Synthesis and absolute structure of (-)-umtatin

Article abstract of DOI:10.1246/bcsj.81.863

A new preparation of 2-(hydroxymethyl)chromones was developed via the new regio-selective six-membered cyclization of 1-[o-(tert-butyldimethylsiloxy) phenyl]but-2-yn-1-ones by a three-step treatment with 1) diethylamine (activation of the γ-position), 2) KF-18-crown-6 (deprotection), and 3) silica-gel (cyclization). A naturally occurring chiral hydroxymethylfurochromone, (-)-umtatin, was synthesized starting from chiral (R)-(-)-2-isopropenyl-4,6-dimethoxy-2,3-dihydrobenzofuran, and the absolute structure was determined to R.

Full text of DOI:10.1246/bcsj.81.863

Ó 2008 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 81, No. 7, 863–868 (2008)
863
Synthesis and Absolute Structure of (À)-Umtatin
ꢀ
Seiji Yamaguchi, Masahide Kobayashi, Shin-ichiro Harada, Masahiro Miyazawa, and Yoshiro Hirai
Department of Chemistry, Graduate School of Science and Engineering, University of Toyama,
3190 Gofuku, Toyama 930-8555
Received October 19, 2007; E-mail: seiji@sci.u-toyama.ac.jp
A new preparation of 2-(hydroxymethyl)chromones was developed via the new regio-selective six-membered
cyclization of 1-[o-(tert-butyldimethylsiloxy)phenyl]but-2-yn-1-ones by a three-step treatment with 1) diethylamine (ac-
tivation of the ꢀ-position), 2) KF-18-crown-6 (deprotection), and 3) silica-gel (cyclization). A naturally occurring chiral
hydroxymethylfurochromone, (ꢁ)-umtatin, was synthesized starting from chiral (R)-(ꢁ)-2-isopropenyl-4,6-dimethoxy-
2,3-dihydrobenzofuran, and the absolute structure was determined to R.
Many naturally occurring chiral isopropenyldihydrobenzo-
furans were isolated from various kinds of plants. There are
different types, R or S, of absolute configurations,1 and these
showed the different types of cyclization which exists in differ-
ent kinds of plants. Our interests were focused on the chemo-
taxonomy, is there any relationship between the absolute con-
figurations and the origin.
Dean et al. isolated a chiral furochromone, (ꢁ)-umtatin
(1), from Ptaeroxylon obliquum (Meliaceae),2 and proposed
the structure of 4-hydroxy-7-(hydroxymethyl)-2-isopropenyl-
2,3-dihydro-5H-furo[3,2-g][1]benzopyran-5-one, shown in
Figure 1, but the absolute configuration was left to be
ambiguous.
culaceae), and showed S configuration.3 The optical rotation
suggested that naturally occurring (ꢁ)-umtatin has the oppo-
site configuration to naturally occurring (+)-cimifugin. To
clear this, the synthesis of chiral (ꢁ)-umtatin was needed.
But, there was no report about the synthesis of umtatin, not on-
ly chiral but also racemic. In this paper, the synthesis of umta-
tin, both racemic and chiral, and the absolute structure of chiral
(ꢁ)-umtatin is described.
We already reported the effective chromone-ring formation
using 2,2-dimethoxy-N,N-dimethylethylamine.4 As shown in
Scheme 1, the 7-methyl analog 2 was synthesized from 5-ace-
tyl-4-(t-butyldimethylsiloxy)-6-hydroxy-2-isopropenyl-2,3-di-
hydrobenzofuran (4d) using 2,2-dimethoxy-N,N-dimethyl-
ethylamine, as described next. Racemic remirol, 5-acetyl-4-hy-
droxy-2-isopropenyl-6-methoxy-2,3-dihydrobenzofuran (4b),
was prepared from 2-isopropenyl-4,6-dimethoxy-2,3-dihydro-
benzofuran (3) according to the reported procedure,5 and then
Kondo and Takemoto isolated (+)-cimifugin, having a
similar dihydrofurochromone structure of 7-(hydroxymethyl)-
2-(1-hydroxy-1-methylethyl)-4-methoxy-2,3-dihydro-5H-furo-
[3,2-g][1]benzopyran-5-one, from Cimicifuga simplex (Ranun-
O
OMe
O
OH
O
OH
4
5
2
2
OH
7
HO
HO
O
O
O
1
O
O
O
(-)-umtatin (1)
(S)-(+)-cimifugin
the 7-methyl analog (2)
Figure 1. Chiral (ꢁ)-umtatin (1), the 7-methyl analog 2, and chiral (+)-cimifugin.
