Synthesis of diazatricyclic core of madangamines from cis- perhydroisoquinolines

Article abstract of DOI:10.1021/jo702340w

(Chemical Equation Presented) Synthesis of the tricyclic core of madangamine alkaloids has been achieved in a 10-step sequence starting from a 4-(aminomethyl)anisole derivative. A Birch reduction and acylation with cyanoacetic acid followed by an intramol

Full text of DOI:10.1021/jo702340w

Synthesis of Diazatricyclic Core of
Madangamines from cis-Perhydroisoquinolines
Josefina Quirante,* Laura Paloma, Fa¨ıza Diaba,
Xavier Vila, and Josep Bonjoch*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia,
Institut de Biomedicina (IBUB), UniVersitat de Barcelona,
AV. Joan XXIII s/n, 08028-Barcelona, Spain
josep.bonjoch@ub.edu
ReceiVed October 30, 2007
FIGURE 1. Madangamine structures.
SCHEME 1. Construction of the Diazatricyclic
Madangamine Core
Synthesis of the tricyclic core of madangamine alkaloids has
been achieved in a 10-step sequence starting from a 4-(ami-
nomethyl)anisole derivative. A Birch reduction and acylation
with cyanoacetic acid followed by an intramolecular Michael
process renders a polyfunctionalized cis-perhydroisoquino-
line. A diastereoselective allylation and reduction of amide,
nitrile, and ketone groups leads to a bicyclic alcohol, which
undergoes aminocyclization through the nosyl derivative to
the diazatricyclic ring.
SCHEME 2. Retrosynthesis for the Diazatricyclic
Madangamine Core
Madangamines are pentacyclic alkaloids with a basic skeleton
consisting of a common diazatricyclic core of perhydro-6,4-
(iminomethano)isoquinoline and two linear bridges (Figure 1).
Madangamines A-E have been isolated from Xestospongia
ingens sponges collected at Madang in Papua New Guinea (A,1
B-E2), and structural variations in this group of alkaloids occur
only in the N(7) to C(9) bridge, which varies both in carbon
length (13-15 atoms) and the position and degree of unsatura-
tion. Madangamine F,3 presenting some new structural trends,
has been recently isolated from the Brazilian sponge Pachy-
chalina alcaloidifera. Madangamine A is of pharmacological
interest as it exhibits in vitro cytotoxicity against murine
leukemia P388 cell lines with an IC50 value of 1 µg/mL.
Although no madangamine synthesis has been described to
date, three synthetic strategies have been developed for
the construction of the diazatricyclic core (Scheme 1). In the
Weinreb approach,4 the bridge framework is assembled in the
last step by an aminomercuriation process. In contrast, Yamazaki-
Kibayashi5,6 and Marazano7 have worked with 2-azabicyclo-
[3.3.1]nonane intermediates in order to elaborate the hydroiso-
quinoline unit in the last step. In the work reported here, we
have introduced a new synthetic pathway to the diazatricyclic
target.
The proposed retrosynthetic analysis, depicted in Scheme 2,
involves an initial formation of the fused perhydroisoquinoline
ring from a carbocyclic starting material followed by the closure
of the bridged ring through an intramolecular alkylation. There
are several reported methodologies leading to cis-perhydroiso-
quinolin-6-one derivatives, unsubstituted at C(4a) and C(8a),8-12
(1) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994,
116, 6007-6008.
(2) Kong, F.; Graziani, E. I.; Andersen, R. J. J. Nat. Prod. 1998, 61,
267-271.
(3) Oliveira, J. H. H. L.; Nascimento, A. M.; Kossuga, M. H.; Cavalcanti,
B. C.; Pessoa, C. O.; Moraes, M. O.; Macedo, M. L.; Ferreira, A. G.; Hajdu,
E.; Pinheiro, U. S.; Berlinck, R. G. S. J. Nat. Prod. 2007, 70, 538-543.
(4) Matzanke, N.; Gregg, R. J.; Weinreb, S. M.; Parvez, M. J. Org. Chem.
1997, 62, 1920-1921.
