Synthesis of an immunomodulator (+)-conagenin and its analogs

Article abstract of DOI:10.1016/j.tet.2007.03.079

Stereoselective synthesis of an immunomodulator (+)-conagenin was achieved. Both amine and carboxylic acid moieties were prepared from commercially available optically active methyl 3-hydroxy-2-methylpropanoate using dirhodium(II)-catalyzed C-H amination

Full text of DOI:10.1016/j.tet.2007.03.079

Tetrahedron 63 (2007) 4429–4438
Synthesis of an immunomodulator (D)-conagenin and its analogs
*
Takayuki Yakura, Yuya Yoshimoto, Chisaki Ishida and Shunsuke Mabuchi
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
Received 3 March 2007; revised 13 March 2007; accepted 13 March 2007
Available online 16 March 2007
Abstract—Stereoselective synthesis of an immunomodulator (+)-conagenin was achieved. Both amine and carboxylic acid moieties were
prepared from commercially available optically active methyl 3-hydroxy-2-methylpropanoate using dirhodium(II)-catalyzed C–H amination
and chelation-controlled reductions as key steps. In addition, demethyl analogs of conagenin were synthesized using similar procedures.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
This report provides a full account of our total synthesis of 1
and synthesis of its demethyl analogs 2 and 3 (Fig. 1).
Ishizuka and co-workers isolated (+)-conagenin (Fig. 1, 1)
from fermentation broths of Streptomyces roseosporus
MI696-AF3 in 1991 as a low molecular weight immunomod-
ulator1 after screening for substances that modulate immune
response in conjunction with T-cell functions. Although most
immunomodulators primarily cause activation of macro-
phages to enhance inflammatory responses, which frequently
down regulates diseases, conagenin stimulates activated
T cells to produce lymphokines and generate antitumor effec-
tor cells in vitro and in vivo.1–3 In tumor bearing mice, con-
agenin administration inhibited tumor growth, and NK
activity remained at normal level,4 and 1 prevents myelosup-
pression induced by antitumor agents such as 5-fluorouracil,
mitomycin C.5,6 In addition, conagenin incubation enhanced
phagocytic function of alveolar macrophages.7,8
2. Results and discussion
Our strategy for total synthesis of 1 was outlined in Scheme
1. Both amine 5 and carboxylic acid 4 moieties were syn-
thesized starting from commercially available methyl 3-
hydroxy-2-methylpropanoate (8) because 8 is widely used in
natural product synthesis as a starting material17 and both
of its enantiomers are commercially available. Synthesis of
a-methylserine moiety 5 should be achieved quickly from
7 based on stereospecific dirhodium(II)-catalyzed C–H ami-
nation reaction18–21 as a key step. Carboxylic acid moiety 4
has been already prepared effectively from diol 6 by the
Hatakeyama9 and the Ichikawa11 groups. Therefore, we
envisioned the use of 6 as a precursor of 4. The diol 6 should
Because of these biological activities and its unique highly
functionalized structure, 1 has attracted much attention
from researchers in the field of synthetic chemistry. To
date, five total syntheses,9–13 including ours12 and a formal
synthesis14 of (+)-1, have been reported, in addition to syn-
theses of its analogs15 and a partial synthesis.16 We have re-
cently reported the stereoselective total synthesis of (+)-1.12
1
OAc OAc
MeO2C
OH
NHBoc
+
CO2H
4
5
OH OH
OAc OAc
known
OH OH
Ph
H
N
H
N
CO2H
OH
CO2Me
OH
R1
MeO2C
O
R2
O
O
H
2 : R1 = H, R2 = Me
(+)-conagenin (1)
H2N
O
3 : R1 = Me, R2 = H
6
7
Figure 1.
MeO2C
(R)- or (S)-8
OH
Keywords: Conagenin; Immunomodulator; Dirhodium(II)-catalyzed C–H
amination; Chelation-controlled reduction.
* Corresponding author. E-mail: yakura@pha.u-toyama.ac.jp
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.079

4430
T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
Table 1. C–H animation reaction of 7a
be prepared by stereoselective introductions of methyl and
phenyl groups to 8.
Entry Rh(II) Solvent Temperature Yield Recovery Yield based
of 9 of 7 (%) on consumed
(%)
7 (%)
2.1. Synthesis of a-methylserine moiety
1
Rh2(OAc)4 CH2Cl2 Reflux
Rh2(OAc)4 CH2Cl2 Reflux
Rh2(OAc)4 CH2Cl2 Reflux
24
30
28
8
25
24
25
0
64
53
41
9
16
15
59
0
67
64
47
9
30
29
63
0
2b
3c
4
We first investigated the utility of C–H amination for short
synthesis of a-methylserine (Scheme 2). Reaction of (R)-8
with trichloroacetyl isocyanate in dichloromethane at room
temperature gave the corresponding trichloroacetyl carba-
mate, which was treated with neutral alumina22 without pu-
rification to afford carbamate 7 in quantitative yield. Then
we examined dirhodium(II)-catalyzed C–H amination of 7
under Du Bois’ conditions.18 Therefore, treatment of 7
with 5 mol % of dirhodium(II) tetraacetate, 1.4 equiv of phe-
nyliodine(III) diacetate, and 2.3 equiv of magnesium oxide
in dichloromethane under reflux for 17 h gave the corre-
sponding C–H amination product 9 in only 9% yield along
with 83% of recovered 7 (53% yield based on the consumed
7). The NH group of oxazolidinone 9 was protected with
tert-butoxycarbonyl (Boc) group in the usual manner to
afford 10 in 88% yield. The oxazolidinone ring of 10 was
opened by treatment with cesium carbonate in methanol23
to give optically pure N-Boc-a-methylserine methyl ester
5, [a]2D8 +2.23 (c 1.33, CHCl3) {lit.24 [a]1D8 +1.9 (c 0.54,
CHCl3)}, in 87% yield. Optical purity of the synthesized
a-methylserine was determined to be 96.8% ee by chiral
HPLC analysis of its N-benzyloxycarbonyl (Cbz) derivative
11,11 which was prepared from 9 by protection of NH group
with Cbz group and following oxazolidinone ring opening,
using Daicel Chiralpak AD-H (hexane/iPrOH, 90:10,
0.5 mL minꢀ1). This result reveals that the dirhodium(II)-
catalyzed C–H amination of 7 proceeded with retention of
configuration, as Espino and Du Bois reported.18
Rh2(OAc)4 CHCl3
Reflux
5
6
7
8
9
10
Rh2(OAc)4 (ClCH2)2 Reflux
Rh2(OAc)4 Benzene Reflux
Rh2(OAc)4 CH3CN 50 ꢁC
Rh2(OAc)4 THF
50 ꢁC
Rh2(oct)4 CH2Cl2 Reflux
Rh2(esp)2 CH2Cl2 Reflux
22
44
0
65
35
67
63
68
0
11d Rh2(OAc)4 CH2Cl2 Reflux
a
The reaction was carried out using 10 mol % of Rh(II) catalyst, 4.2 equiv
of PhI(OAc)2, and 6.9 equiv of MgO for 17 h.
The reaction was heated for 40 h.
Rh(II) catalyst of 30 mol %, 12.6 equiv of PhI(OAc)2, and 20.7 equiv of
MgO were used.
PhI(OCOCF3)2 was used instead of PhI(OAc)2.
b
c
d
isolated 9 along with 35% of recovered 7 (68% yield based
on the consumed 7) were provided (Entry 10).
Alternatively, we attempted C–H amination of N-tosyloxy-
carbamate 12 using Lebel’s procedure.26 According to the
reported protocol, (R)-8 was treated with 1,10-carbonyldi-
imidazole, followed by N-hydroxylamine hydrochloride to
give the corresponding N-hydroxycarbamate, which was to-
sylated with tosyl chloride and triethylamine to afford 12.
Unfortunately, treatment of 12 and potassium carbonate in
the presence of dirhodium(II) tetrakis(triphenylacetate) in
dichloromethane at room temperature gave the oxazolidi-
none 9 in 29% yield without any recovery of 12 (Eq. 1).
