Synthesis of functionalized pyroglutamic acids, part 1: The synthetic utility of N-acylindole and the ugi reaction with a chiral levulinic acid

Article abstract of DOI:10.1055/s-2008-1078173

A variety of pyroglutamic acid derivatives are readily synthesized via N-acylindole intermediates obtained by the Ugi reaction. For the preparation of functionalized pyroglutamic acid derivatives, the diastereoselectivity of the Ugi 4-center 3-component c

Full text of DOI:10.1055/s-2008-1078173

2244
LETTER
Synthesis of Functionalized Pyroglutamic Acids, Part 1: The Synthetic Utility
of N-Acylindole and the Ugi Reaction with a Chiral Levulinic Acid
S
ynthesis of Functiona
a
lized Pyrog
t
lutami
t
A
cids
h
:
Par
t
1
ew J. Buller, Cynthia B. Gilley, Brian Nguyen, Lisa Olshansky, Breena Fraga, Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, Mail Code 0343, La Jolla, CA 92093-0343, USA
E-mail: ykoba@chem.ucsd.edu
Received 2 May 2008
Abstract: A variety of pyroglutamic acid derivatives are readily
synthesized via N-acylindole intermediates obtained by the Ugi re-
action. For the preparation of functionalized pyroglutamic acid de-
rivatives, the diastereoselectivity of the Ugi 4-center 3-component
condensation reaction with a chiral g-keto acid and convertible iso-
cyanide is described.
+
–
C
N
O
O
Me
OMe
OMe
PMB
1
Me
HO
N
(1 equiv)
N
O
H
O
OMe
OMe
PMBNH2
2
3
(1.1 equiv)
CF3CH2OH
60 °C
Key words: pyroglutamic acid, Ugi reaction, convertible isocya-
nide, diastereoselectivity, b-lactone
(1.1 equiv)
CSA (0.5 equiv)
C6H6, 80 °C
96%
99%
In 1997, the Ugi 4-center 3-component condensation (4C-
3C) reaction of levulinic acid (4-oxopentanoic acid) was
reported to afford a 2-methylpyroglutamic acid amide.1
Interestingly, the Passerini reaction, which provides the
corresponding g-lactone, had been reported in 1923, just
two years after the discovery of the Passerini reaction in
O
PMB
Me
N
N
O
4
Scheme 1 Ugi 4C-3C reaction of levulinic acid (2) with convertible
isocyanide 1 reported in 2007
1921.2 Thanks to the mild nature of the reaction condi-
tions and high chemical yield, the Ugi reaction with g-
keto acid derivatives could be an efficient method to ob-
tain pyroglutamic acid derivatives. Nevertheless, in our
opinion, there were two major obstacles to overcome to
apply the reaction in complex natural product synthesis.
First is the difficulty of hydrolysis of the sterically hin-
dered C-terminal amide, which derives from an isocya-
nide.3 Second is the diastereoselectivity in the reaction
when a chiral substrate is used. Because of these difficul-
ties, the application in the total synthesis of natural prod-
ucts has only been reported recently.4 It appears that the
Ugi reaction of g-keto acids for the synthesis of pyro-
glutamic acid derivatives has been underestimated among
synthetic organic chemists due to these problems.
In 2007, we reported convertible isocyanide 1 and demon-
strated the applicability in the synthesis of pyroglutamic
acid (Scheme 1).4a The condensation of levulinic acid (2),
PMBNH2, and isocyanide 1 in trifluoroethanol at 60 °C
afforded pyroglutamic acid anilide 3 in excellent yield.5
The resulting sterically hindered anilide 3 was activated to
N-acylindole 4 for facile hydrolysis. Indeed, the hydroly-
sis of 4 to a carboxylic acid 5a was achieved by treatment
with Cs2CO3 in aqueous DMF (Table 1, entry 1).
In addition, the utility of N-acylindole 4 as a coupling
agent was investigated. The direct conversion of the N-
acylindole to an ester, amide and aldehyde was smoothly
carried out under mild conditions. N-Acylindole 4 was
converted in good yields into the corresponding benzyl es-
ter 5b (entry 2) or butyl thioester 5c (entry 3) with a stoi-
chiometric amount of benzyl alcohol or butanethiol,
respectively. Overall a transamidation process, secondary
amide formation occurred smoothly from 4 by heating the
N-acylindole with a primary amine. The amide 5d was ob-
tained by treatment with excess p-methoxybenzylamine
(entry 4). Although primary alcohols, thiols, and amines
reacted with the N-acylindole, secondary alcohols (iso-
propanol) and amines (morpholine) failed to react, pre-
sumably due to steric hindrance.
