A novel asymmetric route to the 1,3-disubstituted tetrahydroisoquinoline, (-)-argemonine

Article abstract of DOI:10.1021/jo960110h

Chiral bicyclic lactam 13 was converted to the natural product (-)-argemonine 9 in six steps. This novel route to argemonine represents a general strategy for the preparation of chiral 1,3-disubstituted tetrahydroisoquinolines.

Full text of DOI:10.1021/jo960110h

J . Org. Chem. 1996, 61, 4607-4610
4607
A Novel Asym m etr ic Rou te to th e 1,3-Disu bstitu ted
Tetr a h yd r oisoqu in olin e, (-)-Ar gem on in e†
Michael J . Munchhof and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J anuary 17, 1996X
Chiral bicyclic lactam 13 was converted to the natural product (-)-argemonine 9 in six steps. This
novel route to argemonine represents a general strategy for the preparation of chiral 1,3-
disubstituted tetrahydroisoquinolines.
Previous studies utilizing chiral nonracemic bicyclic
lactams as vehicles for elaboration to various alkaloidal
systems has led to the development of several efficient
routes to the preparation of piperidine, indolizidine, and
tetrahydroisoquinoline natural products (Scheme 1).1 To
date this has included the synthesis of (+)-monomorine
(1), (-)-coniceine (2), and (+)-cryptostyline II (3). We now
present the first report of an asymmetric total synthesis
of (-)-argemonine (6), a member of the pavine family of
natural products.2
The approach to be described herein was based on
previous successes involving stereoselective reduction of
chiral lactams containing a fused aromatic such as 4. We
will demonstrate how we have been able to use this
finding to readily access (-)-argemonine (6). The basis
for the present approach lies in the fact the lactam
carbonyl in 4 was observed not to reduce during the
process of cleaving the C-O bond. It was anticipated
that the carbonyl group in 5 could be utilized in subse-
quent steps to facilitate stereoselective introduction of
substituents at the 3-position of the resulting tetrahy-
droisoquinoline.
was not the required intermediate that would lead to
argemonine. Conditions were ultimately found which did
not reduce the lactam carbonyl in 11. By maintaining
the temperature of the Red-Al reduction of 9 below -30
°C, the lactam survived and only the aminal linkage
suffered reductive cleavage to 11. The latter was ob-
tained in 90% yield as a >95:5 mixture of diastereomers.
At this juncture in the study the absolute (or relative)
stereochemistry of 11 was still unknown. The phenyl-
glycinol moiety was, of course, known to be S, but the
stereochemistry of the 1-benzyl group was yet to be
determined. This was nicely accomplished by taking
advantage of the observation which produced the over-
reduction product 12 when the bicyclic lactam 9 was
reduced earlier. It was subsequently found that lithium
aluminum hydride reduction of 11 cleanly gave 12 which
after debenzylation with H2/Pd-C afforded the isoquino-
line 13. Following formalin-formic acid treatment, the
Pictet-Spengler cyclization ensued to give (-)-xylopinine
14 in 90% yield. The latter possessed [R]23D -283 (c 0.32,
CHCl3) and compared well with the literature value of
[R]23 -275.4 The sign of rotation of both compounds
D
The retrosynthetic approach to (-)-argemonine is
shown in Scheme 2. The target may be seen to arise from
the intramolecular electrophilic cyclization of the benzyl
substituent onto imminium ion 7 followed by reductive
cleavage of the tert-butyl carbamate to the corresponding
N-methyl analog. The requisite, transient iminium ion
should present itself after reduction of the lactam 8 to
the carbinol amine followed by treatment with an ap-
propriate Lewis acid. The 3-isoquinolone 8 would be
accessed by reductive cleavage of the lactam 9 (as in 4
f 5) followed by removal of the auxiliary and Boc
acylation of the resulting isoquinolin-3-one.
