4.46-4.52 (m, 1H), 3.50
(dd, J ) 16.2, 5.6 Hz, 1H), 3.05 (dd, J ) 16.2, 4.3 Hz, 1H), 2.00-
2.05 (m, 2H), 1.73-1.86 (m, 2H), 1.29-1.45 (m, 12H); 13C NMR
(75 MHz, CDCl3): δ 168.5, 139.2, 114.3, 71.4, 43.0, 34.8, 33.8,
29.4 (2C), 29.2, 29.1, 29.0, 25.0; MS (EI, 70 eV): m/z 167, 150,
135, 121, 109, 95, 81, 67. HRMS (FAB) m/z cacld for C13H22O2:
210.1620. Found: 210.1626.
(S)-4-(Ben zyloxylm eth yl)oxeta n -2-on e (2h ).2a The general
procedure was followed employing 250 mg of 4-(benzyloxylm-
ethyl)oxetan-2-one (1h ) and 113 mg of benzyl alcohol (72 h
reaction time). Column chromatography (60% pentane, 30%
ethyl ether, 10% toluene) of the crude reaction mixture afforded
110 mg of the title compound (44%). Separation of the enanti-
omers by chiral HPLC (Daicel Chiracel OD-H column, flow rate
1
(NaCl): 1826 cm-1; H NMR (300 MHz, CDCl3): δ 4.51 (ddt, J
) 7.4, 5.9, 4.4 Hz, 1H), 3.51 (dd, J ) 16.3, 5.8 Hz, 1H), 3.07 (dd,
J ) 16.3, 4.3 Hz, 1H), 1.86 (m, 1H), 1.78 (m, 1H), 1.39 (m, 4H),
0.93 (t, J ) 6.7, 3H); 13C NMR (75 MHz, CDCl3): δ 168.3, 71.0,
42.4, 34.0, 26.6, 21.9, 13.5; MS (CI, isobutane): m/z 129 [M +
H]+, 111.
i
0.9 mL/min, 15% PrOH, 85% hexane Tr 14.1(R) and 23.0 (S)
min) determined the enantiomer ratio to be 11.5:1 (84%ee). [R]D
+21.9° (c 5.3, CH2Cl2).
(R)-4-P r op yloxeta n -2-on e (2e).8a The general procedure was
followed employing 1.0 g of 4-isopropyloxetan-2-one (1e) and 759
mg of benzyl alcohol (72 h reaction time). Column chromatog-
raphy (90% hexane, 10% ethyl acetate) of the crude reaction
mixture afforded 261 mg of the title compound (26%). Separation
of the enantiomers by chiral GC (Chiraldex G-TA column, flow
rate 0.5 mL/min, method: 100 °C for 10.00 min, ramp @ 10.00
°C/min to 130 °C for 8.00 min, ramp @ 10.00 °C/min to 160 °C
for 5.00 min, Tr 10.5 (R) and 11.2 (S) min) determined the
enantiomeric excess to be 98%. [R]D +25.9° (c 3.2, CH2Cl2). IR
(R)-4-(Ben zyloxy)-3-h yd r oxybu ta n oic Acid , Ben zyl Es-
ter (3h ). From the resolution of 1h described above, column
chromatography (60% pentane, 30% ethyl ether, 10% toluene)
of the crude reaction mixture afforded 187 mg of the title
compound (48%). Separation of the enantiomers via chiral HPLC
(Daicel Chiracel OD-H column, flow rate 0.9 mL/min, 15%
iPrOH, 85% hexane Tr 12.8 (S) and 15.8 (R) min) determined
the enantiomer ratio to be 50:1 (96% ee). [R]D +6.8° (c 1.7, CH2-
1
Cl2); IR (NaCl) 1733 cm-1; H NMR (300 MHz, CDCl3) δ 7.38-
1
(NaCl): 1826 cm-1; H NMR (300 MHz, CDCl3): δ 4.53 (ddt, J
7.27 (m, 10H), 5.31 (s, 2H), 4.56 (s, 2H), 4.27 (m, 1H), 3.53 (dd,
J ) 9.6 and 4.5 Hz, 1H) 3.48 (dd, J ) 9.6 and 6.5 Hz, 1H) 2.90
(br s, 1H), 2.59 (dd, J ) 18.6 and 6.3 Hz, 2H); 13C (75 MHz,
CDCl3) δ 171.9, 137.8, 135.5, 128.6, 128.4, 128.3, 128.2, 127.8,
127.7, 73.4, 73.0, 67.2, 66.5, 38.2; TLC Rf 0.15 (30% diethyl ether,
60% pentane, 10% toluene); MS (EI, 70 eV): m/z 300 (M+).
