Synthesis of (3S)-2,5-diethoxy-3,6-dihydro-3-isopropyl-6- methylsulfanylpyrazines and stereoselectivity in alkylation of the anions

Article abstract of DOI:10.3987/COM-10-11922

The introduction of a sulfur function into Schoellkopf s bislactim ether was carried out to synthesize the diastereomers of (3S)-2,5-diethoxy-3,6- dihydro-3-isopropyl-6-methylsulfanylpyrazine. Stereoselectivity in the alkylation of the anions derived from

Full text of DOI:10.3987/COM-10-11922

HETEROCYCLES, Vol. 81, No. 5, 2010
1239
HETEROCYCLES, Vol. 81, No. 5, 2010, pp. 1239 - 1251. © The Japan Institute of Heterocyclic Chemistry
Received, 8th February, 2010, Accepted, 23rd March, 2010, Published online, 24th March, 2010
DOI: 10.3987/COM-10-11922
SYNTHESIS OF (3S)-2,5-DIETHOXY-3,6-DIHYDRO-3-ISOPROPYL-6-
METHYLSULFANYLPYRAZINES AND STEREOSELECTIVITY IN
ALKYLATION OF THE ANIONS
Yoshihide Usami,* Masao Arimoto,* Chisaka Kioka, Masako Yamanaka,
Naoko Matsuda, and Hayato Ichikawa
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki 569-1094,
Osaka, Japan; E-mail: usami@gly.oups.ac.jp
Abstract – The introduction of a sulfur function into Schöllkopf’s bislactim ether
was carried out to synthesize the diastereomers of (3S)-2,5-diethoxy-3,6-
dihydro-3-isopropyl-6-methylsulfanylpyrazine. Stereoselectivity in the alkylation
of the anions derived from those compounds was examined as a basic study of the
synthesis of chiral -sulfanylamino acids.
INTRODUCTION
Sulfur-containing diketopiperazines,1 such as gliotoxins,2 gliovictin,3 sporidesmins,4 aranotins,5,6
verticillins,7 chaetocins,8 and leptosins9,10 (Figure 1), make up a large category of natural products with
significant importance because they exhibit various biological activities. We also had reported the
isolation of cytotoxic natural products possessing the diketopiperazine structure with a sulfur function at
the -position, as the metabolites of fungi originally isolated from marine resources.11,12 Several methods
for the total synthesis of this type of natural products are available. However, most of them yielded
racemic compounds.13-19 in spite of the intensive effort to synthesize non-natural but chiral
diketopiperazines bearing sulfur functions20-27 Very recently, a great milestone was achieved by
Movassaghi and co-workers who reported the total synthesis of (+)-11,11’-deoxyverticillin A.28
The asymmetric syntheses of sulfur-containing diketopiperazine natural products pose a great challenge
for organic chemists and are a vital step in the development of new drugs. As we are interested in cyclic
dipeptides consisting of two -thioamino acids, the synthesis of the building block seems to be one
possible way to achieve our goal. We had examined Schöllkopf’s bislactim ether methodology29-31 for the
synthesis of chiral -thioamino acids. Described herein is the synthesis of the diastereomers of
(3S)-2,5-diethoxy-3,6-dihydro-3-isopropyl-6-methylsulfanylpyrazine and the stereoselective alkylation of
the anions derived from them.32

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HETEROCYCLES, Vol. 81, No. 5, 2010
Cl
MeO
O
SMe
OH
X
O
O
MeO
O
H
N
S
MeN
HO
H
S
N
S
MeN
NMe
S
N
H
OAc
O
NMe
O
AcO
O
O
MeS
N
S
H
S
O
NMe
OH
OH
O
gliotoxin
gliovictin
acetylaranotin
sporidesmin A: X = OH
sporidesmin B: X = H
R
O
Me
N
H
S
MeN
N
S
O
R'O
RN
O
SMe
O
X
X
O
NR
S
N
S
NMe
R
N
Me
H
SMe
O
fusaperazine A: R = H, R' = H
(+)-verticillin A: X = OH, R = CH3
natural product33: R = Me, R' = H
(+)-11,11'-dideoxyverticillin A: X = H, R = CH3
(+)-chaetocin A: X = H, R = CH2OH
(+)-leptosin K: X = H, R = CH(CH3)2
Sch 5479434 (antipode): R = H, R' = isoprenyl
cis-bis(methylthio)silvatin33,35(antipode): R = Me, R' = isoprenyl
H
N
SMe
HN
O
X
HN
SMe
O
NH
O
N
N
H
O
R
N
MeS
Me
SMe
glioperazine: R = CH(OH)CH3 ([]D = +52.6)
polanzanine B36: R = CH(CH3)2 ([]D =60)
(relative stereochemistry)
gliocladin A: X = OH
gliocladin B: X = H
(relative stereochemistry)
Figure 1. Structures of naturally occurring sulfur-containing diketopiperazines
RESULTS AND DISCUSSION
As summarized in Scheme 1, there are two ways to furnish -sulfanylamino acid from Schöllkopf’s
bislactim ether 1. Route A involves the initial alkylation, followed by -sulfanylation. and route B
involves the initial introduction of a sulfur function, followed by alkylation.

