A novel convergent method for the synthesis of α-acyl-γ- hydroxylactams and its application in the total synthesis of PI-090 and 091

Article abstract of DOI:10.1016/j.bmcl.2012.05.065

A novel convergent method for the synthesis of α-acyl-γ- hydroxylactams utilizing the aldol reaction of N-Boc-protected γ-methoxylactams was developed. As the first application of this method for the synthesis of biologically active natural products, the total synthesis of platelet aggregation inhibitors PI-090 and PI-091 were also investigated and successfully achieved.

Full text of DOI:10.1016/j.bmcl.2012.05.065

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4765–4768
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Bioorganic & Medicinal Chemistry Letters
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A novel convergent method for the synthesis of
a-acyl-c-hydroxylactams and
its application in the total synthesis of PI-090 and 091
Hiromi Uchiro a,b, , Nobuhiro Shionozaki a, Yu Kobayakawa a, Hiroko Nakagawa a, Kimiko Makino a,b
⇑
a Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
b Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel convergent method for the synthesis of a-acyl-c-hydroxylactams utilizing the aldol reaction of N-
Boc-protected c-methoxylactams was developed. As the first application of this method for the synthesis
of biologically active natural products, the total synthesis of platelet aggregation inhibitors PI-090 and PI-
091 were also investigated and successfully achieved.
Received 17 January 2012
Revised 10 May 2012
Accepted 16 May 2012
Available online 24 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
PI-090
PI-091
a-Acyl-c-hydroxylactam
Platelet aggregation inhibitor
Total synthesis
Result and discussion
(Scheme 2). Although a similar aldol-type reaction utilizing N-ben-
zyl-protected
amp and co-workers,10 it has not been applied for the synthesis
of -acyl- -hydroxylactams. Therefore, we tried to apply this type
of aldol reaction for the efficient introduction of -substituent on
the total synthesis of natural -acyl- -hydroxylactams.
First, the synthesis of N-Boc-protected -benzyl- -methoxylac-
c-methoxylactam was already reported by Speck-
Recently, several
a-acyl-c-hydroxylactam-type natural prod-
ucts such as Oteromycin (1),1 Pyrrocidine A (2),2 Myceliothermo-
phin A (3),3 GKK1032s,4 Hirsutellones,5 PI-090 (4) and PI-091 (5),6
etc. have been reported7 (see Fig. 1). Many research groups have
embarked on the total synthesis of these compounds because of
their interesting chemical structures and attractive biological activ-
a
c
a
a
c
c
c
tam 7a was investigated (Scheme 3). Allylation of bromobenzene 8
and subsequent epoxidation gave the corresponding epoxide 9. An
ities.8 These compounds have different substructures at the
a- and
c-positions of the lactam ring, and show various potent biological
activities depending on the substructure. Therefore, SAR studies
on these substructures should provide important findings con-
cerned with the activity spectrum and the precise mode of action
of this series of compounds. Therefore, we started the project to de-
velop a new efficient method for the synthesis of natural and bio-
H
O
H
H
O
NH
OH
H
O
O
OH
N
H
O
logically active a-acyl-c-hydroxylactams.
In this research field, an interesting biomimetic strategy has
been reported by Snider’s group9 (Scheme 1). That is, a simple
model compound 6 was obtained using a straightforward synthetic
Oteromycin (1)
Pyrrocidine A (2)
route starting from an easily available
a
-amino alcohol. However,
HO
O
the total synthesis of natural -acyl-c-hydroxylactams using this
a
method has not been reported to date. Therefore, we devised a
new convergent synthetic strategy utilizing the aldol reaction of
H
O
O
N
H
N-Boc-protected c-methoxylactam 7 with aldehyde as a key step
OH
N
H
RO
O
Myceliothermophin A (3)
PI-090 (4: R = H)
PI-091 (5: R = Me)
⇑
Corresponding author at: Faculty of Pharmaceutical Sciences, Tokyo University
of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
E-mail address: uchiro@rs.noda.tus.ac.jp (H. Uchiro).
