Preparation and diastereoselective birch reduction-alkylation of chiral 3,4-dihydro-l (2h)-isoquinolinones. Enantiospecific syntheses and opioid receptor affinities of several hydro-2,3dimethyl-1H-7,12a-methanobenzo[6,7]cycloocta[l,2-c]pyridine-9-ols

Article abstract of DOI:10.1021/jo980921g

Synthetic procedures have been developed to provide 2,3-disubstituted-3,4-dihydro-1(2H)-isoquinolinones 6,10, and 15 from (1R,2S)-ephedrine, (1R,2R)-pseudoephedrine, and L-phenylalanine. Birch reduction of 6 and 10 gave enantiomerically related lactam enolates that were alkylated with methyl iodide, allyl bromide, benzyl bromide, p-benzyloxybenzyl bromide, and p-methoxybenzyl bromide to give 7a-7e, lia, and 11b with diastereoselectivities > 20:1. Birch reduction-methylation of 15 gave 19 with a diastereoselectivity of >35:1. Selective reduction of the disubstituted double bond in 19 with diimide and cleavage of the tert-butyldimethylsilyl ether gave 20b, from which iodoetherification under thermodynamic control gave the iodopyran 21a; iodoetherification of 20b under kinetic control gave the iodotetrahydrofuran 22. Enantiospecific syntheses of analogues of 24 (Schultz, A. G.; Kirincich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554) have been developed. Tetracycle 24 is isomeric with the potent analgesic agent levorphanol, but the bridging of the hydroisoquinoline ring by the hydroxybenzyl unit in 24 is at C(7, isoquinoline numbering) and C(8a) rather than at C(1) and C(4a) as in levorphanol. The key step in the transformation of 7d and 7e to tetracyclic phenolic amines (-)-26 and (+)-28 is the Grewe-type cyclization of 7d to 25b and 7e to 25c. K_i values for the inhibition of binding to the μ-,δ-, and κ-opioid receptors by (-)-26, (+)-26, (+)-28, (-)-28, and (+)-32 are reported.

Full text of DOI:10.1021/jo980921g

J . Org. Chem. 1998, 63, 7795-7804
7795
P r ep a r a tion a n d Dia ster eoselective Bir ch Red u ction -Alk yla tion
of Ch ir a l 3,4-Dih yd r o-1(2H)-isoqu in olin on es. En a n tiosp ecific
Syn th eses a n d Op ioid Recep tor Affin ities of Sever a l Hyd r o-2,3-
d im eth yl-1H-7,12a -m eth a n oben zo[6,7]cycloocta [1,2-c]p yr id in e-9-ols
Arthur G. Schultz,* Timothy J . Guzi, Erika Larsson, Rainer Rahm, Kshitij Thakkar, and
J ean M. Bidlack1
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590, and Department
of Pharmacology, University of Rochester Medical Center, Rochester, New York 14642-8711
Received May 14, 1998
Synthetic procedures have been developed to provide 2,3-disubstituted-3,4-dihydro-1(2H)-isoquino-
linones 6, 10, and 15 from (1R,2S)-ephedrine, (1R,2R)-pseudoephedrine, and L-phenylalanine. Birch
reduction of 6 and 10 gave enantiomerically related lactam enolates that were alkylated with methyl
iodide, allyl bromide, benzyl bromide, p-benzyloxybenzyl bromide, and p-methoxybenzyl bromide
to give 7a -7e, 11a , and 11b with diastereoselectivities > 20:1. Birch reduction-methylation of
15 gave 19 with a diastereoselectivity of >35:1. Selective reduction of the disubstituted double
bond in 19 with diimide and cleavage of the tert-butyldimethylsilyl ether gave 20b, from which
iodoetherification under thermodynamic control gave the iodopyran 21a ; iodoetherification of 20b
under kinetic control gave the iodotetrahydrofuran 22. Enantiospecific syntheses of analogues of
24 (Schultz, A. G.; Kirincich, S. J .; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554) have been
developed. Tetracycle 24 is isomeric with the potent analgesic agent levorphanol, but the bridging
of the hydroisoquinoline ring by the hydroxybenzyl unit in 24 is at C(7, isoquinoline numbering)
and C(8a) rather than at C(1) and C(4a) as in levorphanol. The key step in the transformation of
7d and 7e to tetracyclic phenolic amines (-)-26 and (+)-28 is the Grewe-type cyclization of 7d to
25b and 7e to 25c. Ki values for the inhibition of binding to the µ-, δ-, and κ-opioid receptors by
(-)-26, (+)-26, (+)-28, (-)-28, and (+)-32 are reported.
We recently reported the first Birch reduction-alky-
lations of 2-alkyl-3,4-dihydro-1(2H)-isoquinolinones, e.g.,
1 f 2.2 This study was initiated because it appeared that
bicyclic lactams such as 2 possess particularly well
disposed functionality for utilization in the synthesis of
alkaloids and related nitrogen-containing heterocyclic
systems.
Resu lts a n d Discu ssion
Dihydro-1(2H)-isoquinolinone 6 could have been pre-
pared from methamphetamine, but since the amphet-
amines are controlled substances, we decided to prepare
6 from the readily available (1R,2S)-ephedrine (3) (Scheme
1); the enantiomer 10 was prepared from (1R,2S)-
pseudoephedrine (8) (Scheme 2).4
Dihydroisoquinolinone 1 is easily prepared from 2-phe-
nylethylamine by literature procedures.3 Inexpensive,
enantiomerically pure derivatives of 3-phenyl-2-propy-
lamine were expected to provide chiral analogues of 1.
In this paper, we describe the preparation and diaste-
reoselective Birch reduction-alkylation of several chiral
2,3-disubstituted-3,4-dihydro-1(2H)-isoquinolinones. Fur-
thermore, we describe the utilization of this new chem-
istry to prepare structural analogues of the potent
analgesic agent levorphanol.
Reaction of 3 with ethyl chloroformate provided the
urethane 4, and hydrogenolysis of the OH group in 4 with
Raney Ni in refluxing ethanol gave the methamphet-
amine derivative 5. The cyclization of 5 to give 6 was
carried out in methanesulfonic acid/P2O5 (10:1 by weight)
at 120 °C.5
It was necessary to demonstrate that racemization had
not occurred during hydrogenolysis with Raney Ni by a
competing process involving dehydration followed by
olefin hydrogenation. The racemate of 6 was prepared
by reductive amination (NaBH3CN/NH4OAc) of pheny-
lacetone, followed by acylation (ClCO2Et), cyclization
(MeSO3H/P2O5), and N-methylation (NaH/THF, MeI).
HPLC analyses verified that 6 had been prepared from
4 without racemization.
The Birch reduction-alkylations of 6 occurred with
>20:1 diastereoselectivity to give 7a -7e as the major
diastereomers. Product diastereomer ratios were deter-
mined by HPLC analysis (µ Porasil; hexane/2-propanol,
(1) University of Rochester.
(2) (a) Schultz, A. G.; Kirincich, S. J .; Rahm, R. Tetrahedron Lett.
1995, 36, 4551-4554. (b) Kirincich, S. J . Ph.D. Thesis, Rensselaer
Polytechnic Institute, Troy, NY, 1996.
(4) For the direct reduction of ephedrine and pseudoephedrine to
(3) (a) Davies, R. V.; Iddon, B.; Suschitzky, H.; Gittos, M. W. J .
Chem. Soc., Perkin Trans. 1 1978, 180-184. (b) Gramain, J . C.;
Simonet, N.; Vermeersch, G.; Febvay-Garot, N.; Caplain, S.; Lablanche-
Combier, A. Tetrahedron 1982, 38, 539-550.
methamphetamine, see: Emde, H. Helv. Chim. Acta 1929, 12, 365-
376.
(5) Eaton, P.; Carlson, G. R.; Lee, J . T. J . Org. Chem. 1973, 38,
4071-4073.
10.1021/jo980921g CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/07/1998

7796 J . Org. Chem., Vol. 63, No. 22, 1998
Schultz et al.
Sch em e 1a
F igu r e 1. Most stable conformation of the enolate generated
from Birch reduction of 6 (MM2, MacroModel).
Sch em e 3a
a
Reaction conditions: (a) ClCO2Et, CH2Cl2, NaHCO3, H2O, 0
°C; (b) Raney Ni, H2, EtOH, reflux; (c) MeSO3H, P2O5, 120 °C; (d)
Li, NH3/THF, t-BuOH, -78 °C; piperylene; RX.
a
Reaction conditions: (a) 37% CH2O, concentrated HCl, 85 °C;
(b) ClCO2Et, THF, NaHCO3, H2O, 0 °C; (c) LiAlH4, THF, reflux;
(d) TBSCl, DMF, imidazole; (e) RuO2 (cat.), NaIO4, CH3CN.
Sch em e 2a
anions generated from bislactam ethers.7 The most
stable conformation of the enolate generated from Birch
reduction of 6, as determined by molecular modeling
experiments, is shown in Figure 1. It is obvious from
the figure that the C(3) methyl substituent in a pseudo-
axial environment provides very effective shielding of the
â-face of the enolate. Placement of this methyl group in
a pseudoequatorial position would result in serious
eclipsing interactions with the neighboring N-methyl
substituent (Figure 1).8
The conversion of L-phenylalanine (12) to (+)-(3S)-3,4-
dihydro-3-(tert-butyldimethylsiloxymethyl)-2-methyl-1(2H)-
isoquinolinone (15) is shown in Scheme 3. (S)-1,2,3,4-
Tetrahydro-3-isoquinolinecarboxylic acid (13a ) can be
prepared from L-phenylalanine by a literature procedure9
or is available from commerical sources.10 Acylation of
13a with ethyl chloroformate gave 13b, and reduction of
13b with LiAlH4 in THF gave 14a in 77% overall yield
from 13a . Protection of 14a as the tert-butyldimethylsilyl
a
Reaction conditions: (a) ClCO2Et, CH2Cl2, NaHCO3, H2O, 0
°C; (b) Raney Ni, H2, EtOH, reflux; (c) MeSO3H, P2O5, 120 °C; (d)
Li, NH3/THF, t-BuOH, -78 °C; piperylene; RX.
9:1) before chromatographic separation. Stereochemical
assignments were made with a high degree of confidence
by comparison of experimentally determined coupling
constants for protons at C(3) and C(4) with those deter-
mined by utilization of MacroModel. A small amount of
the product of γ-alkylation was detected in the reaction
mixture that provided 7b.
Dihydro-1(2H)-isoquinolinone 10, the enantiomer of 6,
was prepared from (1R,2R)-pseudoephedrine (8) (Scheme
2). Birch reduction-alkylation of 10 gave the enanti-
omers 11a and 11b of the (4′-benzyloxy)benzyl and (4′-
methoxy)benzyl derivatives 7d and 7e.
The high degree of diastereoselectivity exhibited by
alkylations of enolates generated from Birch reduction
of 6 and 10 is striking in light of the modest stereose-
lectivities observed for enolates derived from 4-substi-
tuted cyclohexanecarboxylic acid derivatives.6 Stereo-
control is comparable to that found with alkylations of
(6) (a) House, H. O.; Bare, T. M. J . Org. Chem. 1968, 33, 943-949.
(b) Ziegler, F. E.; Wender, P. A. J . Am. Chem. Soc. 1971, 93, 4318-
4319. (c) Van Bekkum, H.; Van Den Bosch, C. B.; Van Minnen Pathuis,
G.; DeMos, J . C.; Van Wijk, A. M. Recl. Trav. Chim. Pays-Bas 1971,
90, 137-149. (d) Krapcho, A. P.; Dundulis, E. A. J . Org. Chem. 1980,
45, 3236-3245.
(7) (a) Scho¨llkopf, U.; Hartwig, W.; Groth, U. Angew. Chem., Int.
Ed. Engl. 1979, 18, 863-864. (b) Scho¨llkopf, U.; Groth, U. Angew.
Chem., Int. Ed. Engl. 1981, 20, 977-978.
(8) For
a similar pseudoaxial conformation of the C(3) benzyl
substituent of a N(4) methyl diketopiperazine observed in both the solid
state and solution phase, see: Budesinsky, M.; Symersky, J .; J ecny,
J .; VanHecke, J .; Hosten, N.; Angeunis, M.; Borremans, F. Int. J .
Peptide Protein Res. 1992, 39, 123.
(9) Hayashi, K.; Ozaki, Y.; Nunami, K.-I.; Yoneda, N. Chem. Pharm.
Bull. 1983, 31, 312-314.
(10) (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (13a ) is
available in high enantiomeric purity from the Nutra Sweet Company
and Aldrich Chemical Co.

