Synthesis of (-)-benzolactam-V8 by application of asymmetric aziridination

Article abstract of DOI:10.1016/j.tet.2011.11.033

(-)-Benzolactam-V8, an artificially-designed cyclic dipeptide with strong tumor-promoter activity, was synthesized from benzyl (S)-N-(2-formylphenyl)-N- methylvalinate by application of guanidinium ylide-participated asymmetric aziridination followed by t

Full text of DOI:10.1016/j.tet.2011.11.033

Tetrahedron 68 (2012) 878e882
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (ꢀ)-benzolactam-V8 by application of asymmetric aziridination
*
Itsara Khantikaew, Masato Takahashi, Takuya Kumamoto, Noriyuki Suzuki, Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2011
Received in revised form 11 November 2011
Accepted 12 November 2011
Available online 19 November 2011
(ꢀ)-Benzolactam-V8, an artificially-designed cyclic dipeptide with strong tumor-promoter activity, was
synthesized from benzyl (S)-N-(2-formylphenyl)-N-methylvalinate by application of guanidinium ylide-
participated asymmetric aziridination followed by the reductive ring-opening reaction of 3-
arylaziridine-2-carboxylate formed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Benzolactam-V8
Asymmetric synthesis
Guanidinium ylide
3-Arylaziridine-2-carboxylate
Ring-opening reaction
1. Introduction
functionality in these lactams, play an important role for the bi-
ological activity20 (Fig. 1).
Teleocidins [ex. teleocidin B-1 (1)], olivoretins [ex. olivoretin A
(2)], and lyngbyatoxins [ex. lyngbyatoxin B (3)] (summarized as
teleocidins in this paper) have been isolated from microorganisms
(Streptomyces and Streptoverticillium) and blue-green alga (Lyngbya
species) as strong tumor promoters.1e10 They are structurally de-
fined to be nine-membered cyclic dipeptides derived from (S)-
tryptophan and (S)-valine units and their terpene-substituted
structures are minimized to (ꢀ)-indolactam-V (4) as a common
core skeleton,11 which had also been isolated from Actinomycetes,12
albeit with lower activity.13 Chemical approaches to the biological
activity of (ꢀ)-indolactam-V (4) have indicated that the 9S- and
12S-stereochemistries are essential for the tumor-promoting ef-
fects. In addition, although these nine-membered cyclic dipeptides
are in equilibrium between twist and sofa conformations in sol-
ution,7,9,14e17 the designation of an eight-membered (ꢀ)-benzo-
lactam-V8 (5) and a nine-membered (ꢀ)-benzolactam-V9 (6)
carrying phenyl ring, in place of indole unit in the natural tumor
promoters, as model cyclic peptides18 led to the results that the
former eight-membered (ꢀ)-benzolactam-V8 (5) existed in only
twist conformation and was more active than (ꢀ)-indolactam-V (4).
Furthermore, it has been suggested that not only the 5S-configu-
ration of (ꢀ)-benzolactam-V819 (5) as well as the 9S-configuration
of (ꢀ)-indolactam-V13 (4), but also hydrogen of the amide
We have recently developed guanidine chemistry,21 and have
found the unique formation of 3-aryl- (or unsaturated) aziridine-2-
carboxylates, expandable to chiral version, by the reaction of gua-
nidinium salt and aryl (or unsaturated) aldehyde in the presence of
H
N
H
N
Me
Me
OR1
OH
N
N
O
O
R3
R4
N
H
N
H
Me
R2
OH
teleocidin B-1 ( ): R1 = H, R2 = vinyl,
lyngbyatoxin B (3)
1
R
3 = Me, R4 = isopropyl
2
olivoretin A ( ):
R
1 = R4 = Me, R2= vinyl,
R3 = isopropyl
14
12
O
4
2
3
13
NH
5
15
H
9
Me
1
N
13
Me
11
N
11
N
OH
12
10
( )n
10
4
OH
O
1
8
5
6
3
2
7
9
8
N
7
H
(-)-benzolactam-V8 (5): n = 1
(-)-benzolactam-V9 (6): n = 2
(-)-indolactam-V (4)
* Corresponding author. Tel./fax: þ81 43 226 2944; e-mail address: benti@
Fig. 1. Structures of teleocidins and the related compounds [Numbering of benzo-
lactams is for benzolactam-V8 (5)].
