Regioselective synthesis of furan-fused 3-hydroxy-2,2-dimethylchroman, NG-121 model compound

Article abstract of DOI:10.1055/s-2006-941561

Regioselective synthesis of the model compound of NG-121 was achieved. The key steps are ortho-alkylation of the phenol via [2,3]sigmatropic rearrangement of a sulfur ylide and the regioselective construction of the attached lactone ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941561

LETTER
1363
Regioselective Synthesis of Furan-Fused 3-Hydroxy-2,2-dimethylchroman,
NG-121 Model Compound
R
egioselective
e
Synthesis
i
of
a
N
G
i
-121 M
c
odel Com
h
pound i Inoue,*a Chihiro Nakagawa,a Hidetaka Hayakawa,b Fumiyoshi Iwasaki,b Yujiro Hoshino,a Kiyoshi Hondab
a
Graduate School of Environment and Information Sciences, Yokohama National University, Tokiwadai, Hodogaya-ku,
Yokohama 240-8501, Japan
Fax +81(45)3351536; E-mail: s-inoue@ynu.ac.jp
b
Graduate School of Engineering, Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan
Received 26 January 2006
Herein, we would like to report the first regioselective
synthetic method of the model compound, furan-fused 3-
hydroxy-2,2-dimethylchroman 2, using a [2,3]sigma-
tropic rearrangement and the regioselective construction
of the lactone onto the aromatic nucleus as the key steps.
Abstract: Regioselective synthesis of the model compound of NG-
121 was achieved. The key steps are ortho-alkylation of the phenol
via [2,3]sigmatropic rearrangement of a sulfur ylide and the regio-
selective construction of the attached lactone ring.
Key words: phenols, ylides, sigmatropic rearrangement, regio-
selective formylation, lactones
OR
RO
S
HO
OMe
Recently, a new type of biologically active compound,
NG-121 (1),1 was isolated from the culture broth of
Stachybotrys parvispora F-4708 (Figure 1). It shows the
nerve growth stimulating activity of nerve growth factor
(NGF), which is suggested to be effective against Alz-
heimer’s disease.1 Since only small amounts of this com-
pound can be isolated from natural sources, an effective
method for the enantiocontrolled synthesis of NG-121 is
highly desired.
[2,3]sigmatropic
rearrangement
HO
OMe
Route A
O
O
O
Phthalide
O
HO
OMe
2
OH
OR
RO
HO
S
O
NEt2
3a
O
OMe
OMe
[2,3]sigmatropic
rearrangement
OHC
Route B
OH
OH
O
NEt2
O
NEt2
Scheme 1
O
OH
O
OMe
Two possible retrosynthetic routes are shown in
Scheme 1, which differ in the order of the construction of
two fused rings (i.e. pyran and furan ring).
O
O
O
O
NG-121 (1)
Model Compound 2
In route A, the functionalized alkyl group can be intro-
duced into the ortho position of the phenol via [2,3]sigma-
tropic rearrangement to give the desired compound
exclusively. In route B, the functionalized alkyl group
may be introduced into the C-2 or C-4 position of the
benzamide 3a to give a mixture of the desired compound
and a regioisomer, thus, it will be necessary to separate the
two products. Another important point to consider is the
regioselective construction of the lactone, which is re-
quired no matter which route is chosen. Patterson reported
the conversion of N,N-diethylbenzamide to phthalide,5
which we thought would be applicable to the construction
of the lactone in NG-121 and the model compound 2.
Figure 1
We have extensively studied the ortho-alkylation of phen-
ols via the [2,3]sigmatropic rearrangement of a sulfur
ylide under very mild conditions2 and previously reported
its application to the stereoselective synthesis of 2,2-di-
alkylchroman compounds2a,3b and others.2,3 We further
expanded the application of the [2,3]sigmatropic rear-
rangement of a sulfur ylide when we reported the stereo-
selective synthesis of 3-hydroxy-2,2-dialkylchromans.4
Therefore, the [2,3]sigmatropic rearrangement of a sulfur
ylide was expected to be the most suitable reaction for the
enantiocontrolled construction of the 3-hydroxy-2,2-di-
alkylchroman moiety in NG-121 (Figure 1).
Taking into account the regioselectivity of the [2,3]sigma-
tropic rearrangement and the construction of the lactone,
we first studied the synthesis of 2 according to route A.
Initially, we investigated the synthesis of 4-hydroxy-
phthalide 4 (Scheme 2).
