Preparation of a chiral azadiene for the synthesis of 5-aza analogues of angucyclinones

Article abstract of DOI:10.1016/j.tetlet.2011.02.084

We have developed an efficient synthesis of both enantiomers of a key azadiene for the preparation of 5-aza analogues of angucyclinones through a hetero Diels-Alder reaction. These dienes were efficiently prepared via a 4-step procedure from known and rea

Full text of DOI:10.1016/j.tetlet.2011.02.084

Tetrahedron Letters 52 (2011) 2336–2339
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of a chiral azadiene for the synthesis of 5-aza analogues
of angucyclinones
Drissa Sissouma a,b, Geoffroy Dequirez a, Sylvain Collet a, , André Guingant a,
⇑
⇑
a Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS n° 6230, 2, rue de la Houssinière, BP 92208,
44322 Nantes Cedex 3, France
b Laboratoire de Chimie Organique Structurale, UFR SSMT, Université de Cocody-Abidjan, Côte d’Ivoire
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient synthesis of both enantiomers of a key azadiene for the preparation of 5-
aza analogues of angucyclinones through a hetero Diels–Alder reaction. These dienes were efficiently pre-
pared via a 4-step procedure from known and readily available chiral diketoesters.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 November 2010
Revised 14 February 2011
Accepted 18 February 2011
Available online 26 February 2011
Keywords:
Chiral azadiene
Hetero Diels–Alder reaction
Aza-angucyclinone
Enaminone
Ester hydrolysis
The angucyclines and angucyclinones are natural products hav-
ing an angularly condensed benz[a]anthraquinone skeleton which
is biosynthetically derived from a dekaketide chain. These com-
pounds, which are secreted by Actinomycetes, often exhibit an array
of biological activities including antitumor, antiviral, antifungal
and enzyme inhibitory effects. Among the subclass of angucycli-
nones, some members display a ring B fully aromatised and a ste-
reogenic centre at C3 in ring A. A representative example is
provided by (+)-ochromycinone 1 (Scheme 1). Some years ago,
we reported the synthesis of a series of angucyclinone 5-aza-ana-
logues 4 with the aim of creating novel chemical structures with
enhanced biological activities.1 These compounds, which exhibited
encouraging cytotoxicity against MCF-7 (breast) and KB (nasophar-
ynx) cancer cell lines were efficiently prepared following a strategy
based on a regioselective hetero Diels–Alder reaction featuring
push-pull dienes 3a or 3b and a substituted 2-bromo-[1,4]naph-
thoquinone 2 (Scheme 1).
Preparation of diene (S)-3b was considered first and we thought
that diene 5 could serve as a useful equivalent since, after accom-
plishment of the [4+2]cycloaddition-aromatisation sequence
(5 + 9, Scheme 3), the ester moiety (located b to the carbonyl at
C1) was expected to be easily removed. Our strategy to reach diene
5 is pictured in retrosynthetic Scheme 2. Thus, diene 5 would be
prepared by amidination of enaminoketone 6, itself derived from
diketone 7 whose preparation had already been reported by Myers
et al. in the course of their synthesis of (+)-dynemicin A.2
In the synthetic direction (Scheme 3), condensation of (ꢀ)-men-
thylacetoacetate with trans-ethyl crotonate (tert-BuOK, tert-BuOH,
reflux) afforded an approximately 1:1 mixture of trans diastereo-
mers 7 and 8, from which 7 could be isolated by selective crystal-
lisation from toluene.3 Exposure of diketone 7 to a slight excess of
ammonium acetate in toluene at reflux was remarkably regioselec-
tive, affording a single enaminone. A 2D HMBC experiment, and an
infra-red spectroscopic study revealing the absence of an intramo-
lecular hydrogen bond, both suggested that this enaminone was
best represented by formula 6 and this was later fully ascertained
by a single-crystal X-ray analysis (Fig. 1).4,5
In order to prepare chiral variously substituted 5-aza analogues
of angucyclinones 4 (R = Me) and also to best delineate the impor-
tance of the configuration of the methyl group at C3 on the cyto-
toxic properties of these compounds, we became interested in
the preparation of diene 3b in each of its chiral non-racemic form.
Treatment of 6 with N,N-dimethylformamide dimethyl acetal
afforded diene 5 (75% yield) which was next condensed to 2-bro-
mo-quinone to afford the tetracyclic adduct 10 in 67% yield. At this
stage, attempts at saponification or hydrolysis of the (ꢀ)-menthy-
lester moiety in 10 followed by decarboxylation of the resulting b-
ketoacid to give the 5-aza-angucyclinone derivative 11 appeared
unexpectedly difficult. Indeed, we were not able to form 11 under
⇑
Corresponding authors. Tel.: +33 251 125 410; fax: +33 251 125 402 (C.S.); tel.:
+33 251 125 413; fax: +33 251 125 402 (G.A.).
E-mail addresses: sylvain.collet@univ-nantes.fr (S. Collet), andre.guingant@
univ-nantes.fr (A. Guingant).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.084

