Asymmetric synthesis of tetracyclic benzo[a]quinolizidine targets

Article abstract of DOI:10.1021/jo801019h

(Chemical Equation Presented) We report a novel, facile, and asymmetric approach for the synthesis of polycyclic benzo[a]quinolizidine targets. In the formation of more functionalized derivatives, we have observed the generation of an iminium ether salt intermediate, formed during an unprecedented retro-Diels-Alder/N-acyliminium cyclization cascade. The iminium ether intermediate was isolated in good yield, characterized by X-ray crystallography, and subsequently applied as a synthetic building block.

Full text of DOI:10.1021/jo801019h

stereocenter as an added challenge to their synthesis. Other
research groups have also been engaged in the successful
development of alternative stereoselective N-acyliminium cy-
clization reactions to access similar heterocycles.6
Asymmetric Synthesis of Tetracyclic
Benzo[a]quinolizidine Targets
Steven M. Allin,*,† Sean N. Gaskell,† Mark R. J. Elsegood,†
and William P. Martin‡
Department of Chemistry, Loughborough UniVersity,
Loughborough, Leicestershire LE11 3TU, U.K., and
Synthetic Chemistry, GSK Pharmaceuticals, Gunnels Wood
Road, SteVenage, Hertfordshire SG1 2NY, U.K.
s.m.allin@lboro.ac.uk
Our own approach to the target system was similar to that
previously adopted by us in our route to the Erythrina alkaloids,7
in which cyclocondensation of an enantiomerically pure amino
alcohol with a racemic ketoacid substrate would generate a
tricyclic lactam intermediate, which in turn would function as
an appropriate N-acyliminium ion precursor, thus promoting
cyclization of the pendent aromatic nucleus from the original
amino acid substrate. The racemic keto acid 4 required for the
cyclocondensation step was synthesized by application of the
method of Stork.8 Subsequent condensation of this keto acid
with the appropriate R-amino alcohol under Dean-Stark condi-
tions in toluene for 48 h generated the desired tricyclic lactam
5 as a single diastereoisomer in 71% yield, as illustrated in
Scheme 1. The application of racemic, but enolizable, keto acids
in chiral lactam chemistry is now well established.9
The stereochemistry of the cyclopentane moiety within 5 is
represented by analogy to our work in the homologous series,7
with the ring junction fused cis with respect to the aromatic
substituent, and also from the result of the cyclization reaction,
detailed below, to yield 7, the structure of which has been
determined by X-ray crystallography. Treatment of tricyclic
lactam 5 with titanium tetrachloride in dichloromethane at -78
°C generated, presumably, the reactive N-acyliminium ion
intermediate 6, which then underwent a stereoselective cycliza-
tion to afford exclusively the tetracyclic benzo[a]quinolizidine
ReceiVed May 16, 2008
We report a novel, facile, and asymmetric approach for the
synthesis of polycyclic benzo[a]quinolizidine targets. In the
formation of more functionalized derivatives, we have
observed the generation of an iminium ether salt intermediate,
formed during an unprecedented retro-Diels-Alder/N-
acyliminium cyclization cascade. The iminium ether inter-
mediate was isolated in good yield, characterized by X-ray
crystallography, and subsequently applied as a synthetic
building block.
Benzo[a]quinolizidines are of significance since this ring
system is found within a wide range of biologically active
alkaloids, including protoemetinol 1,1 psychotrine,2 and alga-
nine.3 Fusion of additional rings to this parent heterocycle brings
additional interest; indeed, derivatives such as 2 have recently
been applied as synthetic building blocks in a new approach to
the antileukemic Cephalotaxus alkaloids, such as 3, by Li and
co-workers,4 through a transannular reductive rearrangement
strategy from substrate 2.