MeO2C
a
O
MeO2C
(R)-8
Rh2(OCOCPh3)4
O
H
(quant)
(1)
9
H
7 H2N
O
K2CO3
(29%)
HN
O
12
OTs
MeO2C
b
c
O
(88%)
N
H
9
O
2.2. Synthesis of carboxylic acid moiety 4
MeO2C
RNH
CO2Me
OH
d
O
The next subject is the stereoselective synthesis of diol 6 and
its conversion into carboxylic acid moiety 4. From the per-
spective of applicability to syntheses of a wide range of
analogs, we chose a stepwise procedure for 6 from the same
starting material, methyl 3-hydroxy-2-methylpropanoate
(8). Stereoselective construction of three continuing stereo-
centers of 6 is expected to occur by stepwise chelation-con-
trolled reductions of the corresponding ketones (Scheme 3)
from studies related to the chemistry of methyl 3-hydroxy-2-
methylpropanoate.17,27 Then we investigated routes A and B
using stereoselective chelation-controlled reductions. Be-
cause it is known that racemic b-hydroxy phenyl ketone
13a is stereoselectively reduced with zinc borohydride to
give syn diol 14a with high level,28 we first examined route
A. According to reported protocol, treatment of b-hydroxy
phenyl ketones 13a with zinc borohydride in diethyl ether
at 0 ꢁC for 30 min gave rise to syn alcohol 14a stereoselec-
tively in high yield (Table 2, Entry 1). In addition, p-methoxy-
benzyl (PMB) ether 13b was reduced stereoselectively to
afford 14b under identical conditions (Table 2, Entry 2).
(87%)
N
Boc
O
5: R=Boc
11: R=Cbz
10
Scheme 2. Reagents and conditions: (a) CCl3CON]C]O, CH2Cl2, rt, 1 h
then neutral Al2O3; (b) see Table 1; (c) (Boc)2O, Et3N, DMAP, THF, rt, 2 h;
and (d) Cs2CO3, MeOH, rt, 2.5 h.
This method became a convenient procedure for the synthe-
sis of a-methylserine. However, the key C–H amination
reaction is not satisfactory. Therefore, we next examined
other reaction conditions (Table 1). When 10 mol % of
Rh2(OAc)4, 4.2 equiv of PhI(OAc)2, and 6.9 equiv of MgO
were used, the reaction was accelerated and the yield was in-
creased to 24% (Entry 1). Both longer reaction time and fur-
ther larger amounts of reagents were not effective (Entries
2 and 3). Influences of other solvents, dirhodium catalysts,
and hypervalent iodine reagents were investigated (Entries
4–11). Among them, the highest yield was obtained using
the reaction with dirhodium(II) bis(a,a,a0,a0-tetramethyl-
1,3-benzenedipropanoate) [Rh2(esp)2],25 in which 44% of

T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
4431
PGO OH
Ph
PGO
O
O
OH
Ph
(S)-8
(R)-8
Ph
OH OH
2
route A
stereoselective
stereoselective
reduction
Ph
1
3
reduction
OH OPG
OH
O
O
OPG
1,2-syn, 2,3-syn
6
Ph
route B
PG: protecting group
Scheme 3.
Table 2. Stereoselective reduction of a-methyl-b-alkoxy-ketones
PMBO
a
b, c
(72%)
R2O
O
CO2Me
R2O OH R2O OH
(S)-8
Zn(BH4)2
Et2O
R1
R1
R1
16
e
13
14 (syn)
15 (anti)
13a
13b
(66%)
Entry
13
R1
R2
H
PMB
H
PMB
Yield (%)
14:15a
d
d
(94%)
(98%)
1
2
3
4
a
b
c
Ph
Ph
Me
Me
98
94
Low
92
17:1
19:1
PMBO
OH
OH OH
1.1:1b
1.4:1b
e
d
Ph
14a
Ph
14b
(61%)
Determined by 1H NMR.
The stereochemistry of neither diastereomer was determined.
a
b
f
g
(64%)
(94%)
Because a-methylserine moiety 5 was successfully prepared
from (R)-8, we expected route B, starting from the same (R)-
8, should be a more convenient procedure than route A, start-
ing from (S)-8. Reductions of methyl ketones 13c and 13d
were investigated with the hope of obtaining high stereo-
selectivity (Table 2, Entries 3 and 4). Unfortunately, reduc-
tions of 13c and 13d with zinc borohydride afforded
a non-selective mixture of 14 and 15, respectively. There-
fore, we envisioned to prepare 6 according to route A. A sim-
ilar difference of stereoselectivity in between the reduction
of phenyl ketone and that of methyl ketone was observed
in a similar TiCl4 mediated reduction.29
OMe
O
O
4
2
h
(84%)
Ph
17
OPMB
OH OPMB
i
OHC
Ph
19
Ph
18
(85%)
Scheme 4. Reagents and conditions: (a) Ref. 30; (b) LiOH, H2O–MeOH, rt,
4 h; (c) PhLi, Et2O, rt, 30 min; (d) Zn(BH4)2, Et2O, 0 ꢁC, 30 min; (e) DDQ,
CH2Cl2–MeOH, rt, 2 h; (f) DDQ, MS 3A, CH2Cl2, rt, 1.5 h; (g) p-anisalde-
hyde dimethylacetal, CSA, CH2Cl2, rt, 12 h, (h) DIBAL-H, CH2Cl2, ꢀ80 ꢁC
to 0 ꢁC, 1 h; and (i) Dess–Martin periodinane, CH2Cl2, rt, 30 min.
Route A proved to be the most suitable for synthesis of 6.
Therefore, we started stereoselective introduction of phenyl
group according to route A (Scheme 4). The hydroxy group
of starting (S)-8 was protected as PMB ether with 2-
PMBoxy-3-nitropyridine using the Mukaiyama protocol30
to give known 16. Hydrolysis of 16 with lithium hydroxide,
followed by treatment with 2 equiv of phenyl lithium
afforded phenyl ketone 13b. As described above, chela-
tion-controlled reduction of PMBoxy-ketone 13b was ac-
complished using zinc borohydride to afford syn-alcohol
14b in 94% yield as a major isomer. The ratio of syn-isomer
and anti-isomer was estimated as 19:1 by integration of the
respective intensities of the peak heights of the signals due to
the methyl protons at 2-position that appeared at d 0.85 (d)
and 0.75 (d), in the 1H NMR spectrum of the mixture. Treat-
ment of 14b with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
protons (Fig. 2). These results suggested the 1,2-syn relation-
ship of 14b. Alternatively, deprotection of 13b with DDQ
gave hydroxyl ketone 13a, which was reduced with zinc
borohydride to afford the optically active 14a (syn:anti¼
17:1) stereoselectively. The stereochemistry of 14a was de-
termined through the comparison of spectroscopic data to
those of the known authentic sample.28,31,32 Also, de(p-
methoxy)benzylation of 14b with DDQ gave 14a. The
resulting diol 14a was successfully converted into 17 by
treatment with p-anisaldehyde dimethyl acetal in the pres-
ence of camphorsulfonic acid (CSA) in 94% yield.
˚
none (DDQ) in the presence of molecular sieves 3 A (MS
3A) in anhydrous dichloromethane gave benzylideneacetal
Me
17 in 64% yield as a single diastereomer. The stereochemis-
try of 17 was determined by a coupling constant in the H
5
OMe
O
1
H
2
O
Ph
4
NMR spectrum of 17 and nuclear Overhauser effect
(NOE) experiments to be thermodynamically stable 2,4-syn-
4,5-syn-isomer; J4,5 was 2.7 Hz and positive NOEs were
observed between H-2 and H-4 protons and H-4 and H-5
NOE
H
H
NOE
J
4,5 = 2.7 Hz
Figure 2.

4432
T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
Subsequent diisobutylaluminum hydride (DIBAL-H) reduc-
tion of 17 gave rise to the primary alcohol 18 in 84% yield.
Dess–Martin periodinane oxidation of 18 produced 19 in
85% yield.
dicyclohexylcarbodiimide (DCC) in the presence of 1-hy-
droxybenzotriazole (HOBt) in dichloromethane to give ester
23 in 89% yield. The resultant 23 was deprotected by treat-
ment with trifluoroacetic acid to produce amine 24, which
was converted into 25 by O–N intramolecular acyl migration
using sodium bicarbonate to afford diacetylconagenin
methyl ester 25 in 81% yield from 23. Deprotection was car-
ried out under basic conditions to provide (+)-conagenin (1),
mp 154–157 ꢁC, [a]2D8 +56.6 (c 0.20, MeOH) {lit.1 mp 159–
161 ꢁC, [a]2D7 +55.4, lit.11 mp 153–155 ꢁC, [a]2D0 +56.8 (c
0.44, MeOH)}, in 71% yield. Spectroscopic data of 1 were
identical to those of the reported sample.9,11
Next, the stereoselective construction of another chiral cen-
ter was investigated (Scheme 5). Methylation of 19 with
methyllithium in diethyl ether afforded a 4:1 mixture of
two diastereomers33 of secondary alcohol 20 in 91% yield.