In the course of synthetic studies on the proteasome inhib-
itor omuralide in our laboratory, a novel convertible iso-
cyanide, 1-isocyano-2-(2,2-dimethoxyethyl)benzene (1),
was introduced for the facile synthesis of pyroglutamic
acids by use of the Ugi reaction of g-keto acids.4a The hy-
drolysis of the resulting C-terminal anilide was facilitated
by conversion to the corresponding N-acylindole. In this
paper, we report the extended utility of N-acylindole as a
coupling agent and our initial investigation on stereose-
lectivity in the Ugi 4C-3C reaction with chiral g-keto ac-
ids.
An interesting two-step, one-pot sequence was employed
to convert the N-acylindole moiety directly into an alde-
hyde 5e (entry 5). Reduction of the N-acylindole with
SYNLETT 2008, No. 15, pp 2244–2248
Advanced online publication: 28.08.2008
1
5
.0
9
.2
0
0
8
DOI: 10.1055/s-2008-1078173; Art ID: S04208ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Pyroglutamic Acids: Part 1
2245
selectivity7 and a creation of diversity by a post-Ugi mod-
ification of the hydroxy group.
Table 1 Synthetic Utility of N-Acylindole 4 as a Coupling Agent
O
O
PMB
PMB
Me
Me
We synthesized racemic 3-hydroxy-4-oxopentanoic acid
(10), as shown in Scheme 2, to determine first its feasibil-
ity in the Ugi reaction with an a-hydroxyketone, and sec-
ond the resulting diastereoselectivity. The literature
revealed a single report of the synthesis of 108 but, unfor-
tunately, the sequence was inefficient and low yielding.
Our own strategy for the synthesis of 3-hydroxy-4-oxo-
pentanoic acid (10) began with aldol reaction of the lithi-
um enolate of benzyl acetate (6) and a-methyl-
cinnamaldehyde (7), which afforded aldol product 8 in
96% yield (Scheme 1). Use of the enal allows for imme-
diate installation of the carbonyl group at the g-position.
Ozonolysis of 8 conveniently provided b-hydroxy-g-ke-
toester 9 in 84% yield. Lastly, carboxylic acid 10 was
formed in quantitative yield via hydrogenolysis of 9. Hy-
drogenolysis of the benzyl ester generated the carboxylic
acid without elimination of the hydroxy group. This strat-
egy could be a general procedure established to obtain a
series of chiral b-hydroxy-g-keto acid (3-hydroxy-4-oxo-
pentanoic acid) derivatives when stereoselective aldol re-
actions are applied with enals.
N
N
N
X
O
O
4
5
Entry Conditions
Products
Yield
97%
O
O
O
O
O
PMB
Me
Cs2CO3 (1.0 equiv)
DMF–H2O (1:1)
r.t.
N
N
N
N
N
1
2
3
4
OH
O
5a
PMB
Me
Me
Me
Me
Cs2CO3 (1.4 equiv)
BnOH (1.2 equiv)
DMF, r.t.
79%
86%
81%
OBn
Sn-Bu
O
5b
PMB
Cs2CO3 (1.5 equiv)
n-BuSH (1.5 equiv)
DMF, r.t.
O
5c
PMB
PMB
PMBNH2 (10 equiv)
THF, reflux
N
H
O
Ph
Ph
5d
Me
CHO
Me
+
LDA
BnO
BnO
PMB
NaBH4 (1.0 equiv)
MeOH;
aq NaOH, THF
r.t.
THF
–78 °C
96%
O
Me
H
O
OH
5
69%
O
6
7
8
racemic
5e
O3, MeOH
–78 °C; Me2S
84%
NaBH4 provides an N,O-hemiacetal intermediate which is
stable until treated with aqueous NaOH.6 Deprotonation
to form the alkoxide of the hemiacetal hydroxy group
causes concurrent expulsion of indole and aldehyde for-
mation.
H2
Pd/C
O
Me
O
Me
OH
HO
BnO
MeOH
quant.
