Synthesis and lipase-catalyzed resolution of 5-(hydroxymethyl)-1,3-dioxolan-4-ones: Masked glycerol analogs as potential building blocks for pharmaceuticals

Article abstract of DOI:10.1021/jo952021v

(Hydroxymethyl)-1,3-dioxolan-4-ones from mandelic and lactic acids and 1,5,5-trimethyl-3-phenyloxazolidin-2-one from mandelamide were α-alkylated using benzyl chloromethyl ether. Reductive debenzylation of the products of alkylation unmasked the hydroxymethyl groups. The compounds obtained in this fashion were subsequently subjected to lipase-catalyzed resolution in organic media. Depending on the lipase and substrate employed, enantiomeric ratios up to E = 200 were observed. The obtained optically pure compounds can be considered as masked 2-substituted glycerol equivalents, which could be used for the preparation of tertiary (aryloxy)propanolamines, compounds having potential β-blocking activity.

Full text of DOI:10.1021/jo952021v

J . Org. Chem. 1996, 61, 3423-3427
3423
Syn th esis a n d Lip a se-Ca ta lyzed Resolu tion of
5-(Hyd r oxym eth yl)-1,3-d ioxola n -4-on es: Ma sk ed Glycer ol An a logs
a s P oten tia l Bu ild in g Block s for P h a r m a ceu tica ls
Robert P. Hof and Richard M. Kellogg*
Department of Organic and Molecular Inorganic Chemistry, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
Received November 15, 1995X
(Hydroxymethyl)-1,3-dioxolan-4-ones from mandelic and lactic acids and 1,5,5-trimethyl-3-phen-
yloxazolidin-2-one from mandelamide were R-alkylated using benzyl chloromethyl ether. Reductive
debenzylation of the products of alkylation unmasked the hydroxymethyl groups. The compounds
obtained in this fashion were subsequently subjected to lipase-catalyzed resolution in organic media.
Depending on the lipase and substrate employed, enantiomeric ratios up to E ) 200 were observed.
The obtained optically pure compounds can be considered as masked 2-substituted glycerol
equivalents, which could be used for the preparation of tertiary (aryloxy)propanolamines, compounds
having potential â-blocking activity.
In tr od u ction
drugs is of utmost importance, and usually the (S)
enantiomer is by far the most active.8 The common
feature of these active (aryloxy)propanolamines is that,
in addition to the aryloxy and amine functionalities, they
contain a secondary hydroxyl group at the chiral center.
A large variety of aryloxy and amine groups has been
used in the development of new â-blockers.7 The only
position at which no substituent has been introduced is
at the chiral center itself where always a secondary
hydroxyl group is present.
Functionalized chiral C3-synthons, in particular chiral
glycerol derivatives, are of much topical interest. Such
compounds are used for the synthesis of several types of
pharmacologically active compounds,1 of which the anti-
hypertensive â-adrenergic blockers are probably the most
important. Several chiral derivatives of (prochiral) glyc-
erol have been developed.
Chiral glycerol synthons can either be prepared by
stereoselective synthesis from carbohydrates such as
mannitol2 or by enzymatic resolution procedures.3 Chiral
derivatives of glycerol such as the cyclic carbonate or the
acetonide (solketal) have been resolved by enzymatic
hydrolysis or acylation procedures.3 Although these
materials can be obtained in optically pure form this way,
the chiral recognition (expressed as the enantiomeric
ratio E)4 is only moderate (E ) 5-15), resulting in low
product recovery.
The value of these materials is, however, beyond doubt.
It has been shown, for example, that chiral intermediates
like solketal are easily converted to the highly valuable
â-blockers,5 such as (aryloxy)propanolamines like (S)-
propranolol.6 The antihypertensive effect of these ma-
terials stems from their resemblance to the adrenergenic
hormone (R)-noradrenaline, which enables them to block
adrenergenic receptors.7 The stereochemistry of these
Previously, we have shown that compounds having a
tertiary chiral center can be resolved efficiently by the
action of enzymes. For example, we have shown that
R-alkylated R-hydroxy esters are resolved by pig liver
esterase (PLE) in aqueous media,8 and that R,R-disub-
stituted glycols are enantioselectively acylated (at the
primary hydroxyl group) by lipases in organic media.9 We
now report the synthesis and enzymatic resolution of
chiral masked glycerol derivatives having an additional
alkyl substituent at the chiral center. These tertiary
compounds might give rise to the synthesis of a new class
of (aryloxy)propanolamines having potential â-blocking
properties.