D. Sissouma et al. / Tetrahedron Letters 52 (2011) 2336–2339
2337
1
O
Me
3
O
R
O
R
O
O
O
O
O
A
MeCN, 40°C
S
S
B
+
D
C
O
N
5
N
NMe2
3
Br
OH
1
2
4
a R = H
R = Me
b
Scheme 1.
CO2R*
Me
CO2R*
CO2R*
Me
Me
O
O
O
Me
O
N
N
NH2
O
NMe2
3b
NMe2
5
6
7
(
S
)-
R* = (-)-menthyl
Scheme 2.
t-BuOK
CO2R*
CO2R*
Me
t-BuOH
CO2R*
Me
reflux, 2.5 h
O
Me
O
O
+
+
EtO2C
O
7
O
8
R* = (-)-menthyl
AcONH4 (1.2 equiv) ,
tol, reflux, 5h (85%)
DMF-DMA (2 equiv),
THF, reflux, 4h, 75%
6
5
CO2R*
Me
CO2R*
Me
O
O
O
O
O
CH3CN
50°C, 2d
+
N
67%
Br
N
O
NMe2
9
10
5
Scheme 3.
several different acidic and basic conditions, all attempts invari-
ably leading to the formation of the fully aromatised compound
12 (Scheme 4).
The adverse behaviour exhibited by compound 10 led us to de-
vise a new synthetic scheme for the formation of compound 4 fea-
turing the direct use of diene (S)-3b, the synthesis of which was
envisaged as depicted in Scheme 5.
Accordingly (Scheme 6), exposure of diketone ester 7 to meth-
anol in the presence of a catalytic amount of camphorsulphonic
acid (CSA) led to the formation of a chromatographically separable
4:1 mixture of enol ethers 15a and 16a as already described.2 Since
compound 16a was reported to return an apparently thermody-
namic 4:1 mixture of 15a and 16a when resubjected to an acidic
methanolic solution, we anticipated that the use of isopropanol in-
stead of methanol would lead to enol ether products with an im-
proved selectivity due to increased OR/CO2R⁄ interactions in 16b
versus 16a. Indeed, exposure of diketone 7 to an acidic isopropanol
Figure 1.

2338
D. Sissouma et al. / Tetrahedron Letters 52 (2011) 2336–2339
CO2R*
Me
HO
CO2H
Me
O
Me
O
O
O
O
O
O
10
N
N
N
O
11
12
Scheme 4.
CO2R*
Me
O
O
Me
O
Me
(S)-3b
7
OR
15
NH2
OR
13
14
a R = Me
b R = iPr
[R* = (-)-menthyl]
a R = Me
b R = iPr
Scheme 5.
CO2R*
Me
CO2R*
Me
ROH, CSA
rt
O
RO
R = Me, 15a:16a = 4:1
R = iPr, 15b:16b = 11:1
7
+
R* = (-)-menthyl
a R=Me; b R=iPr
OR
O
16a,b
15a,b
14a,b
DMAP, H2O, DMF, 135°C
NH3, MeOH, 70°C
13
DMF-DMA, THF, 70°C
(R)-3b
(S)-3b
8
Scheme 6.
solution afforded a 11:1 mixture of enol ethers 15b and 16b, which
furthermore were more easily separated by column chromatogra-
phy than the diastereomeric pair 15a:16a.
applied to 14b, led to an incomplete transformation and enami-
none 13 was isolated in 65–78% yield. Finally, diene (S)-3b was
reached after the treatment of 13 with DMF-DMA in THF at 70 °C
for 4 h (89%).10 In a parallel manner, enantiomeric diene (R)-3b
was prepared from diketone ester 8 by an identical sequence of
reactions.
According to the general Scheme 1, dienes (S)- and (R)-3b were
condensed with 2-bromonaphthoquinones 17a and 17b in acetoni-
trile under moderate thermal activation to provide adducts 18a
[(S)-5-aza-ochromycinone] and 18b, respectively (Scheme 7).11
In conclusion, we have reported a 5-step preparation of the chi-
ral azadienes (S)- and (R)-3b for the synthesis of chiral 5-aza ana-
logues of angucyclinones displaying an aromatised B-ring.
With 15a and 15b now in hand, we were in a position to effect
the key (ꢀ)-menthylester excision. As for b-ketoester 10 this trans-
formation proved difficult but we finally discovered that it could be
satisfactorily accomplished by heating 15a (15b) in DMF at 135 °C
for 80 h in the presence of DMAP (1 equiv) and H2O (12 equiv).6
Under these conditions, enol ethers 14a (14b) were isolated in
60% yield.7 The remaining steps towards 3b were completed as fol-
lows. Exposure of 14a to ammonia, (ca. 2 N solution in methanol)
in a sealed tube maintained at 70 °C for 2 days afforded enaminone
13 in almost quantitative yield.8,9 The same conditions, when
O
Me
R1
O
O
O
Me
OAc
O
O
O
(S)-3b
CH3CN
3b
(R)-
CH3CN
40°C, 18h
N
Br
N
50°C, 15h
R2
O
OH
58%
49%
18a
17
a
b
18b
R1=H, R2=OH
R1=OAc, R2=H
Scheme 7.

