Synthesis of N-hydroxyenamide, a potential precursor of chartelline

Article abstract of DOI:10.1016/j.tetlet.2007.11.155

In our synthetic plan for chartelline A-C, a compound including N-hydroxyenamide moiety was designed as an important intermediate. Synthesis of the required N-hydroxyenamide by N-acylation of a suitable oxime derivative has been developed using model compounds.

Full text of DOI:10.1016/j.tetlet.2007.11.155

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 594–597
Synthesis of N-hydroxyenamide, a potential precursor of chartelline
Shigeo Kajii, Toshio Nishikawa *, Minoru Isobe
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 21 November 2007; accepted 27 November 2007
Available online 3 December 2007
Abstract
In our synthetic plan for chartelline A–C, a compound including N-hydroxyenamide moiety was designed as an important inter-
mediate. Synthesis of the required N-hydroxyenamide by N-acylation of a suitable oxime derivative has been developed using model
compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: N-Hydroxyenamide; Oxime; Chartelline; Imidazole
Chartelline A and its analogues are unique members of a
marine alkaloid family isolated in the 1980s from a marine
bryozoan, Chartella papyracea, by Christophersen and
co-workers (Fig. 1).1 Chartelline A, which includes indole-
nine, b-lactam, and imidazole (three biologically important
heterocycles), linked together by an unsaturated 10-mem-
bered ring, has to date not been reported to have any
significant biological activity. Nevertheless, the novel struc-
ture of the compound has made it a challenging synthetic
target for organic chemists. Our attempts to synthesize this
class of natural products has thus far resulted in the devel-
opment of an efficient methodology for the preparation of
spiro-b-lactam attached to an indolenine moiety, a core
structure of chartelline A–C alkaloids.2,3 The first total syn-
thesis of chartelline C by Baran et al.4 and extensive reports
toward the synthesis of chartelline alkaloids from the
Weinreb5 and Magnus6 group has prompted us to disclose
our recent synthetic efforts directed toward the synthesis of
these compounds.
Scheme 1 outlines our strategies for the synthesis
of chartelline A–C based on our previously reported
(b)
Ns
(a)
O
X
1
O
N
R
2
N
R
1 - 3
Br
O
N
H
Cl
1
Br
N
H
R
2
N
N
R
I
Br
(a)
(b)
OR
N
H
Br
N
OR
NH
1
1
2
2
2
N
chartelline A (1)
chartelline B (2)
chartelline C (3)
R = Br, R = Br
O
X
1
1
HOOC
R
R
R = Br, R = H
2
2
1
N
N
R
R
R = H, R = H
I
Br
Br
N
H
N
H
Fig. 1. Structure of chartelline alkaloids.
Br
N
H
N
H
Br
II
III
*
Corresponding author. Tel.: +81 052 789 4115; fax: +81 052 789 4111.
Scheme 1. Strategies for the synthesis of chartelline A–C.
E-mail address: nisikawa@agr.nagoya-u.ac.jp (T. Nishikawa).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.155