Resu lts a n d Discu ssion
A common building block used by us previously for the
synthesis of both R-alkylated R-hydroxy acids and R,R-
disubstituted-1,2-diols is dioxolanone 1a . This compound
is easily available from mandelic acid by transacetaliza-
tion with dimethoxypropane,9 and can be R-alkylated by
deprotonation with LDA followed by trapping of the
formed enolate with an electrophile. In principle, the use
of formaldehyde as electrophile should lead to (hy-
droxymethyl)dioxolanone 2a , which can be considered as
a chiral equivalent of 2-phenylglycerol (Scheme 1) in
which two of the three hydroxyl groups are masked.
The unmasked primary hydroxyl group in 2a gives in
turn a nice handle with which to perform enantioselective
lipase catalyzed acylation.
* To whom correspondence should be addressed. Tel.: 31-50-
3634235. Fax: 31-50-3634296. E-mail: <R.M.Kellogg@rugch4.chem.
rug.nl>.
X Abstract published in Advance ACS Abstracts, April 15, 1996.
(1) For a review of the use of 2,3-O-isopropylideneglyceraldehyde
as
a chiral C3-synthon in stereoselective organic synthesis see:
J urczak, J ; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
(2) Baer, E.; Fischer, H. J . Biol. Chem. 1939, 128, 463.
(3) (a) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. J . Org. Chem.
1994, 59, 1751. (b) Parmar, V. S.; Prasad, A. K.; Singh, P. K.; Gupta,
S. Tetrahedron: Asymmetry 1992, 3, 1395. (c) Va¨nttinen, E.; Kanerva,
L. T. J . Chem. Soc., Perkin Trans. 1 1994, 3459. (d) Waagen, V.; Partali,
V.; Hansen, T. V.; Anthonsen, T. Protein Eng. 1994, 7, 589. Murata,
M.,; Terao, Y.; Achiwa, K.; Nishio, T.; Seto, K. Chem. Pharm. Bull.
1989, 37, 2670. (e) Terao, Y.; Murata, M.; Achiwa, K. Tetrahedron Lett.
1988, 29, 5173.
As far as we are aware, compounds 2 have been
described in the literature only once. They were prepared
(4) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.
(5) J ung, M. E.; Shaw, T. J . J . Am. Chem. Soc. 1980, 102, 6304.
(6) The Merck Index, 11th ed.; Budavari, S., Ed.; Merck & Co., Inc:
Rahway, 1989.
(7) Sheldon, R. A. Chirotechnology; M. Dekker: New York, 1993; p
51.
(8) Moorlag, H.; Kellogg, R. M.; Kloosterman, M.; Kaptein, B.;
Kamphuis, J .; Schoemaker, H. E. J . Org. Chem. 1990, 55, 5878.
(9) Hof, R. P.; Kellogg, R. M. Tetrahedron: Asymmetry 1994, 5, 565.
S0022-3263(95)02021-4 CCC: $12.00 © 1996 American Chemical Society

3424 J . Org. Chem., Vol. 61, No. 10, 1996
Hof and Kellogg
Sch em e 1
Sch em e 4
Sch em e 2
Ta ble 1. Lip a se-Ca ta lyzed Resolu tion s of
(Hyd r oxym eth yl)d ioxola n on es 2, 9, a n d 10a
sub-
time convb
ee (%)
ee (%)
entry strate lipase
(h)
(%)
alcoholc acetate
E
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2a
2a
2b
2b
9
9
9
9
9
CCL
CAL
CAL
CCL
CAL
CAL
CCL
HPL
HPL
PPL
PPL
CAL
CCL
48
96
240
20
20
20
20
68
184
20
68
50
32
44
50
38
60
76
31
47
29
46
54
80
66 (R)
46 (S)
79 (S)
80 (R)
59 (S)
>98 (S)
>98 (R)
38 (S)
72 (S)
38 (S)
76 (S)
>98 (S)
59 (S)
66
>99
>99
60
98
64
31
86
82
91
6
>200
>200
10
Sch em e 3
>100
21
7
17
20
40
40
>50
<2
9
10
10
89
82
15
72
184
a
b
Solvent isopropyl ether, temperature 20 °C. Calculated from
c ) ee (alcohol)/(ee (alcohol)+ee (acetate). c See text for a discussion
of the establishment of the absolute configurations.
by condensation of dioxolanones 1 and paraformaldehyde
in the presence of pyridine and triton-B.10 Exact repeti-
tion of this patent procedure, however, gave only mar-
ginal yields (30%) together with a great deal of trans-
acetalized products 3a ,b (Scheme 2).