D. Sissouma et al. / Tetrahedron Letters 52 (2011) 2336–2339
2339
+ 91.7 (c 0.8, CH2Cl2). 1
H
NMR (300 MHz, CDCl3): d = 5.33 (s, 1H), 4.42 (sep, J = 5.8 Hz, 1H); 2.32–2.44 (m,
2H), 2.30–1.97 (m, 3H), 1.29 (t, J = 5.8 Hz, 6H), 1.06 (d, J = 6.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d = 199.9, 176.3, 102.6, 70.9, 45.0, 37.7, 28.8, 21.5, 21.4, 20.9.
IR (KBr) 1647, 1598, 1217 cmꢀ1. MS (EI): m/z (%) = 168 (5), 84 (100). HRMS (EI)
calcd for C10H16O2 [M+] 168.1145, found 168.1143.
(determined by chiral GC on a Lipodex E column). ½a D20
ꢁ
Acknowledgements
The authors would like to thank Dr J. Graton for IR studies and
A. Planchat for the X-ray structure of enaminone 6.
8. Pita, B.; Masaguer, C. F.; Raviña, E. Tetrahedron Lett. 2000, 41, 9829–9833.
9. Mp 128 °C. Ee 98% (determined by chiral GC on a Lipodex E column). ½a D20
ꢁ
+82.3
References and notes
(c 0.75, MeOH). 1H NMR (300 MHz, MeOD): d = 5.12 (s, 1H), 2.40–2.30 (m, 2H),
2.05–2.24 (m, 3H), 2.00–1.85 (m, 1H), 1.00 (d, J = 6 Hz, 3H). 13C NMR (75 MHz,
MeOD): d = 199.7, 178.1, 102.9, 45.1, 35.9, 29.7, 20.9. IR (KBr): 3117, 1680,
1559, 1268 cmꢀ1. MS (EI): m/z (%) = 125 (24) [M+], 83 (100). HRMS (EI) calcd for
C7H11NO [M+] 125.0835, found 125.0835.
1. (a) Collet, S.; Rémi, J.-F.; Cariou, C.; Laïb, S.; Guingant, A.; Vu, N. Q.; Dujardin, G.
Tetrahedron Lett. 2004, 45, 4911–4915; (b) Vu, N. Q.; Dujardin, G.; Collet, S.;
Raiber, E.-A.; Guingant, A.; Evain, M. Tetrahedron Lett. 2005, 46, 7669–7673.
2. Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc.
1997, 119, 6072–6094.
10. Compound (S)-3b: ½a D20
ꢁ
+295.3 (c 0.76, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d = 7.56 (s, 1H), 5.41 (s, 1H), 3.04 (s, 3H), 3.01 (s, 3H), 2.53–2.37 (m, 2H), 2.29–
2.10 (m, 2H), 2.06–1.97 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3): d = 200.1, 172.0, 152.1, 110.2, 45.0, 40.4, 38.9, 34.4, 29.4, 20.9. IR (neat):
1614–1620, 1555, 1108 cmꢀ1. MS: m/z (%) = 180 (79) [M+], 123 (85), 109 (100).
HRMS (EI) calcd for C10H16N2O [M+] 180.1263, found 180.1261. Compound (R)-
3. After two crystallisations from toluene the purity of 7 was better than 99% as
judged by HPLC analysis; ½a 2D0 +67.9 (c 0.77 MeOH) (lit.2 +66.9). Mp 186 °C (lit.2
ꢁ
180–181 °C). The diastereomeric diketone 8 was isolated as described in Ref.2
along with 6% of 7 (measured by HPLC analysis). ½a D20
ꢀ51.4 (c 0.77 MeOH). Mp
ꢁ
143 °C (lit.2 140–141 °C).
3b: ½a 2D0
ꢁ ꢀ270.7 (c 1.02, CH2Cl2). Contamination with (S)-enantiomer is due to
4. A similar regioselectivity has already been observed for enamination of b-
diketones structurally closed to 7. Foster, J. E.; Nicholson, J. M.; Butcher, R.;
Stables, J. P.; Edafiogho, I. O.; Goodwin, A. M.; Henson, M. C.; Smith, C. A.; Scott,
K. R. Bioorg. Med. Chem. 1999, 7, 2415–2425.
