Improved robust method for preparing optically active 3-alkyl-3-phenyl-1,4- dioxane-2,5-diones; A promising new chiral template

Article abstract of DOI:10.1055/s-0028-1083211

A robust method for preparing (3S)-3-alkyl-3-phenyl-1,4-dioxane-2,5-diones was developed using an improved cyclocondensation reaction between (S)-α-alkylmandelic acids and 2-bromocarbonyl halides. Subtle differences in the reaction conditions, including separate additions of triethylamine, significantly increased the yield compared with Schollkopf s original method. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083211

3670
PAPER
Improved Robust Method for Preparing Optically Active 3-Alkyl-3-
phenyl-1,4-dioxane-2,5-diones; A Promising New Chiral Template
A
P
romising Ne
w
y
Chiral
D
ix
o
ne
T
emplatehei Nagase, Yuuki Iida, Mikiko Sugi, Tomonori Misaki, Yoo Tanabe*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyougo 669-1337, Japan
Fax +81(79)5659077; E-mail: tanabe@kwansei.ac.jp
Received 23 June 2008; revised 28 July 2008
improved and robust method for preparing chiral (3S)-3-
Abstract: A robust method for preparing (3S)-3-alkyl-3-phenyl-
alkyl-3-phenyl-1,4-dioxane-2,5-diones 6 from (S)-a-alkyl-
1,4-dioxane-2,5-diones was developed using an improved cyclo-
condensation reaction between (S)-a-alkylmandelic acids and 2-
bromocarbonyl halides. Subtle differences in the reaction condi-
mandelic acids 4 based on Schöllkopf’s method. In our
hands, however, a subtle difference in the reaction condi-
tions, including separate additions of triethylamine, significantly in- tions sometimes affected the yield of the original method.
creased the yield compared with Schöllkopf’s original method.
The noteworthy features of the present method, compared
with the original one, are as follows: (i) the method has led
to the first preparation of chiral analogues 6, (ii) to signif-
Key words: 1,4-dioxan-2,5-diones, cyclocondensation, a-alkyl-
mandelic acids, chiral template
icantly higher yields, and (iii) the method is more robust
and reproducible. The advantages of the present approach
are attributed to the one-pot procedure of separate addi-
tion of triethylamine in each step of the reaction sequence.
Racemic 1,4-dioxane-2,5-diones ( )-3 comprise useful
precursors of biologically active compounds.1,2 The non-
chiral synthesis of ( )-3 was originally developed by
Schöllkopf’s group:2 cyclocondensation between 2-alkyl-
2-hydroxycarboxylic acids ( )-1 and 2-bromocarbonyl
chlorides ( )-2 promoted by two equivalents of triethyl-
amine as the HX (X = Cl and Br) binder (Scheme 1). The
precursor ( )-3 was synthetically valuable for providing
tetronic acids and 2-alkoxy-2¢-hydroxyketones utilizing a
characteristic lactide-ring-contraction reaction.
Recently, we reported two robust preparative methods for
the synthesis of chiral a-alkylmandelic acids, including
atrolactic acid (a-methyl),5 and its useful five-membered
derivatives, Seebach and Fráter’s chiral template6 (cis-
2,5-disubstituted 1,3-dioxolan-4-ones).7 Thus, (S)-alkyl
mandelic acids 4a–c were readily obtained in good yields
with high optical purities. Based on the results, we extend-
ed our investigation to the preparation of a six-membered
chiral analogue 6.
CO2H
OH
i) 80 °C, 0.5–2 h, neat
R1
R2
R3
COCl
Initial experiments were guided by a cyclocondensation
reaction between (S)-atrolactic acid (4a) and 2-bromopro-
panoyl bromide to give (3S)-3,6-dimethyl-3-phenyl-1,4-
dioxane-2,5-dione (6a) (Scheme 2). The optimized condi-
tions increased the yield to 91%. Screening of various
conditions revealed that the increase in yield was solvent-
dependent [toluene (20%), acetone (30%), DMF (43%),
NMP (58%), THF (60%), and MeCN (91%)].
+
ii) Et3N (2.0 equiv),
acetone, 50–60 °C, 1 h
Br
( )-1
( )-2
O
R3
O
R1
60–85%
R1, R2 = H, alkyl
O
R2
O
( )-3
R
3 = alkyl
This reaction involved the following sequence: (i) forma-
tion of the mixed anhydride intermediate 5A; (ii) intramo-
lecular acyl-transfer giving carboxylic acid intermediate
5B, and (iii) nucleophilic substitution of carboxylate inter-
mediate 5C derived from 5B giving the desired product
6a. The proposed mechanism was rationally supported by
successful isolation of the relatively stable intermediate
5B (86%).8 Each separate addition of 1.1 equivalent of tri-
ethylamine was considered to contribute to the formation
of the carboxylates as well as acting as an HBr scavenger.