2-Methyl-3,4-dihydroisoquinolin-1-ones
J . Org. Chem., Vol. 63, No. 22, 1998 7797
Sch em e 4a
Sch em e 5a
a
Reaction conditions: (a) LiAlH4, THF, reflux; (b) TBSCl, DMF,
imidazole; (c) ClCO2Et, THF, NaHCO3, H2O, 0 °C; (d) RuO2 (cat.),
NaIO4, CH3CN; NaOMe, MeOH; (e) n-BuLi, THF; MeI.
ether 14b and oxidation of 14b with catalytic ruthenium
11
tetroxide and NaIO4 gave 15. A chiral HPLC analysis
of 15 prepared from L-phenylalanine compared to racemic
15 demonstrated that (+)-15 had been prepared with no
detectable racemization.
a
Reaction conditions: (a) Li, NH3/THF, t-BuOH, -78 °C;
Although the oxidation of 14b to 15 was relatively
successful on a small scale, attempts to scale-up the
process were disappointing. For this reason, another
preparation of 15 was developed (Scheme 4). The ru-
thenium tetroxide oxidation of carbamate 17 followed by
carbamate cleavage with NaOMe provided lactam 18 in
75% yield; N-methylation gave 15.
piperylene; RX; (b) p-TosNHNH2, NaOAc, DME, reflux; (c) TBAF,
THF; (d) I2, THF, H2O, 25 °C, 96 h; (e) NIS, CH2Cl2, NaHCO3, 0
°C, 3 h; (f) MeLi, THF; (g) AIBN, Bu3SnH, benzene, reflux.
of iodopyran 21a with MeLi in THF to give 20b in
essentially quantitative yield.
Ap p lica tion to th e En a n tiosp ecific Syn th esis of
New Liga n d s for th e Op ioid Recep tor s. N-Methyl-
morphinan was first synthesized in 1946 by Grewe;13 the
levo isomer called levorphanol (23) is 4 times as potent
as morphine.13c Tetracycle 24 is isomeric with levorpha-
nol, but the bridging of the perhydroisoquinoline ring by
the hydroxybenzyl unit in 24 is at C(7, isoquinoline
numbering) and C(8a) rather than at C(1) and C(4a) as
in levorphanol. The distance from the phenolic hydroxy
group to the nitrogen atom in 24 is greater than that in
23; that is, levorphanol can be considered to be an
arylethylamine, while 24 is an arylpropylamine.14
Molecular models of levorphanol (23) reveal that the
C(9, morphinan numbering)-N bond resides in a plane
that is approximately orthogonal to the phenolic ring. The
relatively high degree of chirality15 of 23 results in high
stereospecificity for binding to the opioid receptors.16
Stereospecificity also has been observed for the unnatural
enantiomers of codeine, morphine, and heroin, all of
which showed no antinociceptive activity on subcutane-
ous injection in mice.17
Birch reduction-alkylation (MeI) of 15 gave the 1,4-
cyclohexadiene derivative 19 with a diastereoselectivity
(>35:1) exceeding that observed for the conversion of 6
to 7a (Scheme 5). It is believed that the higher diaste-
reoselectivity is a result of the larger TBSOCH2 group
at C(3), which more effectively shields the R-face of the
enolate from the alkylation reagent (see Figure 1).
Additional value from the C(3) stereodirecting group
in 19 was expected by way of cyclization reactions with
the C(4a)-C(5) double bond. Selective reduction of the
disubstituted double bond with diimide gave 20a , and
cleavage of the silyl ether in 20a gave 20b. Treatment
of olefinic alcohol 20b with I2 in THF and H2O under
conditions of thermodynamic control (25 °C, 96 h) gave
the iodopyran 21a in 94% isolated yield.12a Reduction of
21a with AIBN and Bu3SnH in benzene gave pyran 21b.
Treatment of 20b under conditions of kinetic control
with N-iodosuccinimide (1.1 equiv) in CH2Cl2 at 0 °C in
the presence of NaHCO3 gave a 9:1 mixture of 22 and
21a , from which the iodotetrahydrofuran 22 was obtained
in 78% yield by flash chromatography on silica gel. Thus,
both the cis- and trans-perhydroisoquinolone ring sys-
tems 21 and 22 are available by experimentally simple
iodoetherification reactions. Iodotetrahydrofuran 22 was
cleanly converted to the iodopyran 21a on treatment with
I2 in THF and H2O at 25 °C. Furthermore, it was
possible to reverse the iodoetherification12b by treatment
(13) (a) Grewe, R. Naturwissenschaften 1946, 33, 333-336. (b)
Grewe, R.; Mondon, A. Chem. Ber. 1948, 81, 279-286. (c) Benson, W.
M.; Stefko, P. L.; Randall, L. O. J . Pharmacol. Exp. Ther. 1953, 109,
189(1. 4) The meperidines and methadons contain an arylpropylamine
unit.
(15) (a) Avnir, D.; Katzenelson, O.; Zabrodsky Hel-Or, H. Chem. Eur.
J . 1996, 2, 744-746, and references therein. (b) Seri-Levy, A.; Richards,
W. G. Tetrahedron: Asymmetry 1993, 4, 1917-1923, and references
therein. (c) Crossley, R. Chirality and the Biological Activity of Drugs;
CRC Press: Boca Raton, FL, 1995; pp 21-47.
(16) Levorphanol and its inactive enantiomer dextrophan showed
4 orders of magnitude difference in their ability to displace 3H-labeled
ligand; see: (a) Terenius, L. Acta Pharmacol. Toxicol. 1973, 32, 317.
(b) Pert, C. B.; Snyder, S. H. Science 1973, 179, 1011-1014. (c) Simon,
E. J .; Hiller, J . M.; Edelman, I. Proc. Natl. Acad. Sci., U.S.A. 1973,
70, 1947-1949.
(11) Tangari, N.; Tortorella, V. J . Chem. Soc., Chem. Commun. 1975,
71-72.
(12) (a) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J . D.,
Ed.; Academic: New York 1984; Vol. 3, pp 411-454. (b) Ireland, R.
E.; Ha¨bich, D.; Norbeck, D. W. J . Am. Chem. Soc. 1985, 107, 3271-
3278.

7798 J . Org. Chem., Vol. 63, No. 22, 1998
Schultz et al.
Sch em e 6a
Sch em e 7a
a
Reaction conditions: (a) H2, 5% Pd/C, EtOAc, 79 psi; (b)
p-TosOH, HO(CH2)2OH, benzene, reflux; (c) LiAlH4, THF, reflux;
(d) BBr3, CH2Cl2, -78 °C to room temperature; (e) Li, NH3/THF,
t-BuOH, -78 °C.
a
Reaction conditions: (a) MeSO3H, CH2Cl2, 0 °C; (b) PDC (cat.),
Celite, t-BuOOH, benzene; (c) NaBH4, CeCl3, MeOH, 0 °C; (d)
BBr3, CH2Cl2, -78 °C to room temperature; (e) LiAlH4, THF,
reflux.
derivatives 25a -25c. A distinct advantage of the O-
benzyl ether 7d is that benzyl ether cleavage occurs along
with cyclization to give the phenol 25b. Reduction of the
lactam with LiAlH4 in THF gave the phenolic amine (-)-
26.
Allylic oxidation of the methyl ether analogue 25c
provided keto lactam 27; 27 was converted to the phenolic
amine (+)-28 containing the allylic alcohol moiety char-
acteristic of morphine (Scheme 6). The enantiomers of
(-)-26 and (+)-28, (+)-26 and (-)-28, were prepared from
the corresponding 1,4-cyclohexadiene derivatives 11a and
11b.
The phenolic amino ketone (+)-32 with a cis-perhy-
droisoquinoline ring fusion was prepared as shown in
Scheme 7. The cis ring junction was obtained by hydro-
genation of the enone double bond in 29. It is clear that
the axial methyl substituent is responsible for the
observed stereoselectivity. In the absence of the axial
methyl substituent, hydrogenation of the corresponding
bridgehead olefin provides the trans ring junction.2 The
trans-perhydroisoquinoline (+)-33 was obtained from 29
by the lithium in ammonia reduction (53% yield); how-
ever, a small amount of cis-fused 30 also was produced.
Op ioid Recep tor Affin ities. Opioid receptor affini-
ties for the enantiomerically pure ligands (-)-26, (+)-26,
(+)-28, (-)-28, and (+)-32 are shown in Table 1. Al-
By contrast, the nitrogen atom in 24 resides very
nearly coplanar with the phenolic ring. Thus, the polar
binding elements in 24 and its enantiomer are spatially
nearly equivalent; only hydrocarbon portions of the
perhydroisoquinoline ring system reside on opposite faces
of the aromatic ring in 24 and its enantiomer.18a Another
major difference between levorphanol and 24 is that the
orientation of the electron pair on nitrogen in 23 is anti
to the aromatic ring, whereas in 24 the orientation is
syn.18b
Tetracycle 24 was prepared as a racemate, and pre-
liminary opiate receptor binding studies showed modest
affinity for the µ- and κ-receptors: Ki (nM) >100 at the
µ-receptor, 2620 at the κ-receptor, and no binding de-
tected at the δ-receptor.2 With a lead structure estab-
lished, we decided to make structural modifications that
were expected to enhance opiate receptor affinity and
selectivity (Schemes 6 and 7). Potential ligands were
prepared as single enantiomers to test for stereoselec-
tivity of binding to the opiate receptors.
(18) (a) For a discussion of µ-opioid receptor models, see: Aldrich,
J . V. In Burger’s Medicinal Chemistry and Drug Discovery; Wolff, M.
E., Ed.; Wiley: New York, 1996; Vol. 3, pp 369-372. For a discussion
of uncertainty associated with the importance of nitrogen lone pair
orientation with respect to analgesic activity, see: (b) Belleau, B.;
Conway, T.; Ahmed, F. R.; Hardy, A. D. J . Med. Chem. 1974, 17, 907-
908. (c) Belleau, B.; Morgan, P. J . Med. Chem. 1974, 17, 908-909. (d)
Shiotani, S.; Kometani, T.; Iitaka, Y.; Itai, A. J . Med. Chem. 1978, 21,
153-154.
Grewe cyclization of 7c-7e with trifluoromethane-
sulfonic acid in CH2Cl2 gave the bridged cyclohexene
(17) Iijima, I.; Minamikawa, J .; J acobson, A. E.; Brossi, A.; Rice, K.
J . Org. Chem. 1978, 43, 1462-1463.

2-Methyl-3,4-dihydroisoquinolin-1-ones
J . Org. Chem., Vol. 63, No. 22, 1998 7799
Ta ble 1. Ki Va lu es (n M ( SEM) for th e In h ibition of
Bin d in g to µ-, δ-, a n d K-Op ioid Recep tor s on Bovin e
Str ia ta l Mem br a n es by (-)-26, (+)-26, (+)-28, (-)-28, a n d
(+)-32a
Tetrahydrofuran was dried over sodium/benzophenone ketyl
and distilled. All other reagents were used as purchased.
Reactions requiring anhydrous conditions were performed
under a nitrogen atmosphere. Baker silica gel (40 µm) was
used for flash column chromatographies. All chiral HPLC
analyses were carried out on a Chiracel OD column using a
9:1 mixture of hexane and 2-propanol.
compound [3H]DAMGO (µ) [3H]naltrindole (δ) [3H]U69,593 (κ)
(-)-26
(+)-26
(+)-28
(-)-28
(+)-32
2150 ( 210
3320 ( 230
4920 ( 530
4450 ( 440
2080 ( 150
3540 ( 310
5030 ( 800
3770 ( 470
4260 ( 1080
928 ( 85
244 ( 37
541 ( 26
1190 ( 250
1080 ( 100
887 ( 69
(-)-(1R,2S)-2-(Meth yl)eth oxyca r bon yla m in o-1-p h en yl-
1-p r op a n ol (4). To a solution of (1R,2S)-ephedrine (3) (4.28
g, 25.9 mmol) in CH2Cl2 (16 mL) was added a saturated
solution of NaHCO3 (24 mL). The resulting two-phase system
was stirred vigorously at 0 °C, and ethyl chloroformate (2.81
g, 2.48 mL, 25.9 mmol) in CH2Cl2 (4 mL) was added dropwise.
The reaction mixture was allowed to warm to room temper-
ature and stirred for 3 h, and then the CH2Cl2 layer was
separated. The water phase was extracted with CH2Cl2 (2 ×
100 mL), and the combined CH2Cl2 layers were dried over
MgSO4. Concentration and crystallization of the viscous oil
from hexane/ethyl acetate at 0 °C gave 4 as colorless crystals
a
Bovine striatal membranes, 0.5 mg of membrane protein, were
incubated in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5,
with at least six different concentrations of compounds in the
presence of either 0.25 nM [3H]DAMGO, 0.2 nM [3H]naltrindole,
or 1 nM [3H]U69,593 to measure binding to µ-, δ-, and κ-opioid
receptors, respectively. Naloxone at a final concentration of 1 µM
was used to measure nonspecific binding. Samples incubated with
either [3H]DAMGO or [3H]U69,593 were incubated at 25 °C for
60 min. To measure binding to δ-receptors, 5 mM MgCl2 and 1
mM PMSF were included with [3H]naltrindole and the test
compound. These samples were incubated at 25 °C for 3 h. Binding
was terminated by filtering samples through Schleicher & Scheull
No. 32 glass fiber filters. The filters were subsequently washed
three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and were
counted in 2 mL of Ecoscint A scintillation fluid. For [3H]pCl-
DPDPE and [3H]U69,593 binding, the filters were soaked in 0.25%
polyethylenimine for at least 60 min before use. IC50 values were
determined using the least-squares fit to a logarithm-probit
analysis. Ki values were calculated according to the equation
1
(6.03 g, 98%), mp 52-55 °C:21 IR (KBr) 3370, 1615 cm-1; H
NMR δ (500 MHz, 60 °C, CDCl3) 7.36-7.23 (m, 5 H), 4.82 (br
s, 1 H), 4.14-4.06 (m, 3 H), 2.90-2.50 (br s, 1 H, exchangeable
with D2O), 2.73 (s, 3 H), 1.23 (d, J ) 6.0 Hz, 3 H), 1.20 (t, J )
7.1 Hz, 3 H) ppm; 13C NMR δ (125.7 MHz, 60 °C, CDCl3) 156.8,
142.3, 128.0, 127.3, 126.1, 76.7, 61.1, 58.5, 31.5, 14.4, 12.0;
[R]23 -40 (c 0.7, CHCl3); CIMS, m/z (rel intensity) 238 (M+
+
D
1, 100). Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90.