(5) Yamazaki, N.; Kusanagi, T.; Kibayashi, C. Tetrahedron Lett. 2004,
45, 6509-6512.
(6) For the synthesis of an azatricyclic compound embodying the ACE
madangamine skeleton, see: Yoshimura, Y.; Inoue, J.; Yamazaki, N.;
Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2006, 47, 3489-3492.
(7) Tong, H. M.; Martin, M.-T.; Chiaroni, A.; Be´ne´chie, M.; Marazano,
C. Org. Lett. 2005, 7, 2437-2440.
(8) Stork, G.; Livingston, D. A. Chem. Lett. 1987, 105-108.
10.1021/jo702340w CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/21/2007
768
J. Org. Chem. 2008, 73, 768-771

as required for our madangamine diazatricyclic core approach.13-17
We chose a Michael process since it would allow the N(9) and
C(10) atoms18 to be incorporated in a latent form as a nitrile,
using a cyanoacetamide as the Michael donor group.19 More-
over, this synthetic approach could be extended to the elabora-
tion of the eastern macrocycle if the carbonyl group of the
Michael acceptor allowed a functionalization at C(7).
SCHEME 3. Synthesis of the Diazatricyclic Madangamine
Core
The synthesis began with a Birch reduction of the N-methyl-
4-methoxybenzylamine.20 The secondary amine 1a was coupled
with cyanoacetic acid using several coupling agents,21 the best
results being obtained with EDC (Scheme 3). The resulting
dihydroanisole (not shown) was submitted to an acid treatment
to hydrolyze its enol ether, thus generating the achiral nitrogen-
tethered cyanoacetamide and cyclohexenone 2a, the key precur-
sor of the perhydroisoquinoline ring. Compound 2a was found
to be a mixture of rotamers around the amide bond. Treatment
of â,γ-enone 2a with a substoichiometric quantity of NaOEt
induced the isomerization of the double bond and then an
intramolecular Michael process to diastereoselectively give the
cis-perhydroisoquinoline 3a in 77% overall yield. The mixture
(9) Godleski, S. A.; Villhauer, E. B. J. Org. Chem. 1984, 49, 2246-
2252.
(10) Hutchinson, D. R.; Khau, V. V.; Martinelli, M. J.; Nayyar, N. K.;
Peterson, B. C.; Sullivan, K. A. Org. Synth. 1998, 75, 223-234.
(11) MaGee, D. I.; Lee. M. L. Tetrahedron Lett. 2001, 42, 7177-7180.
(12) Vila, X.; Quirante, J.; Paloma, L.; Bonjoch, J. Tetrahedron Lett.
2004, 45, 4661-4664.
(13) For other procedures for the synthesis of functionalized cis-
perhydroisoquinolines without substituents at the methine ring carbons, see
the following references: (a) from an acyclic precursor through an
intramolecular Diels-Alder, ref 14; (b) from a nitrogen-containing ring
and further elaboration of the carbocyclic ring, ref 15; (c) from a
functionalized carbocyclic ring and later piperidine ring formation, ref 16;
(d) from a bicyclic carbocyclic derivative and a insertion of the nitrogen
atom, ref 17.
(14) (a) Leonard, J.; Appleton, D.; Fearnley, S. P. Tetrahedron Lett. 1994,
35, 1071-1074. (b) Murray, W. V.; Sun, S.; Turchi, I. J.; Brown, F. K.;
Gauthier, A. D. J. Org. Chem. 1999, 64, 5930-5940. (c) Sparks, S. M.;
Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003, 68, 5274-5285. (d) Zeng,
Y.; Reddy, D. S.; Hirt, E.; Aube´, J. Org. Lett. 2004, 6, 4993-4995.
(15) (a) Aldol process: McElvain, S. M.; Parker, P. H. J. Am. Chem.
Soc. 1956, 78, 5312-531. McElvain, S. M.; Remy, D. C. J. Am. Chem.
Soc. 1960, 82, 3960-3966. (b) Intermolecular Diels-Alder: Ma, J.;
Nakagawa, M.; Torisawa, Y.; Hino, T. Heterocycles 1994, 38, 1609-1613.