O
O
R4X, NaH
R3
R4O
i) OH–
ii) H+
R3
OH
R1
O
R1
OR4 R2
R2
O
Scheme 1 Preparation of 1,4-dioxane-2,5-diones ( )-3 by Schöll-
kopf’s method and transformation into tetronic acids and 2-alkoxy-2¢-
hydroxyketones
Chiral 1,4-dioxane-2,5-diones 3 have recently attracted
attention as the precursor for polylactides, which repre-
sent synthetically biocompatible or biodegradable poly-
mers,3 and as an antidiabetic drug.4 Here, we present an
The original method using a one-portion addition of tri-
ethylamine resulted in 20–40% yield, probably because
the initial step from 4a to 5A and/or 5B, was retarded by
using less reactive, stereocongested substrate 4a, which
has both Ph and R4 groups on the asymmetric center.
Eventually, the formation of 5B was established to have a
key roll in the present method.
SYNTHESIS 2008, No. 22, pp 3670–3674
Advanced online publication: 29.10.2008
DOI: 10.1055/s-0028-1083211; Art ID: F13908SS
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x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Promising New Chiral Dioxane Template
3671
Table 1 Cyclocondensation Using Chiral a-Alkyl Mandelic Acids
(S)-4a–c and 2-Bromocarbonyl Halides
Table 1 lists the generality of the present protocol. All ex-
amples examined proceeded smoothly to give the desired
products 6a–j in 76% to 98% yield. The diastereoselectiv-
ity fluctuated between 8:1 and 2:1; (3S,6R)-isomers con-
sistently predominated over the (3S,6S)-isomer. The
absolute configuration of the major isomer of 6a was de-
duced from an NOE-NMR measurement (see Figure 1 in
experimental). In general, the use of linear 2-bromocarbo-
nyl halides (Cl, Br) resulted in relatively higher yields and
diastereomeric excess ratios. Unfortunately, these diaste-
reomers could not be separated by simple chromatogra-
phy. The reaction using (S)-mandelic acid (R1 = H),
however, resulted in nearly complete racemization.
i) Et3N (1.1 equiv)
O
ii) R2CHBrCOX (1.1 equiv),
R2
Ph
R1
CO2H
MeCN, 0–5 °C, 0.5 h
O
R1
Ph
6a–j
OH
O
iii) Et3N (1.1 equiv),
MeCN, 50 °C, 3 h
(S)-4a–c
O
and
70 °C, 0.5 h
Entry R1
R2CHBrCOX
Product dra
Yield (%)b
COBr
Me
1
6a
6b
6c
7:1
7:1
6:1
91
98
76
(4a)
Br
COCl
In conclusion, we have developed a practical method for
preparing (3S)-3-alkyl-3-phenyl-1,4-dioxane-2,5-diones
utilizing an improved, robust cyclocondensation reaction.
The present method utilized readily available substrates
and reactants and the yields were good to excellent. Fur-
ther investigation of asymmetric synthesis using this
chiral template candidate is in progress from the view-
point of process chemistry.
2
3
Br
COCl
Br
4
5
6d
7:1
81c
COCl
Br
COCl
6e
6f
3:1
5:1
5:1
83
98
94
NMR spectra were recorded on a JEOL DELTA 300 spectrometer
Br
1
operating at 300 MHz for H NMR and 75 MHz for 13C NMR.
COBr
Allyl
(4b)
Chemical shifts (d, ppm) in CDCl3 are reported downfield from
6
1
TMS (d = 0 ppm) or CHCl3 (d = 7.26 ppm) for H NMR. For 13
C
Br
NMR, chemical shifts are reported relative to CDCl3 (d = 77.00
ppm) as an internal reference. IR spectra were recorded on a JASCO
FT/IR-5300 spectrophotometer. Optical rotations were measured
on a JASCO DIP-370 (D 589 nm). HPLC data were obtained on a
Shimadzu HPLC system (consisting of the following: SLC-10A,
DGU-12A, LC-10AD, SIL-10A, CTO-10A, and detector SPD-
10AV, measured at 254 nm) using DAICEL Chiralpak AD-H col-
umn (0.46 cm x 25 cm) at 35 °C. Mass spectra were measured on a
JEOL JMS-T1000LC spectrometer.
COCl
7
8
6g
Br
6h
4:1
95c
COCl
Br
COBr
Bn
9
6i
6j
8:1
4:1
91
97
(4c)
Br
(2S)-2-Hydroxy-2-phenyl-4-pentenoic acid (4b)7a,9
COCl
n-BuLi (1.66 M in hexane, 18.1 mL, 30.0 mmol) was added to a
stirred solution of i-Pr2NH (3.29 g, 32.5 mmol) in THF (50 mL) at
–10 °C under an Ar atmosphere, and the mixture was stirred at the
same temperature for 30 min. After cooling to –78 °C, a solution of
(2S,5S)-2-tert-butyl-5-phenyl-1,3-dixolan-4-one7a (5.51 g, 25.0
mmol) in THF (40 mL) was slowly added to the mixture, which was
stirred at the same temperature for 30 min. A solution of allyl bro-
mide (5.94 mL, 50.0 mmol) in THF (10 mL) was slowly added to
the mixture, which was then stirred at the same temperature for 5
min, and then warmed to 0–5 °C during ~3 h. The mixture was
10
11
Br
85c
COCl
Br
6k
2:1
a Ratio (3S,6R):(3S,6S) determined by 1H NMR spectroscopy.
b Isolated yield.
c Reaction time: 20 h.
