Synthesis of optically active 1,3-dioxin-4-one derivatives having a hydroxymethyl group at the 2-position and their use for regio-, diastereo-, and enantioselective synthesis of substituted cyclobutanols

Article abstract of DOI:10.1016/S0957-4166(02)00760-7

A new method for preparing optically active 1,3-dioxin-4-one derivatives is presented. A series of prochiral 2,2-bis(hydroxymethyl)-1,3-dioxin-4-ones was synthesized by [4+2]cycloaddition of acylketene to protected 1,3-dihydroxy-2-propanone derivatives followed by deprotection of the hydroxyl groups. Desymmetrization of the prochiral dioxinones by lipase-catalyzed monoacetylation afforded optically active 2-(hydroxymethyl)dioxinones. Intramolecular photo[2+2]cycloaddition of ω-alkenyl esters of these alcohols provided an efficient method for regio-, diastereo-, and enantioselective synthesis of cyclobutanols.

Full text of DOI:10.1016/S0957-4166(02)00760-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 201–215
Synthesis of optically active 1,3-dioxin-4-one derivatives having a
hydroxymethyl group at the 2-position and their use for regio-,
diastereo-, and enantioselective synthesis of substituted
cyclobutanolsꢀ
Masayuki Murakami,a Hiroshi Kamaya,b Chikara Kanekoc and Masayuki Satod,*
aProcess Development Laboratories, Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka 254-8560, Japan
bMedicinal Chemistry Department, Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-5-Kawagishi,
Toda 335-8505, Japan
cEmeritus Professor of Tohoku and Kanazawa Universities, 2-35-19 Yagiyama-Honcho, Taihaku-ku, Sendai 982-0801, Japan
dSchool of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
Received 18 September 2002; accepted 11 November 2002
Abstract—A new method for preparing optically active 1,3-dioxin-4-one derivatives is presented. A series of prochiral 2,2-bis(hy-
droxymethyl)-1,3-dioxin-4-ones was synthesized by [4+2]cycloaddition of acylketene to protected 1,3-dihydroxy-2-propanone
derivatives followed by deprotection of the hydroxyl groups. Desymmetrization of the prochiral dioxinones by lipase-catalyzed
monoacetylation afforded optically active 2-(hydroxymethyl)dioxinones. Intramolecular photo[2+2]cycloaddition of v-alkenyl
esters of these alcohols provided an efficient method for regio-, diastereo-, and enantioselective synthesis of cyclobutanols. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
for the preparation of enantiomerically pure or
enriched dioxinones in view of the synthetic potential of
this class of compounds. Previously, we reported a
regio- and stereocontrolled synthesis of cyclobutanol
derivatives by intramolecular photo[2+2]cycloaddition
of dioxinone (D: racemic) in which the alkene part is
tethered by readily cleavable ester linkage.7 In this
context, our attention was focused on developing a new
method for preparing optically active dioxinones hav-
ing a functional group at the 2-position. Herein, we
report the enantioselective synthesis of 2-(hydroxy-
methyl)dioxinones (E) by lipase-catalyzed monoacetyl-
ation of prochiral substrates8 and the use of E as chiral
enones in the regio-, diastereo-, and enantioselective
synthesis of cyclobutanols by intramolecular photo[2+
2]-cycloaddition.
Optically active 1,3-dioxin-4-one derivatives having a
stereogenic center at the 2-position (A,1 B,2,3 and C4)
are useful intermediates for the enantioselective synthe-
sis of numerous types of biologically active compounds,
since the enone moiety shows excellent diastereofacial
selectivity in a variety of addition reactions and the
dioxane ring in the addition products can be readily
cleaved owing to its acetal structure.5 So far, these
dioxinones have been prepared by a chirality transfer
method starting from (R)- or (S)-3-hydroxybutanoic
acid,1 a diastereomer separation method using chiral
ketones2–4 or resolution of racemic compounds by
HPLC with chiral columns.6 However, it is highly
desirable to develop a new and more efficient method
ꢀ Use of 1,3-dioxin-4-ones and related compounds in synthesis, Part 50. Part 49: Sato, M.; Uehara, F.; Sato, K.; Yamaguchi, M.; Kabuto, C. J.
Am. Chem. Soc. 1999, 121, 8270–8276.
* Corresponding authors. Tel./fax: +81-54-264-5754; e-mail: msato@u-shizuoka-ken.ac.jp
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00760-7

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M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
2. Results and discussion
afforded 11b. This compound, which is somewhat
unstable at room temperature, was purified using a
cooled silica gel column. Synthesis of 11b from dibenzyl
derivative 9b was unsuccessful because the desired
hydrogenolytic cleavage of the benzyl groups was
accompanied with hydrogenation of the dioxinone CꢀC
double bond also occurred under the hydrogenolysis
conditions.
2.1. Synthesis of prochiral dioxinones
Initially, we examined various protecting groups to
synthesize the prochiral 6-methylated dioxinone 11a.
Four protected 1,3-dihydroxy-2-propanones 1–4 pre-
pared according to known methods9–12 were converted
to their corresponding dioxinones 7a–10a by reaction
with the acetylketene generated from 2,2,6-trimethyl-
1,3-dioxin-4-one 5a13 or the acetylated Meldrum’s acid
6a14 in refluxing toluene. The desired dioxinones 7a–10a
were obtained in good yields. It was difficult to obtain
the requisite alcohol 11a from 7a and 8a because 11a
was unstable under the deprotection conditions
(K2CO3–methanol or heating in aqueous HCl). The
removal of the benzyl and tert-butyldimethylsilyl
groups in 9a and 10a was successful with H2/Pd(OH)2–
C in methanol–chloroform and with trifluoroacetic acid
in methanol, respectively, and crystalline 11a was
obtained without further chromatographic purification
(Scheme 1).
Hydroxyl-protected 6-phenyl dioxinones 9c and 10c
were prepared by the reaction of the corresponding
ketones (3 or 4) and benzoylketene generated from the
benzoylated Meldrum’s acid 6c16 or 2,2-dimethyl-6-
phenyl-1,3-dioxin-4-one 5c,17 respectively. Desilylation
of 10c afforded diol 11c. Synthesis of 11c from 9c by
hydrogenolysis was unsuccessful because the initially
formed 11c was again readily hydrogenated to 12.
Thus, it was concluded that tert-butyldimethylsilyl
group is the best protecting group for the synthesis of
bis(hydroxymethyl)-dioxinones 11a–c (Scheme 2).
2.2. Desymmetrization of prochiral dioxinones
We next studied the synthesis of the prochiral 6-unsub-
situted dioxinone 11b. The protected 1,3-dihydroxy-2-
propanones 3 and 4 were converted to dioxinones 9b
and 10b, respectively, by the reaction of formylketene
generated from formylated Meldrum’s acid 6b15 in
refluxing toluene in good yields. Upon treatment with
trifluoroacetic acid in methanol, compound 10b
Preliminary tests for optimization of the conditions for
the desymmetrization of prochiral dioxinones 11a–c
with different lipases and solvents were carried out.
Lipase A, AY, AK, PS, AH, Pancreatin F (Amano),
Lipase MY (Meito), and Toyocheme LIP (Toyobo)
were screened as a catalyst. Acetone, acetonitrile, 1,4-
Scheme 1.
Scheme 2.

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
Table 1. Preliminary tests for acetylation of prochiral dioxinones 11a–c
203
Run
R%
Lipasea (mg)
Solventb (mL/mL)
Temp. (°C)
Time (h)
HPLC parc (%) E.e.c of 13 (R/S)
7
13
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
AY (20)
AY (20)
AY (20)
PS (20)
PS (20)
AK (20)
LIP (20)
AY (20)
AY (20)
MY (20)
PS (40)
LIP (10)
LIP (5)
LIP (5)
PS (40)
PS (40)
AH (20)
AH (20)
LIP (20)
LIP (20)
A/VA=1/4
VA=5
28
28
28
28
28
28
26
28
28
28
28
30
30
30
30
30
31
31
30
30
11
63
19
22
15
16
12
10
8
20
25
2.5
20
36
60
36
18
18
7
52
49
44
40
36
37
25
29
38
25
51
33
39
36
26
20
43
48
31
39
48
50
54
60
64
62
75
71
62
75
49
67
62
64
74
79
57
52
69
61
59% e.e. (R)
82% e.e. (R)
70% e.e. (R)
82% e.e. (S)
80% e.e. (S)
80% e.e. (S)
99% e.e. (S)
97% e.e. (R)
98% e.e. (R)
96% e.e. (R)
82% e.e. (S)
96% e.e. (S)
95% e.e. (S)
88% e.e. (S)
90% e.e. (S)
80% e.e. (S)
95% e.e. (S)
96% e.e. (S)
88% e.e. (R)
88% e.e. (R)
IPE/VA=1/4
A/VA=1/4
D/VA=1/4
D/VA=1/4
AN/VA=1/4
AN/VA=1/4
A/VA=1/4
A/VA=1/4
D/VA=1/4
AN/VA=1/4
D/VA=1/4
VA=5
A/VA=1/4
VA=5
A/VA=1/4
D/VA=1/4
AN/VA=1/4
A/VA=1/4
9
10
11
12
13
14
15
16
17
18
19
20
1.5
a AY: Lipase AY, PS: Lipase PS, AH: Lipase AH, MY: Lipase MY, LIP: Toyocheme LIP.
b A: acetone, AN: acetonitrile, D: 1,4-dioxane, VA: vinyl acetate, IPE: diisopropyl ether.
c par: peak area ratio. HPLC conditions for R%=Me, Ph: Chiralpak AS (4.6×250 mm), eluent: n-hexane/ethanol=90/10 (containing 0.1% acetic
acid), detection; 254 nm (UV), flow rate: 1.0 mL/min. HPLC conditions for R%=H: Chiralpak AS (4.6×250 mm), eluent: n-hexane/2-propanol=
80/20 (containing 0.1% acetic acid), detection: 254 nm (UV), flow rate: 1.0 mL/min.
dioxane, ethyl acetate, THF, and diisopropyl ether
were examined as a reaction solvent. Vinyl acetate
was used as an acetyl donor (Scheme 3).
use of a chiral column and the absolute configuration
at the 2-position was determined by the method men-
tioned in Section 2.3.
A typical procedure for the reaction involved stirring
a mixture of prochiral dioxinones (10 mg), solvent (1
mL), vinyl acetate (4 mL), and lipase (5–40 mg) at
room temperature (26–31°C). The reaction was moni-
tored by HPLC analysis using Chiralpak AS (Daicel).
Some of the results obtained are summarized in Table
1.
Based on the above results, 1–6 mmol of 11a–c was
used to prepare (R)- or (S)-13 on a larger scale by
asymmetric acetylation. The results are shown in
Table 2. Chromatographic purification of the product
by silica gel column cooled at −15°C gave 13a–c.‡
6-Substituted compounds 13a and 13c were isolated
in satisfactory yields. The 6-unsubstituted compound
13b was isolated in low yields due to some decompo-
sition on the column (runs 1 and 2). (R)- and (S)-13c
with high e.e.s were obtained by prolonged reaction,
though their yields were lower (runs 7 and 9). A
more efficient method to obtain 13c with high e.e. is
purification of 13c by recrystallization. Only one
recrystallization run of (R)-13c (83% e.e.) obtained in
run 8 was enough to afford (R)-13c (97% e.e.) in 47%
yield.
As can be seen from Table 1, monoacetate 13 was
obtained with high e.e. In addition, both enantiomers
of 13 were obtained by the use of a suitable enzyme
and solvent. For example, acetylation of 11a in the
presence of Lipase AY and acetone gave (R)-13a with
98% e.e. (run 9) and the use of Toyocheme LIP in
acetonitrile afforded (S)-13a with 96% e.e. (run 12).
The e.e.s were determined by HPLC analyses with the
Scheme 3.
‡ Chromatography at room temperature resulted in significant level of decomposition of (R)- and (S)-13a–c. These compounds were stable for a
few months in a refrigerator.