O
OR1
O
O
OH
OMe
a
e
R2O
O
O
O
48%
20%
(two steps)
MeO
3
4a (R1 = Me, R2 = Me)
b (R1 = H, R2 = Me)
c (R1 = TBS, R2 = Me)
d (R1 = TBS, R2 = H)
2
b
d
c
Reaction conditions: a) CH3CO2H, (CF3CO)2O, room temperature, 1 h; b) MgI2-OEt2, benzene, reflux, 3 h, 82%;
c) TBSCl, NaH, THF, room temperature, 30 min, 83%; d) MgI2-OEt2, benzene, reflux, 15 h, 82%;
e) 1) CH3C(OMe)2NMe2, xylene, reflux, 24h; 2) 1M TBAF, THF, room temperature, 1h, 20% (two steps)
Scheme 1. Synthesis of methylfurochromones 2 from dimethoxydihydrobenzofuran 3.
Published on the web July 10, 2008; doi:10.1246/bcsj.81.863

864 Bull. Chem. Soc. Jpn. Vol. 81, No. 7 (2008)
Synthesis and Structure of (ꢁ)-Umtatin
O
O
O
O
O
OTHP
O
OTHP
chromone B
intermediate B'
OTHP
OTHP
OR
O
O
O
ethynyl phenyl ketone
A (R = H or TBS)
intermediate A'
OTHP
OTHP
O
O
3(2H)-furanone C
intermediate C'
Scheme 2. Construction of 2-(hydroxymethyl)chromones.
O
OMOM
O
O
OH
O
OMOM
MOMO
KF, 18-crown-6
MOMO
7
H
DMF
HO
O
O
O
TBSO
TBSO
1 (racemic umtatin)
5
6g
Scheme 3. Synthetic strategy for racemic umtatin 1.
O
O
OR1
OMOM
h - i
a
H
MOMO
3
O
O
49%
b
TBSO
R2O
5
6a (R1 = R2 = Me)
b (R1 = H, R2 = Me)
c (R1 = TBS, R2 = Me)
d (R1 = TBS, R2 = H)
e (R1 = H, R2 = TBS)
f (R1 = R2 = TBS)
c
d
e
f
g
g (R1 = MOM, R2 = TBS)
Reaction conditions: a) DMF-POCl3, 50 oC, 1 h; b) MgI2-OEt2, benzene, reflux, 10 min, 99%;
c) TBSOTf, 2,6-lutidine, dichloromethane, 0 oC, 45 min, 99%; d) AlBr3, acetonitrile, room
temperature, 30 min, 6d (39%), 6e (43%); e) TBSCl, NaH, THF, room temperature, 40 min, 94%;
f) MgI2-OEt2, benzene, 60 oC, 20 min, 99%; g) MOMCl, NaH, THF, room temperature, 1 h, 91%;
o
h) 7, n-BuLi, THF, -78 C, 30 min, 74%; i) MnO2, dichloromethane, room temperature, 32 h, 89%
Scheme 4. Preparation of 1-(dihydrobenzofuran-5-yl)butynone 5 via benzofuran-5-carbaldehyde 6.
converted to 4d by TBS protection followed by demethylation.
The chromone-ring construction of 4d effectively gave the 7-
methyl analog 2 by treating with 2,2-dimethoxy-N,N-dimethyl-
ethylamine in refluxing xylene followed by deprotection with
TBAF. However, any side-chain conversion of 2 caused the
oxidation on the dihydrofuran ring and the result was unsuc-
cessful.