SYNLETT 2006, No. 9, pp 1363–1366
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941561; Art ID: U01106ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
6
We started the synthesis of 4 from commercially available
ester 5; one of the two hydroxyl groups present was pro-

1364
S. Inoue et al.
LETTER
R1O
OMe
MOMO
OHC
OMe
HO
OH
MOMO
OMe
a, b, c
d
e, f
O
O
NEt2
O
OMe
O
NEt2
O
8: R1 = MOM
4: R1 = H
7
6
5
g)
OR
RO
HO
S
OMe
h, i
4
+
S
RO
OR
R = COCHCl2
O
O
9
10
Scheme 2 Reagents and conditions: a) MeI, K2CO3, acetone, 0 °C → r.t., 15 h (38%); b) MOMCl, NaH, DMF, r.t., 3 h (95%); c) Et2NH,
AlMe3, toluene, 75 °C, 18 h (95%); d) t-BuLi, DMF, TMEDA, THF, –78 °C, 3 h, (62%); e) NaBH4, EtOH, 50 °C, 24 h; f) AcOH, EtOAc, r.t.,
1 h (79%); g) 1 N HCl, CH3CN–H2O (10:1), reflux, 5 h (97%); h) SO2Cl2, s-collidine, CH2Cl2–DMF (10:1), –78 °C, 12 min; i) Et3N, CH2Cl2,
–78 → 0 °C, 5 h (10%).
tected as the methyl ether, the remaining hydroxyl group
HO
OMe
was protected as a methoxymethyl group. Then, the ester
was converted into diethylamide 6 by reaction with alumi-
num amide prepared from diethylamine and trimethylalu-
minum.6 The amide 6 was lithiated by reaction with t-
BuLi and the resulting o-lithioamide quenched with DMF
to give aldehyde 7. The other ortho position of the car-
bamoyl group of 6 was partly formylated to give a regio-
isomer as the minor product in 31% yield. Reduction of 7
with sodium borohydride gave the corresponding alcohol,
which was cyclized to phthalide 8 in the presence of acetic
acid. Finally, the methoxymethyl group was removed to
give the desired compound 4.
a, b
S
+
RO
OR
R = COCHCl2
O
NR'2
9
3a: R' = Et
3b: R' = n-Bu
RO
RO
RO
RO
H
H
H
H
S
S
4
HO
OMe
3
HO
OMe
5
+
2
6
1
The ortho-alkylation of phthalide 4 with sulfide 97 was
effected by the [2,3]sigmatropic rearrangement of the
phenoxysulfonium ylide intermediate. Thus, a mixture of
4 and 9 in dichloromethane–DMF (10:1) was treated with
sulfuryl chloride at –78 °C, followed by addition of a
solution of triethylamine in dichloromethane. The reac-
tion mixture was allowed to warm to room temperature
and usual work-up followed by column chromatography
on silica gel afforded the desired product 10 in 10% yield
along with unreacted starting materials. We looked at the
reaction conditions in detail; however, we failed to im-
prove the yield of 10. Therefore, we decided to shift our
attention from route A to route B.
O
NR'2
O
NR'2
11a: R' = Et
11b: R' = n-Bu
12a: R' = Et
12b: R' = n-Bu
R' = Et 30%
R' = n-Bu 42%
RO
RO
H
H
RO
H
RO
H
S
S
O
O
2
HO
HO
3
+
NR'2
NR'2
1
6
4
5
OMe
OMe
N,N-Diethylbenzamide 3a was reacted with sulfide 9 to
give the desired ortho-alkylphenols, 11a and 12a, along
with the regioisomers, 13a and 14a, in moderate yields in
a 1:1 ratio (Scheme 3). Fortunately, the desired benz-
amides 11a and 12a and the regioisomers 13a and 14a8,9
were separable by column chromatography on silica gel.
In order to improve the regioselectivity of 11 and 12 over
13 and 14, we decided to increase the bulkiness of the
amide group. When N,N-dibutylbenzamide 3b was
reacted with sulfide 9, we obtained the desired ortho-
alkylphenols and their regioisomers in a 3:1 ratio.10,11
13a: R' = Et
13b: R' = n-Bu
14a: R' = Et
14b: R' = n-Bu
R' = Et 30%
R' = n-Bu 14%
Scheme 3 Reagents and conditions: a) SO2Cl2, s-collidine, CH2Cl2,
–78 °C, 12 min; b) Et3N, CH2Cl2, –78 → 0 °C, 5 h.