Indeed, it was the recent work of Li that inspired us to
investigate the possible application of the stereoselective N-
acyliminium cyclization of “Meyers-type” chiral lactams5 as a
new asymmetric approach to nonracemic tetracyclic ben-
zo[a]quinolizidine ring systems, such as the heterocyclic core
found within 2. Such targets contain a quaternary benzylic
(5) For recent examples of Meyers-type lactams as substrates for stereose-
lective cyclizations by our group, see: (a) Allin, S. M.; Khera, J. S.; Witherington,
J.; Elsegood, M. R. J. Tetrahedron Lett. 2006, 47, 5737. (b) Allin, S. M.; Duffy,
L. J.; Page, P. C. B.; McKee, V.; Edgar, M.; McKenzie, M. J.; Amat, M.; Bassas,
O.; Santos, M. M. M.; Bosch, J. Tetrahedron Lett. 2006, 47, 5713. (c) Allin,
S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.; Doyle, K.; Elsegood, M. R. J.;
Edgar, M. Tetrahedron Lett. 2006, 47, 1961. (d) Allin, S. M.; Thomas, C. I.;
Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Eur. J. Org. Chem. 2005, 4179. (e)
Allin, S. M.; Thomas, C. I.; Doyle, K.; Elsegood, M. R. J. J. Org. Chem. 2005,
70, 357. (f) Allin, S. M.; Thomas, C. I.; Allard, J. E.; Doyle, K.; Elsegood,
M. R. J. Tetrahedron Lett. 2004, 45, 7103. (g) Allin, S. M.; Thomas, C. I.;
Allard, J. E.; Duncton, M.; Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett.
2003, 44, 2335.
(6) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano, C.; Gomez-
Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J. Org. Chem. 2007,
72, 5193. Garcia, E.; Arrasate, A.; Lete, E.; Sotomayor, N. J. Org. Chem. 2005,
70, 10368. Garcia, E.; Arrasate, S.; Ardeo, A.; Lete, E.; Sotomeyer, N.
Tetrahedron Lett. 2001, 42, 1511. Ardeo, A.; Garcia, E.; Arrasate, S.; Lete, E.;
Sotomeyer, N. Tetrahedron Lett. 2003, 44, 8445.
† Loughborough University.
‡ GSK Pharmaceuticals.
(1) Battersby, A. R.; Kapil, R. S.; Bhakuni, B. S.; Popli, S. P.; Merchant,
J. R.; Salgar, S. S. Tetrahedron Lett. 1965, 4965.
(2) Takacs, J. M.; Boito, S. C. Tetrahedron Lett. 1995, 36, 2941, and
references therein.
(7) Allin, S. M.; James, S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org.
Chem. 2002, 67, 9464. Allin, S. M.; Streetley, G. B.; Slater, M.; James, S. L.;
Martin, W. P. Tetrahedron Lett. 2004, 45, 5493.
(8) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R.
J. Am. Chem. Soc. 1963, 85, 207.
(3) Itoh, A.; Ikuta, Y.; Tanahashi, T.; Nagakura, N. J. Nat. Prod. 2000, 63,
723. (a) Takayama, H.; Arai, M.; Kitajima, M.; Aimi, N. Chem. Pharm. Bull.
2002, 50, 1141.
(9) For recent examples, see: Amat, M.; Canto, M.; Llor, N.; Escolano, C.;
Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343. (b) Amat,
M.; Bassas, O.; Llor, N.; Canto, M.; Perez, M.; Molins, E.; Bosch, J. Chem.
Eur. J. 2006, 12, 7872.
(4) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. Li, W.-D. Z.; Ma,
B.-C. J. Org. Chem. 2005, 70, 3277.
6448 J. Org. Chem. 2008, 73, 6448–6451
10.1021/jo801019h CCC: $40.75 2008 American Chemical Society
Published on Web 07/18/2008

SCHEME 1a
SCHEME 3a
a Key: (i) toluene, ∆, 48 h (45%).
SCHEME 4a
a Key: (i) toluene, ∆, 48 h (71%); (ii) TiCl4, -78 °C, 48 h, DCM (73%).
SCHEME 2a
a Key: (i) TiCl4, - 78 °C, DCM; (ii) BF3 ·OEt2, DCM, ∆ (91%).
a Key: (i) TiCl4, -78 °C, 48 h, DCM (68%).
With lactam 11 in hand, we had visualized an asymmetric
N-acyliminium ion cyclization upon treatment with a Lewis acid
at low temperature to form target 12, containing a masked olefin
unit, that could be realized at a later stage through a retro-
Diels-Alder reaction (Scheme 4).
derivative 7 in 73% yield, and as a single diastereoisomer. The
absolute stereochemistry of target 7 was confirmed by single-
crystal X-ray analysis. The relative stereochemistry of 7 was
identical to that seen in the homologous series in our work on
the Erythrina alkaloids,7 with the cyclopentane ring fused anti
to the hydroxymethyl group.