The mixture was oxidized with Dess–Martin periodinane
to provide methyl ketone 21. Then stereoselective reduction
of 21 was examined. In contrast to the reduction of 13b,
unfortunately, reduction of PMBoxy-ketone 21 with zinc
borohydride in diethyl ether occurred with a low level of dia-
stereoselectivity (2:1)33 to give 20, which might be caused
by the difficulty of formation of chelation of ether oxygen
with zinc atom because of the steric hindrance of large sub-
stituents, such as phenyl and PMB groups, around the ether
oxygen (Fig. 3, A). To form the more rigid chelated complex
B (Fig. 3), PMB group was removed: compound 21 was
reacted with DDQ in dichloromethane to give b-hydroxyke-
tone 22 in 83% yield. The desired stereoselective reduction
of 22 was accomplished by treatment with zinc borohydride,
in diethyl ether at 0 ꢁC to afford the known diol 6 (>50:1),
[a]D27 +35.4 (c 1.06, CHCl3) {lit.9 [a]2D4 +35.5 (c 0.46,
CHCl3), lit.11 [a]D18 +41.0 (c 1.05, CHCl3)}, in 83% yield.
According to the reported procedure,9,11 protection of both
hydroxy groups as acetates and oxidation of phenyl group
with ruthenium tetraoxide afforded the carboxylic acid
moiety 4 (86%).
OAc OAc
a
b
O
+
4
5
(89%)
HN
Boc
CO2Me
O
23
OAc OAc
c
O
(81% from 23)
H2N
CO2Me
O
24
OAc OAc
H
N
CO2Me
OH
d
1
(71%)
O
25
Scheme 6. Reagents and conditions: (a) DCC, HOBt, DMAP, CH2Cl2, rt,
1.5 h; (b) CF3CO2H, CH2Cl2, rt, 4 h; (c) saturated NaHCO3, THF, rt,
10 h; and (d) 1 M K2CO3–MeOH (1:3), rt, 2 h.
OH OPMB
Ph
O
OPMB
Ph
a
b
The total synthesis of (+)-conagenin was accomplished.
Therefore, we applied our methodology to the synthesis of
its analogs by using the synthetic intermediates (Scheme
7). The diol 14a was acetylated (97%) and then its phenyl
group was oxidized to afford 26, which was used as the carb-
oxylic acid moiety lost one carbon. Amido formation of 26
with methylserine 5 was accomplished via ester 27 accord-
ing to the same procedure of conagenin synthesis to give
19
(91%)
(quant)
20
21
O
OH
OH OH
Ph
c
d
(83%)
Ph
(83%)
22
6
OAc OAc
CO2H
e, f
(86%)
4
OH OH
Ph
14a
OAc OAc
CO2H
26
a,b
(97%)
Scheme 5. Reagents and conditions: (a) MeLi, Et2O, ꢀ80 ꢁC to 0 ꢁC, 1 h;
(b) Dess–Martin periodinane, CH2Cl2, rt, 30 min; (c) DDQ, CH2Cl2–
MeOH, rt, 2 h; (d) Zn(BH4)2, Et2O, 0 ꢁC, 30 min; (e) Ac2O, pyridine,
DMAP, rt, 30 min; and (f) cat. RuCl3, H5IO6, CH3CN–CCl4–H2O, rt, 18 h.
OAc OAc
c
d
+
2
2.3. Completion of synthesis of conagenin and applica-
tion to preparation of demethyl analogs
3
26
O
(57%)
(34%)
CO2Me
HN
O
27
Boc
Finally, conversion to (+)-conagenin (1) was accomplished
using a modified Ichikawa’s procedure11 (Scheme 6).
Thereby, condensation of 4 and 5 proceeded using 1,3-
BocHN
CO2Me
c
+
4
(80%)
OH
28
Zn
OAc OAc
Me
Me
Me
Ph
H
Me
Ph
H
O
O
O
H
d
3
Zn
(72%)
O
O
HN
O
CO2Me
H
H
H
Boc
29
rigid complex
B
OMe
Scheme 7. Reagents and conditions: (a) Ac2O, pyridine, DMAP, rt; (b) cat.
RuCl3, H5IO6, CH3CN–CCl4–H2O, rt; (c) DCC, HOBt, DMAP, CH2Cl2, rt;
(d) CF3CO2H, CH2Cl2, rt then saturated NaHCO3, THF, rt.
A
Figure 3.

T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
4433
demethyl derivative 2. It is known that the a-alkyl a-amino
acids increase conformational restrictions in peptides and
thereby change their biological activity and stability.34
Therefore, it is very interesting to investigate the difference
of conformations and activities of between conagenin and its
serine derivative that has no methyl group at a-position
of amino acid moiety. Coupling of pentanoic acid 4 with
N-Boc-serine methyl ester 2835 gave ester 29 (72%), which
was converted into 3 by deprotection of Boc group and O–N
acyl migration as a single diastereomer in 80% yield.
(75 MHz, CDCl3) d: 13.6, 39.2, 51.8, 66.0, 156.7, 174.4;
Anal. Calcd for C6H11NO4: C, 44.72; H, 6.88; N, 8.69.
Found: C, 45.09; H, 6.85, N, 8.53.
4.1.2. Methyl (S)-4-methyl-2-oxooxazolidine-4-carboxyl-
ate (9). A suspension of 7 (98 mg, 0.61 mmol), PhI(OAc)2
(823 mg, 2.55 mmol), MgO (169 mg, 4.19 mmol), and
Rh2(esp)2 (46 mg, 0.06 mmol) in CH2Cl2 (3.0 mL) was re-
fluxed for 17 h. After the mixture was cooled to room tem-
perature, it was passed through a short Celite pad and the
filtrate was concentrated. The residue was chromatographed
on silica gel (50% EtOAc in hexane) to give 9 (43 mg, 44%)
and starting 7 (34 mg, 35%). The compound 9 was obtained
as colorless crystals: mp 45–47 ꢁC (EtOAc–hexane); [a]2D8
ꢀ11.5 (c 1.06, CHCl3); IR (KBr) cmꢀ1: 3230, 3125, 1793,
3. Conclusion
The convergent total synthesis of (+)-1 was accomplished
starting from commercially available methyl 3-hydroxy-2-
methylpropanoate 8. Amine moiety 5 was synthesized using
C–H amination reaction as a key step. Carboxylic acid moi-
ety 4 was prepared based on chelation-controlled reductions
with zinc borohydride. As applications of this methodology,
demethyl derivatives 2 and 3 were synthesized. Conversion
of 2 and 3 to their free acids and investigation of their con-
formations and biological activities are now underway in
our laboratory.
1
1743, 1730; H NMR (270 MHz, CDCl3) d: 1.59 (3H, s),
3.81 (3H, s), 4.15 (1H, d, J¼8.9 Hz), 4.70 (1H, d,
J¼8.9 Hz), 6.30 (1H, br s); 13C NMR (67.5 MHz, CDCl3)
d: 24.3, 53.2, 60.8, 73.0, 158.1, 172.6; HRMS m/z calcd
for C6H9NO4 (M+) 159.0532, found 159.0536.
4.1.3. 3-tert-Butyl 4-methyl (S)-4-methyl-2-oxooxazol-
idine-3,4-dicarboxylate (10). A mixture of 9 (147 mg,
0.92 mmol), (Boc)2O (403 mg, 1.85 mmol), Et3N (327 mg,
3.23 mmol), and DMAP (23 mg, 0.18 mmol) in THF
(9 mL) was stirred at room temperature under a nitrogen at-
mosphere for 2 h. The mixture was diluted with Et2O. The
solution was washed with saturated aqueous NH4Cl, water,
and brine, dried (MgSO4) and concentrated. The residue
was chromatographed on silica gel (25% EtOAc in hexane)
to give 10 (263 mg, 88%) as a colorless oil: [a]2D7 ꢀ0.34 (c
4. Experimental
4.1. General
Melting points are uncorrected. IR spectra were recorded
using JASCO FT/IR-460 Plus spectrophotometer. 1H NMR
spectra were determined with Varian Unity plus 500
(500 MHz), Varian Gemini 300 (300 MHz), and JEOL
JNM-FX270 (270 MHz) spectrometers, tetramethylsilane
as an internal standard. 13C NMR spectra were determined
with Varian Unity plus 500 (125 MHz), Varian Gemini 300
(75 MHz), and JEOL JNM-FX270 (67.5 MHz) spectrome-
ters. All 13C NMR spectra were determined with complete
proton decoupling. High resolution MS were determined
with JEOL JMS-GCmate and JEOL JMS-AX505HAD in-
struments. Optical rotations were measured with JASCO
DIP-1000 polarimeter. Column chromatography was per-
formed on Silica Gel 60 PF254 (Nacalai Tesque) under pres-
sure. Methyl (R)-3-hydroxy-2-methylpropanoate [(R)-8]
was purchased from Aldrich and methyl (S)-3-hydroxy-2-
methylpropanoate [(S)-8] was gifted by Mitsubishi Rayon
Co. Ltd.
1
1.43, CHCl3); IR (neat) cmꢀ1: 1823, 1752, 1730; H NMR
(300 MHz, CDCl3) d: 1.52 (9H, s), 1.75 (3H, s), 3.81 (3H,
s), 4.05 (1H, d, J¼8.8 Hz), 4.32 (1H, d, J¼8.8 Hz); 13C
NMR (75 MHz, CDCl3) d: 22.1, 28.1 (3), 53.4, 63.4,
71.0, 84.8, 148.5, 151.6, 170.8; HRMS m/z calcd for
C11H17NO6 (M+) 259.1056, found 259.1073.