204
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
Table 2. Production of (R)- or (S)-13 on a larger scale by asymmetric acetylation of 11a–c
Runa
R%
Lipase
Solvent
Temp. (°C)
Time (h)
Isolated yield (%)
E.e.b of 13 (R/S)
7
13
1
2
3
4
5
6
7
8
9
H
H
LIP
AY
AY
AY
LIP
LIP
LIP
LIP
AH
AH
AN/VA=1/4
VA
25
27
27
27
28
28
29
28
28
28
21
20 days
16
28
23
29
54
27
56
27
44
34
50
22
76
68
46
70
26
70
45
66
98% e.e. (S)
67% e.e. (R)
96% e.e. (R)
98% e.e. (R)
98% e.e. (S)
94% e.e. (S)
91% e.e. (R)
83% e.e. (R)
96% e.e. (S)
86% e.e. (S)
Me
Me
Me
Me
Ph
Ph
Ph
Ph
A/VA=1/4
A/VA=1/4
AN/VA=1/4
AN/VA=1/4
AN/VA=1/4
AN/VA=1/4
D/VA=1/4
D/VA=1/4
24
22
2.5
9
10
3
16
11
10
a All reactions were carried out using 1–6 mmol of 11.
b E.e.s were determined by HPLC analysis as in Table 1.
2.3. Determination of absolute configuration at the
2-position
The absolute configuration of the 6-unsubstituted ana-
logue 13b was determined in the same manner as 13a.
Kinetic resolution via Toyocheme LIP-catalyzed acetyl-
ation of racemic alcohol 16b derived from 5b and 14 in
two steps provided (+)-17b and crude optically active
16b having opposite configuration. Jones’ oxidation of
16b followed by condensation with l-menthol yielded
diastereomers (R)- and (S)-18b in a 9:1 ratio.4b This
result shows that alcohol 16b and therefore (+)-17b
have R-configuration. Next, (−)-13b was converted to
the iodide 19b by Arbuzov reaction. Hydrogenolysis of
19b gave (+)-17b. Thus, we could conclude that (−)-13b
has S-configuration at the 2-position (Scheme 5).
The absolute configuration of the 6-methyl compound
13a was determined as follows: [4+2]cycloaddition of
ketone 1418 to the acetylketene generated from 6a gave
dioxinone 15a, which, upon treatment with trifluoro-
acetic acid, yielded racemic alcohol 16a. Kinetic resolu-
tion by Lipase MY-catalyzed acetylation of 16a pro-
vided (−)-17a and (+)-16a in 55 and 42% yields,
respectively. Jones’ oxidation of (+)-16a gave a car-
boxylic acid, and without purification, this was con-
densed with l-menthol to produce the known
compounds (R)- and (S)-18a4b in a 1:5 ratio, showing
that (+)-16a has S-configuration. Arbuzov reaction of
(−)-13a with methyltriphenoxyphosphonium iodide
gave iodide 19a, and hydrogenolysis of 19a with H2/
Pd–C gave (+)-17a in 86% yield. From the positive sign
of the specific rotation of this compound, the configura-
tion was determined to be S. Therefore, the configura-
tion of (−)-13a was assigned as S (Scheme 4).
The absolute configuration of the 6-phenyl compound
13c was determined as follows: (+)-13c was transformed
into its tert-butyldimethylsilyl ether 20. Hydrogenation
of this compound afforded a 2:1 diastereomeric mixture
of cis- and trans-21. NOE experiments on this mix-
ture indicated that the major isomer has cis configura-
tion. Alkaline-hydrolysis of this mixture followed by
Scheme 4.

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
205
Scheme 5.
Scheme 6.
enriched dioxinone (R)-13a was condensed with vari-
ous commercially available v-alkenoic acids 23–27 by
the DCC method to give 28–32 in excellent yields
(Scheme 7).
esterification with diazomethane lead to methyl 3-
hydroxy-3-phenyl propionate 22 in 79% yield. This
compound showed a positive sign for the specific rota-
tion, revealing the configuration to be R.19 Conse-
quently, cis-21 is considered to be the 2R,6R-diastereo-
mer, and (+)-13c is found to have R-configuration
(Scheme 6).
Next, intramolecular photo[2+2]cycloaddition reactions
of 28–32 were examined. A solution of 28–32 in ethyl
acetate (1–2 mM) was irradiated (300 nm) at room
temperature. The results summarized in Table 3 show
that parallel adducts were predominantly formed in all
cases. A shorter spacer afforded a higher endo/exo
2.4. Intramolecular photo[2+2]cycloaddition
In order to utilize the optically active dioxinones
obtained here, we examined the enantioselective syn-
thesis of cyclobutanols using intramolecular photo[2+
2]cycloaddition of dioxinones whose side chain is
attached to an appropriate olefin by an ester group.
The merits of this strategy are: (1) both the acetal and
ester groups in the photoadduct can be cleaved read-
ily; (2) by varying the length of the spacer, it is possi-
ble to perform regio- and diastereocontrolled synthesis
of cyclobutanols, and (3) because we now have an
enantiomerically enriched starting material, it is also
possible to achieve enantioselective synthesis of
cyclobutanols.
1
ratio, as determined by H NMR analysis of the crude
products and photoreaction of 28 gave endo-parallel
adduct 33a exclusively. Diastereoselectivities from the
photochemical reactions of 29 and 30 were slightly
improved when the reaction was conducted at a low
temperature (−30°C). Photoreaction of 32 gave unsep-
arable photoadducts. 500 MHz 1H NMR analysis
indicated that there are at least three different pho-
toadducts in this mixture. However, the structures
were not determined. The stereochemistry of 34a and
1
1
36b were determined by H NMR, H–1H COSY, 13C–
1H COSY, and NOE experiments. The structures of
the other photoadducts were established by systemati-
1
cally comparing their H NMR data to those of 34a
According to this strategy, the enantiomerically
and 36b.

206
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
Scheme 7.
Table 3. Intramolecular photo[2+2]cycloaddition of 28–32
n
Substrate
Yielda (%) of 33–37
exo-Parallel (b)
endo-Parallel
exo-parallel
endo-Parallel (a)
Cross (c)
1
2
3
4
7
28
29
30
31
32
47
72
44
0
13
30
0
0
0
33a alone
6 (9 at −30°C)
1.4 (1.5 at −30°C)
0.6
25
40
10
NDb
NDb
NDb
NDb
a Isolated yield.
b ND: not determined.
ing cyclobutanols were acetylated with acetic anhydride
to produce 38 and 39, respectively (Scheme 8).
3. Conclusions
Optically active dioxinones having a hydroxymethyl
group at the 2-position were synthesized by lipase-cata-
lyzed acetylation of prochiral diols. Both enantiomers
were obtained with high enantiomeric purity by use of
a suitable combination of an appropriate lipase and
solvent. The optically active 2-hydroxymethyldioxi-
Finally, the synthesis of cyclobutanols from the
intramolecular photoadducts was studied using com-
pounds 34a and 36b as representatives. Compounds 34a
and 36b were treated with excess LiAlH4 and the result-
Scheme 8.

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
207
nones thus obtained were transformed into v-alkenyl
carboxylates, whose intramolecular photo[2+
61.1, 94.3, 103.2, 158.3, 168.6, 169.9. MS m/z: 258
(M+).
2]cycloaddition provided an excellent method for the
regio-, diastereo-, and enantioselective synthesis of sub-
stituted cyclobutanols.
4.2.2. 4,9,9-Trimethyl-1,5,8,10-tetraoxaspiro[5.5]undec-
3-en-2-one, 8a. A solution of 5a (3.55 g, 25 mmol) and
2,2-dimethyl-1,3-dioxan-5-one (2, 2.60 g, 20 mmol)10 in
toluene (50 mL) was heated under reflux for 3 h and
then the solvent was evaporated in vacuo. Purification
of the residue by recrystallization from hexane–ether
gave 8a (4.29 g, 95%) as colorless prisms having a mp
of 97–98°C. Anal. calcd for C10H14O5: C, 56.07; H,
6.59. Found: C, 55.89; H, 6.54%. MS m/z: 215 (MH+).
IR (CHCl3): 1740, 1642 cm−1. 1H NMR (60 MHz,
CDCl3) l 1.40 (6H, s, C4’-CH3×2), 2.03 (3H, s, C6-
CH3), 4.00 (4H, s, CH2O×2), 5.20 (1H, s, C5-H).
4. Experimental
4.1. General
All melting points were determined with a Yazawa
micro melting point apparatus BY-1 and left uncor-
rected. Optical rotations were measured on a JASCO
DIP-360 digital polarimeter. IR spectra were measured
on a JASCO FT/IR-5MP spectrometer, and 1H and 13
C
NMR spectra were recorded on a JEOL JNM PMX
60SI or a JEOL JNM-GX 500 spectrometer with tetra-
methylsilane used as an internal standard. Mass spectra
were recorded on a JEOL JMS-DX-303, a JMS-AX-
500, a JEOL JMS-SX102, a JEOL JMS-BU20, a JEOL
JMS-MS700, a JEOL JMS-700V, or a JEOL JMS-
MS700QQ mass spectrometer. High-performance liquid
chromatography (HPLC) analyses were carried out on
a JASCO LC-800 system (pump, 880-PU; detector,
875-UV; system controller, 802-SC; integrator, Chro-
mato-recorder 12) using Chiralpak AS or Chiralcel OD
(Daicel). Merck silica gel 60 was employed for silica gel
column chromatography. Merck silica gel 60 F254 was
employed for thin-layer chromatography (PTLC).
Kanto Chemicals silica gel 60N (spherical, neutral) was
employed for medium-pressure liquid chromatography
(MPLC). A column with a jacket in which cold solvent
(ca. −20°C) was circulated was used for the isolation of
11b, (R)- and (S)-13a–c. The ratios of solvent mixtures
for chromatography are shown as volume/volume. The
photoreactions were carried out in a quartz Rayonet
4.2.3.
2,2-Bis[(benzyloxy)methyl]-6-methyl-4H-1,3-
dioxin-4-one, 9a. (a) Compound 6a (5.0 g, 26.9 mmol)
was added over a 15 min period to a refluxing solution
of 1,3-bis(benzyloxy)-2-propanone (3, 14.5 g, 53.6
mmol)11 in toluene (400 mL). The solution was heated
under reflux for an additional 45 min and then the
solvent was evaporated in vacuo. The residue was
chromatographed on a silica gel column. Elution with
hexane–ethyl acetate (7:1) gave 9a (6.91 g, 73%) as a
colorless oil. (b) A solution of 5a (3.55 g, 25 mmol) and
3 (5.40 g, 20 mmol) in toluene (100 mL) was heated
under reflux for 2 h and then the solvent was evapo-
rated in vacuo. Following the same steps as in (a) gave
9a (5.96 g, 84%). HRMS calcd for C21H23O5 (MH+):
355.1545. Found: 355.1555. IR (CHCl3): 1736, 1644
cm−1. 1H NMR (500 MHz, CDCl3) l 1.97 (3H, d,
J=1.0 Hz, C6-CH3), 3.79 and 3.87 (each 2H, d, J=11.0
Hz, CH2OCH2Ph×2), 4.58 and 4.62 (each 2H, d, J=
12.0 Hz, CH2Ph×2), 5.17 (1H, d, J=1.0 Hz, C5-H),
7.27–735 (10H, m, Ph×2). 13C NMR (125.65 MHz,
CDCl3) l 19.8, 68.2, 73.8, 94.0, 105.8, 127.6, 127.8,
128.4, 137.3, 159.5, 168.6.
,
Photochemical Reactor equipped with RPR 3000 A
lamps.
4.2.4. 2,2-Bis({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-
methyl-4H-1,3-dioxin-4-one, 10a. Compound 6a (7.0 g,
37.6 mmol) was added to a refluxing solution of 1,3-
bis(tert-butyldimethylsilyloxy)-2-propanone (4, 12.0 g,
37.7 mmol)12 in toluene (560 mL) over a 0.5 h period.
The solution was heated under reflux for an additional
2 h and then the solvent was evaporated in vacuo. The
residue was chromatographed on a silica gel column.
Elution with hexane–ethyl acetate (40:1) gave 4 (1.40 g,
12%) and then 10a (12.33 g, 81%) as a colorless oil.
HRMS calcd for C19H38NaO5Si2 (MNa+): 425.2155.
Found: 425.2148. MS m/z: 403 (MH+). IR (CHCl3):
4.2. Synthesis of prochiral dioxinones
4.2.1. 2,2-Bis[(acetoxy)methyl]-6-methyl-4H-1,3-dioxin-
4-one, 7a. (a) Acetylated Meldrum’s acid (6a, 5.0 g, 26.9
mmol)14 was added over a 15 min period to a refluxing
solution of 1,3-di(acetoxy)-2-propanone (1, 9.35 g, 53.7
mmol)9 in toluene (400 mL). The solution was heated
under reflux for an additional 45 min and then the
solvent was evaporated in vacuo. The residue was
chromatographed on a silica gel column. Elution with
hexane–ethyl acetate (4:1) gave 7a (5.84 g, 84%) as a
colorless oil. (b) A solution of 2,2,6-trimethyl-1,3-
dioxin-4-one (5a, 178 mg, 1.25 mmol)13 and 1 (174 mg,
1.0 mmol) in toluene (5 mL) was heated under reflux
for 3 h and then the solvent was evaporated in vacuo.
The residue was chromatographed on a silica gel
column. Elution with hexane–ethyl acetate (3:1) gave 7a
(187 mg, 72%) as a colorless oil. HRMS calcd for
C11H14O7 (M+): 258.0740. Found: 258.0760. IR
(CHCl3): 1750, 1647 cm−1. 1H NMR (500 MHz, CDCl3)
l 2.01 (3H, s, C6-CH3), 2.13 (6H, s, Ac×2), 4.33 and
4.59 (each 2H, d, J=12.0 Hz, CH2O×2), 5.30 (1H, s,
C5-H). 13C NMR (125.65 MHz, CDCl3) l 19.7, 20.6,
1
1732, 1644 cm−1. H NMR (500 MHz, CDCl3) l 0.03
and 0.04 (each 6H, s, Si(CH3)2×2), 0.85 (18H, s, tert-
Bu×2), 1.95 (3H, s, C6-CH3), 3.82 and 3.89 (2H, d,
J=11.0 Hz, OCH2×2), 5.121 (1H, s, C5-H). 13C NMR
(125.65 MHz, CDCl3) l −5.6, −5.5, 18.1, 19.7, 25.6,
62.0, 93.7, 106.6, 160.0, 168.4.
4.2.5. 2,2-Bis(hydroxymethyl)-6-methyl-4H-1,3-dioxin-4-
one, 11a. (a) Compound 9a (354 mg, 1.0 mmol) was
hydrogenated in methanol (5 mL) and chloroform
(three drops) with 10% Pd(OH)2/C (20 mg) for 4 h.
Removal of the catalyst and solvent left crude 11a.