faculty.chiba-u.jp (T. Ishikawa).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.033

I. Khantikaew et al. / Tetrahedron 68 (2012) 878e882
879
base.22e25 In this paper we will present a new synthetic approach to
(ꢀ)-benzolactam-V8 (5) by application of the asymmetric aziridi-
nation followed by the reductive ring-opening reaction of 3-
arylaziridine-2-carboxylate formed.
group and (2) asymmetric induction at the 2 position of 3-
arylaziridine-2-carboxylates is controlled by the chiral center of
guanidinium salt used; e.g., the predominant production of (2S,3R)-
trans-3-[(3,4-methylenedioxy)phenyl]aziridine-2-carboxylate in
the reaction of (3,4-methylenedioxy)benzaldehyde (piperonal) and
(4R,5R)-1,3-dimethyl-4,5-diphenylimidazolidinium salt. Thus, the
key aziridine 9 should be obtained by asymmetric aziridination of
the (S)-valine-substituted benzaldehyde 10 and the (R,R)-guanidi-
nium bromide 11 and, then, be converted to the (S)-valine-
substituted (S)-phenylalaninate 8 by regioselectively reductive
ring-opening reaction of the aziridine 9 formed as a precursor for
the benzolactam skeleton 7 with a cyclic dipeptide structure.
The known benzyl (S)-N-(2-formylphenyl)-N-methylvalinate
(10) was prepared from 2-iodobenzyl alcohol according to the re-
ported procedure38 with a slight modification of the amination
step40 (Scheme 2). The successive reactions of copper-catalyzed
coupling reaction between 2-iodobenzyl alcohol and (S)-valine,
lactonization, reductive N-methylation, alkaline hydrolysis fol-
lowed by esterification with benzyl alcohol, and oxidation of the
hydroxymethyl function in the N-phenyl substituent provided the
benzaldehyde substrate 10 in overall 57% yield.
2. Results and discussion
In the synthesis of benzolactam-V8 (5) and its analogs, con-
struction of two amino acid components tethered by phenyl ring is
crucial and, previously, the N-aryl-substituted (S)-valine unit had
majorly been prepared by the displacement reaction of oxygen-
substituted (R)-isovalerate with an aniline derivative,26e37 instead
Ma and co-workers had adopted the amination of either phenyl
ring38 or 1,3-cyclohexadienone39 with (S)-valine. On the other
hand, some variations were reported for the construction of (S)-
phenylalanine unit except the use of phenylalanine itself29e32 or its
derivatives:28,32,33 (1) diastereoselective alkylation of amino-
malonate with benzyl bromide dependent on the stereochemistry
of valine unit introduced,26e28 (2) diastereoselective aldol-type
condensation between valine-substituted benzaldehyde and
nitroacetate,38 (3) asymmetric alkylation of iminoacetate with
benzyl alcohol in the presence of a chiral quinine-type phase
transfer catalyst,33 (4) use of the amine functionality of (R)-phe-
nylglycinate acted as a chiral auxiliary after reductive cleav-
age,34,36,37,39 and (5) oxyamination of allylbenzene.35
(S)-valine
CuI, Cs2CO3
DMSO
I
CO2H
OH
H
N
OH
2. NaBH3CN
HCHO, AcOH
MeCN
90 °C, 48 h
100%
1. DCC, HOBt
Et3N, CH2Cl2
rt, 15 h
The direct amination of phenyl ring reported by Ma’s group38
attracted us as the ready preparation of N-aryl-substituted (S)-va-
line. On the other hand, for the preparation of (S)-phenylalanine
unit our original asymmetric aziridination followed by regiose-
lective ring-opening reaction of the formed aziridine was focused.
The retrosynthesis is shown in Scheme 1, in which (2S)-3-
phenylaziridine-2-carboxylate 9 carrying (S)-valine unit at the or-
tho position of the phenyl pendant is designed as a key in-
termediate. In the aziridination,22e25 the following stereochemical
evidences have generally been established: (1) trans-aziridines are
diastereoselectively produced when electron-rich benzaldehydes
are used, whereas cis-aziridines in the case of either benzaldehyde
itself or benzaldehydes substituted with electron-withdrawing
0 °C, 53 h
88%
86%
1. 1 N NaOH
THF
rt, 2 h
1. (COCl)2
DMSO
-65 °C, 0.5 h
O
O
CO2Bn
O
CO2Bn
Me
Me
Me
N
N
N
H
2. Et3N, 15 min
77%
2. BnBr
DMF
rt, 24 h
OH
10
97%
Scheme 2. Preparation of benzyl (S)-N-(2-formylphenyl)-N-methylvalinate (10) from
2-iodobenzyl alcohol.