Better results were obtained by generation of the
enolate of 1a , followed by trapping with paraformalde-
hyde as shown in Scheme 1. Compound 2a was obtained
in higher (44%) yield, but still 3a was produced as a
major side product. An alternative (masked) hydroxy-
methylating reagent is benzyl chloromethyl ether.11
Previously, it has been shown to be a powerful masked
hydroxymethylating agent.12 Alkylation of the enolate
of 1a proceeded smoothly using benzyl chloromethyl ether
and gave 6 in good yield. This compound can either be
purified or directly converted to 2a by reductive hydro-
genation (Scheme 3).
Via this approach, analogs 9 and 10 have been pre-
pared as well. Owing to the fact that it is crystalline,
2b could be obtained pure by direct condensation of
dioxolanone 1b and paraformaldehyde as shown in
Scheme 2.
Resolutions of compounds 2, 9, and 10 were carried
out by lipase-catalyzed acylation in isopropyl ether (ipe)
as solvent using the enol ester vinyl acetate as acyl donor
(Scheme 4).
For substrate 2a lipases AKG, PS, PPL, and HPL gave,
even after 17 days, no conversion. Of the two other
lipases, CCL gave only moderate enantiodiscrimination
(E ) 6, entry 1), but CAL was very enantioselective
giving, even at conversion approaching 50%, optically
pure product 11a (Table 1, entries 2 and 3). This
corresponds to an E value of greater than 200.13 The
chiral discrimination in this kinetic resolution must
therefore be nearly absolute, since it is the product which
is obtained enantiomerically pure. It is also necessary
to stress that CCL shows an opposite chiral preference
for this substrate compared to CAL. Results analogous
to those for 2a were observed for bromo derivative 2b.
Again, CCL showed only moderate enantiodiscrimination
(E ) 10, Table 1, entry 4) and its preference was opposite
to that of CAL. Enantiodiscrimination by CAL was
nearly absolute, and product 11b was obtained in 98%
ee (E ) 100, Table 1, entry 5). For lactic acid derivative
9, not only CAL and CCL catalyzed transacylation, but
HPL and PPL as well. This is probably due to less steric
repulsion for this substrate, making it more accessible
for reaction. As observed more often, the substitution of
an aromatic ring by a methyl group increases reactivity,
but, unfortunately, decreases chiral discrimination sig-
nificantly.9 For example, in 20 h CAL converted 9 to 11c
in 60% yield. In this way the remaining alcohol 9 is
obtained enantiomerically pure (Table 1, entry 6), but at
the cost of an E ratio of only 21 compared to E > 200 for
2a .
A total of six lipases (lipases AKG and PS from Amano,
pig pancreatic lipase (PPL), hog pancreatic lipase (HPL),
and Candida cylindracae lipase (CCL) from Sigma and
Candida antarctica lipase (CAL) from Novo) were screened
for reactivity and enantioselectivity. Results are listed
in Table 1.
Also, CCL was more reactive with 9, and as for 2a ,b,
the other enantiomer was converted preferentially. Enan-
tiomerically pure 9 was obtained after 76% conversion
(E ) 7) using this specific lipase (Table 1, entry 7). HPL
(10) Kunz, W. (Ciba-Geigy AG) Eur. Pat. 0 044 276 A2, 1982; Chem.
Abstr. 1982, 96, p162710r.
(11) Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI,
101.
(12) (a) Hill, A. J .; Keach, D. T. J . Am. Chem. Soc. 1926, 48, 257.
(b) Graham, C. L.; McQuillin, F. J . J . Chem. Soc. 1963, 4634.
(13) In fact, for such good discriminations the logarithmic formula
to calculate E can give bizarre values approaching infinity. It therefore
makes no sense to give E values of greater than around 100-200 as a
change in determined ee or conversions of less than 0.1% have a
dramatic influence on the calculated E value.