Clearly, the availability of enantiomeric amino alcohol
reagents is a significant strength of this approach and allows
for the corresponding synthesis of the enantiomeric series of
cyclized products. Hence, condensation of the corresponding
S-amino alcohol with keto acid 4 in toluene for 48 h under
Dean-Stark conditions generated tricyclic lactam 8 as a single
diastereoisomer, in 76% yield. Treatment of the tricyclic lactam
8 with the Lewis acid afforded the tetracyclic target 9 in 68%
yield and as a single diastereoisomer. The absolute stereochem-
istry of 9 was confirmed by single-crystal X-ray analysis
(Scheme 2).
Unfortunately, treatment of the N-acyliminium ion precursor
11 with titanium tetrachloride at -78 °C failed to produce the
desired product 12 and resulted only in the degradation of the
starting material. Attempts to generate the N-acyliminium
intermediate and encourage the desired cyclization using an
alternative Lewis acid, boron trifluoride etherate, was also
unsuccessful at low temperatures with only starting materials
being recovered. In a final attempt to drive this cyclization, the
temperature of the reaction was elevated to refluxing dichlo-
romethane. After 24 h under these revised conditions, we were
delighted to observe, and isolate in good yield, the unexpected
iminium ether salt 13, shown in Scheme 4, as a single
diastereoisomer. A preference for boron trifluoride etherate over
titanium tetrachloride in the cyclization of L-DOPA-derived
acyliminium precursors has previously been noted by Lete and
co-workers.11 The structure of iminium salt 13 was unequivo-
cally determined by single-crystal X-ray crystallography (Figure
1), also confirming that the relative stereochemistry of this
densely functionalized product followed the same stereochemical
trends observed in the model tetracyclic systems and thus
confirming the relative stereochemistry of 11 by analogy.
Clearly, in the presence of excess boron trifluoride etherate, and
at moderately elevated temperatures, an unexpected reaction
cascade is occurring, although it is not clear at what point in
the sequence the retro-Diels-Alder reaction is occurring.
The intermediacy of iminium ethers in chiral lactam chemistry
has previously been proposed by Ennis,12 and more recently, a
range of bicyclic iminium ether salts were prepared and applied
We were pleased to observe that the stereochemical outcome
of these cyclizations could be rationalized using the same
conformational models previously proposed by us to explain
all related cyclizations.5
With the success of the N-acyliminium methodology dem-
onstrated with the preparation of model systems 7 and 9, we
focused our attention on the preparation of a more functionalized
tetracyclic target. Our attention turned to work by Lete and co-
workers describing a synthesis of functionalized polycyclic
lactam derivatives, in which a masked olefin moiety was
introduced in the form of a Diels-Alder adduct.10 With this
approach in mind, the highly functionalized polycyclic lactam
11 was then successfully prepared in 45% yield, as a single
diastereoisomer, by cyclocondensation of the racemic keto acid
10 and an enantiomerically pure amino alcohol under Dean-Stark
conditions (Scheme 3).
(11) Garcia, E.; Arrasate, S.; Lete, E.; Sotomeyer, N. J. Org. Chem. 2005,
70, 10368.
(10) Manteca, I.; Etxarri, B.; Ardeo, A.; Arrasate, S.; Osante, I.; Sotomayor,
N.; Lete, E. Tetrahedron 1998, 54, 12361.
(12) Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney,
P. A. J. Org. Chem. 1996, 61, 5813.
J. Org. Chem. Vol. 73, No. 16, 2008 6449

(NCO) and 2950 (aliphatic CH); HMR δH (400 MHz, CDCl3)
1.37-1.46 (2H, m), 1.60-1.66 (2H, m), 1.73-1.80 (2H, m),
1.87-1.91 (1H, m), 2.01-2.16 (2H), 2.34-2.37 (2H, m), 2.67 (1H,
dd, J 10.0, 13.4), 3.31 (1H, dd, J 3.6, 13.3), 3.70 (1H, dd, J 8.0,
9.1), 3.86 (3H, s), 3.88 (3H, s), 3.96 (1H, dd, J 7.8, 9.2), 4.39-4.48
(1H, m), 6.74-6.81 (3H, m); NMR δC (100 MHz, CDCl3) 21.9,
25.0, 29.4, 30.6, 36.1, 38.8, 42.1, 56.0, 55.9, 56.2, 67.3, 102.0,
111.2, 112.5, 121.3, 129.7, 147.7, 148.9, 169.8; MS (EI) m/z 331
[M+, 28.5] (M+, 331.1782; C19H25NO4 requires 331.1784).