4.1.4. Methyl (S)-2-tert-butoxycarbonylamino-3-
hydroxy-2-methylpropanoate (5). A mixture of 10
(263 mg, 1.01 mmol) and Cs2CO3 (66 mg, 0.2 mmol) in
MeOH (10 mL) was stirred at room temperature for 2.5 h.
The mixture was diluted with Et2O. The solution was
washed with saturated aqueous NH4Cl, water, and brine,
dried (MgSO4) and concentrated. The residue was chroma-
tographed on silica gel (40% EtOAc in hexane) to give 5
(206 mg, 87%) as a colorless oil: [a]2D8 +2.23 (c 1.34,
CHCl3) {lit.23 [a]D18 +1.9 (c 0.54, CHCl3)}; IR (neat) cmꢀ1
:
1
3600–3200, 1717, 1696; H NMR (300 MHz, CDCl3) d:
1.44 (9H, s), 1.47 (3H, s), 3.78 (3H, s), 3.78 (1H, d,
J¼11.0 Hz), 3.96 (1H, d, J¼11.3 Hz), 5.35 (1H, br s); 13C
NMR (75 MHz, CDCl3) d: 21.1, 28.5 (3), 52.9, 61.2, 67.1,
80.5, 155.4, 173.9; HRMS m/z calcd for C10H19NO5 (M+)
233.1263, found 233.1237.
4.1.1. Methyl (R)-3-carbamoyloxy-2-methylpropanoate
(7). Trichloroacetyl isocyanate (1.75 g, 9.31 mmol) was
added to a solution of (R)-8 (1.0 g, 8.47 mmol) in CH2Cl2
(50 mL) at room temperature under a nitrogen atmosphere
and the mixture was stirred for 1 h. Then a mixture was
passed through a short neutral Al2O3 column with ethyl ace-
tate and the mixture was concentrated. The residue was chro-
matographed on silica gel (40% EtOAc in hexane) to give 7
(1.39 g, quant) as colorless crystals: mp 55–57 ꢁC (EtOAc–
4.1.5. 3-Benzyl 4-methyl (S)-4-methyl-2-oxooxazolidine-
3,4-dicarboxylate. A mixture of 9 (18 mg, 0.11 mmol),
(Cbz)2O (65 mg, 0.22 mmol), Et3N (63 mg, 0.6 mmol),
and DMAP (3 mg, 0.02 mmol) in THF (1.5 mL) was stirred
at room temperature under a nitrogen atmosphere for 48 h.
The mixture was diluted with Et2O. The solution was
washed with saturated aqueous NH4Cl, water, and brine,
dried (MgSO4) and concentrated. The residue was
hexane); [a]2D8 ꢀ109.0 (c 1.18, CHCl3); IR (KBr) cmꢀ1
:
1
3445, 3353, 3301, 3208, 1740, 1716; H NMR (300 MHz,
CDCl3) d: 1.20 (3H, d, J¼7.1 Hz), 2.81 (1H, quintet d,
J¼7.1, 5.8), 3.71 (3H, s), 4.17 (1H, dd, J¼10.7, 5.8 Hz),
4.23 (1H, dd, J¼10.7, 7.4 Hz), 4.74 (2H, br s); 13C NMR

4434
T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
chromatographed on silica gel (30% EtOAc in hexane) to
give the titled compound (21 mg, 64%) as a colorless oil:
[a]2D7 ꢀ18.8 (c 1.00, CHCl3); IR (neat) cmꢀ1: 1826, 1808,
(ca. 0.15 mol Lꢀ1, 2.4 mL, 0.36 mmol), prepared from
NaBH4 and ZnCl2 according to the reported procedure,
was added to a solution of 13b (93 mg, 0.33 mmol) in
Et2O (5 mL) at 0 ꢁC under a nitrogen atmosphere. The mix-
ture was stirred at the same temperature for 30 min. The
mixture was poured into 10% HCl, and extracted with
EtOAc. The extract was washed with saturated aqueous
NaHCO3, water, and brine, dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel
(10% EtOAc in hexane) to give a 19:1 mixture of 14b and
its anti-isomer (88 mg, 94%) as a colorless oil: IR
(neat) cmꢀ1: 3600–3200, 1612, 1586, 1513, 1248; 1H
NMR for the major isomer (500 MHz, CDCl3) d: 0.85
(3H, d, J¼7.3 Hz), 2.12–2.22 (1H, m), 3.22 (1H, s), 3.45
(1H, dd, J¼9.2, 6.3 Hz), 3.50 (1H, dd, J¼9.2, 4.3 Hz),
3.82 (3H, s), 4.46 (2H, s), 4.91 (1H, d, J¼3.3 Hz), 6.90 (2H,
d, J¼6.6 Hz), 7.22–7.32 (7H, m); selected signals for the mi-
nor isomer d: 0.75 (3H, d, J¼7.3 Hz); 13C NMR for the ma-
jor isomer (125 MHz, CDCl3) d: 11.2, 40.1, 55.3, 73.1, 73.7,
76.3, 113.8 (2), 126.1 (2), 126.9, 127.9 (2), 129.3 (2), 130.1,
142.9, 159.3; HRMS m/z calcd for C18H22O3 (M+) 286.1569,
found 286.1541. The ratio of 14b and its anti-isomer was es-
timated to be 19:1 by integration of the intensities of the peak
height of the signals due to the methyl protons at 2-position,
which appeared at d 0.85 (d) and 0.75 (d), respectively.
1
1751; H NMR (300 MHz, CDCl3) d: 1.75 (3H, s), 3.64
(3H, s), 4.07 (1H, d, J¼9.1 Hz), 4.34 (1H, d, J¼9.1 Hz),
5.26 (1H, A of ABq, J¼12.4 Hz), 5.35 (1H, B of ABq,
J¼12.4 Hz), 7.26–7.43 (5H, m); 13C NMR (75 MHz,
CDCl3) d: 21.7, 53.3, 63.4, 68.9, 71.2, 128.1 (2), 128.5 (3),
134.5, 150.2, 151.0, 170.3; HRMS m/z calcd for
C14H15NO6 (M+) 293.0899, found 293.0887.
4.1.6. Methyl (S)-2-benzyloxycarbonylamino-3-hydroxy-
2-methylpropanoate (11). A mixture of 3-benzyl 4-methyl
(S)-4-methyl-2-oxooxazolidine-3,4-dicarboxylate (20 mg,
0.06 mmol) and Cs2CO3 (5 mg, 0.01 mmol) in MeOH
(1 mL) was stirred at room temperature for 2 h. The mixture
was diluted with Et2O. The solution was washed with satu-
rated aqueous NH4Cl, water, and brine, dried (MgSO4) and
concentrated. The residue was chromatographed on silica
gel (40% EtOAc in hexane) to give 11 (12 mg, 67%) as a col-
orless oil: [a]D27 +5.36 (c 0.50, CHCl3) {lit.11 [a]2D1 +3.9
(c 0.31, CHCl3)}; IR (neat) cmꢀ1: 3600–3200, 1724, 1514;
1H NMR (270 MHz, CDCl3) d: 1.51 (3H, s), 2.93 (1H, br
s), 3.77 (3H, s), 3.81 (1H, dd, J¼11.2, 6.9 Hz), 4.02 (1H,
dd, J¼11.2, 5.28 Hz), 5.10 (2H, s), 5.66 (1H, br s), 7.30–
7.41 (5H, m); 13C NMR (67.5 MHz, CDCl3) d: 20.5, 52.9,
61.4, 66.6, 67.0, 128.1 (2), 128.2, 128.6 (2), 136.1, 155.5,
173.6; HRMS m/z calcd for C13H17NO5 (M+) 267.1107,
found 267.1114. HPLC (Daicel Chiralpak AD-H (0.46ꢂ
25 mm); hexane/iPrOH, 9:1; flow rate 0.5 mL minꢀ1; UV
254 nm): (R)-11: tR 33.8 min (1.6%); (S)-11, tR 51.8 min
(98.4%).