Langlois, Y.; Magnier, E. Tetrahedron Lett. 1995, 36, 9475-9478. (c) Ring-
closing metathesis: Amat, M.; Pe´rez, M.; Minaglia, A. T.; Casamitjana,
N.; Bosch, Org. Lett. 2005, 7, 3653-3656.
(16) (a) Photocyclization: Xu, W.; Zhang, X.-M.; Mariano, P. S. J. Am.
Chem. Soc. 1991, 113, 8863-8878. Jung, Y. S.; Swartz, W. H.; Xu, W.;
Mariano, P. S. J. Org. Chem. 1992, 57, 6037-6047. (b) Radical cycliza-
tion: Stork, G.; Mash, R. Heterocycles 1989, 28, 723-727. Kaoudi, T.;
Miranda, L. D.; Zard, S. Z. Org. Lett. 2001, 3, 3125-3127. (c) N-Alkylation
and related processes: Hansen, M. M.; Bertsch, C. F.; Harkness, A. R.;
Huff, B. E.; Hutchinson, D. R.; Khau, V. V.; LeTourneau, M. E.; Martinelli,
M. J.; Misner, J. W.; Peterson, B. C.; Rieck, J. A.; Sullivan, K. A.; Wright,
I. G. J. Org. Chem. 1998, 63, 775-785. Hart, D. J.; Ellis, D. A. Heterocycles
1998, 49, 117-120. Hattori, K.; Grossman, R. B. J. Org. Chem. 2003, 68,
1409-1417.
(17) (a) Aube´, J.; Ghosho, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116,
9009-9018. (b) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V.
Tetrahedron Lett. 2002, 43, 947-950.
(18) The systematic nomenclature is used throughout this paper (see
Scheme 2), while the madangamine numbering has been showed in Figure
1.
(19) For an approach to 3-oxabicyclo[4.4.0]decan-4,8-diones based on
an intramolecular Michael process of a cyanoacetate upon enones, see: (a)
Grossman, R. B.; Ley, S. V. Tetrahedron 1994, 50, 11533-11568. (b) de
la Puente, M. L.; Grossman, R. B.; Ley, S. V.; Simmonds, M. S. J.; Blaney,
W. M. J. Chem. Soc., Perkin Trans. 1 1996, 1517-1521.
(20) Quirante, J.; Vila, X.; Paloma, L.; Guiu, J. M.; Bonjoch, J.
Tetrahedron 2007, 63, 1372-1379.
(21) For other coupling conditions using cyanoacetic acid, see: Lemaire,
S.; Giambastiani, G.; Prestat, G.; Poli, G. Eur. J. Org. Chem. 2004, 2840-
2847.
SCHEME 4. Diastereoselective Allylation of the Epimeric
Mixture of 3
of epimers (7:3) at C(4) in compound 3a is synthetically
irrelevant since in the next step both evolve through the same
carbanion intermediate to give the stereogenic quaternary center
at this carbon. The allylation takes place from the top face under
a sterically controlled kinetic reaction to give exclusively 4a
(Scheme 4). The stereochemistry as well as the preferred
conformation for 4a were established unequivocally from NMR
data: (i) the 1H NMR coupling pattern for the methylene proton
at C-1ax, which appears as dd (J ) 13.2 and 10.4 Hz); (ii) the
NOESY interaction between the H-8a and the methylene of the
allyl substituent at C-4; (iii) the chemical shift of C-7 (δ 36.2),
J. Org. Chem, Vol. 73, No. 2, 2008 769

SCHEME 5. Aminocyclization of 5 Using AlH2Cl
allow the synthetic process to be extended to more elaborate
derivatives en route to the madangamines.