At first, guanidinium ylide-participated aziridination under
achiral conditions was preliminarily examined (see, Scheme 3).
Treatment of the valine-substituted benzaldehyde 10 with the
guanidinium bromide lacking phenyl pendants (see, 11) in the
presence of sodium hydride (NaH) in dimethylformamide (DMF) at
ꢀ20 ꢁC for 24 h, followed by stirring the resultant mixture with
silica gel (SiO2) in chloroform (CHCl3) at room temperature (rt) for
24 h, afforded a crude product, showing two spots except that of
the starting 10 on thin layer chromatography (TLC) (Rf¼0.6 and 0.5
O
NH
Me
N
(-)-benzolactam-V8
CO2tBu
5
(
)
reduction of the
ester function
7
Me
Me
Me
Me
N
CO2Bn
CHO
CO2Bn
NBn
Me
N
N
BnO2C
BnO2C
N
N
CO2H
NBn
NBn
1. NaH, DMF,
-20 °C, 24 h
2. SiO2, CHCl3,
rt, 24 h
NH2
CO2tBu
CO2tBu
CO2tBu
CO2tBu
10
cis-9b
reductive ring-opening
and deprotections
cis-9a
9
8
+
CH2CO2tBu
+
N
Bn
N
asymmetric
aziridination
O
Me
Me
Me
Me
N
BnO2C
N
BnO2C
N
Br-
Ph
NBn
NBn
Me
Me
N
N
Ph
CO2tBu
Ph
12
CO2tBu
11
Ph
(94%)
CH2CO2tBu
+
N
Bn
N
CO2Bn
O
trans-9d
trans-9c
Me
N
Me
Me
N
+
H
Br-
Ph
total 86% yield
9d
Ph
9a
9b
9c
: trans- : trans-
(cis- : cis-
= 15 : 1 : 4 : 2)
10
11
Scheme 3. Asymmetric aziridination of the valine-substituted benzaldehyde 10 and
the (R,R)-guanidinium bromide 11 in the presence of NaH.
Scheme 1. Retrosynthesis of (ꢀ)-benzolactam-V8 (5).

880
I. Khantikaew et al. / Tetrahedron 68 (2012) 878e882
in diethyl ether/n-hexane¼1:3). In general, a larger coupling con-
stant between C2eH ( ca. 2.5 ppm) and C3eH ( ca. 3.5 ppm) is
two ones by destruction of the C3 chiral center in the aziridine
system in next reductive ring-opening reaction. Stirring the azir-
idine mixture 9 in methanol in the presence of palladium hydroxide
on carbon as a catalyst at rt for 90 min under hydrogen atmo-
sphere22,23,41 afforded a high polar product, which was expected to
d
d
observed in cis-3-arylaziridine-2-carboxylates (J¼ca. 7 Hz) than in
the trans-derivative (J¼ca. 2 Hz) in their 1H NMR spectra.22 Al-
though each 1H NMR spectrum of two products separated by pre-
parative TLC showed relatively complicated signal patterns because
of not homogeneous but a mixture composed of four possible
aziridine isomers 9aed with a different composition ratio, we
found that the ratio of each diastereoisomer could be reasonably
determined by the careful analysis of characteristic signals due to
the 3-arylaziridine-2-carboxylate skeleton in both the separates;
e.g., for the less polar product, cis-9a (dC2eH 2.557: J2,3¼7.2 Hz): cis-
9b (dC2eH 2.563: J2,3¼6.8 Hz): trans-9c (dC2eH 2.60: J2,3¼2.4 Hz):
trans-9d (dC2eH 2.65: J2,3¼2.4 Hz)¼ca. 6:2:9:3.