Garcia et al. reported, in the cyclization of 1-(o-hydroxy-
phenyl)butynone A (R ¼ H), as shown in Scheme 2, both five-
and six-membered cyclization might be possible to give a mix-
ture of 3(2H)-furanone C (as a kinetically favored product) and
chromone B (as a thermodynamically favored product).6 But
recently, Nakatani et al. reported the regio-selective cycliza-
tion by treating 1-[o-(t-butyldimethylsiloxy)phenyl]butynone
A (R ¼ TBS) with potassium fluoride–18-crown-6 to give cor-
responding chromones B.7
zation of 1-[6-(t-butyldimethylsiloxy)dihydrobenzofuran-5-yl]-
butynone 5, which might be prepared by the propynylation
of 6-(tert-butyldimethylsiloxy)-4-(methoxymethyloxy)dihydro-
benzofuran-5-carbaldehyde 6g with 3-(methoxymethyloxy)-1-
propyne (7) followed by oxidation with manganese dioxide.
Similarly to the conversion from 4a to 4d, the starting sub-
strate 6g was prepared, as shown in Scheme 4, from 4,6-dime-
thoxy-2,3-dihydrobenzofuran-5-carbaldehyde 6a, described
next.
According to the reported procedure,8 6a was prepared by
Vilsmeier formylation of 2-isopropenyl-4,6-dimethoxy-2,3-di-
hydrobenzofuran (3), then converted to 4-(t-butyldimethyl-
siloxy)-6-methoxy-5-carbaldehyde 6c by regio-selective de-
methylation with magnesium iodide etherate, giving 4-hy-
droxy-6-methoxy-5-carbaldehyde 6b followed by TBS protec-
tion with t-butyldimethylsilyl trifluoromethanesulfonate. The
demethylation of 6c with magnesium etherate caused the re-
moval of TBS to recover 6b in major (80%), and the desired
4-(t-butyldimethylsiloxy)-6-hydroxy-5-carbaldehyde 6d was
So, a new strategy for racemic umtatin 1 was planned, as
shown in Scheme 3, using the Nakatani’s regio-selective cycli-
zation. The racemic umtatin 1 might be obtained by the cycli-

S. Yamaguchi et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 7 (2008)
865
OMOM
O
O
O
OMOM
O
KF, 18-crown-6
H
5
MOMO
O
o
MOMO
O
DMF, 0 C, 5 min
8
9
(66%)
Scheme 5. Cyclization of 1-(dihydrobenzofuran-5-yl)butynone 5 in Nakatani’s procedure.
O
O
OMOM
8 ( for 1 )
MOMO
O
8'
O
O
OMOM
KF, 18-crown-6
5
MOMO
O
5'
OMOM
O
O
9
MOMO
O
9'
Scheme 6. Cyclization mechanism of 1-(dihydrobenzofuran-5-yl)butynone 5.
obtained in minor (trace). The demethylation of 6c was, how-
ever, effective with aluminum tribromide in acetonitrile, but
accompanied with a migration of t-butyldimethylsilyl group,
to give a mixture of the desired 4-(t-butyldimethylsiloxy)-6-
hydroxy-5-carbaldehyde 6d and the TBS group migrated to
might be favorable to the five-membered intermediate 90 lead-
ing the benzodifuranone 9 in any condition.
Recently, Torii et al. reported a new six-membered chro-
mone cyclization via Pd-catalyzed carbonylation of o-iodophe-
nols with acetylenes,10 as shown in Scheme 7, where the use of
diethylamine was effective for the six-membered cyclization
of a supposed intermediate, 1-(2-hydroxyphenyl)butynone.
A similar cyclization was attempted after treating 5 with di-
ethylamine (Scheme 8). The mixture of 5 and diethylamine
was treated with potassium fluoride–18-crown-6, and the re-
sulting mixture was then treated with silica gel to give the de-
sired six-membered chromone 8. This might be explained in
the following three steps mechanism; 1) activation of the ꢁ-
carbon of the conjugated ynone 5 either the regio-selective nu-
cleophilic attach of diethylamine to form an enaminone 10 or
the nucleophilic attach of diethylamine on the carbonyl carbon
to form an iminium 11, 2) deprotection of TBS, and 3) acidic
cyclization. Acidic deprotection of 8 gave racemic umtatin 1,
which was identical with the natural (ꢁ)-umtatin in all report-
ed spectra data.2
Either chiral 4,6-dimethoxydihydrobenzofuran (ꢁ)-3 or
(+)-3 was needed for the synthesis of chiral (ꢁ)-umtatin.