HETEROCYCLES, Vol. 81, No. 5, 2010
1241
N
N
OEt
R'
Route A
SR
CO2H
EtO
EtO
R'
N
N
OEt
SR
N
N
OEt
H2N
EtO
EtO
chiral-sulfanylamino acid
R'
N
N
OEt
SR
Route B
Scheme 1. Strategy for the preparation of chiral -sulfanylamino acids
1. INTRODUCTION OF SULFUR FUNCTION INTO BENZYLATED BISLACTIM ETHER
Route A, our initial approach, is summarized in Scheme 2. Schöllkopf’s bislactim ether 1 was lithiated
with n-BuLi, and this was followed by the addition of benzyl bromide to give a mixture of benzylated
diastereomers 2a and 2b in 94% d.e. Purely isolated major trans-isomer 2a was treated with n-BuLi, and
this was followed by the addition of dimethyl disulfide to afford products 3a and 3b in 95% yield with a
ratio of approximately 70 : 30. The stereochemistry of 3a and 3b was deduced from the chemical shift of
H-3, which was observed in the higher field at 2.98 ppm for 3a due to the anisotropic effect of the benzyl
group located on the same side, compared to 3.78 ppm for 3b, as illustrated in Figure 2. This speculation
was confirmed by NOESY analysis.
N
OEt
N
OEt
N
OEt
n-BuLi
+
PhCH2Br
EtO
N
EtO
N
CH2Ph
EtO
N
CH2Ph
1
2a (86%: isolate yield)
2b (2%: isolate yield)
94% d.e. (1HNMR analysis on a crude mixture)
N
N
OEt
N
N
OEt
n-BuLi
N
OEt
+
SMe
SMe
MeSSMe
EtO
EtO
EtO
N
CH2Ph
CH2Ph
CH2Ph
95%
70:30
3b
2a
3a
Scheme 2. Benzylation of Schöllkopf’s bislactim ether 1 and methylsulfanylation of major product 2a
A NOESY cross peak between H-3 and 6-SMe was observed for 3b whereas 6-SMe/3-isopropyl methyls
or 6-SMe/3-isopropyl methine cross peaks were observed for 3a. It is generally accepted that the
carbanion derived from 1 has an sp2 hybrid and it mainly reacts with the electrophile at the side opposite

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HETEROCYCLES, Vol. 81, No. 5, 2010
to the 3-isopropyl group to yield excellent stereoselectivity. Thus, the low stereoselectivity may be
explained by the preference of the sp3-like carbanion derived from 2a for the - stabilizing interaction
between the bislactim ether ring and the benzyl group.
(3.78 ppm)
(3.78 ppm)
H
H
N
OEt
OEt
(3.24 ppm)
H
(2.89 ppm)
H
H
N
SMe
N
N
OEt
OEt
EtO
EtO
N
N
3
6
N
N
EtO
EtO
H
SMe
(0.78, 0.20 ppm)
(0.91, 0.35 ppm)
(0.62, 0.93 ppm)
(0.65, 0.73 ppm)
2a
3a
2b
3b
Figure 2. Conformations and 1H-NMR chemical shifts of 2 and 3
2. SYNTHESIS OF (3S)-6-METHYLSULFANYL-3-ISOPROPYLBISLACTIM ETHER
As the second approach via route B, bislactim ether 1 was treated with n-BuLi in THF at 78 oC, and this
was followed by the addition of dimethyl disulfide to afford a mixture of diastereomers 4a and 4b in a
ratio of ca. 1:2. To our surprise, major diastereomer 4b had a cis-configuration between the 3-isopropyl
group and the newly introduced 6-methylsulfanyl group. A cross peak between 3-isopropyl
methyl/6-SMe in the NOESY spectrum of 4b and cross peaks between H-3/6-SMe and 3-isopropyl
methyl/6-H in the NOESY spectrum of 4a confirmed their relative stereochemistry, as illustrated in
Scheme 3. One possible explanation for this unusual stereoselectivity is the re-deprotonation of initially
formed 4a or 4b by methylthiolate anion in the reaction system, followed by protonation from the less
hindered side during the quenching process. However, quenching of the reaction with D2O did not give
any deuterated 4a or 4b, negating the above deduction. The reason why 4b was formed predominantly
under kinetically controlled conditions remains unknown.
1) n-BuLi
2) MeSSMe
N
N
OEt
N
N
OEt
N
N
OEt
+
EtO
EtO
SMe
EtO
SMe
84%
4a
1 : 2
4b
1
Scheme 3. Reaction of anion derived from Schöllkopf’s bislactim ether 1 with dimethyldisulfide
3. ALKYLATION OF (3S)-6-METHYLSULFANYL-3-ISOPROPYLBISLACTIM ETHER
The stereoselectivity in the alkylation of the carbanion derived from 4a or 4b was investigated. The