208
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
Recrystallization from acetone–hexane gave 11a (174
mg, 100%) as colorless needles having a mp of 105–
107°C. (b) A solution of 10a (7.78 g, 19.3 mmol) and
trifluoroacetic acid (7.4 mL) in methanol (78 mL) was
stirred at room temperature for 45 h and then the
solvent was evaporated in vacuo. Recrystallization of
the residue gave 11a (2.12 g, 63%) as colorless needles
having a mp of 105–107°C. Anal. calcd for C7H10O5: C,
48.27; H, 5.79. Found: C, 48.05; H, 5.75%. MS m/z:
then the solvent was evaporated in vacuo. The residue
was chromatographed on a silica gel column. Elution
with hexane–ethyl acetate (10:1) gave 10b (467 mg,
60%) as a colorless oil. HRMS calcd for C18H36NaO5Si2
(MNa+): 411.1999. Found: 411.1997. MS m/z: 389
1
(MH+). IR (CHCl3): 1738, 1620 cm−1. H NMR (500
MHz, CDCl3) l −0.02 and −0.01 (each 6H, s, SiCH3×
4), 0.80 (18H, s, tert-Bu×2), 3.80 and 3.85 (2H, d,
J=11.5 Hz, OCH2×2), 5.23 (1H, d, J=6.0 Hz, C5-H),
7.03 (1H, d, J=6.0 Hz, C6-H). 13C NMR (125.65 MHz,
CDCl3) l −5.5, −5.4, 18.2, 25.7, 62.2, 97.1, 107.4, 157.7,
159.0.
1
175 (MH+). IR (CHCl3): 3401 (br), 1734, 1644 cm−1. H
NMR (500 MHz, CDCl3) l 1.64 (2H, brs, OH×2), 2.06
(3H, d, J=1.0 Hz, C6-CH3), 3.96 and 4.00 (each 2H, d,
J=12.5 Hz, CH2O×2), 5.25 (1H, d, J=1.0 Hz, C5-H).
13C NMR (125.65 MHz, CDCl3) l 19.9, 62.0, 94.0,
106.1, 159.5, 169.2.
4.2.9. 2,2-Bis(hydroxymethyl)-4H-1,3-dioxin-4-one, 11b.
A solution of 10b (467 mg, 1.2 mmol) and trifluoro-
acetic acid (0.5 mL) in methanol (10 mL) was stirred at
room temperature for 40 h and then the solvent was
evaporated in vacuo. The residue was purified by
MPLC with ether (the column temperature was kept at
−15 to −20°C) to give 11b (182 mg, 93%) as a colorless
oil. HRMS calcd for C6H8O5 (M+): 160.0371. Found:
160.0381. IR (neat): 3391 (br), 1732, 1618 cm−1. 1H
NMR (500 MHz, acetone-d6) l 3.03 (2H, brs, OH×2),
3.84 and 3.93 (2H, d, J=12.5 Hz, OCH2×2), 5.32 (1H,
4.2.6. 2,2-Bis[(acetoxy)methyl]-4H-1,3-dioxin-4-one, 7b.
Formylated Meldrum’s acid (6b, 10.0 g, 58.1 mmol)15
was added to a refluxing solution of 1 (20.0 g, 114.8
mmol) in toluene (400 mL) over a 0.5 h period. The
solution was heated under reflux for an additional 0.5 h
and then the solvent was evaporated in vacuo. The
residue was chromatographed on a silica gel column.
Elution with hexane–ethyl acetate (4:1) gave 1 (13.79 g)
as colorless needles and then 7b (5.87 g, 41%) as a
colorless oil. HRMS calcd for C10H13O7 (MH+):
245.0661. Found: 245.0662. MS m/z: 245 (MH+). IR
(CHCl3): 1750, 1622 cm−1. 1H NMR (500 MHz, CDCl3)
l 2.13 (6H, s, Ac×2), 4.40 and 4.55 (each 2H, d,
J=12.5 Hz, CH2O×2), 5.48 (1H, d, J=6.0 Hz, C5-H),
7.13 (1H, d, J=6.0 Hz, C6-H). 13C NMR (125.65 MHz,
CDCl3) l 20.4, 61.0, 97.7, 103.7, 157.2, 157.4, 169.7.
d, J=5.5 Hz, C5-H), 7.36 (1H, d, J=5.5 Hz, C6-H). 13
C
NMR (125.65 MHz, acetone-d6) l 61.4, 97.6, 108.3,
159.3.
4.2.10. 2,2-Bis[(acetoxy)methyl]-6-phenyl-4H-1,3-dioxin-
4-one, 7c. Benzoylated Meldrum’s acid (6c, 7.50 g, 30.2
mmol) was added over a 0.5 h period to a refluxing
solution of 1 (21.0 g, 120.6 mmol) in toluene (400 mL).
The solution was heated under reflux for an additional
45 min and then the solvent was evaporated in vacuo.
The residue was chromatographed on a silica gel
column. Elution with hexane–ethyl acetate (4:1) gave
the mixture of 7c and 1. Methanol (10 mL) and water
(40 mL) were added to this mixture. Insoluble crystals
were filtered and dried to give 7c (6.83 g, 71%). Recrys-
tallization from ether–hexane gave an analytical sample
as colorless needles having a mp of 76–77°C. Anal.
calcd for C16H16O7: C, 60.00; H, 5.04. Found: C, 60.09;
H, 5.09%. MS m/z: 321 (MH+). IR (CHCl3): 1748, 1624
cm−1. 1H NMR (500 MHz, CDCl3) l 2.13 (6H, s,
Ac×2), 4.54 and 4.61 (each 2H, d, J=12.0 Hz, CH2O×
2), 5.94 (1H, s, C5-H), 7.46–7.68 (5H, m, Ph). 13C NMR
(125.65 MHz, CDCl3) l 20.5, 61.3, 91.4, 103.4, 126.3,
128.9, 129.9, 132.6, 159.1, 164.7, 169.8.
4.2.7. 2,2-Bis[(benzyloxy)methyl]-4H-1,3-dioxin-4-one,
9b. Compound 6b (1.72 g, 9.99 mmol) was added over
a 0.5 h period to a refluxing solution of 3 (1.35 g, 4.99
mmol) in toluene (100 mL). The solution was heated
under reflux for an additional 0.5 h and then the
solvent was evaporated in vacuo. The residue was
chromatographed on a silica gel column. Elution with
hexane–ether (3:1) gave 9b (0.82 g, 48%) as colorless
needles having a mp of 56–57°C (recrystallized from
ether–hexane). Anal. calcd for C20H20O5: C, 70.57; H,
5.92. Found: C, 70.52; H, 5.94%. MS m/z: 341 (MH+).
IR (CHCl3): 1742, 1622 cm−1. 1H NMR (500 MHz,
CDCl3) l 3.82 and 3.89 (each 2H, d, J=11.0 Hz,
CH2OCH2Ph×2), 4.59 and 4.62 (each 2H, d, J=12.0
Hz, CH2Ph×2), 5.34 (1H, d, J=6.0 Hz, C5-H), 7.10
(1H, d, J=6.0 Hz, C6-H), 7.29–7.35 (10H, m, Ph×2).
13C NMR (125.65 MHz, CDCl3) l 68.3, 73.9, 97.5,
106.5, 127.7, 127.9, 128.4, 137.2, 157.6, 158.5.
4.2.11.
2,2-Bis[(benzyloxy)methyl]-6-phenyl-4H-1,3-
dioxin-4-one, 9c. (a) Compound 6c (5.0 g, 20.1 mmol)
was added to a refluxing solution of 3 (10.9 g, 40.3
mmol) in toluene (400 mL) over a 0.5 h period. The
solution was heated under reflux for an additional 45
min and then the solvent was evaporated in vacuo. The
residue was chromatographed on a silica gel column.
Elution with hexane–ethyl acetate (10:1) gave a mixture
of 9c and 3. Fractional recrystallization from ether–
hexane gave 3 (2.35 g) and 9c (6.00 g, 72%, colorless
needles, mp 66–67°C). (b) A solution of 2,2-dimethyl-6-
phenyl-1,3-dioxin-4-one (5c, 408 mg, 2.0 mmol) and 3
(540 mg, 2.0 mmol) in toluene (10 mL) was heated
under reflux for 1.5 h and then the solvent was evapo-
4.2.8. 2,2-Bis({[tert-butyl(dimethyl)silyl]oxy}methyl)-4H-
1,3-dioxin-4-one, 10b. (a) Compound 6b (10.0 g, 58.1
mmol) was added to a refluxing solution of 4 (18.5 g,
58.1 mmol) in toluene (400 mL) over a 0.5 h period.
The solution was heated under reflux for an additional
2.5 h and then the solvent was evaporated in vacuo.
The residue was chromatographed on a silica gel
column. Elution with hexane–ether (40:1) gave 10b
(10.98 g, 49%) as a colorless oil. (b) A solution of 5b
(256 mg, 2.0 mmol) and 4 (624 mg, 2.0 mmol) in
toluene (60 mL) was heated under reflux for 1 h and

