10th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-10). 1-30 November 2006. http://www.usc.es/congresos/ ecsoc/10/ECSOC10.htm & http://www.mdpi.org/ecsoc-10/
[a014]
Université des Sciences et Technologies de Lille
UMR CNRS 8009 COM
Synthèse Organique, Réactivité, Fonctionnalisation
First Total Synthesis of Narceine Imide Axel Couture,* Eric Deniau, Pierre Grandclaudon, Marc Lamblin UMR 8009 "Chimie Organique et Macromoléculaire", associée à l'ENSCL, Laboratoire de Chimie Organique Physique, Bâtiment C3(2), Université des Sciences et Technologies de Lille 1, F-59655 Villeneuve d'Ascq Cédex, France *
[email protected]
Introduction The creeper Fumaria parviflora Lam (Fumariaceae) is widespread in Pakistan where it is commonly known as Pit Papra and where its extracts are used in folk medicine as a blood purifier and as an anthelmintic, as well as in the treatment of skin diseases and diarrhea [1]. The crude alkaloidal extracts have initially indicated the presence of seventeen isoquinoline bases [2] and additionally four enelactams, i.e; narceine imide (1), fumaramidine (2), fumaramine (3) and fumaridine (4) (Fig. 1) were isolated from the strongly basic ethanolic extracts of dried plant material [3].
2
R O
O
R 1O
NH R5
OR
3
OR
Me
4
N Me
1
2
3
4
5
1
Narceine imide
R = R = Me ; R ,R = -CH2- ; R = OMe
2
Fumaramidine
R1,R2 = -CH2- ; R3 = R4 = Me ; R5 = H
3
Fumaramine
R1,R2 = R3,R4 = -CH2- ; R5 = H
4
Fumaridine
R1 = R2 = Me ; R3,R4 = -CH2- ; R5 = H
These enelactams are not generally considered to be true alkaloids but are regarded conceivably as artefacts formed during their basic extraction since their biogenetic precursors have been reported to be present in all the previously quoted Fumariaceae species [4.] In the course of our ongoing project dealing with the synthesis of a variety of compounds comprising an arylmethyleneisoindolinone unit in opened [5] or in fused models [6] (e.g. aristolactams) we became interested in the synthesis of these enelactams and we embarked on the first total synthesis of the exemplary representative narceine imide 1.
Results and Discussion 1. Retrosynthetic analysis A conceptually new synthetic approach to this enelactamic compound 1, bearing diverse and dense functionalities on the environmentally different aromatic units, has been developed and is presented in the Retrosynthetic Scheme. MeO
OMe
O
MeO
O
MeO NH OMe
N PG OMe
E1cb
O
Me
O
O
N
O
(Me)2N 1
MeO
5
OMe
O
MeO
Me N GP
+
O
N
I O
6
7
PG = protecting group
The key step was an E1cb elimination process applied to the polycyclic adduct 5 that allowed the creation of the pendant arylmethyene unit and the concomitant formation of the required dimethylaminoethyl chain present on the "southern" aromatic nucleus. Adduct 5 could be in turn assembled by reaction of the metalated isoindolinone 6 with an iminium salt deriving from a suitably substituted isoquinoline 7.
2. Construction of the Eschenmoser salt 7 The key step for the synthesis of the poly and diversely substituted isoquinolinium salt 7 was a Pomeranz-Fritsch type cyclization reaction of a suitably substituted aromatic aminoacetal 8.