HETEROCYCLES, Vol. 81, No. 5, 2010
1243
electrophiles selected here will be useful for the synthesis of natural sulfur-containing diketopiperazines.
The results are summarized in Table 1. Benzylation showed remarkable stereoselectivity, giving single
product 3a from either starting material 4a or 4b or mixture of both (entries 1-3). Methylation also
showed the same stereoselectivity (5a:5b = ca. 3:1) from either starting material (entries 4 and 5). Similar
low stereoselectivity in the methylation was seen in a previous study by Nagao and co-workers using
(L)-serine-derived Schöllkopf’s bislactim ether.37 From the results described above, it became apparent
that the stereochemistry of the starting material has no effect on the stereoselectivity of this reaction.
Ethylation using iodoethane as an electrophile gave higher stereoselectivity than methylation whereas
bromoethane did not yield the same result (entries 7 and 8). The reaction with iodopropane proceeded
with excellent stereoselectivity (entry 9). The reaction with piperonyl bromide gave a single diastereomer
8d in 30% yield along with aromatized product 11 (entry 10). The stereoselectivity of this reaction
seemed to be related to the bulkiness of the electrophiles.
1) n-BuLi
2) electrophile
THF, 78oC to rt
N
N
OEt
N
N
OEt
N
N
OEt
R
+
R
EtO
SMe
EtO
EtO
SMe
SMe
3a: R = Bn
5a: R = Me
6a: R = Et
7a: R = iso-Pr
8a: R = piperonyl
4a: -SMe
4b: -SMe
3b: R = Bn
5b: R = Me
6b: R = Et
7c: R = iso-Pr
8b: R = piperonyl
Scheme 4. Alkylation of anion derived from 6-methylsulfanyl-Schöllkopf’s bislactim ether 4a or 4b
Table 1. Alkylation of 4a or 4b
run
1
substrate
electrophile
PhCH2Br
product (yield, %)
4b
3a (70)
3b (0)
3b (0)
3b (0)
5b (15)
5b (16)
5a (19)
6b (0)
6b (8)d
7b (4)d
8b (0)
2
3
4a
PhCH2Br
PhCH2Br
MeI
3a (69)
3a (81)
5a (47)
5a (48)
5a (58)
6a (0)
mixture of 4a and 4ba
4
4b
5
4a
MeI
6
mixture of 4aand 4ba
mixture of 4a and 4ba
mixture of 4a and 4ba
mixture of 4a and 4ba
MeI
7
8b
EtBr
EtI
6a (48)
7a (65)
8a (30)
9
10c
iso-PrI
mixture of 4a and 4ba piperonyl bromide
a.
Ratio 4a: 4b = ca 1:2. b. Starting material was recovered in 9% yield. c. Aromatized 13 was obtained in 20% yield.
d. Pure compounds could not be isolated. Yields were calculated from the 1H-NMR spectra of the crude products.

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HETEROCYCLES, Vol. 81, No. 5, 2010
4. ETHANOLYSIS OF 6-METHYLSULFANYL-BISLACTIM ETHER
The ethanolysis of bislactim ethers with trifluoroacetic acid was examined. Unfortunately, desulfanylated
pyrazines were obtained as products 913 instead of the desired ethyl esters of -methylsulfanylamino
acids. Nevertheless, it is interesting that the resultant pyrazines, such as 9 or 13, are closely related to
fungal metabolites terezine A38 and septorine.39
OH
HO
N
N
N
N
OEt
N
N
OEt
R
0.2 M TFA in EtOH
rt
R
OMe
EtO
EtO
SMe
terezine A
3a: R = benzyl
5a: R = Me
6a: R = Et
9: R = benzyl (86%)
10: R = Me (51%)
11: R = Et (11%)
O
N
HO
7a: R = iPr
12: R = iPr (31%)
8a: R = piperonyl
13: R = piperonyl (89%)
N
OMe
OH
septorine
Scheme 5. Ethanolysis of 6-methylsulfanyl-bislactim ether
CONCLUSION
We have synthesized the diastereomers of (3S)-2,5-diethoxy-3-isopropyl-6-methylsulfanylpiperazine and
examined the stereoselectivity in the alkylation of the anions derived from them. Benzylation showed
excellent stereoselectivity whereas methylsulfanylation of benzylated bislactim ether showed low
selectivity. Acid-catalyzed hydrolysis gave not the desired -sulfur substituted amino acids but
desulfanylated and aromatized pyrazines.
EXPERIMENTAL
General Procedure. IR spectra were obtained with a JEOL FT/IR-680 Plus spectrometer. HRMS were
determined with a JEOL JMS-700 (2) mass spectrometer. NMR spectra were recorded at 27 oC on Varian
UNITY INOVA-500, Gemini-2000, and Mercury-3000 spectrometers in CDCl3 with tetramethylsilane
(TMS) as the internal standard. Melting points were determined on a Yanagimoto micromelting point
apparatus and are uncorrected. Specific rotations were determined by ORD measurements using a JASCO
J-820 spectrometer. Liquid column chromatography was conducted over silica gel (SILICYCLE,
SiliaFlash® F60, mesh 230400). Analytical TLC was performed on precoated Merck aluminum sheets
(DC-Alufolien Kieselgel 60 F254), and compounds were viewed by spraying an ethanol solution of
phosphomolybdic acid, followed by heating. Dry THF was distilled over sodium-benzophenone ketyl