Figure 1. Structure of natural a-acyl-c-hydroxylactams.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.065

4766
H. Uchiro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4765–4768
OH
NH2
O
OH
O
OH
O
b, c
a
a
b
+
HN
O
O
OH
O
O
N
Boc
N
Boc
N
Boc
MeO
MeO
MeO
O
7a
13
14
O
O
O
SePh
O
O
c
e
d
O
OH
O
O
d
N
Boc
N
Boc
MeO
MeO
O
N
N
H
15
16
H
O
O
f or g
+
OH
O
O
O
O
N
H
N
H
HO
MeO
O
O
N
H
N
H
6
17
HO
6
Scheme 4. Convergent synthesis of
a-acyl-c-hydroxylactam 6. Reagents and
conditions: (a) LDA, cyclohexanecalbaldehyde, THF, ꢀ78 °C, 86%; (b) DMP, NaHCO3,
CH2Cl2, rt, 90%; (c) LDA, PhSeCl, THF, ꢀ78 °C; (d) mCPBA, CH2Cl2, ꢀ78 °C, 68% (2
steps); (e) DDQ, K2CO3, dioxane, rt, 81%; (f) TFA, CH2Cl2–H2O, 0 °C, 41% of 6, 52% of
17; (g) 47% HF aq, CH3CN–H2O, rt, 80% of 6.
Scheme 1. Snider’s method for the synthesis of
Reagents and conditions: (a) Toluene, 65 °C, 62%; (b) EDC, Cl2CHCOOH, DMSO-
toluene, rt; (c) 1 N NaOH aq, Et2O–CH2Cl2; (d) DMDO, CH2Cl2, ꢀ40 °C, 35% (3 steps).
a
-acyl-c-hydroxylactam 6.
O
R
N
Table 1
R'
R'
MeO
Substrate generality in the aldol reaction
Boc
OH
O
O
7
+
Aldol reaction
Oxidation
O
R'
R
R
N
N
OH
LDA
MeO
MeO
Boc
Boc
O
R' CHO
+
R'
H
R
MeO
N
Boc
THF, -78 °C
O
R
MeO
O
N
Boc
R'
R'
O
O
O
18a-18c
7a: R = Bn
7b: R = iPr
7c: R = iBu
Dehydrogenation
Deprotection
O
R
MeO
R
N
N
H
HO
Boc
Entry
Lactam
Aldehyde
Yield (%)
Scheme 2. Our convergent strategy for the synthesis
a
-acyl-
c
-hydroxylactams.
1
2
3
4
5
6
7
8
9
7a
7a
7a
7b
7b
7b
7c
7c
7c
18a
18b
18c
18a
18b
18c
18a
18b
18c
86
92
84
96
83
75
66
99
86
c, d
e, f
O
a, b
O
O
Br
8
9
10
O
g
h
NH2
O
O
O
O
O
N
H
N
Boc
O
MeO
MeO
H
H
H
11
12
7a
18c
18a
18b
Scheme 3. Preparation of a-benzyl-c-methoxylactam 7a. Reagents and conditions:
(a) Mg, allyl bromide, THF, rt; (b) DMDO, NaHCO3, acetone-H2O, rt, 52% (2 steps); (c)
diethyl malonate, Na, EtOH–THF, rt; (d) NaCl, DMSO, 150 °C, 88% (2 steps); (e)
Me3Al, NH4Cl, toluene, 40 °C; (f) SO3ꢁPy, DIPEA, CH2Cl2–DMSO, rt, 91% (2 steps); (g)
cat.PPTS, MeOH, rt; (h) Boc2O, Et3N, DMAP, CH2Cl2, rt, 66% (2 steps).
With the key intermediate in hand, we next examined the aldol
reaction of the lithium enolate of 7a with cyclohexanecarbalde-
hyde, which was chosen as a model compound (see Scheme 4).
The desired reaction proceeded smoothly, and adduct 13 was ob-
tained in good yield as a mixture of two diastereomers (ca. 1:1).