Synlett 2006, No. 9, 1363–1366 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of a NG-121 Model Compound
1365
HO
H
HO
H
S
TIPSO
OMe
a, b
11a
OH
OH
O
HO
O
NEt2
15a
TIPSO
OMe
TIPSO
OMe
O
OMe
c
f, g
d, e
HO
H
HO
H
S
O
NEt2
TIPSO
OMe
O
NEt2
O
NEt2
17
18
a, b
16
12a
O
NEt2
15b
OMOM
OMOM
OMOM
OMOM
O
OMe
O
OMe
O
OMe
O
OMe
k
l
j
h
i
2
HO
OHC
O
O
NEt2
O
NEt2
O
NEt2
O
21
22
19
20
Scheme 4 Reagents and conditions: a) TIPSOTf, Et3N, CH2Cl2, r.t., 1 h (98%); b) NaBH4, CH2Cl2, reflux, 2 h (90%); c) Raney Ni T-4, r.t.,
30 min (90%); d) MsCl, py, r.t., 3 h; e) K2CO3, r.t., 1 h (50%); f) Sc(OTf)3, CH2Cl2, r.t., 1 h (90%); g) 1 N HCl–EtOH (1:1), r.t., 9 h (90%);
h) MOMCl, Et3N, CH2Cl2, r.t., 2 h (98%); i) t-BuLi, DMF, THF, –78 → 0 °C, 4 h (60%); j) NaBH4, EtOH, r.t., 2 h (90%); k) AcOH, EtOAc,
r.t., 3 h (90%); l) 1 N HCl, r.t., 3 h (90%).
Subsequently, the phenolic hydroxyl groups of 11a and excellent yields. The structure of 22 was determined by
12a were protected with a TIPS group. Then, the dichlo- 1H NMR spectroscopy and NOE studies. Irradiation of the
roacetyl groups were deprotected to give 15a and 15b, protons of the methoxy group resulted in a 9% enhance-
respectively (Scheme 4). The isopropylsulfanyl groups of ment to the aromatic proton. Finally, the MOM group
15a and 15b were removed by hydrogenolysis with was removed to obtain the tricyclic chroman model
freshly prepared Raney Ni (T-4) in ethanol at room tem- compound 2.13
perature to give the same alcohol 16. Based on this ex-
perimental result we can safely conclude that 11a and 12a
OMOM
were the required diastereomers.
H
H
The secondary hydroxyl group in 16 was selectively
mesylated, followed by conversion of the mesylate into
epoxide 17 by treatment with potassium carbonate. Al-
though the TIPS group is usually removed by TBAF, the
reaction did not occur in the case of 17. After several
efforts, the TIPS group was cleanly cleaved by the action
of Sc(OTf)3 followed by treatment with 1 N HCl at room
temperature to furnish 2,2-dimethylchroman-3-ol 18.
O
O
Me
tBuLi
O
NEt2
Figure 2
To the best of our knowledge, this is the first method for
the synthesis of furan-fused 3-hydroxy-2,2-dialkylchro-
man. The key steps were the ortho-alkylation of the phe-
nol via the [2,3]sigmatropic rearrangement of a sulfur
ylide and the regioselective construction of the lactone.
As the [2,3]sigmatropic rearrangement proceeds under
mild conditions, this method has an important advantage
that an optically active side chain can be introduced into
the aromatic ring. Currently, the synthetic application of
this methodology to the total synthesis of NG-121 is in
progress.
We then explored the construction of the third ring. After
the hydroxyl group of 18 was protected as the MOM
ether, chroman 19 was lithiated with t-BuLi and the result-
ing o-lithioamide quenched with DMF to afford aldehyde
20 as the sole product.12 To our surprise, no regioisomer
was obtained, which can probably be attributed to the
vicinal repulsion of the two hydrogen atoms on the pyran
ring, which results in the methoxy group of the chroman
19 taking up the orientation shown in Figure 2. Thus, ap-
proach of t-BuLi from this side will be hindered providing
20 selectively. Reduction of 20 with NaBH4 gave the
alcohol 21 which cyclized to the tricyclic compound 22 in
Synlett 2006, No. 9, 1363–1366 © Thieme Stuttgart · New York

1366
S. Inoue et al.
LETTER
(9) In support of the assigned regiochemistry for 11a and 12a, a
strong NOESY correlation was observed between the
signals for the methoxy group and the C-6 proton of the
aromatic ring. On the other hand, for 13a and 14a, a strong
NOESY correlation was observed between the signals for
the methoxy group and the C-4 and C-6 protons of the
aromatic ring.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
(B) (No. 09450339 and 13555252), and Priority Area (No.
17035030) from the Ministry of Education, Science, Sport, and
Culture of Japan.
