Construction of the six- and five-membered aza-heterocyclic units of the isoindoloisoquinolone nucleus by parham-type cyclization sequences - Total synthesis of nuevamine

Article abstract of DOI:10.1002/ejoc.200500312

An efficient methodology for the synthesis of isoindolo[1,2-α] isoquinolones based on two Parham-type cyclizations allowing the formation of the five- and six-membered nitrogenated rings from carbamate or diacylamine precursors is described. The synthetic potential of this method has been further illustrated by the total synthesis of the alkaloid nuevamine. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500312

FULL PAPER
Construction of the Six- and Five-Membered Aza-Heterocyclic Units of the
Isoindoloisoquinolone Nucleus by Parham-Type Cyclization Sequences –
Total Synthesis of Nuevamine
Anne Moreau,[a] Axel Couture,*[a] Eric Deniau,[a] and Pierre Grandclaudon[a]
Keywords: Carbanion / Cyclization / Natural products / Total synthesis
An efficient methodology for the synthesis of isoindolo[1,2-
further illustrated by the total synthesis of the alkaloid nuev-
a]isoquinolones based on two Parham-type cyclizations al- amine.
lowing the formation of the five- and six-membered nitro-
genated rings from carbamate or diacylamine precursors is
described. The synthetic potential of this method has been
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
main categories, which differ in the nature of the carbon–
carbon bond formed in the ultimate step. Thus, generation
of the carbon–carbon bond (a) has been achieved by an
intramolecular amidoarylation reaction involving a tran-
sient N-acyliminium species obtained by treatment with
Lewis acid catalysts of α-hydroxy (X1 = OH),[4] α-alkoxy
(X1 = OMe)[5] or α-benzotriazolyl (X1 = Bt)[6] lactamic pre-
cursors 2 (retrosynthesis: Scheme 1). Formation of the car-
bon–carbon bond (a) has also been secured by an anionic
cyclization mechanism (Parham cyclization) applied to N-
[(iodoaryl)ethyl]-imides 3[7] and by a base-induced aryne-
mediated cyclization of a N-[(fluoroaryl)ethyl]isoindolinone
derivative 4.[8] The isoindolinone nucleus has also been ac-
cessed by formation of carbon–carbon bond (b) through
intramolecular Heck cyclization of aromatic enamides 5
performed in the presence of a hydride source which favors
the regiocontrolled formation of the five-membered pro-
duct.[9] Other procedures involving the cyclization of β-
phenylethylaminophthalide[10] or the palladium-catalyzed
carbonylation processes[11] have been used occasionally for
the assembling of the isoindoloisoquinolinone framework.
However, most of these methods are rather limited in scope
and have been claimed to give access only to the isoindolo-
isoquinoline skeleton of nuevamine-type alkaloids.
Thus, the α-substituted precursors 2 are generally ob-
tained from the corresponding imides (X1 = O) but the lack
of regioselectivity of this chemical transformation requires
the absolute necessity of having bare models or symmetri-
cally substituted isoindolinone parent compounds.[4–6] The
Parham cyclization process is also fraught with difficulties
associated with the regioselectivity of the aromatic metalla-
tion/cyclization sequence applied to unsymmetrically sub-
stituted imides 3.[7] At last, all models structurally related
to 1 which have been elaborated by intramolecular Heck
cyclizations are invariably alkylated at the C-12b position
Introduction
Nuevamine (1a) is the first isoindolo[1,2-a]isoquinol-
inone known to occur in nature and can still be considered
the lone representative of this class of isoquinoline alka-
loids. Initially, the structure of this natural product which
has been isolated from Berberis darwinii Hook, gathered in
southern Chile, in the vicinity of Cuidad Osorno,[1] was er-
roneously assigned but later revision led unambiguously to
structure 1a (Figure 1).[2]
Figure 1. Structure of nuevamine (1a).
This alkaloid occupies a rather peculiar place since it is
an eminent member of the isoindoloisoquinolone family
but all of the synthetic methods developed for the construc-
tion of this class of tetracyclic lactams 1 are inadequate for
the synthesis of this unique natural product. Several general
approaches to the synthesis of isoindolo[1,2-a]isoquino-
lones, which are interesting due to the real and potential
biological activities of many of their derivatives[3] have ap-
peared in print. They can be broadly classified into two
[a] UMR 8009 “Chimie Organique et Macromoléculaire”, Labora-
toire de Chimie Organique Physique, Bâtiment C3(2), Uni-
versité des Sciences et Technologies de Lille 1,
59655 Villeneuve d’Ascq Cedex, France
Fax: +33-3-20336309
E-mail: axel.couture@univ-lille1.fr
Eur. J. Org. Chem. 2005, 3437–3442
DOI: 10.1002/ejoc.200500312
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3437

A. Moreau, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
We assumed that the assemblage of these (haloaryl)isoquin-
olones would be achieved by acylation with 7e,f of the ap-
propriate isoquinolones 8c,d which could be in turn ob-
tained by anionic cyclization of the N-[(bromoaryl)ethyl]-
carbamates 9c,d (retrosynthesis: Scheme 2).