be phenylalaninate 8 incorporating (S)-valine as an additional a-
amino acid unit. The crude 8, without any purification, was further
subjected to lactamization by the use of diphenyl phosphoryl azide
(DPPA) as a condensation reagent according to the reported con-
ditions38 to give a benzolactam skeleton 7 as only an isolable
product, after purification by SiO2 column chromatography, in total
41% yield from the aziridine mixture 9. We speculated above that
the C2-stereochemistry of major cis-9a and trans-9c in the starting
aziridine mixture could be deduced to be S and that the ratio of
these 2S-diastereoisomers was estimated to be 86%. Therefore, the
benzolactam skeleton 7 isolated could be assigned as a desired
(2S,5S)-isomer. Additional trials for the construction of 7 using al-
ternative condensation reagents, such as 1-[bis(dimethylamino)
methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexa-
fluorophosphate (HATU) and 2-chloro-1,3-dimethylimidazolinium
chloride (DMC),42 in place of DPPA, resulted in not improving the
conversion yields from 9 (42% with HATU; 37% with DMC).
Next, we attempted asymmetric aziridination using the (R,R)-
guanidinium bromide 11 under the same reaction conditions as
achiral version (Scheme 3). Reaction was smoothly proceeded to
provide a crude mixture of aziridine 9 (almost one spot on TLC:
Rf¼0.6 in diethyl ether/n-hexane¼1:3) and the co-formed urea 12.
After removal of a chiral urea 12 (94% yield), which is re-useable as
the precursor of guanidinium bromide 11, by washing with n-
hexane, purification of the combined washings by SiO2 column
chromatography after evaporation afforded an expected aziridine
product 9 in 86% yield. The ratio of cis-9a/cis-9b/trans-9c/trans-9d
was estimated to be 15:1:4:2 based on the assignment under the
achiral version. Among them, the C2-stereochemistry of cis-9a and
trans-9c obtained as each major isomer could be reasonably
assigned to be S-configuration based on asymmetric induction as
discussed above.22e25 This means that these 2S-diastereoisomers
are totally calculated to be 86% of the aziridine mixture 9 (72%
excess).
Finally, reduction of the tert-butyl ester function of the benzo-
lactam skeleton 7 with lithium borohydride in methanol at 70 ꢁC
for 3 h gave a desired alcohol in 73% yield, the data of which, in-
cluding [
a
]D, was completely identical with those of (ꢀ)-benzo-
lactam-V8 (5)29 (Scheme 4).
Pd(OH)2/C, H2
MeOH, rt, 1.5 h
Me
Me
BnO2C
N
HO2C
N
NBn
Preferred formation of cis-isomers to trans-ones seems to be
contrary to the expected preference of trans-isomers in the use of
an electron-rich 2-aminobenzaldehyde derivative as an electro-
phile. However, the discrepancy may be explained by supposition
that the steric bulkiness of the valine function located at the ortho
position prohibits effective conjugation between amine group and
aldehyde functionality through benzene ring, resulting in pre-
dominance by the electro-negative character of nitrogen atom due
to inductive effect. In fact, this speculation could be supported by
model study (Fig. 2). The geometry optimization of the valine-
substituted benzaldehyde 10 using PM3 method allowed us to
deduce two conformations 10A and 10B as the most stable con-
formations. The heat of formation of them was calculated to be
ꢀ84.56 kcal/mol and ꢀ85.48 kcal/mol, respectively, and, in the
more stable latter conformation 10B, dihedral angles between the
substituents and the phenyl ring were estimated to be 101.3ꢁ
NH2
CO2tBu
CO2tBu
9
8
reagent, base
reagent, base
DMF, rt, 24 h
DPPA, Et3N: 41%
HATU, DIPEA: 42%
DMC, DIPEA: 37%
O
O
LiBH4, MeOH
70 °C, 3 h
NH
NH
Me
N
Me
N
CO2tBu
CH2OH
73%
7
(-)-benzolactam-V8 (5)
Scheme 4. Preparation of (ꢀ)-benzolactam-V8 (5) from the aziridine mixture 9.