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
209
rated in vacuo. The residue was chromatographed on a
silica gel column. Elution with benzene gave 9c (585
mg, 70%) as colorless needles having a mp of 66–67°C
(recrystallized from hexane–ether). Anal. calcd for
C26H24O5: C, 74.98; H, 5.81. Found: C, 75.02; H,
5.80%. MS m/z: 417 (MH+). IR (CHCl3): 1726, 1622
CHCl3). HRMS m/z calcd for C9H12O6 (M+): 216.0634.
Found: 216.0634. IR (CHCl3): 3420 (br), 1748, 1645
cm−1. 1H NMR (500 MHz, CDCl3) l 2.03 (3H, d,
J=1.0 Hz, C6-CH3), 2.12 (3H, s, Ac), 3.21 (1H, brs,
OH), 3.90 (2H, s, HOCH2), 4.31 and 4.68 (each 1H, d,
J=12.0 Hz, AcOCH2), 5.27 (1H, d, J=1.0 Hz, C5-H).
13C NMR (125.65 MHz, CDCl3) l 19.8, 20.7, 60.2,
62.2, 94.1, 104.9, 159.4, 169.3, 170.4.
1
cm−1. H NMR (500 MHz, CDCl3) l 3.91 and 4.02
(each 2H, d, J=11.0 Hz, CH2OCH2Ph×2), 4.60 and
4.65 (each 2H, d, J=12.0 Hz, CH2Ph×2), 5.83 (1H, s,
C5-H), 7.27–771 (15H, m, Ph×3). 13C NMR (125.65
MHz, CDCl3) l 68.1, 73.8, 91.5, 106.0, 126.6, 127.6,
127.8, 128.4, 128.8, 130.6, 132.3, 137.4, 160.4, 164.9.
4.3.2. (R)-[2-(Hydroxymethyl)-6-methyl-4-oxo-4H-1,3-
dioxin-2-yl]methyl acetate, (R)-13a. To a solution of 11a
(1.0 g, 5.74 mmol) in acetone (25 mL) was added vinyl
acetate (100 mL) and Lipase AY (2.0 g) and the whole
was stirred at room temperature for 22 h. The mixture
was filtered through Celite and the filtrate was evapo-
rated in vacuo. The residue was purified by MPLC with
hexane–ethyl acetate (2:1) (the column temperature was
kept at −15 to −20°C) to give first 7a (423 mg, 29%)
and then (R)-13a (839 mg, 98% e.e., 68%, [h]2D5=+20.2
(c 1.14, CHCl3)) as colorless oils, respectively.
4.2.12. 2,2-Bis({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-
phenyl-4H-1,3-dioxin-4-one, 10c. Compound 6c (8.0 g,
32.2 mmol) was added to a refluxing solution of 4
(20.54 g, 64.5 mmol) in toluene (400 mL) over a 0.5 h
period. The solution was heated under reflux for an
additional hour and then the solvent was evaporated in
vacuo. The residue was chromatographed on a silica gel
column. Elution with hexane–ethyl acetate (50:1) gave 4
(10.53 g) and then 10c (9.66 g, 65%) as colorless needles
having a mp of 44–46°C (recrystallized from methanol–
water). Anal. calcd for C24H40O5Si2: C, 62.03; H, 8.68.
Found: C, 61.77; H, 8.64%. HRMS calcd for
C24H40NaO5Si (MNa+): 487.2312. Found: 487.2318.
4.3.3. (S)-[2-(Hydroxymethyl)-4-oxo-4H-1,3-dioxin-2-
yl]-methyl acetate, (S)-13b. To a solution of 11b (300
mg, 1.87 mmol) in acetonitrile (30 mL) was added vinyl
acetate (120 mL) and Toyocheme LIP (600 mg) and the
whole was stirred at room temperature for 22 h. The
mixture was filtered through Celite and the filtrate was
evaporated in vacuo. The residue was purified by
MPLC with hexane–ethyl acetate (3:2) (the column
temperature was kept at −15 to −20°C) to give first 7b
(71 mg, 16%) and then (S)-13b (191 mg, 98% e.e., 50%)
as colorless oils, respectively. [h]2D6=+15.5 (c 1.07,
CHCl3). HRMS calcd for C8H10O6 (M+): 202.0477.
Found: 202.0492. IR (CHCl3): 3484 (br), 1748, 1622
1
MS m/z: 403 (MH+). IR (CHCl3): 1721, 1622 cm−1. H
NMR (500 MHz, CDCl3) l 0.00 and 0.02 (each 6H, s,
SiCH3×4), 0.84 (18H, s, tert-Bu×2), 3.93 and 4.03 (2H,
d, J=11.0 Hz, OCH2×2), 5.78 (1H, s, C5-H), 7.37–7.67
(5H, m, Ph). 13C NMR (125.65 MHz, CDCl3) l −5.6,
−5.5, 18.1, 25.7, 61.4, 91.3, 106.7, 126.5, 128.7, 130.8,
132.1, 160.7, 164.8.
1
4.2.13. 2,2-Bis(hydroxymethyl)-6-phenyl-4H-1,3-dioxin-
4-one, 11c. A solution of 10c (715 mg, 1.5 mmol) and
trifluoroacetic acid (0.6 mL) in methanol (15 mL) was
stirred at room temperature for 40 h and then the
solvent was evaporated in vacuo. Recrystallization
from ethanol–pentane gave 11c (330 mg, 93%) as color-
less needles having a mp of 116–117°C. HRMS calcd
for C12H12O5 (M+): 236.0684. Found: 236.0712. IR
cm−1. H NMR (500 MHz, CDCl3) l 2.13 (3H, s, Ac),
2.83 (1H, brs, OH), 3.90 and 3.94 (each 1H, d, J=12.5
Hz, CH2OH), 4.40 and 4.64 (each 1H, d, J=12.5 Hz,
CH2OAc), 5.45 (1H, d, J=6.0 Hz, C5-H), 7.17 (1H, d,
J=6.0 Hz, C6-H). 13C NMR (125.65 MHz, CDCl3) l
20.6, 60.2, 62.1, 97.6, 105.4, 157.8, 158.1, 170.3.
4.3.4. (R)-[2-(Hydroxymethyl)-4-oxo-4H-1,3-dioxin-2-
yl]methyl acetate, (R)-13b. To a solution of 11b (100
mg, 0.62 mmol) in vinyl acetate (50 mL) was added
lipase AY (300 mg) and the whole was stirred at room
temperature for 20 days. The mixture was filtered
through Celite and the filtrate was evaporated in vacuo.
The residue was purified by MPLC with hexane–ethyl
acetate (3:2) (the column temperature was kept at −15
to −20°C) to give first 7b (42 mg, 28%) and then
(R)-13b (28 mg, 67% e.e., 22%, [h]2D6=−4.1 (c 0.98,
CHCl3)) as colorless oils, respectively.
1
(CHCl3): 3385 (br), 1725, 1622 cm−1. H NMR (500
MHz, CDCl3) l 1.90 (2H, brs, OH×2), 4.08 and 4.14
(each 2H, d, J=12.5 Hz, OCH2×2), 5.88 (1H, s, C5-H),
7.45–7.74 (5H, m, Ph). 13C NMR (125.65 MHz, CDCl3)
l 61.8, 91.2, 106.2, 126.5, 129.0, 130.3, 132.6, 160.4,
165.4.
4.3. Desymmetrization of prochiral dioxinones
4.3.1. (S)-[2-(Hydroxymethyl)-6-methyl-4-oxo-4H-1,3-
dioxin-2-yl]methyl acetate, (S)-13a. To a solution of 11a
(400 mg, 2.30 mmol) in acetonitrile (10 mL) was added
vinyl acetate (40 mL) and Toyocheme LIP (200 mg)
and the whole was stirred at room temperature for 9 h.
The mixture was filtered through Celite and the filtrate
was evaporated in vacuo. The residue was purified by
MPLC with hexane–ethyl acetate (2:1) (the column
temperature was kept at −15 to −20°C) to give first 7a
(160 mg, 27%) and then (S)-13a (349 mg, 94% e.e.,
70%) as colorless oils, respectively. [h]2D7=−19.7 (c 1.06,
4.3.5. (R)-[2-(Hydroxymethyl)-4-oxo-6-phenyl-4H-1,3-
dioxin-2-yl]methyl acetate, (R)-13c. To a solution of 11c
(400 mg, 1.69 mmol) in acetonitrile (10 mL) was added
vinyl acetate (40 mL) and Toyocheme LIP (300 mg)
and the whole was stirred at room temperature for 3 h.
The mixture was filtered through Celite and the filtrate
was evaporated in vacuo. The residue was purified by
MPLC with hexane–ethyl acetate (3:1) (the column
temperature was kept at −15 to −20°C) to give first 7c