4.1.9. (2R,4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-phe-
nyl[1,3]dioxane (17). After a suspension of 14b (31 mg,
0.11 mmol) and MS 3A (40 mg) in CH2Cl2 (2 mL) was
stirred at room temperature for 30 min under a nitrogen at-
mosphere, DDQ (20 mg, 0.12 mmol) was added to the mix-
ture and stirred at the same temperature for further 1.5 h. The
mixture was diluted with Et2O, washed with saturated aque-
ous NaHCO3, water, and brine, dried (MgSO4) and concen-
trated. The purification of the residue by chromatography on
silica gel (10% EtOAc in hexane) and recrystallization from
EtOAc–hexane gave 17 (20 mg, 64%) with >99% purity de-
4.1.7. (S)-3-(4-Methoxybenzyloxy)-2-methyl-1-phenyl-
propan-1-one (13b). An aqueous solution of LiOH (1.5 N,
2.5 mL, 3.78 mmol) was added to a solution of 16
(300 mg, 1.26 mmol) in MeOH (6 mL) and the mixture
was stirred at room temperature for 4 h. After the reaction
mixture was acidified by adding 10% HCl solution the mix-
ture was extracted with EtOAc, washed with water, and
brine, dried (MgSO4) and concentrated to give crude acid
(282 mg, quant), which was used without purification. A so-
lution of PhLi in Et2O (1.5 mol Lꢀ1, 0.32 mL, 0.47 mmol)
was added to a solution of the crude acid (52 mg,
0.23 mmol) in Et2O (3 mL) at 0 ꢁC under a nitrogen atmo-
sphere. The mixture was stirred at room temperature for
30 min. The mixture was diluted with Et2O. The solution
was washed with saturated aqueous NH4Cl, water, and brine,
dried (MgSO4) and concentrated. The residue was chroma-
tographed on silica gel (10% EtOAc in hexane) to give
13b (48 mg, 72%) as a colorless oil: [a]2D7 +27.4 (c 2.70,
1
termined by H NMR as colorless crystals: mp 52–53 ꢁC;
[a]2D8 +51.7 (c 1.74, CHCl3); IR (KBr) cmꢀ1: 1616, 1588,
1518, 1498; H NMR (300 MHz, CDCl3) d: 0.96 (3H, d,
1
J¼6.9 Hz), 1.92 (1H, qtd, J¼6.9, 2.6, 1.4 Hz, 5-H), 3.82
(3H, s), 4.12 (1H, dd, J¼11.3, 1.4 Hz, 6-Heq), 4.30 (1H,
dd, J¼11.3, 2.5 Hz, 6-Hax), 5.14 (1H, d, J¼2.7 Hz, 4-H),
5.67 (1H, s, 2-H), 6.93 (2H, d, J¼8.8 Hz), 7.20–7.30 (1H,
m), 7.30–7.4 (4H, m), 7.53 (2H, d, J¼8.5 Hz), positive
NOEs were observed between protons appearing at d 1.92
and 4.30, d 1.92 and 5.14, d 4.30 and 5.14, d 4.30 and
5.67, and d 5.14 and 5.67; 13C NMR (75 MHz, CDCl3) d:
11.6, 34.3, 55.5, 73.5, 80.9, 102.0, 113.7 (2), 125.4 (2),
127.0, 127.6 (2), 128.2 (2), 131.5, 140.6, 160.0; Anal. Calcd
for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.15; H, 7.16;
HRMS m/z calcd for C18H20O3 (M+) 284.1413, found
284.1403.
1
CHCl3); IR (neat) cmꢀ1: 1681, 1612; H NMR (300 MHz,
CDCl3) d: 1.21 (3H, d, J¼6.9 Hz), 3.47–3.56 (1H, m),
3.73–3.86 (2H, m), 3.78 (3H, s), 4.40 (1H, d, J¼11.5 Hz),
4.46 (1H, d, J¼11.5 Hz), 6.83 (2H, d, J¼8.8 Hz), 7.18
(2H, d, J¼8.8 Hz), 7.42–7.48 (2H, m), 7.51–7.58 (1H, m),
7.91–7.98 (2H, m); 13C NMR (75 MHz, CDCl3) d: 15.0,
41.5, 55.2, 72.2, 73.0, 113.6 (2), 128.2 (2), 128.4 (2),
129.0 (2), 130.2, 132.8, 136.5, 158.9, 202.6; HRMS m/z
calcd for C18H20O3 (M+) 284.1413, found 284.1405.
4.1.10. (S)-3-Hydroxy-2-methyl-1-phenylpropan-1-one
(13a). A mixture of 13b (77 mg, 0.272 mmol) and DDQ
(65 mg, 0.285 mmol) in CH2Cl2–MeOH (10:1, 5 mL) was
stirred at room temperature for 2 h. The mixture was diluted
with CH2Cl2. The solution was washed with saturated aque-
ous NaHCO3, water, and brine, dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel (20%
EtOAc in hexane) to give 13a (29 mg, 66%) as a colorless
oil: [a]2D9 +45.2 (c 0.95, EtOH) {lit.36 (R)-isomer: [a]2D4
4.1.8. (1R,2S)-3-(4-Methoxybenzyloxy)-2-methyl-1-phe-
nylpropan-1-ol (14b). A solution of Zn(BH4)2 in Et2O

T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
4435
ꢀ42.1 (c 0.28, EtOH)}; IR (neat) cmꢀ1: 3600–3200, 1678;
1H NMR (270 MHz, CDCl3) d: 1.24 (3H, d, J¼6.9 Hz),
2.41 (1H, br s), 3.68 (1H, quintet d, J¼6.9, 4.3 Hz), 3.80
(1H, dd, J¼11.2, 4.3 Hz), 3.94 (1H, dd, J¼11.2, 6.9 Hz),
7.48 (2H, t, J¼7.3 Hz), 7.58 (1H, t, J¼7.3 Hz), 7.97 (2H,
d, J¼7.3 Hz); 13C NMR (67.5 MHz, CDCl3) d: 14.5, 42.9,
64.5, 128.4 (2), 128.7 (2), 133.3, 136.1, 204.4; HRMS m/z
calcd for C10H12O2 (M+) 164.0837, found 164.0853.
chromatographed on silica gel (20% EtOAc in hexane) to
give 18 (16 mg, 84%) as a colorless oil: [a]2D9 +97.5 (c
1.44, CHCl3); IR (neat) cmꢀ1: 3600–3200, 1613, 1586,
1
1514, 1249; H NMR (300 MHz, CDCl3) d: 0.86 (3H, d,
J¼7.1 Hz), 2.00–2.10 (1H, m), 2.24 (1H, br), 3.47 (1H,
dd, J¼10.7, 4.4 Hz), 3.57 (1H, dd, J¼10.7, 7.1 Hz), 3.81
(3H, s), 4.18 (1H, A of ABq, J¼11.5 Hz), 4.47 (1H, B of
ABq, J¼11.5 Hz), 4.51 (1H, d, J¼4.9 Hz), 6.88 (2H, d,
J¼8.8 Hz), 7.22 (2H, d, J¼8.8 Hz), 7.30–7.39 (5H, m);
13C NMR (75 MHz, CDCl3) d: 11.8, 41.6, 55.3, 65.8, 70.4,
83.2, 113.8 (2), 127.3 (2), 127.5, 128.3 (2), 129.4 (2),
130.2, 139.8, 159.2; HRMS m/z calcd for C18H22O3 (M+)
286.1569, found 286.1544.
4.1.11. (1R,2S)-2-Methyl-1-phenylpropane-1,3-diol (14a).
(i) From 13a. A solution of Zn(BH4)2 in Et2O (ca.
0.15 mol Lꢀ1, 9.3 mL, 1.4 mmol) was added to a solution
of 13a (209 mg, 1.27 mmol) in Et2O (12 mL) at 0 ꢁC un-
der a nitrogen atmosphere. The mixture was stirred at the
same temperature for 30 min. The mixture was poured
into 10% HCl, and extracted with EtOAc. The extract
was washed with saturated aqueous NaHCO3, water,
and brine, dried (MgSO4) and concentrated. The residue
was chromatographed on silica gel (50% EtOAc in hex-
ane) to give 14a (208 mg, 98%) as colorless crystals: mp
73–75 ꢁC (EtOAc–hexane); [a]D27 +56.1 (c 0.75, CHCl3)
{lit.31 [a]2D0 +57.8 (c 0.45, CHCl3), lit.32 [a]2D0 +52.6 (c
0.57, CHCl3)}; IR (KBr) cmꢀ1: 3600–3200, 1603, 1493,
1452. 1H NMR (270 MHz, CDCl3) d: 0.82 (3H, d,
J¼7.3 Hz), 2.00–2.10 (1H, m), 2.87 (2H, s), 3.64 (2H, d,
J¼4.9 Hz), 4.92 (1H, d, J¼4.0 Hz), 7.23–7.42 (5H, m);
13C NMR (67.5 MHz, CDCl3) d: 10.7, 41.3, 66.4, 76.5,
126.1 (2), 127.2, 128.1 (2), 142.6; Anal. Calcd for
C10H14O2: C, 72.26; H, 8.49. Found: C, 71.99; H, 8.40.
(ii) From 14b. A mixture of 14b (6 mg, 0.02 mmol) and
DDQ (5 mg, 0.02 mmol) in CH2Cl2–MeOH (10:1,
1 mL) was stirred at room temperature for 2 h. The mix-
ture was diluted with CH2Cl2. The solution was washed
with saturated aqueous NaHCO3, water, and brine, dried
(MgSO4) and concentrated. The residue was chromato-
graphed on silica gel (50% EtOAc in hexane) to give
14a (6 mg, 61%), whose spectroscopic data were identical
with those of the samples prepared from 13a.