We already reported the effective preparation of both enan-
tiomers using kinetic resolution of racemic 4,6-dimethoxy-
dihydrobenzofuran 3.1d (+)-Cimifugin, having a similar dihy-
drofurochromone structure of 7-(hydroxymethyl)-2-(1-hy-
droxy-1-methylethyl)-4-methoxy-2,3-dihydro-5H-furo[3,2-g]-
[1]benzopyran-5-one, showed S configuration.3 So, naturally
occurring chiral (ꢁ)-umtatin, showing an opposite optical
afford
6-(t-butyldimethylsiloxy)-4-hydroxy-5-carbaldehyde
6e. Being difficult to separate each component, the mixture
was converted to 4,6-bis(t-butyldimethylsiloxy)-5-carbalde-
hyde 6f, and then subjected to regio-selective deprotection
with magnesium iodide etherate in mild condition to give the
desired pure 6e. 6-(t-Butyldimethylsiloxy)-4-hydroxy-5-carb-
aldehyde 6e, thus obtained, was then treated with chloromethyl
methyl ether to give 6g, and converted to 5 by the propynyla-
tion with 3-(methoxymethyloxy)-1-propyne (7)–n-butyllithium
followed by oxidation with manganese dioxide.
The 1-(dihydrobenzofuran-5-yl)butynone 5, thus obtained,
was then subjected to the six-membered chromone cycliza-
tion.7 In spite of the use of the Nakatani’s procedure, as shown
in Scheme 5, the cyclization of 5 showed the five-membered
cyclization to give only the undesired 3(2H)-benzodifuranone
9, and none of the desired six-membered furochromone 8 was
observed. Nakatani et al. described that the kinetic protonation
causes the five-membered cyclization and the equilibrium
leads the six-membered cyclization.
This might be explained by a steric repulsion between the
bulky 4-methoxymethyl group and the carbonyl.9 As shown
in Scheme 6, the bulky 4-methoxymethyloxy group destabiliz-
es the six-membered intermediate 80 leading the furochromone
8, and the equilibrium in the intermediates (50, 80, and 90)

866 Bull. Chem. Soc. Jpn. Vol. 81, No. 7 (2008)
Synthesis and Structure of (ꢁ)-Umtatin
O
O
I
Pd, CO
+
Y
Y
Y
carbonylative coupling
R
OH
R
O
R
OH
Scheme 7. A new chromone cyclization via Pd-catalyzed carbonylation.
O
OMOM
MOMO
Et2N
O
O
TBS
2) KF, 18-crown-6
3) Silica gel
1) Et2NH
enaminone 10
5
8
Et Et
N+ OMOM
HCl MeOH
MOMO
O
O
1
iminium 11
TBS
racemic umtatin
Scheme 8. Revised cyclization of 1-(dihydrobenzofuran-5-yl)butynone 5.
ethylidene)-5,6-dihydrobenzo[1,2-b;5,4-b0]difuran-3-one (9)
(23 mg, 66%).
rotation, was supposed to be R configuration, and the chiral
(R)-(ꢁ)-3 might be suitable as starting material.
6-Isopropenyl-4-(methoxymethyloxy)-2-(2-methoxymethyl-
oxyethylidene)-5,6-dihydrobenzo[1,2-b;5,4-b0]difuran-3-one (9);
pale yellow oil; IR (liquid film) 1703 cmꢁ1 (C=O); 1H NMR
(CDCl3): ꢂ 1.76 (3H, s), 3.02 (1H, dd, J ¼ 7:3 and 15.5 Hz),
3.37 (1H, dd, J ¼ 9:7 and 15.5 Hz), 3.41 (3H, s), 3.52 (3H, s),
4.46 (2H, d, J ¼ 7:0 Hz), 4.69 (2H, s), 4.96 (1H, br s), 5.09
(1H, br s), 5.32 (1H, dd, J ¼ 7:3 and 9.7 Hz), 5.49 (2H, s), 6.05
(1H, t, J ¼ 7:0 Hz), 6.32 (1H, s).