HETEROCYCLES, Vol. 81, No. 5, 2010
1245
under argon atmosphere.
Benzylation of 1
To a solution of 1 (862.5 mg, 4.1 mmol) in dry THF (50 mL) was added n-BuLi (1.6 M 2.8 mL, 4.5
o
mmol) at 78 C under nitrogen atmosphere. After stirring for 30 min, benzyl bromide (0.53 mL, 4.5
mmol) was added and the reaction mixture was stirred overnight to allow the reaction temperature to
reach rt. The reaction mixture was treated with aq NH4Cl, evaporated to reduce the organic solvent, and
extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and evaporated under reduced
pressure to afford the crude product, which was purified by silica gel column chromatography (eluent:
hexane:CH2Cl2 = 4:1) and preparative TLC (eluent: hexane:CH2Cl2 = 4:1) to give 2a in 86% yield (1.08
1
g) and 2b in 2% yield (23.2 mg). The product ratio appearing in the text was estimated from the NMR
spectrum of the crude product. (3S,6R)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-benzylpyrazine 2a;
oil; []D25 101.3 (c 0.43, EtOH); IR (liquid film) max 1693 (C=C) cm-1; 1H-NMR (CDCl3)  0.62 (3H,
d, J = 6.9 Hz, iPr-CH3), 0.93 (3H, d, J = 6.9 Hz, iPr-CH3), 1.25 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.32 (3H,
t, J = 7.1 Hz, -OCH2CH3), 2.16 (1H, sept d, J = 6.9, 3.3 Hz, -CH(CH3)2), 3.07 (1H, dd, J = 13.2, 4.7 Hz,
PhCHH-), 3.11 (1H, dd, J = 13.2, 4.7 Hz, PhCHH-), 3.24 (1H, t, J = 3.3 Hz, H-3), 4.054.21 (4H, m, 2x
13
-OCH2CH3), 4.30 (1H, td, J = 4.7, 3.3 Hz, H-6), 7.097.22 (5H, m, Ph); C-NMR (CDCl3) 14.3 (q),
14.4 (q), 16.4 (q), 19.0 (q), 31.1 (d), 40.0 (t), 56.6 (d), 60.1 (t), 60.4 (t), 60.5 (d), 126.1 (d), 127.7 (d),
130.0 (d), 137.4 (s), 161.9 (s), 163.5 (s); HRMS m/z calcd for C18H26N2O2 (M)+ 302.1994, found
25
302.1993. (3S,6S)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-benzylpyrazine 2b; oil; []D +105.5 (c
1
0.32, EtOH); IR (liquid film) max 1692 (C=C) cm-1; H-NMR (CDCl3)  0.35 (3H, d, J = 6.9 Hz,
iPr-CH3), 0.91 (3H, d, J = 6.9 Hz, iPr-CH3), 1.25 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.30 (3H, t, J = 7.1 Hz,
-OCH2CH3), 1.86 (1H, sept d, J = 6.9, 4.6 Hz, -CH(CH3)2), 3.04 (1H, dd, J = 13.3, 6.9 Hz, PhCHH-), 3.13
(1H, dd, J = 13.3, 4.6 Hz, PhCHH-), 3.78 (1H, dd, J = 5.0, 4.3 Hz, H-3), 3.994.21 (4H, m, 2x
13
-OCH2CH3), 4.27 (1H, dt, J = 6.9, 4.6 Hz, H-6), 7.097.25 (5H, m, Ph); C-NMR (CDCl3) 14.4 (q),
14.4 (q), 16.9 (q), 19.6 (q), 31.3 (d), 40.7 (t), 56.9 (d), 60.3 (t), 60.3 (t), 60.7 (d), 126.2 (d), 127.9 (d),
130.0 (d), 138.2 (s), 161.8 (s), 162.8 (s); HRMS m/z calcd for C18H26N2O2 (M)+ 302.1994, found
302.1991.
Introduction of sulfur function into 2a
To a solution of 2a (486.5 mg, 1.6 mmol) in THF (10 mL) was added n-BuLi (1.6 M 2.8 mL, 4.5 mmol)
o
at 78 C under nitrogen atmosphere. After stirring for 30 min, dimethyl disulfide (0.14 mL, 1.6 mmol)
was added and the reaction mixture was stirred overnight to allow the reaction temperature to reach rt
from 78 oC. The reaction mixture was evaporated to reduce the organic solvent, treated with aq Na2CO3,