Found: C, 65.77; H, 7.95; N, 5.88.
(+)-(2S )-[N -2-(1-p h e n ylp r op yl)-N -m e t h yl]e t h ylfor -
m a te (5). To a mechanically stirred suspension of Raney Ni
(wet, prepared from 200 g of aluminum-nickel alloy, Raney
type Ni-Al 50:50)22 in ethanol (700 mL) was added 4 (29.55
g, 0.125 mol), and the mixture was heated to reflux for 2 h.
After cooling to room temperature the mixture was filtered
through Celite. Concentration, flash chromatography (hexane/
ethyl acetate, 2:1) on silica gel (218 g), and distillation (88 °C/
0.35 mmHg) gave 5 as a colorless liquid (23.80 g, 86%): IR
IC50 value of the test compound
Ki )
1 + [Concentration of 3H-ligand]/Kd value of 3H-ligand
The equation was first reported by Cheng and Prusoff (Biochem.
Pharmacol. 1973, 22, 3099-3108). The Kd values for [3H]DAMGO,
[3H]naltrindole, and [3H]U69,593 binding to bovine striatal mem-
branes were 0.99, 0.12, and 0.60 nM, respectively.
(film) 1670, 1665 cm-1 1H NMR δ (500 MHz, CDCl, 70 °C)
;
though none of these new ligands display high affinity
for the opioid receptors, we believe that (-)-26 and (+)-
26 deserve further study since the κ-receptor affinity of
26 is an order of magnitude greater than that determined
for the lead structure 24. Analogue 26 is prepared in
only three steps from the chiral dihydro-1(2H)-isoquino-
linones 6 or 10, and it should be possible to modify the
substituent on nitrogen to enhance κ-receptor affinity and
selectivity.19 Utilization of the chemistry developed with
phenylalanine (Schemes 4 and 5) will allow the instal-
lation of a hydroxymethyl or related polar substituent20
at C(3) of the dihydroisoquinolin-1-one ring system. As
alluded to in the discussion concerning the degree of
chirality of 24, the absence of significant stereospecificity
for opioid receptor binding (Table 1) indicates that the
out-of-plane hydrocarbon units of 24 play little if any role
in the binding of 24 to the opioid receptors.
7.27-7.24 (m, 2 H), 7.18-7.15 (m, 3 H), 4.44 (br s, 1 H), 4.05
(broad q, 2 H), 2.75 (s, 3 H), 2.82 (dd, J ) 13.7, 7.1 Hz, 2 H),
1.17 (t, J ) 7.1 Hz, 3 H), 1.15 (d, J ) 6.0 Hz, 3 H); 13C NMR
(125.7 MHz, CDCl3) δ 156.3, 138.7, 128.8, 128.2, 126.1, 60.8,
52.2, 40.5, 27.8, 17.9, 14.5; [R]23 +37 (c 1.3, CHCl3); CIMS,
D
m/z (rel intensity) 222 (M+ + 1, 100). Anal. Calcd for C13H19
-
NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.45; H, 8.28; N,
6.31.
(-)-(3S)-3,4-Dih yd r o-2,3-d im eth yl-1(2H)-isoqu in olin o-
n e (6). Urethane 5 (4.734 g, 20.82 mmol) was added to Eaton’s
acid (28.51 g, MeSO3H/P2O5, 10:1.6 equiv by weight)5 at 120
°C. The reaction mixture was kept at 120 °C for 2 h, then
cooled to room temperature, and then poured into a saturated
solution of NaHCO3. The mixture was stirred for 30 min and
then extracted with CH2Cl2 (3 × 100 mL). The combined CH2-
Cl2 layers were washed with water (100 mL), dried over
MgSO4, and concentrated. Flash chromatography (EtOAc) on
silica gel and vacuum distillation (102 °C/0.35 mmHg) provided
6 as a colorless oil (2.63 g, 72%): IR (film) 1628, 1600 cm-1
;
1H NMR δ (500 MHz, CDCl3) 8.06 (m, 1 H), 7.39 (m, 1 H),
7.31 (m, 2 H), 7.15 (dd, J ) 6.9 Hz, 0.5 Hz, 1 H), 3.72 (m, 1 H),
3.35 (dd, J ) 15.9, 6.1 Hz, 2 H), 3.12 (s, 3 H), 2.66 (dd, J )
15.9, 2.5 Hz, 1 H), 1.15 (d, J ) 6.6 Hz, 1 H); 13C NMR δ (125.7
MHz, CDCl3) 163.6, 135.9, 131.4, 127.5, 126.6, 128.6, 53.5, 33.9,
Exp er im en ta l Section
Gen er a l P r oced u r es. Chemical ionization mass spectra
were obtained on a Hewlett-Packard 5987A GC-MS system
(isobutane). High-resolution mass spectra were obtained from
the University of Illinois facilities at Urbana-Champaign.
Thin-layer chromatography was performed with Merck Kie-
selgel 60 F-254 and Whatman Linear-K silica gel precoated
glass plates. Melting points are reported without correction.
Elemental analyses were obtained from Atlantic Microlab, Inc.,
Norcross, GA. Methylene chloride, methyl alcohol, tert-butyl
alcohol, and triethylamine were dried over CaH2 and distilled.
33.1, 17.3. [R]24D -300 (c 0.9, CHCl3); HRMS calcd for C11H13
-
NO (M + H+) 176.1075, found 176.1068. Anal. Calcd for
11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 74.69; H,
C
7.52; N, 7.89.
(+)-(3S,8aR)-3,4,6,8a-Tetr ah ydr o-8a-[(4-m eth oxyph en yl)-
m eth yl]-2,3-d im eth yl-1(2H)-isoqu in olin on e (7e). To a
solution of 6 (1.156 g, 9.90 mmol) and tert-butyl alcohol (0.88
(21) For a prior report of the preparation of 4 (viscous colorless oil)
see: Ettel, V.; Weichet, J . Collect. Czech. Chem. Commun. 1948, 13,
316.
(22) Fieser, L. F.; Fieser, M. In Reagents for Organic Synthesis;
Wiley: New York, 1967; Vol. 1, p 729.
(19) Rees, D. C. Prog. Med. Chem. 1992, 29, 109-139.
(20) Schultz, A. G.; Wang, A.; Alva, C.; Sebastian, A.; Glick, S. D.;
Deecher, D. C.; Bidlack, J . M. J . Med. Chem. 1996, 39, 1956-1966.

7800 J . Org. Chem., Vol. 63, No. 22, 1998
Schultz et al.
mL, 1.2 equiv) in THF (30 mL) at -78 °C was added liquid
ammonia (∼280 mL). Lithium was added in small pieces until
the blue coloration persisted, after which the solution was
stirred at -78 °C for 30 min. The blue coloration was
dissipated with piperylene, 4-methoxybenzyl chloride (4.83 gm,
31.00 mmol) in THF (5 mL) was introduced by syringe, and
the mixture was stirred for an additional 150 min at -78 °C.
Solid NH4Cl was added, and then the ammonia was allowed
to evaporate. The resulting pale yellow residue was parti-
tioned between CH2Cl2 (30 mL) and water (40 mL), and the
water layer was extracted with CH2Cl2 (2 × 30 mL). The
combined organic layers were washed with 10% sodium
thiosulfate solution (20 mL), dried over MgSO4, and concen-
trated. Flash chromatography (ethyl acetate/hexane, 2:1) on
(d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 172.1,
156.9, 136.7, 131.4, 131.3, 129.9, 129.0, 128.3, 128.2, 128.0,
127.4, 127.0, 126.0, 125.9, 124.1, 113.2, 113.1, 69.4, 53.6, 49.7,
43.9, 35.3, 34.0, 25.9, 18.1; [R]24 +120 (c 1.0, CHCl3); CIMS,
D
m/z (rel intensity) 374 (M+ + 1, 100). Anal. Calcd for C25H27
NO2: C, 80.38; H, 7.29. Found: C, 80.26; H, 7.19.
-
(+)-(1R,2R)-2-(Meth yl)eth oxyca r bon yla m in o-1-p h en yl-
1-p r op a n ol. (1R,2R)-Pseudoephedrine (8) (25.01 g, 151.3
mmol) in CH2Cl2 (100 mL) was treated as described for
preparation of 4 to give colorless crystals (29.94 g, 84%), mp
1
57-58 °C: IR (KBr) 3370, 1615 cm-1; H NMR δ (500 MHz,
60 °C, CDCl3) 7.36-7.23 (m, 5 H), 4.84 (br s, 1 H), 4.15-4.04
(m, 3 H), 2.90-2.50 (br s, 1 H), 2.76 (s, 3 H), 1.27 (d, J ) 6.0
Hz, 3 H), 1.20 (t, J ) 7.1 Hz, 3 H); 13C NMR δ (125.7 MHz, 60
°C, CDCl3) 157.2, 141.8, 127.9, 127.3, 126.2, 76.3, 61.2, 58.5,
silica gel gave 7e (2.21 gm, 75%): IR (CHCl3) 3025, 1622 cm-1
;
1H NMR δ (500 MHz, CDCl3) 6.88 (dd, J ) 7.8, 2.3 Hz, 2 H),
6.61 (dd, J ) 7.8, 2.3 Hz, 2 H), 6.03 (d, J ) 10.1 Hz, 1 H), 5.62
(m, 1 H), 5.39 (bm, 1 H), 3.66 (s, 3 H), 3.52 (m, 1 H), 2.95 (d,
J ) 12.5 Hz, 1 H), 2.84 (s, 3 H), 2.78 (d, J ) 12.5 Hz, 1 H),
2.71 (m, 1 H), 2.20 (dt, J ) 22.5, 4.5 Hz, 1 H), 1.92 (dd, J )
8.5, 3 Hz, 1 H), 1.63 (dt, J ) 22.5, 3.1 Hz, 1 H), 1.01 (d, J )
6.0 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 172.2, 157.8,
131.4, 130.0, 128.8, 128.3, 126.0, 124.2, 112.2, 54.7, 54.7, 53.7,
49.8, 43.9, 35.4, 34.1, 34.1, 25.9, 18.2; [R]24D +66 (c 1.0, CHCl3);
CIMS, m/z (rel intensity) 298 (M+ + 1, 100). Anal. Calcd for
31.5, 14.4, 11.7; [R]23 +16 (c 0.70, CHCl3); CIMS, m/z (rel
D
intensity) 238 (M+ + 1, 100). This material was used to
prepare 9 as described below. Anal. Calcd for C13H19NO3: C,
65.80; H, 8.07. Found: C, 65.90; H, 8.02.
(-)-(2R )-[N -2-(1-p h e n ylp r op yl)-N -m e t h yl]e t h ylfor -
m a te (9): 81% isolated yield from 8; IR (film) 1670, 1665 cm-1
;
1H NMR δ (500 MHz, CDCl3, 70 °C) 7.27-7.24 (m, 2 H), 7.18-
7.15 (m, 3 H), 4.44 (br s, 1 H), 4.05 (br q, 2 H), 2.75 (s, 3 H),
2.82 (dd, J ) 13.7, 7.1 Hz, 2 H), 1.17 (t, J ) 7.1 Hz, 3 H), 1.15
(d, J ) 6.0 Hz, 3 H); 13C NMR (125.7 MHz, CDCl3) δ 156.3,
138.7, 128.8, 128.2, 126.1, 60.8, 52.2, 40.5, 27.8, 17.9, 14.5;
C
19H23NO2: C, 76.74; H, 7.80. Found: C, 76.71; H, 7.87.