4.1.14. (2R,3R)-3-(4-Methoxybenzyloxy)-2-methyl-3-
phenylpropan-1-al (19).
A mixture of 18 (57 mg,
0.2 mmol) and Dess–Martin periodinane (127 mg,
0.30 mmol) in CH2Cl2 (3 mL) was stirred at room tempera-
ture for 30 min. The mixture was diluted with Et2O, the
whole was washed with saturated aqueous Na2S2O3, satu-
rated aqueous NaHCO3, and brine, dried (MgSO4), and con-
centrated. The residue was chromatographed on silica gel
(10% EtOAc in hexane) to give 19 (48 mg, 85%) as a color-
less oil: [a]2D9 +60.9 (c 1.40, CHCl3); IR (neat) cmꢀ1: 1725,
1612, 1513, 1249; 1H NMR (270 MHz, CDCl3) d: 1.08 (3H,
d, J¼6.9 Hz), 2.66 (1H, br quintet, J¼6.5 Hz), 3.81 (3H, s),
4.21 (1H, A of ABq, J¼11.5 Hz), 4.48 (1H, B of ABq,
J¼11.5 Hz), 4.77 (1H, d, J¼4.9 Hz), 6.87 (2H, d, J¼
8.6 Hz), 7.19 (2H, d, J¼8.6 Hz), 7.27–7.42 (5H, m), 9.66
(1H, s); 13C NMR (67.5 MHz, CDCl3) d: 8.6, 53.1, 55.3,
70.2, 79.7, 113.8 (2), 127.1, 127.9 (2), 128.6 (2), 129.4
(2), 130.0, 139.1, 159.3, 203.6; HRMS m/z calcd for
C18H20O3 (M+) 284.1413, found 284.1411.
4.1.15. (2R,3S,4R)- and (2S,3S,4R)-4-(4-Methoxybenzyl-
oxy)-3-methyl-4-phenylbutan-2-ol (20). An ether solution
of MeLi (2 M, 0.13 mL, 0.26 mmol) was added to a solution
of 19 (48 mg, 0.17 mmol) in Et2O (2 mL) at ꢀ80 ꢁC under
a nitrogen atmosphere and stirred at the same temperature
for 1 h. After the reaction was allowed to warm to 0 ꢁC,
the mixture was poured into saturated aqueous NH4Cl and
extracted with Et2O. The extract was washed with brine,
dried (MgSO4), and concentrated. The residue was chroma-
tographed on silica gel (20% EtOAc in hexane) to give a 4:1
mixture of diastereomers of 20 (46 mg, 91%), which was
used quickly in the next step. The diastereomeric mixture
4.1.12. (2R,4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-
phenyl[1,3]dioxane (17) from 14a. A mixture of 14a
(50 mg, 0.18 mmol), CSA (4 mg, 0.018 mmol), and p-anis-
aldehyde dimethyl acetal (39 mg, 0.21 mmol) in CH2Cl2
(2 mL) was stirred at room temperature for 12 h under a
nitrogen atmosphere. The mixture was diluted with EtOAc.
The solution was washed with saturated aqueous NaHCO3,
water, and brine, dried (MgSO4) and concentrated. The
residue was chromatographed on silica gel (10% EtOAc in
hexane) to give 17 (47 mg, 94%), whose melting point and
spectroscopic data were identical with those of the samples
prepared from 14b.
of 20 was obtained as a colorless oil: IR (neat) cmꢀ1
:
3600–3300, 1613, 1514, 1250; 1H NMR (300 MHz,
CDCl3) d: 0.78 (3/5H, d, J¼7.1 Hz), 0.87 (12/5H, d, J¼
7.1 Hz), 1.13 (12/5H, d, J¼6.6 Hz), 1.14 (3/5H, d, J¼
6.6 Hz), 1.64 (4/5H, qdd, J¼7.1, 3.8, 1.9 Hz), 1.81 (1/5H,
quintet d, J¼7.0, 3.6 Hz), 3.00 (4/5H, br s), 3.20 (1/5H,
br s), 3.70 (1/5H, quintet, J¼6.6 Hz), 3.81 (3H, s), 4.00
(4/5H, qd, J¼6.6, 1.9 Hz), 4.20 (1/5H, A of ABq,
J¼11.3 Hz), 4.22 (4/5H, A of ABq, J¼11.3 Hz), 4.49
(4/5H, B of ABq, J¼11.3 Hz), 4.50 (1/5H, B of ABq,
J¼11.3 Hz), 4.61 (4/5H, d, J¼3.8 Hz), 4.69 (1/5H, d,
J¼3.6 Hz), 6.88 (2H, d, J¼8.6 Hz), 7.22 (2H, d, J¼
8.6 Hz), 7.27–7.42 (5H, m); HRMS m/z calcd for
C19H24O3 (M+) 300.1726, found 300.1711.
4.1.13. (2S,3R)-3-(4-Methoxybenzyloxy)-2-methyl-3-phe-
nylpropan-1-ol (18). A toluene solution of DIBAL-H (1 M,
0.11 mL, 0.11 mmol) was added to a solution of 17 (19 mg,
0.07 mmol) in CH2Cl2 (2 mL) at ꢀ80 ꢁC under a nitrogen at-
mosphere and then stirred at the same temperature for 1 h.
The reaction mixture was allowed to warm to 0 ꢁC and ace-
tone (1 mL), MeOH (1 mL), and saturated aqueous NH4Cl
(1 mL) were added to the mixture. The whole mixture was
diluted with Et2O and dried (MgSO4). After filtration using
Celite, the filtrate was concentrated. The residue was
4.1.16. (3R,4R)-4-(4-Methoxybenzyloxy)-3-methyl-4-
phenylbutan-2-one (21). A mixture of 20 (46 mg,

4436
T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
0.15 mmol) and Dess–Martin periodinane (111 mg,
0.26 mmol) in CH2Cl2 (3 mL) was stirred at room tempera-
ture for 30 min. The mixture was diluted with Et2O, the
whole was washed with saturated aqueous Na2S2O3, satu-
rated aqueous NaHCO3, and brine, dried (MgSO4), and con-
centrated. The residue was chromatographed on silica gel
(20% EtOAc in hexane) to give 21 (46 mg, quant) as a color-
less oil: [a]2D9 +55.8 (c 1.06, CHCl3); IR (neat) cmꢀ1: 1712,
(3H, d, J¼6.9 Hz), 1.20 (3H, d, J¼6.3 Hz), 1.98 (3H, s),
2.09 (3H, s), 2.00–2.10 (1H, m), 4.67 (1H, qd, J¼6.3,
4.1 Hz), 5.72 (1H, d, J¼6.9 Hz), 7.20–7.35 (5H, m); 13C
NMR (75 MHz, CDCl3) d: 10.2, 17.9, 21.3 (2), 43.6, 70.8,
76.9, 126.4 (2), 127.8, 128.3 (2), 139.2, 179.9, 170.1;
HRMS m/z calcd for C15H20O4 (M+) 264.1362, found
264.1350.
1
1514, 1249; H NMR (270 MHz, CDCl3) d: 1.18 (3H, d,
4.1.20. (2R,3S,4R)-2,4-Diacetoxy-3-methylpentanoic acid
(4). A mixture of (1R,2S,3R)-1,3-diacetoxy-2-methyl-1-phe-
nylbutane (58 mg, 0.219 mmol), RuCl3$nH2O (9 mg,
0.044 mmol), and periodic acid (998 mg, 4.38 mmol) in
CCl4–CH3CN–H2O (2:2:3, 2 mL) was vigorously stirred at
room temperature for 18 h. 2-Propanol (2.4 mL) was added
to the resultant mixture and the whole was stirred at the same
temperature for further 30 min. The reaction was poured into
water and extracted with CH2Cl2. The extract was washed
with brine, dried (MgSO4), and concentrated to give 4
J¼6.6 Hz), 1.87 (3H, s), 2.89 (1H, quintet, J¼6.9 Hz),
3.80 (3H, s), 4.16 (1H, A of ABq, J¼11.2 Hz), 4.40 (1H,
B of ABq, J¼11.2 Hz), 4.53 (1H, d, J¼7.3 Hz), 6.86 (2H,
d, J¼8.7 Hz), 7.19 (2H, d, J¼8.7 Hz), 7.27–7.40 (5H, m);
13C NMR (67.5 MHz, CDCl3) d: 12.6, 30.0, 54.3, 55.2,
70.2, 81.4, 113.7 (2), 127.3 (2), 127.8, 128.4 (2), 129.4
(2), 130.2, 140.1, 159.2, 210.8; HRMS m/z calcd for
C19H22O3 (M+) 298.1569, found 298.1570.