Scheme 1. Retrosynthetic disconnections of the (a) and (b) carbon–
carbon bonds of the isoindoloisoquinolinone framework.
Scheme 2. Retrosynthetic disconnection of models 6a,b to give the
carbamates 9c,d.
(1, R ϶ H).[9] Consequently, all these structural require-
ments and synthetic limitations preclude the synthesis of
the poly-, differentially and unsymmetrically substituted al-
kaloid nuevamine (1a), so that the elegant synthetic method
reported by Castedo et al.[2] from pseudomeconine and the
synthetic approach recently developed in our group[8] are
the sole total syntheses to date of this natural product.
The first facet of the synthesis was then the formation of
the halogenated (arylalkyl)amines 10c,d. These compounds
were easily synthesized as depicted in Scheme 3 by a re-
ductive amination process involving the N-[2-(bromoaryl)
ethyl]amines 11c,d and 4-methoxybenzaldehyde. These bro-
minated aromatic amines were initially obtained by bromi-
nation of the commercially available N-[2-(3,4-dimeth-
oxyphenyl)ethyl]amine (12d) and of the methylenedioxy de-
rivative 12c. Subsequent treatment of amines 10c,d with
methyl chloroformate delivered almost quantitatively the
Results and Discussion
We wish to delineate in this paper a concise and strategi- carbamates 9c,d equipped with the appropriate functionali-
cally new synthetic approach to isoindoloisoquinolones il- ties liable to secure the generation of the isoquinoline unit
lustrated by the total synthesis of the alkaloid nuevamine. by an anionic cyclization mechanism. The literature gave
Our strategy relies on two Parham cyclization reactions for sound support for the feasibility of such an approach.[4d,13]
the construction of the isoquinoline unit, i.e. ring B in 1,
Exposure of compounds 9c,d to 1.1 equiv. of tBuLi at
and of the lactam ring A embedded in the alkaloid frame- –100 °C in THF ensured bromine/lithium exchange and sub-
work in the sequel. Our synthetic plan then enriches the sequent intramolecular aromatic acylation with the carba-
repertoire of the few synthetic methods relying on carbon– mate acting as the internal electrophile then provided the
carbon bond formation of (b) in the ultimate step.[9] The annulated compounds 13c,d with good yields (Scheme 4).
protocol developed by Parham hinges upon aromatic lithi- Removal of the N-(4-methoxybenzyl) protection by treat-
ation usually carried out by lithium/halogen exchange, and ment of 13c,d with trifluoroacetic acid (TFA) in the pres-
subsequent reaction with an internal electrophile, thus al- ence of the cation scavenger anisole proceeded uneventfully
lowing the construction of carbo- and heterocyclic sys- to afford the N-unsubstituted models 8c and 8d. The syn-
tems.[12] We then anticipated that the assemblage of the thesis of the parent compounds 6a,b – candidates for the
fused isoindolinones could be obtained by using this annu- ultimate annulation step – was readily achieved by coupling
lation protocol and that problems of regioselectivity pre- the appropriate carboxylic chlorides 7e,f with the anion of
viously encountered with imides 3 for the creation of the the secondary aromatic amides 8c,d. This operation deliv-
lactam nucleus A in 1 could be circumvented by the tailored ered the N-[(haloaryl)carbonyl]-amides 6a,b required for the
generation of the aryllithium species on the environmentally anionic cyclization in fairly good yields (Scheme 4).
different aromatic unit, i.e. C in 6 instead of D in 3
(Scheme 1).
Applications of the Parham cyclization protocol for the
formation of five-membered lactams are quite scanty and
To test the feasibility of this tactically different approach to the best of our knowledge only a few examples dealing
we set out to prepare the two representative models 6a,b. with the synthesis of dibenzoindolones,[14] chromeno-[13a]
3438
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3437–3442

Total Synthesis of Nuevamine
FULL PAPER
imide functionality and that the initially formed aromatic
anion was trapped intramolecularly by the isoquinolone
carbonyl group to afford the 12b-hydroxyisoindolo[1,2-a]-
isoquinolones 14a,b.