Experimental Section
N-Benzyl-2-cyano-N-(4-oxocyclohex-1-enylmethyl)aceta-
mide (2b). To a cooled (0 °C) solution of amine 1b (3.77 g, 16.74
mmol) in CH2Cl2 (55 mL) were added N-(3-dimethylaminopropyl)-
N-ethylcarbodiimide (EDC, 8 g, 41.3 mmol), cyanoacetic acid (3.55
g, 41.3 mmol), and DMAP (2 g, 16.4 mmol). The resulting solution
was stirred overnight at rt, diluted with CH2Cl2, and washed
sequentially with 10% aqueous citric acid, saturated NaHCO3, and
brine. The organic phase was concentrated to give the crude
cyanoacetamide. To a solution of the above enol ether in EtOH
(45 mL) was added aqueous 1% HCl (45 mL). After the reaction
mixture was stirred 5 h at rt, EtOH was evaporated and the resulting
aqueous phase was neutralized with 1 N NaOH and extracted with
CH2Cl2. The organic extracts were dried and concentrated, and the
residue was purified by chromatography (SiO2, 1:1 hexane/EtOAc)
to give 2b (3.5 g, 9.4 mmol, 75%) as an orange oil: IR(NaCl)
1714, 1660; 1H NMR (400 MHz, CDCl3, gCOSY) mixture of
rotamers 2.32 and 2.41 (2m, H-6), 2.40-2.60 (m, 2H, H-5), 2.89
and 2.91 (2s, 2H, H-3), 3.53 and 3.57 (2s, 2H, CH2CN), 3.82 and
4.12 (2s, 2H, NCH2), 4.51 and 4.61 (2s, 2H, CH2Ph), 5.57 and
5.62 (2s, 1H, H-2), 7.10-7.50 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3, gHSQC) 25.0 and 25.2 (CH2CN), 26.3 and 26.5 (C-6), 37.6
and 37.9 (C-5), 39.0 and 39.3 (C-3), 49.6 and 50.6 (CH2Ph), 50.9
and 52.1 (NCH2), 113.8 and 113.9 (CN), 121.1 and 122.2 (C-2),
127.9, 128.0, 128.3, 128.8, 129.4 (Ar), 132.3 and 133.1 (ipso-Ar),
134.8 and 136.0 (C-1), 162.4 and 162.6 (NCO), 208.4 and 209.2
(C-4); HRMS (ESI-TOF) calcd for C17H19N2O2 283.1441 [M +
H]+, found 283.1436.
SCHEME 6. Stereochemical Course of the Final Cyclization
which is diagnostic for cis-perhydroisoquinolin-6-ones with the
depicted conformation.22
After carbonyl protection of ketone 4a, we initiated studies
for the reduction of amide and cyano groups of 5a to achieve
the required diamino derivative 6a. Interestingly, when we used
an equimolecular mixture of LiAlH4 and AlCl3 at room
temperature (AlH2Cl in the reaction medium) we obtained a
mixture of the expected 6a together with the diazatricyclic
compound 7 (23%) and the byproduct 8 (Scheme 5). Attempts
to optimize the formation of 7 either from 6a or 8 using the
same reagents but varying the reaction time were unsuccessful.
In search of the best conditions to exclusively obtain 6a, the
hydrogenolysis process was minimized by carrying out the
reduction using a 3:1 mixture of LiAlH4 and AlCl3 to generate
alane. Thus, 6a was isolated in 68% overall yield (85% yield
on 0.3 mmol scale).
(4RS,4aRS,8aSR)- and (4RS,4aSR,8aRS)-2-Benzyl-3,6-dioxo-
decahydroisoquinoline-4-carbonitrile (3b). To a solution of 2b
(3 g, 10.64 mmol) in EtOH (110 mL) was added NaOEt (1 M
solution in EtOH (5.3 mL, 5.3 mmol). After the resulting solution
was stirred at rt for 1 h, acetic acid was added (7 mL) and the
mixture was concentrated. The obtained residue was taken up in
CH2Cl2 and washed with 5% aqueous NaHCO3 and H2O. The
organic phase was dried, concentrated, and purified by chroma-
tography (SiO2, 20:80 hexane/EtOAc) to afford 3b (2.3 g, 8.16
mmol, 77%) as an orange oil and as an epimeric mixture at C-4
For the final ring closure of the bridged subunit, the nosyl
group at the exocyclic nitrogen and a hydroxyl group at C-6
were required to attempt an alkylation of amines with alcohol
derivatives using the Fukuyama protocol.23 After nosylation and
cleavage of the acetal group, ketone 9a was isolated. Considering
that the conformation of this compound differs from the one
needed for the cyclization process (see Scheme 6), we carried
out the reduction using L-Selectride to prepare the corresponding
axial alcohol. Then, 10a was treated with Ph3P, DEAD, and
Et3N, undergoing the corresponding SN2 substitution through a
conformational inversion of the azabicyclic ring to give the
target 11a in 68% yield.