Oxidation of 13 by Dess-Martin periodinane gave the correspond-
addition reaction of diethyl malonate with 9 and successive decar-
boxylation afforded
subsequent oxidation, the resulting
with MeOH under the acidic condition to give the cyclized
c
-benzyllactone 10. After ammonolysis and
-ketoamide 11 was treated
-meth-
c
c
ing
a
-acyl-
c
-methoxylactam 14. For the dehydrogenation of 14,
-position and its
oxylactam 12. Finally, Boc-protection of the nitrogen atom of 12
gave the desired key intermediate 7a.
introduction of a phenylselenenyl group at the
a

H. Uchiro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4765–4768
4767
O
O
a, b
c
HO
HO
H
20
22
23
21
O
d, e
f
MeO2C
PPh3
TESO
H
OTES
OTES
19
24
Scheme 5. Preparation of chiral aldehyde 19. Reagents and Conditions: (a) yield 21, CH2Cl2, rt; (b) DIBAL, CH2Cl2, ꢀ78 °C, 86% (2 steps): (E/Z = 50:1); (c) Ti(OiPr)4, D-(ꢀ)-DIPT,
TBHP, MS4A, CH2Cl2, ꢀ23 °C, 82% (96%ee); (d) LAH, THF, rt; (e) TESCl, imidazole, DMF, 80 °C, 87% (2 steps); (f) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to ꢀ40 °C, 54% (SM 45%
recovered).
O
subsequent oxidative elimination were carried out. As a result, the
desired a,b-unsaturated lactam 16 was obtained in 68% yield in 2
H
OTES
TESO
HO
steps. On the other hand, direct dehydrogenation of 14 with DDQ
under the basic condition was also tried and gave the same product
16 in 71% yield from 14. The final deprotection step, including re-
moval of the N-Boc-group and hydrolysis of the methoxyaminal
moiety, was then investigated. The acidic condition (TFA-dichloro-
methane-H2O) reported by Hayashi’s group11 gave the desired
19
a
b
+
O
N
Boc
O
MeO
c, d
N
Boc
MeO
25
7b
a
-acyl-
c
-hydroxylactam 6 in 48% yield with an incompletely
-acyl- -methoxylactam 17 (48% yield). On the other
deprotected
a
c
TESO
O
TESO
O
hand, the yield of 6 was significantly improved (up to 80%) by use
of aqueous hydrofluoric acid in acetonitrile at room temperature.
O
O
Thus, a new convergent method for the synthesis of
hydroxylactam 6 was successfully developed.
a-acyl-c-
N
Boc
N
Boc
MeO
MeO
Next, the substrate generality of the aldol reaction of N-Boc-
protected -methoxylactam was elucidated. Reactions between
three types of -methoxylactams having a different substituent
at the -position (7a–c) with three types of aldehydes (cyclohexan-
26
27
c
HO
O
HO
c
O
c
carbaldehyde (18a), benzaldehyde (18b), and trans-2-hexenal
(18c)) were examined. As a result, the desired products were ob-
tained in satisfactory yield in all cases (Table 1). These results sug-
gested that our developed aldol reaction would be useful for the
e
O
O
+
N
H
N
H
MeO
HO
PI-090 (4)
PI-091 (5)
synthesis of natural a-acyl-c-hydroxylactams.
Scheme 6. Total synthesis of PI-090 (4) and PI-091 (5). Reagents and conditions: (a)
LDA, THF, ꢀ78 °C, 72%; (b) PDC, MS4A, CH2Cl2–DMF, rt, 55%; (c) LHMDS, PhSeCl,
THF, ꢀ78 °C; (d) H2O2 aq, NH4Cl, CH2Cl2, 0 °C, 94% (2 steps); (e) TFA, CH2Cl2–H2O,
0 °C, 63% of 4, 35% of 5
Therefore, we tried the total synthesis of platelet aggregation
inhibitors PI-090 (4)12 and PI-091 (5) as the first application of
our convergent synthetic method. Although the total synthesis of
PI-091 has been reported by two groups,13,14 our intent was to de-
velop a more applicable method for the structure–activity relation-
ship studies through the efficient preparation of various synthetic
analogues.