210
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
(144 mg, 27%) as colorless needles having mp of 76–
77°C (recrystallized from hexane–ether) and then (R)-
13c (330 mg, 83% e.e., 70%) as crystals.
Recrystallization from hexane–ether gave a sample with
97% e.e. (228 mg, 48%) as colorless needles having a
mp of 99–100°C. [h]D25=+51.9 (c 1.07, CHCl3). Anal.
calcd for C14H14O6: C, 60.43; H, 5.07. Found: C, 60.43;
H, 5.13%. MS m/z: 279 (MH+). IR (CHCl3): 3420 (br),
of 51–52°C (recrystallized from pentane–ether). HRMS
calcd for C7H10O4 (M+): 158.0579. Found: 158.0598.
MS m/z: 159 (M++1), 158 (M+). IR (CHCl3): 3435 (br),
1
1725, 1642 cm−1. H NMR (500 MHz, CDCl3) l 1.70
(3H, s, C2-CH3), 2.07 (3H, s, C6-CH3), 3.86 (1H, br s,
OH), 3.81 and 3.87 (each 1H, d, J=12.5 Hz, CH2O),
5.28 (1H, s, C5-H). 13C NMR (125.65 MHz, CDCl3) l
19.7, 19.8, 64.7, 93.3, 106.7, 160.9, 169.3.
1
1732, 1622 cm−1. H NMR (500 MHz, CDCl3) l 2.13
(3H, s, Ac), 2.46 (1H, brs, OH), 4.00 and 4.05 (1H, d,
J=12.5 Hz, HOCH2), 4.52 and 4.70 (1H, d, J=12.5
Hz, AcOCH2), 7.46–7.70 (5H, m, Ph). 13C NMR
(125.65 MHz, CDCl3) l 20.6, 60.3, 62.2, 91.4, 104.9,
126.5, 129.0, 130.2, 132.7, 159.7, 165.1, 170.4.
4.4.3. Kinetic resolution of 16a and conversion of (+)-16a
to a mixture of (R)- and (S)-18a. To a solution of 16a
(370 mg, 2.34 mmol) in vinyl acetate (50 mL) was
added Lipase MY (740 mg) and the mixture was
shaken for 2 weeks at 27°C. The mixture was filtered
through Celite and the filtrate was evaporated under
reduced pressure. The residue was purified by MPLC
with hexane–ethyl acetate (2:1) (the column tempera-
ture was kept under −19°C) to give first (R)-(−)-17a
(257 mg, 55%, [h]2D7=−1.52 (c 1.02, CHCl3)) as a color-
less oil and then (S)-(+)-16a (157mg, 42%, [h]2D7=+16.9
(c 1.13, CHCl3)) as crystals. To a solution of (S)-(+)-
16a (144 mg) in acetone (4 mL) was added 2.67 M
Jones reagent (1.2 mL) with ice-cooling and the mixture
was stirred for 24 h at room temperature. After another
addition of 2.67 M Jones reagent (0.6 mL) with ice-
cooling, the whole was stirred for 4 h at room tempera-
ture. 2-Propanol was added and the mixture was
evaporated under reduced pressure. The residue was
diluted with water and extracted with ether. The water
layer was saturated with NaCl and then extracted with
ether. The organic layer was combined, dried over
MgSO4, and evaporated to leave crude carboxylic acid
as crystals. N,N%-Dicyclohexylcarbodiimide (DCC, 225
mg, 1.1 mmol) and 4-dimethylaminopyridine (DMAP,
20 mg, 0.28 mmol) were added to a solution of the acid
and l-menthol (170 mg, 1.1 mmol) in dichloromethane
(5 mL), and the whole was stirred for 17 h at room
temperature. The mixture was passed through a short
column of silica gel and eluted with ether. The solvent
was evaporated and the residue was purified by PTLC
with dichloromethane to give a 5:1 mixture of (S)- and
(R)-18a (137 mg, 49%)4 as colorless crystals.
4.3.6. (S)-[2-(Hydroxymethyl)-4-oxo-6-phenyl-4H-1,3-
dioxin-2-yl]methyl acetate, (S)-13c. To a solution of 11c
(400 mg, 1.69 mmol) in 1,4-dioxane (10 mL) was added
vinyl acetate (40 mL) and Lipase AH (400 mg) and the
whole was stirred at room temperature for 11 h. The
mixture was filtered through Celite and the filtrate was
evaporated in vacuo. The residue was purified by
MPLC with hexane–ethyl acetate (3:1) (the column
temperature was kept at −15 to −20°C) to give first 7c
(187 mg, 34%) as colorless needles having a mp of
76–77°C (recrystallized from hexane–ether) and then
(S)-13c (310 mg, 87% e.e., 66%) as crystals. Recrystal-
lization from hexane–ether gave 98% e.e. sample (216
mg, 46%, [h]2D6=−53.6 (c 0.94, CHCl3)) as colorless
needles having a mp of 99–100°C.
4.4. Determination of absolute configuration at the 2-
position
4.4.1.
2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,6-
dimethyl-4H-1,3-dioxin-4-one, 15a. A solution of 5a
(1.70 g, 12.0 mmol) and 1-tert-butyldimethylsilanyloxy-
2-propanone (14, 2.0 g, 10 mmol) in toluene (40 mL)
was heated under reflux for 1.5 h and then the solvent
was evaporated in vacuo. The residue was chro-
matographed on a silica gel column. Elution with hex-
ane–ethyl acetate (20:1) gave 14 (0.75 g) and then 15a
(2.21 g, 86%) as colorless oils, respectively. Anal. calcd
for C13H22O4Si: C, 57.74; H, 8.02. Found: C, 57.79; H,
8.25%. MS m/z: 173 (M+−tert-Bu). IR (CHCl3): 1726,
4.4.4.
(S)-(2,6-Dimethyl-4-oxo-4H-1,3-dioxin-2-yl)-
methyl acetate, (S)-(+)-17a, from (S)-(−)-13a. To a solu-
tion of (S)-(−)-13a (100 mg, 0.46 mmol, 94% e.e.) in
DMF (4 mL) was added methyltriphenoxyphospho-
nium iodide (418 mg, 0.92 mmol). The mixture was
stirred at room temperature for 1 h and then at 60°C
for an additional hour. After addition of water (10
mL), the product was extracted with benzene (25 mL)
and the organic layer was washed with saturated
aqueous Na2S2O3 (10 mL), water (10 mL) and dried
over MgSO4. The residue obtained after evaporation in
vacuo was purified by PTLC with hexane–ethyl acetate
(2:1) to give iodide 19a. Compound 19a was hydro-
genated with 5%Pd–C (60 mg) and triethylamine (97
mL, 0.70 mmol) in methanol (8 mL) under 1 atm at
room temperature for 2 h. After removal of the cata-
lyst, the solvent was evaporated in vacuo. The residue
obtained was chromatographed on a silica gel column.
Elution with hexane–ether (2:1) gave (S)-(+)-17a (80
mg, 86%) as a colorless oil. [h]2D7=+2.5 (c 1.27, CHCl3).
1
1642 cm−1. H NMR (500 MHz, CDCl3) l 0.00 and
0.01 (each 3H, s, Si(CH3)2), 0.83 (9H, s, tert-Bu), 1.57
(3H, s, C2-CH3), 1.92 (3H, d, J=1.0 Hz, C6-CH3), 3.63
and 3.86 (each 1H, d, J=11.0 Hz, OCH2×2), 5.13 (1H,
d, J=1.0 Hz, C5-H). 13C NMR (125.65 MHz, CDCl3) l
−5.6, 18.0, 19.7, 20.7, 25.6, 65.3, 93.6, 106.7, 160.4,
168.5.
4.4.2. 2-(Hydroxymethyl)-2,6-dimethyl-4H-1,3-dioxin-4-
one, 16a. A solution of 15a (2.72 g, 10.0 mmol) in
trifluoroacetic acid:water:THF (1:10:10, 10 mL) was
stirred for 3 h at room temperature. The reaction
mixture was extracted with dichloromethane. The
organic layer was washed with brine, dried over
MgSO4, and then the solvent was evaporated in vacuo.
The residue was purified by MPLC with hexane–ethyl
acetate (1:1) (the column temperature was kept at
−30°C) to give 16a (0.88 g, 56%) as prisms having a mp

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
211
HRMS calcd for C9H12O5 (M+): 200.0685. Found:
extracted with ether and ethyl acetate, successively. The
organic layers were combined, dried over MgSO4, and
evaporated to give a residue. DCC (429 mg, 2.1 mmol)
and DMAP (20 mg, 0.28 mmol) was added to a solu-
tion of the residue and l-menthol (244 mg, 1.6 mmol) in
dichloromethane (5 mL), and the whole was stirred for
6 h at room temperature. The mixture was passed
through a short column of silica gel and eluted with
ether. After evaporation of the solvent, the residue was
chromatographed on a silica gel column. Elution with
hexane–ethyl acetate (20:1) roughly gave a 9:1 mixture
of (R)- and (S)-18b (81 mg, 10%)4 as colorless crystals.
1
200.0677. IR (CHCl3): 1740, 1644 cm−1. H NMR (500
MHz, CDCl3) l 1.70 (3H, s, C2-CH3), 2.00 (3H, d,
J=1.0 Hz, C6-CH3), 2.12 (3H, s, Ac), 4.18 and 4.55
(1H, d, J=12.0 Hz, CH2O), 5.27 (1H, d, J=1.0 Hz,
C5-H). 13C NMR (125.65 MHz, CDCl3) l 19.9, 20.7,
21.7, 63.9, 94.1, 104.8, 159.8, 168.8, 170.1.
4.4.5.
2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-
methyl-4H-1,3-dioxin-4-one, 15b. Compound 5b (2.85 g,
16.6 mmol) was added to a refluxing solution of 14
(3.12 g, 16.6 mmol) in toluene (120 mL) over a 0.5 h
period. The solution was heated under reflux for an
additional hour and then evaporated in vacuo. The
residue was chromatographed on a silica gel column.
Elution with hexane–ethyl acetate (50:1) gave 14 (1.08
g, 35%) and 15b (2.49 g, 58%) as colorless oils, respec-
tively. HRMS calcd for C12H22NaO4Si (MNa+):
281.1185. Found: 281.1191. MS m/z: 259 (MH+). IR
(CHCl3): 1738, 1620 cm−1. 1H NMR (500 MHz, CDCl3)
l 0.00 and 0.01 (each 3H, s, SiCH3×2), 0.82 (9H, s,
tert-Bu), 1.59 (3H, s, C2-CH3), 3.65 and 3.88 (1H, d,
J=11.5 Hz), 5.28 (1H, d, J=6.0 Hz, C5-H), 7.05 (1H,
d, J=6.0 Hz, C6-H). 13C NMR (125.65 MHz, CDCl3) l
−5.6, 18.1, 20.7, 25.6, 65.4, 97.1, 107.5, 157.7, 159.5.
4.4.8.
(S)-(+)-(2-Methyl-4-oxo-4H-1,3-dioxin-2-
yl)methyl acetate, (S)-(+)-17b, from (S)-(−)-13b. To a
solution of (S)-(−)-13b (140 mg, 0.69 mmol, 98% e.e.)
in DMF (5 mL) was added methyltriphenoxyphospho-
nium iodide (626 mg, 1.39 mmol). The mixture was
stirred at room temperature for 1 h and then at 60°C
for 3 h. After addition of water (10 mL), the product
was extracted with benzene (25 mL) and the organic
layer was washed with saturated aqueous Na2S2O3 (10
mL) and water (10 mL) and dried over MgSO4. The
residue obtained after evaporation in vacuo was
purified by PTLC with hexane–ethyl acetate (2:1) to
give 19b. Compound 19b was hydrogenated with 5%
Pd–C (60 mg) and triethylamine (145 mL, 1.04 mmol) in
methanol (8 mL) under 1 atm at room temperature for
3 h. After removal of the catalyst, the solvent was
evaporated in vacuo. The residue was chromatographed
on a silica gel column. Elution with hexane–ether (2:1)
gave (S)-(+)-17b (94 mg, 73%) as a colorless oil. [h]2D5=
+41.7 (c 1.00, CHCl3). HRMS calcd for C8H10O5Na
(MNa+): 209.0426. Found: 200.0432. MS m/z: 187
4.4.6. 2-Hydroxymethyl-2-methyl-4H-1,3-dioxin-4-one,
16b. A solution of 15b (1.45 g, 5.61 mmol) and triflu-
oroacetic acid (2.05 mL, 26.6 mmol) in methanol (14.5
mL) was stirred at room temperature for 23 h and then
the solvent was evaporated in vacuo. Recrystallization
of the residue from ether gave 16b (0.43 g, 53%) as
colorless prisms having a mp of 53–55°C. The mother
liquid was concentrated in vacuo. The residue was
purified by MPLC with hexane–ethyl acetate (1:1) (the
column temperature was kept at −18°C) to give addi-
tional 16b (0.27 g, 33%). Anal. calcd for C6H8O4: C,
50.00; H, 5.59. Found: C, 49.93; H, 5.58%. MS m/z:
1
(MH+). IR (CHCl3): 1746, 1620 cm−1. H NMR (500
MHz, CDCl3) l 1.74 (3H, s, C2-CH3), 2.13 (3H, s, Ac),
4.27 and 4.49 (each 1H, d, J=12.0 Hz, CH2O), 5.45
(1H, d, J=5.5 Hz, C5-H), 7.16 (1H, d, J=5.5 Hz,
C6-H). 13C NMR (125.65 MHz, CDCl3) l 20.4, 21.2,
63.9, 97.4, 105.3, 157.6, 158.6, 169.8.
1
145 (MH+). IR (CHCl3): 3445 (br), 1738, 1620 cm−1. H
NMR (500 MHz, CDCl3) l 1.70 (3H, s, CH3), 3.06
(1H, br s, OH), 3.80 and 3.86 (1H, d, J=12.5 Hz,
CH2O), 5.41 (1H, d, J=6.0 Hz, C5-H), 7.19 (1H, d,
J=6.0 Hz, C6-H). 13C NMR (125.65 MHz, CDCl3) l
20.0, 65.2, 97.3, 107.6, 158.3, 159.9.
4.4.9.
(S)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-
oxo-6-phenyl-4H-1,3-dioxin-2-yl-methyl acetate, 20. To
a solution of (R)-(+)-13c (210 mg, 0.75 mmol) in DMF
(5 mL) were added imidazole (206 mg, 3.03 mmol) and
tert-butylchlorodimethylsilane (228 mg, 1.51 mmol)
with ice-cooling and the mixture was stirred at room
temperature for 20 h. The reaction mixture was diluted
with ether (50 mL), washed with water (20 mL×2) and
then with brine (20 mL). The organic layer was dried
over MgSO4 and the solvent was evaporated. The
residue was chromatographed on a silica gel column
(hexane–ethyl acetate, 10:1) to give 20 (297 mg, 100%)
as a colorless oil. [h]2D5=−7.4 (c 1.12, CHCl3). HRMS
calcd for C20H28NaO6Si (MNa+): 415.1553. Found:
415.1552. MS m/z: 393 (MH+). IR (CHCl3): 1732, 1622
4.4.7. Kinetic resolution of 16b and conversion of (R)-16b
to the mixture of (R)- and (S)-18b. To a solution of 16b
(400 mg, 2.78 mmol) in acetonitrile (40 mL) and vinyl
acetate (160 mL) was added Toyocheme LIP (800 mg)
and the mixture was shaken for 0.5 h at 25°C. The
mixture was filtered through Celite and the filtrate was
evaporated in vacuo. The residue was purified by
MPLC with hexane–ethyl acetate (3:2) (the column
temperature was kept at −18°C) to give first (S)-(+)-17b
(282 mg, 55%, [h]2D4=+18.6 (c 1.05, CHCl3)) as a color-
less oil and then crude (R)-16b (153 mg) as an oil. To
a solution of the crude (R)-16b (153 mg) in acetone (4
mL) was added 2.67 M Jones reagent (2.0 mL) with
ice-cooling and the mixture was stirred for 10 h at room
temperature. 2-Propanol (2.0 mL) was added and the
whole was evaporated under reduced pressure. The
residue was diluted with water and extracted with ether.
The water layer was saturated with NaCl and then
1
cm−1. H NMR (500 MHz, CDCl3) l 0.04 and 0.07
(each 3H, s, Si(CH3)2), 0.90 (9H, s, tert-Bu), 2.11 (3H,
s, Ac), 3.94 and 4.14 (1H, d, J=11.0 Hz, CH2OSi), 4.55
and 4.61 (1H, d, J=11.5 Hz, CH2OAc), 5.89 (1H, s,
C5-H), 7.44–7.72 (5H, m, Ph). 13C NMR (125.65 MHz,
CDCl3) l −5.6, 18.1, 20.9, 25.7, 61.5, 61.8, 91.4, 105.2,
126.5, 128.9, 130.4, 132.5, 160.0, 164.8, 170.1.