1
(7:3 ratio): IR (NaCl) 1715, 1656; H NMR (400 MHz, CDCl3,
gCOSY) major epimer 1.84 (m, 2H, H-8), 2.39 (m, 2H, H-7), 2.50
(dd, J ) 15.2, 6.8, 1H, H-5), 2.55 (m, 1H, H-8a), 2.62 (dd, J )
15.2, 5.2, 1H, H-5), 2.84 (m, 1H, H-4a), 3.22 (dd, J ) 12.8, 5.2,
1H, H-1), 3.38 (d, J ) 9.2, 1H, H-4), 3.50 (dd, J ) 12.8, 5.2, 1H,
H-1), 4.48 and 4.77 (2d, J ) 14.8, 2H, CH2Ph), 7.20-7.40 (m,
5H, ArH); minor epimer 1.92 (m, 2H, H-8), 2.29-2.35 (m, 3H,
H-4, H-5, H-7), 2.43 (m, 1H, H-8a), 2.70 (dq, J ) 12 and 5 Hz,
1H, H-4a), 2.76 (m, 1H, H-5), 3.33 (dd, J ) 13, 6.8, 1H, H-1),
3.44 (t, J ) 12.8 Hz, H-1), 3.90 (d, J ) 5.6, 1H, H-4), 4.65 (s, 2H,
CH2Ph), 7.20-7.40 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3,
gHSQC) major epimer 25.3 (C-8), 30.9 (C-8a), 38.0 (C-4), 38.2
(C-4a), 38.5 (C-7), 43.0 (C-5), 48.8 (C-1), 50.8 (CH2Ph), 116.7
(CN), 128.1, 128.3 and 129.0 (Ar), 135.6 (ipso-Ar), 160.4 (C-3),
206.9 (C-6); minor epimer 25.9 (C-8), 30.2 (C-8a), 36.0 (C-7), 36.3
(C-4a), 39.3 (C-5), 40.0 (C-4), 46.3 (C-1), 51.0 (CH2Ph), 115.4
(CN), 135.7 (ipso-Ar), 161.1 (C-3), 206.7 (C-6); HRMS (ESI-TOF)
calcd for C17H19N2O2 283.1441 [M + H]+, found 283.1434.
(4RS,4aSR,8aRS)-4-Allyl-2-benzyl-3,6-dioxodecahydroiso-
quinoline-4-carbonitrile (4b). To a cooled (-78 °C) solution of
3b (2.36 g, 8.36 mmol) in THF (120 mL) was added LDA (1.5 M
in cyclohexane, 4.2 mL, 8.36 mmol), and the reaction mixture was
stirred for 1 h. Allyl bromide (0.9 mL, 10.03 mmol) was added,
and stirring was continued for 2 h at the same temperature and
overnight at rt. After being quenched with saturated NH4Cl (5 mL),
the resulting mixture was stirred, the organic phase was separated,
The same sequence (2 f 11) was also carried out working
with N-benzyl-substituted derivatives (series b). In this case,
the starting compound 2b was prepared by the Birch reduction
of 4-methoxybenzylamine, followed by a reductive amination
of the resulting dihydroanisole.20 The overall synthetic sequence
resulted in similar yields to those of series a, as depicted in
Scheme 3.
In conclusion, we have described a concise 10-step synthesis
of the diazatricyclic core of madangamines. Our approach
features canonical reactions such as Michael and N-alkylation
intramolecular processes in the ring-closure steps, which could
(22) Bailey, J. M.; Booth, H.; al-Shirayda, H. A. R. Y. J. Chem. Soc.,
Perkin Trans. 2 1984, 583-587. See also reference 12.
(23) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 1891-1893 and references therein.