The starting chiral material, (R)-(ꢁ)-3 of 99%ee, was pre-
pared by the kinetic resolution of racemic 3 using Sharpless
asymmetric dihydroxylation, treating with K2[Os(OH)4O2],
K3[Fe(CN)6], K2CO3, CH3SO2NH2, and chiral ligand
(DHQ)2AQN.1d,11 Similarly to the conversion from racemic
3 to racemic 6c, chiral (R)-(ꢁ)-3 was converted chiral (R)-6c
in three steps; 1) Vilsmeier formylation, 2) selective demeth-
ylation giving (R)-(ꢁ)-6b, and 3) TBS protection. And, the
chiral umtatin was similarly synthesized from chiral (R)-6c,
via mild demethylation with aluminum tribromide, TBS
protection giving, 4) selective deprotection with magnesium
iodide etherate giving (R)-6e,12 and 5) methoxymethyl protec-
tion. Propynylation of (R)-6g with 7–n-butyllithium following
oxidation with manganese dioxide effectively gave chiral buty-
none (R)-5. Chiral (R)-5 was treated with diethylamine and
then with potassium fluoride–18-crown-6, and a final treatment
with silica gel effectively gave the corresponding chromone,
which was then deprotected to (R)-(ꢁ)-umtatin. The synthe-
sized chiral (R)-(ꢁ)-umtatin was identical with the natural
(ꢁ)-umtatin in all spectral data and showed the same rotation
with the natural (ꢁ)-umtatin.2 Naturally occurring (ꢁ)-umtatin
was thus synthesized starting from chiral (R)-(ꢁ)-2-isopro-
penyl-4,6-dimethoxy-2,3-dihydrobenzofuran (3) in 5.5% (13
steps), and so the absolute structure of natural (ꢁ)-umtatin
was determined to R.
Conversion of 5 to Racemic Umtatin 1 by Cyclization Using
Diethylamine, KF–18-crown-6, Silica Gel Followed by
Deprotection. Under an argon atmosphere, to a solution of 5
(80 mg, 0.17 mmol) was added diethylamine (1 mL), and the mix-
ture was stirred at room temperature for 5 min. The mixture was
treated with 18-crown-6 (88 mg, 0.33 mmol) and potassium fluo-
ride (23 mg, 0.40 mmol) at 0 ꢂC, and stirred at room temperature
for 1 h, and concentrated in vacuo. The residue was diluted with
diethyl ether and stirred with silica gel (1.50 g) for 3.5 h. The mix-
ture was filtered through a short celite pad, and concentrated in
vacuo. The residue gave crude 2-isopropenyl-4-(methoxymethyl-
oxy)-7-(methoxymethyloxymethyl)-2,3-dihydro-5H-furo[3,2-g]-
[1]benzopyran-5-one (8) (40 mg, crude 65%).
2-Isopropenyl-4-(methoxymethyloxy)-7-(methoxymethyloxy-
methyl)-2,3-dihydro-5H-furo[3,2-g][1]benzopyran-5-one (8); col-
orless crystal; IR (liquid film) 1661 cmꢁ1 (C=O); 1H NMR
(CDCl3): ꢂ 1.76 (3H, s), 3.14 (1H, dd, J ¼ 7:7 and 16.0 Hz),
3.42 (3H, s), 3.49 (1H, dd, J ¼ 9:3 and 16.0 Hz), 3.58 (3H, s),
4.42 (2H, s), 4.73 (2H, s), 4.96 (1H, br s), 5.10 (1H, br s), 5.18
(2H, s), 5.31 (1H, dd, J ¼ 7:7 and 9.3 Hz), 6.23 (1H, s), 6.60
(1H, s).
Experimental
Cyclization of 5 by Treating with Potassium Fluoride–18-
Under an argon atmosphere, to a soluition of 5
Under an argon atmosphere, to a solution of crude 8 (40 mg,
0.083 mmol) in methanol (3 mL) was added a catalytic amount
of concd hydrochloric acid at room temperature, and the mixture
was refluxed for 30 min. After cooling, the mixture was concen-
trated in vacuo, and diluted with diethyl ether. The organic layer
was washed with a saturated sodium hydrogencarbonate solution
and brine, dried over anhydrous magnesium sulfate, and concen-
trated in vacuo. The residue was recrystallized from cyclohex-
ane–ethyl acetate to give 4-hydroxy-7-(hydroxymethyl)-2-isopro-
penyl-2,3-dihydro-5H-furo[3,2-g][1]benzopyran-5-one (racemic
Crown-6.