(C2eC1eC¼O), ꢀ81.4ꢁ (C6eC1eC¼O), 62.4ꢁ (C3eC2eNeC
a), and
ꢀ119.3ꢁ (C1eC2eNeC
a), indicating difficult conjugation of the
In conclusion, we succeeded in the synthesis of (ꢀ)-benzo-
lactam-V8, an artificially-designed cyclic dipeptide with strong
tumor-promoter activity, from benzyl (S)-N-(2-formylphenyl)-N-
methylvalinate through four steps by application of guanidinium
ylide-participated asymmetric aziridination followed by reductive
ring-opening reaction of the 3-arylaziridine-2-carboxylate formed
as key steps.
amine group with the aldehyde one through benzene ring.
3. Experimental
3.1. General
Fig. 2. Optimized structures of the valine-substituted benzaldehyde 10 using PM3
method.
All melting points were measured on a micro-melting point hot
stage (Yanaco) and are uncorrected. IR spectra were recorded with
ATR (attenuated total reflectance system) on a JASCO FT/IR-300E
spectrophotometer. 1H and 13C NMR spectra were recorded on
JOEL JNM-ECP-400 (400 MHz for 1H and 100 MHz for 13C) in CDCl3.
It is not necessarily easy to separate the aziridine mixture 9 to
each four pure component. Thus, we decided to detour the difficult
separation because four components could at least convergent to

I. Khantikaew et al. / Tetrahedron 68 (2012) 878e882
881
Chemical shifts (
d
) were reported as parts per million from tetra-
128.26 (cis-9a),128.29,128.34, 128.35, 128.42,128.43, 128.57,128.58,
128.64 (cis-9a), 129.4 (cis-9a), 129.78, 129.84 (cis-9a), 132.7, 135. 6
(cis-9a), 135. 7, 135. 8, 138.1 (cis-9a), 138.3, 139.5, 139.6, 150.8, 151.5
(cis-9a),151.79,151.80,166.8 (cis-9a),167.5,167.7,168.0,171.3 (cis-9a),
171.5, 171.7, 172.5; HRFABMS m/z: 529.3079 (calcd for C33H41N2O4:
methylsilane (0.00 ppm) as an internal standard for 1H and from
the middle resonance of CDCl3 (77.00 ppm) as an internal standard
for 13C, respectively. MS spectra were measured on JEOL JMS-
HX110A for FABMS and JEOL JMS-T100LP for ESIMS. Optical rota-
tions were recorded on a JASCO P-1020 digital polarimeter. For SiO2
column chromatography were used Kanto silica gel 60 (37564-85),
529.3066); ½a 2D6
ꢀ6.1 (c 0.55, CHCl3).
ꢃ
spherical particle size 63e210
mm, or FL100D SiO2 (Fuji Silysia
Chemical Ltd). For TLC was used Merck DC-Fertigplatten Kieselgel
60 F254 (5715). Dehydrated DMF was purchased from Kanto
Chemical Co. Inc.
3.3. Reductive ring-opening reaction of an aziridine mixture
9 followed by lactamization
3.2. Asymmetric aziridination of 10 and 11
3.3.1. With DPPA. A mixture of the aziridine mixture 9 (0.0761 g,
0.144 mmol), and 20% Pd(OH)2/C (0.0153 g) in MeOH (0.3 mL) was
stirred at rt for 1.5 h at atmospheric pressure underhydrogen and the
catalyst was filtered off through Celite pad. Evaporation of the filtrate
gave a crude ring-opened 8 (0.0663 g) as solids, which was dissolved
in DMF (15 mL). After addition of Et3N (0.04 mL, 0.287 mmol) and
DPPA (0.04 mL, 0.176 mmol) at 0 ꢁC under argon atmosphere the