(10) Amides 11b, 12b, 13b, and 14b were also isolated by
column chromatography on silica gel.
References and Notes
(11) The [2,3]sigmatropic rearrangement of 3-hydroxy-5-
methoxy-N,N-diisopropylbenzamide and a higher terpenyl
sulfide, prepared from geraniol according to a method
similar to the synthesis of 9, afforded the para-alkylated
benzamide and the ortho-alkylated isomer in a 2:1 ratio.
Similar alkylation of 3-hydroxy-5-methoxy-N,N-
dibutylbenzamide 3b afforded the para-alkylated
benzamide and the ortho-alkylated isomer in a 3:1 ratio and
alkylation of 3-hydroxy-5-methoxy-N,N-dihexylbenzamide
also afforded the para-alkylated benzamide and the ortho-
alkylated isomer in a 3:1 ratio.
(12) After a terpenyl sulfide was synthesized from (E,E)-farnesol
according to the previously reported procedure,4 the terpenyl
sulfide was reacted with 3b to give the para-alkylated
benzamide and the ortho-alkylated isomer in a 3:1 ratio. The
para-alkylated benzamide was converted to the
(1) Orii, Y.; Ito, M.; Mizoue, K.; Mizobe, F.; Sakai, N.; Hanada,
K. Jpn. Kokai Tokkyo Koho JP 05,176,782, 1993; Chem.
Abstr. 1993, 119, 179349.
(2) (a) Inoue, S.; Ikeda, H.; Sato, S.; Horie, K.; Ota, T.;
Miyamoto, O.; Sato, K. J. Org. Chem. 1987, 52, 5495.
(b) Sato, K.; Inoue, S.; Miyamoto, O.; Ikeda, H.; Ota, T.
Bull. Chem. Soc. Jpn. 1987, 60, 4184. (c) Sato, K.; Inoue,
S.; Ozawa, K.; Kobayashi, T.; Ota, T.; Tazaki, M. J. Chem.
Soc., Perkin Trans. 1 1987, 1753.
(3) (a) Ota, T.; Hasegawa, S.; Inoue, S.; Sato, K. J. Chem. Soc.,
Perkin Trans. 1 1988, 3029. (b) Inoue, T.; Inoue, S.; Sato,
K. Chem. Lett. 1989, 653. (c) Inoue, T.; Inoue, S.; Sato, K.
Chem. Lett. 1990, 55. (d) Inoue, T.; Inoue, S.; Sato, K. Bull.
Chem. Soc. Jpn. 1990, 63, 1062. (e) Inoue, T.; Inoue, S.;
Sato, K. Bull. Chem. Soc. Jpn. 1990, 63, 1647.
(4) Inoue, S.; Asami, M.; Honda, K.; Shrestha, K. S.; Takahashi,
T.; Yoshino, T. Synlett 1998, 679.
corresponding 3-hydroxy-2,2-dialkylchroman according to
a similar synthetic route to that shown in Scheme 4. The
chroman compound was regioselectively formylated in 58%
yield.
(5) Patterson, J. W. J. Org. Chem. 1995, 60, 4542.
(6) Weinreb, S. M. Synth. Commun. 1982, 989.
(7) The sulfide 9 was synthesized from commercially available
2-methyl-3-buten-2-ol according to the previously reported
procedure, see ref. 4.
(8) The structures of 11a, 12a, 13a, and 14a were determined by
1H NMR, 13C NMR, 1H-1H COSY, 1H- 13C COSY, and
DEPT spectroscopy. It was impossible to determine the
relative configuration of 11a, 12a, 13a, and 14a.
(13) Spectral data for 2: IR (neat): 3454, 2926, 1730, 1623, 1468,
1349, 1138, 1110 cm–1; 1H NMR (270 MHz, CDCl3): d =
6.90 (s, 1 H, ArH), 5.20 (s, 2 H, ArCH2), 3.89 (s, 4 H, OCH3,
H-3), 2.97 (dd, J = 4.95, 18.47 Hz, 1 H, H-4), 2.77 (dd,
J = 5.28, 18.47 Hz, 1 H, H-4), 1.39 (s, 3 H, CH3-2), 1.33 (s,
3 H, CH3-2); 13C NMR (67.8 MHz, CDCl3): d = 171.8,
159.5, 147.9, 127.6, 125.2, 114.5, 97.14, 77.59, 68.64,
68.09, 55.90, 26.97, 24.58, 22.03.
Synlett 2006, No. 9, 1363–1366 © Thieme Stuttgart · New York