(+)-(3S,8aR)-3,4,6,8a-Tetr ah ydr o-2,3,8a-tr im eth yl-1(2H)-
[R]23 -33 (c 1.3, CHCl3); CIMS, m/z (rel intensity) 222 (M+
+
D
isoqu in olin on e (7a ): 72% isolated yield; IR (CHCl3) 1610
cm-1; 1H NMR δ (500 MHz, CDCl3) 6.17 (dt, J ) 10.0, 1.5 Hz,
1 H), 5.76-5.72 (m, 1 H), 5.55-5.53 (m, 1 H), 3.48 (m, J )
6.0, 1.6, 6.6 Hz, 1 H), 2.98-2.94 (m, 1 H), 2.90 (s, 3 H), 2.68-
2.66 (m, 2 H), 2.06 (dd, J ) 13.2, 1.6 Hz, 1 H), 1.38 (s, 3 H),
1.13 (d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 173.1,
133.2, 130.7, 123.0, 120.9, 53.7, 43.5, 35.1, 34.0, 28.4, 26.1, 18.1;
[R]21D +170 (c 0.80, CHCl3); CIMS, m/z (rel intensity) 192 (M+
+ 1, 100). Anal. Calcd for C12H17NO: C, 75.36; H, 8.96; N,
7.32. Found: C, 74.24; H, 8.99; N, 7.23.
1, 100). Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33.
Found: C, 70.29; H, 8.36; N, 6.32.
(+)-(3R)-3,4-Dih yd r o-2,3-d im eth yl-1(2H)-isoqu in olin o-
n e (10): 68% isolated yield; IR (film) 1628, 1600 cm-1; 1H NMR
δ (500 MHz, CDCl3) 8.06 (m, 1 H), 7.39 (m, 1 H), 7.31 (m, 2
H), 7.15 (dd, J ) 6.9, 0.5 Hz, 1 H), 3.72 (m, 1 H), 3.35 (dd, J
) 15.9, 6.1 Hz, 2 H), 3.12 (s, 3 H), 2.66 (dd, J ) 15.9, 2.5 Hz,
1 H), 1.15 (d, J ) 6.6 Hz, 1 H); 13C NMR δ (125.7 MHz, CDCl3)
163.6, 135.9, 131.4, 127.5, 126.6, 128.6, 53.5, 33.9, 33.1, 17.3;
[R]23D +330 (c 0.70, CHCl3); CIMS, m/z (rel intensity) 176 (M+
+ 1, 100). Anal. Calcd for C11H13NO: C, 75.40; H, 7.48.
Found: C, 75.89; H, 6.46.
(-)-(3S,8a R)-3,4,6,8a -Tet r a h yd r o-2,3-d im et h yl-8a -(2-
p r op en yl)-1(2H)-isoqu in olin on e (7b): 66% isolated yield;
IR (film) 3060, 3022, 1625 cm-1; 1H NMR δ (500 MHz, CDCl3)
6.06 (dt, J ) 10.0, 2.0 Hz, 1 H), 5.88-5.84 (m, 1 H), 5.70-5.62
(m, 2 H), 5.02-4.97 (m, 2 H), 3.48 (m, J ) 5.7, 0.8 Hz, 1 H),
2.91-2.88 (m, 4 H), 2.62 (m, 2 H), 2.51 (d, J ) 7.3 Hz, 2 H),
2.03 (d, J ) 13.2 Hz, 1 H), 1.14 (d, 3 H); 13C NMR δ (125.7
MHz, CDCl3) 172.2, 133.5, 130.4, 128.2, 125.0, 122.9, 117.0,
(-)-(3R,8a S)-3,4,6,8a -Tet r a h yd r o-2,3-d im et h yl-8a -[[4-
(p h en ylm et h oxy)p h en yl]m et h yl]-1(2H )-isoq u in olin on e
(11a ): 66% isolated yield; IR (CHCl3) 3027, 1620 cm-1; 1H NMR
δ (500 MHz, CDCl3) 7.42-7.23 (m, 5 H), 6.98 (dd, J ) 7.8, 2.3
Hz, 2 H), 6.79 (dd, J ) 7.8, 2.3 Hz, 2 H), 6.10 (d, J ) 10.1 Hz,
1 H), 5.71 (m, 1 H), 5.47 (br m, 1 H), 5.02 (s, 2 H), 3.43 (m, 1
H), 3.03 (d, J ) 12.5 Hz, 1 H), 2.92 (s, 3 H), 2.87 (d, J ) 12.5
Hz, 1 H), 2.81 (m, 1 H), 2.28 (dt, J ) 22.5, 4.5 Hz, 1 H), 1.99
(dd, J ) 8.5, 3 Hz, 1 H), 1.70 (dt, J ) 22.5, 3.1 Hz, 1 H), 1.01
(d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 172.1,
156.9, 136.7, 131.4, 131.3, 129.9, 129.0, 128.3, 128.2, 128.0,
127.4, 127.0, 126.0, 125.9, 124.1, 113.2, 113.1, 69.4, 53.6, 49.7,
53.7, 47.7, 43.9, 35.2, 34.0, 26.5, 18.3; [R]23 -170 (c 1.2,
D
CHCl3); CIMS, m/z (rel intensity) 218 (M+ + 1, 100).
(+)-(3S,8a R)-3,4,6,8a -Tetr a h yd r o-2,3-d im eth yl-8a -(p h e-
n ylm eth yl)-1(2H)-isoqu in olin on e (7c): 68% isolated yield;
IR (CHCl3) 1620 cm-1 1H NMR δ (500 MHz, CDCl3) 7.18-
;
7.14 (m, 3 H), 7.09-7.06 (m, 2 H), 6.13 (dd, J ) 9.8, 2.5 Hz, 1
H), 5.74-5.70 (m, 1 H), 5.49 (dt, J ) 3.1, 1.6 Hz, 1 H), 3.46
(dd, J ) 6.0, 1.6 Hz, 1 H), 3.10 (d, J ) 12.5 Hz, 1 H), 2.95 (s,
3 H), 2.94 (d, J ) 12.5 Hz, 1 H), 2.86-2.81 (m, 1 H), 2.28 (dt,
J ) 22.2, 4.8 Hz, 1 H), 2.04 (dd, J ) 13.1, 1.3 Hz, 1 H), 1.66
(m, 1 H), 1.12 (d, J ) 6.4 Hz, 3 H); 13C NMR δ (125.7 MHz,
CDCl3) 172.4, 137.0, 130.8, 130.2, 128.5, 127.0, 126.3, 126.0,
43.9, 35.3, 34.0, 25.9, 18.1; [R]24 -110 (c 1.0, CHCl3); CIMS,
D
m/z (rel intensity) 374 (M+ + 1, 100). Anal. Calcd for C25H27
NO2: C, 80.38; H, 7.29. Found: C, 80.24; H, 7.27.
-
(-)-(3R,8aS)-3,4,6,8a-Tetr ah ydr o-8a-[(4-m eth oxyph en yl)-
m eth yl]-2,3-d im eth yl-1(2H)-isoqu in olin on e (11b): 51% iso-
lated yield; IR (CHCl3) 3025, 1622 cm-1; 1H NMR δ (500 MHz,
CDCl3) 6.88 (dd, J ) 7.8, 2.3 Hz, 2 H), 6.61 (dd, J ) 7.8, 2.3
Hz, 2 H), 6.03 (d, J ) 10.1 Hz, 1 H), 5.62 (m, 1 H), 5.39 (br m,
1 H), 3.66 (s, 3 H), 3.52 (m, 1 H), 2.95 (d, J ) 12.5 Hz, 1 H),
2.84 (s, 3 H), 2.78 (d, J ) 12.5 Hz, 1 H), 2.71 (m, 1 H), 2.20
(dt, J ) 22.5, 4.5 Hz, 1 H), 1.92 (dd, J ) 8.5, 3 Hz, 1 H), 1.63
(dt, J ) 22.5, 3.1 Hz, 1 H), 1.01 (d, J ) 6.0 Hz, 3 H); 13C NMR
δ (125.7 MHz, CDCl3) 172.2, 157.8, 131.4, 130.0, 128.8, 128.3,
126.0, 124.2, 112.2, 54.7, 54.7, 53.7, 49.8, 43.9, 35.4, 34.1, 34.1,
124.5, 54.0, 50.0, 45.0, 35.7, 34.4, 26.2, 18.5; [R]24 -150 (c
D
1.0, CHCl3); CIMS, m/z (rel intensity) 268 (M+ + 1, 100);
HRMS calcd for C18H21NO (M + H+) 268.1701, found 268.1704.
The minor diastereomer: 1H NMR δ (500 MHz, CDCl3)
7.18-7.16 (m, 3 H), 7.09-7.06 (m, 2 H), 6.14 (dd, J ) 10.1,
1.7 Hz, 1 H), 5.71-5.68 (m, 1 H), 5.51 (m, 1 H), 3.39 (m, 1 H),
3.11 (d, J ) 12.5 Hz, 1 H), 3.01 (s, 3 H), 2.98 (d, J ) 12.5 Hz,
1 H), 2.42-2.38 (m, 1 H), 2.37 (dd, J ) 10.1, 1.7 Hz, 1 H),
2.27-1.76 (m, 2 H), 1.27 (d, J ) 6.3 Hz, 3 H).
25.9, 18.2; [R]22 -59 (c 1.1, CHCl3); CIMS, m/z (rel intensity)
D
(+)-(3S,8a R)-3,4,6,8a -Tet r a h yd r o-2,3-d im et h yl-8a -[[4-
(p h en ylm et h oxy)p h en yl]m et h yl]-1(2H )-isoq u in olin on e
(7d ): 68% isolated yield; IR (CHCl3) 3027, 1620 cm-1; 1H NMR
δ (500 MHz, CDCl3) 7.42-7.23 (m, 5 H), 6.98 (dd, J ) 7.8 Hz,
2.3 Hz, 2 H), 6.79 (dd, J ) 7.8, 2.3 Hz, 2 H), 6.10 (d, J ) 10.1
Hz, 1 H), 5.71 (m, 1 H), 5.47 (bm, 1 H), 5.02 (s, 2 H), 3.43 (m,
1 H), 3.03 (d, J ) 12.5 Hz, 1 H), 2.92 (s, 3 H), 2.87 (d, J ) 12.5
H, 1 H), 2.81 (m, 1 H), 2.28 (dt, J ) 22.5, 4.5 Hz, 1 H), 1.99
(dd, J ) 8.5, 3 Hz, 1 H), 1.70 (dt, J ) 22.5, 3.1 Hz, 1 H), 1.01
298 (M+ + 1, 100). Anal. Calcd for C19H23NO2: C, 76.74; H,
7.80. Found: C, 76.57; H, 7.79.
2-Ca r b oet h oxy-1,2,3,4-t et r a h yd r o-3-isoq u in olin eca r -
boxylic Acid (13b). To a solution of 13a 9,10 (4.50 g, 25.3
mmol) and NaHCO3 (6.37 g, 5.0 equiv) in a 1:1 mixture of THF
and water (60 mL) at 0 °C was added ethyl chloroformate (2.54
mL, 1.05 equiv). The resulting solution was warmed slowly
to room temperature, stirred for 3 h, and then diluted with
water (25 mL) and adjusted to pH 8-10 with 10% NaOH. The

2-Methyl-3,4-dihydroisoquinolin-1-ones
J . Org. Chem., Vol. 63, No. 22, 1998 7801
solution was extracted with ether (2 × 25 mL). The aqueous
layer was acidified with 10% HCl before extracting with EtOAc
(3 × 25 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give colorless crystals
(3S)-1,2,3,4-Tetr a h yd r o-3-isoqu in olin em eth a n ol (16a ).
To a slurry of LiAlH4 (3.20 g, 2.5 equiv) in THF (120 mL) was
added 13a (6.30 g, 35.2 mmol). The resulting mixture was
heated at reflux for 6 h. The reaction was quenched by
addition of NaOH solution until a white precipitate was
formed. More THF was added, and the mixture was heated
at reflux for 10 min. The precipitate was filtered, and the
remaining solution was dried over MgSO4 and concentrated
to give yellow crystals (86%), mp 105-107 °C: IR (film) 3300
cm-1; 1H NMR (500 MHz, CDCl3) 7.12 (m, 2 H), 7.07 (m, 1 H),
7.00 (m, 1 H), 4.03 (s, 2 H), 2.06 (dd, J ) 11.0, 3.7 Hz, 1 H),
3.51 (dd, J ) 11.0, 7.8 Hz, 1 H), 3.09 (s, 1 H), 3.05 (m, 2 H),
2.68 (dd, J ) 16.4, 4.4 Hz, 1 H), 2.59 (dd, J ) 16.4, 11.0 Hz, 1
H); 13C NMR (CDCl3) 135.1, 133.8, 129.2, 126.2, 126.0, 125.8,
65.3, 55.0, 47.6, 30.7; CIMS m/z 164 (M + 1).
(6.34 g, 100%), mp 129-130 °C: [R]23 +74 (c 1.0, CHCl3); 1H
D
NMR (CDCl3) 7.22-7.09 (m, 4 H), 5.14 (q, J ) 6.4, 3.2 Hz, 1
H), 4.77-4.71 (m, 1 H), 4.52-4.42 (m, 1 H), 4.24-4.20 (m, 2
H), 3.27-3.13 (m, 2 H), 1.31 (t, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3) 176.5, 156.5, 132.2, 131.3, 128.4, 127.9, 126.8, 126.1,
62.1, 52.6, 44.1, 30.6, 14.5; IR (Nujol) 2968, 1733, 1645, 1462,
1350; CIMS m/z (rel intensity) 250 (M+ + 1, 100), 204 (12.5).