770 J. Org. Chem., Vol. 73, No. 2, 2008

and the aqueous phase was extracted with CH2Cl2. The organic
extracts were dried, concentrated, and purified by chromatography
(SiO2, CH2Cl2/MeOH, 95:5) to give 4b (2.2 g, 6.85 mmol, 81%)
53.2 (C-1), 54.9 (C-3), 63.2 (CH2Ar), 64.1, 64.3 (CH2O), 109.7
(C-6), 117.1 (dCH2), 126.9, 128.1 and 128.8 (Ar), 135.2 (dCH),
139.1 (ipso-Ar); HRMS (ESI-TOF) calcd for C22H33N2O2 357.2536
[M + H]+, found 357.2535.
1
as an orange oil: IR (NaCl) 1714, 1652; H NMR (400 MHz,
CDCl3, gCOSY, NOESY) 1.84 (m, H-8ax), 1.97 (m, H-8eq), 2.30
(dtd, J ) 16.5, 5.5, 1.5 Hz, 1H, H-7eq), 2.31-2.53 (m, 2H, H-7ax
and H-5), 2.45-2.53 (m, 2H, H-4a, H-8a), 2.77 (m, 1H, CH2), 2.92
(ddt, J ) 14.2, 6, 1.2 Hz, 1H, CH2), 3.30 (dd, J ) 13.2, 3.3 Hz,
1H, H-1eq), 3.49 (dd, J ) 13.2, 10.4 Hz, 1H, H-1ax), 4.53 and
4.74 (2d, J ) 14.4 Hz, 1H each, CH2Ph), 5.25 (dq, J ) 16.8, 1.2
Hz, 1H, )CH2), 5.30 (d, J ) 10.4 Hz, 1H, )CH2), 5.89 (dddd, J
(4RS,4aRS,6RS,8aSR)-4-Allyl-3-benzyl-9-(2-nitrophenylsulfo-
nyl)perhydro-6,4-(iminomethano)isoquinoline (11b). To a stirred
solution of 2-nitrobenzenesulfonamide 10b (365 mg, 0.71 mmol)
and PPh3 (413 mg, 1.77 mmol) in benzene (7 mL) was slowly added
DEAD (0.28 mL, 1.77 mmol) at rt. After being stirred for 2 days,
the reaction mixture was concentrated and purified by chromatog-
raphy (Al2O3, hexane to hexane/EtOAc, 80:20) to give 11b (0.15
g, 0.3 mmol, 42%) as a yellow oil: IR (NaCl) 3077, 2929, 2801,
) 16.8, 10.4, 8, 6.4 Hz, 1H, )CH), 7.25-7.40 (m, 5H, ArH); 13
C
1
NMR (100 MHz, CDCl3, gHSQC) 25.8 (C-8), 27.0 (C-8a), 36.2
(C-7), 38.4 (C-4a), 40.4 (C-5), 40.9 (CH2), 46.3 (C-1), 49.1 (C-4),
51.1 (CH2Ar), 117.7 (CN), 121.3 (dCH2), 128.1, 128.2, 129.0 (Ar),
130.8 (dCH), 135.9 (ipso-Ar), 164.1 (C-3), 206.9 (C-6); HRMS
(ESI-TOF) calcd for C20H23N2O2 323.1754 [M + H]+, found
323.1751.