(45 mg, 0.87 mmol) in dry DMF (3 mL) was added 18-crown-6
(45 mg, 0.17 mmol) and potassium fluoride (10 mg, 12 mmol) at
0 ꢂC, and the mixture was stirred at 0 ꢂC for 5 min. The mixture
was treated with aqueous ammonium chloride solution, and ex-
tracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified on a silica-gel column to give
6-isopropenyl-4-(methoxymethyloxy)-2-(2-methoxymethyloxy-

S. Yamaguchi et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 7 (2008)
867
umtatin) (1) (14 mg, 31% in two steps).
hydride (73 mg, 1.64 mmol) in dry THF (10 mL) and then treated
with TBSCl (196 mg, 1.31 mmol) under stirring at room tempera-
ture for 40 min to give crude chiral (R)-6f (602 mg, crude 123%).
The regio-selective deprotection of crude chiral (R)-6f (602 mg)
with a magnesium iodide etherate solution, prepared from magne-
sium (turning, 52 mg, 2.18 mmol), dry diethyl ether (8 mL), dry
benzene (4 mL), and iodine (282 mg, 1.09 mmol), under stirring
at room temperature for 1 h gave chiral (R)-6e (305 mg, 84% in
two steps from (R)-6c) as a pale yellow oil.
Also, the chiral (R)-6e (305 mg, 0.913 mmol) was protected by
treating it with a suspension of 60% sodium hydride (61 mg,
1.37 mmol) in dry THF (13 mL) followed by treating it with
MOMCl (0.08 mL, 1.10 mmol) at room temperature for 1.5 h, to
give the crude chiral (R)-6g (257 mg, 74%) as a pale yellow oil.
The chiral (R)-6g was identical with the racemic 6g in IR and
1H NMR spectra.
4-Hydroxy-7-(hydroxymethyl)-2-isopropenyl-2,3-dihydro-5H-
furo[3,2-g][1]benzopyran-5-one (1); colorless crystals; IR (liquid
film) 3407 (OH) and 1674 cmꢁ1 (C=O); 1H NMR (CDCl3): ꢂ
1.77 (3H, s), 2.06 (1H, br s), 3.10 (1H, dd, J ¼ 7:3 and
15.9 Hz), 3.35 (1H, dd, J ¼ 9:3 and 15.9 Hz), 4.56 (2H, s), 4.95
(1H, br s), 5.09 (1H, br s), 5.33 (1H, dd, J ¼ 7:3 and 9.3 Hz),
6.23 (1H, s), 6.34 (1H, s), 12.85 (1H, s); Mass (m=z): 274 (Mþ),
259 (Mþ ꢁ CH3), 233 (Mþ ꢁ C3H5).
This was identical with natural umtatin in all reported spectral
data.2
Acetylation of 1. Under an argon atmosphere, to a solution
of 1 (16 mg, 0.058 mmol) in dry dichloromethane (1 mL) and
pyridine (0.010 mL, 0.15 mmol) was added acetic anhydride
(0.01 mL, 0.12 mmol), and the mixture was stirred at room tem-
perature for 6 h. After the reaction, the mixture was treated with
brine, and extracted with diethyl ether. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate,
and concentrated in vacuo. The residue was purified on a silica
gel to give 7-acetoxymethyl-4-hydroxy-2-isopropenyl-2,3-dihy-
dro-5H-furo[3,2-g][1]benzopyran-5-one, acetate of racemic umta-
tin, (16 mg, 89%).
Conversion of Chiral (R)-6g to Chiral (R)-5. The chiral (R)-
6g (257 mg, 0.68 mmol) was alkylated with the acetylide, prepared
from propargyl MOM ether 7 (106 mg, 1.02 mmol) and 1.6
mol dmꢁ3 n-butyllithium hexane solution (0.55 mL, 0.88 mmol)
under stirring at ꢁ78 ꢂC for 20 min to give the corresponding
chiral (R)-alcohol (90 mg, 28%) as a pale yellow oil.
7-Acetoxymethyl-4-hydroxy-2-isopropenyl-2,3-dihydro-5H-
furo[3,2-g][1]benzopyran-5-one; pale yellow oil; 1H NMR
(CDCl3): ꢂ 1.77 (3H, s), 2.19 (3H, s), 3.01 (1H, dd, J ¼ 7:3 and
15.8 Hz), 3.36 (1H, dd, J ¼ 9:5 and 15.8 Hz), 4.95 (1H, br s),
4.96 (2H, s), 5.10 (1H, br s), 5.34 (1H, dd, J ¼ 7:3 and 9.5 Hz),
6.22 (1H, s), 6.36 (1H, s), 12.74 (1H, s).