COBr
Et3N
O
O
Ph
O
Ph
Ph
CO2H
Br
HO
O
O
OH
MeCN, 0–5 °C
– Et3N+HBr–
OH
Br
5A
Br
O
(S)-4a
5B
O
Et3N
MeCN, 50–70 °C
Ph
O
6
O
–O
O
– Et3N+HBr–
O
3
Br
Ph
O
O
5C
6a
Scheme 2 Novel procedure and proposed mechanism of the cyclocondensation
Synthesis 2008, No. 22, 3670–3674 © Thieme Stuttgart · New York

3672
R. Nagase et al.
PAPER
quenched with H2O (30 mL), then extracted with Et2O (2 × 30 mL).
The combined organic phases were washed with H2O (1 × 30 mL),
brine (1 × 30 mL), dried (Na2SO4), and concentrated to give crude
(2S,5S)-5-allyl-2-tert-butyl-5-phenyl-1,3-dioxolan-4-one (>95% de
based on 1H NMR measurement).
Et3N (51 mg, 1.0 mmol) in MeCN (1.0 mL) at 0–5 °C under an Ar
atmosphere. The mixture was stirred at the same temperature for 30
min then the reaction was quenched with aq HCl (1 M, 5 mL) and
extracted with EtOAc (2 × 5 mL). The combined organic phase was
washed H2O (1 × 5 mL), brine (1 × 5 mL), dried (Na2SO4) and con-
centrated. The obtained crude product was purified by column chro-
matography (SiO2, hexane–EtOAc, 4:1) to give the intermediate 5B
as a diastereomeric mixture.
Orange oil.
1H NMR (300 MHz, CDCl3): d = 0.96 (9 H, s), 2.72 (1 H, dd, J = 7.2
Hz, Jgem = 14.5 Hz), 2.85 (1 H, dd, J = 7.2 Hz, Jgem = 14.5 Hz),
5.10–5.24 (2 H, m), 5.39 (1 H, s), 5.75 (1 H, ddt, J = 7.2, 10.0, 14.5
Hz), 7.27–7.43 (3 H, m), 7.59–7.70 (2 H, m).
13C NMR (75 MHz, CDCl3): d = 23.5, 35.1, 43.9, 82.3, 109.2, 120.7,
124.9, 128.0, 128.2, 130.8, 138.1, 173.2.
Yield: 130 mg (86%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.88 (3 H × 1/2, d, J = 6.9 Hz),
1.91 (3 H × 1/2, d, J = 6.9 Hz), 1.99 (3 H × 1/2, s), 2.00 (3 H × 1/2,
s), 4.46 (1 H × 1/2, q, J = 6.9 Hz), 4.52 (1 H × 1/2, q, J = 6.9 Hz),
7.32–7.44 (3 H, m), 7.53–7.61 (2 H, m), 9.41 (1 H, br s).
The obtained oil was dissolved in MeOH (15 mL), and aq NaOH
(3M, 12.5 mL) was added to the mixture at 0–5 °C. After stirring at
r.t. for 2 h, the mixture was extracted with Et2O (2 × 15 mL). The
aqueous layer was adjusted to pH 2–3 using 6M aq HCl, then ex-
tracted with EtOAc (2 × 15 mL). The combined organic phases
were washed with H2O (1 × 15 mL), brine (1 × 15 mL), dried
(Na2SO4), and concentrated. The obtained crude solid was purified
by recrystallization from toluene to give the product.
13C NMR (75 MHz, CDCl3): d = 21.4, 21.5, 22.7, 22.8, 39.9, 40.1,
82.3, 82.4, 124.8, 124.9, 128.7, 138.4, 168.5, 168.7, 175.8, 176.0.
(3S)-3,6-Dimethyl-3-phenyl-1,4-dioxane-2,5-dione (6a)
2-Bromopropanoyl bromide (1.12 mL, 10.7 mmol) was added to a
stirred solution of (S)-atrolactic acid (4a; 1.62 g, 9.7 mmol) and
Et3N (1.48 mL, 10.7 mmol) in MeCN (19.4 mL) at 0–5 °C under an
Ar atmosphere and the mixture was stirred for 30 min. Et3N (1.48
mL, 10.7 mmol) was added to the mixture at the same temperature,
then the reaction was stirred at 50–55 °C for 3 h and at 70–75 °C for
30 min. The mixture was allowed to cool to r.t. then aq HCl (1 M,
15 mL) was added and the mixture was extracted with EtOAc (3 ×
15 mL). The combined organic phase was washed with H2O (1 × 15
mL), brine (1 × 15 mL), dried (Na2SO4) and concentrated. The ob-
tained crude product was purified by column chromatography
(SiO2, hexane–EtOAc, 9: 1) to give the desired product 6a.
Yield: 3.49 g (73% in 2 steps); colorless crystals; mp 133–134 °C
(Lit.9 132–133 °C); [a]26D +29.9 (c 1.11, EtOH) [Lit.9 [a]D26 +29.1
(c 1.0, CHCl3)]; >99% ee.
