Synthesis of the core ring system of awajanomycin from N-Boc-3-methoxycarbonyl-2-pyridinone

Article abstract of DOI:10.1016/j.tetlet.2009.02.141

Awajanomycin, which was isolated from marine-derived fungus, possesses unique structural features and cytotoxic activity against A549 cells. Due to its unique structure, no total synthesis has yet been reported, and neither the relative stereochemistry no

Full text of DOI:10.1016/j.tetlet.2009.02.141

Tetrahedron Letters 50 (2009) 2115–2118
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Synthesis of the core ring system of awajanomycin from
N-Boc-3-methoxycarbonyl-2-pyridinone
a
a
Kou Hiroya a,b, , Kei Kawamoto , Kiyofumi Inamoto , Takao Sakamoto a,b, Takayuki Doi a
*
a Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
b Tohoku University 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation’, 6-3 Aramaki,
Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Awajanomycin, which was isolated from marine-derived fungus, possesses unique structural features
and cytotoxic activity against A549 cells. Due to its unique structure, no total synthesis has yet been
reported, and neither the relative stereochemistry nor the absolute configuration has been determined.
We report the synthesis of the core ring system of awajanomycin, which includes: (i) regioselective addi-
tion of the acetate unit onto C4-position of N-Boc-3-methoxycarbonyl-2-pyridinone; (ii) stereoselective
installation of a hydroxyl group on C3-position; and (iii) stereo- and regioselective epoxide-opening reac-
tion by Me3Al.
Received 30 December 2008
Revised 9 February 2009
Accepted 19 February 2009
Available online 25 February 2009
Keywords:
Awajanomycin
2-Pyridinone
Ó 2009 Elsevier Ltd. All rights reserved.
Silyl ketene acetal
Trimethylaluminum
Conjugate addition
Because nitrogen-containing six-membered compounds are fre-
quently found in natural products and many are known to possess
valuable biological activities, they have long been of interest to
organic and bio-organic chemists.1 Utilization of nitrogen-contain-
ing six-membered heteroaromatic compounds seems to be a useful
method to achieve stereoselective construction of functionalized
piperidine ring systems because they are readily available. Reac-
tions of pyridinium salts or dihydropyridine derivatives have been
thoroughly investigated recently,2 and the syntheses of many bio-
logically active compounds have also been reported.3 On the other
hand, the utilization of the 2-pyridinone derivatives has been
mainly carried out for the Diels–Alder reaction.4 To the best of
our knowledge, a few examples for the introduction of the allyl
group to 2-pyridinone derivatives5 and some literatures about
the reactions of the related compounds and their applications to
the organic synthesis also could be found.6
pyridinone derivative 5 (Scheme 1B).8 In this Letter, we describe
an application of this methodology to the synthesis of the core ring
system of awajanomycin (1), which has anti-cancer activity.
Awajanomycin (1) was isolated in 2006 from extracts of the mar-
ine-derived fungus Acremonium sp. AWA16-1 by Jang et al., and
reported to possess cytotoxic activity against A549 cells
(IC50 = 27.5
are: (i)a bicyclo[3.2.1]-ring system includinga
tam; (ii) four adjacent asymmetric centers (C1, C8, C5, and C4); (iii) a
l
g/mL).9 The structural features of awajanomycin (1)
-lactoneand a d-lac-
c
tertiaryalcoholat the a-positionof c-lactoneand d-lactam(C1–OH);
and (iv) an axially oriented C4-methyl group (Fig. 1).10
Due to its unique structure and difficulties in the stereo-con-
trolled introduction of stereogenic centers, total synthesis of 1 is
yet to be reported; in addition the absolute configuration and rel-
ative stereochemistry of the allylic alcohol of 1 have, so far, also not
been determined.