These N,O-hemiaminals which can be regarded as imme-
diate precursors of N-acyliminium species have been ele-
gantly implicated in the formation of C12b-substituted iso-
indoloisoquinolone derivatives.[7] Reduction of the hydroxy
group of hydroxy-lactams 14a,b was readily achieved with
triethylsilyl hydride (Et3SiH)/TFA at 0 °C to afford the tar-
get natural product nuevamine (1a) and the structurally re-
lated congener 1b in almost quantitative yield (Scheme 4).
Conclusions
In summary, the versatility and the regiospecificity of the
synthetic protocol disclosed in this paper clearly emphasize
the central position of the Parham cyclization reaction in
the arsenal of annulation techniques leading to heterocyclic
ring systems. Sequential application of this concept with
Scheme 3. Synthesis of carbamates 9c,d: a) Br2, AcOH; b) 4-Me-
OC6H4CHO, toluene, reflux, 3 h; c) NaBH4, MeOH, 20 °C, 2 h; d)
ClCOOMe, Et3N, CH2Cl2, 0 °C to 20 °C, 12 h. PMB = p-meth-
oxybenzyl.
and (arylmethylene)isoindolinones[15] have appeared in carbamate and diacylamine precursors has allowed the con-
print. Furthermore, this concept has been rarely applied to struction of the isoindolinone template and of the isoquino-
the diacylamine functionality as the internal electrophile.[16] line nucleus embedded in the isoindolo[1,2-a]isoquinolone
The parent compounds 6a,b were then tested as substrates framework. The synthetic potential of this method has been
for the Parham cyclization and we were pleased to observe further demonstrated by the third known total synthesis of
that treatment of 6a,b with tBuLi at –100 °C spared the the alkaloid nuevamine.
Scheme 4. Synthesis of nuevamine (1a) and 1b: a) tBuLi, THF, –100 °C, 30 min; b) TFA, anisole, reflux, 24 h; c) 8c or 8d, THF, nBuLi,
–78 °C to 20 °C, 30 min, then –78 °C, 7e or 7f in THF, –78 °C to 20 °C, 2 h; d) tBuLi, THF, –100 °C, 30 min; e) Et3SiH (2 equiv.), TFA
(1 equiv.), CH2Cl2, 20 °C, 2 h. PMB = p-methoxybenzyl.
Eur. J. Org. Chem. 2005, 3437–3442
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3439

A. Moreau, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
Methyl [2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl](4-methoxybenzyl)-
carbamate (9c): 6.39 g (89 %), white crystals, m.p. 59–60 °C. 1H
NMR (mixture of two rotamers, 40:60): δ = 2.79–2.86 (m, 2 H,
CH2), 3.26–3.38 (m, 2 H, NCH2), 3.73 (br. s, 3 H, OCH3), 3.77 (s,
3 H, CH3), 4.31 and 4.35 (2×s, together 2 H, NCH2Ar), 5.92 (s, 2
H, OCH2O), 6.58 and 6.69 (2×s, together 1 H, aromatic H), 6.83
(d, J = 8.3 Hz, 2 H, aromatic H), 6.95 (s, 1 H, aromatic H), 7.11–
7.21 (m, 2 H, aromatic H) ppm. 13C NMR (mixture of two rota-
mers): δ = 34.4 and 35.0, 46.0 and 47.0, 50.2 and 50.4, 52.7, 55.2,
101.6, 110.45 and 110.5, 112.7, 113.9, 114.4, 128.8 and 129.4, 129.9,
131.3, 147.0, 147.4, 156.7 and 157.2, 159.0 ppm. C19H20BrNO5
(422.3): calcd. C 54.04, H 4.77, N 3.32; found C 54.25, H 4.49, N
3.19.