The key intermediate 9 was prepared by condensation
of the known keto acid 10,3 with (S)-phenylglycinol under
reflux with toluene as the solvent (Scheme 3). Azeotropic
removal of water left the bicyclic lactam 9 as a single
diastereomer in 90% yield. When 9 was treated with
Red-Al, under previously used conditions1c (-78 °C
warming to 0 °C) a significant amount (20-30%) of over-
reduction occurred producing the isoquinoline 12. Al-
though this was a useful reduction path (vide supra), it
being the same, confirmed that we had prepared xylopi-
nine in its natural configuration of S. Thus, we may
safely conclude that the C-1 position of 11 was also S
and that reductive cleavage of 9 had occurred with
retention at the aminal center.
Having shown that not only did we access the proto-
berberine alkaloid family (e.g. 14), but we were also
confident regarding the absolute stereochemistry of 11.
With this information in hand, we continued our study
en route to argemonine.
Cleavage of the phenylglycinol moiety in 11 was the
next step to be addressed, and we found that this could
be accomplished using dissolving metal reduction condi-
tions. Treatment of 11 with sodium and liquid ammonia
resulted in clean formation of isoquinolin-3-one 15.5 It
was observed that the reaction mixture must be quenched
with solid ammonium chloride as soon as an excess of
sodium was added in order to prevent decomposition of
the product (Scheme 4). Following N-Boc protection of
15, it was necessary to reduce the lactam to the corre-
sponding carbinolamine 16. Attempted reduction of 8
following Speckamp’s procedure6 with sodium borohy-
dride in acidic ethanol at -20 °C led only to starting
material. This prompted an examination of the proce-
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) (a) Munchhof, M. J .; Meyers, A. I. J . Am. Chem. Soc. 1995, 117,
5399. (b) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7084.
(c) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7086.
(2) For previous synthesis of argemonine see: (a) Nomoto, T.;
Takayama, H. J . Chem. Soc., Chem. Commun. 1982, 19, 1113. (b) Rice,
K. C.; Ripka, W. C.; Reden, J .; Brossi, A. J . Org. Chem. 1980, 45, 601.
(3) Palmquist, U.; Nilsson, A.; Pettersson, T.; Rola´n, A. J . Org. Chem.
1979, 44, 196.
(4) Meyers, A. I.; Boes, M.; Dickman, D. A. Angew. Chem., Int. Ed.
Engl. 1984, 23, 458.
(5) Burgess, L. E.; Meyers, A. I. J . Org. Chem. 1992, 57, 1656.
(6) Hubert, J . C.; Wijnberg, J . B.; Speckamp, N. C. Tetrahedron
1975, 31, 1437.
S0022-3263(96)00110-7 CCC: $12.00 © 1996 American Chemical Society

4608 J . Org. Chem., Vol. 61, No. 14, 1996
Munchhof and Meyers
Sch em e 1
the natural product.8 Furthermore, the spectroscopic
data for our synthetic sample was identical to the
literature values.2b
Sch em e 2
In summary, the previously reported route1c to 1-sub-
stituted tetrahydroisoquinolines has now been extended
to include 1,3-disubstituted tetrahydroisoquinolines. This
has led to the first asymmetric synthesis of (-)-argemo-
nine.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under argon in
septum-stoppered flasks. Unless otherwise noted, reagents
were added by syringe, and organic extracts were dried over
anhydrous Na2SO4, filtered through a fritted glass funnel, and
concentrated with a rotary evaporator at aspirator pressure
(30-40 mm). Flash chromatography was performed with
Amicon (200-400 mesh) silica gel. Thin layer chromatography
(TLC) was performed with Merck F-254 silica gel plates.
Preparative thin layer chromatography was carried out on
Merck PSC-Fertirplatten Kieselgel 60 F254 plates.
Unless otherwise noted, starting materials were obtained
from commercial suppliers and used without further purifica-
tion. Tetrahydrofuran (THF) and ether were distilled under
N2 from sodium/benzophenone immediately prior to use.
Dichloromethane (CH2Cl2), benzene, toluene, and triethyl-
amine were distilled from CaH2 immediately prior to use.
dure reported by Chamberlin7 in which the analogous
reduction was carried out in methanol at 0 °C without
the addition of acid. Under these conditions the lactam
8 was cleanly reduced to the carbinolamine 16. The
latter was treated directly with tert-butyldimethylsilyl
triflate to generate the intermediate imminium ion which
was rapidly captured by the electron rich aromatic ring.