O
O
NH2
O
O
N
toluene, Dean-Stark 100%
O
1) BuLi, THF, -78 °C 2) B(OMe)3
O
3) AcOH, H2O2 4) H3O+ 65%
OMe
OH O
MeI, KOH
O
EtOH, ∆ 73%
O
O
toluene, Dean-Stark
OMe O
EtO
H2NCH2CH(OEt)2
100%
OMe N
O
NaBH4 MeOH 76%
O
HN EtO
OEt
O
CH2O, NaBH3CN
O
Acetonitrile 91%
OEt
OMe
OMe Me
1) HCl 6N , rt , 24 h (74%)
O
N
EtO
O OEt
Me
3) H2 , Pd/C, EtOh (85%)
56% yield over 3 steps
OMe KOAc, I2 EtOH, ∆ 82%
Me
O
N
O
I 7
O O
2) AcCl , CH2Cl2, rt (90%)
8
N
3. Elaboration of the parent dimethoxylated isoindolinone 6 Our strategy for the construction of the five-membered lactam embedded in the isoindolinone framework was based upon the Parham cyclization process which hinges upon aromatic lithiation and subsequent reaction with an internal electrophile [7]. OH
OH Br2, AcONa, Fe
MeO
MeO
OMe Br
AcOH 65%
O
MeI, KOH
MeO
EtOH, ∆ 70%
O
Br O
OMe OMe
H2N
OMe
MeO
NaBH4, MeOH
Br
MeO
Br
96%
toluene, ∆, Dean-Stark
N PMB
NH PMB
100%
OMe ClCO2Me
MeO
OMe O
Br
BuLi
OMe
Et2O, 0 °C 70%
N
O
MeO
THF, -100 °C 61%
N PMB
PMB 6 (19% over 6 steps)
4. Synthesis of the polyaza-adduct 5 For the assembling of the congested adduct 5 we have taken advantage of the nucleophilicity of the benzylic α-aminocarbanionic species generated by basic treatment of the isoindolinone precursor 6 [8.] OMe
OMe
O
MeO
O
MeO
KHMDS
N PMB
N PMB THF, -78 °C
K
6
OMe
OMe Me
O
N
I
O
MeO N PMB OMe
O 7
Me
-78 °C 71%
5
N
O O
5. The E1cb elimination / deprotection-isomerization sequence. Total synthesis of narceine imide (1)
OMe
OMe
O
MeO
O
MeO N PMB OMe Me
MeI
N PMB OMe
EtOH, ∆
Me
O
N
I
Me
THF O
N
O
OMe
KHMDS
O
OMe
O
68% (2 steps)
O
MeO
MeO N PMB OMe
Me
N Me
NH
TFA, anisole, ∆ O
79%
O
deprotection and isomerization
E/Z (50:50)
OMe
(Z) Me
N
O O
Me Narceine imide (1)
It is noteworthy that the choice of the para-methoxybenzyl (PMB) group as the lactam protecting group was rewarded here since deprotection at high temperature under acidic conditions delivered the thermodynamically more stable (Z)-configurated natural product 1. The target alkaloid 1 was obtained with a 38% yield over the last four steps.
References [1] [2] [3] [4] [5]
Ikram, M.; Hussain, S. F. Compendium of Medicinal Plants; PCSIR: Peshawar, Pakistan, 1978. Santavy, F. in The Alkaloids; Manske, R. H. F.; Rodrigo, R., Eds; Academic Press: New York, 1979, vol. XVII, p. 385 Hussain, S. F.; Minard, R. D.; Freyer, A. J.; Shamma, M. J. Nat. Prod. 1981, 44, 169-178. Blasko, G.; Elando, V.; Sener, B.; Freyer, A. J.; Shamma, M. J. Org. Chem. 1982, 47, 880885. (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.; Rys, V. Tetrahedron Lett. 2002, 43, 2207-2210. (b) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 1997, 53, 10313-10330.
[6]
[7]
[8]
(a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. J. Org. Chem. 1998, 63, 31283132. (b) Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; Léonce, S.; Pfeiffer, B.; Renard, P. Bioorg. Med. Chem. Lett. 2002, 12, 3557-3559. Reviews: (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300–305; (b) Wakefield, B. J. The Chemistry of Organolithium Compounds, 2nd ed., Pergamon, New York, 1990; (c) Gray, M.; Tinkl, M.; Snieckus, V. In Comprehensive Organometallic Chemistry II, Abel, E. W.; Stone, F. G. A.; Wilkinson, G.; eds., Pergamon, Exeter, 1995, vol. 11, pp. 66–92; (d) Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in Heterocyclic Systems, Atanassi, O.; Spinelli, D.; eds., Italian Society of Chemistry, Rome, 2001, vol. 5, pp. 393–418; (e) Clayden, J. Organolithiums: Selectivity for Synthesis, Elsevier Science Ltd, Oxford, 2002; (f) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59–67; (g) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275–300; (h) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255–9303. Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetrahedron Lett. 1998, 39, 23192321.