1
4.1.17. (3R,4R)-4-Hydroxy-3-methyl-4-phenylbutan-2-
one (22). A mixture of 21 (112 mg, 0.40 mmol) and DDQ
(95 mg, 0.42 mmol) in CH2Cl2–MeOH (10:1, 5 mL) was
stirred at room temperature for 2 h. The mixture was diluted
with CH2Cl2, washed with saturated aqueous NaHCO3, wa-
ter, and brine, dried (MgSO4) and concentrated. The residue
was chromatographed on silica gel (20% EtOAc in hexane)
to give 22 (54 mg, 83%) as a colorless oil: [a]2D7 +51.0
(c 0.95, CHCl3); IR (neat) cmꢀ1: 3600–3300, 1703, 1453,
1357; 1H NMR (270 MHz, CDCl3) d: 1.09 (3H, d,
J¼7.3 Hz), 2.15 (3H, s), 2.84 (1H, qd, J¼7.3, 3.6 Hz),
3.05 (1H, s), 5.11 (1H, d, J¼3.6 Hz), 7.26–7.35 (5H, m);
13C NMR (67.5 MHz, CDCl3) d: 10.1, 29.3, 53.1, 73.0,
125.9 (2), 127.4, 128.3 (2), 141.7, 213.5; HRMS m/z calcd
for C11H14O2 (M+) 178.0994, found 178.0990.
(110 mg), which was used without purification: H NMR
(300 MHz, CDCl3) d: 1.08 (3H, d, J¼7.3 Hz), 1.24 (3H, d,
J¼6.8 Hz), 2.05 (3H, s), 2.15 (3H, s), 2.21–2.32 (1H, m),
4.95–5.01 (1H, m), 5.15 (1H, d, J¼3.5 Hz).
4.1.21. (R)-2-tert-Butoxycarbonylamino-2-methoxycar-
bonylpropyl (2R,3S,4R)-2,4-diacetoxy-3-methylpenta-
noate (23). DCC (20 mg, 0.09 mmol) was added to
a solution of a-methylserine 5 (14 mg, 0.06 mmol), crude
pentanoic acid 4 (17 mg, 0.073 mmol), and HOBt (13 mg,
0.096 mmol) in CH2Cl2 (0.7 mL) at room temperature. After
the mixture was stirred for 30 min, DMAP (9 mg,
0.072 mmol) was added in one portion. After being stirred
at room temperature for 1.5 h, the reaction mixture was fil-
tered and the filtrate was concentrated under reduced pres-
sure. The residue was chromatographed on silica gel (30%
EtOAc in hexane) to give 23 (24 mg, 89%) as a colorless
oil: [a]2D7 +22.5 (c 0.91, CHCl3); IR (neat) cmꢀ1: 1743,
1719, 1507, 1455, 1371, 1240; 1H NMR (300 MHz,
CDCl3) d: 1.00 (3H, d, J¼6.9 Hz), 1.22 (3H, d, J¼6.6 Hz),
1.43 (9H, s), 1.52 (3H, s), 2.05 (3H, s), 2.13 (3H, s), 2.21
(1H, quintet d, J¼6.0, 3.8 Hz), 3.77 (3H, s), 4.43–4.64 (2H,
m), 4.93 (1H, quintet, J¼6.3 Hz), 5.07 (1H, d, J¼3.8 Hz),
5.38 (1H, br s); 13C NMR (75 MHz, CDCl3) d: 10.6, 17.4,
20.6, 21.3, 28.3 (3), 39.5, 52.9, 58.7, 66.2, 71.1, 72.8,
153.9, 168.7, 170.1, 170.2, 172.3; HRMS m/z calcd for
C18H30NO8 (M+ꢀOCOCH3) 388.1971, found 388.1965.
4.1.18. (1R,2S,3R)-2-Methyl-1-phenylbutane-1,3-diol (6).
A solution of Zn(BH4)2 in Et2O (ca. 0.15 mol Lꢀ1, 1.1 mL,
0.17 mmol) was added to a solution of 22 (24 mg,
0.13 mmol) in Et2O (2 mL) at 0 ꢁC under a nitrogen atmo-
sphere. The mixture was stirred at the same temperature
for 30 min. The mixture was poured into 10% HCl, and ex-
tracted with EtOAc. The extract was washed with saturated
aqueous NaHCO3, water, and brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica
gel (30% EtOAc in hexane) to give 6 (20 mg, 83%) as a col-
orless oil: [a]D27 +35.4 (c 1.06, CHCl3) {lit.9 [a]2D4 +35.5 (c
0.46, CHCl3), lit.11 [a]D18 +41.0 (c 1.05, CHCl3)}; IR
(neat) cmꢀ1: 3600–3200, 1451; 1H NMR (500 MHz,
CDCl3) d: 0.83 (3H, d, J¼6.5 Hz), 1.23 (3H, d, J¼6.5 Hz),
1.72 (1H, qt, J¼7.3, 2.5 Hz), 4.24 (1H, qd, J¼6.5, 2.0 Hz),
5.04 (1H, d, J¼3.0 Hz), 7.26–7.35 (5H, m); 13C NMR
(125 MHz, CDCl3) d: 4.1, 21.6, 45.1, 72.1, 78.5, 125.6 (2),
127.0, 128.1 (2), 143.4; HRMS m/z calcd for C11H16O2
(M+) 180.1150, found 180.1137.
4.1.22. Methyl (S)-2-((2R,3S,4R)-2,4-diacetoxy-3-methyl-
pentanoylamino)-3-hydroxy-2-methylpropanoate (25).
Trifluoroacetic acid (0.12 mL) was added to a solution of
23 (56 mg, 0.125 mmol) in CH2Cl2 (1.2 mL) and the reaction
mixture was stirred at room temperature for 4 h. The mixture
was concentrated to give crude 24 (91 mg), which was dis-
solved in THF (2.5 mL). Saturated aqueous NaHCO3
(2.5 mL) was added at 0 ꢁC and the mixture was stirred at
room temperature for 10 h. The resultant mixture was con-
centrated and the residue was chromatographed on silica
gel (75% EtOAc in hexane) to give 25 (35 mg, 81% from
23) as a colorless oil: [a]2D8 +32.1 (c 1.285, CHCl3) {lit.11
[a]2D1 +32.9 (c 0.35, CHCl3)}; IR (neat) cmꢀ1: 3700–3200,
1739, 1523, 1452, 1375, 1243; 1H NMR (270 MHz,
CDCl3) d:1.02 (3H, d, J¼7.1 Hz), 1.26 (3H, d, J¼6.3 Hz),
1.55 (3H, s), 2.07 (3H, s), 2.18 (3H, s), 2.28 (1H, qt, J¼7.1,
5.2 Hz), 3.28 (1H, br s), 3.80 (3H, s), 3.82 (1H, d,
4.1.19. (1R,2S,3R)-1,3-Diacetoxy-2-methyl-1-phenyl-
butane. A mixture of 6 (46 mg, 0.254 mmol), pyridine
(0.5 mL), Ac2O (0.5 mL), and DMAP (1 mg) was stirred at
room temperature for 30 min. The mixture was concentrated
and the residue was chromatographed on silica gel (10%
EtOAc in hexane) to give (1R,2S,3R)-1,3-diacetoxy-2-
methyl-1-phenylbutane (58 mg, 86%) as a colorless oil:
[a]2D8 +68.4 (c 1.52, CHCl3); IR (neat) cmꢀ1: 1739, 1454,
1
1373, 1237, 1020; H NMR (300 MHz, CDCl3) d: 1.04

T. Yakura et al. / Tetrahedron 63 (2007) 4429–4438
4437
J¼11.8 Hz), 4.14 (1H, d, J¼11.8 Hz), 4.94–5.06 (1H, m),
5.02 (1H, d, J¼5.5 Hz), 7.14 (1H, s); 13C NMR (67.5 MHz,
CDCl3) d: 9.8, 18.1, 19.7, 19.9, 21.3, 39.7, 53.1, 62.5, 65.4,
71.0, 75.2, 168.7, 170.3, 170.8, 173.3; HRMS m/z calcd for
C15H26NO8 (M++H) 348.1658, found 348.1628.
8.8 Hz), 4.02 (1H, dd, J¼11.0, 6.0 Hz), 4.50–4.70 (3H, m),
5.12 (1H, d, J¼3.3 Hz).