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62.
Found: C, 62.57; H, 6.04; N, 5.67.
2-Met h yl-1,2,3,4-t et r a h yd r o-3-isoq u in olin em et h a n ol
(14a ). To a solution of LiAlH4 (4.37 g, 5.0 equiv) in THF (100
mL) was added 13b (5.75 g, 23.0 mmol). The solution was
heated at reflux for 5 h and then was quenched by the
sequential addition of water (4.37 mL), 10% NaOH (4.37 mL),
and water (4.37 mL). Anhydrous Na2SO4 was added, and the
resulting slurry was filtered through Celite. The pale yellow
solution was concentrated under reduced pressure, and the
residue was crystallized from CH2Cl2/hexanes to give colorless
(3S )-1,2,3,4-Te t r a h yd r o-3-t er t -b u t yld im e t h ylsiloxy-
m eth ylisoqu in olin e (16b). To a solution of 16a (200 mg,
1.23 mmol) and imidazole (209 mg, 2.5 equiv) in DMF (1 mL)
was added tert-butyldimethylsilyl chloride (203 mg, 1.1 equiv).
The resulting solution was stirred at room temperature
overnight and then was poured into saturated NaHCO3,
extracted with EtOAc, dried over MgSO4, and concentrated
to a yellow oil. Flash chromatography (1% acetone in CH2-
crystals (3.14 g, 77%), mp 104-106 °C: [R]23 -64 (c 1.0,
D
Cl2) gave a yellow oil (59%): IR (film) 1100 cm-1 1H NMR
;
CHCl3); 1H NMR (CDCl3) 7.15-7.11 (m, 2 H), 7.09-7.07 (m, 1
H), 7.03-7.01 (m, 1 H), 3.87 (d, J ) 15.6 Hz, 1 H), 3.70-3.67
(m, 2 H), 3.59 (dd, J ) 6.4, 1.3 Hz, 1 H), 3.34 (s, 1 H), 2.86-
2.80 (m, 1 H), 2.77 (d, J ) 6.9 Hz, 2 H), 2.41 (s, 3 H); 13C NMR
(CDCl3) 133.9, 133.6, 128.7, 126.5, 126.4, 125.9, 62.5, 60.0, 55.9,
40.0, 28.0; IR (Nujol) 2924, 1458, 1377, 1144, 723; CIMS m/z
(rel intensity) 178 (M+ + 1, 100), 146 (10), 160 (6). Anal. Calcd
for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.63;
H, 8.54; N, 7.94.
(500 MHz, CDCl3) 7.07 (m, 4 H), 4.08 (d, J ) 4.2 Hz, 2 H),
3.77 (dd, J ) 9.8, 3.9 Hz, 1 H), 3.61 (dd, J ) 9.8, 6.9 Hz, 1 H),
3.02 (m, 1 H), 2.65 (m, 2 H), 2.37 (bs, 1 H), 0.90 (s, 9 H), 0.10
(s, 6 H).
(3S)-2-Ca r b oet h oxy-1,2,3,4-t et r a h yd r o-3-ter t-b u t yld i-
m eth ylsiloxym eth ylisoqu in olin e (17). To a solution of 16b
(2.72 g, 9.8 mmol) and NaHCO3 (2.06 g, 2.5 equiv) in a 1:1
mixture of THF and water (40 mL) at 0 °C was added ethyl
chloroformate (1.03 mL, 1.1 equiv). The resulting solution was
warmed slowly to room temperature, stirred for 4 h, and then
diluted with water. The mixture was extracted with EtOAc,
dried over MgSO, and concentrated to a yellow oil. Flash
chromatography using ethyl acetate and hexane (1:9) as eluent
gave a colorless oil (82%): IR (film) 3300, 1680, 1100 cm-1; 1H
NMR (500 MHz, CDCl3) 7.23-7.17 (m, 4 H), 4.78 (t, J ) 20
Hz, 1 H), 4.49 (m, 1 H), 4.35 (d, J ) 16.6 Hz, 1 H), 4.24 (m, 2
H), 3.61 (m, 1 H), 3.38 (m, 1 H), 3.00 (m, 1 H), 1.34 (m, 1 H),
0.90 (s, 9 H), 0.02 (s, 6 H); CIMS m/z 350 (M+ + 1). Anal.
Calcd for C19H31NO3Si: C, 65.29; H, 8.94; N, 4.01. Found: C,
65.03; H, 8.93; N, 3.99.
2-Meth yl-1,2,3,4-tetr a h yd r oisoqu in olin e-3-ter t-bu tyld i-
m eth ylsiloxym eth a n e (14b). To a solution of 14a (1.00 g,
5.62 mmol) and imidazole (0.96 g, 2.5 equiv) in DMF (5 mL)
was added tert-butyldimethylsilyl chloride (0.93 g, 1.1 equiv).
The resulting solution was stirred at room temperature for 3
h. The reaction mixture was poured into saturated NaHCO3
(20 mL), and the resulting solution was extracted with EtOAc
(3 × 20 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo. The residue was chro-
matographed using ethyl acetate and hexane (65:35) as eluent
to give a colorless oil (1.38 g, 84%): [R]24 -97 (c 1.0, CHCl3);
D
1H NMR (CDCl3) 7.14-7.09 (m, 4 H), 7.02 (d, J ) 7.3 Hz, 1
H), 3.86-3.81 (m, 2 H), 3.65-3.59 (m, 2 H), 2.89 (dd, J ) 16.4,
4.9 Hz, 1 H), 2.80 (dd, J ) 16.3, 8 Hz, 1 H), 2.72-2.70 (m, 1
H), 2.51 (s, 3 H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C NMR (CDCl3)
134.4, 133.9, 128.6, 126.1, 126.0, 125.8, 64.1, 60.8, 56.9, 42.0,
30.8, 25.8, 18.2, -5.5; IR (film) 1471, 1255, 1104, 1072, 776;
CIMS, m/z (rel intensity) 292 (M+ + 1) 292 (100), 146 (18).
Anal. Calcd for C17H29NOSi: C, 70.04; H, 10.03; N, 4.81.
Found: C, 69.92; H, 10.00; N, 4.76.
(3S)-3,4-Dih yd r o-3-ter t-b u t yld im et h ylsiloxym et h yl-
1(2H)-isoqu in olin on e (18). To a stirred solution of 17 (6.02
g, 17.7 mmol) and NaIO4 (15.6 g, 4.1 equiv) in CCl4 (60 mL),
CH3CN (60 mL), and water (90 mL) was added RuO2 (52 mg,
2.2 mol %). The resulting solution was stirred at room
temperature for 1 h before diluting with CH2Cl2 and water.
The layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated. Without further purifica-
tion the residue was dissolved in a solution of CH3ONa (1.13
g, 1.2 equiv) in MeOH (300 mL). The mixture was heated at
reflux for 1 h before diluting with 10% NH4Cl. The mixture
was then extracted with CH2Cl2, after which the combined
organic layers were dried over MgSO4 and concentrated. Flash
chromatography (2% acetone in CH2Cl2) gave off-white crystals
(+)-(3S)-3,4-Dih ydr o-3-ter t-bu tyldim eth ylsiloxym eth yl-
2-m eth yl-1(2H)-isoqu in olin on e (15). To a well-stirred solu-
tion of 14b (500 mg, 1.71 mmol) and NaIO4 (1.49 g, 4.1 equiv)
in CCl4 (5 mL), CH3CN (5 mL), and water (7.5 mL) was added
RuO2 (5 mg, 2.2 mol %). The resulting solution was stirred at
room temperature for 3.5 h before diluting with CH2Cl2 (10
mL) and water (10 mL). The layers were separated and the
aqueous layer extracted with CH2Cl2 (2 × 15 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure. Flash chromatography using
a 5% acetone in CH2Cl2 solution as eluent gave a white solid
(75%), mp 48-51 °C: IR (CHCl3) 3185, 1665, 1600, 1100 cm-1
;
1H NMR (500 MHz, CDCl3) 8.08 (d, J ) 7.5 Hz, 1 H), 7.45 (t,
J ) 7.6 Hz, 1 H), 7.35 (t, J ) 7.6 Hz, 1 H), 7.20 (d, J ) 7.3 Hz,
1 H), 6.28 (s, 1 H), 3.83 (m, 1 H), 3.74 (dd, J ) 10, 4.7 Hz, 1
H), 3.60 (dd, J ) 10, 8.5 Hz, 1 H), 2.86 (m, 2 H), 0.90 (s, 9 H),
0.07 (s, 6 H); 13C NMR (500 MHz, CDCl3) 193.2, 165.8, 137.1,
132.1, 127.8, 127.4, 126.9, 65.3, 52.3, 29.9, 25.6, 18.0; CIMS
m/z 292 (M+ + 1). Anal. Calcd for C16H25NO2Si: C, 65.93; H,
8.71; N, 4.81. Found: C, 65.86; H, 8.71; N, 4.75.
(0.34 g, 65%), mp 57-59 °C: [R]25 +190 (c 1.0, CHCl3); 1H
D
NMR (CDCl3) 8.10 (d, J ) 7.8 Hz, 1 H), 7.44 (t, J ) 7.3 Hz, 1
H), 7.35 (t, J ) 7.6 Hz, 1 H), 7.19 (d, J ) 7.6 Hz, 1 H), 3.72-
3.69 (m, 2 H), 3.50 (t, J ) 10 Hz, 1 H), 3.34 (dd, J ) 16.1, 5.9
Hz, 1 H), 3.26 (s, 3 H), 3.05 (d, J ) 16.1 Hz, 1 H), 0.9 (s, 9 H),
0.01 (s, 6 H); 13C NMR (CDCl3) 163.9, 135.8, 131.6, 128.9,
127.7, 127.6, 126.8, 61.8, 59.4, 34.9, 28.7, 25.6, 18.0, -5.7, -5.8;
IR (Nujol) 1660, 1262, 1107, 850; CIMS, m/z (rel intensity) 306
(M+ + 1, 100), 248 (10). An alternative preparation of 15 is
described below. Anal. Calcd for C17H27NO2Si: C, 66.84; H,
8.91; N, 4.59. Found: C, 66.90; H, 8.94; N, 4.65.
Alter n a tive Meth od for P r ep a r a tion of 15. To a stirred
solution of 18 (113 mg, 0.48 mmol) in THF (1 mL) at -78 °C
was added n-BuLi (210 µL, 1.1 equiv). The mixture was
warmed to 0 °C and stirred for 45 min before MeI (89 µL, 3
equiv) was added. The mixture was warmed to room temper-
ature, diluted with water, and then extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and

7802 J . Org. Chem., Vol. 63, No. 22, 1998
Schultz et al.
concentrated. Flash chromatography (2% acetone in CH2Cl2)
gave 15 (80%).
48.1, 42.1, 33.9, 33.0, 32.7, 28.9, 17.6; IR (Nujol) 1651, 1244,
1075; CIMS, m/z (rel intensity) 336 (M+ + 1, 100), 208 (45).
Anal. Calcd for C12H18INO2: C, 43.00; H, 5.41; N, 4.18.
Found: C, 43.53; H, 5.26; N, 4.01.
(+)-(3S,8a S)-3,4,6,8a -Tetr a h yd r o-2,8a -d im eth yl-3-ter t-
bu t yld im et h ylsiloxym et h yl-1(2H)-isoq u in olin on e (19).
To a well-stirred solution of 15 (200 mg, 0.65 mmol) and tert-
butyl alcohol (62.2 µL, 1.05 equiv) in THF (4 mL) and NH3
(20 mL) was added lithium until a blue coloration persisted
for 15 min. Excess metal was quenched by the dropwise
addition of piperylene, and then MeI (0.20 µL, 5.0 equiv) was
added. The resulting solution was stirred at -78 °C for 1 h,
quenched with solid NH4Cl, and warmed to room temperature.