In the course of this cyclization, the Boc group was also
cleaved to yield amine 17. The synthesis was completed
by treating the secondary amine with formalin followed
by sodium borohydride which afforded (-)-argemonine
Microanalyses were performed by Atlantic Microlab, Inc.,
Norcross, GA.
Bicyclic La cta m 9. Keto-acid 103 (2.0 g, 5.32 mmol) was
dissolved in 44 mL of toluene, and 0.73 g (5.32 mmol) of (S)-
phenylglycinol was added. The flask was equipped with a
Dean-Stark apparatus, and the solution was heated to reflux.
After 14 h the reaction mixture was cooled and concentrated
to afford 2.4 g of crude product. Chromatography on 50 g of
silica gel with ethyl acetate afforded 2.27 g (90%) of bicyclic
lactam 10: mp 148-150 °C, [R]23 +90.7 (c 1.5, CHCl3); IR
D
(neat) 2955, 1664, 1515 cm-1
.
1H NMR (300 MHz) δ 2.43 (d,
(6) in 60% yield ([R]25D -229 (c ) 0.38, EtOH), lit.8 [R]25
J ) 18.4, 1), 3.04 (m, 3), 3.49 (s, 3), 3.78 (s, 3), 3.83 (s, 6), 4.37
(t, J ) 7.26, 1), 4.52 (dd, J ) 5.20, 8.8, 1), 5.53 (m, 1), 5.91 (s,
1), 6.21 (d, J ) 7.90, 1), 6.44 (s, 1), 6.57 (d, J ) 8.0, 1), 6.83 (s,
1), 7.42 (m, 7); 13C NMR (75 MHz) δ 37.2, 47.0, 55.4, 55.9, 56.0,
59.1, 69.1, 96.9, 107.4, 109.0, 110.3, 113.5, 122.8, 123.6, 126.7,
127.0, 127.7, 128.2, 128.6, 139.0, 147.9, 149.1, 168.7. Anal.
Calcd for C28H29NO6‚1/2 H2O : C: 69.42; H: 6.20; Found: C:
69.51; H: 6.10.
D
-214). Once again, the sign of rotation and the absolute
configuration of the synthetic material matched that of
(7) Chamberlin, R. A.; Nguyen, H. D., Chung, J . Y. J . Org. Chem.
1984, 49, 1682.
(8) Chan, R. P.; Graig, J . C.; Manske, R. H.; Soine, T. O. Tetrahedron
1967, 23, 4209, reports [R]D -214 (c ) 3.3, EtOH).

Asymmetric Route to (-)-Argemonine
J . Org. Chem., Vol. 61, No. 14, 1996 4609
Sch em e 3
Sch em e 4
1), 2.69 (m, 1), 2.89 (dd, J ) 6.4, 13.6, 1), 3.13 (m, 2), 3.65 (s,
3), 3.75 (m, 2), 3.80 (s, 3), 3.82 (s, 3), 3.95 (t, J ) 5.1, 1), 4.10
(t, J ) 6.1, 1), 6.20 (s, 1), 6.36 (d, J ) 1.8, 1), 6.48 (s, 1), 6.56
(d, J ) 8.1, 1), 6.73 (d, J ) 8.2, 1), 7.28 (m, 5). 13C NMR (75
MHz) δ 26.4, 39.9, 41.4, 55.7, 55.7, 55.8, 60.3, 62.2, 65.1, 110.8,
111.0, 112.7, 121.2, 127.3, 127.7, 128.2, 128.7, 129.3, 131.6,
138.5, 146.6, 147.3, 147.4, 148.2. Anal. Calcd for C28H33NO5:
C: 72.57; H: 7.13. Found: C: 72.33; H: 7.28.
1-Ben zylisoqu in olin e 13. Isoquinoline 12 (230 mg, 0.49
mmol) was dissolved in 10 mL of EtOH and 1.7 mL of 1 N
HCl. A 500 mg amount of 10% Pd/C was added, and the
solution was placed under a balloon of hydrogen. After 12 h
the reaction mixture was filtered and concentrated. The
resulting solid was taken up in 1 N HCl and extracted with
Et2O (2 × 10 mL). The aqueous solution was made basic with
saturated NaHCO3 and extracted with CHCl3 (3 × 20 mL).