O
OH
O
10
9
As shown in Table 1, the N-acylindole 4 is a versatile syn-
thetic intermediate, which can be directly converted to a
variety of acid derivatives as well as an aldehyde. Due to
the steric hindrance in particular, the formation of the N-
acylindole is a convenient method to activate the exo
amide derived from the isocyanide, instead of sequential
manipulations; hydrolysis to a carboxylic acid followed
by condensation with a coupling agent like DCC.
Scheme 2 Synthesis of racemic 3-hydroxy-4-oxopentanoic acid
(10)
With the chiral substrate in hand, we set out to investigate
the diastereoselectivity in the Ugi 4C-3C reaction. Our
concerns were a potential side reaction from a-hydroxyl-
imine to a-amino carbonyl compound, known as Amadori
rearrangement,9 and N-acylindole formation in the pres-
ence of the unprotected hydroxy group at the b-position,
in addition to the stereoselective outcome of the reaction.
Next, we were interested in investigating a substrate-con-
trolled stereoselective Ugi 4C-3C reaction with a chiral g-
keto acid. We envisioned that stereocenters on the carbon
backbone connecting the carboxyl group and the carbonyl
group might affect the stereochemistry at the a-carbon of
the resulting amino acid. Based on the reaction mecha-
nism, the stereodetermining step is the addition of an iso-
cyanide toward a putative iminium ion. Therefore, a
stereocenter at the a-position of the carbonyl group could
be the most effective to achieve the stereoselective addi-
tion of an isocyanide. We chose an unprotected hydroxy
group as our chiral substituent, as this was the most in-
triguing for us. We expected a chelation of unprotected
hydroxy group with a putative imine to enhance the
Ugi reaction of 3-hydroxy-4-oxopentanoic acid (10) with
isocyanide 1 and p-methoxybenzylamine in trifluoroetha-
nol provided an inseparable 2:1 diastereomeric mixture of
anilides 11a and 11b in 65% yield (Scheme 3).10 The
chemical shifts of the methyl group of 11 were at d = 1.37
ppm for the major isomer and at d = 1.40 ppm for the mi-
nor. Fortunately, a side product resulting from an Ama-
dori rearrangement was not observed with this substrate.
The relative stereochemistry of the minor diastereomer
was assigned as syn as shown in Scheme 3. That assign-
1
ment was established by comparison of the H NMR
Synlett 2008, No. 15, 2244–2248 © Thieme Stuttgart · New York

2246
M. J. Buller et al.
LETTER
chemical shifts after conversion of the Ugi product mix-
ture to the corresponding methyl esters. The selective for-
mation of syn methyl ester was achieved via methanolysis
of the b-lactone (vide infra).
δ = 1.37 ppm
O
PMB
Me
N
N
–
+
O
H
For the assignment of the relative stereochemistry, meth-
anolysis of the Ugi product anilide 11 via N-acylindole
formation was attempted (Scheme 4). Unfortunately, ex-
clusive formation of N-acylindole 12 was not successful
like the sequence with levulinic acid. When anilide 11 was
subjected to acidic conditions, N,O-acetal 13 was ob-
tained as a 1:1 mixture of two diastereomers (unknown
stereochemistry),11 in addition to two diastereomers (dr =
5:1) of N-acylindole 12 (12/13 = 2:1). The acetal was sta-
ble and could not be converted to N-acylindole 12 under
any conditions we attempted. As we foresaw, during the
N-acylindole formation the hydroxy group intercepted the
putative N-acyliminium ion to form the acetal before the
isomerization to indole. However, such a side reaction
could be avoided by protection of the hydroxy group.
OMe
OMe
C
N
OH
OMe
OMe
1
O
Me
OH
11a
anti (major)
HO
O
(1 equiv)
+
PMBNH2
δ = 1.40 ppm
(1.1 equiv)
CF3CH2OH
60 °C
10
(1.1 equiv)
O
PMB
65%
dr = 2:1
Me
N
N
O
H
OMe
OMe
OH
syn (minor)
11b
Scheme 3 Ugi 4C-3C reaction of 3-hydroxy-4-oxopentanoic acid
(10) with convertible isocyanide 1
O
PMB
Me
The secondary alcohol of the diastereomeric mixture of
anilide 11 was acetylated to afford 14 (dr = 2:1) before the
formation of the N-acylindole (Scheme 5). Protection of
the alcohol prevents side product formation of N,O-acetal
during the N-acylindole formation step as described be-
low. Treatment of the acetate 14 with CSA in benzene at
reflux afforded N-acylindole 15 (dr = 2:1) in excellent
yield. Concomitant methanolysis of the N-acylindole and
the acetate was achieved successfully to afford ester 16ab
(dr = 2:1) by treatment with excess Et3N in MeOH at room
temperature. The diastereomeric mixture of anilide 11
was converted to the corresponding methyl ester 16ab in
94% overall yield in three steps, and the 1H NMR chemi-
cal shifts of the syn/anti mixture of methyl ester 16ab
were measured (see below). The major isomer showed
two singlet peaks at d = 1.42 and 3.46 ppm, while the mi-
nor at d = 1.47 and 3.42 ppm.