Experimental Section
General: Tetrahydrofuran (THF) was pre-dried with anhydrous
Na2SO4 and distilled from sodium benzophenone ketyl under Ar
before use. Dichloromethane (CH2Cl2), triethylamine (Et3N) and
toluene were distilled from CaH2. Dry glassware was obtained by
oven-drying and assembly was done under Ar. The glassware was
equipped with rubber septa and reagent transfer was performed by
syringe techniques. For flash chromatography, Merck silica gel 60
(230–400 mesh ASTM) was used. The melting points were per-
formed with a Reichert–Thermopan apparatus and are not cor-
rected. NMR: Bruker AM 300 (300 MHz and 75 MHz, for 1H and
1
13C); for H and 13C NMR, CDCl3 was used as solvent and TMS
as internal standard. The CNRS microanalysis centre performed
the microanalyses. N-[(Bromoaryl)ethyl]amine derivatives 11c[17]
and 11d[18] were prepared according to literature methods. The bro-
mobenzoyl chloride 7e was obtained from 2-bromo-3,4-dimeth-
oxybenzoic acid synthesized according to a reported procedure.[19]
Methyl [2-(2-Bromo-4,5-dimethoxyphenyl)ethyl](4-methoxybenzyl)-
1
carbamate (9d): 7.23 g (97%), oil. H NMR (mixture of two rota-
mers, 45:55): δ = 2.81–2.88 (m, 2 H, CH2), 3.32–3.37 (m, 2 H,
NCH2), 3.74 (br. s, 3 H, OCH3), 3.75 (s, 3 H, CH3), 3.81 (s, 6 H,
2×CH3), 4.29 and 4.33 (2×br. s, together 2 H, NCH2Ar), 6.55 and
6.70 (2×br. s, together 1 H, aromatic H), 6.82 (d, J = 8.6 Hz, 2 H,
aromatic H), 6.95 (s, 1 H, aromatic H), 7.10–7.19 (m, 2 H, aromatic
H) ppm. 13C NMR (mixture of two rotamers): δ = 34.0 and 34.8,
46.1 and 46.9, 50.1 and 50.3, 52.7, 55.2, 56.0, 56.1, 113.5, 113.9,
114.1, 115.5, 128.8 and 129.5, 129.9, 130.3, 148.2, 148.4, 156.7 and
157.0, 159.0 ppm. C20H24BrNO5 (438.3): calcd. C 54.81, H 5.52, N
3.20; found C 55.12, H 5.75, N 3.01.
General Procedure for the Synthesis of the Brominated (Arylalkyl)-
amine Derivatives 10c,d: A solution of para-anisaldehyde (18 mmol,
2.45 g) and amine 11c or 11d (18 mmol) in toluene (60 mL) was
refluxed in a Dean–Starck apparatus for 3 h. After removal of tolu-
ene in vacuo, the N-[2-(bromoaryl)ethyl]-N-(4-methoxybenzyl-
idene)amine derivative was used directly in the next step without
further purification. NaBH4 (35 mmol, 1.33 g) was added portion-
wise to a solution of the previously obtained Schiff base in MeOH
(70 mL) at room temperature. The mixture was stirred at room tem-
perature for 2 h and then saturated aqueous NH4Cl solution
(30 mL) was added. After stirring for 30 min, the solvent was re-
moved under vacuo. The crude mixture was dissolved in CH2Cl2
(50 mL), washed with water (20 mL) and brine (30 mL). The or-
ganic solution was dried (Na2SO4), filtered, and concentrated in
vacuo. The crude oily amines 10c,d were purified by flash column
chromatography with ethyl acetate (AcOEt)/hexanes/Et3N
(80:10:10) as eluent.
General Procedure for the Synthesis of the Protected Dihydroisoqui-
nolones 13c,d: A solution of tBuLi (2.5 mL, 1.7 m in pentane,
4.25 mmol, 1.1 equiv.) was added dropwise by syringe at –100 °C
under Ar to a solution of carbamate 9c,d (3.86 mmol) in dry THF
(50 mL). The reaction mixture was allowed to warm to 0 °C over a
period of 30 min followed by addition of saturated aqueous NH4Cl
(5 mL). The mixture was diluted with water (30 mL), extracted with
Et2O (2 × 25 mL) and the combined organic layers were dried
(Na2SO4). Evaporation of solvent in vacuo left a solid residue
which was purified by flash column chromatography with AcOEt/
hexanes (50:50) as eluent. Dihydroisoquinolones 13c,d were finally
purified by recrystallization from hexane/toluene.
N-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-N-(4-methoxybenzyl)-
amine (10c): 4.68 g (73%), yellow-orange oil. 1H NMR: δ = 1.45
(br. s, 1 H, NH), 2.84 (s, 4 H, CH2), 3.75 (s, 2 H, CH2), 3.79 (s, 3
H, CH3), 5.93 (s, 2 H, OCH2O), 6.72 (s, 1 H, aromatic H), 6.85 (d,
J = 8.3 Hz, 2 H, aromatic H), 6.98 (s, 1 H, aromatic H), 7.23 (d, J
= 8.3 Hz, 2 H, aromatic H) ppm. 13C NMR: δ = 36.5, 49.0, 53.2,
55.3, 101.6, 110.2, 112.7, 113.8, 114.5, 129.3, 132.4, 146.8, 147.3,
158.6 ppm. C17H18BrNO3 (364.2): calcd. C 56.06, H 4.98, N 3.85;
found C 56.35, H 4.85, N 4.09.