The chiral (R)-alcohol (90 mg, 0.19 mmol), thus obtained, was
oxidized with manganese dioxide (534 mg, 6.1 mmol) under stir-
ring at room temperature for 3 days to give the chiral (R)-5
(77 mg, 87%) as a pale yellow oil. The chiral (R)-5 was identical
1
with the racemic 5 in IR and H NMR spectra.
Conversion of Chiral (R)-5 to Chiral Umtatin (R)-1. The
chiral 1-(dihydrobenzofuran-5-yl)butynone (R)-5 (77 mg, 0.16
mmol) was treated with diethylamine (1 mL) under stirring at
room temperature for 15 min. Then, the mixture was treated with
18-crown-6 (89 mg, 0.34 mmol) and potassium fluoride (23 mg,
0.40 mmol) under stirring at room temperature for 1 h. After
dilution with a dry diethyl ether (1 mL), the mixture was treated
with silica gel (3.5 g) at room temperature for 1 day, and filtered
through a short celite pad. The filtrate was concentrated in vacuo
to give crude chiral (R)-8 (124 mg) as a pale yellow oil.
The acetate was also identical with the acetate of natural umta-
1
tin in all H NMR data.2
Conversion of (R)-(À)-3 to (R)-6g. According to the reported
procedure,1d chiral (R)-(ꢁ)-3 was prepared by the kinetic resolu-
tion of racemic 3 via Sharpless dihydroxylation using potassium
osmate(IV) dehydrate, (DHQ)2AQN, potassium hexacyano-
ferrate(III).
According to the reported procedure,8 chiral (R)-(ꢁ)-3 (652 mg,
2.96 mmol, 99%ee) was formylated with DMF (647 mg,
8.86 mmol) and phosphoryl chloride (0.55 mL, 5.92 mmol) to give
To the solution of chiral (R)-8 (124 mg) in methanol (4 mL)
was added a catalytic amount of concentrated hydrochloric acid,
and the mixture was refluxed for 1 h. The chiral umtatin (R)-1
25
chiral (R)-(ꢁ)-6a (297 mg, 45%, 99%ee, ½ꢃꢃD ꢁ35:4ꢂ) as pale
yellow crystal. The optical purity was determined on a HPLC
using chiral column OJ-H (eluent; 2-propanol in hexane).
According to the racemic conversion, the region-selective de-
methylation of chiral (R)-(ꢁ)-6a (751 mg, 3.03 mol) with a solu-
tion of anhydrous aluminum bromide (729 mg, 2.73 mmol) in
dry acetonitrile (10 mL) at room temperature for 10 min, to give
25
(30 mg, 68%, ½ꢃꢃD ꢁ48:6ꢂ) was obtained as colorless crystal.
The chiral umtatin (R)-(ꢁ)-1 was identical with the natural umta-
tin2 and the synthetic racemic 1, described above, in IR and
21
1H NMR spectra. The natural umtatin showed ½ꢃꢃD ꢁ56:3ꢂ
and the optical purity of the synthesized chiral umtatin was
86%ee, and this showed that the partial racemization, through
the ring-opening and the recyclization, might occur in acidic
deprotections.
25
the chiral (R)-(ꢁ)-6b (510 mg, 72%, 96%ee, ½ꢃꢃD ꢁ74:8ꢂ) as col-
orless crystal. The optical purity was determined by HPLC using
chiral column OJ-H, 0.5% ethanol in hexane) The chiral of (R)-
(ꢁ)-6b was identical with the racemic 6b in IR and 1H NMR
spectra.
Supporting Information
Then, chiral (R)-(ꢁ)-6b (510 mg, 2.18 mmol) was protected
with TBSOTf (0.60 mL, 2.62 mmol) in dry dichloromethane
(8 mL) at 0 ꢂC for 45 min to give the chiral (R)-6c (763 mg,
99%) as a pale yellow oil.