During our ongoing research to develop novel methods for the
introduction of functional groups in heterocyclic compounds, we
reported the regioselective addition of the acetate unit into 2-pyrid-
inone derivatives in the presence of catalytic amounts of Lewis acid.7
In particular, we successively carried out both the C4-selective func-
tionalization of N-substituted-3-methoxycarbonyl-2-pyridinone
derivatives 2a and 2b (Scheme1A) and theintroduction of an acetate
unit into the C6-position of N-substituted-5-methoxycarbonyl-2-
The retrosynthetic analysis of 1 is shown in Scheme 2. In this
convergent strategy, 1 could be synthesized from 1-decen-3-ol
(8) and the core ring system 9 by a cross-metathesis reaction.
The vinyl group of 9 could be prepared from the ethoxycarbonyl
group of 10, by sequential reduction of the ester and dehydration
of the resultant alcohol. We designed two synthetic strategies to
synthesize 10. In first route, acetal 11a, sulfide 11b, or the sul-
fone 11c was postulated as precursors to introduce the C6-
methyl group. Epoxide 12 was envisioned as precursor to 10 in
the second strategy. All these precursors 11a–c and 12 could
be obtained from the enamine 13, which was projected to arise
* Corresponding author. Tel.: +81 22 795 6867; fax: +81 22 795 6864.
E-mail address: hiroya@mail.tains.tohoku.ac.jp (K. Hiroya).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.141

2116
K. Hiroya et al. / Tetrahedron Letters 50 (2009) 2115–2118
[A]
CO2Et
OTBS
CO2Me
O
CO2Me
O
Lewis acid,
CO2Me
OEt
EtO2C
+
N
R
N
R
N
R
O
2a: R = Bn
2b: R = Boc
4a: R = Bn
4b: R = Boc
3a: R = Bn
3b: R = Boc
For 2a: Et2AlCl (1,1 eq.), −40 °C, 2 h: 3a (40%) and 4a (11%)
For 2b: Me3Al (0.15 eq.), −78 °C, 1.5 h: 3b (56%) and 4b (0%)
3a and 3b were isolated as a mixture of diastereomers (cis:trans = ca. 1:10)
[B]
CO2Et
OTBS
OEt
MeO2C
EtO2C
Me3Al (0.05 eq.),
MeO2C
MeO2C
+
N
O
CH2Cl2, −78 °C, 3 h
N
O
N
O
Boc
Boc
5
Boc
6 (19%)
7 (71%)
Scheme 1.
O
EtO2C
7
EtO2C
SO Ph
14
2
O
N
O6
OH
CO2Me
CO2Me
O
3
OH
O
NaH,Ph
2
NH
HO
1
5
4
THF, −78 °C, 1 h
N
8
N
O
84%
Me
Bn
3a
Bn
Awajanomycin (1)
13a
(cis:trans = 1:10)
Figure 1.
OMe
nOe
Bn
O
1) H2, Pd-C, AcOEt, r.t., 6.5 h, 96%
2) KOH, MeOH-H2O, 0 °C to r.t.
2 h, 69%
H
O
N
H
from the stereoselective hydroxylation reaction of either
O
a
-methoxycarbonyl-d-lactam 3a or 3b.
We selected 3a7b,8 as the starting material for the first synthetic
3) EDCI, DMAP, CH2Cl2, 0 °C to r.t.
1.5 h, 70%
H
15
O
trial. Installation of the hydroxyl group was carried out using N-sul-
fonyloxaziridine 1411 in the presence of NaH, and afforded 13a as a
sole product in 84% yield. The stereochemistry of the hydroxyl group
in 13a was determined by nOe experiment on 15, which was
converted from 13a by reduction of the double bond, selective
hydrolysis of the ethyl ester, and lactone ring formation (Scheme 3).
Scheme 3.
With the desired 13a in hand, the next task was functionaliza-
tion of the enamine moiety. Fortunately, bicyclic acetal 1612 was
O
O
OH
O
O
O
N
O
R1
HO
N
R1
1
+
HO
8
EtO2C
Me
9
Me
10
EtO2C
HO
OH
CO2Me
R2
N
O
R1
EtO2C
EtO2C
OH
CO2Me
11a: R2 = OMe
11b: R2 = SPh
11c: R2 = SO2Ph
CO2Me
O
10
N
O
N
R1
R1
EtO2C
OH
3a (R1 = Bn)
or
3b (R1 = Boc)
13
CO2Me
O
N
R1
O
12
Scheme 2.