1H NMR (300 MHz, acetone-d6): d = 2.76 (1 H, ddt, J = 1.0, 7.2 Hz,
Jgem = 14.1 Hz), 3.00 (1 H, ddt, J = 1.0, 7.2 Hz, Jgem = 14.1 Hz),
4.97–5.20 (2 H, m), 5.83 (1 H, ddt, J = 7.2, 10.3, 14.1 Hz), 7.20–
7.41 (3 H, m), 7.59–7.74 (2 H, m).
13C NMR (75 MHz, acetone-d6): d = 45.3, 78.9, 119.2, 126.9, 128.6,
129.1, 134.3, 143.6, 176.1.
Yield: 1.94 g (91%); diastereomeric mixture [(3S,6R):(3S,6S) =
7:1]; colorless crystals; mp 55–58 °C.
HPLC (0.80 mL/min; hexane–2-propanol–TFA, 90:10:1):
tR(racemic) = 15.22 and 21.61 min, tR(4b) 15.33 min.
1H NMR (300 MHz, CDCl3): d = 1.10 (3 H × 1/8, d, J = 7.6 Hz),
1.54 (3 H × 7/8, d, J = 6.9 Hz), 1.90 (3 H × 7/8, s), 1.94 (3 H × 1/8,
s), 4.45 (1 H × 7/8, q J = 6.9 Hz), 5.12 (1 H × 1/8, q, J = 7.6 Hz),
7.35–7.51 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 16.0, 18.3, 28.2, 29.0, 72.8, 74.4,
83.5, 84.5, 123.8, 124.0, 129.4, 129.5, 129.7, 137.0, 139.0, 166.0,
167.2, 167.3, 167.7.
(2S)-2,3-Diphenyl-2-hydroxypropanoic acid (4c)
Following the procedure for 4b, the reaction of (2S,5S)-5-allyl-2-
tert-butyl-5-phenyl-1,3-dioxolan-4-one5 (5.51 g, 25.0 mmol) and
benzyl bromide (5.94 mL, 50.0 mmol) gave crude (2S,5S)-5-ben-
zyl-2-tert-butyl-5-phenyl-1,3-dioxolan-4-one (>95% de based on
1H NMR measurement).
IR (KBr): 3005, 1759, 1279, 1111, 704 cm–1.
HRMS (ESI): m/z [C13H16O5 + MeOH + Na+] calcd for C13H16O5:
Orange oil.
1H NMR (300 MHz, CDCl3): d = 0.84 (9 H, s), 3.14 (1 H, d,
Jgem = 13.8 Hz), 3.42 (1 H, d, Jgem = 13.8 Hz), 4.55 (1 H, s), 7.21–
7.41 (8 H, m), 7.70–7.74 (2 H, m).
275.0895; found: 275.0891.
Figure 1 indicates NOE correlations obtained for compound 6a.
13C NMR (75 MHz, CDCl3): d = 23.4, 34.9, 46.6, 83.3, 109.5, 124.8,
127.4, 127.9, 128.2, 128.4, 130.4, 134.4, 138.8, 173.3.
NOE
The oil was treated as described for 4b but at 60 °C for 2 h. The ob-
tained crude solid was purified by recrystallization from toluene to
give the product.
O
Me
O
H
O
Me
Ph
Yield: 3.68 g (61% in 2 steps); colorless crystals; mp 155–156 °C;
[a]26D +8.0 (c 1.13, EtOH); 98% ee.
O
1H NMR (300 MHz, acetone-d6): d = 3.22 (1 H, d, J = 13.4 Hz),
3.60 (1 H, d, J = 13.4 Hz), 7.12–7.41 (8 H, m), 7.69–7.78 (2 H, m).
NOE
13C NMR (75 MHz, acetone-d6): d = 46.9, 79.8, 127.2, 127.7, 128.8,
128.9, 129.3, 132.1, 137.9, 144.0, 176.2.
Figure 1
Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.1; H, 5.6.
(3S)-6-Butyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione (6b)
Following the procedure for the preparation of 6a, the reaction of 4a
(997 mg, 6.0 mmol) and 2-bromohexanoyl chloride (1.41 g, 6.6
mmol) using Et3N (2 × 668 mg, 2 × 6.6 mmol) gave the desired
product 6b.
HPLC (0.80 mL/min; hexane–2-propanol–TFA, 90:10:1):
tR(racemic) = 15.95 and 25.31 min, tR(4c) 15.91 min.
Isolation of Intermediate (2S)-2-(2-Bromopropanoyloxy)-2-
phenylpropanonic Acid (5B)
2-Bromopropanoyl bromide (53 mL, 1.0 mmol) was added to a
stirred solution of (S)-atrolactic acid (4a; 83 mg, 1.0 mmol) and
Yield: 1.54 g (98%); diastereomeric mixture [(3S,6R):(3S,6S) =
7:1]; colorless oil.
Synthesis 2008, No. 22, 3670–3674 © Thieme Stuttgart · New York

PAPER
A Promising New Chiral Dioxane Template
3673
1H NMR (300 MHz, CDCl3): d = 0.72 (3 H × 1/8, t, J = 7.2 Hz),
0.88 (3 H × 7/8, t, J = 7.2 Hz), 1.15–1.55 (4 H, m), 1.80–2.03 (2 H,
m), 1.90 (3 H × 7/8, s), 1.94 (3 H × 1/8, s), 4.31 (1 H × 7/8, dd,
J = 4.1, 7.2 Hz), 4.92 (1 H × 1/8, dd, J = 4.8, 10.0 Hz), 7.32–7.50
(5 H, m).