6-(4-Methoxybenzyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquinolin-
5-one (13c): 0.68 g (57 %), white crystals, m.p. 118–119 °C. 1H
NMR: δ = 2.75 (t, J = 6.6 Hz, 2 H, CH2), 3.36 (t, J = 6.6 Hz, 2 H,
NCH2), 3.73 (s, 3 H, OCH3), 4.64 (s, 2 H, NCH2Ar), 5.92 (s, 2 H,
OCH2O), 6.52 (s, 1 H, aromatic H), 6.81 (d, J = 8.5 Hz, 2 H, aro-
matic H), 7.21 (d, J = 8.5 Hz, 2 H, aromatic H), 7.54 (s, 1 H,
aromatic H) ppm. 13C NMR: δ = 28.1, 45.2, 49.7, 55.2, 101.4,
106.8, 108.3, 114.0, 123.5, 129.4, 129.6, 133.6, 146.8, 150.3, 159.0,
164.1 ppm. C18H17NO4 (311.3): calcd. C 69.44, H 5.50, N 4.50;
found C 69.22, H 5.69, N 4.41.
N-[2-(2-Bromo-4,5-dimethoxyphenyl)ethyl]-N-(4-methoxybenzyl)-
amine (10d): 5.22 g (78%), yellow-orange oil. 1H NMR: δ = 1.41
(br. s, 1 H, NH), 2.87 (s, 4 H, CH2), 3.76 (s, 2 H, CH2), 3.78 (s, 3
H, CH3), 3.82 (s, 3 H, CH3), 3.83 (s, 3 H, CH3), 6.73 (s, 1 H,
aromatic H), 6.84 (d, J = 8.7 Hz, 2 H, aromatic H), 6.99 (s, 1 H,
aromatic H), 7.22 (d, J = 8.7 Hz, 2 H, aromatic H) ppm. 13C NMR:
δ = 36.3, 49.1, 53.2, 55.3, 56.0, 56.1, 113.3, 113.8, 114.2, 115.6,
129.2, 131.4, 132.5, 148.0, 148.3, 158.6 ppm. C18H22BrNO3 (380.3):
calcd. C 56.85, H 5.83, N 3.68; found C 56.65, H 6.09, N 3.89.
6,7-Dimethoxy-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-
one (13d): 0.88 g (70%), white crystals, m.p. 86–87 °C. 1H NMR: δ
= 2.80 (t, J = 6.7 Hz, 2 H, CH2), 3.40 (t, J = 6.7 Hz, 2 H, NCH2),
3.74 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3),
4.66 (s, 2 H, NCH2Ar), 6.57 (s, 1 H, aromatic H), 6.81 (d, J =
8.5 Hz, 2 H, aromatic H), 7.22 (d, J = 8.5 Hz, 2 H, aromatic H),
7.62 (s, 1 H, aromatic H) ppm. 13C NMR: δ = 27.7, 45.4, 49.8,
55.2, 56.0, 56.05, 109.3, 110.6, 113.9, 122.0, 129.4, 129.7, 131.7,
147.9, 151.8, 158.9, 164.5 ppm. C19H21NO4 (311.3): calcd. C 69.71,
H 6.47, N 4.50; found C 69.84, H 6.59, N 4.39.
General Procedure for the Synthesis of the Methyl Carbamates 9c,d:
Methyl chloroformate (2.39 g, 25 mmol) was added dropwise at
0 °C to a stirred solution of the secondary amine 10c,d (17 mmol)
and Et3N (2.43 g, 34 mmol) in CH2Cl2 (50 mL). The mixture was
allowed to warm to room temperature and then stirred for an ad-
ditional 3 h. The mixture was washed with water (30 mL) and brine
(30 mL). The organic layer was dried (MgSO4) and concentrated in
vacuo and left an oily residue which was purified by flash column
chromatography on silica gel with AcOEt/hexanes (40:60) as eluent.
General Procedure for the Synthesis of the Dihydroisoquinolones
8c,d: A solution of 13c,d (1.73 mmol) in a mixture of anisole (2 mL)
and TFA (1.5 mL) was heated under reflux under Ar for 24 h. The
solvent was removed under vacuum and the residue was dissolved
in CH2Cl2 (20 mL). Et3N (0.5 mL) was then added with stirring.
3440
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3437–3442

Total Synthesis of Nuevamine
FULL PAPER
After addition of water (10 mL), the organic layer was separated
and the aqueous layer extracted with CH2Cl2 (2 ×20 mL). The
combined organic layers were washed with water and brine, dried
(Na2SO4), and concentrated under vacuum to yield 8c,d as a white
solid residue which was finally recrystallized from hexane/toluene.
8c: 288 mg (87%), white crystals, m.p. 183–184 °C (ref.[20] 185 °C);
8d: 301 mg (84%), white crystals, m.p. 174–175 °C (ref.[21] 175 °C).