The combined organic portions were dried and concentrated
to give 141 mg (82%) of 13. [R]23 -27.6 (c 2.5, CHCl3); IR
D
(neat) 2913, 1513, 1261 cm-1
.
1H NMR (300 MHz) δ 1.95 (s,
Isoqu in olin -3-on e 11. Lactam 9 (2 g, 4.21 mmol) was
dissolved in 10.5 mL of THF and cooled to -78 °C. To the
stirring solution was added 2.80 mL (8.41 mmol, 3 M) of Red-
Al in toluene down the side of the flask. The flask was placed
in a -30 °C cooling bath and stirred 6 h. The reaction mixture
was quenched by addition of 3.5 mL of H2O and then allowed
to warm to rt. The resulting solution was diluted with CHCl3
and stirred 30 min, after which time the solution was further
diluted with H2O, and the two phases were separated. The
aqueous phase was extracted with CHCl3 (5 × 50 mL), and
the combined organic extracts were dried and concentrated to
afford 1.83 g (90%) of 11: [R]23D -6.18 (c 1.4, CHCl3); IR (neat)
1), 2.63-2.94 (m, 4), 3.18 (m, 2), 3.82 (s, 3), 3.85 (s, 6), 3.86 (s,
3), 4.12 (dd, J ) 4.40, 9.30, 1), 6.58 (s, 1), 6.66 (s, 1), 6.81 (m,
3). 13C NMR (75 MHz) δ 29.4, 40.8, 42.1, 55.7 (2), 55.8, 55.8,
56.7, 109.2, 111.1, 111.7, 112.2, 121.3, 127.3, 130.3, 131.3,
146.8, 147.3, 147.5, 148.8. Anal. Calcd for C20H25NO4‚H2O:
C: 66.48; H: 7.48. Found: C: 66.26; H: 7.01.
(-)-Xylop in in e 14. Amine 13 (56 mg, 0.16 mmol) was
dissolved in 0.40 mL of 37% formalin and 0.62 mL of 88%
formic acid. The flask was equipped with a cold finger
condenser and heated to 90 °C. After 2 h the reaction mixture
was cooled and concentrated in vacuo. The resulting yellow
oil was taken up in CHCl3 and made basic with saturated
NaHCO3. The solution was extracted with CHCl3 (3 × 10 mL),
3400, 2936, 1629, 1515, 1261 cm-1 1H NMR (300 MHz) δ 2.70
.
(m, 3), 3.31 (d, J ) 19.3, 1), 3.60 (s, 3), 3.67 (s, 3), 3.82 (s, 3),
3.85 (s, 3), 4.13 (dd, J ) 6.1, 1), 4.33 (m, 2), 5.20 (m, 1), 5.97
(s, 1), 6.18 (s, 1), 6.26 (d, J ) 7.67, 1), 6.53 (s, 1), 6.66 (d, J )
8.1, 1), 7.30 (m, 5); 13C NMR (75 MHz) δ 37.4, 41.3, 55.6, 55.8,
55.9, 63.2, 64.0, 64.6, 109.1, 109.6, 110.7, 113.0, 122.3, 124.6,
126.2, 128.1, 128.8, 136.9, 147.2, 148.0, 148.3, 171.6. Anal.
Calcd for C28H31NO6: C: 70.44; H: 6.50; Found: C: 70.20;
H: 6.64.
dried, and concentrated to afford 52 mg (90%) of xylopinine
1
(14): mp 179-180 °C, [R]23 -283.1(c 0.32, CHCl3); H NMR
D
(300 MHz) δ 2.65 (m, 2), 2.84 (dd, J ) 11.2, 15.3, 1), 3.14 (m,
2), 3.24 (dd, J ) 3.72, 16.0, 1), 3.59 (dd, J ) 3.60, 11.2, 1),
3.67 (d, J ) 14.7, 1), 3.85 (s, 3), 3.86 (s, 3), 3.87 (s, 3), 3.89 (s,
3), 3.94 (d, J ) 14.6, 1), 6.58 (s, 1), 6.62 (s, 1), 6.67 (s, 1), 6.74
(s, 1); 13C NMR (75 MHz) δ 29.4, 36.7, 51.7, 56.1, 56.2, 56.3,
56.3, 58.6, 59.9, 108.8, 109.3, 111.6 (2), 126.6, 126.7, 127.0,
130.1, 147.7 (2), 147.9 (2).