13C NMR (75 MHz, CDCl3): d = 13.4, 13.7, 21.6, 22.2, 26.3, 26.9,
28.2, 29.2, 29.9, 32.0, 76.3, 78.2, 83.4, 84.3, 123.8, 129.3, 129.4,
129.5, 129.7, 137.1, 139.3, 166.2, 166.9, 167.3, 167.4.
× 3/4, m), 5.57 (1 H × 1/4, ddt, J = 6.9, 10.3, 17.2 Hz), 5.77 (1 H ×
3/4, ddt, J = 6.9, 10.3, 17.2 Hz), 7.35–7.51 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 27.9, 28.8, 34.1, 36.4, 75.2, 77.0,
83.1, 84.0, 119.4, 119.6, 123.6, 123.8, 129.2, 129.3, 129.5, 130.1,
130.4, 136.8, 139.0, 165.5, 165.7, 166.2, 166.7.
IR (neat): 2996, 1763, 1495, 1447, 1379, 1285, 1258, 1121, 999,
978 cm–1.
HRMS (ESI): m/z [C15H18O5 + MeOH + Na+] calcd for C15H18O5:
IR (neat): 2961, 1767, 1265, 1209, 1123, 702 cm–1.
HRMS (ESI): m/z [C16H22O5 + MeOH + Na+] calcd for C16H22O5:
301.1052; found: 301.1049.
317.1365; found: 317.1357.
(3S)-3-Allyl-6-methyl-3-phenyl-1,4-dioxane-2,5-dione (6f)
Following the procedure for the preparation of 6a, the reaction of
(S)-2-hydroxy-2-phenyl-4-pentenoic acid (4b; 384 mg, 2.0 mmol)
and 2-bromopropanoyl bromide (475 mg, 2.2 mmol) using Et3N (2
× 223 mg, 2 × 2.2 mmol) gave the desired product 6f.
(3S)-6-Isobutyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione (6c)
Following the procedure for the preparation of 6a, the reaction (20
h reaction period) of 4a (50 mg, 0.30 mmol) and 2-bromo-4-meth-
ylpentanoyl chloride (70 mg, 0.33 mmol) using Et3N (2 × 33 mg, 2
× 0.33 mmol) gave the desired product 6c.
Yield: 488 mg (98%); diastereomeric mixture [(3S,6R):(3S,6S) =
5:1]; colorless oil.
Yield: 60 mg (76%); diastereomeric mixture [(3S,6R):(3S,6S) =
6:1]; colorless oil.
1H NMR (300 MHz CDCl3): d = 1.10 (3 H × 1/6, d, J = 7.2 Hz), 1.54
(3 H × 5/6, d, J = 6.9 Hz), 2.74–2.87 (1 H, m), 2.99–3.15 (1 H, m),
4.43 (1 H × 5/6, q, J = 6.9 Hz), 5.09 (1 H × 1/6, q, J = 7.6 Hz), 5.11–
5.26 (2 H, m), 5.68–5.87 (1 H, m), 7.36–7.52 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 15.8, 18.5, 44.9, 45.9, 72.3, 73.9,
74.0, 85.5, 86.1, 121.0, 121.4, 124.2, 129.3, 129.5, 129.9, 135.3,
137.5, 164.8, 166.1, 167.1, 167.4.
1H NMR (300 MHz, CDCl3): d = 0.71 (3 H × 1/7, d, J = 6.5 Hz),
0.75 (3 H × 6/7, d, J = 6.2 Hz), 0.78 (3 H × 1/7, d, J = 6.5 Hz), 0.90
(3 H × 6/7, dd, J = 6.2 Hz), 1.57–1.94 (3 H, m), 1.90 (3 H × 6/7, s),
1.93 (3 H × 1/7, s), 4.31 (1 H × 6/7, dd, J = 5.9, 7.2 Hz), 5.00 (1 H
× 1/7, dd, J = 4.8, 11.0 Hz), 7.37–7.51 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 20.96, 21.03, 22.4, 22.9, 23.7, 24.0,
28.1, 29.2, 38.6, 40.1, 74.7, 76.7, 83.5, 84.3, 123.8, 123.9, 129.3,
129.4, 129.5, 129.7, 137.1, 139.3, 166.2, 167.2, 167.3, 167.7.
IR (KBr): 2995, 1765, 1286, 1120, 702 cm–1.
HRMS (ESI): m/z [C15H18O5 + MeOH + Na+] calcd for C15H18O5:
301.1052; found: 301.1053.
IR (neat): 2961, 1765, 1285, 1258, 1213, 1115 cm–1.
HRMS (ESI): m/z [C16H22O5 + MeOH + Na+] calcd for C16H22O5:
317.1365; found: 317.1360.
(3S)-3-Allyl-6-butyl-3-phenyl-1,4-dioxane-2,5-dione (6g)
Following the procedure for the preparation of 6a, the reaction of 4b
(384 mg, 2.0 mmol) and 2-bromohexanoyl chloride (470 mg, 2.2
mmol) using Et3N (2 × 223 mg, 2 × 2.2 mmol) gave the desired
product 6g.