61.7, 88.1, 101.1, 108.4, 109.0, 113.5, 119.8, 124.3, 128.8, 129.9,
139.9, 144.6, 146.5, 147.7, 157.1, 166.6 ppm. C19H17NO6 (355.3):
calcd. C 64.22, H 4.82, N 3.94; found C 63.98, H 5.01, N 4.17.
12b-Hydroxy-2,3-dimethoxy-5,12b-dihydro-6H-isoindolo[1,2-a]iso-
quinolin-8-one (14b): 299 mg (62%), white crystals, m.p. 159–160 °C
(ref.[4d] 157–159 °C).
General Procedure for the Synthesis of the Target Products 1a,b:
TFA (114 mg, 1.0 mmol) was added to a stirred solution of com-
pounds 14a,b (1.0 mmol) in dry CH2Cl2 (20 mL), followed by the
addition of triethylsilyl hydride (233 mg, 2.0 mmol). After stirring
at room temperature for 2 h, aqueous saturated NaHCO3 solution
(10 mL) was added and the organic layer was separated. The aque-
ous layer was extracted twice with CH2Cl2 (2×15 mL). The com-
bined organic layers were washed with brine (2×10 mL) and dried
(Mg SO4). Evaporation of the solvent under vacuum afforded a
white solid which was recrystallized from hexane/toluene. The ana-
lytical data of the synthesized nuevamine (1a, 299 mg, 88%) match
those reported for the natural product[1,2] and the data of 2,3-di-
methoxy-5,12b-dihydro-6H-isoindolo[1,2-a]isoquinolin-8-one (1b,
272 mg, 92%) match those of the previously synthesized prod-
uct.[11]
General Procedure for the Synthesis of the N-Acyldihydroisoquino-
lones 6a,b: A solution of dihydroisoquinolone 8c,d (2.9 mmol) in
THF (40 mL) was added to a solution of nBuLi (1.6 m in hexane,
2.0 mL, 3.2 mmol) at –78 °C under Ar. The solution was then al-
lowed to warm to room temperature over a period of 30 min and
then recooled to –78 °C. A solution of acyl chloride 7e,f (2.9 mmol)
in dry THF (5 mL) wad added and the mixture was stirred at
–78 °C for 10 min and then at room temperature for 2 h. Aqueous
saturated NH4Cl solution (10 mL) was added and the mixture was
extracted with AcOEt (2×25 mL). The organic layers were dried
(MgSO4) and concentrated under vacuum. The white solid residue
was purified by flash column chromatography with acetone/hex-
anes (40:60) as eluent. N-Acyldihydroisoquinolones 6a,b were fi-
nally purified by recrystallization from hexane/toluene.
6-(2-Bromo-3,4-dimethoxybenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-
g]isoquinolin-5-one (6a): 0.98 g (78 %), white crystals, m.p. 149–
150 °C. H NMR: δ = 3.05 (t, J = 6.0 Hz, 2 H, CH2), 3.83 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3), 4.20 (t, J = 6.0 Hz, 2 H, NCH2), 6.00
(s, 2 H, OCH2O), 6.68 (s, 1 H, aromatic H), 6.92 (d, J = 8.5 Hz, 1
H, aromatic H), 7.11 (d, J = 8.5 Hz, 1 H, aromatic H), 7.42 (s, 1
H, aromatic H) ppm. 13C NMR: δ = 28.3, 43.2, 56.0, 60.6, 101.9,
107.2, 108.8, 111.2, 114.6, 122.1, 123.7, 132.8, 137.0, 146.3, 147.4,
152.3, 154.4, 164.0, 170.4 ppm. C19H16BrNO6 (434.2): calcd. C
52.55, H 3.71, N 3.23; found C 52.33, H 3.79, N 3.36.
[1] E. Valencia, A. J. Freyer, M. Shamma, V. Fajardo, Tetrahedron
Lett. 1984, 25, 599–602.
1
[2] R. Alonso, L. Castedo, D. Dominguez, Tetrahedron Lett. 1985,
26, 2925–2928.
[3] a) A. Mertens, H. Zilch, B. Koenig, W. Schaefer, T. Poll, W.
Kampe, H. Seidel, U. Leser, H. Leinert, J. Med. Chem. 1993,
36, 2526–2535; b) W. Schafer, W. G. Friebe, H. Leinert, A. Mer-
tens, T. Poll, W. von der Saal, H. Zilch, B. Nuber, M. L. Ziegler,
J. Med. Chem. 1993, 36, 726–732; c) S. M. Allin, C. J. North-
field, M. I. Page, A. M. Z. Slawin, Tetrahedron Lett. 1997, 38,
3627–3630; d) S. M. Allin, C. J. Northfield, M. I. Page,
A. M. Z. Slawin, Tetrahedron Lett. 1999, 40, 141–142; e) S. M.
Allin, C. J. Northfield, M. I. Page, A. M. Z. Slawin, Tetrahe-
dron Lett. 1999, 40, 143–146; f) S. M. Allin, C. C. Hodkinson,
N. Taj, Synlett 1996, 781–782.
[4] a) M. Win, H. E. Zaugg, J. Org. Chem. 1969, 34, 249–250; b)
G. J. Hitchings, M. Helliwell, J. M. Vernon, J. Chem. Soc., Per-
kin Trans. 1 1990, 83–87; c) G. J. Hitchings, J. M. Vernon, J.