212
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
4.4.10. Methyl (R)-3-hydroxy-3-phenylpropanoate, (R)-
22. Compound 20 (290 mg, 0.74 mmol) was hydro-
genated in ethyl acetate (30 mL) with 20% Pd(OH)2/C
(30 mg) for 17 h. Removal of the catalyst and the
solvent left a 2:1 mixture of cis- and trans-21 as crys-
tals. 1H NMR (500 MHz, CDCl3) l 0.09 and 0.11 (each
3H, s, cis- and trans-21-SiMe×2), 0.91 (9H, s, cis- and
trans-21-tert-Bu), 2.08 (3H, s, cis-21-Ac), 2.12 (3H, s,
trans-21-Ac), 2.68 (1H, dd, J=17.5, 11.0 Hz, trans-21-
C5-axial H), 2.77 (1H, dd, J=17.5, 11.5 Hz, cis-21-C5-
axial H), 2.85 (1H, dd, J=17.5, 3.5 Hz, cis- and
trans-21-C5-equatorial H), 3.80 and 3.84 (each 1H, d,
J=11.5 Hz, cis-21-CH2OSi), 3.95 and 3.98 (each 1H, d,
J=11.0 Hz, trans-21-CH2OSi), 4.24 and 4.37 (each 1H,
d, J=12.0 Hz, trans-21-CH2OAc), 4.26 and 4.64 (each
1H, d, J=12.0 Hz, cis-21-CH2OAc), 5.24 (1H, dd,
J=11.5, 3.5 Hz, cis-21-C6-H), 5.53 (1H, dd, J=11.0,
3.5 Hz, trans-21-C6-H), 7.44–7.72 (5H, m, cis- and
trans-21-Ph). To a solution of the mixture of cis- and
trans-21 in methanol (5 mL) was added aqueous (1 mL)
KOH (159 mg) and the whole was heated under reflux
for 5 min. After evaporation of methanol, the residue
was acidified with 10% HCl (4 mL) and extracted with
ether (10 mL×2). The organic layer was dried over
MgSO4, and treated with ethereal diazomethane. The
oily product obtained after evaporation of the solvent
was purified by PTLC (CHCl3) to give (R)-22 (105 mg,
79%) as a colorless oil. [h]2D5=+6.4 (c 1.01, ethanol)
[lit.19 R: [h]2D4=+18.3 (c 4.78, ethanol)].
eluted with ether and then evaporated. Purification of
the residue by PTLC with hexane–ethyl acetate (2:1)
gave 29 (136 mg, 98%) as a colorless oil. [h]2D6=+1.6 (c
1.02, CHCl3). HRMS calcd for C14H19O7 (MH+):
299.1131. Found: 299.1120. MS m/z: 299 (MH+), 298
(M+). IR (CHCl3): 1748, 1647 cm−1. 1H NMR (500
MHz, CDCl3) l 2.00 (3H, d, J=1.0 Hz, C6-CH3), 2.12
(3H, s, Ac), 2.39 and 2.49 (each 2H, m, CH2CH2), 4.31
and 4.34 (each 1H, d, J=4.5 Hz, CH2O), 4.57 and 4.63
(each 1H, d, J=12.0 Hz, CH2O), 5.01–5.10 (2H, m,
-CHꢁCH2), 5.30 (1H, d, J=1.0 Hz, C5-H), 5.82 (1H, m,
-CH=CH2). 13C NMR (125.65 MHz, CDCl3) l 19.8,
20.6, 28.6, 33.1, 60.9, 61.3, 94.4, 103.3, 115.9, 136.2,
158.4, 168.7, 169.9, 172.0.
4.5.3.
(S)-{2-[(Acetyloxy)methyl]-6-methyl-4-oxo-4H-
1,3-dioxin-2-yl}methyl hex-5-enoate, 30. DCC (115 mg,
0.56 mmol) and DMAP (10 mg, 0.08 mmol) were added
to a solution of (R)-13a (100 mg, 0.46 mmol) and
5-hexenoic acid (25, 63 mg, 0.55 mmol) in
dichloromethane (3 mL) at ice-cooling temperature and
the mixture was stirred for 4 h with ice-cooling. The
whole was passed through a short column of silica gel
eluted with ether and then evaporated. Purification of
the residue by PTLC with hexane–ethyl acetate (2:1)
gave 30 (133 mg, 92%) as a colorless oil. [h]2D7=+3.9 (c
1.00, CHCl3). HRMS calcd for C15H20O7 (M+):
312.1208. Found: 312.1195. IR (CHCl3): 1748, 1647
cm−1. 1H NMR (500 MHz, CDCl3) l 1.74 (2H, m,
OꢁCCH2CH2CH2), 2.00 (3H, d, J=1.0 Hz, C6-CH3),
2.10 (2H, m, OꢁCCH2CH2CH2), 2.12 (3H, s, Ac), 2.39
(2H, m, OꢁCCH2CH2CH2), 4.31 and 4.34 (each 1H, d,
J=3.0 Hz, CH2O), 4.56 and 4.62 (each 1H, d, J=12.5
Hz, CH2O), 4.98–5.06 (2H, m, -CHꢁCH2), 5.30 (1H, d,
J=1.0 Hz, C5-H), 5.77 (1H, m, -CHꢁCH2). 13C NMR
(125.65 MHz, CDCl3) l 19.8, 20.6, 23.9, 32.9, 33.1,
60.9, 61.3, 94.4, 103.3, 115.6, 137.4, 158.4, 168.7, 169.9,
172.5.
4.5. Intramolecular photo[2+2]cycloaddition
4.5.1.
(S)-{2-[(Acetyloxy)methyl]-6-methyl-4-oxo-4H-
1,3-dioxin-2-yl}methyl but-3-enoate, 28. DCC (115 mg,
0.56 mmol) and DMAP (10 mg, 0.08 mmol) were added
to a solution of (R)-13a (100 mg, 0.46 mmol) and
3-butenoic acid (23, 48 mg, 0.56 mmol) in
dichloromethane (3 mL) at ice-cooling temperature and
the mixture was stirred for 4 h with ice-cooling. The
whole was passed through a short column of silica gel
eluted with ether and then evaporated. Purification of
the residue by PTLC with hexane–ethyl acetate (2:1)
gave 28 (123 mg, 94%) as a colorless oil. [h]2D6=+5.8 (c
1.00, CHCl3). HRMS calcd for C13H17O7 (MH+):
285.0973. Found: 285.0991. IR (CHCl3): 1750, 1647
cm−1. 1H NMR (500 MHz, CDCl3) l 2.00 (3H, d,
J=1.0 Hz, C6-CH3), 2.12 (3H, s, Ac), 3.16 (2H, m,
CH2CO), 4.32 and 4.35 (each 1H, d, J=6.0 Hz, CH2O),
4.57 and 4.64 (each 1H, d, J=12.0 Hz, CH2O), 5.10–
5.20 (1H, m, -CHꢁCH2(trans)), 5.21–5.23 (1H, m,
-CHꢁCH2(cis)), 5.30 (1H, d, J=1.0 Hz, C5-H), 5.86–
5.95 (1H, m, -CHꢁCH2). 13C NMR (125.65 MHz,
CDCl3) l 19.8, 20.6, 38.6, 61.2, 94.4, 103.2, 119.3,
129.3, 158.3, 168.7, 169.9, 170.5.
4.5.4.
(S)-{2-[(Acetyloxy)methyl]-6-methyl-4-oxo-4H-
1,3-dioxin-2-yl}methyl hept-6-enoate, 31. DCC (115 mg,
0.56 mmol) and DMAP (10 mg, 0.08 mmol) were added
to a solution of (R)-13a (100 mg, 0.46 mmol) and
6-heptenoic acid (26, 71 mg, 0.55 mmol) in
dichloromethane (3 mL) at ice-cooling temperature and
the whole was stirred for 4 h with ice-cooling. The
whole was passed through a short column of silica gel
eluted with ether and then evaporated. Purification of
the residue by PTLC with hexane–ethyl acetate (2:1)
gave 31 (143 mg, 95%) as a colorless oil. [h]2D5=+3.5 (c
1.24, CHCl3). HRMS calcd for C16H22O7 (M+):
326.1364. Found: 326.1352. IR (CHCl3): 1748, 1647
1
cm−1. H NMR (500 MHz, CDCl3) l 1.43 and 1.65
(each 2H, m, OꢁCCH2CH2CH2CH2), 2.00 (3H, d, J=
1.0 Hz, C6-CH3), 2.07 (2H, m, OꢁCCH2CH2CH2CH2),
2.12 (3H, s, Ac), 2.38 (2H, m, OꢁCCH2CH2CH2CH2),
4.31 and 4.34 (each 1H, d, J=5.5 Hz, CH2O), 4.57and
4.62 (each 1H, d, J=12.0 Hz, CH2O), 4.94–5.03 (2H,
m, -CHꢁCH2), 5.30 (1H, d, J=1.0 Hz, C5-H), 5.78 (1H,
m, -CHꢁCH2). 13C NMR (125.65 MHz, CDCl3) l 19.8,
20.6, 24.2, 28.2, 33.3, 33.7, 60.9, 61.3, 94.4, 103.3, 114.8,
138.2, 158.4, 168.7, 169.9, 172.6.
4.5.2.
(S)-{2-[(Acetyloxy)methyl]-6-methyl-4-oxo-4H-
1,3-dioxin-2-yl}methyl pent-4-enoate, 29. DCC (115 mg,
0.56 mmol) and DMAP (10 mg, 0.08 mmol) were added
to a solution of (R)-13a (100 mg, 0.46 mmol) and
4-pentenoic acid (56 mg, 0.56 mmol) in
dichloromethane (3 mL) at ice-cooling temperature and
the mixture was stirred for 3 h with ice-cooling. The
whole was passed through a short column of silica gel