(3S)-6-Isopropyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione (6d)
Following the procedure for the preparation of 6a, the reaction (20
h reaction time) of 4a (166 mg, 1.0 mmol) and 2-bromo-3-methyl-
butanoyl chloride (219 mg, 1.1 mmol) using Et3N (2 × 111 mg, 2 ×
1.1 mmol) gave the desired product 6d.
Yield: 543 mg (94%); diastereomeric mixture [(3S,6R):(3S,6S) =
5:1]; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.71 (3 H × 1/6, t, J = 7.2 Hz),
0.88 (3 H × 5/6, d, J = 6.9 Hz), 1.03–1.54 (4 H, m), 1.79–2.05 (2 H,
m), 2.69–2.86 (1 H, m), 2.99–3.14 (1 H, m), 4.29 (1 H × 5/6, dd,
J = 4.1, 7.2 Hz), 4.89 (1 H × 1/6, dd, J = 5.2, 9.6 Hz), 5.10–5.26
(2 H, m), 5.67–5.86 (1 H, m), 7.34–7.54 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 13.3, 13.7, 21.6, 22.2, 26.2, 26.8,
29.9, 32.4, 44.9, 46.2, 75.9, 77.8, 85.5, 85.9, 121.1, 121.5, 124.2,
124.3, 127.9, 128.2, 129.3, 129.5, 129.9, 135.5, 137.7, 165.2, 166.4,
166.8, 167.2.
Yield: 202 mg (81%); diastereomeric mixture [(3S,6R):(3S,6S) =
7:1]; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.83 (3 H × 1/8, d, J = 6.5 Hz),
0.85 (3 H × 1/8, d, J = 6.9 Hz), 1.02 (3 H × 7/8, d, J = 6.9 Hz), 1.03
(3 H × 7/8, d, J = 7.2 Hz), 1.25–1.41 (1 H × 1/8, m), 1.90 (3 H × 7/8,
s), 1.94 (3 H × 1/8, s), 2.32–2.48 (1 H × 7/8, m), 4.18 (1 H × 7/8, d,
J = 2.8 Hz), 4.56 (1 H × 1/8, d, J = 8.9 Hz), 7.37–7.52 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 15.7, 18.1, 18.3, 18.5, 28.1, 29.4,
29.5, 31.4, 80.3, 83.1, 83.2, 84.0, 123.7, 123.8, 129.18, 129.22,
129.4, 129.6, 137.2, 139.4, 165.4, 166.4, 166.6, 167.4.
IR (neat): 2961, 2932, 1763, 1451, 1320, 1260, 1121, 1100, 1001,
718 cm–1.
HRMS (ESI): m/z [C18H24O5 + MeOH + Na+] calcd for C18H24O5:
IR (neat): 2973, 1767, 1294, 1262, 1217, 1127 cm–1.
HRMS (ESI): m/z [C15H20O5 + MeOH + Na+] calcd for C15H20O5:
343.1521; found: 343.1518.
303.1208; found: 303.1211.
(3S)-3-Allyl-6-isopropyl-3-phenyl-1,4-dioxane-2,5-dione (6h)
Following the procedure for the preparation of 6a, the reaction (20
h reaction time) of 4b (577 mg, 3.0 mmol) and 2-bromo-3-methyl-
butanoyl chloride (658 mg, 3.3 mmol) using Et3N (2 × 334 mg, 2 ×
3.3 mmol) gave the desired product 6h.
(3S)-6-Allyl-3-methyl-3-phenyl-1,4-dioxane-2,5-dione (6e)
Following the procedure for the preparation of 6a, the reaction (20
h reaction time) of 4a (499 mg, 3.0 mmol) and 2-bromo-4-pen-
tenoyl chloride (652 mg, 3.3 mmol) using Et3N (2 × 334 mg, 2 × 3.3
mmol) gave the desired product 6e.
Yield: 785 mg (95%); diastereomeric mixture [(3S,6R):(3S,6S) =
Yield: 615 mg (83%); diastereomeric mixture [(3S,6R):(3S,6S) =
4:1]; colorless oil.
3:1]; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.82 (3 H × 1/5, d, J = 6.9 Hz),
0.86 (3 H × 1/5, d, J = 6.9 Hz), 1.00 (3 H × 4/5, d, J = 6.9 Hz), 1.02
(3 H × 4/5, d, J = 6.9 Hz), 1.44 (1 H × 1/5, dsept, J = 6.9, 8.3 Hz),
2.41 (1 H × 4/5, dsept, J = 2.8, 6.9 Hz), 2.72–2.88 (1 H, m), 2.99–
3.15 (1 H, m), 4.18 (1 H × 4/5, d, J = 2.8 Hz), 4.56 (1 H × 1/5, d,
1H NMR (300 MHz, CDCl3): d = 1.90 (3 H × 3/4, s), 1.95 (3 H ×
1/4, s), 2.10–2.23 (2 H × 1/4, m), 2.58–2.78 (2 H × 3/4, m), 4.37
(1 H × 3/4, dd, J = 4.5, 6.9 Hz), 4.81–4.89 (2 H × 1/4, m), 5.00 (1 H
× 1/4, dd, J = 4.5, 6.9 Hz), 5.02–5.08 (2 H × 1/4, m), 5.12–5.24 (2 H
Synthesis 2008, No. 22, 3670–3674 © Thieme Stuttgart · New York

3674
R. Nagase et al.
PAPER
J = 8.6 Hz), 5.10–5.29 (2 H, m), 5.67–5.87 (1 H, m), 7.35–7.55
(5 H, m).