N
N
O
H
OMe
OMe
OH
11ab
syn/anti mixture
CSA (0.1 equiv)
C6H6, heat, 77%
O
O
PMB
PMB
Me
Me
N
N
N
N
+
O
O
OH
O
2:1
12
13
N-acylindole
N,O-acetal
Scheme 4 Attempted N-acylindole formation from 11ab
δ = 1.38 ppm (major)
δ = 1.52 ppm (minor)
O
PMB
O
PMB
Ac2O
Me
Me
pyridine
CH2Cl2
98%
N
N
N
N
H
H
O
O
OMe
OMe
OMe
OMe
OH
O
Ac
11
14
CSA (0.4 equiv)
C6H6, heat, 98%
δ = 1.42 ppm (major)
δ = 1.47 ppm (minor)
δ = 1.51 ppm (major)
δ = 1.57 ppm (minor)
δ = 3.46 ppm (major)
δ = 3.42 ppm (minor)
O
O
PMB
PMB
Et3N
Me
Me
(14 equiv)
N
N
OMe
N
O
O
MeOH
r.t.
OH
16ab
O
Ac
15
98%
syn/anti mixture
(anti major)
Scheme 5 Hydrolysis of anilide 11 via N-acylindole 15 and diagnostic chemical shifts of 1H NMR spectra
Synlett 2008, No. 15, 2244–2248 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized Pyroglutamic Acids: Part 1
2247
References and Notes
O
O
PMB
Me
PMB
Me
Et3N
(1) (a) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997,
38, 359. (b) Harriman, G. C. B. Tetrahedron Lett. 1997, 38,
5591. (c) Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett.
1998, 39, 2725. (d) Tye, H.; Whittaker, M. Org. Biomol.
Chem. 2004, 2, 813. For recent reviews on multicomponent
condensation reactions, see: (e) Ramon, D. J.; Yus, M.
Angew. Chem. Int. Ed. 2005, 44, 1602. (f) Dömling, A.
Chem. Rev. 2006, 106, 17.
N
N
N
OH
O
O
THF–H2O
70 °C
O
OH
17
15
Ac
91%
syn/anti mixture
syn/anti mixture
DCC, CH2Cl2
r.t., 19%
δ = 1.47 ppm
δ = 3.42 ppm
(2) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51,
126. (b) Passerini, M. Gazz. Chim. Ital. 1923, 53, 331.
(3) For convertible isocyanides, see: (a) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168; see page numbers
3183 and 3184 and references therein. (b) Keating, T. A.;
Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
(c) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T.
Synlett 2004, 41. (d) Rikimaru, K.; Mori, K.; Kan, T.;
Fukuyama, T. Chem. Commun. 2005, 394. (e) Pirrung,
M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128, 11772.
(4) (a) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett.
2007, 9, 3631. (b) Vamos, M.; Ozboya, K.; Kobayashi, Y.
Synlett 2007, 1595. (c) Kreye, O.; Westermann, B.;
Wessjohann, L. A. Synlett 2007, 3188.
(5) Ammonium acetate or HMDS could be used to prepare
unprotected g-lactams: (a) Isaacson, J.; Loo, M.; Kobayashi,
Y. Org. Lett. 2008, 10, 1461. (b) Isaacson, J.; Gilley, C. B.;
Kobayshi, Y. J. Org. Chem. 2007, 72, 3913.
(6) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 71.
(7) Faggi, C.; Marcaccini, S.; Pepino, R.; Pozo, M. C. Synthesis
2002, 2756.
(8) Lueoend, R. M.; Walker, J.; Neier, R. W. J. Org. Chem.
1992, 57, 5005.
(9) For a recent application of the Amadori rearrangement in
natural product synthesis, see: Guzi, T. J.; Macdonald, T. L.