Isoqu in olin e 12. Isoquinolin-3-one 11 (600 mg, 1.25 mmol)
was dissolved in 6.3 mL of THF and cooled to 0 °C. To the
solution 95 mg (2.50 mmol) of lithium aluminum hydride was
added, and the cooling bath was removed. After 3 h the
reaction mixture was cooled to 0 °C, and 95 µL of H2O was
added followed by 95 µL of 10% NaOH then 0.29 mL of H2O.
Chloroform was added, and the solution was stirred 30 min,
filtered, and concentrated. Chromatography on 18 g of silica
gel with 1:1 hexane:ethyl acetate afforded 486 mg (84%) of
Isoqu in olin -3-on e 15. Isoquinolin-3-one 11 (560 mg, 1.17
mmol) was dissolved in 20 mL of THF and cooled to -78 °C.
The flask was equipped with a cold finger condenser, ap-
proximately 40 mL of ammonia was condensed into the flask,
and the cooling bath was removed. After the solution reached
reflux sodium was added in several small portions until the
blue color persisted. Once the blue color persisted for 30 s
the reaction mixture was quenched by addition of solid
ammonium chloride. The cold finger was removed, and the
12: mp 60-62 °C, [R]23 +44.7 (c 2.0, CHCl3); IR (neat) 2934,
D
1514, 1262 cm-1
.
1H NMR (300 MHz) δ 2.32 (m, 1), 2.56 (m,

4610 J . Org. Chem., Vol. 61, No. 14, 1996
Munchhof and Meyers
ammonia was allowed to evaporate under a stream of argon.
The resulting slurry was diluted with H2O and CHCl3, the two
phases were separated, and the aqueous layer was extracted
with CHCl3 (5 × 40 mL). The combined organic portions were
dried and concentrated. Chromatography on 20 g of silica gel
with 5% MeOH:CH2Cl2 afforded 355 mg (85%) of lactam 15:
material was dissolved in 1.26 mL of CH2Cl2 and cooled to 0
°C. To the solution was added 66 µL (0.38 mmol) of TMSOTf,
and the solution was warmed to rt. After 20 min the flask
was equipped with a cold finger condenser and heated to
reflux. After 2 h the reaction mixture was cooled to rt and
quenched by addition of saturated NaHCO3. The aqueous
layer was extracted with CHCl3 (3 × 10 mL), the combined
organic portion was dried and concentrated to give 52 mg (70%)
of 17: mp 212 °C, [R]23D -118.3 (c 2.7, CH2Cl2); IR (neat) 2916,
2832, 1515, 1262, 1120 cm-1; 1H NMR (300 MHz) δ 2.76 (d, J
) 16.1, 2), 3.32 (dd, J ) 5.6, 16.1, 2), 3.77 (s, 6), 3.84 (s, 6),
4.41 (d, J ) 6.9, 2), 6.44 (s, 2), 6.61 (s, 2). 13C NMR (75 MHz)
δ 37.4, 50.2, 56.0, 56.3, 109.8, 112.0, 124.6, 130.7, 147.8, 148.3.
Ar gem on in e (6). Isoquinoline 17 (13 mg, 0.038 mmol) was
dissolved in 1 mL of MeOH, and 62 µL of formalin was added.