13C NMR (75 MHz, CDCl3): d = 15.6, 18.1, 18.3, 29.5, 31.7, 44.9,
46.6, 79.9, 82.7, 85.5, 85.7, 121.0, 121.7, 124.1, 124.3, 129.1,
129.2, 129.4, 129.9, 135.5, 137.9, 165.2, 165.4, 166.4, 166.5 cm–1.
2.35 (1 H × 2/3, dsept, J = 2.8, 6.9 Hz), 3.31 (1 H × 1/3, d,
Jgem = 14.1 Hz), 3.36 (1 H × 2/3, d, Jgem = 14.5 Hz), 3.60 (1 H ×
2/3, d, Jgem = 14.5 Hz), 3.74 (1 H × 1/3, d, Jgem = 14.1 Hz), 3.89 (1 H
× 1/3, d, J = 6.5 Hz), 4.17 (1 H × 2/3, d, J = 2.8 Hz), 7.04–7.64
(10 H, m).
13C NMR (75 MHz, CDCl3): d = 15.4, 17.4, 18.0, 18.2, 29.6, 31.5,
46.2, 47.9, 79.9, 81.8, 86.0, 86.4, 124.5, 124.7, 127.1, 127.76,
127.82, 128.5, 128.9, 129.1, 129.2, 129.4, 131.1, 133.2, 135.4,
138.1, 164.7, 165.7, 166.1, 166.4.
IR (neat): 2975, 1763, 1451, 1320, 1293, 1248, 1105, 1015, 928,
700 cm–1.
HRMS (ESI): m/z [C17H22O5 + MeOH + Na+] calcd for C17H22O5:
329.136; found: 329.1368.
IR (neat): 2973, 1763, 1497, 1451, 1368, 1291, 1254, 1078, 702
cm–1.
HRMS (ESI): m/z [C21H24O5 + MeOH + Na+] calcd for C21H24O5:
(3S)-3-Benzyl-6-methyl-3-phenyl-1,4-dioxane-2,5-dione (6i)
Following the procedure for the preparation of 6a, the reaction of
(S)-2-hydroxy-2,3-diphenylpropanoic acid (4c; 242 mg, 1.0 mmol)
and 2-bromopropanoyl bromide (237 mg, 1.1 mmol) using Et3N (2
× 111 mg, 2 × 1.1 mmol) gave the desired product 6i.
379.1521; found 379.1523.
Acknowledgment
Yield: 269 mg (91%); diastereomeric mixture [(3S,6R):(3S,6S) =
8:1]; colorless crystals; mp 96—99 °C.
This research was partially supported by Grant-in-Aids for Scienti-
fic Research on Basic Areas (B) ‘18350056’, Priority Areas (A)
‘17035087’ and ‘18037068’, and Exploratory Research ‘17655045’
from the Ministry of Education, Culture, Sports, Science and Tech-
nology (MEXT).
1H NMR (300 MHz, CDCl3): d = 1.13 (3 H × 1/8, d, J = 7.9 Hz),
1.48 (3 H × 7/8, d, J = 6.9 Hz), 3.36 (1 H, d, J = 14.1 Hz), 3.61 (1 H,
d, J = 14.1 Hz), 4.40 (1 H × 7/8, q, J = 6.9 Hz), 4.59 (1 H × 1/8, q,
J = 7.9 Hz), 7.11–7.58 (10 H, m).
13C NMR (75 MHz, CDCl3): d = 15.9, 18.5, 46.3, 47.5, 72.4, 73.7,
86.4, 86.5, 124.5, 124.7, 127.2, 127.6, 127.9, 128.3, 129.2, 129.3,
129.4, 129.5, 131.2, 131.3, 133.2, 133.3, 135.2, 137.7, 165.2, 166.2,
166.7, 167.3.
IR (KBr): 3063, 1755, 1267, 1091, 700 cm–1.
HRMS (ESI): m/z [C19H20O5 + MeOH + Na+] calcd for C19H20O5:
References
(1) Guillarumet, G. Comprehensive Heterocyclic Chemistry II,
Vol. 6; Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.;
Pergamon: Oxford, 1996, 447.
(2) Schöllkopf, V. U.; Hartwig, W.; Sprotte, U.; Jung, W.
Angew. Chem., Int. Ed. Engl. 1979, 18, 310.
351.1208; found: 351.1209.
(3) (a) Coates, G. W.; Moore, D. R. Angew. Chem. Int. Ed. 2004,
43, 2215. (b) Dechy-Cabaret, O.; Martin-Vaca, B.;
Bourissou, D. Chem. Rev. 2004, 104, 6147.