Resolution of 5-(Hydroxymethyl)-1,3-dioxolan-4-ones
J . Org. Chem., Vol. 61, No. 10, 1996 3425
Sch em e 5
obtained in overall good yields. Compounds 2a ,b and 10,
all of which have a phenyl substituent at the chiral
center, are efficiently resolved by Candida antarctica
lipase with E factors of up to 200. For these substrates
Candida cylindracae lipase is only marginally enantiose-
lective. Probably due to steric repulsion, four other
lipases were shown not to catalyze the acylation of these
compounds. The less sterically crowded 9 was also
transformed by these other lipases but the enantiomeric
ratios observed were somewhat lower. For this substrate
the best results were obtained using pig pancreatic lipase
(E ) 40). By conversion of 2a to the known methyl ester
12a the stereochemical preference of the lipases toward
substrates 2 has been established. Since both PPL and
CAL are cheap and readily available lipases, this opens
the way to perform resolutions on larger scale. Optimal-
ization and scale up of the synthesis of (aryloxy)propan-
olamines and other potential drugs are currently in
progress.
and PPL were less reactive (Table 1, entries 8-11), but
especially PPL was more enantioselective. After 68 h, a
conversion of 46% was achieved combined with an E of
40 (Table 1, entry 11).
A compound which is especially interesting to resolve
is (hydroxymethyl)oxazolidinone 10. Oxazolidinones like
10 already have a built-in nitrogen functionality, making
them easier, via reduction, to convert to tertiary (aryl-
oxy)propanolamines. Analogously to dioxolanones 2a ,b,
10 was resolved smoothly by CAL. At 54% conversion
(72 h) the remaining alcohol had an ee of >98%, which
corresponds to E > 50 (Table 1, entry 12).14 Resolution
by CCL for this specific substrate gave only the barest
selectivity since E was < 2 (Table 1, entry 13)!
Exp er im en ta l Section
All solvents were reagent grade and were dried and distilled
prior to use, following standard procedures. All reagents were
purchased from either Acros Chimica (previously J anssen
Chimica), Aldrich, Merck, or Fluka and used without purifica-
tion. Benzyl chloromethyl ether (90%) was obtained from TCI.
Melting points are uncorrected. 1H NMR spectra were re-
corded at 200 or 300 MHz. 13C NMR spectra (APT) were
recorded at either 50.32 or 75.48 MHz. Analytical HPLC
analysis was carried out using photodiode array detection.
Mass spectra were recorded by EI by Mr. A. Kiewiet in our
department. Elemental analyses were performed in the mi-
croanalytical group of this department by Mr. H. Draaijer, Mr.
J . Ebels, and Mr. J . Hommes. Dioxolanones 1a and 4 were
prepared as described previously.9
5-(4-Br om oph en yl)-2,2-dim eth yl-1,3-dioxolan -4-on e (1b).
A mixture of 4-bromomandelic acid19 (20.0 g, 86.6 mmol) and
acetone (25 g) in 100 mL of benzene containing a catalytic
amount of H2SO4 was azeotropically refluxed for 8 h. After
cooling, the mixture was washed three times with a saturated
NaHCO3 solution followed by brine. After drying (Na2SO4) the
solution was evaporated to dryness to yield 1b (13.2 g, 48.9
mmol, 57% yield) mp 62.0-63.0 °C (lit.20 65-66 °C): 1H-NMR
(CDCl3) δ 1.66 (s, 3H), 1.71 (s, 3H), 5.34 (s, 1H), 7.33-7.37
(m, 2H), 7.50-7.56 (m, 2H); 13C-NMR (CDCl3) δ 26.07 (q), 27.19
(q), 75.09 (d), 111.13 (s), 122.82 (s), 127.93 (d), 131.82 (d),
133.52 (s), 172.06 (s).