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
213
4.5.5.
(S)-{2-[(Acetyloxy)methyl]-6-methyl-4-oxo-4H-
C13-CH3), 1.79 (1H, dt, J=12.0, 2.5 Hz, C8-H), 1.90
(1H, dd, J=9.5, 2.0 Hz, C6-H), 2.09 (3H, s, Ac),
2.25–2.33 (3H, m, C5-H, C6-H, and C7-H), 2.38 (1H,
ddd, J=12.0, 10.0, 7.5 Hz, C8-H), 2.69 (1H, dt, J=
14.0, 7.5 Hz, C5-H), 2.85 (1H, dt, J=10.0, 2.5 Hz,
C9-H), 4.05 (2H, d, J=11.0 Hz, CH2O), 4.14 (1H, d,
1,3-dioxin-2-yl}methyl dec-9-enoate, 32. DCC (95 mg,
0.46 mmol) and DMAP (10 mg, 0.08 mmol) were added
to a solution of (R)-13a (83 mg, 0.38 mmol) and
9-decenoic acid (27, 79 mg, 0.46 mmol) in
dichloromethane (2.5 mL) at ice-cooling temperature
and the mixture was stirred for 4 h with ice-cooling.
The whole was passed through a short column of silica
gel eluted with ether and then evaporated. Purification
of the residue by PTLC with hexane–ethyl acetate (2:1)
gave 32 (127 mg, 90%) as a colorless oil. [h]2D7=+1.3 (c
1.39, CHCl3). HRMS calcd for C19H28O7 (M+):
368.1833. Found: 368.1829. IR (CHCl3): 1748, 1647
cm−1. 1H NMR (500 MHz, CDCl3) l 1.27–1.41 and
1.63 (10H, m, OꢁCCH2(CH2)5CH2), 2.00 (3H, d, J=1.0
Hz, C6-CH3), 2.04 (2H, m, OꢁCCH2(CH2)5CH2), 2.12
(3H, s, Ac), 2.37 (2H, m, OꢁCCH2(CH2)5CH2), 4.31
and 4.33 (each 1H, d, J=10.5 Hz, CH2O), 4.57 and
4.63 (1H, d, J=12.0 Hz, J=12.0 Hz, CH2O), 4.93 (1H,
m, -CHꢁCH2(trans)), 4.99 (1H, m, -CHꢁCH2(cis)), 5.30
(1H, d, J=1.0 Hz, C5-H), 5.80 (1H, m, -CHꢁCH2). 13C
NMR (125.65 MHz, CDCl3) l 19.8, 20.6, 24.8, 28.8,
28.9, 28.97, 29.04, 33.7, 33.9, 60.8, 61.3, 94.4, 103.3,
114.2, 139.0, 158.4, 168.7, 169.9, 172.8.
J=11.0 Hz, CHO), 4.93 (1H, d, J=11.0 Hz, CHO). 13
C
NMR (125.65 MHz, CDCl3) l 20.6, 26.1, 28.0, 29.1,
35.0, 39.7, 47.0, 65.6, 69.1, 104.4, 169.4, 170.4, 175.1.
34b: [h]2D5=−105.2 (c 0.26, CHCl3). HRMS calcd for
C14H18O7 (M+): 298.1053. Found: 298.1029. IR
1
(CHCl3): 1752 cm−1. H NMR (500 MHz, CDCl3) l
1.29 (3H, s, C13-CH3), 1.65–1.72 (2H, m, C6-H and
C8-H), 1.87 (1H, ddt, J=14.0, 7.0, 9.5 Hz, C6-H), 1.98
(1H, t, J=10.0 Hz, C8-H), 2.07 (3H, s, Ac), 2.40 (1H,
ddd, J=11.5, 7.0, 2.0 Hz, C5-H), 2.46 (1H, dt, J=11.5,
9.5 Hz, C5-H), 2.78 (1H, d, J=7.5 Hz, C9-H), 3.69 (1H,
m, C7-H), 3.97 (1H, d, J=12.0 Hz, CHO), 4.07 (1H, d,
J=11.5 Hz, CHO), 4.11 (1H, d, J=11.5 Hz, CHO),
4.98 (1H, d, J=12.0 Hz, CHO). 13C NMR (125.65
MHz, CDCl3) l 18.8, 20.5, 20.7, 25.8, 33.6, 44.4, 44.5,
65.6, 66.0, 78.6, 104.8, 169.8, 171.1, 172.1.
4.5.8. (1S,8S,10R,14S)-(14-Methyl-4,11-dioxo-3,12,13-
trioxatricyclo[6.4.2.010,14]tetradec-1-yl)methyl
acetate,
4.5.6. (1R,3R,6S,11S)-(11-Methyl-4,9-dioxo-5,8,12-tri-
oxatricyclo[4,4,2,03,11]dodec-6-yl)methyl acetate, 33a. A
solution of 28 (30 mg, 0.11 mmol) in ethyl acetate (70
mL) was irradiated (300 nm) under argon atmosphere
for 6 h. The residue obtained after evaporation of the
solvent was purified by PTLC with hexane–ethyl ace-
tate (2:1) to give a crystalline product. Recrystallization
from hexane–dichloromethane gave 33a (14 mg, 47%)
as colorless needles having a mp of 126–128°C. [h]2D0=
+17.5 (c 1.11, CHCl3). Anal. calcd for C13H16O7: C,
54.93; H, 5.67. Found: C, 54.18; H, 5.60. MS m/z: 285
35a
and
(1S,8R,10R,14S)-(14-methyl-4,11-dioxo-
3,12,13 - trioxatricyclo[6.4.2.010,14]tetradec - 1 - yl)methyl
acetate, 35b. A solution of 30 (104 mg, 0.33 mmol) in
ethyl acetate (310 mL) was irradiated (300 nm) under
an argon atmosphere for 10 h. The residue obtained
after evaporation of the solvent was purified on a
Merck lobar column (hexane–ether (2:1)) to give a less
polar isomer 35b (32 mg, 30%) as colorless prisms
having a mp of 132–133°C (crystallized from hexane–
dichloromethane) and a more polar isomer 35a (46 mg,
44%) as colorless needles having a mp of 111–112°C
(recrystallized from hexane–dichloromethane). 35a:
[h]2D6=+5.3 (c 0.53, CHCl3). Anal. calcd for C15H20O7:
C, 57.68; H, 6.46. Found: C, 57.69; H, 6.40%. HRMS
calcd for C15H20O7 (M+): 312.1208. Found: 312.1180.
(MH+). IR (CHCl3): 1750 cm−1. H NMR (500 MHz,
1
CDCl3) l 1.49 (3H, s, C11-CH3), 2.11 (3H, s, Ac), 2.56
(1H, dd, J=16.0, 2.5 Hz, C5-H), 2.58 (1H, dd, J=12.5,
7.5 Hz, C7-H), 2.64 (1H, dt, J=12.5, 11.0 Hz,C7-H),
2.71 (1H, dd, J=16.0, 7.0 Hz, C5-H), 2.82 (1H, m,
C6-H), 3.13 (1H, dd, J=11.0, 7.5 Hz, C8-H), 4.13 and
4.16 (each 1H, d, J=11.5 Hz, CH2O), 4.23 and 4.97
(each 1H, d, J=12.0 Hz, CH2O). 13C NMR (125.65
MHz, CDCl3) l 20.6, 26.3, 30.5, 33.7, 37.8, 41.9, 66.5,
70.2, 106.0, 167.2, 170.0, 176.1.
1
IR (CHCl3): 1748 cm−1. H NMR (500 MHz, CDCl3) l
1.32 (1H, dt, J=8.0, 13.0 Hz, C6-H), 1.55 (3H, s,
C14-CH3), 1.66–1.73 (1H, m, C7-H), 1.74 (1H, dt, J=
12.5, 2.5 Hz, C9-H), 1.97 (1H, dt, J=6.5, 13.0 Hz,
C7-H), 2.02–2.18 (2H, m, C7-H and C8-H), 2.11 (3H, s,
Ac), 2.26 (1H, dd, J=11.0, 1.5 Hz, C5-H), 2.34 (1H, dd,
J=11.0, 6.5 Hz, C5-H), 2.42 (1H, dt, J=10.0, 12.5 Hz,
C9-H), 2.90 (1H, dt, J=10.0, 2.5 Hz, C10-H), 3.91 (1H,
d, J=12.0 Hz, CHO), 4.06 (1H, d, J=12.0 Hz, CHO),
4.22 (1H, d, J=12.0 Hz, CHO), 5.13 (1H, d, J=12.0
Hz, CHO). 13C NMR (125.65 MHz, CDCl3) l 20.6,
26.07, 26.14, 28.2, 29.2, 35.1, 39.8, 46.8, 64.8, 65.4, 77.2,
103.4, 169.7, 171.2, 176.0. 35b: [h]2D7=−33.2 (c 0.30,
CHCl3). Anal. calcd for C15H20O7: C, 57.68; H, 6.46.
Found: C, 57.69; H, 6.30. HRMS calcd for C15H20O7
(M+): 312.1208. Found: 312.1201. IR (CHCl3): 1750
cm−1. 1H NMR (500 MHz, CDCl3) l 1.36 (3H, s,
C14-CH3), 1.49–1.64 (3H, m, C9-H and C7-H×2), 1.81
(1H, m, C6-H), 1.96 (1H, t, J=9.0 Hz, C9-H), 2.00–2.10
(1H, m, C6-H), 2.07 (3H, s, Ac), 2.29 (1H, dd, J=12.5,
10.5 Hz, C5-H), 2.56 (1H, dd, J=12.5, 10.0 Hz, C5-H),
2.73 (1H, d, J=9.0 Hz, C10-H), 3.45 (1H, m, C8-H),
3.89 (1H, d, J=12.0 Hz, CHO), 4.07 (1H, d, J=12.0
4.5.7.
(1S,7S,9R,13S)-(13-Methyl-4,10-dioxo-3,11,12-
trioxatricyclo[5.4.2.09,13]tridec-1-yl)methyl acetate, 34a
and (1S,7R,9R,13S)-(13-methyl-4,10-dioxo-3,11,12-tri-
oxatricyclo[5.4.2.09,13]tridec-1-yl)methyl acetate, 34b. A
solution of 29 (11 mg, 0.037 mmol) in ethyl acetate (20
mL) was irradiated (300 nm) under argon atmosphere
for 4 h. After evaporation of the solvent, the residue
was purified by PTLC with hexane-ethyl acetate (5:1) to
give 29 (0.6 mg, 5%), a less polar isomer 34b (1.4 mg,
13%) as colorless needles having a mp of 117–119°C
(crystallized from hexane–ether) and a more polar iso-
mer 34a (8.0 mg, 72%) as colorless needles having a mp
of 151–152°C (recrystallized from pentane-ether). 34a:
[h]2D5=−54.4 (c 0.95, CHCl3). HRMS calcd for C14H18O7
(M+): 298.1053. Found: 298.1075. IR (CHCl3): 1752
cm−1. 1H NMR (500 MHz, CDCl3) l 1.52 (3H, s,