(4) Kumar, P. R.; Murthy, K. N.; Raju, S.; Sarma, M. R.; Reddy,
G. O.; Venkateswarlu, A. WO 03010157, 2003; Chem.
Abstr. 2003, 138, 137316.
(3S)-3-Benzyl-6-butyl-3-phenyl-1,4-dioxane-2,5-dione (6j)
Following the procedure for the preparation of 4a, the reaction of 4c
(1.45 g, 6.0 mmol) and 2-bromohexanoyl chloride (1.41 g, 6.6
mmol) using Et3N (2 × 668 mg, 2 × 6.6 mmol) gave the desired
product 6j.
(5) Misaki, T.; Ureshino, S.; Nagase, R.; Oguni, Y.; Tanabe, Y.
Org. Process Res. Dev. 2006, 10, 500.
Yield: 1.97 g (97%); diastereomeric mixture [(3S,6R):(3S,6S) =
4:1]; colorless oil.
(6) (a) Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
(b) Fráter, G.; Müller, U.; Günther, W. Tetrahedron Lett.
1981, 22, 4221. (c) Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (d) Clayden,
J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry;
Oxford University Press: New York, 2001, 855.
(7) (a) Nagase, R.; Oguni, Y.; Misaki, T.; Tanabe, Y. Synthesis
2006, 3915. For related studies of stereocomplementary
cyclocondensation reaction for preparing thiazolidine-4-
ones, see: (b) Tanabe, Y.; Suzukamo, G.; Komuro, Y.;
Imanishi, N.; Morooka, S.; Enomoto, M.; Kojima, A.;
Sanemitsu, Y.; Mizutani, M. Tetrahedron Lett. 1991, 32,
379. (c) Tanabe, Y.; Kubota, Y.; Sanemitsu, Y.; Itaya, N.;
Suzukamo, G. Tetrahedron Lett. 1991, 32, 383. (d) Tanabe,
Y.; Yamamoto, H.; Murakami, M.; Yanagi, K.; Kubota, Y.;
Okumura, H.; Sanemitsu, Y.; Suzukamo, G. J. Chem. Soc.,
Perkin Trans. 1 1995, 935.
1H NMR (300 MHz, CDCl3): d = 0.71 (3 H × 1/5, t, J = 6.9 Hz),
0.77–1.50 (4 H, m), 0.84 (3 H × 4/5, t, J = 6.5 Hz), 1.71–2.02 (2 H,
m), 3.31 (1 H × 1/5, d, Jgem = 14.1 Hz), 3.35 (1 H × 4/5, d,
Jgem = 14.5 Hz), 3.60 (1 H × 4/5, d, Jgem = 14.5 Hz), 3.70 (1 H ×
1/5, d, Jgem = 14.1 Hz), 4.27 (1 H × 4/5, dd, J = 4.1, 1.6 Hz), 4.40
(1 H × 1/5, dd, J = 4.8, 8.6 Hz), 7.11–7.71 (10 H, m).
13C NMR (75 MHz, CDCl3): d = 13.4, 13.7, 21.6, 22.1, 26.2, 26.6,
29.9, 32.2, 46.3, 47.6, 75.9, 77.2, 77.3, 86.3, 124.5, 124.7, 127.2,
127.7, 127.9, 128.3, 129.1, 129.3, 129.35, 129.44, 131.2, 131.3,
133.2, 133.4, 135.4, 137.9, 165.4, 166.1, 166.3, 166.8.
IR (neat): 3063, 1755, 1267, 1091, 700 cm–1.
HRMS (ESI): m/z [C22H26O5 + MeOH + Na+] calcd for C22H26O5:
393.1678; found: 393.1675.
(3S)-3-Benzyl-6-isopropyl-3-phenyl-1,4-dioxane-2,5-dione (6k)
Following the procedure for the preparation of 6a, the reaction (20
h reaction time) of 4c (242 mg, 1.0 mmol) and 2-bromo-3-methyl-
butanoyl chloride (219 mg, 1.1 mmol) using Et3N (2 × 111 mg, 2 ×
1.1 mmol) gave the desired product 6k.
(8) Direct formation of 5B from (S)-4a (not through 5A) might
be considered. However, we speculate that this reaction does
not proceed because carboxylate anion of (S)-4a has higher
reactivity than the tertiary hydroxy group.
(9) (a) Chang, J.-W.; Jang, D.-P.; Uang, B.-J.; Liao, F.-L.;
Wang, S.-L. Org. Lett. 1999, 1, 2061. (b) Ooi, T.;
Fukumoto, K.; Maruoka, K. Angew. Chem. Int. Ed. 2006, 45,
3839.
Yield: 274 mg (85%); diastereomeric mixture [(3S,6R):(3S,6S) =
2:1]; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.79 (3 H × 1/3, d, J = 6.9 Hz),
0.82 (3 H × 1/3, d, J = 6.9 Hz), 0.89 (3 H × 2/3, d, J = 6.9 Hz), 0.97
(3 H × 2/3, d, J = 6.9 Hz), 1.66 (1 H × 1/3, dsept, J = 6.5, 6.9 Hz),
Synthesis 2008, No. 22, 3670–3674 © Thieme Stuttgart · New York