resultant solution was stirred at the same temperature for 5 min and
then at rt for 24 h, and evaporated under reduced pressure. The
residue was partitioned with EtOAc (80 mL) and H2O (4 mL). The
aqueous solution was extracted with EtOAc (20 mLꢂ2). The com-
bined EtOAc solution was washed with H2O (2 mLꢂ2) and brine
(2 mLꢂ2) and dried (Na2SO4), and evaporated. After removal of an
insoluble solid by trituration with Et2O, the oily residue was evapo-
rated and purified by SiO2 column chromatography (EtOAc/n-
hexane¼1:5) afforded lactam 7 (0.0196 g, 41%) as a yellow oil; TLC: Rf
0.4 (EtOAc/n-hexane¼1:2); IR nmax cmꢀ1: 3380 (NH),1730,1665(CO);
A mixture of the benzaldehyde 1038 (0.1065 g, 0.37 mmol), the
guanidinium bromide 11 (0.2125 g, 0.386 mmol) in DMF (0.7 mL) in
the presence of NaH (60% oil suspension, 0.029 g, 0.721 mmol) was
stirred at ꢀ20 ꢁC for 24 h underargon atmosphere and, after addition
of CHCl3 (20 mL) and SiO2 (0.47 g), the resultant mixture was stirred
at rt for 24 h. The SiO2 was filtered off and washed with CHCl3
(20 mL). The filtrate was combined with the washing and concen-
trated under reduced pressure. The yellow residual oil was dissolved
in Et2O (80 mL), and the ethereal solution was washed with H2O
(2 mLꢂ3) and brine (2 mL), dried (MgSO4), and evaporated to give
a yellow oil (0.329 g). Trituration of the yellow oil with n-hexane
afforded the urea 12 (0.0821 g, 94%) as colorless solids and a crude
aziridine mixture 9 (0.172 g, 99%) as a yellow oil from the soluble part
after evaporation. Purification of the crude 9 by SiO2 column chro-
matography (Et2O/n-hexane¼1:10) afforded an oily aziridine mix-
ture (0.149 g, 86%), composed of cis-9a, cis-9b, trans-9c, and trans-9d
in ratio of 15:1:4:2 based on the 1H NMR spectrum; TLC: Rf 0.7 (very
1H NMR
d: 0.95,1.08 (each 3H, d, J¼6.8 Hz, CHMe2),1.50 (9H, s, CMe3),
2.42 (1H, octet, J¼7.0 Hz, CHCHMe2), 2.78 (3H, s, NMe), 3.00 (1H, dd,
J¼16.3, 8.8 Hz, ArCH2CH), 3.37 (1H, d, J¼7.7 Hz, NCHCH), 3.54 (1H, dd,
J¼16.1, 3.8 Hz, ArCH2CH), 4.92 (1H, br s, NHCH(CH)CH2), 6.23 (1H, d,
J¼4.0 Hz, NH, exchangeable), 6.97 (1H, t, J¼7.4 Hz, ArH), 7.07 (1H, d,
J¼7.7 Hz, ArH), 7.12 (1H, d, J¼7.9 Hz, ArH), 7.22 (1H, t, J¼7.3 Hz, ArH);
small spot), 0.6 (main spot) (EtOAc/n-hexane¼1:5); IR nmax cmꢀ1
:
1723 (CO); 1H NMR
d: 0.80 (4/22ꢂ3H, d, J¼6.6 Hz, CHMe2 in trans-9c),
0.87 (3/22ꢂ3H, d, J¼6.6 Hz, CHMe2 in cis-9b and trans-9d), 0.90 (1/
22ꢂ3H, d, J¼6.6 Hz, CHMe2 in cis-9b), 0.94 (15/22ꢂ3H, d, J¼6.4 Hz,
CHMe2 in cis-9a),1.10 (15/22ꢂ9H, s, CMe3 in cis-9a),1.10 (4/22ꢂ3H, d,
J¼5.1 Hz, CHMe2 in trans-9c),1.19 (15/22ꢂ3H, d, J¼6.8 Hz, CHꢂMe2 in
cis-9a),1.19 (1/22ꢂ9H, s, CMe3 in cis-9b),1.22 (2/22ꢂ3H, d, J¼6.6 Hz,
CHMe2 in trans-9d), 1.35 (2/22ꢂ9H, s, CMe3 in trans-9d), 1.40 (4/
22ꢂ9H, s, CMe3 in trans-9c), 2.2e2.4 (1H, m, CHCHMe2), 2.56 (16/
22ꢂ1H, d, J¼7.0 Hz, C2eH in cis-9a and cis-9b), 2.60 (2/22ꢂ1H, d,