Chem. Soc., Perkin Trans. 1 1990, 1757–1763; d) M. I. Collado,
I. Manteca, N. Sotomayor, M.-J. Villa, E. Lete, J. Org. Chem.
1997, 62, 2080–2092.
2-(2-Bromobenzoyl)-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-
one (6b): 0.905 g (80%), white crystals, m.p. 148–179 °C. 1H NMR:
δ = 3.08 (t, J = 6.2 Hz, 2 H, CH2), 3.82 (s, 3 H, OCH3), 3.93 (s, 3
H, OCH3), 4.27 (t, J = 6.2 Hz, 2 H, NCH2), 6.70 (s, 1 H, aromatic
H), 7.23–7.29 (m, 1 H, aromatic H), 7.32–7.41 (m, 2 H, aromatic
H), 7.49 (s, 1 H, aromatic H), 7.53 (d, J = 7.8 Hz, 1 H) ppm. 13C
NMR: δ = 27.8, 43.0, 56.0, 56.2, 109.4, 111.1, 117.9, 120.3, 127.4,
127.8, 130.4, 132.5, 135.0, 140.0, 148.4, 153.8, 164.4, 170.6 ppm.
C18H16BrNO4 (390.2): calcd. C 55.40, H 4.13, N 3.59; found C
55.49, H 3.89, N 3.46.
[5] a) J. L. Moniot, D. M. Hindenlang, M. Shamma, J. Org. Chem.
1979, 44, 4347–4351; b) H. Heaney, K. F. Shuhaibar, Synlett
1995, 47–48; c) M. T. El Gihani, H. Heaney, K. F. Shuhaibar,
Synlett 1996, 871–872; d) H. Heaney, M. T. Simcox, A. M. Z.
Slawin, R. G. Giles, Synlett 1998, 640–642; e) S. M. Allin, C. J.
Northfield, M. I. Page, A. M. Z. Slawin, Tetrahedron Lett.
1998, 39, 4905–4908; f) Y. Koseki, S. Kusano, H. Sakata, T.
Nagasaka, Tetrahedron Lett. 1999, 40, 2169–2172.
[6] A. R. Katritzky, S. Mehta, H. Y. He, J. Org. Chem. 2001, 66,
148–152.
General Procedure for the Synthesis of the Hydroxyisoindolo[1,2-
a]isoquinolone Derivatives 14a,b: A solution of tBuLi (1.0 mL, 1.7 m
in pentane, 1.69 mmol, 1.1 equiv.) was added dropwise by syringe
at –100 °C under Ar to a solution of the N-acyl-lactames 6a,b
(1.55 mmol) in dry THF (30 mL). The reaction mixture was al-
lowed to warm to room temperature over a period of 30 min fol-
lowed by addition of saturated aqueous NH4Cl (5 mL). The mix-
ture was diluted with water (30 mL), extracted with Et2O
(2×25 mL) and the combined organic layers were dried (Na2SO4).
Evaporation of solvent in vacuo left an oily residue which was puri-
fied by flash column chromatography with acetone/hexanes (60:40)
as eluent. Compounds 14a,b were finally purified by recrystalli-
zation from hexane/toluene.
[7] I. Osante, E. Lete, N. Sotomayor, Tetrahedron Lett. 2004, 45,
1253–1256.
[8] A. Moreau, A. Couture, E. Deniau, P. Grandclaudon, S. Leb-
run, Tetrahedron 2004, 60, 6169–6176.
[9] a) B. Burns, R. Grigg, V. Santhakumar, V. Sridharan, P. Steven-
son, T. Worakun, Tetrahedron 1992, 48, 7297–7320; b) A. Bom-
brun, O. Sageot, Tetrahedron Lett. 1997, 38, 1057–1060.
[10] G. N. Walker, R. J. Kempton, J. Org. Chem. 1971, 36, 1413–
1416.
[11] R. Grigg, W. S. MacLachlan, D. T. MacPherson, V. Sridharan,
S. Suganthan, M. Thornton-Pett, J. Zhang, Tetrahedron 2000,
56, 6585–6594.