After evaporation of NH3 was complete, the residue was
diluted with CH2Cl2 (50 mL) and water (50 mL) and the layers
were separated. The aqueous layer was extracted with CH2-
Cl2 (2 × 15 mL), and the combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. Flash
chromatography using ether and hexane (20:80) as eluent gave
Iod ofu r a n 22. To a solution of 20b (18 mg, 0.086 mmol)
in CH2Cl2 (0.5 mL) with suspended NaHCO3 at 0 °C was added
N-iodosuccinimide (21.4 mg, 1.1 equiv). The resulting solution
was stirred at 0 °C for 3 h, diluted with CH2Cl2 (5 mL), washed
with saturated Na2S2O3 (2 × 2 mL) and 10% NaOH (1 × 2
mL), dried over Na2SO4, and concentrated under reduced
1
pressure. An H NMR spectrum of the resulting oil showed a
9:1 mixture of 22 and 21a . Flash chromatography using
EtOAc and hexane (80:20) as eluent gave 22 as a white solid
(22.5 mg, 78%). An analytical sample was obtained by
crystallization from EtOAc and hexane, mp 166-168 °C: [R]26
D
+70 (c 0.5, CHCl3); 1H NMR (CDCl3) 4.39 (bs, 1 H), 3.92 (d, J
) 8 Hz, 1 H), 3.79 (d, J ) 8 Hz, 1 H), 3.75 (s, 1 H), 2.91 (s, 3
H), 2.75 (d, J ) 12 Hz, 1 H), 2.20-2.30 (m, 1 H), 2.04 (d, J )
14.1 Hz, 1 H), 1.90-1.87 (m, 3 H), 1.76-1.74 (m, 1 H), 1.70 (s,
3 H), 1.63-1.60 (m, 1 H); 13C NMR (CDCl3) 176.3, 83.2, 73.6,
61.4, 49.6, 39.3, 34.2, 34.0, 30.9, 28.6, 26.8, 17.2; IR (Nujol)
1633, 1322, 1147; CIMS, m/z (rel intensity) 336 (M+ + 1, 100),
208 (30). Anal. Calcd for C12H18INO2: C, 43.00; H, 5.41; N,
4.18. Found: C, 43.29; H, 5.45; N, 4.20.
a colorless solid (0.15 g,71%), mp 47-48 °C: [R]24 +88 (c 1.0,
D
CHCl3); 1H NMR (CDCl3) 6.15 (d, J ) 10 Hz, 1 H), 5.75-5.71
(m, 1 H), 5.53 (bs, 1 H), 3.59 (dd, J ) 9.5, 4.4 Hz, 1 H), 3.43 (t,
J ) 9 Hz, 1 H), 3.37-3.33 (m, 1 H), 2.97 (s, 3 H), 2.78-2.75
(m, 1 H), 2.66-2.65 (m, 2 H), 2.50 (d, J ) 13.4 Hz, 1 H), 1.38
(s, 3 H), 0.90 (s, 9 H), 0.04 (s, 6 H); 13C NMR (CDCl3) 173.5,
133.1, 130.6, 123.1, 120.9, 61.7, 59.5, 43.7, 35.3, 29.7, 28.6, 26.1,
25.6; IR (CHCl3) 3000, 1610, 1200, 750, 655 cm-1; CIMS, m/z
(rel intensity) 322 (M+ + 1, 100), 176 (5).
P yr a n 21b. A solution of 21a (13.1 mg, 0.0389 mmol),
n-Bu3SnH (0.013 mL, 1.2 equiv), and AIBN (1 mg) in benzene
(1.5 mL) was deoxygenated for 15 min prior to reflux. After
60 min, the solution was cooled, concentrated under reduced
pressure, and diluted with ether (5 mL). The resulting
solution was treated with DBU (1 equiv), filtered through silica
gel, and concentrated. Flash chromatography (EtOAc) gave
Red u ction of 19 w ith Diim id e. P r ep a r a tion of 20a . To
a well-stirred solution of 19 (240 mg, 0.68 mmol) and p-
TOSNHNH2 (1.27 g, 10.0 equiv) in DME (20 mL) was added
NaOAc (1.12 g, 20 equiv) in water (15 mL) over 2 h; the
resulting solution was refluxed overnight. The reaction mix-
ture was cooled to room temperature, poured into water (50
mL), and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. Flash chromatography (EtOAc) gave a colorless oil (230
a white solid (5.8 mg, 71%), mp 119-121 °C: [R]23 -170 (c
D
1
0.24, CHCl3); H NMR (CD3CN) 3.82 (dt, J ) 11.3, 2.4 Hz, 1
H), 3.71 (bs, 1 H), 3.47 (d, J ) 11.3 Hz, 1 H), 3.36-3.35 (m, 1
H), 2.86 (s, 3 H), 2.48 (dq, J ) 13.2, 6.6, 2.7 Hz, 1 H), 2.42-
2.38 (m, 1 H), 1.83-1.79 (m, 2 H), 1.60-1.52 (m, 2 H), 1.48-
1.42 (m, 1 H), 1.36-1.31 (m, 1 H), 1.21 (s, 3 H), 1.06-1.00 (m,
1 H); 13C NMR (CD3CN) 177.2, 74.9, 66.8, 55.2, 41.1, 40.3, 35.9,
33.3, 31.8, 29.0, 27.1, 18.1; IR (CHCl3) 1624, 1210, 764; HRMS
calcd for C12H19NO2 (M+) 209.1415, found 209.1416.
mg, 80%): [R]22 +65 (c 1.0, CHCl3); 1H NMR (CDCl3) 5.42
D
(bs, 1 H), 3.59 (dd, J ) 9.2, 4.4 Hz, 1 H), 3.38 (t, J ) 9 Hz, 1
H), 3.34-3.31 (m, 1 H), 2.97 (s, 3 H), 2.62-2.59 (m, 1 H), 2.39
(d, J ) 13.2 Hz, 1 H), 2.06-1.97 (m, 3 H), 1.72-1.67 (m, 2 H),
1.45 (ddd, J ) 25.4, 12.70, 4.90 Hz, 1 H), 1.33 (s, 3 H), 0.90 (s,
9 H), 0.05 (s, 6 H); 13C NMR (CDCl3) 175.6, 134.4, 123.6, 62.2,
59.7, 41.9, 35.3, 32.7, 30.4, 25.7, 25.3, 24.5, 17.9; IR (film)
1633.2, 1251.9, 1102.2, 837.4; HRMS calcd for C18H34NO2Si
(M + H+) 324.2359, found 324.2355.
Regen er a tion of 20b fr om 21a . MeLi (0.12 mL of a 1.4M
solution, 3.5 equiv) was added to a solution of 20b (10 mg,
0.048 mmol) in THF (0.4 mL) at 0 °C. The resulting solution
was stirred for 3 h at 0 °C and then warmed to room
temperature and stirred an additional 2 h. The reaction
mixture was quenched with water and extracted with EtOAc
(3 × 5 mL). The combined organic layers were dried over Na2-
SO4 and concentrated under reduced pressure to give 20b
La cta m Alcoh ol 20b. A solution of 20a (100 mg, 0.31
mmol) in THF (2 mL) and TBAF (0.46 mL, 1.5 equiv) was
stirred 3 h and then diluted with water (5 mL) and extracted
with EtOAc (3 × 5 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Flash chroma-
tography (3% MeOH in CH2Cl2) gave 20b (52 mg, 81%). An
1
(quantitative, H NMR analysis).
Cycliza tion of 7c to th e Meth a n oben zo[6,7]cycloocta -
[1,2-c]p yr id in e Rin g System . P r ep a r a tion of 25a . To a
solution of 7c (3.42 g, 12.7 mmol) in CH2Cl2 (80 mL) at 0 °C
was added triflic acid (0.55 mL). The reaction mixture was
stirred at 0 °C for 15 min and then allowed to warm to room
temperature and stirred for 14 h. The yellow solution was
diluted with additional CH2Cl2 (125 mL) and then was
carefully washed with a saturated NaHCO3 solution (120 mL).
The CH2Cl2 layer separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 80 mL). The combined CH2Cl2
layers were dried over MgSO4 and concentrated. Flash
chromatography (EtOAc) on silica gel gave 25a as a colorless
analytical sample was obtained by crystallization from EtOAc
1
and hexane, mp 104-106 °C: [R]24 -72 (c 0.40, CHCl3); H
D
NMR (CDCl3) 5.50 (bs, 1 H), 3.68 (dd, J ) 10.7, 3.9 Hz, 1 H),
3.52 (t, J ) 8.5 Hz, 1 H), 3.39-3.36 (m, 1 H), 2.98 (s, 3 H),
2.71-2.68 (m, 1 H), 2.41 (d, J ) 13.5 Hz, 1 H), 2.21 (bs, 1 H),
2.07-1.95 (m, 3 H), 1.71-1.66 (m, 2 H), 1.46 (td, J ) 13, 4.7
Hz, 1 H), 1.34 (s, 3 H); 13C (CDCl3) 176.1, 134.9, 123.6, 62.1,
60.0, 42.1, 35.1, 32.6, 31.0, 25.3, 24.5, 17.9; IR (Nujol) 3297,
1602, 1048; CIMS, m/z (rel intensity) 210 (M+ + 1, 100), 178
(10). Anal. Calcd for C12H19NO2: C, 68.86; H, 9.15; N, 6.69.
Found: C, 68.58; H, 9.24; N, 6.56.
Iod op yr a n 21a . A solution of 20b (10 mg, 0.048 mmol)
and I2 (30.35 mg, 2.5 equiv) in THF and H2O was stirred at
room temperature for 96 h. Saturated sodium thiosulfate was
added, and the mixture was extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried over Na2SO4 and
concentrated. Flash chromatography using EtOAc and hexane
(80:20) as eluent gave 21a (15 mg, 94%). An analytical sample
was obtained by crystallization from EtOAc and hexane, mp
solid (2.98 g, 86%), mp 113-115 °C: IR (CHCl3) 1610 cm-1
;
1H NMR δ (500 MHz, CDCl3) 7.14-7.09 (m, 3 H), 7.02 (d, J )
6.6 Hz, 1 H), 5.38 (m, 1 H), 3.49 (m, 1 H), 3.40 (d, J ) 16.5 Hz,
1 H), 3.25-3.23 (m, 1 H), 2.97 (s, 3 H), 2.84 (dd, J ) 16.5 Hz,
2.2 Hz, 1 H), 2.79-2.75 (m, 1 H), 2.60-2.55 (m, 1 H), 2.43
(ddd, J ) 12.5 Hz, 4.0 Hz, 1.5 Hz, 1 H), 2.03 (m, 1 H), 2.00
(dd, J ) 13.4 Hz, 1 H), 1.74 (dt, J ) 12.5, 2.2 Hz, 1 H), 1.17 (d,
J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 173.9, 140.2,
134.5, 132.9, 128.6, 128.5, 126.0, 125.8, 122.4, 53.9, 42.3, 38.9,
132-134 °C: [R]24 +30 (c 0.5, CHCl3); 1H NMR (CDCl3) 4.16
D
(t, J ) 2.7 Hz, 1 H), 3.88 (dt, J ) 11.2, 2.5 Hz, 1 H), 3.55 (d,
J ) 11.5 Hz, 1 H), 3.30-3.26 (m, 1 H), 3.18, 3.17 (m, 1 H),
2.89 (s, 3 H), 2.65 (dd, J ) 13.2, 2.4 Hz, 1 H), 2.46-2.36 (m, 2
H), 1.86-1.83 (m, 1 H), 1.78-1.69 (m, 1 H), 1.49 (s, 3 H), 1.43-
1.35 (m, 2 H); 13C NMR (CDCl3) 171.5, 82.2, 66.8, 59.1, 58.2,
35.7, 35.5, 34.2, 33.0, 32.2, 18.6; [R]23 -150 (c 1.0, CHCl3);
D
CIMS, m/z (rel intensity) 268 (M+ + 1, 100). Anal. Calcd for
C
18H21NO: C, 80.86; H, 7.92. Found: C, 80.46; H, 8.10.
(25b). 7d (0.739 g, 1.98 mmol) provided a colorless viscous
oil (0.454 g, 81%): IR (CHCl3) 3400, 1610 cm-1 1H NMR δ
;

2-Methyl-3,4-dihydroisoquinolin-1-ones
J . Org. Chem., Vol. 63, No. 22, 1998 7803
(500 MHz, CDCl3) 6.86 (d, J ) 8.0 Hz, 1 H), 6.62 (m, 2 H),
5.39 (m, 1 H), 3.51 (m, 1 H), 3.30 (d, J ) 16.5 Hz, 1 H), 3.20-
3.18 (bm, 1 H), 2.97 (s, 3 H), 2.77 (dd, J ) 16.5, 2.2 Hz, 1 H),
2.79-2.75 (m, 1 H), 2.57-2.53 (m, 1 H), 2.40 (ddd, J ) 12.5,
4.0, 1.5 Hz, 1 H), 2.05 (m, 1 H), 2.00 (dd, J ) 13.4, 0.5 Hz, 1
H), 1.70 (dt, J ) 12.5, 2.2 Hz, 1 H), 1.16 (d, J ) 6.6 Hz, 3 H);
13C NMR δ (125.7 MHz, CDCl3) 173.8, 157.4, 140.6, 131.6,
128.2, 127.3, 123.2, 111.1, 112.1, 54.9, 42.2, 37.9, 35.4, 35.2,
by adding NH4Cl (5 mL) and a few drops of HCl (10%). The
resulting mixture was extracted with EtOAc (4 × 15 mL). The
organic layers were combined, washed with brine (10 mL),
dried over MgSO4, and filtered. Evaporation in vacuo gave
the alcohol (0.065 g, 74%) as a colorless foam: IR (CHCl3) 3400,
1
1663, 1640 cm-1; H NMR δ (500 MHz, CDCl3) 7.01 (d, J )
8.0 Hz, 1 H), 6.80-6.75 (m, 2 H), 5.34 (s, 1 H), 4.52 (d, J ) 6.0
Hz, 1 H), 3.79 (s, 3 H), 3.53 (m, 1 H), 3.32 (d, J ) 16.5 Hz, 1
H), 3.25 (m, 1 H), 2.97 (s, 3 H), 2.78 (d, J ) 16.5 Hz, 2 H), 2.50
(dd, J ) 13.5, 3 Hz, 1 H), 2.01 (dd, J ) 14.6, 1.5 Hz, 1 H), 1.85
(dd, J ) 13.5 Hz, 1 H), 1.17 (d, J ) 6.6 Hz, 3 H); 13C NMR δ
(125.7 MHz, CDCl3) 173.1, 157.1, 134.7, 133.9, 129.8, 127.6,
127.3, 115.4, 113.2, 70.4, 55.1, 53.4, 42.7, 39.4, 38.0, 35.0, 34.2,
32.5, 18.7; CIMS, m/z (rel intensity) 314 (M+ + 1, 100). Anal.