S. Kajii et al. / Tetrahedron Letters 49 (2008) 594–597
595
spiro-b-lactam chemistry. This methodology implements
nucleophilic substitution at the amide nitrogen by the
carbon atom at the 3 position of indole.3 Employing this
methodology for the formation of b-lactam in a trans-
annular manner requires a 12-membered macrolactam
containing a N-hydroxyenamide moiety, viz. compound I.
However, there are few reports regarding the synthesis of
N-hydroxyenamide.7,8 Our retrosynthetic consideration
led us to two disconnections that potentially could give
the desired N-hydroxyenamide (compound I); (a) a direct
intramolecular coupling between hydoroxamic acid and
vinyliodide (compound II), or (b) N-acylation of alkyl-
oxime (compound III). Since our preliminary experiments
regarding route (a) were unsuccessful,2,9 our attention
was turned to route (b).
Our studies commenced with a model experiment for N-
acetylation of O-benzyl oxime 5a prepared from phenyl-
acetaldehyde (Table 1). The reaction proceeded smoothly
in refluxing dichloromethane to afford benzyloxyenamide
6a in 85% yield (Table 1, entry 1).10 However, deprotection
of the benzyl group by hydrogenolysis (H2, Pd/C, AcOEt)
failed due to preferential reduction of the C–C double
bond. To find a suitable protective group for hydroxy-
enamide, several oximes 5b–e11 were exposed to the same
N-acetylation condition affording the corresponding
N-alkoxyenamides 6b–e (entries 2–5).12 The low yields for
the Dmb (3,4-dimethoxybenzyl)- and SEM-protected
hydroxyenamide 6c and 6d may be caused by the labile
nature of the protective group under acidic conditions.
After conducting the deprotection experiments, we found
that the allyl group in compound 6e was smoothly depro-
tected with palladium(0) catalyst in the presence of mor-
pholine affording the desired product in 68% yield (entry
5). The forgoing results encouraged us to synthesize
N-allyloxyenamide indole 6f (entry 6). In this specific case,
the addition of molecular sieves (MS 3A) improved the
yield.13 Deprotection of the allyl group was carried out
under the conditions mentioned above in good yield.
Based on the above results, we attempted to synthesize
N-allyloxyenamide appended to an imidazole unit found
in the chartelline alkaloids (Table 2).14 Surprisingly, the
oxime containing N-benzylimidazole 8a did not react when
treated with acetyl chloride at reflux in dichloromethane
(entry 1), while the same conditions applied to compound
Table 2
Synthesis of N-allyloxyenamide containing imidazole
O
OAllyl
N
1
1
OAllyl
N
R
N
R
N
3
3
R
R
Cl
2
2
R
R
O
MS 3A, CH2Cl2
reflux
N
N
COOEt
COOEt
9a-e
8a-c
Entry
Oxime
R1 R2
Bn
Bn Br
Acid chloride
R3
Product Yield (%)
1
2
3
4
8a
8b
8c
8c
H
4a
Me
9a
9b
9c
9d
0
13a
47
48
Me
Me
PhCH2
H
H
Br
Br 4c
CH
2
5
8c
H
Br
9e
39b,c
N
Boc
4b
a
b
c
Starting material was recovered in 74%.
Starting material was recovered in 27%.
After treatment with TsOH in aq. CH3CN.
Table 1
N-Acylation of oxime derivatives
N
-acylation of
deprotection
O
O
O
oxime derivatives
+
Ph
Ph
Ph
R1
Cl
N
R1
N
R1
N
CH Cl
OR2
OR2
OH
7a,b
2
2
reflux
4a,b
5a-e
6a-f
Entry
N-Acylation of oxime derivatives
R2
Product
Deprotection
R1
Yield (%)
Conditions
Result
1
2
4a
Me
5a
5b
Bn
6a
6b
85
56
H2, Pd–C/EtOAc
See the text
Me
PMB
DDQ/CH2Cl2–H2O
CAN/aq CH3CN
Decomposed
Decomposed
3
4
5
Me
Me
Me
5c
5d
5e
Dmb
SEM
Allyl
6c
6d
6e
35
30
78
DDQ/CH2Cl2–H2O
TBAF/THF
Pd2[dba]3, Ph3P, morpholine/THF
Decomposed
7a 13%
7a 68%
CH
2
6
5e
Allyl
6f
45 (58)a
Pd2[dba]3, Ph3P, morpholine/THF
7b 75%
N
Boc
4b
The yield was obtained in the presence of MS 3A.
a