(5R,10bR,13aR)-5-Hydroxymethyl-8,9-dimethoxy-1,2,5,6,11,12,-
13,13a-octahydrocyclopenta[2,3]pyrido[2,1-a]isoquinolin-3-one, 7.
(3R,7aR,10aS)-3-(3,4-Dimethoxybenzyl)hexahydro-1-oxa-3a-azacy-
clopenta[d]inden-5-one 5 (426 mg, 1.29 mmol) was dissolved in
dry dichloromethane (25 mL) under nitrogen. The mixture was
cooled to -78 °C, and titanium tetrachloride (732 mg, 0.43 mL,
3.86 mmol) was added dropwise. After being stirred at -78 °C for
10 min, the reaction was allowed to warm to room temperature
and stirred for 48 h. The reaction mixture was quenched with
saturated aqueous ammonium chloride (50 mL), extracted with
dichloromethane (3 × 50 mL), and dried over anhydrous magne-
sium sulfate. The product was filtered and the solvent removed by
rotary evaporation to yield the target compound, a single diaste-
reoisomer, which was purified by column chromatography over
silica gel with ethyl acetate as eluent to yield a colorless solid (310
mg, 73%): mp 138-141 °C; [R]D + 141.2 (c ) 1.01 in CH2Cl2);
IR νmax (thin film, CH2Cl2)/cm-1 1621, 2947, 3379; NMR δH (400
MHz, CDCl3) 1.70-1.82 (5H, m), 1.95-2.02 (1H, m), 2.14-2.25
(2H, m), 2.29-2.36 (1H, m), 2.52-2.57 (1H, m), 2.69-2.80 (2H,
m), 3.24 (1H, dd, J 9.4, 16.2), 3.71-3.75 (2H, m), 3.87 (3H, s),
3.88 (3H, s), 4.07-4.13 (1H, m), 6.64 (1H, s), 6.69 (1H, s); NMR
δC (100 MHz, CDCl3) 22.7, 23.9, 30.1, 30.2, 30.4, 43.1, 43.9, 55.9,
56.3, 56.5, 63.7, 72.0, 108.5, 112.0, 127.9, 134.0, 147.2, 147.9,
173.1; MS (EI) m/z 331 [M+, 46.5] (M+, 331.1784; C19H25NO4
requires 331.1784). The product was recrystallized from dichlo-
romethane/hexane by vapor diffusion to produce clear, colorless
crystals. The relative stereochemistry was confirmed by single-
crystal X-ray analysis.
(3S,6aS,10aR)-3-(3,4-Dimethoxybenzyl)hexahydro-1-oxa-3a-aza-
cyclopenta[d]inden-5-one, 8. (2S)-2-Amino-3-(3,4-dimethyloxy)phe-
nyl)propan-1-ol (900 mg, 4.26 mmol) and 3-(2-oxocyclopentyl)-
propionic acid 4 (798 mg, 5.11 mmol) were dissolved in toluene
(60 mL) and refluxed under Dean-Stark conditions for 48 h. The
reaction was allowed to cool to room temperature and the solvent
removed by rotary evaporation. The crude product was adsorbed
onto silica and chromatographed over silica gel using 3% methanol/
dichloromethane as eluent to produce the target compound as a
yellow oil (1.07 g, 76%): [R]D +80.8 (c ) 1.00 in CH2Cl2); IR
νmax (thin film, CH2Cl2)/cm-1 1648, 2950; NMR δH (400 MHz,
CDCl3) 1.37-1.46 (2H, m), 1.59-1.66 (2H, m), 1.74-1.81 (2H,
m), 1.87-1.90 (1H, m), 2.01-2.15 (2H, m), 2.34-2.37 (2H, m),
2.66 (1H, dd, J 10.0, 13.4), 3.32 (1H, dd, J 3.6, 13.3), 3.69 (1H,
dd, J 8.0, 9.1), 3.86 (3H, s), 3.88 (3 H, s), 3.96 (1H, dd, J 7.8, 9.2),
4.39-4.47 (1H, m), 6.73-6.80 (3 H, m); NMR δC (100 MHz,
CDCl3) 21.8, 24.9, 29.3, 30.6, 36.0, 38.8, 42.1, 55.9, 55.9, 56.1,
67.2, 102.0, 111.1, 112.4, 121.3, 129.7, 147.7, 148.9, 169.6; MS
(EI) m/z 331 [M+, 28.5] (M+, 331.1782; C19H25NO4 requires
331.1784).