214
M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
Hz, CHO), 4.09 (1H, d, J=12.0 Hz, CHO), 5.00 (1H,
d, J=12.0 Hz, CHO). 13C NMR (125.65 MHz, CDCl3)
l 19.4, 20.5, 24.0, 25.9, 29.5, 33.7, 42.8, 43.3, 64.1, 66.3,
78.3, 105.2, 169.5, 171.6, 175.2.
4.54 (1H, d, J=12.0 Hz, CHO). 13C NMR (125.65
MHz, CDCl3) l 20.6, 23.6, 24.9, 27.2, 28.1, 33.1, 34.2,
38.1, 42.8, 64.8, 77.5, 104.3, 166.5, 169.8, 173.1.
4.5.10. (1S, 2S, 3S)-3-{3-[(Acetyloxy)methyl]-2-hydroxy-
2-methylcyclobutyl}propyl acetate, 38. To a suspension
of LiAlH4 (46 mg, 1.3 mmol) in dry THF (2 mL) was
added a solution of 34a (60 mg, 0.2 mmol) in dry THF
(2 mL) dropwise under an argon atmosphere at ice-
cooling temperature. The mixture was stirred for 4 h at
room temperature. After decomposition of excess
LiAlH4 with 50% aqueous NaOH, the precipitate was
removed by filtration through Celite. To the residue
obtained after evaporation of the solvent was added
acetic anhydride (2 mL) and pyridine (0.5 mL). After
stirring for 3 h, the whole was diluted with ether, and
washed with saturated aqueous NH4Cl, saturated
aqueous NaHCO3, and brine, successively. The organic
layer was dried over MgSO4, and the residue obtained
after evaporation of the solvent was chromatographed
on a silica gel column. Elution with hexane–ethyl ace-
tate (5:1) gave 38 (36 mg, 69%) as a colorless oil.
[h]2D5=−3.5 (c 0.79, CHCl3). HRMS m/z calcd for
C13H23O5 (MH+): 259.1544. Found: 259.1533. IR
4.5.9. (1S,9S,11R,15S)-(15-Methyl-4,12-dioxo-3,13,14-
trioxatricyclo[7.4.2.011,15]pentadec-1-yl)methyl acetate,
36a, (1S,9R,11R,15S)-(15-methyl-4,12-dioxo-3,13,14-tri-
oxatricyclo[7.4.2.011,15]pentadec-1-yl)methyl acetate, 36b,
and (1S,3R,11S,13R)-(1-methyl-8,13-dioxo-9,12,15-tri-
oxatricyclo[9.3.1.03,14]pentadec-11-yl)methyl
acetate,
36c. A solution of 31 (213 mg, 0.65 mmol) in ethyl
acetate (426 mL) was irradiated (300 nm) under an
argon atmosphere for 5 h. The residue obtained after
evaporation of the solvent was purified on a silica gel
column (hexane–ether (2:1)) to give a less polar isomer
36b (86 mg, 40%) as colorless needles having a mp of
75–76°C (recrystallized from hexane–ether), a more
polar isomer 36a (54 mg, 25%) as colorless needles
having a mp of 126–127°C (recrystallized from hexane–
ether) and a cross isomer 36c (23 mg, 11%) as a
colorless oil. 36a: [h]2D7=+2.0 (c 1.00, CHCl3). Anal.
calcd for C16H22O7: C, 58.89; H, 6.79. Found: C, 59.06;
H, 6.75%. MS m/z: 327 (MH+). IR (CHCl3): 1746 cm−1.
1H NMR (500 MHz, CDCl3) l 1.21 (1H, ddt, J=6.0,
2.5, 13.0 Hz, C8-H), 1.37 (1H, m, C7-H), 1.44 (1H, dt,
J=13.0, 2.5 Hz, C7-H), 1.50–1.60 (1H, m, C6-H), 1.54
(3H, s, C15-CH3), 1.82 (1H, dt, J=13.0, 3.0 Hz), 1.86
(1H, dq, J=13.0, 2.0 Hz, C8-H), 1.95 (1H, dddd,
J=16.5, 13.0, 6.5, 3.5 Hz, C6-H), 2.07 (1H, m, C9-H),
2.12 (3H, s, Ac), 2.44–2.52 (2H, m, C5-H and C10-H),
2.62 (1H, dt, J=13.0, 6.5 Hz, C5-H), 2.91 (1H, ddd,
J=10.5, 3.0, 1.0 Hz, C11-H), 3.81 (1H, d, J=12.0 Hz,
CHO), 4.04 (1H, d, J=12.0 Hz, CHO), 4.31 (1H, dd,
J=12.0, 1.5 Hz, CHO), 5.13 (1H, dd, J=12.0, 1.5 Hz,
CHO). 13C NMR (125.65 MHz, CDCl3) l 20.5, 23.2,
25.2, 25.7, 28.51, 28.54, 31.7, 38.9, 45.8, 64.0, 64.1, 76.7,
103.0, 169.7, 170.8, 172.9. 36b: [h]2D7=−49.3 (c 0.98,
CHCl3). Anal. calcd for C16H22O7: C, 58.89; H, 6.79.
Found: C, 58.60; H, 6.77. MS m/z: 327 (MH+). IR
1
(CHCl3): 3463 (br), 1725 cm−1. H NMR (500 MHz,
CDCl3) l 1.23 (3H, s, C2-CH3), 1.25–1.44 (2H, m, C4-H
and C1%-H), 1.54–1.63 (3H, m, C1%-H and C2%-H×2), 1.98
(2H, m, C3-H and C4-H), 2.05 (3H, s, Ac), 2.06 (3H, s,
Ac), 2.24 (1H, ddt, J=8.0, 4.0, 10.0 Hz, C1-H), 2.69
(1H, brs, OH), 3.86 (1H, dd, J=11.5, 4.0 Hz, C1-CH2),
4.05 (2H, t, J=6.0 Hz, C3%-H×2), 4.40 (1H, dd, J=11.5,
10.0 Hz, C1-CH2). 13C NMR (125.65 MHz, CDCl3) l
21.0, 21.1, 25.1, 25.4, 26.5, 29.0, 42.0, 42.3, 63.7, 64.7,
75.3, 171.3, 172.1.
4.5.11. (1R,2S,3S)-5-{3-[(Acetyloxy)methyl]-2-hydroxy-
2-methylcyclobutyl}pentyl acetate, 39. To a suspension
of LiAlH4 (49 mg, 1.3 mmol) in dry THF (3 mL) was
added a solution of 36b (70 mg, 0.21 mmol) in dry THF
(2.5 mL) dropwise under an argon atmosphere at ice-
cold temperature. The mixture was stirred for 3 h at
room temperature. After decomposition of the excess
LiAlH4 with 50% aqueous NaOH, the precipitate was
removed by filtration through Celite. To the residue
obtained after evaporation of the solvent was added
acetic anhydride (5 mL) and pyridine (0.5 mL). After
stirring for 2 h, the whole was diluted with ether, and
washed with saturated aqueous NH4Cl, saturated
aqueous NaHCO3, and brine, successively. The organic
layer was dried over MgSO4, and the residue obtained
after evaporation of the solvent was chromatographed
on a silica gel column. Elution of hexane-ethyl acetate
(3:1) gave 39 (45 mg, 73%) as a colorless oil. [h]2D7=
−48.1 (c 1.13, CHCl3). HRMS m/z calcd for C15H27O5:
287.1859. Found: 287.1862. IR (CHCl3): 3482 (br),
1
(CHCl3): 1750 cm−1. H NMR (500 MHz, CDCl3) l
1.16 (1H, m, C7-H), 1.20 (1H, m, C8-H), 1.33 (3H, s,
C15-CH3), 1.53 (1H, dt, J=13.0, 6.5 Hz, C8-H), 1.64
(1H, dt, J=9.0, 11.5 Hz, C10-H), 1.69 (1H, m, J=11.5,
7.5 Hz, C7-H), 1.78 (2H, m, C6-H), 1.98 (1H, ddd,
J=10.5, 9.0, 1.0 Hz, C10-H), 2.09 (3H, s, Ac), 2.41 (1H,
ddd, J=15.0, 9.0, 6.5 Hz, C5-H), 2.61 (1H, dt, J=15.0,
5.5 Hz, C5-H), 2.80 (1H, dd, J=9.0, 1.0 Hz, C11-H),
3.04 (1H, m, C9-H), 3.75 (1H, d, J=12.0 Hz, CHO),
4.07 (1H, d, J=11.5 Hz, CHO), 4.11 (1H, d, J=11.5
Hz, CHO), 5.06 (1H, d, J=12.0 Hz, CHO). 13C NMR
(125.65 MHz, CDCl3) l 19.2, 20.4, 22.5, 22.8, 26.0,
27.5, 34.5, 43.0, 44.3, 63.2, 66.4, 78.5, 104.0, 169.3,
171.8, 171.9. 36c: [h]2D6=+3.9 (c 2.46, CHCl3). HRMS
calcd for C16H23O7: 327.1444. Found: 327.1454. MS
m/z: 327 (MH+). IR (CHCl3): 1748 cm−1. 1H NMR
(500 MHz, CDCl3) l: 1.50 (3H, s, C1-CH3), 1.55–1.67
(2H, m, C6-H×2), 1.70–1.80 (3H, m, C4-H and C5-H×
2), 1.94 (1H, m, C4-H), 2.13 (3H, s, Ac), 2.17 (2H, d,
J=6.5 Hz, C2-H×2), 2.42 (2H, m, C7-H), 2.87 (1H, tq,
J=10.0, 6.5 Hz, C3-H), 3.16 (1H, d, J=10.0 Hz, C13-
H), 4.19 (1H, d, J=12.5 Hz, CHO), 4.29 (1H, d,
J=12.5 Hz, CHO), 4.42 (1H, d, J=12.0 Hz, CHO),
1
1730 cm−1. H NMR (500 MHz, CDCl3) l 1.25 (3H, s,
C2-CH3), 1.20–1.28 (3H, m, C1%-H and C2%-H×2), 1.28–
1.39 (3H, m, C4-H and C3%-H×2), 1.51 (1H, m, C1%-H),
1.62 (2H, quint, J=7.0 Hz, C4%-H×2), 1.68 (1H, ddd,
J=12.0, 9.5, 4.0 Hz, C4-H), 2.05 (3H, s, Ac), 2.07 (3H,
s, Ac), 2.09 (1H, brs, OH), 2.22 (1H, m, C3-H), 2.28
(1H, m, C1-H), 4.05 (2H, t, J=7.0 Hz, C5%-H×2), 4.14
(1H, dd, J=11.5, 6.0 Hz, C1-CH2), 4.42 (1H, dd, J=

M. Murakami et al. / Tetrahedron: Asymmetry 14 (2003) 201–215
215
11.5, 8.0 Hz, C1-CH2). 13C NMR (125.65 MHz, CDCl3)
l 20.9, 21.0, 22.6, 23.4, 26.0, 27.0, 28.5, 29.9, 42.6, 45.3,
64.46, 64.52, 74.6, 171.2, 171.4.
6. Seebach, D.; Muller, S. G.; Gysel, U.; Zimmermann, J.
Helv. Chim. Acta 1988, 71, 1303–1318.
7. (a) Sato, M.; Abe, Y.; Ohuchi, H.; Kaneko, C. Heterocy-
cles 1990, 31, 2115–2119; (b) Sato, M.; Ohuchi, H.; Abe,
Y.; Kaneko, C. Tetrahedron: Asymmetry 1992, 3, 313–
328.
Acknowledgements
8. Desymmetrization of 2,2-disubstituted-1,3-proopanediol
by lipase-catalyzed monoacetylation: (a) Fadel, A.;
Arzel, P. Tetrahedron: Asymmetry 1997, 8, 283–291; (b)
Kirihara, M.; Takuwa, T.; Kawasaki, M.; Kakuda, H.;
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(c) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Tsujino,
T.; Kita, Y. J. Org. Chem. 2002, 67, 411–419.
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The authors thank Dr. Y. Hirose of Amano Enzyme
Inc., Japan for the gift of lipases and to Dr. M. Uchida
of the School of Pharmaceutical Sciences, University of
Shizuoka for the mass spectra measurements. This
work was supported in part by Grant-in-Aid for Scien-
tific Research No. 12470484 from the Ministry of Edu-
cation, Science, Sports, Culture and Technology, Japan.
10. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetra-
hedron 1989, 45, 687–694.
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