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HETEROCYCLES, Vol. 81, No. 5, 2010
and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and evaporated under
reduced pressure to afford the crude product, which was purified by silica gel column chromatography
(eluent: hexane:CH2Cl2 = 4:1) to give 3a and 3b in 95% yield (531.0 mg). The product ratio appearing in
the text was estimated from the 1H-NMR spectrum.
(3S,6S)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-benzyl-6-methylsulfanylpyrazine 3a; pale yellow
25
crystals (CH2Cl2); mp 6573oC; []D 11.4 (c 1.16, EtOH); IR (KBr) max 1677 (C=C), 1495 (C=C),
cm1; 1H-NMR (CDCl3)  0.65 (3H, d, J = 7.0 Hz, iPr-CH3), 0.93 (3H, d, J = 7.0 Hz, iPr-CH3), 1.28 (3H,
t, J = 7.1 Hz, -OCH2CH3), 1.38 (3H, t, J = 7.1 Hz, -OCH2CH3), 2.11 (3H, s, SCH3), 2.16 (1H, sept d, J =
7.0, 3.0 Hz, -CH(CH3)2), 2.98 (1H, d, J = 3.4 Hz, H-3), 3.10 (1H, d, J = 12.6 Hz, PhCHH-), 3.40 (1H, d, J
= 12.6 Hz, PhCHH-), 4.074.29 (4H, m, -OCH2CH3), 7.037.07 (2H, m, Ar-H), 7.167.21 (3H, m, Ar
-H); 13C-NMR (CDCl3) 12.8 (q), 14.3 (q), 14.5 (q), 17.1 (q), 19.4 (q), 30.4 (d), 45.9 (t), 60.2 (d), 60.91
(2 x t), 67.5 (s), 126.6 (d), 127.7 (d), 130.2 (d), 136.1 (s), 159.6 (s), 164.4 (s); HRMS m/z calcd for
C19H29N2O2S (M+H)+ 349.1950, found 349.1949.
(3S,6R)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-benzyl-6-methylsulfanylpyrazine 3b; oil; []D25 6.2
(c 0.33, CHCl3); IR (liquid film) max 1680 (C=C), 1495 (C=C) cm1; 1H-NMR (CDCl3)  0.20 (3H, d, J
= 6.9 Hz, iPr-CH3), 0.83 (3H, d, J = 6.9 Hz, iPr-CH3), 1.30 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.42 (3H, t, J
= 7.1 Hz, -OCH2CH3), 1.93 (3H, s, SCH3), 2.03 (1H, sept d, J = 6.9, 3.4 Hz, -CH(CH3)2 ), 3.12 (1H, d, J
= 12.8 Hz, PhCHH-), 3.55 (1H, d, J = 12.8 Hz, PhCHH-), 3.80 (1H, d, J = 3.4 Hz, H-3), 4.144.28 (4H,
m, -OCH2CH3), 7.117.21 (5H, m, Ar-H); 13C-NMR (CDCl3) 12.2 (q), 14.4 (q), 14.5 (q), 14.9 (q), 19.2
(q), 30.6 (d), 44.4 (t), 60.5 (d), 60.8 (t), 60.9 (t), 67.5 (s), 126.6 (d), 127.7 (d), 130.8 (d), 136.5 (s), 158.9
(s), 165.1 (s); HRMS m/z calcd for C19H29N2O2S (M+H)+ 349.1950, found 349.1944.
Introduction of sulfur function into 1
To a solution of 1 (202.2 mg, 0.9 mmol) in dry THF (4 mL) was added n-BuLi (1.6 M 0.62 mL, 0.99
o
mmol) at 78 C under nitrogen atmosphere. After stirring for 30 min, dimethyl disulfide (0.1 mL, 1.08
mmol) was added and the reaction mixture was stirred overnight to allow the reaction temperature to
reach rt. The reaction mixture was evaporated to reduce the organic solvent, treated with aq NH4Cl, and
extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and evaporated under reduced
pressure to afford the crude product, which was purified by silica gel column chromatography (eluent:
hexane:CH2Cl2 = 4:1) and preparative TLC (eluent: hexane:CH2Cl2 =10:1) to give a mixture of 4a and 4b
in 84% yield (194.3 mg). The product ratio appearing in the text was estimated from the 1NMR spectrum
of the crude product.
25
(3S,6R)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-methylsulfanylpyrazine 4a; pale yellow oil; []D
94.2 (c 0.33, EtOH); IR (liquid film) max 1685 (C=C) cm-1; 1H-NMR (CDCl3)  0.67 (3H, d, J = 6.8 Hz,