FIGURE 1. Single-crystal X-ray structure of iminium ether salt 13.
SCHEME 5a
a Key: (i) DiBAL (2.5 equiv), DCM, 0 °C, then ∆, 5 h (65%).
as synthetic building blocks by Aube and co-workers, since these
compounds can display a range of useful reactivities.13 In our
hands, reductive ring-opening of the pentacyclic iminium ether
13 was achieved using diisobutylaluminium hydride to furnish
the enantiomerically pure target amine 14 in 65% yield (Scheme
5). It is noteworthy that the intermediacy of this iminium ether
effectively acts to remove the lactam carbonyl group from the
template through reductive ring opening. Although not subse-
quently performed in this current study, removal of the pendent
hydroxymethyl auxiliary group from similar heterocyclic tem-
plates has now been well established and documented by our
research group.14
In summary, we report a facile new asymmetric route to
access novel functionalized tetracyclic benzo[a]quiolizidine
targets. We have observed the generation of a pentacyclic
iminium ether intermediate, formed during an unprecedented
retro-Diels-Alder/N-acyliminium cyclization cascade sequence.
The iminium ether intermediate was isolated and characterized
by X-ray crystallography and further applied as a synthetic
building block. Current work in our group is focused on applying
nonracemic cyclopentene-containing building blocks, such as
14, in an approach to natural products.
Experimental Section
(3R,6aR,10aS)-3-(3,4-Dimethoxybenzyl)hexahydro-1-oxa-3a-aza-
cyclopenta[d]inden-5-one, 5. (2R)-2-Amino-3-(3,4-dimethyloxy)-
phenyl)propan-1-ol (584 mg, 2.77 mmol) and 3-(2-oxocyclopen-
tyl)propionic acid 4 (518 mg, 3.32 mmol) were dissolved in toluene
(60 mL) and refluxed under Dean-Stark conditions for 48 h. The
reaction was allowed to cool to room temperature and the solvent
removed by rotary evaporation. The crude product was adsorbed
onto silica and chromatographed using 3% methanol in dichlo-
romethane as eluent to produce a yellow oil (652 mg, 71%): [R]D
-86.3 (c ) 1.05 in CH2Cl2); IR νmax (thin film, CH2Cl2)/cm-1 1651
(5S,10bS,13aS)-5-Hydroxymethyl-8,9-dimethoxy-1,2,5,6,11,-
12,13,13a-octahydro-cyclopenta[2,3]pyrido[2,1-a]isoquinolin-
3-one, 9. (3S,7aS,10aR)-3-(3,4-Dimethoxybenzyl)hexahydro-1-oxa-
3a-azacyclopenta[d]inden-5-one 8 (438 mg, 1.32 mmol) was
dissolved in anhydrous dichloromethane (25 mL) under nitrogen.
The mixture was cooled to -78 °C, and titanium tetrachloride (752
mg, 0.43 mL, 3.97 mmol) was added dropwise. After being stirred
at -78 °C for 10 min, the reaction was allowed to warm to room
temperature and stirred for 48 h. The reaction mixture was quenched
with saturated ammonium chloride (50 mL), extracted with dichlo-
romethane (3 × 50 mL), and dried over anhydrous magnesium
sulfate. The product was filtered and the solvent removed by rotary
(13) Fenster, E.; Smith, B. T.; Gracias, V.; Milligan, G. L.; Aube, J. J. Org.
Chem. 2008, 73, 201.
(14) Allin, S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P.
Tetrahedron Lett. 2007, 48, 5669. Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.;
Page, P. C. B.; Saha, B.; McKenzie, M. J.; Martin, W. P. J. Org. Chem. 2007,
72, 8972.