First, chiral aldehyde 19 was prepared (see Scheme 5). Wittig
reaction of hexanal 20 with ylide 21, followed by reduction using
DIBAL, gave the corresponding allylic alcohol 22. Sharpless asym-
metric epoxidation of 22 afforded the desired epoxy alcohol 23
in 82% yield. The optical purity of 23 was determined by HPLC
analysis to be 96% ee.15 A ring-opening reaction using LAH fol-
lowed by TES protection of the resulting tertiary hydroxyl group
gave the bis-TES ether 24. The primary-TES ether moiety was
selectively deprotected and subsequently oxidized using the Swern
condition16 to give the desired chiral aldehyde 19.
achieved by a treatment of
Hayashi’s condition. We intentionally chose this condition to ob-
tain both of the corresponding -hydroxy- and -methoxylactams.
As a result, the desired -hydroxylactam PI-090 (4) and -meth-
a,b-unsaturated lactam 27 with the
c
c
c
c
oxylactam PI-091 (5) were respectively obtained in 63% and 35%
yield.17 These compounds were easily separated by silica-gel col-
umn chromatography. All the spectral data18,19 were in good accor-
dance with those reported in the literature.
In conclusion, a new convergent method for the synthesis of
a
-acyl-
c
-hydroxylactams utilizing the aldol reaction of N-Boc-pro-
tected
c
-methoxylactam 7 as a key step was developed. As the first
Completion of the total synthesis of PI-090 (4) and PI-091 (5) is
application of this method for the synthesis of natural products,
the total synthesis of PI-090 (4) and PI-091 (5) were also studied
and successfully achieved. As an additional remark, we recently
accomplished the first total synthesis of Myceliothermophin A
(3) based on the above described convergent synthetic strategy.20
Further investigations into the total synthesis of these more com-
demonstrated in Scheme 6. Aldol reaction of N-Boc-protected
c-
methoxylactam 7b with chiral aldehyde 19 afforded the desired
adduct 25 in 72% yield. Although Dess-Martin oxidation of 25 gave
poor result, the yield of the desired
was improved by use of PDC as a substitute oxidant. Unfortunately,
the direct dehydrogenation of -acyl- -methoxylactam 26 with
DDQ did not proceed at all. It is probably due to the steric hin-
drance of the -substituent preventing the approach of DDQ to
a-acyl-c-methoxylactam 26
a
c
plex a-acyl-c-hydroxylactams will be reported in the near future.
a
the b-position of lactam 26. Therefore, we attempted a conven-
Acknowledgments
tional method using penylselenenylation and subsequent oxidative
elimination. In a series of reactions, the desired
lactam 27 was obtained in high yield. Final deprotection was
a
,b-unsaturated
This research was partially supported by a Grants-in-Aid for Sci-
entific Research (KAKENHI) from the Ministry of Education,

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H. Uchiro et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4765–4768
13. (a) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. Tetrahedron Lett. 1995, 36,
5551; (b) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. J. Org. Chem. 1996, 61,
2845.
Culture, Sports, Science and Technology of JAPAN (Basic Research
(C), No.18590108).
14. Iwasawa, N.; Maeyama, K. J. Org. Chem. 1918, 1997, 62.
15. The optical purity of epoxy alcohol 23 was determined as the corresponding p-
nitrobenzoate by HPLC analysis using a DAICEL CHIRALCEL OD-H column
(hexane: 2-propanol = 200: 1).
16. Rodriguez, A.; Nomen, M.; Spur, W. B.; Godfroid, J. J. Tetrahedron Lett. 1999, 40,
5161.
References and notes
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Tetrahedron Lett. 2002, 43, 1633–1636; b) Shiono, Y.; Shimanuki, K.; Hiramatsu,
F.; Koseki, T.; Maruyama, T.; Fujisawa, N.; Kimura, K. Bioorg. Med. Chem. Lett.
2008, 18, 6050.
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2007, 13, 6985.
4. Koizumi, F.; Hasegawa, K.; Ando, K.; Ogawa, T.; Hara, A. Jpn. Pat. Appl. 2001. JP
2001247574 A2 20010911.
5. (a) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.;
Thebtaranonth, Y. Tetrahedron 2005, 61, 5577; (b) Isaka, M.; Prathumpai, W.;
Wongsa, P.; Tanticharoen, M. Org. Lett. 2006, 8, 2815.
6. Kawashima, A.; Yoshimura, Y.; Sakai, N.; Kamigoori, K.; Mizutani, T.; Omura, S.
Jpn. Pat. Appl. 1990. JP 02062859 A 19900302.