the fact that the starting diketone ester 8 was difficult to be obtained in pure
form and remained contaminated with some amount of 7 (cf. Ref.3).
11. Characteristic data for (S)-5-aza-ochromycinone 18a. Yellow powder, mp 159–
160 °C. 1H NMR (300 MHz, CDCl3): d = 12.12 (s, 1H), 9.51 (s, 1H), 7.73–7.67 (m,
2H), 7.33 (dd, J = 4.2, 5.5 Hz, 1H), 3.34 and 2.91 (AB part of ABX system, J = 17,6,
10,4, 4,3 Hz, 2H), 3.02 and 2.64 (AB part of ABX system, J = 15,1, 11.2, 4.5 Hz,
2H), 2.58–2.45 (m, X part of ABX systems 1H), 1.25 (d, J = 6.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d = 197.4, 187.0, 182.1, 169.7, 162.1, 151.4, 141.0, 137.5,
134.5, 128.2, 126.4, 124.6, 120.0, 115.1, 47.4, 41.6, 29.5, 21.3. IR (KBr): 1771,
5. Crystal data for enaminone 6:
C
18H29NO3, Mr = 307.43, monoclinic, P21,
a = 8.8546(5),
b = 14.1110(14), c = 7.2647(6) Å, b = 98.944(6),
V = 896.66(11) Å3, Z = 2, calcd = 1.1383 g cmꢀ3 = 0.076 mmꢀ1, F(0 0 0) = 336,
q , l
colourless block, 0.13 ꢂ 0.10 ꢂ 0.08 mm3, 2hmax = 56°, T = 298 K, 18192
reflections, 2229 unique (99% completeness), Rint = 0.0584, 206 parameters,
GOF = 1.45, wR2 = 0.1317, R = 0.0584 for 3124 reflections with I > 2r(I). CCDC
1700, 1685, 1633 cmꢀ1
C
.
MS (CI): m/z = 308 [M+H]+. HRMS (ESI) calcd for
+5 (c 0.1, CHCl3).
799310 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
18H14NO4 [M+H]+ 308.0917, found 308.0910. a 2D0
½ ꢁ
Characteristic data for (R)-18b. Dark powder, mp 192 °C. 1H NMR (300 MHz,
CDCl3): d = 9.45 (s, 1H), 8.16 (dd, J = 7.8, 1.2 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.47
(dd, J = 7.8, 1.2 Hz, 1H), 3.33 and 2.91 (AB part of ABX system, J = 17.8, 9.8,
4.2 Hz, 2H), 2.97 and 2.59 (AB part of ABX system, J = 15.1, 11.2, 3.4 Hz, 2H),
2.55–2.41 (m, X part of ABX systems 1H), 2.44 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3): d = 196.5, 181.8, 181.1, 169.6, 168.4, 151.5, 149.3,
142.5, 134.7, 133.9, 130.3, 127.3, 125.9, 125.0, 47.2, 41.5, 29.3, 21.2, 20.9. IR
(KBr): 1771, 1700, 1685, 1633 cmꢀ1. MS (CI): m/z = 350 [M+H]+. HRMS (ESI)
6. (a) Taber, D. F.; Amedio, J. C., Jr.; Gulino, F. J. Org. Chem. 1989, 54, 3474–3475;
(b) Koyama, Y.; Yamaguchi, R.; Suzuki, K. Angew. Chem., Int. Ed. 2008, 47, 1084–
1087.
7. Compound 14a: Ee 98% (determined by chiral GC on a Lipodex E column). ½a D20
ꢁ
+82.6 (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3): d = 5.29 (s, 1H), 3.62 (s, 3H),
2.37–2.43 (m, 2H), 2.30–1.97 (m, 3H), 1.01 (d, J = 6.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d = 199.7, 178.1, 102.9, 55.7, 45.1, 36.9, 29.7, 20.9. IR (KBr)
1647, 1598, 1218 cmꢀ1. MS (CI): m/z = 141.0 [M+H]+, 158.0 [M+NH4]+. HRMS
(EI) calcd for C8H12O2 [M+] 140.0837, found 140.0839. 14b: Mp 42 °C. Ee 98%
calcd for C20H16NO5 [M+H]+ 350.1028, found 350.1030. ½a 2D0
ꢀ39 (c 0.1, CHCl3)
ꢁ
(ee 88% measured by HPLC analysis on a Chiralcel OJ-H column).