HETEROCYCLES, Vol. 81, No. 5, 2010
1247
iPr-CH3), 1.07 (3H, d, J = 7.0 Hz, iPr-CH3), 1.30 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.32 (3H, t, J = 7.1 Hz,
-OCH2CH3), 2.02 (3H, s, 6-SCH3), 2.352.42 (1H, qqd, J = 7.0, 6.8, 3.3 Hz, -CH(CH3)2), 3.95 (1H, dd, J
13
=3.3, 3.1 Hz, H-3), 4.134.25 (4H, m, -OCH2CH3), 4.97 (1H, d, J = 3.1 Hz, H-6); C-NMR (CDCl3)
11.8 (q), 14.2 (q), 14.3 (q), 16.3 (q), 19.1 (q), 31.2 (d), 58.2 (d), 60.4 (d), 61.2 (t), 61.3 (t), 159.6 (s),
166.2 (s); HRMS m/z calcd for C12H21N2O2S (MH)+ 257.1324, found 257.1328.
25
(3S,6S)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-methylsulfanylpyrazine 4b; pale yellow oil; []D
1
15.1 (c 0.11, EtOH); IR (liquid film) max 1685 (C=C) cm1; H-NMR (CDCl3)  0.86 (3H, d, J = 6.8
Hz, iPr-CH3) 1.07 (3H, d, J = 6.8 Hz, iPr-CH3), 1.29 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.32 (3H, t, J = 7.1
Hz, -OCH2CH3), 2.20 (1H, sept d, J = 6.8, 4.6 Hz, -CH(CH3)2), 2.36 (3H, s, 6-SCH3), 3.90 (1H, dd, J =
13
4.6, 3.7 Hz, H-3), 4.074.29 (4H, m, 2x -OCH2CH3), 4.89 (1H, d, J = 3.7 Hz, H-6); C-NMR (CDCl3)
14.2 (q), 14.3 (q), 15.9 (q), 18.4 (q), 19.8 (q), 32.1 (d), 58.9 (d), 61.2 (t), 61.7 (d), 161.2 (s), 166.8 (s);
HRMS m/z calcd for C12H22N2O2S (M)+ 258.1383, found 258.1397.
Alkylation of 4a or 4b
General procedure (Table 1): To a solution of 4a or 4b (ca. 50 mg) in dry THF (2.0 mL) was added
n-BuLi (1.6 M 1.2 equiv.) at 78 oC under nitrogen atmosphere. After stirring for 30 min, an electrophile
was added and the reaction mixture was stirred overnight to allow the reaction temperature to reach rt
from 78 oC. The solvent was removed under reduced pressure to give a residue, which was treated with
aq Na2CO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4,
filtered, and evaporated under reduced pressure to afford a crude product that was purified by
chromatography (eluent: hexane:EtOAc = 10:1) to afford the desired products. The product yield
appearing in Table 1 was estimated from the isolated yield of the product mixture and the integration of
the signals in the 1H-NMR spectrum.
(3S,6S)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-methyl-6-methylsulfanylpyrazine 5a; pale yellow
oil; []D25  (c 0.33, EtOH); IR (liquid film) max 1681 (C=C) cm1; 1H-NMR (CDCl3)  0.79 ( 3H,
d, J = 6.6 Hz, iPr-CH3) 1.10 (3H, d, J = 6.8 Hz, iPr-CH3), 1.28 (3H, t, J = 8.1Hz, -OCH2CH3), 1.31 (3H, t,
J = 7.1Hz, -OCH2CH3), 1.64 (3H, s, 6-Me), 2.10 (3H, s, 6-SCH3), 2.33 (1H, m, -CH(CH3)2), 3.89 (1H, d,
13
J = 3.9 Hz, H-3), 4.104.34 (4H, m, 2x -OCH2CH3); C-NMR (CDCl3) 13.1 (q), 14.2 (q), 14.3 (q),
17.6 (q), 19.7 (q), 28.2 (q), 31.1 (d), 60.9 (d), 61.00 (t), 61.02 (d), 62.7 (s), 162.3 (s), 163.7 (s); HRMS
m/z calcd for C13H25N2O2S (M+H)+ 273.1637, found 273.1634.
(3S,6R)-2,5-Diethoxy-3,6-dihydro-6-ethyl-3-isopropyl-6-methylsulfanylpyrazine 5b; pale yellow oil;
[]D25  (c 0.11, EtOH); IR (liquid film) max 1677 (C=C) cm1; 1H-NMR (CDCl3)  0.66 ( 3H, d, J
= 7.0 Hz, iPr-CH3), 1.08 (3H, d, J = 7.0 Hz, iPr-CH3), 1.28 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.30 (3H, t, J
= 7.1 Hz, -OCH2CH3), 1.66 (3H, s, 6-Me), 1.88 (3H, s, 6-SCH3), 2.32 (1H, sept d, J = 7.0, 3.2 Hz,