1,5,5-Tr im eth yl-3-p h en yloxa zolid in -2-on e (5). Under a
nitrogen atmosphere using dried glassware, 5,5-dimethyl-3-
phenyloxazolidine-2-one21 (1.91 g, 10 mmol) was dissolved in
20 mL of dry THF. After the mixture was cooled to -20 °C,
KOtBu (1.12 g, 10 mmol) was added. The mixture was stirred
for 5 min and methyl iodide (2.13 g, 0.93 mL, 15 mmol) was
added. The mixture was stirred for 3 h and quenched with
NH4Cl solution. The reaction mixture was extracted three
times with EtOAc, and the combined organic layers were
washed with brine. After drying (Na2SO4) and evaporation a
yellow oil (1.97 g, 9.6 mmol, 96% yield) was obtained which
was purified by column chromatography (silica, CH2Cl2) to
provide pure 5 (1.50 g, 7.3 mmol, 73% yield): 1H-NMR (CDCl3)
δ 1.49 (s, 3H), 1.57 (s, 3H), 2.84 (s, 3H), 5.26 (s, 1H), 7.24-
7.48 (m, 5H); 13C-NMR (CDCl3) δ 25.2 (q), 25.5 (q), 26.9 (q),
78.1 (d), 93.9 (s), 126.5 (d), 128.3 (d), 128.5 (d), 137.0 (s), 169.4
(s).
The absolute stereochemistry of compound 2a was
subsequently established by methanolysis to the known
methyl ester 12a (Scheme 5).
This compound had previously been prepared in opti-
cally enriched form by asymmetric dihydroxylation. It
was shown by Sharpless et al.15 that the enantiomeric
excess of 12a can easily be enriched by a single recrys-
tallization. By correlation of the optical rotation of 12a
with literature values16 the stereochemistry of 2a re-
solved by CAL was established as (S). As lipases usually
show the same enantiopreference throughout a series of
analogous substrates,16 we expect that also 2b, 9, and
10 have the same absolute stereochemistry as 2a . The
stereochemistry of the acetates produced by CAL must
therefore be R.
Compound (S)-2a can also be hydrolyzed to phenyl-
glycolic acid (S)-13a (Scheme 5). This has previously
been shown to be the acid moiety in the tropane alkaloid
anisodine,17 an alkaloid showing ganglio blocking proper-
ties and used clinically for the treatment of motion
sickness, migraine, and vascular spasms of fundus oc-
culi.18 By modification of synthetic procedures, optically
active 2a might also be used for the preparation of
analogs of the antifungal agent Sch 42427.18 We are
currently exploring the possibilities of employing com-
pounds 2, 9, and 10 in the syntheses of potentially active
pharmaceutical compounds. Such transformations have
been achieved and will be described in due course.
Con clu sion s a n d Ou tlook
We have shown that 5-(hydroxymethyl)1,3-dioxolan-
4-ones 2 and 9 and 3-(hydroxymethyl)oxazolidine-2-one
10 are easily prepared from mandelic or lactic acid via
their acetonides. Alkylation of the acetonide proceeds
smoothly and selectively with benzyl chloromethyl ether.
By reductive debenzylation compounds 2, 9, and 10 are
(14) The ee determination of 11d was difficult due to the peak shape
of the second eluting minor enantiomer on HPLC. The ee was,
therefore, conservatively estimated which results in an E of “only” 50.
(15) Wang, Z.-M.; Sharpless, K. B. Synlett 1993, 603.
(16) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656.
(17) J ingxi, X.; J inghua, Y.; Yaoxing, Z.; Chunzhen, Z Sci. Sin. Ser.
B. 1983, 26, 931.
(18) Girijavallabhan, V. M.; Ganguly, A. K.; Pinto, P. A.; Sarre, O.
Z. Bioorg. Med. Chem. Lett. 1991, 1, 349.
2,2-Dim eth yl-5-(h ydr oxym eth yl)-5-ph en yl-1,3-dioxolan -
4-on e (2a ) Usin g P a r a for m a ld eh yd e. In a nitrogen atmo-
sphere using dried glassware, diisopropylamine (3.5 mL, 25
(19) (19) Organic Syntheses; Wiley: New York, 1941; Collect. Vol.
I, p 336.
(20) Fuson, R. C.; Rachlin, A. I. J . Am. Chem. Soc. 1942, 64, 1567.
(21) Fischer, H. O. L.; Dangschat, G.; Stettiner, H. Ber. 1932, 65,
1032.