Tetrahedron Lett. 1996, 37, 2939.
(10) Solvent effects in the stereoselective Ugi 4C-3C reaction of
4-oxopentanoic acid(10), PMBNH2, and isocyanide 1 was
examined in H2O, MeOH, i-PrOH, CH2Cl2, MeCN, THF,
EtOAc and dioxane. No Ugi product 11 was observed by the
reaction in those solvents; instead, N-(4-methoxybenzyl)-
acetamide was isolated as a product (28–52%). The reaction
in hexafluoroisopropanol, (CF3)2CHOH, furnished the
desired Ugi products 11a and 11b in 70% yield as 1.2:1
diastereomixture.
(11) The formation of the N,O-acetal 13 was enhanced and the
stability was increased by the g-lactam. For example, the
linear anilide was converted into N-acylindole without
formation of N,O-acetal as shown in Scheme 7.
O
PMB
PMB
Me
Me
O
Et3N
N
N
OMe
O
O
MeOH
r.t.
quant
O
OH
16b
18
Scheme 6 Selective formation of syn methyl ester 16b via methano-
lysis of b-lactone 18
1
The H NMR spectrum of the pure syn methyl ester de-
rived from Ugi product 11 was obtained as follows
(Scheme 6). Because the separation of the syn and anti
isomers was difficult at any stage, we decided to use to our
advantage a unique structural property of fused g-lactam-
b-lactone heterobicyclic ring systems. The syn/anti mix-
ture of the N-acylindole 15 was hydrolyzed and the result-
ing carboxylic acid 17 was converted into g-lactam-b-
lactone bicycle 18. At this point, only the syn isomer could
form the b-lactone, while the anti isomer formed oligo-
mers by intermolecular esterification.12 Methanolysis of
the b-lactone exclusively gave syn methyl ester 16b. The
1H NMR spectrum of syn methyl ester 16b showed two
singlet peaks at d = 1.47 and 3.42 ppm. It was compared
to a spectrum containing the 2:1 mixture of methyl ester
diastereomers 16ab, obtained from methanolysis of the N-
acylindole derived from mixture of Ugi products 11. We
1
determined by comparison of H NMR chemical shifts
that the minor isomer of 11 is the syn diastereomer.13
In conclusion, we have shown the synthetic utility of an
N-acylindole derivative of a pyroglutamic acid as a cou-
pling agent to afford the corresponding carboxylic acid,
ester, thioester, amide and aldehyde. We also disclosed
the stereoselective outcome of the Ugi reaction of 3-hy-
droxy-4-oxopentanoic acid. The relative stereochemistry
of the Ugi product was established via chemoselective
transformation of the syn isomer to a b-lactone. In the fol-
lowing Letter, to further explore the utility of the Ugi re-
action in the synthesis of functionalized pyroglutamic
acids, we describe a general method for the synthesis of a
series of levulinic acid derivatives and their use in the ste-
reoselective Ugi 4C-3C reaction.14
O
O
O
TSA
N
H
N
MeOH
heat
OMe
OMe
O
MeO2C
OH
quant
O
Me
N-acylindole
Me
Acknowledgment
Scheme 7
We greatly acknowledge the University of California, a Kaplan fel-
lowship (M.J.B.), and a GAANN fellowship (C.B.G.) for financial
support of this research.
(12) The formation of 3-mer, 4-mer and 5-mer of the anti isomer
shown in Figure 1 were detected by mass spectrometry.
Synlett 2008, No. 15, 2244–2248 © Thieme Stuttgart · New York

2248
M. J. Buller et al.
LETTER
J = 8.7 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 6.74–6.86 (m, 4
H), 6.05 (br s, 1 H), 4.36 (q, J = 13.8 Hz, 2 H), 4.26 (dd, J =
6.3, 14.4 Hz 1 H), 3.91 (dd, J = 5.1, 14.4 Hz, 1 H), 3.78 (s, 3
H), 3.76 (s, 3 H), 2.26–2.45 (m, 3 H), 1.84–2.04 (m, 1 H),
1.44 (s, 3 H). Compound 5e: 1H NMR (300 MHz, CDCl3):
d = 9.04 (s, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.7
Hz, 2 H), 4.60 (d, J = 15.0 Hz, 1 H), 4.13 (d, J = 14.7 Hz, 1
H), 3.74 (s, 3 H), 2.47 (t, J = 7.5 Hz, 2 H), 2.07–2.16 (m, 1
H), 1.77 (td, J = 8.7, 13.8 Hz, 1 H), 1.31 (s, 3 H). Compound
8: 1H NMR (400 MHz, CDCl3): d = 7.38–7.21 (m, 10 H),
6.59 (s, 1 H), 5.18 (s, 2 H), 4.64 (t, J = 6.4 Hz, 1 H), 2.94 (br
s, 1 H), 2.73 (d, J = 2.0 Hz, 1 H), 2.71 (s, 1 H), 1.88 (s, 3 H).