After stirring 30 min 31 mg (0.82 mmol) of sodium borohydride
was added, and the solution was stirred an additional 3 h and
concentrated in vacuo. The resulting white solid was parti-
tioned between 5% NaOH and CHCl3. The two phases were
separated, and the aqueous phase was extracted with CHCl3
(3 × 5 mL). The combined organic portions were dried and
concentrated to afford analytically pure 13 mg (96%) argemo-
mp 137-138 °C, [R]23 -36.2 (c 0.32, CHCl3); IR (neat) 3221,
D
2936, 1665, 1516, 1261 cm-1; 1H NMR (300 MHz) δ 2.76 (d, J
) 20.2, 1), 2.88 (dd, J ) 5.8, 13.4, 1), 3.02 (dd, J ) 4.6, 13.2,
1), 3.18 (d, J ) 20.2, 1), 3.66 (s, 3), 3.82 (s, 3), 3.84 (s, s, 6),
4.69 (m, 1), 6.29 (s, 1), 6.46 (s, 1), 6.58 (m, 2), 6.72 (d, J ) 8.2,
1), 6.85 (m, 1); 13C NMR (75 MHz) δ 34.9, 45.0, 55.7, 55.8, 55.9,
56.1, 57.2, 108.9, 110.1, 111.0, 112.9, 122.4, 124.1, 125.2, 128.0,
147.7, 148.0, 148.5, 171.6. Anal. Calcd for C20H23NO5: C:
67.23; H: 6.44. Found: C: 67.15; H: 6.46.
Isoqu in olin -3-on e 8. Lactam 15 (50 mg, 0.14 mmol) was
dissolved in 0.50 mL of CH2Cl2 and 0.039 mL (0.28 mmol) of
Et3N, and 0.13 mL (0.56 mmol) of (Boc)2O and 34 mg (0.28
mmol) of 4-(dimethylamino)pyridine were added. The flask
was equipped with a cold finger condenser, and the solution
was heated to reflux. After 4 h the solution was concentrated
in vacuo and chromatographed on 3 g of silica gel with 80%
ethyl acetate:hexane to afford 32 mg (50%) of lactam 8: [R]23
nine (6): mp 138-140 °C, [R]23 -229.5 (c 0.38, EtOH); 1H
D
D
+45.7 (c 4.0, CHCl3); IR (neat) 2935, 2835, 1768, 1717, 1515,
1233 cm-1; 1H NMR (300 MHz) δ 1.55 (s, 9), 2.90 (d, J ) 19.8,
1), 3.01 (m, 2), 3.31 (d, J ) 19.8, 1), 3.64 (s, 3), 3.70 (s, 3), 3.81
(s, 3), 3.81 (s, 3), 5.32 (t, J ) 4.9, 1), 6.22 (s, 1), 6.32 (s, 1), 6.42
(d, J ) 7.1, 1), 6.47 (s, 1), 6.68 (d, J ) 8.1, 1); 13C NMR (75
MHz) δ 28.0, 38.6, 42.2, 55.6, 55.8, 55.9 (2), 61.2, 83.2, 109.5,
109.6, 110.9, 113.0, 122.4, 123.4, 125.8, 128.4, 147.4, 148.0,
148.4, 148.6, 152.1, 169.6.
Tetr a cyclic Isoqu in olin e 17. Isoquinolin-3-one 8 (78 mg,
0.17 mmol) was dissolved in 0.85 mL of MeOH and cooled to
0 °C. To the solution was added 64 mg (1.7 mmol) of NaBH4.
After 80 min the reaction mixture was poured onto 2 mL of
saturated NaHCO3 and 2 mL of CHCl3 that had been cooled
to 0 °C. The aqueous layer was extracted with CHCl3 (3 × 10
mL), and the combined organic portions were dried and
concentrated to afford 58 mg of the aminal. The crude
NMR (300 MHz) δ 2.53 (s, 3), 2.59 (d, J ) 16.2, 2), 3.40 (dd, J
) 5.58, 2), 6.45 (s, 2), 6.61 (s, 2); 13C NMR (75 MHz) δ 33.6,
40.9, 55.7, 55.9, 56.4, 110.0, 111.4, 123.9, 129.9, 147.4, 147.8.
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for financial support. An
NIH-NSRA Postdoctoral Fellowship (M.J .M.) is also
warmly acknowledged.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for 6,
8, 15, and 17 (7 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O960110H