J¼2.7 Hz, C2eH in trans-9d), 2.65 (4/22ꢂ1H, d, J¼2.2 Hz, C2eH in
trans-9c), 2.77 (15/22ꢂ3H, s, NMein cis-9a), 2.82(4/22ꢂ3H, s, NMe in
trans-9c), 2.85 (2/22ꢂ3H, s, NMe in trans-9d), 2.90 (1/22ꢂ3H, s, NMe
in cis-9b), 3.15 (1/22ꢂ1H, d, J¼7.0 Hz, C3eH in cis-9b), 3.30 (15/
22ꢂ1H, d, J¼10.6 Hz, NCHCH(C) in cis-9a), 3.40 (2/22ꢂ1H, d,
J¼10.6 Hz, NCHCH(C) in trans-9d), 3.43 (4/22ꢂ1H, d, J¼7.0 Hz,
NCHCH(C) in trans-9c), 3.44 (15/22ꢂ1H, d, J¼7.0 Hz, C3eH in cis-9a),
3.49, 3.64 (each 1/22ꢂ1H, d, J¼14.2 Hz, NCH2Ph in cis-9b), 3.57 (1/
22ꢂ1H, d, J¼10.1 Hz, NCHCH(C)incis-9b), 3.65 (4/22ꢂ1H,d, J¼1.6 Hz,
C3eH in trans-9c), 3.69, 3.82 (each 15/22ꢂ1H, d, J¼14.3 Hz, NCH2Ph
in cis-9a), 3.69 (2/22ꢂ1H, d, J¼2.6 Hz, C3eH in trans-9d), 4.07, 4.23
(each 2/22ꢂ1H, d, J¼14.2 Hz, NCH2Ph in trans-9d), 4.16, 4.25 (each 4/
22ꢂ1H, d, J¼14.2 Hz, NCH2Ph in trans-9c), 4.91, 4.97 (each 15/22ꢂ1H,
d, J¼12.2 Hz, OCH2Ph in cis-9a), 4.94 (each 2/22ꢂ2H, s, OCH2Ph in
trans-9d), 5.05, 5.10 (each 4/22ꢂ1H, d, J¼12.1 Hz, OCH2Ph in trans-
9c), 5.11, 5.22 (each 1/22ꢂ1H, d, J¼12.2 Hz, OCH2Ph in cis-9b), 7.1e7.6
13C NMR
d: 19.5, 20.2, 28.0, 28.6, 36.8, 39.3, 54.8, 73.3, 82.8, 121.6,
123.3, 128.1, 131.6, 131.9, 151.9, 170.9, 171.8; HRFABMS m/z: 333.2174
(calcd for C19H29N2O3: 333.2178); ½a D27
ꢀ150 (c 0.348, CHCl3).
ꢃ
3.3.2. With HATU. After ring-opening reaction using 9 (0.0762 g,
0.144 mmol) and 20% Pd(OH)2/C (0.0153 g) and MeOH (0.3 mL) as
described above, the crude 8 (0.0637 g) was dissolved in DMF
(26 mL). After the resultant solution was stirred with DIPEA
(0.06 mL, 0.344 mmol) at 0 ꢁC for 10 min under argon atmosphere
HATU (0.0786 g, 0.207 mmol) was added at 0 ꢁC and the whole was
stirred at the same temperature for 20 min and then at rt for 24 h,
and evaporated under reduced pressure. The residue was dissolved
in EtOAc (30 mL) and the resultant solution was washed with 10%
citric acid (2 mlꢂ2), satd NaHCO3 aq (2 mlꢂ2), and brine (2 mlꢂ2),
and dried (Na2SO4), and evaporated. Purification of the residue by
SiO2 column chromatography (EtOAc/n-hexane¼1:5) afforded lac-
tam 7 (0.0200 g, 42%).
3.3.3. With DMC. After ring-opening reaction using 9 (0.0358 g,
0.068 mmol) and 20% Pd(OH)2/C (0.0072 g) and MeOH (0.3 mL) as
described above, the crude 8 (0.0382 g) was dissolved in DMF
(12 mL). After the resultant solution was stirred with DIPEA
(0.03 mL, 0.173 mmol) at 0 ꢁC for 10 min under argon atmosphere
a 1 M solution of DMC in DMF (0.09 mL, 0.09 mmol) was added at
0 ꢁC and the whole was stirred at the same temperature for 10 min
and then at rt for 24 h, and evaporated under reduced pressure. The
residue was dissolved in EtOAc (30 mL) and the resultant solution
was washed with 10% citric acid (2 mlꢂ2), satd NaHCO3 aq
(2 mlꢂ2), and brine (2 mlꢂ2), dried (Na2SO4), and evaporated.
Purification of the residue by SiO2 column chromatography (EtOAc/
n-hexane¼1:5) afforded lactam 7 (0.0084 g, 37%).