Calcd for C19H23NO3: C, 72.82; H, 7.40. Found: C, 72.72; H,
7.35.
The alcohol (0.065 g, 0.21 mmol) was dissolved in CH2Cl2
(5 mL) under N2 and cooled to -78 °C. BBr3 in CH2Cl2 solution
(1 M, 1 mL) was added, and the reaction mixture was allowed
to warm to room temperature. After stirring overnight at room
temperature, the reaction was cooled to 0 °C and quenched
with water. The resulting mixture was extracted with EtOAc
(4 × 15 mL). The organic layers were combined, washed with
brine (10 mL), dried over MgSO4, and filtered. Flash chro-
matography (CH2Cl2/MeOH, 10:1) on silica gel afforded the
phenol as a foam (0.041 g, 68%): IR (CHCl3) 3500, 1661, 1637
cm-1; 1H NMR δ (500 MHz, (CD3)2CO) 8.02 (bs, exchangeable
with D2O), 6.83 (d, J ) 8.0 Hz, 1 H), 6.70 (d, J ) 1.5 Hz, 1 H),
6.53 (dd, J ) 8.0 Hz, 1.5 Hz, 1 H), 5.30 (s, 1 H), 4.52 (bd, J )
6.0 Hz, 1 H), 3.58 (m, 1 H), 3.35 (d, J ) 9.5 Hz, 1 H), 3.10 (d,
J ) 16.5 Hz, 1 H), 2.97 (s, 3 H), 2.87 (m, 1 H), 2.78 (d, J )
16.5 Hz, 2 H), 2.69 (m, 1 H), 2.32 (dd, J ) 13.5, 3 Hz, 1 H),
1.78 (dt, J ) 13.5, 3.5 Hz, 1 H), 1.14 (d, J ) 6.6 Hz, 3 H); 13C
NMR δ (125.7 MHz, (CD3)2CO) 173.1, 155.8, 136.4, 135.6,
130.4, 129.0, 127.0, 119.7, 115.5, 71.9, 55.6, 44.6, 41.4, 39.5,
36.0, 35.1, 34.1, 19.4; CIMS, m/z (rel intensity) 300 (M+ + 1,
100). Anal. Calcd for C18H21NO3: C, 72.72; H, 7.07. Found:
C, 72.89; H, 6.81.
34.2, 33.4, 32.2, 18.5; [R]23 +240 (c 1.0, CHCl3); CIMS, m/z
D
(rel intensity) 284 (M+ + 1, 100). Anal. Calcd for C18H21NO2:
C, 76.30; H, 7.47. Found: C, 76.35; H, 7.55.
25c. 7e (2.21 g, 7.07 mmol) provided a colorless viscous oil
1
(2.01 g, 91%): IR (CHCl3) 3400, 1610 cm-1; H NMR δ (500
MHz, CDCl3) 6.91 (d, J ) 8.0 Hz, 1 H), 6.68 (m, 2 H), 5.39 (m,
1 H), 3.86 (s, 3 H), 3.47 (m, 1 H), 3.30 (d, J ) 16.5 Hz, 1 H),
3.20-3.18 (bm, 1 H), 2.95 (s, 3 H), 2.75 (dd, J ) 16.5, 2.2 Hz,
1 H), 2.79-2.75 (m, 1 H), 2.57-2.53 (m, 1 H), 2.40 (ddd, J )
12.5, 4.0, 1.5 Hz, 1 H), 2.08 (m, 1 H), 1.98 (dd, J ) 13.4, 0.5
Hz, 1 H), 1.69 (dt, J ) 12.5, 2.2 Hz, 1 H), 1.15 (d, J ) 6.6 Hz,
3 H); 13C NMR δ (125.7 MHz, CDCl3) 173.8, 157.4, 141.1, 132.6,
129.2, 126.3, 122.2, 113.1, 112.1, 54.9, 53.7, 42.2, 37.9, 35.4,
35.2, 34.0, 33.2, 32.0, 18.4; [R]23 +210 (c 1.6, CHCl3); CIMS,
D
m/z (rel intensity) 298 (M+ + 1, 100). Anal. Calcd for C19H23
NO2: C, 76.74; H, 7.80. Found: C, 76.71; H, 7.87.
-
(-)-(3S,7S,12a S)-2,3,4,6,7,12-Hexa h yd r o-2,3-d im eth yl-
1H -7,12a -m et h a n ob en zo[6,7]cyclooct a [1,2-c]p yr id in -9-
ol (26). A solution of 25b (0.080 g, 0.29 mmol) in THF (5 mL)
was added to a stirred suspension of LiAlH4 (0.022 g, 0.58
mmol) in THF (5 mL). The mixture was heated to reflux for
2 h. Water (2 mL) was added, followed by a 10% KOH solution
(2 mL) and some additional water (2 mL). The organic phase
was separated, a precipitate was removed by filtration, THF
(4 mL) was added, and the mixture was refluxed for 1 h. The
mixture was washed with a saturated NaCl solution (2 mL),
dried over MgSO4, and concentrated. Chromatography (CH2-
Cl2/MeOH, 10:1) on neutral alumina gave 26 as a colorless
1
foam (0.056 g, 71%): IR (CHCl3) 3400, 2910, 1620, 1460; H
NMR δ (500 MHz, CDCl3) 6.84 (d, J ) 8.0 Hz, 1 H), 6.61-6.57
(m, 2 H), 5.26 (d, J ) 6.0 Hz, 1 H), 3.29 (dd, J ) 8.0, 1.5 Hz,
1 H), 3.09 (m, 2 H), 2.70 (m, 1 H), 2.54 (d, J ) 16.0 Hz, 2 H),
2.45 (d, J ) 11.5 Hz, 1 H), 2.41 (d, J ) 11.5 Hz, 1 H), 2.34 (s,
3 H), 1.98 (dq, J ) 11.5, 2 Hz, 1 H), 1.80 (dd, J ) 16.5, 2.5 Hz,
1 H), 1.69 (dd, J ) 10.5, 2.5 Hz, 1 H), 1.56 (dt, J ) 10.5, 2.0
Hz, 1 H), 0.87 (d, J ) 7.0 Hz, 3 H); 13C NMR δ (125.7 MHz,
CDCl3) 153.9, 142.6, 135.3, 129.9, 127.6, 121.1, 115.0, 113.7,
A solution of the phenol (0.080 g, 0.27 mmol) in THF (5 mL)
was added to a stirred suspension of LiAlH4 (0.022 g, 0.59
mmol) in THF (5 mL). The mixture refluxed for 2 h. Water
(2 mL) was added, followed by a 10% KOH solution (2 mL)
and some additional water (2 mL). The organic phase was
separated, and a precipitate was removed by filtration. THF
(4 mL) was added, and the mixture was refluxed for 1 h, then
washed with saturated NaCl (2 mL), dried over MgSO4, and
concentrated. Chromatography (CH2Cl2/MeOH, 10:1) on neu-
tral alumina gave 28 as a colorless foam (0.054 g, 71%): IR
60.8, 55.0, 43.0, 39.8, 38.1, 36.0, 35.2, 35.0, 33.7, 7.9; [R]24
D
-210 (c 0.70, CHCl3); CIMS, m/z (rel intensity) 270 (M+ + 1,
100). Anal. Calcd for C18H23NO: C, 80.26; H, 8.61. Found:
C, 80.31; H, 8.41.
1
(CHCl3) 3400, 2900, 1610, 1450 cm-1; H NMR δ (500 MHz,
(-)-(3S,7S,12a S)-2,3,4,6,7,12-Hexa h yd r o-9-m eth oxy-2,3-
d im eth yl-1H-7,12a -m eth a n oben zo[6,7]cycloocta [1,2-c]p y-
r id in e-1,6-d ion e (27). To a solution of 25c (2.01 g, 6.76
mmol) in benzene at 10 °C (20 mL) was added Celite (0.20 g),
pyridinium dichromate (0.23 g), and tert-butyl hydroperoxide
(1.8 mL, 16 mmol). The mixture was stirred at 10 °C for 2 h
and then allowed to warm to room temperature and stirred
for 16 h. Filtration, concentration, and flash chromatography
(EtOAc) on silica gel gave 27 as a colorless oil (1.08 g, 51%):
(CD3)2CO/CD3OD (3:1)), 6.89 (d, J ) 8.5 Hz, 1 H), 6.77 (d, J )
1.5 Hz, 1 H), 6.70 (d, J ) 8.5 Hz, 1 H), 5.30 (s, 1 H), 4.50 (d,
J ) 5.5 Hz, 1 H), 3.77 (bs, 1 H), 3.52 (m, 1 H), 3.28 (d, J )
17.5 Hz, 2 H), 3.16 (s, 1 H), 2.98 (s, 3 H), 2.73 (m, 2 H), 2.48
(dd, J ) 8.0, 4.5 Hz, 1 H), 1.97 (d, J ) 13.5 Hz, 1 H), 1.97 (d,
J ) 13.0 Hz, 1 H), 1.17 (d, J ) 7.0 Hz, 3 H); 13C NMR δ (125.7
MHz, (CD3)2CO/CD3OD (3:1)), 153.9, 142.6, 135.3, 129.9, 127.6,
121.1, 115.0, 113.7, 60.8, 55.0, 43.0, 39.8, 38.1, 36.0, 35.2, 35.0,
33.7, 7.9; [R]24 +21 (c 0.98, CHCl3); CIMS, m/z (rel intensity)
D
IR (CHCl3) 1663, 1652, 1640 cm-1
;
1H NMR δ (500 MHz,
286 (M+ + 1, 100). Anal. Calcd for C18H23NO2: C, 75.76; H,
CDCl3) 6.95 (d, J ) 8.0 Hz, 1 H), 6.80-6.75 (m, 2 H), 5.70 (s,
1 H), 3.76 (s, 3 H), 3.69-3.66 (m, 2 H), 3.57 (d, J ) 16.5 Hz,
1 H), 3.03 (s, 3 H), 3.01-2.98 (m, 1 H), 2.81 (dd, J ) 16.6, 2.8
Hz, 1 H), 2.66 (dd, J ) 13.5, 3.2 Hz, 1 H), 2.31 (dd, J ) 13.5,
1.5 Hz, 1 H), 2.22 (m, 1 H), 1.19 (d, J ) 6.6 Hz, 3 H); 13C NMR
δ (125.7 MHz, CDCl3) 198.1, 171.3, 157.8, 157.5, 132.4, 130.1,
125.1, 125.0, 114.7, 112.7, 55.1, 52.4, 48.7, 44.1, 36.2, 35.9, 34.2,
8.12. Found: C, 75.52; H, 8.38.
(+)-(3R,7R,12a R)-2,3,4,6,7,12-H exa h yd r o-9-m et h oxy-
2,3-d im eth yl-1H-7,12a -m eth a n oben zo[6,7]cycloocta [1,2-
c]p yr id in e-1,6-d ion e (29). 29 was prepared as described for
the preparation of 27 (colorless oil, 55%): IR (CHCl3) 1663,
1
1652 (CdO), 1640 (CdC) cm-1; H NMR δ (500 MHz, CDCl3)
6.95 (d, J ) 8.0 Hz, 1 H), 6.80-6.75 (m, 2 H), 5.70 (s, 1 H),
3.76 (s, 3 H), 3.69-3.66 (m, 2 H), 3.57 (d, J ) 16.5 Hz, 1 H),
3.03 (s, 3 H), 3.01-2.98 (m, 1 H), 2.81 (dd, J ) 16.6, 2.8 Hz, 1
H), 2.66 (dd, J ) 13.5, 3.2 Hz, 1 H), 2.31 (dd, J ) 13.5, 1.5 Hz,
1 H), 2.22 (m, 1 H), 1.19 (d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7
MHz, CDCl3) 198.1, 171.3, 157.8, 157.5, 132.4, 130.1, 125.1,
125.0, 114.7, 112.7, 55.1, 52.4, 48.7, 44.1, 36.2, 35.9, 34.2, 33.4,
33.4, 18.9; [R]24 +90 (c 1.0, CHCl3); CIMS, m/z (rel intensity)
D
312 (M+ + 1, 100). Anal. Calcd for C19H21NO3: C, 73.29; H,
6.80. Found: C, 73.08; H, 6.58.
(+)-(3S,6S,7S,12aS)-2,3,4,6,7,12-Hexah ydr o-2,3-dim eth yl-
1H-7,12a -m eth a n oben zo[6,7]cycloocta [1,2-c]p yr id in e-6,9-
d iol (28). A mixture of 27 (0.087 g, 0.27 mmol) and CeCl3‚
4H2O (0.075 g, 0.20 mmol) in MeOH (3 mL) was stirred at
room temperature for 30 min. To the resulting suspension was
added NaBH4 (0.015 g). After 1.5 h, the reaction was quenched
18.9; [R]24 -93.0 (c ) 1.27, CHCl3); CIMS, m/z (rel intensity)
D
312 (M+ + 1, 100). Anal. Calcd for C19H21NO3: C, 73.29; H,
6.80. Found: C, 72.61; H, 6.77.

7804 J . Org. Chem., Vol. 63, No. 22, 1998
Schultz et al.