596
S. Kajii et al. / Tetrahedron Letters 49 (2008) 594–597
(c) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159–
3166.
6. Black, P. J.; Hecker, E. A.; Magnus, P. Tetrahedron Lett. 2007, 48,
6364–6367.
7. To the best of our knowledge, there is only one report regarding the
synthesis of cycloalkoxy enamide, see: Lee, V. J.; Woodward, R. B. J.
Org. Chem. 1979, 44, 2487–2491.
8. Enamide has been synthesized by N-acylation of oxime in the
presence of iron as a reducing agent, see: (a) Barton, D. H. R.; Zard,
S. Z. J. Chem. Soc., Perkin Trans. 1 1985, 2191–2192; (b) Laso, N. M.;
Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 1605–
1608.
9. We attempted copper-catalyzed coupling of hydroxamate with
vinylhalide under the conditions developed for enamide synthesis.
For example, see: (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S.
L. . Org. Lett. 2003, 5, 3667–3669; (b) Shen, R.; Lin, C. T.; Bowman,
E. J.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125,
7889–7901.
10. All reactions in Tables 1 and 2 gave E isomers exclusively. The
geometry was determined by the coupling constant, J = 14–15 Hz.
11. O-Substituted hydroxylamines were prepared from N-hydroxyl-
phthalimide by alkylation or Mitsunobu reaction with the corres-
ponding alcohol. See Ramsay, S. L.; Freeman, C.; Grace, P. B.;
Redmond, J. W.; MacLeod, J. K. Carbohydr. Res. 2001, 333, 59–
71.
12. Typical procedure of N-acylation of oxime: To a solution of O-benzyl
oxime 5a (210 mg, 0.932 mmol) in CH2Cl2 (10.0 ml) at rt was added
acetyl chloride (0.27 ml, 3.73 mmol). After refluxing the reaction
mixture for 24 h, the reaction mixture was treated with saturated
NaHCO3 solution, and extracted with CH2Cl2 (Â2). The combined
organic extracts were washed with H2O and brine, dried over Na2SO4
and concentrated. The residue was purified by silica gel column
chromatography (AcOEt–hexane = 1:9) to afford N-benzyloxy-
enamide 6a (222 mg, 85%) as a colorless oil.
8b gave a poor yield of the corresponding product 9b along
with a considerable amount of the starting material 8b
(entry 2). Interestingly, these results indicate that substitu-
tion of the imidazole ring might affect the reactivity of the
oxime toward N-acylation. The N-benzylimidazole 8a
might rapidly react with acetyl chloride to form an acyl
imidazolium cation, which prevents further N-acylation
of the oxime through the high-energy dicationic intermedi-
ate.15 On the other hand, the bromo substitution in com-
pound 8b decreases the nucleophilicity of the imidazole,
which probably hinders the corresponding acyl imidazo-
lium cation to be formed. We anticipated that debenzylated
imidazole 8c would react with acyl chlorides to form acyl
imidazole, not acyl imidazolium cation, which might allow
N-acylation of the oxime. As expected, N-acylation of
compound 8c with acetyl chloride and phenylacetyl chlo-
ride gave the corresponding allyloxyenamides 9c16 and
9d, respectively, in moderate yields (entries 3 and 4). When
the reaction was carried out using phenylacetyl chloride, an
unstable less polar product was observed by TLC analy-
sis.17 Upon purification by silica gel chromatography this
compound was converted to the desired product 9d. When
the same oxime 8c was reacted with indoleacetyl chloride
4b, the corresponding allyloxyenamide 9e18 could be
obtained after treatment with TsOH in aqueous CH3CN.19
Compound 9e has a structure similar to the one found in
compound I depicted in Scheme 1 (Table 2, entry 5).
Although these model experiments gave E-enamides exclu-
sively, intramolecular cyclization would afford Z-enamide
due to the strained structure of cyclic E-enamide.
Compound 6a: 1H NMR (CDCl3, 400 MHz): d 2.19 (3H, s, –CH3),
4.98 (2H, s, –CH2–), 6.30 (1H, d, J = 14.5 Hz, –CH@CH–Ph), 7.17–
7.46 (10H, m, aromatic), 7.76 (1H, d, J = 14.5 Hz, –CH@CH–Ph).
HRMS (FAB) (M+H)+ calcd for C17H18NO2 268.1338, found
268.1347.
Compound 6b: 1H NMR (CDCl3, 300 MHz): d 2.16 (3H, s, –CH3),
3.84 (3H, s, –O–CH3), 4.91 (2H, s, –CH2–), 6.30 (1H, d, J = 15 Hz,
–CH@CH–Ph), 6.96 (2H, d, J = 9 Hz, PMB), 7.17–7.42 (7H, m,
aromatic), 7.76 (1H, d, J = 15 Hz, –CH@CH–Ph). HRMS (FAB)
(M+H)+ calcd for C18H20NO3 298.1443, found 298.1422.
Compound 6e: 1H NMR (CDCl3, 300 MHz): d 2.28 (3H, s, –CH3),
4.50 (2H, d, J = 6 Hz, –CH2–CHCH2), 5.42 (1H, br d, J = 11 Hz,
–CH@CHAHB), 5.48 (1H, dd, J = 17, 1.5 Hz, –CH@CHAHB), 6.05
(1H, ddt, J = 17, 11, 6 Hz, –CH@CH2), 6.21 (1H, d, J = 15 Hz,
–CH@CH–Ph), 7.16–7.39 (5H, m, –Ph), 7.71 (1H, d, J = 15 Hz,
–CH@CH–Ph). HRMS (FAB) (M+H)+ calcd for C13H18NO2
218.1181, found 218.1155.
In summary, a new synthetic method for the formation
of N-hydroxyenamide by N-acylation of oxime has been
developed. The current method should be applicable to
the synthesis of the 12-membered macrolactam I, a possible
precursor of chartelline A–C. Further synthetic studies
toward chartelline along the synthetic pathway outlined
in Scheme 1 are currently underway in our laboratories.
Acknowledgements
This work was financially supported by PRESTO, JST,
Astellas Foundation for Research on Medicinal Resources,
and Grant-in-Aid for the 21st century COE program and
Global-COE program from MEXT.
Compound 6f: IR (KBr) mmax 2977, 1728, 1683, 1645, 1458, 1370,
1136 cmÀ1 1H NMR (CDCl3, 400 MHz): d 1.68 (9H, s, –Boc), 2.69
.
(3H, s, –Me), 3.96 (2H, s, –CH2–), 4.55 (2H, d, J = 6 Hz, –CH2–
CHCH2), 5.46 (1H, d, J = 11 Hz, –CH2CH@CHAHB), 5.50 (1H, d,
J = 19 Hz, –CH2CH@CHAHB), 6.09 (1H, m, –CH2–CH@CH2), 6.24
(1H, d, J = 14.5 Hz, –CH@CH–Ph), 7.15–7.36 (7H, m, aromatic),
7.48 (1H, d, J = 7 Hz, indole), 7.69 (1H, br d, J = 14.5 Hz,
–CH@CH–Ph), 8.10 (1H, d, J = 7 Hz, indole). 13C NMR (CDCl3,
100 MHz): d 14.4, 28.3, 28.8, 75.6, 83.7, 111.0, 111.1, 115.5, 117.9,
121.6, 122.6, 123.6, 125.9, 126.8, 128.7, 129.7, 130.5, 135.4, 135.7,
135.8, 150.6, 168.7. Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77;
N, 6.27. Found: C, 72.63; H, 6.80; N, 6.23.
References and notes
1. (a) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.; Larsen, C.; Anthoni,
U.; Christophersen, C. J. Am. Chem. Soc. 1985, 107, 4542–4543; (b)
Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen,
C. J. Org. Chem. 1987, 52, 4709–4712.
2. Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett. 2004, 33, 440–441.
3. Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025–2027.
4. (a) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed.
2005, 44, 3714–3717; (b) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc.
2006, 128, 14028–14029.
13. We assume that molecular sieves scavenge hydrochloric acid gener-
ated during the reaction. The acid is thought to cause decomposition
of the product and/or substrate. On the other hand, when Et3N or
pyridine was added for the same purpose, the yield of the product
decreased.
5. (a) Lin, X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42, 2631–2633; (b)
Sun, C.; Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779–1781;