(14H, m, ArH); 13C NMR
d: 18.9,19.2 (cis-9a),19.3,19.5,19.6,19.75 (cis-
9a), 19.80, 20.0, 27. 7 (cis-9a), 27.9, 27.98, 27.99, 28.09 (cis-9a), 28.14,
28.5, 28.9, 34.6 (cis-9a), 35.3, 35.7, 36.3, 44.1, 44.7, 45.3 (cis-9a), 45.80,
45.83, 46.2, 47.65, 47.70 (cis-9a), 54.6, 54. 7, 63.1, 63.3 (cis-9a), 65.4,
65.5 (cis-9a), 65.7, 66.0, 71.4, 72.0 (cis-9a), 72.29, 72.31, 81.0, 81.2 (cis-
9a), 81. 5, 81.6,120.4,121.6,121.9 (cis-9a),122.0,122.05,122.06,123.5
(cis-9a), 123.85, 123.93, 125.8, 126.1, 126.6, 126.7, 126.88, 126.91 (cis-
9a), 127.6 (cis-9a), 127.66 (cis-9a), 127.67, 127.69, 127.74, 127.86,
127.92, 127.95, 127.97 (cis-9a), 128.1, 128.18, 128.20, 128.23 (cis-9a),

882
I. Khantikaew et al. / Tetrahedron 68 (2012) 878e882
8. Irie, K.; Hagiwara, N.; Koshimizu, K.; Hayashi, H.; Murao, S.; Tokuda, H.; Ito, Y.
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for 3 h and, after quenched with H2O (1 mL) at rt, was extracted
with EtOAc (15 mLꢂ2). The organic solution was washed with H2O
(1 mLꢂ2) and brine (1 mLꢂ2), dried (MgSO4), and evaporated.
Purification of the residual yellow solids by SiO2 column chroma-
tography (EtOAc/n-hexane¼2:1) afforded (ꢀ)-benzolactam-V8 (5)
(0.0062 g, 73%) as colorless prisms, mp 113e114 ꢁC (lit. no data);
TLC: Rf 0.2 (EtOAc/n-hexane¼1:1); IR nmax cmꢀ1: 3349 (NH), 3300
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: 0.89, 1.07 (each 3H, d, J¼6.6 Hz,
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CHMe2), 2.40e2.49 (1H, m, CHCHMe2), 2.81 (3H, s, NMe), 2.82 (1H,
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3.47 (1H, d, J¼8.6 Hz, NCH(C)CH), 3.54 (1H, dd, J¼10.7, 8.7 Hz,
CHCH2OH), 3.73 (1H, dd, J¼10.7, 4.0 Hz, CHCH2OH), 4.06 (1H, br s,
CH2CH(N)CH2), 6.48 (1 h, br s, NH), 6.88 (1H, dt, J¼7.2, 1.2 Hz, ArH),
7.02 (1H, dd, J¼8.0, 1.0 Hz, ArH), 7.04 (1H, dd, J¼8.0, 1.0 Hz, ArH),
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7.19 (1H, dt, J¼7.7, 1.4 Hz, ArH); 13C NMR
d: 19.9, 20.3, 28.4, 35.6,
37.3, 54.1, 65.8, 70.9, 120.2, 121.8, 127.7, 131.4, 131.7, 151.8, 174.2;
HRESIMS m/z: 285.16023 (calcd for C15H22N2NaO2: 285.15790);
a 22
a 20
½ ꢃD ꢀ276 (c 0.36, CHCl3) {lit.29 ½ ꢃD ꢀ271 (c 0.08, CHCl3)}.
Acknowledgements
27. Endo, Y.; Ohno, M.; Takehana, S.; Driedger, P. E.; Stabel, S.; Shudo, K. Chem.
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One of authors (I.K.) greatly thanks Rajamangala University of
Technology Thanyaburi, Thailand, for scholarship.
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Supplementary data
NMR charts of an aziridine mixture 9, a benzolactam skeleton 7,
and (ꢀ)-benzolactam-V8 (5). Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2011.11.033.
32. Ma, D.; Tang, W.; Kozikowski, A. P.; Lewin, N. E.; Blumberg, P. M. J. Org. Chem.
1999, 64, 6366e6373.
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