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cited therein.
8. Takao, K.; Aoki, S.; Tadano, K. J. Synth. Org. Chem. Jpn. 2007, 65, 460. and
references cited therein.
9. Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952.
10. Klaver, W. J.; Moolenaar, M. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
1988, 44, 3805.
11. Yamaguchi, J.; Kakeya, H.; Uno, T.; Shoji, M.; Osada, H.; Hayashi, Y. Angew.
Chem. Int. Ed. 2005, 44, 3110.
12. Although the inhibitory activity of PI-090 (5) toward the platelet aggregation
has not been published, it is almost same level as that of PI-091 (4). The
authors would like to thank to Drs. Akira Kawashima and Hiromasa Horikiri
(Taisho Pharmaceutical Co., Ltd) for the provision of this valuable information.
17. PI-090 (4) and PI-091 (5) were respectively obtained ca. 1:1 mixture of
diastereomers at the
samples.
c-position of lactam ring in similar form as their natural
18. Spectral data of PI-090 (4): 1H-NMR(d,400 MHz,CDCl3) 0.84–0.91 (3H, m) 0.99,
1.01 (each 1.5H, 2d, J = 6.8 Hz) 1.04, 1.05 (each 1.5H, 2d, J = 6.8 Hz) 1.18–1.30
(8H, m) 1.34, 1.36 (each 1.5H, s) 1.55–1.64 (1H, m) 1.66–1.85 (1H, m) 2.13 (1H,
heptet, J = 6.8 Hz) 3.04, 3.42 (each 0.5H, s) 5.64, 5.93 (each 0.5H, s) 6.49, 6.56
(each 0.5H, br s) 7.64, 7.65 (each 0.5H, s); 13C NMR (d,100 MHz,CDCl3) 14.0,
14.1, 16.8, 16.9, 17.0, 17.1, 22.5, 22.6, 22.9, 23.2, 23.3, 24.0, 29.6, 29.6, 29.7,
31.6, 31.7, 34.7, 34.8, 38.4, 38.6, 77.2, 79.3, 90.6, 90.6, 136.2, 136.4, 158.9,
159.6, 170.1, 170.1, 198.4, 199.2; IR(neat, cmꢀ1) 3305(br), 3020, 2931, 2858,
1695, 1369, 1214, 758; HRMS (FAB, positive) calculated for C16H28NO4(M+H)
298.2019 found 298.2018; ½a D24
= ꢀ35.8° (0.12c, CHCl3).
ꢂ
19. Spectral data of PI-091 (5): 1H NMR(d,400 MHz,CDCl3) 0.85–0.88 (3H, m) 0.97,
0.98 (each 1.5H, 2d, J = 6.8 Hz) 1.00, 1.01 (each 1.5H, 2d, J = 6.8 Hz) 1.21–1.35
(8H, m) 1.37, 1.38 (each 1.5H, s) 1.56–1.72 (1H, m) 1.76–1.83 (1H, m) 2.11 (1H,
heptet, J = 6.8 Hz) 3.17, 3.18 (each 1.5H, s) 5.68, 5.71 (each 0.5H, s) 5.94–6.20
(1H, brs) 7.56, 7.57 (each 0.5H, 2d, J = 1.9, 2.2 Hz),; 13C NMR (d,100 MHz,CDCl3)
14.0, 14.1, 17.0, 17.0, 17.2, 22.5, 23.4, 23.4, 29.7, 29.7, 31.7, 31.9, 35.3, 38.5,
38.6, 51.1, 51.2, 77.2, 78.6, 94.4, 139.5, 139.6, 157.9, 158.0, 169.7, 198.6, 198.7,;
IR(neat, cmꢀ1) 3247(br), 2929, 2860, 1695, 1462, 1375, 1219, 758; HRMS(FAB,
positive) calculated for
C17H30NO4(M+H) 312.2176 found 312.2171,;
½ ꢂ = ꢀ39.4° (0.072c, CHCl3).
a 2D3
20. Shionozaki, N.; Yamaguchi, T.; Kitano, H.; Tomizawa, M.; Makino, K.; Uchiro, H.
under preparation.