S. Kajii et al. / Tetrahedron Letters 49 (2008) 594–597
597
14. Oximes 8a–c were prepared from the corresponding aldehydes. The
synthesis of these aldehydes will be reported elsewhere.
15. Dicationic intermediate referred to in the text.
HRMS (FAB) (M+H)+ calcd for C16H23BrN3O4 402.0851, found
402.0889.
17. The structure of the less polar product is assumed to be the
corresponding enamide, which has an N-phenylacetyl group attached
to the imidazole ring.
AllylO
Bn
N
N
18. Compound 9e: IR (KBr) mmax 3203, 2978, 1729, 1652, 1460, 1358,
1257, 1137 cmÀ1 1H NMR (CD3OD, 400 MHz): d 1.20 (3H, t,
.
O
N
J = 7 Hz, –OCH2–CH3), 1.56 (6H, br s, dimethyl), 1.72 (9H, s, Boc),
2.58 (3H, s, –CH3), 4.01 (2H, br s, –CH2–), 4.15 (2H, q, J = 7 Hz,
–O–CH2–CH3), 4.62 (2H, br s, –CH2–CH@CH2), 5.50 (1H, br d,
J = 10.5 Hz, –CH@CHAHB), 5.60 (1H, br d, J = 17 Hz,
–CH@CHAHB), 6.19 (1H, br d, J = 14.5 Hz, –CH@CH–), 6.20 (1H,
br s, –CH@CH2), 7.20 (1H, t, J = 7 Hz, indole), 7.24 (1H, t, J = 7 Hz,
indole), 7.47 (1H, d, J = 7 Hz, indole), 7.51 (1H, br d, J = 14.5 Hz, –
CH@CH–), 8.12 (1H, d, J = 8 Hz, indole). HRMS (FAB) (M+H)+
calcd for C30H38BrN4O6 631.1954, found 631.1928.
COOEt
O
16. Compound 9c: IR (KBr) mmax 3172, 2982, 1727, 1652, 1550, 1437,
1388, 1258, 1143 cmÀ1 1H NMR (CDCl3, 400 MHz): d 1.19 (3H, t,
.
J = 7 Hz, –OCH2–CH3), 1.58 (6H, s, dimethyl), 2.44 (3H, s, –Ac),
4.13 (2H, q, J = 7 Hz, –O–CH2–CH3), 4.47 (2H, d, J = 7 Hz, –CH2–
CH@CH2), 5.47 (1H, d, J = 10 Hz, –CH@CHAHB), 5.53 (1H, d,
J = 17 Hz, –CH@CHAHB), 6.09 (1H, m, –CH@CH2), 6.20 (1H, d,
J = 14.5 Hz, –CH@CH–), 7.77 (1H, d, J = 14.5 Hz, –CH@CH–).
13C NMR (CDCl3, 100 MHz): d 14.2, 20.8, 26.3, 43.5, 60.9, 75.8,
100.0, 114.9, 118.7, 122.4, 125.3, 129.8, 143.9, 169.9, 176.6.
19. Before the acid treatment, the product was an allyloxyenamide
containing N-indoleacetyl imidazole, which could be isolated by silica
gel TLC.