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HETEROCYCLES, Vol. 81, No. 5, 2010
-CH(CH3)2), 3.99 (1H, d, J = 3.2 Hz, H-3), 4.104.30 (4H, m, 2x -OCH2CH3); 13C-NMR (CDCl3) 12.4
(q), 14.2 (q), 14.4 (q), 16.3 (q), 19.2 (q), 27.6 (q), 31.1 (d), 61.0 (t), 61.04 (d), 63.6 (t), 63.6 (s), 161.4 (s),
164.0 (s); HRMS m/z calcd for C13H25N2O2S (M+H)+ 273.1637, found 273.1639.
25
(3S,6S)-2,5-Diethoxy-6-ethyl-3,6-dihydro-3-isopropyl-6-methylsulfanylpyrazine 6a; oil; []D +55.4
(c 0.73, EtOH); IR (liquid film) max 1681 (C=C) cm1; 1H-NMR (CDCl3) 0.74 (3H, t, J = 7.3 Hz,
6-CH2CH3), 0.78 (3H, d, J = 6.9 Hz, iPr-CH3), 1.10 (3H, d, J = 6.9 Hz, iPr-CH3), 1.29 (3H, t, J = 7.1 Hz,
-OCH2CH3), 1.30 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.85 (1H, dq, J = 13.1, 7.3 Hz, 6-CHAHBCH3), 2.07
(3H, s, SCH3), 2.12 (1H, dq, J = 13.1, 7.3 Hz, 6-CHAHBCH3), 2.34 (1H, sept d, J = 6.9, 3.7 Hz,
3-CH(CH3)2), 3.89 (1H, d, J = 3.7 Hz, H-3), 4.124.28 (4H, m, -OCH2CH3); 13C-NMR (CDCl3)  8.8 (q),
12.7 (q), 14.3 (q), 14.4 (q), 17.5 (q), 19.7 (q), 31.0 (d), 33.1 (t), 60.9 (t), 60.95 (d), 60.96 (t), 66.7 (s),
160.8 (s), 164.4 (s); HRMS m/z calcd for C14H27N2O2S (M+H)+ 287.1794, found 287.1789.
25
(3S,6S)-2,5-Diethoxy-3,6-dihydro-3,6-diisopropyl-6-methylsulfanylpyrazine 7a: oil; []D +59.0 (c
1
0.40, EtOH); IR (liquid film) max 1681 (C=C) cm1; H-NMR (CDCl3)0.75 (3H, d, J = 6.9 Hz,
6-iPr-CH3), 0.76 (3H, d, J = 6.9 Hz, 6-iPr-CH3), 1.10 (3H, d, J = 6.9 Hz, 3-iPr-CH3), 1.10 (3H, d, J = 6.9
Hz, 3-iPr-CH3), 1.29 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.31 (3H, t, J = 7.1 Hz, -OCH2CH3), 2.01 (3H, s,
-SCH3), 2.32 (1H, sept, J = 6.9 Hz, 6-CH(CH3)2),  (1H, sept d, J = 6.9, 3.7 Hz, 3-CH(CH3)2), 3.84
(1H, d, J = 3.7 Hz, H-3), 4.114.27 (4H, m, -OCH2CH3); 13C-NMR (CDCl3) 13.2 (q), 14.3 (q), 14.4 (q),
16.1 (q), 17.5 (q), 17.8 (q), 19.7 (q), 30.8 (d), 35.8 (d), 60.5 (d), 60.87 (t), 60.9 (t), 70.1 (s), 161.3 (s),
164.2 (s); HRMS m/z calcd for C15H29N2O2S (M+H)+, 301.1950, found 301.1950.
*Minor product 6b or 7b could not be isolated due to instability during the purification by silica gel
chromatography or preparative TLC.
25
(3S,6S)-2,5-Diethoxy-3,6-dihydro-3-isopropyl-6-piperonyl-6-methylsulfanylpyrazine 8a: oil; []D
9.2 (c 0.33, CHCl3); IR (liquid film) max 1646 (C=C) cm1; 1H-NMR (CDCl3)  0.68 (3H, d, J = 6.9 Hz,
iPr-CH3), 0.97 (3H, d, J = 6.9 Hz, iPr-CH3), 1.29 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.37 (3H, t, J = 7.1 Hz,
-OCH2CH3), 2.11 (3H, s, -SCH3), 2.21 (1H, sept d, J = 6.9, 3.7 Hz, -CH(CH3)2), 3.01 (1H, d, J = 12.8 Hz,
ArCHH-), 3.20 (1H, d, J = 3.7 Hz, H-3), 3.32 (1H, d, J = 12.8 Hz, ArCHH-), 4.064.30 (4H, m,
-OCH2CH3), 5.89 (1H, d, J = 1.6 Hz, -OCHHO-), 5.90 (1H, d, J = 1.6 Hz, -OCHHO-), 6.52 (1H, dd, J =
13
7.8, 1.6 Hz, Ar-H), 6.55 (1H, d, J = 1.6 Hz, Ar-H), 6.62 (1H, d, J = 7.8 Hz, Ar-H); C-NMR (CDCl3)
12.8 (q), 14.4 (q), 14.5 (q), 17.2 (q), 19.5 (q), 30.6 (d), 45.6 (t), 60.4 (d), 60.9 (t), 61.0 (t), 67.3 (s),
100.7 (t), 107.7 (d), 110.5 (d), 123.3 (d), 129.9 (s), 146.2 (s), 146.9 (s), 159.7 (s), 164.5 (s); HRMS m/z
calcd for C20H28N2O4S (M)+ 392.1769, found 392.1765.
Ethanolysis of 6-methylsulfanyl-bislactim ether
General procedure (Scheme 5): Compound 3a (19.3 mg, 0.061 mmol) was dissolved in 0.2 M TFA