3426 J . Org. Chem., Vol. 61, No. 10, 1996
Hof and Kellogg
mmol) was dissolved in 50 mL of dry THF. After the mixture
was cooled to -80 °C, n-Buli (14 mL, 1.6 N in hexane, 22 mmol)
was added. After being stirred for 15 min the mixture was
recooled to -80 °C, and a solution of dioxolanone 1a (3.84 g,
20 mmol) in dry THF was added dropwise. The mixture was
stirred for 15 min and again recooled to -80 °C. Paraform-
aldehyde (750 mg, 25 mmol) was added, and the mixture was
slowly allowed to reach room temperature and allowed to stir
overnight. Saturated NH4Cl solution (50 mL) was added, and
the reaction mixture was extracted twice with ether. The
combined organic layers were washed with brine, dried (Na2-
SO4), and evaporated to give crude 2a (3.22 g, 14.5 mmol, 73%
yield). This material was distilled (125 °C/0.02 mmHg) to give
2a as a nearly pure yellow oil (1.97g, 8.87 mmol, 44% yield).
For physical data see below.
2,2,5-Tr im e t h yl-5-(h yd r oxym e t h yl)-1,3-d ioxola n -4-
on e (9). Dioxolanone 4 (2.60 g, 20 mmol) was alkylated with
benzyl chloromethyl ether (3.46 mL) analogously to the
procedure described above for 1a to give 7 (5.85g, 100% yield)
contaminated with benzyl alcohol. A part of the crude 7 (1.90
g, 7.6 mmol) was dissolved in EtOH and hydrogenated in a
Parr apparatus with a catalytic amount of Pd/C (5%) for 48 h.
After filtration, crude 9 was obtained (1.19 g, 7.44 mmol, 98%
yield) of which a part was purified by column chromatography
(silica, EtOAc/hexane 1:9) to give the pure title compound: 1H-
NMR (CDCl3) δ 1.35 (s, 3H), 1.56 (s, 3H), 1.58 (s, 3H), 2.93 (br
dd, J ) 7.4 and 4.7 Hz, 1H), 3.50 (dd, J AB ) 12 Hz, J ) 4.7
Hz, 1H), 3.68 (dd, J AB ) 12 Hz, J ) 7.4 Hz, 1H); 13C-NMR
(CDCl3) δ 20.92 (q), 27.66 (q), 28.73 (q), 66.09 (t), 81.74 (s),
110.81 (s), 174.17 (s); HRMS m/ z (- CH3) calcd 145.050, found
145.050.
2,2-Dim eth yl-5-(h ydr oxym eth yl)-5-ph en yl-1,3-dioxolan -
4-on e (2a ) via th e Ben zyl Eth er 6. In a nitrogen atmo-
sphere using dried glassware, diisopropylamine (10.5 mL, 75
mmol) was dissolved in 100 mL of dry THF. After the mixture
was cooled to -80 °C n-Buli (27 mL, 2.5 N in hexane, 67 mmol)
was added. After being stirred for 15 min, the mixture was
recooled to -80 °C and a solution of dioxolanone 1a (11.5 g,
60 mmol) in dry THF was added dropwise. The mixture was
stirred for 15 min and again recooled to -80 °C. Benzyl
chloromethyl ether (90%) (10.4 mL, 65 mmol) in dry THF was
added dropwise, and the mixture was allowed to reach room
temperature (3 h) and stirred overnight. Saturated NH4Cl
solution (100 mL) was added, and the reaction mixture was
extracted three times with ether. The combined organic layers
were washed with brine, dried (Na2SO4), and evaporated to
give crude 6 (19.9 g) containing a small amount of benzyl
alcohol. A part of this crude material (13.23 g, 42 mmol) was
dissolved in 50 mL of EtOH, and 200 mg of 5% Pd on carbon
was added. The mixture was hydrogenated at 40 psi for 48 h
in a Parr apparatus, after which time it was filtered and
evaporated to give crude 2a (8.55 g, 38.5 mmol, 91% yield) as
an oil. Pure material was obtained by bulb-to-bulb distillation
(145 °C/ 0.25 mmHg), giving the title compound 2a as a
colorless oil (7.35 g, 33 mmol, 78% yield). An analytically pure
sample was obtained by column chromatography (silica, ether/
hexane 1:2): 1H-NMR (CDCl3) δ 1.47 (s, 3H), 1.76 (s, 3H), 2.47
(dd, J ) 4.4 and 8.3 Hz, 1H), 3.67 (dd, J AB ) 11 HZ, J OH ) 4.4
Hz, 1H), 4.01 (dd, J AB ) 11 HZ, J OH ) 8.3 Hz, 1H), 7.25-7.36
(m, 3H), 7.62-7.66 (m, 2H); 13C-NMR (CDCl3) δ 27.56 (q), 27.91
(q), 68.13 (t), 85.23 (s), 110.91 (s), 125.06 (d), 128.56 (d), 136.11
(s). HRMS m/ z (- CH2O) calcd 192.079, found 192.079. Anal.
Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.47; H,
6.32.
The rest of crude 7 was purified by column chromatography
(silica, EtOAc/hexane 1:9) to give a colorless oil, which solidi-
fied upon standing; mp 48-51 °C; 1H-NMR (CDCl3) δ 1.34 (s,
3H), 1.53 (s, 3H), 1.57 (s, 3H), 3.45 (d, J AB ) 10 Hz, 1H), 3.57
(d, J AB ) 10 Hz, 1H), 7.26 (s, 5H); 13C-NMR (CDCl3) δ 21.55
(q), 27.51 (q), 28.99 (q), 73.40 (t), 80.82 (s), 110.18 (s), 127.50
(d), 127.66 (d), 128.36 (d), 137.64 (s), 173.91 (s). HRMS m/ z
calcd 250.120, found 250.120. Anal. Calcd for C14H18O4: C,
67.18; H, 7.25. Found: C, 67.09; H, 7.23.
1,5,5-Tr im et h yl-3-(h yd r oxym et h yl)-3-p h en yloxa zoli-
d in e-2-on e (10). Using a procedure analogous to 2a and 9,
oxazolidinone 5 (1.47 g, 7.2 mmol) was alkylated with benzyl
chloromethyl ether (1.26 mL). The quantitatively obtained 8
(contaminated with benzyl alcohol) was dissolved in EtOH and
hydrogenated in a Parr apparatus (72 h) using a catalytic
amount of Pd/C (5%). After filtration and evaporation there
remained crude 10 (1.28 g, 5.4 mmol, 76% yield). This was
purified by column chromatography (silica, gradient ether/
hexane 1:1 to pure ether) to provide the title compound (0.50
g, 2.13 mmol, 30% yield) as an oil which solidified upon
1
standing: mp 87.0-89.3 °C; H-NMR (CDCl3) δ 1.39 (s, 3H),
1.82 (s, 3H), 2.60 (br, 1H), 2.83 (s, 3H), 3.60 (dd, J ) 12, 4.6
Hz, 1H), 4.02 (dd, J ) 12, 8.1 Hz, 1H), 7.27-7.37 (m, 3H),
7.68-7.73 (m, 2H); 13C-NMR (CDCl3) δ 25.62 (q), 26.61 (q),
26.90 (q), 67.89 (t), 85.92 (s), 93.70 (s), 125.55 (d), 127.89 (d),
128.15 (d), 138.70 (s). HRMS m/ z (- CH2O) calcd 205.110,
found 205.109. Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28;
N, 5.95. Found: C, 66.52; H, 7.27; N, 5.98.
Gen er a l P r oced u r e for th e Lip a se-Ca ta lyzed Resolu -
tion of 2. (Hydroxymethyl)dioxolanone 2 (0.3 mmol) was
dissolved in a mixture of 1 mL of isopropyl ether and 0.2 mL
of vinyl acetate. Lipase (20 mg) was added, and the mixture
was stirred at room temperature. At regular intervals a 0.1
mL sample was taken which was filtered over celite in a
Pasteur pipette. The Celite was washed with 1 mL of CH2-
Cl2, and the filtrate was evaporated to dryness. The residue
was dissolved in 1 mL of isopropanol and analyzed by chiral
HPLC (Daicel OJ ) or GC (FS-LIPODEX C); see the supporting
information for details.
P r ep a r a tive Sca le Resolu tion of (S)-2a Usin g CAL.22
Alcohol 2a (573 mg, 2.58 mmol) was dissolved in 10 mL of dipe
and 2 mL of vinyl acetate. CAL (300 mg) was added, and the
mixture was stirred at room temperature. After 19 days the
lipase was removed by filtration and the filtrate was purified
by column chromatography (silica ether/hexane 1:2) to yield
(S)-2a (214 mg, 0.96 mmol, 73% ee) and (R)-11a (203 mg, 0.77
mmol, >99% ee) both as colorless solids.