(+)-(3R,4aR,7R,12aR)-2,3,4,4a,5,6,7,12-Octah ydr o-9-m eth -
oxy-2,3-d im eth yl-1H-7,12a -m eth a n oben zo[6,7]cycloocta -
[1,2-c]p yr id in e-1,6-d ion e (30). To a solution of 29 (0.500 g,
1.60 mmol) in EtOAc (20 mL) was added 5% Pd/C (0.220 g),
and the suspension was shaken under an atmosphere of H2
(79 PSI) for 72 h. The mixture was filtered through Celite
and concentrated. Flash chromatography (EtOAc) on silica
gel provided 30 as a colorless solid (0.498 g, 98%); IR (CHCl3)
(+)-(3R,4a R,7R,12a R)-2,3,4,4a ,5,6,7,12-Octa h yd r o-9-h y-
dr oxy-2,3-dim eth yl-1H-7,12a-m eth an oben zo[6,7]cycloocta-
[1,2-c]p yr id in -6-on e (32). 31 (0.407 g, 1.18 mmol) was
dissolved in CH2Cl2 (5 mL) under N2 and cooled to -78 °C.
BBr3 in CH2Cl2 (6 mL, 1 M) was added, and the reaction
mixture was allowed to warm to room temperature. After
stirring overnight, the reaction was cooled to 0 °C and
quenched with water. The resulting mixture was extracted
with EtOAc (4 × 15 mL). The organic layers were combined,
washed with brine (10 mL), dried over MgSO4, and filtered.
Flash chromatography (CH2Cl2/MeOH, 10:1) on silica gel
afforded 32 as a white foam (0.209 g, 60%): IR (CHCl3) 3400,
1
1703, 1612 cm-1; H NMR δ (500 MHz, CDCl3) 7.10 (d, J )
8.0 Hz, 1 H), 6.72 (dd, J ) 8.0, 2.5 Hz, 1 H), 6.58 (d, J ) 2.5
Hz, 1 H), 4.25 (d, J ) 13.0 Hz, 1 H), 3.72 (s, 3 H), 3.50 (m, 2
H), 2.93 (s, 3 H), 2.80 (dd, J ) 15.0, 7 Hz, 1 H), 2.71 (d, J )
17.5 Hz, 1 H), 2.48 (br m, 1 H), 2.38 (d, J ) 13.0 Hz, 1 H), 2.34
(d, J ) 13.0 Hz, 1 H), 1.87 (d, J ) 15.0 Hz, 1 H), 1.80 (d, J )
15.0 Hz, 1 H), 1.70 (q, J ) 10.0, 4.5 Hz, 1 H), 1.27 (d, J ) 6.6
Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 210.1, 173.6, 157.2,
134.9, 130.0, 128.4, 114.1, 114.3, 112.4, 55.1, 53.3, 52.9, 41.2,
1
3500, 1703 cm-1; H NMR δ (500 MHz, CD3OD), 6.95 (d, J )
8.0 Hz, 1 H), 6.75 (d, J ) 2.5 Hz, 1 H), 6.65 (dd, J ) 8.0 Hz,
2.5 Hz, 1 H), 5.48 (bs, 1 H, exchangeable with D2O), 3.53 (bs,
1 H), 3.27 (d, J ) 18.5 Hz, 1 H), 3.10 (m, 1 H), 2.53 (d, J )
18.5 Hz, 1 H), 2.44 (d, J ) 12.0 Hz, 1 H), 2.33 (d, J ) 13.0 Hz,
1 H), 2.28 (s, 3 H), 2.22 (m, 3 H), 2.01-1.93 (m, 2 H), 1.66 (dd,
J ) 13.0, 3.5 Hz, 1 H), 1.30 (d, J ) 13.0 Hz, 1 H), 1.07 (d, J )
6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CD3OD) 213.1, 156.7,
138.1, 131.6, 128.4, 116.4, 115.6, 68.8, 68.5, 55.0, 49.8, 46.2,
40.7, 38.1, 34.8, 33.3, 31.9, 21.6; [R]25 +12 (c 0.60, CHCl3);
D
CIMS, m/z (rel intensity) 314 (M+ + 1, 100). Anal. Calcd for
C19H23NO3: C, 72.82; H, 7.40. Found: C, 72.85; H, 7.41.
Keta l of 32: P r ep a r a tion of 31. To the solution of 30
(0.498 g, 1.59 mmol) in benzene (15 mL) was added ethylene
glycol (0.217 g, 3.32 mmol). PTSA (15 mg) was added, and
the reaction mixture was refluxed overnight. After cooling to
room temperature, the mixture was carefully poured into a
saturated NaHCO3 solution. The mixture was stirred for 30
min and then was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (150 mL),
dried over MgSO4, and concentrated. Flash chromatography
(ethyl acetate/hexane, 2:1) on silica gel gave the ketal as a
colorless foam (0.51 g, 90%): IR (CHCl3) 2850, 1612 cm-1; 1H
NMR δ (500 MHz, CDCl3) 6.97 (d, J ) 8.0 Hz, 1 H), 6.70 (dd,
J ) 8.0, 2.5 Hz, 1 H), 6.61 (d, J ) 2.5 Hz, 1 H), 4.15-3.98 (m,
5 H), 3.73 (m, 1 H), 3.72 (s, 3 H), 3.50 (m, 1 H), 2.92 (s, 3 H),
2.54 (d, J ) 17.5 Hz, 1 H), 2.48 (bm, 2 H), 2.12-1.96 (m, 2 H),
1.80 (dd, J ) 15.0 Hz, 6 Hz, 1 H), 1.80 (dt, J ) 15.0, 6 Hz, 1
H), 1.28 (q, J ) 10.0, 4.5 Hz, 1 H), 1.26 (d, J ) 6.6 Hz, 3 H);
13C NMR δ (125.7 MHz, CDCl3) 175.3, 156.3, 136.8, 129.2,
128.6, 115.2, 112.4, 109.2, 64.6, 63.7, 54.9, 53.9, 43.4, 41.4, 39.4,
43.5, 41.9, 39.0, 34.9, 33.7, 19.9; [R]24 +69 (c 0.23, CHCl3);
D
CIMS, m/z (rel intensity) 286 (M+ + 1, 100). Anal. Calcd for
C
18H23NO2: C, 75.76; H, 8.12. Found: C, 75.50; H, 8.32.
(+)-(3R,4aS,7R,12aR)-2,3,4,4a,5,6,7,12-Octah ydr o-9-m eth -
oxy-2,3-d im eth yl-1H-7,12a -m eth a n oben zo[6,7]cycloocta -
[1,2-c]p yr id in e-1,6-d ion e (33). To a solution of 29 (3.00 g,
9.6 mmol) and tert-butyl alcohol (2.80 mL, 28.8 mmol) in THF
(150 mL) was added NH3 (∼480 mL) at -78 °C. Lithium was
added in small pieces until a blue coloration persisted. The
solution was stirred at -78 °C for 120 min, and then the blue
coloration was dissipated with piperylene. The mixture was
stirred for an additional 30 min at -78 °C, and then solid NH4-
Cl was added at -78 °C and the NH3 was allowed to evaporate
overnight. The resulting pale yellow residue was partitioned
between CH2Cl2 (30 mL) and water (40 mL), and the water
layer was extracted with CH2Cl2 (2 × 30 mL). The combined
organic layers were washed with 10% sodium thiosulfate
solution (20 mL), dried over MgSO4, and concentrated. Flash
chromatography (ethyl acetate/hexane, 2:1) on silica gel gave
30 (0.31 g, 10%) and then a second fraction which contained
33 (1.54 g, 51%): IR (CHCl3) 1709, 1615 cm-1; 1H NMR δ (500
MHz, CDCl3) 7.04 (d, J ) 8.0 Hz, 1 H), 6.75 (dd, J ) 8.0, 2.5
Hz, 1 H), 6.61 (d, J ) 2.5 Hz, 1 H), 3.74 (s, 3 H), 3.63 (m, 1 H),
3.60 (p, J ) 7 Hz, 1 H), 3.20 (d, J ) 17.5 Hz, 1 H), 3.16 (d, J
) 17.5 Hz, 1 H), 2.93 (s, 3 H), 2.80 (dd, J ) 13.0, 3 Hz, 1 H),
2.42 (td, J ) 13.0, 3 Hz, 1 H), 2.38 (d, J ) 13.0 Hz, 1 H), 2.31
(ddd, J ) 13.0, 6, 3 Hz, 1 H), 2.04 (dq, J ) 15.0, 3 Hz, 2 H),
1.44 (dd, J ) 12.0, 2 Hz, 1 H), 1.29 (d, J ) 6.6 Hz, 3 H); 13C
NMR δ (125.7 MHz, CDCl3) 209.3, 174.1, 157.5, 135.4, 129.5,
127.6, 114.3, 112.4, 55.1, 53.9, 53.3, 41.0, 40.2, 37.6, 35.6, 34.3,
39.1, 35.0, 33.6, 31.7, 29.6, 21.6; [R]25 +52 (c 0.61, CHCl3);
D
CIMS, m/z (rel intensity) 358 (M+ + 1, 100). Anal. Calcd for
C
21H27NO4: C, 70.56; H, 7.61. Found: C, 70.55; H, 7.63.
A solution of the ketal (0.51 g, 1.43 mmol) in THF (10 mL)
was added to a stirred suspension of LiAlH4 (0.076 g, 2.01
mmol) in THF (5 mL) at 0 °C, and the mixture was refluxed
for 2 h. After cooling to room temperature, water (2 mL) was
added, followed by a 10% KOH solution (2 mL) and some
additional water (2 mL). The organic phase was separated,
and a precipitate was removed by filtration. THF (4 mL) was
added, and the mixture was refluxed for 1 h, washed with a
saturated NaCl solution (2 mL), dried over MgSO4, and
concentrated. Chromatography (CH2Cl2/MeOH, 10:1) on neu-
tral alumina afforded 31 as a colorless foam (0.407 g, 83%):
IR (CHCl3) 3500, 2930, 1590, 1410 cm-1; 1H NMR δ (500 MHz,
CDCl3) 6.95 (d, J ) 8.0 Hz, 1 H), 6.72 (dd, J ) 8.0, 2.5 Hz, 1
H), 6.62 (d, J ) 2.5 Hz, 1 H), 4.08-3.97 (m, 3 H), 3.90 (m, 1
H), 3.76 (s, 3 H), 2.84 (d, J ) 2.5 Hz, 1 H), 2.72 (dd, J ) 13.0
Hz, 1 H), 2.58 (d, J ) 17.5 Hz, 1 H), 2.50 (d, J ) 17.5 Hz, 1 H),
2.48 (d, J ) 13.0 Hz, 1 H), 2.20 (s, 3 H), 2.16 (m, 1 H), 1.97 (d,
J ) 10.5 Hz, 1 H), 1.75 (dt, J ) 10.5, 6 Hz, 2 H), 1.60 (m, 1 H),
1.40 (ddd, J ) 10.5, 6, 2.0 Hz, 1 H), 1.24 (m, 2 H), 1.26 (d, J )
6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 156.4, 138.7,
129.1, 128.4, 115.2, 112.2, 109.6, 69.7, 64.4, 63.4, 59.6, 54.9,
32.6, 31.8, 20.1; [R]25 +35 (c 1.6, CHCl3); CIMS, m/z (rel
D
intensity) 314 (M+ + 1, 100). Anal. Calcd for C19H23NO3: C,
72.82; H, 7.40. Found: C, 72.87; H, 7.46.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 33061 for the syn-
thesis and DA 01674 for the receptor binding studies).
We thank the Fonds der Chemischen Industrie for a
postdoctoral fellowship to R.R. and BASF AG-Ludwig-
shafen for additional financial assistance.
43.6, 43.1, 42.7, 41.4, 37.4, 33.5, 32.7, 29.6, 20.2; [R]24 +20 (c
D
0.99, CHCl3); CIMS, m/z (rel intensity) 344 (M+ + 1, 100). Anal.
Calcd for C21H29NO3: C, 73.44; H, 8.51. Found: C, 73.79; H,
8.25.
J O980921G