HETEROCYCLES, Vol. 81, No. 5, 2010
1249
solution in ethanol (1.22 mL). After stirring for 6 days at rt, the reaction mixture was evaporated directly
to afford a crude residue that was purified by preparative TLC (solvent: hexane:EtOAc = 10:1) to give 9
(15.7 mg, 86%).
6-Benzyl-2,5-diethoxy-3-isopropylpyrazine 9: oil; IR (liquid film) max 1636 (C=C), 1495 (C=C) cm-1;
1H-NMR (CDCl3)  1.18 (6H, d, J = 6.9 Hz, ArCH(CH3)2), 1.33 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.35 (3H,
t, J = 7.1 Hz, -OCH2CH3), 3.22 (1H, sept, J = 6.9 Hz, ArCH(CH3)2), 3.99 (2H, s, PhCH2-), 4.30 (2H, q, J
= 7.1 Hz, -OCH2CH3), 4.32 (2H, q, J = 7.1 Hz, -OCH2CH3), 7.17 (1H, t, J = 7.1 Hz, Ar-H), 7.25(1H, t, J
= 7.1 Hz, Ar-H), 7.35 (1H, t, J = 7.1 Hz, Ar-H); 13C-NMR (CDCl3) qq20.7 (q), 28.8 (d),
37.8 (t), 61.7 (t), 61.8 (t), 125.9 (d), 128.1 (d), 129.2 (d), 136.1 (s), 139.5 (s), 143.9 (s), 151.3 (s), 151.9
(s); HRMS m/z calcd for C18H24N2O2 (M)+ 300.1837, found 300.1834.
1
2,5-Diethoxy-3-isopropyl-6-methylpyrazine 10: oil; IR (liquid film) max 1637 (C=C) cm-1; H-NMR
(CDCl3)  1.20 (6H, d, J = 6.9 Hz, ArCH(CH3)2), 1.35 (3H, t, J = 7.1 Hz, -OCH2CH3), 1.36 (3H, t, J =
7.1Hz, -OCH2CH3), 2.32 (3H, s, 6-CH3), 3.25 (1H, sept, J = 6.9Hz, ArCH(CH3)2), 4.30 (2H, q, J = 7.1Hz,
13
-OCH2CH3), 4.34 (2H, q, J = 7.1 Hz, -OCH2CH3); C-NMR (CDCl3) 14.8 (q), 14.9 (q), 18.0 (q), 20.8
(q), 28.7 (d), 61.7 (t), 61.8 (t), 134.4 (s), 143.0 (s), 151.1 (s), 152.4 (s); HRMS m/z calcd for C12H20N2O2
(M)+ 224.1524, found 224.1523.
1
2,5-Diethoxy-6-ethyl-3-isopropylpyrazine 11: oil; IR (liquid film) max 1635 (C=C) cm-1; H-NMR
(CDCl3)  1.20 (6H, d, J = 6.9 Hz, ArCH(CH3)2), 1.22 (3H, t, J = 7.6 Hz, ArCH2CH3), 1.356 (3H, t, J =
7.1Hz, -OCH2CH3), 1.358 (3H, t, J = 7.1Hz, -OCH2CH3), 2.68 (2H, q, J = 7.6 Hz, ArCH2CH3), 3.25 (1H,
sept, J = 6.9Hz, ArCH(CH3)2), 4.33 (2H, q, J = 7.1Hz, -OCH2CH3), 4.34 (2H, q, J = 7.1 Hz, -OCH2CH3);
13C-NMR (CDCl3) 11.8 (q), 14.8 (q), 20.8 (q), 24.5 (t), 28.7 (d), 61.6 (t), 61.7 (t), 134.4 (s), 139.0 (s),
142.7 (s), 151.2 (s), 151.9 (s); HRMS m/z calcd for C13H22N2O2 (M)+ 238.1681, found 238.1684.
2,5-Diethoxy-3,6-diisopropylpyrazine 12: oil; IR (liquid film) max 1635 (C=C) cm-1; 1H-NMR (CDCl3)
 1.20 (12H, d, J = 6.9 Hz, ArCH(CH3)2), 1.35 (6H, t, J = 7.1Hz, -OCH2CH3), 3.24 (1H, sept, J = 6.9Hz,
ArCH(CH3)2), 4.34 (4H, q, J = 7.1 Hz, -OCH2CH3); 13C-NMR (CDCl3) 14.9 (q), 20.9 (q), 28.7 (d), 61.5
(t), 142.4 (s), 151.1 (s); HRMS m/z calcd for C14H24N2O2 (M)+ 252.1837, found 252.1834.
2,5-Diethoxy-3-isopropyl-6-piperonylpyrazine 13: oil; IR (liquid film) max 1635 (C=C), 1504 (C=C)
1
cm-1; H-NMR (CDCl3)  1.18 (6H, d, J = 6.9 Hz, ArCH(CH3)2), 1.34 (3H, t, J = 6.8 Hz, -OCH2CH3),
1.36 (3H, t, J = 6.8 Hz, -OCH2CH3), 3.23 (1H, sept, J = 6.9 Hz, ArCH(CH3)2), 3.89 (2H, s, -CH2Ar), 4.31
(2H, q, J = 6.8 Hz, -OCH2CH3), 4.33 (2H, q, J = 6.8 Hz, -OCH2CH3), 6.73 (1H, d, J = 8.0 Hz, Ar-H),
6.81 (1H, dd, J = 8.0, 1.6 Hz, Ar-H), 6.87 (1H, d, J = 1.6 Hz, Ar-H); 13C-NMR (CDCl3)
qq20.7 (2x q), 28.8 (d), 37.4 (t), 61.75 (t), 61.78 (t), 100.7 (t), 107.9 (d), 109.7 (d),
122.0 (d), 133.3 (s), 136.1 (s), 144.0 (s), 145.7 (s), 147.3 (s), 151.3 (s), 151.8 (s); HRMS m/z calcd for

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C19H24N2O4 (M)+ 344.1736, found 344.1739.
ACKNOWLEDGEMENTS
This paper is dedicated to Professor Manabu Node on the occasion of his retirement from
Kyoto Pharmaceutical University. We are grateful to Dr. K. Minoura and Ms. M. Fujitake of this
University for NMR and MS measurements, respectively. We also thank N. Kita and M. Takakuwa of our
laboratory for some experimental supports.
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