1543, 1368; H NMR (400 MHz, CDCl3, gCOSY) 1.40 (dt, J )
13.2, 3 Hz, 1H, H-5), 1.44-1.54 (m, 2H, H-4a, and H-7), 1.58-
1.72 (m, 1H, H-8), 1.80 (m, 1H, H-8a), 1.86-1.97 (m, 2H, H-1
and H-8), 1.97-2.06 (m, 3H, H-3, CH2), 2.18 (dm, J ) 12.2 Hz,
1H, H-5), 2.28 (m, 1H, H-7), 2.27 (tt, J ) 13.2, 6.6 Hz, 1H, H-7),
2.43 (dd, J ) 11.6, 1.2 Hz, 1H, H-1), 2.58 (d, J ) 11.2 Hz, 1H,
H-3), 3.16 (d, J ) 13.6 Hz, 1H, H-10), 3.39 and 3.50 (2d, J )
13.4 Hz, 1H each, CH2Ar), 3.99 (d, J ) 12.8 Hz, 1H, H-10), 4.13
(m, W1/2 ) 9 Hz, 1H, H-6), 4.68 (dd, J ) 15, 2 Hz, 1H, dCH2),
4.89 (dd, J ) 10, 2 Hz, 1H, dCH2), 5.55 (m, 1H, dCH), 7.20-
7.35 (m, 5H, ArH), 7.67 and 8.08 (2 m, 4H, H-Ns); 13C NMR (100
MHz, CDCl3, gHSQC) 24.8 (C-7), 28.7 (C-5), 30.6 (C-8), 34.6
(C-8a), 35.0 (C-4a), 36.0 (C-4), 40.9 (CH2), 47.4 (C-6), 49.5 (C-
10), 58.8 (C-3), 61.4 (C-1), 62.8 (CH2Ar), 118.4 (dCH2), 124.2,
126.9, 128.2, 128.6, 131.3, and 131.4 (Ar), 133.0 (dCH), 133.2,
133.6, 138.9, and 147.9 (Ar); HRMS (ESI-TOF) calcd for
C26H32N3O4S 482.2103 [M + H]+, found 482.2108.
(4RS,4aSR,8aRS)-4-Allyl-4-(aminomethyl)-2-benzyloctahy-
droisoquinolin-6(2H)-one Ethylene Acetal (6b). A solution of
AlCl3 (350 mg, 2.62 mmol) in THF (12 mL) was added to LiAlH4
(1 M in THF, 7.9 mL). The mixture was stirred for 15 min, and 5b
(1 g, 2.62 mmol) in THF (10 mL) was added dropwise. After being
stirred overnight at rt, the mixture was cooled to 0 °C and quenched
with aqueous 30% KOH. The reaction mixture was extracted
sequentially with CH2Cl2, CHCl3, and CHCl3/i-PrOH (4:1). The
dried organic extracts were concentrated and purified by chroma-
tography (Al2O3, CH2Cl2/MeOH, 99:1) to yield diamine 6b (0.65
g, 1.76 mmol, 67%): IR (NaCl) 3382, 3027, 2931, 2803, 1451; 1H
NMR (400 MHz, CDCl3, gCOSY) 1.48 (m, 2H, H-5 and H-8),
1.48-1.56 (m, 2H, H-7), 1.68-1.74 (m, 2H, H-5 and H-8), 1.73
(d, J ) 12.8 Hz, 1H, H-3), 1.87 (dm, J ) 13.2 Hz, 1H, H-4a), 2.24
(m, 2H, H-1 and H-8a), 2.26-2.32 (m, 2H, H-3 and CH2), 2.32
and 2.38 (2d, J ) 7.2 Hz, 1H each, CH2NH2), 2.45 (m, 1H, H-1),
2.73 (dd, J ) 13.8, 7.2 Hz, 1H, CH2), 3.41 and 3.48 (2d, J ) 13.2
Hz, 1H each, CH2Ar), 3.88-3.98 (m, 4H, OCH2), 5.01 (dd, J )
10.4, 2 Hz, 1H, )CH), 5.08 (dm, J ) 17.2 Hz, 1H, )CH2), 5.73
Acknowledgment. This research was supported by the MEC
(Spain)-FEDER through project CTQ2004-04701/BQU. Thanks
are also due to the DURSI (Catalonia) for Grant No. 2005SGR-
00442.
Supporting Information Available: Experimental and NMR
data for all compounds reported. Copies of 1H and 13C NMR spectra
of all compounds as well as COSY and HSQC spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(dddd, 1H, 17, 10, 9, 7.2 Hz, )CH), 7.20-7.40 (m, 5H, ArH); 13
C
NMR (100 MHz, CDCl3, gHSQC) 26.8 (C-8), 29.2 (C-8a), 30.0
(C-7), 30.9 (C-5), 36.9 (C-4a), 37.5 (CH2), 40.5 (C-4), 44.5 (CH2N),
JO702340W
J. Org. Chem, Vol. 73, No. 2, 2008 771