K. Hiroya et al. / Tetrahedron Letters 50 (2009) 2115–2118
2117
EtO2C
O
OH
CO2Me
Sc(OTf)3, PhSH
MCPBA
O
O
MeOH, 60 °C, 1 h
34%
MeCN, 50 °C, 5 h
49%
N
Bn
HO
N
O
EtO2C
OMe
Bn
16
13a
O
O
for 17a
O
O
O
O
MCPBA
N
N
Bn
HO
HO
Bn
R1
CH2Cl2, 0 °C to r.t., 4 h
quant.
SO2Ph
EtO2C
EtO2C
R2
18
17a: R1 = SPh, R2 = H
17b: R1 = H, R2 = SPh
17a:17b = 2:1
O
O
O
17a
Reagent B
THF, −78 °C to r.t.
Reagent A
N
HO
Bn
or
16
THF, −78 °C to r.t.
EtO2C
18
19 Me
Reagent A: Me2CuLi-BF3 or Me2Cu(CN)Li2-BF3
Reagent B: Me2Zn-Zn(OTf)2 or Me2Zn-AgOTf or Me2Cu(CN)Li2-BF3 or MeMgBr-ZnCl2
Scheme 4.
EtO2C
OTBS
CO2Me
Me3Al (0.05 eq.),
OEt
2b
CH2Cl2, −78 °C, 1.5 h
N
OTBS
O
Boc
20
N
Ph
SO2Ph
KF, 18-crown-6,
14
MeCN, 30 °C, 6.5 h
55% (2 steps)
EtO2C
O
OH
CO2Me
N
NaH,Ph
SO Ph
14
2
Oxone, NaHCO3
3b
(cis:trans = 1:10)
acetone-H2O-CH2Cl2 (3:2:2)
r.t., 2 h, 54%
THF, −78 °C, 1 h
N
O
69%
Boc
13b
EtO2C
CO2Me
O
OR
CO2Me
N
AlMe2
Me3Al (6.0 eq.)
TMSO
EtO2C
3
H
H
O
CH2Cl2, −40 °C, 2 h
N
O
73%
CO2, CH4
(Me)2CCH2
O
Boc
AlMe3
A
21: R = H
22: R = TMS
TMSCN, THF
reflux, 6.5 h, 81%
CO2Me
CO2Me
1) PDC, MS 3Å, CH2Cl2
reflux, 3.5 h, 69%
O
3
OTMS
NH
H2O
TMSO
EtO2C
N
O
6
5
O
2) NaBH4, MeOH, −40 °C
2 h, 39% (23: 15%)
HO
AlMe2
EtO2C
Me
Me
Al
Me
23
Me
B
O
O
7
O
O
O
O
NH
2
HO 1
HF
NH
TMSO
EtO2C
MeCN
0 °C, 2.5 h
56%
4
5
4
EtO2C
8
Me
Me
24
25
Scheme 5.

2118
K. Hiroya et al. / Tetrahedron Letters 50 (2009) 2115–2118
obtained from the reaction of 13a with MCPBA in methanol. This
product 16 was then converted to the corresponding sulfides 17a
and 17b (2:1) by reaction with Sc(OTf)3 and thiophenol.13 Sulfide
17a was finally oxidized by MCPBA to afford sulfone 18 in quanti-
tative yield (Scheme 4).
In conclusion, we successfully synthesized the core ring system
of awajanomycin in seven steps from 2b. Synthesis of 25 in an opti-
cally active form and total synthesis of awajanomycin are under-
way in our laboratory.
Installation of the methyl group at the C6-position proved more
challenging. Neither methyl cuprate (Me2CuLi–BF3) nor the higher-
order cuprate [Me2Cu(CN)Li2–BF3] did produce the desired product
19 from compound 16.14 Reaction of either sulfide 17a or sulfone
18 with the methyl anion equivalents [Me2Zn–Zn(OTf)2,15
Me2Zn–AgOTf, Me2Cu(CN)Li2–BF3,14 or MeMgBr–ZnCl216] did not
provide satisfactory results, and only recovery or decomposition
of the starting material was observed (Scheme 4).