(S)-2,3-Dih yd r oxy-2-p h en ylp r op a n oic Acid Meth yl Es-
ter (12a ). Optically enriched alcohol (S)-2a (214 mg, 0.96
mmol, 73% ee) was dissolved in 10 mL of MeOH. A catalytic
amount of H2SO4 was added, and the mixture was refluxed
for 4 days. Water (10 mL) was added, and the methanol was
removed by evaporation. The remaining water layer was
washed three times with EtOAc, and the combined organic
layers were washed with brine and dried (Na2SO4). After
The rest of crude 6 was purified by column chromatography
(silica ether/hexane 1:25) to provide pure 6: 1H-NMR (CDCl3)
δ 1.53 (s, 3H), 1.78 (s, 3H), 3.62 (d, J AB ) 11 Hz, 1H), 3.92 (d,
J AB ) 11 Hz, 1H), 4.67 (s, 2H), 7.27-7.45 (m, 8H), 7.69-7.75
(m, 2H); 13C-NMR (CDCl3) δ 27.44 (q), 28.18 (q), 73.65 (t), 75.14
(t), 84.10 (s), 110.58 (s), 125.20 (d), 127.50 (d), 127.66 (d),
128.36 (d), 128.45 (d), 128.52 (d), 136.18 (s), 137.50 (s); HRMS
m/z calcd 312.136, found 312.136.
2,2-Dim et h yl-5-(h yd r oxym et h yl)-5-(4-b r om op h en yl)-
1,3-d ioxola n -4-on e (2b).11 Dioxolanone 1b (5.42 g, 20 mmol)
was dissolved in 35 mL of pyridine, and paraformaldehyde (2.4
g, 80 mmol) and triton-B (2 mL, 40% in MeOH) were added.
The mixture was stirred overnight and cooled to -5 °C. Acetic
acid was added until the pH reached 6.5-7.0, and the mixture
was poured into ice-water. The slurry was extracted three
times with CH2Cl2, and the combined organic layers were dried
(Na2SO4). The organic fraction was evaporated on a rotary
evaporator, and subsequently most of the pyridine was evapo-
rated at low pressure (0.01 mm) at 50 °C. The remaining oil
was dissolved in ether and stored overnight at 4 °C to give 2b
as white needles (1.33 g, 4.42 mmol, 22% yield): mp 131-132
°C (lit.,11 mp 123-127 °C): 1H-NMR (CDCl3) δ 1.47 (s, 3H),
1.75 (s, 3H), 2.05 (br, 1H), 3.65 (d, J AB ) 12 Hz, 1H), 3.97 (d,
J AB ) 12 Hz, 1H), 7.54 (s, 4H); 13C-NMR (CDCl3) 27.54 (q),
27.97 (q), 68.00 (t), 84.60 (s), 110.81 (s), 123.03 (s), 126.87 (d),
131.77 (d), 135.06 (s).
(22) This experiment was performed only once to establish the
absolute stereochemistry of 8a . So far, no attempts have been
undertaken to improve yields or shorten reaction times.

Resolution of 5-(Hydroxymethyl)-1,3-dioxolan-4-ones
J . Org. Chem., Vol. 61, No. 10, 1996 3427
evaporation there remained (S)-12a as a colorless oil (163 mg,
0.83 mmol, 87% yield). This material was purified by column
chromatography (silica ether/hexane 2:1) to yield (S)-12a as a
white solid (145 mg, 0.74 mmol, 77% yield): [R]D ) - 6.6° (c
1.50 in EtOH), o.p. 67% (lit.16 [R]D ) +8.7° (c 1.05 in EtOH))
for a sample of the (R) enantiomer having an ee of 88%. The
ee of the sample was determined as 68% by chiral HPLC
(Daicel OJ -column); NMR in accordance with reference NMR.
thank Amano Enzyme Ltd. for a generous gift of several
lipases.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR
spectra of 2a ,b, 9, and 10, tables containing data for chiral
HPLC and GC separations of compounds 2a ,b, 9 and 10, 11,
and 12, and selected HPLC chromatograms (20 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. This work was supported in the
form of a grant to R.P.H. from The Netherlands Orga-
nization for Scientific Research (N.W.O.) administered
through the Office for Chemical Research (S.O.N.). We
J O952021V