Compound 9: 1H NMR (400 MHz, CDCl3): d = 7.31–7.39
(m, 5 H), 5.17 (d, J = 12.4 Hz, 1 H), 5.13 (d, J = 12.4 Hz, 1
H), 4.39 (q, J = 4.8, 10.8 Hz, 1 H), 3.77 (d, J = 5.2 Hz, 1 H),
2.93 (dd, J = 4.4, 16.8 Hz, 1 H), 2.79 (dd, J = 6.0, 16.4 Hz, 1
H), 2.26 (s, 3 H). Compound 10: 1H NMR (400 MHz,
CDCl3): d = 5.61 (br s, 1 H), 4.39 (dd, J = 4.0, 6.4 Hz, 1 H),
2.93 (dd, J = 4.4, 16.8 Hz, 1 H), 2.79 (dd, J = 6.4, 16.8 Hz, 1
H), 2.27 (s, 3 H). Compound 11a: 1H NMR (400 MHz,
CDCl3): d = 8.96 (br s, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.10–
7.24 (m, 5 H), 6.78 (d, J = 8.4 Hz, 2 H), 4.94 (d, J = 15.2 Hz,
1 H), 4.41–4.46 (m, 2 H), 4.10–4.18 (m, 1 H), 3.74 (s, 3 H),
3.38 (s, 3 H), 3.36 (s, 3 H), 2.74–2.94 (m, 3 H), 2.45 (dd, J =
2.8, 17.2 Hz, 1 H), 1.37 (s, 3 H). Compound 18: 1H NMR
(400 MHz, CDCl3): d = 7.21 (d, J = 8.8 Hz, 2 H), 6.83 (d,
J = 8.8 Hz, 2 H), 4.78 (t, J = 4.0 Hz, 1 H), 4.72 (d, J = 14.8
Hz, 1 H), 4.38 (d, J = 15.2 Hz, 1 H), 3.78 (s, 3 H), 2.88 (d,
J = 3.6 Hz, 2 H), 1.50 (s, 3 H).
OMe
Me
OH
O
N
OMe
O
O
Me
O
N
OMe
O
O
Me
O
N
n
O
OH
Figure 1
(13) 1H NMR data of the selected compounds are shown below.
Compound 5b: 1H NMR (300 MHz, CDCl3): d = 7.21–7.38
(m, 5 H), 7.17 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 2 H),
4.97 (d, J = 12.3 Hz, 1 H), 4.73 (d, J = 12.3 Hz, 1 H), 4.46
(d, J = 15.3 Hz, 1 H), 4.31 (d, J = 15.6 Hz, 1 H), 3.75 (s, 3
H), 2.36–2.61 (m, 2 H), 2.23–2.31 (m, 1 H), 1.80–1.91 (m, 1
H), 1.43 (s, 3 H). Compound 5c: 1H NMR (300 MHz,
CDCl3): d = 7.20 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2
H), 4.96 (d, J = 15.3 Hz, 1 H), 3.86 (d, J = 15.6 Hz, 1 H), 3.77
(s, 3 H), 2.85 (t, J = 6.6 Hz, 2 H), 2.41–2.65 (m, 2 H), 2.21–
2.29 (m, 1 H), 1.83–1.94 (m, 1 H), 1.53 (p, J = 7.8 Hz, 2 H),
1.39 (p, J = 7.2 Hz, 2 H), 1.36 (s, 3 H), 0.92 (t, J = 7.5 Hz, 3
H). Compound 5d: 1H NMR (300 MHz, CDCl3): d = 7.18 (d,
(14) See the following paper: Gilley, C. B.; Buller, M. J.;
Kobayashi, Y. Synlett 2008, 2249.
Synlett 2008, No. 15, 2244–2248 © Thieme Stuttgart · New York

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