References and notes
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2003, 59, 2953–2989.
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A.; Sandoval-Chavez, C.; Herson, P.; Daran, J.-C. Angew. Chem., Int. Ed. 2008, 47,
6843–6846; (b) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
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Fujita, R.; Watanabe, K.; Ikeura, W.; Ohtaka, Y.; Hongo, H.; Harigaya, Y.;
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Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 2000, 41, 8317–8321; (g) Afarinkia,
K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111–9171.
and references cited therein.
These disappointing results let us to focus on our second strat-
egy; Boc-carbamate 3b was selected as starting material. The
hydroxylation reaction of 3b was carried out under the above-de-
scribed conditions, and 13b was obtained as the sole product in
69% yield (Scheme 5). Alternatively, 13b could be prepared from
20, obtained by the reaction of 2b with TBS-ketene acetal catalyzed
by Me3Al without acidic workup,8 by reaction with 14 in the pres-
ence of KF and 18-crown-617 (overall yield of 55%). The stereose-
lective epoxidation of 13b was conducted by DMDO prepared
in situ18 and epoxide 21 was isolated as a single isomer in 54%
yield. The epoxide-opening reaction in 21 failed with either Me3Al
or methyl cuprate, even in the presence of an additive (e.g., BF3ÁOE-
14
t2,19a TMSOTf,19b H2O19c for the former reagent, or BF3ÁOEt2 for
the latter reagent) and the decomposition of 21 was observed in
these cases. This difficulty could be overcome by protection of
the C3-hydroxyl group. When TMS-ether 22 (prepared from 21
and TMSCN20) was reacted with excess Me3Al, the methyl group
could be installed in a regioselective and stereoselective manner,
and the desired alcohol 23 was obtained in 73% yield as a sole
product. The methyl group at C6 in 23 was assumed to be axial,
as unambiguous stereochemical assessment could not be obtained
at this point (see below). In this reaction, three steps may be in-
volved: (i) removal of Boc group with the action of Me3Al to pro-
duce A; (ii) Me3Al-coordinated epoxide opening by the lone pair
on the nitrogen atom to give iminium cation B; and (iii) incorpora-
tion of the methyl group in an intramolecular manner to B from an
axial direction (Scheme 5).
´
´
5. (a) Sosnicki, J. G. Tetrahedron Lett. 2006, 47, 6809–6812; (b) Sosnicki, J. G.
Tetrahedron Lett. 2005, 46, 4295–4298.
6. (a) Sasaki, Y.; Niida, A.; Tsuji, T.; Shigenaga, A.; Fujii, N.; Otaka, A. J. Org. Chem.
2006, 71, 4969–4979; (b) Niida, A.; Mizumoto, M.; Narumi, T.; Inokuchi, E.;
Oishi, S.; Ohno, H.; Otaka, A.; Kitaura, K.; Fujii, N. J. Org. Chem. 2006, 71, 4118–
4129; (c) Niida, A.; Tanigaki, H.; Inokuchi, E.; Sasaki, Y.; Oishi, S.; Ohno, H.;
Tamamura, H.; Wang, Z.; Peiper, S. C.; Kitaura, K.; Otaka, A.; Fujii, N. J. Org. Chem.
2006, 71, 3942–3951; (d) Amat, M.; Llor, N.; Huguet, M.; Molins, E.; Espinosa, E.;
Bosch, J. Org. Lett. 2001, 3, 3257–3260; (e) Brewster, A. G.; Broady, S.; Hughes,
M.; Moloney, M. G.; Woods, G. Org. Biomol. Chem. 2004, 2, 1800–1810.
7. (a) Hiroya, K.; Jouka, R.; Katoh, O.; Sakuma, T.; Anzai, M.; Sakamoto, T. Arkivoc
2003, viii, 232–246; (b) Hiroya, K.; Kawamoto, K.; Sakamoto, T. Synlett 2006,
2636–2640.