4.1.27. Methyl (S)-2-((2R,3S)-2,4-diacetoxy-3-methyl-
butanoylamino)-3-hydroxy-2-methylpropanoate (2). Ac-
cording to the procedure described for the preparation of
25, 2 (21 mg, 34%) was prepared from 27 (81 mg,
0186 mmol), CF3CO2H (0.14 mL), and saturated aqueous
NaHCO3 (1.6 mL) as a colorless oil: [a]2D7 +34.6 (c¼1.01,
CHCl3); IR (neat) cmꢀ1: 3600–3200, 1741, 1674, 1523,
4.1.23. (D)-Conagenin (1). Aqueous K2CO3 (1.0 M,
0.1 mL) was added to
a solution of 25 (10 mg,
0.0287 mmol) in MeOH (0.3 mL) at 0 ꢁC and the mixture
was stirred at room temperature for 2 h. The reaction
mixture was neutralized with aqueous KHSO4 (1.0 M,
0.29 mL). The reaction mixture was concentrated and the
residue was purified by ODS column chromatography (Cos-
mosil 75 C18-OPN, H2O followed by 19:1 H2O–MeCN as
an eluent) to give 1 (5 mg, 71%) as colorless crystals: mp
154–157 ꢁC (lit.1 mp 159–161 ꢁC, lit.11 mp 153–155 ꢁC);
[a]2D8 +56.6 (c 0.2, MeOH) {lit.1 [a]D27 +55.4, lit.11 [a]2D0
+56.8 (c 0.44, MeOH)}; IR (KBr) cmꢀ1: 3488, 3369,
3327, 3058, 1702, 1636, 1529, 1457, 1253; 1H NMR
(300 MHz, CD3OD) d: 0.94 (3H, d, J¼7.1 Hz), 1.22 (3H,
d, J¼6.3 Hz), 1.52 (3H, s), 1.89 (1H, qdd, J¼6.9, 5.5,
2.5 Hz), 3.82 (1H, d, J¼11.0 Hz), 3.85 (1H, quintet,
J¼6.0 Hz), 4.01 (1H, d, J¼11.0 Hz), 4.16 (1H, d,
J¼2.7 Hz), 8.05 (1H, s, exchanged with CD3OD); 13C
NMR (75 MHz, CD3OD) d: 8.2, 19.9, 21.2, 43.7, 62.4,
66.0, 71.2, 75.3, 175.8, 176.1; FABHRMS m/z calcd for
C10H20NO6 (M++H) 250.1291, found 250.1294.
1
1457, 1373, 1231; H NMR (300 MHz, CDCl3) d: 1.00
(3H, d, J¼7.1 Hz), 1.56 (3H, s), 2.07 (3H, s), 2.21 (3H, s),
2.52 (1H, qd, J¼6.9, 3.6 Hz), 3.18 (1H, br s), 3.81 (3H, s),
3.82 (1H, d, J¼11.8 Hz), 4.00 (2H, d, J¼7.1 Hz), 4.15
(1H, d, J¼11.8 Hz), 5.21 (1H, d, J¼3.6 Hz), 7.10 (1H, s);
13C NMR (75 MHz, CDCl3) d: 11.4, 19.9, 21.0, 21.1, 35.0,
53.4, 62.5, 65.0, 65.7, 73.9, 168.9, 170.2, 171.0, 173.5;
HRMS m/z calcd for C14H23NO8 (M+) 333.1424, found
333.1470.
4.1.28. (R)-2-tert-Butoxycarbonylamino-2-methoxycar-
bonylethyl (2R,3S,4R)-2,4-diacetoxy-3-methylpenta-
noate (29). According to the procedure described for the
preparation of 23, 29 (145 mg, 80%) was prepared from
N-Boc-L-serine methyl ester (28)34 (92 mg, 0.42 mmol),
crude 4 (117 mg, 0.5 mmol), DCC (139 mg, 0.67 mmol),
HOBt (91 mg, 0.67 mmol), and DMAP (62 mg, 0.5 mmol)
1
as a colorless oil, which was used without purification: H
4.1.24. (1R,2S)-1,3-Diacetoxy-2-methyl-1-phenylpro-
pane. According to the procedure described for the prepara-
tion of (1R,2S,3R)-1,3-diacetoxy-2-methyl-1-phenylbutane,
the tiltled compound (191 mg, 97%) was prepared from
14a (131 mg, 0.79 mmol), pyridine (1.5 mL), Ac2O
(1.5 mL), and DMAP (3 mg) as a colorless oil: [a]2D7 +38.7
NMR (300 MHz, CDCl3) d: 1.01 (3H, d, J¼7.1 Hz), 1.22
(3H, d, J¼6.3 Hz), 1.46 (9H, s), 2.04 (3H, s), 2.14 (3H, s),
2.12–2.24 (1H, m), 3.77 (3H, s), 4.40 (1H, dd, J¼11.3,
3.0 Hz), 4.53 (1H, dd, J¼11.3, 3.3 Hz), 4.55–4.62 (1H, m),
4.92 (1H, quintet, J¼6.0 Hz), 5.05 (1H, d, J¼3.8 Hz), 5.38
(1H, br d, J¼8.0 Hz).
1
(c 1.50, CHCl3); IR (neat) cmꢀ1: 1737, 1376; H NMR
(300 MHz, CDCl3) d: 0.98 (3H, d, J¼6.9 Hz), 2.04 (3H,
s), 2.11 (3H, s), 2.29 (1H, septet, J¼6.6 Hz), 3.79 (1H, dd,
J¼11.0, 5.8 Hz), 4.02 (1H, dd, J¼11.0, 6.6 Hz), 5.79 (1H,
d, J¼6.0 Hz), 7.25–7.37 (5H, m); 13C NMR (75 MHz,
CDCl3) d: 12.6, 21.1, 21.4, 38.6, 66.0, 76.2, 126.5 (2),
128.0, 128.5 (2), 139.0, 170.1, 171.0; HRMS m/z calcd for
C14H18O4 (M+) 250.1205, found 250.1163.
4.1.29. Methyl (S)-2-((2R,3S,4R)-2,4-diacetoxy-3-methyl-
pentanoylamino)-3-hydroxypropanoate (3). According to
the procedure described for the preparation of 25, 3 (82 mg,
72%) was prepared from 29 (145 mg, 0.33 mmol), CF3CO2H
(0.25 mL), and saturated aqueous NaHCO3 (4.3 mL) as a col-
orless oil: [a]2D7 +45.8 (c 1.42, CHCl3); IR (neat) cmꢀ1
:
1
3600–3200, 1741, 1672, 1532, 1440, 1375, 1241; H NMR
(300 MHz, CDCl3) d: 1.04 (3H, d, J¼7.1 Hz), 1.25 (3H, d,
J¼6.3 Hz), 2.07 (3H, s), 2.17 (3H, s), 2.26–2.40 (1H, m),
3.05 (1H, br s), 3.81 (3H, s), 3.84–4.05 (2H, m), 4.64 (1H,
dt, J¼6.9, 3.3 Hz), 4.90–5.00 (1H, m), 5.08 (1H, d,
J¼6.0 Hz), 6.88 (1H, d, J¼7.1 Hz); 13C NMR (75 MHz,
CDCl3) d: 9.6, 18.1, 20.9, 21.4, 39.8, 52.9, 54.7, 62.7, 70.9,
75.1, 168.8, 170.1, 170.3, 171.0; HRMS m/z calcd for
C14H24NO8 (M++H) 334.1502, found 334.1501.
4.1.25. (2R,3S,4R)-2,4-Diacetoxy-3-methylpentanoic acid
(26). According to the procedure described for the prepara-
tion of 4, crude 26 (146 mg) was prepared from (1R,2S)-1,3-
diacetoxy-2-methyl-1-phenylpropane (97 mg, 0.39 mmol),
RuCl3$nH2O (24 mg, 0.11 mmol), and periodic acid
(1.77 g, 7.75 mmol) as a colorless oil: 1H NMR (300 MHz,
CDCl3) d: 1.03 (3H, d, J¼7.1 Hz), 2.07 (3H, s), 2.16 (3H,
s), 2.51–2.54 (1H, m), 3.94–4.09 (2H, m), 5.21 (1H, d,
J¼3.0 Hz).
Acknowledgements
4.1.26. (R)-2-tert-Butoxycarbonylamino-2-methoxycar-
bonylpropyl (2R,3S)-2,4-diacetoxy-3-methylbutanoate
(27). According to the procedure described for the prepara-
tion of 23, 27 (81 mg, 57%) was prepared from 3 (76 mg,
0.32 mmol), crude 26 (85 mg, 39 mmol), DCC (108 mg,
0.52 mmol), HOBt (71 mg, 0.52 mmol), and DMAP
(48 mg, 0.39 mmol) as a colorless oil, which was used with-
out purification: 1H NMR (300 MHz, CDCl3) d: 0.96 (3H, d,
J¼7.1 Hz), 1.44 (9H, s), 1.53 (3H, s), 2.07 (3H, s), 2.14 (3H,
s), 2.38–2.50 (1H, m), 3.77 (3H, s), 3.96 (1H, dd, J¼11.0,
We wish to thank Mitsubishi Rayon Co. Ltd. for providing
methyl (S)-3-hydroxy-2-methylpropanoate.
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