6450 J. Org. Chem. Vol. 73, No. 16, 2008

evaporation to yield the target compound as a single diastereoiso-
mer, which was purified by column chromatography using silica
gel and ethyl acetate as eluent to yield a colorless solid (300 mg,
68%): mp 138-141 °C; [R]D -136.8 (c ) 5.00 in CH2Cl2); IR
νmax (thin film, CH2Cl2)/cm-1 1620, 2947, 3376; NMR δH (400
MHz, CDCl3) 1.70-1.82 (5H, m), 1.95-2.02 (1H, m), 2.14-2.25
(2H, m), 2.29-2.36 (1H, m), 2.52-2.57 (1H, m), 2.69-2.80 (2 H,
m), 3.24 (1H, dd, J 9.4, 16.2), 3.71-3.75 (2 H, m), 3.87 (3 H, s),
3.88 (3 H, s), 4.07-4.13 (1 H, m), 4.72 (1 H, br, s), 6.64 (1 H, s),
6.69 (1 H, s); NMR δC (100 MHz, CDCl3) 22.7, 23.9, 30.1, 30.2,
30.4, 43.1, 43.9, 55.9, 56.3, 56.5, 63.7, 72.0, 108.5, 112.0, 127.9,
134.0, 147.2, 147.9 and 173.1; MS (EI) m/z 331 [M+, 46.5] (M+,
331.1782; C19H25NO4 requires 331.1784). The product was recrys-
tallized from dichloromethane/hexane via vapor diffusion to produce
clear, colorless crystals. The relative stereochemistry was confirmed
by single-crystal X-ray analysis.
(3S,6aR,10aS)-3-(3,4-Dimethoxybenzyl)octahydro-1-oxa-3a-aza-
cyclopenta[d]inden-4-one-8,9-bicyclo[2.2.1]hept-2-ene, 11. (2S)-2-
Amino-3-(3,4-dimethyloxy)phenyl)propan-1-ol (1.88 g, 8.91 mmol)
and 3-(1-oxo-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-2-yl)-
propionic acid 10 (1.96 g, 8.91 mmol) were dissolved in toluene
(50 mL) and refluxed under Dean-Stark conditions for 48 h. The
reaction was allowed to cool to room temperature and the solvent
removed by rotary evaporation. The crude product was adsorbed
onto silica and chromatographed over silica gel using 3:2 ethyl
acetate/light petroleum as eluent to produce the target compound
as a yellow oil (1.59 g, 45%): [R]D -34.1 (c 1.08, CHCl3); IR νmax
(thin film)/cm-1 1650, 2956; NMR δH (400 MHz, CDCl3) 1.38-1.46
(2H, m), 1.56-1.73 (3H, m), 1.77-1.85 (1H, m), 2.05-2.09 (1H,
m), 2.28-2.37 (1H, m), 2.54 (1H, dt, J 5.6, 18.0), 2.68-2.77 (3H,
m), 2.98-3.05 (2H, m), 3.41 (1H, dd, J 4.0, 13.2), 3.75 (1H, dd,
J 7.6, 8.8), 3.83-3.88 (4H, m), 3.90 (3H, s), 4.56-4.60 (1H, m),
6.12 (1H, dd, J 3.2, 6.0), 6.23 (1H, dd, J 2.8, 5.6), 6.81 (2H, s),
6.84 (1H, s); NMR δC (100 MHz, CDCl3) 24.1, 30.3, 31.8, 39.5,
44.8, 45.2, 46.7, 47.2, 53.8, 55.9, 55.9, 56.1, 57.1, 67.6, 101.3,
111.2, 112.2, 121.1, 130.0, 133.7, 137.0, 147.9, 149.1, 170.1; MS
(FAB) m/z 396 [MH+, 0.4] (MH+, 396.2181; C24H29NO4 requires
396.2175).
91%): mp 206-207 °C; [R]D -286.3 (c 1.01, CH2Cl2); IR νmax
(thin film, CH2Cl2)/cm-1 1652, 2942; NMR δH (400 MHz, CDCl3)
2.01-2.13 (2H, m), 2.55-2.62 (1H, m), 2.81-2.88 (2H, m), 2.98
(1H, ddt, J 2.4, 9.2, 18.0), 3.17-3.23 (3H, m), 3.84 (3H, s), 3.86
(3H, s), 4.78-4.87 (1H, m), 4.95 (1H, dd, J 4.4, 9.6), 5.30 (1H,
dd, J 6.0, 9.2), 5.87-5.90 (1H, m), 6.15-6.17 (1H, m), 6.53 (1H,
s), 6.61 (1 H, s); NMR δC (100 MHz, CDCl3) 20.1, 22.1, 33.8,
37.3, 42.9, 56.1, 56.1, 56.2, 74.1, 77.7, 108.3, 111.6, 122.9, 128.3,
132.9, 135.2, 148.9, 149.1, 175.2; MS (EI) m/z 312 [M+, 3.4] (M+,
312.1595; C19H22NO3 requires 312.1600). The product was recrys-
tallized from dichloromethane/hexane via vapor diffusion to produce
clear, colorless crystals. The relative stereochemistry was confirmed
by single-crystal X-ray analysis.