[12] Reviews: a) W. E. Parham, C. K. Bradsher, Acc. Chem. Res.
1982, 15, 300–305; b) B. J. Wakefield, The Chemistry of Organo-
12b-Hydroxy-5,12b-dihydro-6H-11,12-dimethoxy-1,3-dioxolo[4,5-g]-
isoindolo[1,2-a]isoquinolin-8-one (14a): 358 mg (65%), white crys-
tals, m.p. 192–193 °C. 1H NMR: δ = 2.69–2.75 (m, 1 H, CH2),
2.82–2.93 (m, 1 H, CH2), 3.30–3.40 (m, 1 H, NCH2), 3.95 (s, 3 H,
OCH3), 3.97–4.06 (m, 1 H, NCH2), 4.09 (s, 3 H, OCH3), 5.85 (s, 1
H, OCH2O), 5.90 (s, 1 H, OCH2O), 6.53 (s, 1 H, aromatic H), 7.00
(d, J = 8.2 Hz, 1 H, aromatic H), 7.41 (d, J = 8.2 Hz, 1 H, aromatic
H), 8.03 (s, 1 H, aromatic H) ppm. 13C NMR: δ = 29.0, 34.9, 56.4,
Eur. J. Org. Chem. 2005, 3437–3442
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3441

A. Moreau, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
lithium Compounds, 2nd ed., Pergamon, New York, 1990; c) M.
Gray, M. Tinkl, V. Snieckus, in: Comprehensive Organometallic
Chemistry II (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson),
Pergamon, Exeter, 1995, vol. 11, pp. 66–92; d) A. Ardeo, M. I.
Collado, I. Osante, J. Ruiz, N. Sotomayor, E. Lete, in: Targets
in Heterocyclic Systems (Eds.: O. Atanassi, D. Spinelli), Italian
Society of Chemistry, Rome, 2001, vol. 5, pp. 393–418; e) J.
Clayden, Organolithiums: Selectivity for Synthesis, Pergamon,
New York, 2002; f) M. J. Mealy, W. F. Bailey, J. Organomet.
Chem. 2002, 646, 59–67; g) N. Sotomayor, E. Lete, Curr. Org.
Chem. 2003, 7, 275–300; h) C. Nájera, J. M. Sansano, M. Yus,
Tetrahedron 2003, 59, 9255–9303.
S. B. Hendi, J. A. Campbell, T. D. Greenwood, J. F. Wolfe, Tet-
rahedron Lett. 1989, 30, 275–278.
[16] For the sensitivity of the carbonyl group of imides to organo-
lithium reagents, see: a) E. Lete, A. Egiarte, N. Sotomayor, T.
Vincente, M.-J. Villa, Synlett 1993, 41–42; b) M. I. Collado, E.
Lete, N. Sotomayor, M.-J. Villa, Tetrahedron 1995, 51, 4701–
4710; c) E. Lete, M. I. Collado, N. Sotomayor, T. Vincente, M.-
J. Villa, J. Heterocycl. Chem. 1995, 32, 1751– 1758.
[17] G. Rodriguez, M. M. Cid, S. Saá, L. Castedo, D. Dominguez,
J. Org. Chem. 1996, 61, 2780–2782.
[18] G. Rodriguez, L. Castedo, D. Dominguez, C. Saá, W. Adam,
J. Org. Chem. 1999, 64, 4830–4833.
[13] a) D. L. Comins, P. M. Thakker, M. F. Baevski, M. M. Badawi, [19] K. Orito, M. Miyazawa, R. Kanbayashi, M. Tokuda, H. Sugin-
Tetrahedron 1997, 53, 16327–16340; b) K. Orito, M. Miyazawa,
R. Kanbayashi, T. Tatsuzawa, M. Tokuda, H. Suginome, J.
Org. Chem. 2000, 65, 7495–7500; c) M. C. de la Fuente, D. Do-
minguez, Tetrahedron 2004, 60, 10019–10028.
ome, J. Org. Chem. 1999, 64, 6583–6596.
[20] Y. Kondo, T. Takemoto, Chem. Pharm. Bull. 1972, 20, 2134–
2136.
[21] K. Wiesner, Z. Valenta, A. J. Manson, F. W. Stonner, J. Am.
Chem. Soc. 1955, 77, 675–683.
[14] R. K. A. Giger, Swiss Patent CH648300, 1985; Chem. Abstr.
1985, 103, 71188.
[15] a) V. Rys, A. Couture, E. Deniau, P. Grandclaudon, Eur. J.
Org. Chem. 2003, 1231–1237; b) M. S. Hendi, K. J. Natalie,
Received: May 23, 2005
Published Online: July 1, 2005
3442
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3437–3442