HRMS (FAB) m/z cacld for C11H13O4 (M+ - C7H7): 209.0814.
Found: 209.0812.
) 7.4, 5.8, 4.4 Hz, 1H), 3.52 (dd, J ) 16.2, 5.7 Hz, 1H), 3.07 (dd,
J ) 16.2, 4.3 Hz, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.46 (m, 2H),
0.99 (t, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3): δ 168.2, 70.8,
42.4, 36.2, 17.9, 13.2; MS (CI, isobutane): m/z 115 [M + H]+,
97, 73.
(R)-4-(2-Meth ylp r op yl)oxeta n -2-on e (2f). The general pro-
cedure was followed employing 500 mg of 4-(2-methylpropyl)-
oxetan-2-one (1f) and 338 mg of benzyl alcohol (72 h reaction
time). Column chromatography (90% hexane, 10% ethyl acetate)
of the crude reaction mixture afforded 200 mg of the title
compound (40%). Separation of the enantiomers by chiral GC
(Chiraldex G-TA column, flow rate 0.5 mL/min, method: 100
Assign m en t of Ster eoch em istr y. Stereochemical assign-
ment of the enantiomerically enriched â-lactones 2c and 2h was
made by their conversion to the corresponding 1,3-diol deriva-
tives and comparison of the specific rotations to literature values.
General procedure: Lithium aluminum hydride (2.0 equiv) was

1230 J . Org. Chem., Vol. 65, No. 4, 2000
Notes
added in portions to a 0 °C solution of lactone 2 in Et2O (0.3 M).
After the reactions were complete as monitored by TLC, water
(n mL/n g LAH) was carefully added to the reaction followed by
3 N aqueous NaOH (n mL/n g LAH) and water (3n mL/n g LAH).
The resulting granular precipitate was removed by filtration and
washed with additional Et2O. The combined filtrates were
concentrated, and the diol product was isolated by column
chromatography. Lactone 2c afforded (R)-5-phenyl-1,3-pen-
tanediol [R]D +9.6° (c 2.3 EtOH) [lit. (S) [R]D -7.2° (c 1.52,
EtOH)];11 lactone 2h afforded (S)-1-O-benzyl-1,2,4-butanetriol
[R]D -8.4° (c 3.6 MeOH) [lit. [R]D -7.56° (c 3.67, MeOH)].12
Stereochemical assignment of the remaining lactones of un-
known configuration (2f and 2g) was made by analogy to these
determinations. Resolved lactones 2a , 2c, and 2h were converted
to the corresponding â-hydroxy benzyl esters by reaction with
BnOH (1.0 equiv) and La(OtBu)3 (5 mol %) in THF and shown
by chiral HPLC to be enantiomeric to the analogous â-hydroxy
esters derived from the resolution reactions.5
Ack n ow led gm en t. The National Science Founda-
tion (CHE-9875735) and the University of Pittsburgh
are gratefully acknowledged for support of this work.
J O9913412
(11) Nun˜ez, M. T.; Mart´ın, V. S. J . Org. Chem. 1990, 55, 2370-
2374.
(12) Schreiber, S. L.; Wang, Z. J . Am. Chem. Soc. 1985, 107, 5303-
5305.