(5S,10bR,13aR)-(8,9-Dimethoxy-2,3,5,6,13,13a-hexahydro-1H-
cyclopenta[2,3]pyrido[2,1-a]isoquinolin-5-yl)methanol,14.(5S,10bR,
13aR)-(8,9-Dimethoxy-1,2,5,6,13,13a hexahydrocyclopenta[e]ox-
azolo[3,2-a]pyrido[2,1-a]isoquinolinylium tetrafluoroborate 13 (612
mg, 1.53 mmol) was dissolved in anhydrous dichloromethane (5
mL) under nitrogen and cooled to 0 °C in an ice bath. A 1 M
solution of diisobutylaluminium hydride in hexane (3.83 mL, 3.83
mmol) was added dropwise at 0 °C, and the reaction was heated
under reflux for 5 h. The reaction was then cooled to 0 °C, and
methanol (5 mL) followed by saturated ammonium chloride (10
mL) were added carefully. The organics were washed with water
(5 mL), dried over magnesium sulfate, and concentrated to give an
oily residue, which was purified by column chromatography on
silica gel and 3:2 ethyl acetate/light petroleum as eluent to yield a
yellow oil (315 mg, 65%): [R]D -177.5 (c 1.02, CH2Cl2); IR νmax
(thin film, CH2Cl2)/cm-1 2930, 3389; NMR δH (400 MHz, CDCl3)
1.42-1.54 (2H, m), 1.70-1.77 (2H, m), 2.14-2.20 (1H, m),
3.32-2.43 (2H, m), 2.64-2.71 (3H, m), 2.75-2.82 (1H, m),
3.40-3.46 (1H, m), 3.52-3.63 (2H, m), 3.85 (3H, s), 3.86 (3H,
s), 5.89-5.91 (1H, m), 5.94-5.98 (1H, m), 6.58 (1H, s) and 6.76
(1H, s); NMR δC (100 MHz, CDCl3) 21.3, 24.0, 25.5, 35.7, 38.0,
44.0, 54.9, 55.8, 56.0, 60.8, 70.6, 109.7, 111.7, 126.6, 131.0, 132.7,
139.9, 147.4, 147.7; MS (FAB) m/z 316 (MH+, 316.1920;
C19H25NO3 requires 316.1913).
Acknowledgment. We thank Loughborough University and
GSK Pharmaceuticals for joint studentship support to S.N.G.
We also thank the ESPRC for beam time at Daresbury
Laboratory and Dr. J. Warren, the Station Scientist, for technical
support.
(5S,10bR,13aR)-(8,9-Dimethoxy-1,2,5,6,13,13a-hexahydrocyclo-
penta[e]oxazolo[3,2-a]pyrido[2,1-a]isoquinolinylium Tetrafluorobo-
rate, 13. To a stirred solution of (3S,6aR,10aS)-3-(3,4-dimethoxy-
benzyl)octahydro-1-oxa-3a-azacyclopenta[d]inden-4-one-8,9-
bicyclo[2.2.1]hept-2-ene 11 (723 mg, 1.83 mmol) in anhydrous
dichloromethane (15 mL) was added boron trifluoride diethyl
etherate (778 mg, 0.68 mL, 5.48 mmol) dropwise at room
temperature, and the resultant solution was heated under reflux.
After 15 h, the reaction was cooled to room temperature and
quenched with a saturated aqueous solution of ammonium chloride
(15 mL). The product was then extracted with dichloromethane (3
× 20 mL), dried over anhydrous magnesium sulfate, and evaporated
to yield the crude product, which was recrystallized from dichlo-
romethane/hexane to yield a colorless crystalline solid (664 mg,
1
Supporting Information Available: Copies of H and 13C
NMR spectra of representative compounds 5, 7-9, 11, 13, and
14. Crystallographic data for compounds 7, 9, and 13. Experi-
mental procedures for the synthesis of compounds 4 and 10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801019H
J. Org. Chem. Vol. 73, No. 16, 2008 6451