8. Hiroya, K.; Kawamoto, K.; Inamoto, K.; Sakamoto, T.; Doi, T., in preparation.
9. Jang, J.-H.; Kanoh, K.; Adachi, K.; Shizuri, Y. J. Nat. Prod. 2006, 69, 1358–1360.
10. In this Letter, the numbering of the atoms of awajanomycin (1) was done
following the IUPAC rules, which is different from the numbering written in
Ref. 9. IUPAC name for awajanomycin (1) is (E)-1-hydroxy-8-(3-hydroxyundec-
1-enyl)-4-methyl-6-oxa-3-azabicyclo[3.2.1]octane- 2,7-dione.
The hydroxyl group on C5 was inverted by an oxidation/reduc-
tion sequence to afford lactone 24 and recovered 23 in 39% and 15%
yields, respectively. The axial configuration of the methyl group on
C4 in 24 was determined by a NOESY spectrum. The 1H NMR and
13C NMR spectra of 25 (obtained by treatment of 24 with HF in ace-
tonitrile at 0 °C) were identified primarily from the reported val-
ues.9 We thereby furnished the synthesis of a core ring system of
awajanomycin (Table 1).
11. Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. Coll. 1993, 8, 546–550
(1988, 66, 203À207).
12. The stereochemistry of methoxy group in 16 could not be determined by either
1H NMR or NOESY spectrum.
Table 1
1H NMR and 13C NMR spectral data for 1 and 25 in DMSO-d6
13. Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809–823.
14. (a) Ibuka, T.; Yamamoto, Y. In Organocopper Reagents: A Practical Approach;
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Ishibuchi, S.; Ikematsu, Y.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1991, 32,
3523–3526; (c) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573–582; (d)
Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am. Chem. Soc. 1988, 110, 4834–
4835; (e) Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron 1986, 42, 5607–
5619; (f) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S. L. Tetrahedron
Lett. 1984, 25, 5959–5962.
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6839; (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett. 2000, 2, 1971–1973.
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Q.; Tang, X.; Chen, A. Q. Synth. Commun. 2000, 30, 2259–2268.
Carbon number
1H NMR d (multiplicity, J)
13C NMR d
1a
25b
1a
25b,c
1
2
—
—
—
—
77.1
165.9
—
51.6
79.6
172.5
43.7
18.1
—
75.8
165.1
—
50.9
78.6
171.9
38.4
17.6
—
3-NH
4
5
7
8.20 (s)
3.68 (d, 6.7)
4.64 (s)
8.21 (br s)
3.68 (m)
4.62 (t, 1.8)
—
2.93 (dd, 9.9 and 4.5)
1.19 (d, 6.9)
6.26 (s)
—
8
3.30 (d, 6.4)
1.22 (d, 6.7)
5.92 (d, 4.1)
C4-Me
C1-OH
17. Artamkina, G. A.; Kovalenko, S. V.; Beletskaya, I. V.; Reutov, O. A. J. Organomet.
Chem. 1987, 329, 139–150.
18. Murray, R. W.; Singh, M. Org. Synth. Coll. 1997, 9, 288–293 (1997, 74, 91À96).
19. (a) Fotsch, C. H.; Chamberlin, A. R. J. Org. Chem. 1991, 56, 4141–4147; (b)
Crawley, G. C.; Briggs, M. T. J. Org. Chem. 1995, 60, 4264–4267; (c) Miyazawa, M.;
Ishibashi, N.; Ohnuma, S.; Miyashita, M. Tetrahedron Lett. 1997, 38, 3419–3422.
20. Mai, K.; Patil, G. J. Org. Chem. 1986, 51, 3545–3548.
a
Values were reproduced from Ref.9 (750 MHz for 1H NMR and 250 MHz for 13C
NMR).
b
c
600 MHz for 1H NMR and 150 MHz for 13C NMR.
Assignment of 13C-signals was carried out using HMQC and HMBC spectra.