Preparation of 4d and the following chromone-ring formation
with 2,2-dimethoxy-N,N-dimethylethylamine to 2a. Preparation
of 6g and following conversion to 5. This material is available free
of charge on the web at http://www.csj.jp/journals/bcsj/.
Demethylation of chiral (R)-(ꢁ)-6c (763 mg, 2.19 mol), with a
solution of anhydrous aluminum bromide (523 mg, 1.96 mmol) in
dry acetonitrile (12 mL) at room temperature for 50 min, gave a
mixture (365 mg, 50%) of chiral (R)-6d and (R)-6e (a pale yellow
oil) and (R)-6-dihydroxy-4-methoxy-5-carbaldehyde (R)-6b
(114 mg, 22%) was also recovered.
References
1
a) W. A. Bonner, N. I. Burke, W. E. Fleck, R. K. Hill,
J. A. Joule, B. Sjoberg, J. H. Zalkow, Tetrahedron 1964, 20,
1419. b) I. Harada, Y. Hirose, M. Nakazaki, Tetrahedron Lett.
1968, 9, 5463. c) Y. Kawase, S. Yamaguchi, O. Inoue, M.
Sannomiya, K. Kawabe, Chem. Lett. 1980, 1581. d) S.
The solution of chiral (R)-6d and (R)-6e (365 mg, 1.09 mmol)
in dry THF (5 mL) was treated with a suspension of 60% sodium

868 Bull. Chem. Soc. Jpn. Vol. 81, No. 7 (2008)
Synthesis and Structure of (ꢁ)-Umtatin
Yamaguchi, S. Muro, M. Kobayashi, M. Miyazawa, Y. Hirai,
J. Org. Chem. 2003, 68, 6274.
2 F. M. Dean, B. Parton, A. W. Price, N. Somvichien,
D. A. H. Taylor, Tetrahedron Lett. 1967, 8, 2737.
the cyclization of 1-[2-(t-butyldimethylsiloxy)-6-methoxyphen-
yl]butynone 12b showed the five-membered cyclization to give
the corresponding 3(2H)-furanone 14.
O
O
OMe
KF, 18-crown-6
OMe
3
1940.
4
Y. Kondo, T. Takemoto, Chem. Pharm. Bull. 1972, 20,
S. Yamaguchi, A. Saitoh, Y. Kawase, J. Heterocycl. Chem.
MOMO
MOMO
DMF, 0 oC, 2 h
(75%)
O
TBSO
12a
13
1995, 32, 511.
OMe
O
OMe
5
S. Yamaguchi, M. Takai, I. Hanazome, Y. Okada, Y.
Kawase, Bull. Chem. Soc. Jpn. 1987, 60, 3603.
O
KF, 18-crown-6
H
MOMO
DMF, 0 oC, 2 h
(75%)
6 H. Garcia, S. Iborra, J. Primo, M. A. Miranda, J. Org.
Chem. 1986, 51, 4432.
O
TBSO
MOMO
12b
14
7
a) K. Nakatani, A. Okamoto, M. Yamanuki, I. Saito,
10 S. Torii, H. Okumoto, L. H. Xu, M. Sadakane, M. V.
Shostakovsky, A. B. Ponomaryov, V. N. Kalinin, Tetrahedron
1993, 49, 6773.
J. Org. Chem. 1994, 59, 4360. b) K. Nakatani, A. Okamoto,
I. Saito, Tetrahedron 1996, 52, 9427.
8
S. Yamaguchi, R. Miyakawa, S. Yonezawa, Y. Kawase,
Bull. Chem. Soc. Jpn. 1989, 62, 3593.
The steric repulsion effects in Nakatani’s cyclization were
11 a) H. B. Kolb, M. S. VanNieuwenhze, K. B. Sharpless,
Chem. Rev. 1994, 94, 2483. b) H. Becker, K. B. Sharpless, Angew.
Chem., Int. Ed. Engl. 1996, 35, 448.
9
also observed in the cyclizations of two phenyl butynones.
As shown in scheme, the cyclization of 1-[2-(t-butyldimethyl-
siloxy)-5-methoxyphenyl]butynone 12a showed the six-mem-
bered cyclization to give the corresponding chromone 13, while
12 Use of excess Lewis acids, magnesium iodide etherate
or aluminium tribromide, caused partial racemization, due to a
dihydrofuran-ring opening and a following re-cyclization.