Chiral amino alcohols as intermediates in the stereocontrolled synthesis of 1,3-disubstituted tetrahydroisoquinolines and protoberberines

Article abstract of DOI:10.1021/jo981326h

An efficient stereocontrolled synthetic approach to (3S)-3- aryltetrahydroisoquinoline 3d and (1S,3S)3-aryl-1- methyltetrahydroisoquinolines 3a-c by a Pictet-Spengler heterocyclization reaction of optically active (95% ee) (S)-1,2-diarylethylamines 2a-c is presented. An alternative route toward obtaining the epimeric derivative of 3a, tetrahydroisoquinoline (1R,3S)-6, was also achieved by a stereocontrolled ring opening process carried out on the oxazolotetrahydroisoquinoline 9. Tetrahydroisoquinoline 8 was employed for the stereoselective preparation of (5S,6S,14S)-6-phenyl-2,3,10,11-tetramethoxyprotoberberin-5-ol (12), a new type of 5,6-disubstituted protoberberine derivative with excellent (d.e>95% by ¹H NMR) stereoselection.

Full text of DOI:10.1021/jo981326h

J . Org. Chem. 1999, 64, 1115-1120
1115
Ch ir a l Am in o Alcoh ols As In ter m ed ia tes in th e Ster eocon tr olled
Syn th esis of 1,3-Disu bstitu ted Tetr a h yd r oisoqu in olin es a n d
P r otober ber in es
Luisa Carrillo, Dolores Bad´ıa,* Esther Dom´ınguez,* Eneritz Anakabe, In˜aki Osante,
Imanol Tellitu, and J ose´ L. Vicario
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apdo. 644-48080 Bilbao, Spain
Received J uly 8, 1998
An efficient stereocontrolled synthetic approach to (3S)-3-aryltetrahydroisoquinoline 3d and (1S,3S)-
3-aryl-1-methyltetrahydroisoquinolines 3a -c by a Pictet-Spengler heterocyclization reaction of
optically active (95% ee) (S)-1,2-diarylethylamines 2a -c is presented. An alternative route toward
obtaining the epimeric derivative of 3a , tetrahydroisoquinoline (1R,3S)-6, was also achieved by a
stereocontrolled ring opening process carried out on the oxazolotetrahydroisoquinoline 9. Tetrahy-
droisoquinoline 8 was employed for the stereoselective preparation of (5S,6S,14S)-6-phenyl-2,3,10,11-
tetramethoxyprotoberberin-5-ol (12), a new type of 5,6-disubstituted protoberberine derivative with
1
excellent (d.e>95% by H NMR) stereoselection.
In tr od u ction
Our continuous interest in the synthesis of alkaloids
incorporating the isoquinoline core encouraged us to find
versatile methodologies for the stereoselective prepara-
tion of 3-aryltetrahydroisoquinolines and epimeric C-1
methyl-substituted 3-aryltetrahydroisoquinolines. More-
over, in connection with a related project aiming at the
stereocontrolled synthesis of isopavines and tetrahy-
droisoquinolin-4-ols, we have recently achieved the syn-
thesis of a series of optically active â-amino alcohols 1
(95% ee) by reaction of a chiral imine with benzylic
Grignard reagents.5 Now, we wish to present the results
obtained when â-amino alcohols 1 were used as starting
materials for the stereocontrolled synthesis of the pair
of epimeric C-1 methylated 6,7-dimethoxy-3-(3,4-dimeth-
oxyphenyl)tetrahydroisoquinolines (3a ) and (6).
Finally, having established an optimum strategy for
the access to enantiopure 3-aryltetrahydroisoquinolines
of type 3, in order to extend its applicability, a new
stereoselective synthetic route to 5- and/or 6-substituted
protoberberine derivatives has also been developed. To
the best of our knowledge, the projected approach would
lead to the first example of a stereocontrolled preparation
of a protoberberine derivative with three stereogenic
centers.
During the last years a lot of attention has been paid
to the development of new strategies directed toward the
stereocontrolled preparation of heterocyclic systems, and
in this context, much progress has been made in the field
of tetrahydroisoquinolines, a family of alkaloids with a
widespread occurrence in nature and with an important
physiological action.1 Thereby, several original method-
ologies for the synthesis of chiral 1-substituted tetrahy-
droisoquinolines have been reported.2 However, very few
examples of the enantioselective syntheses of 1,3-disub-
stituted tetrahydroisoquinolines are known,3 and in all
cases reported, alkyl, but not aryl, substituents were
placed at C-3. Only one example reported by our group,
an enzyme-mediated enantioselective synthesis of 3-phen-
yl-1-methyl-1,2,3,4-tetrahydroisoquinolin-4-ols, has been
described, but the reported procedure suffers from serious
limitations.4
* To whom correspondence should be addressed. Tel.: +34-94-
4647700 (Extension 2622). Fax: +34-94-4648500. Prof. E. Dom´ınguez
e-mail: qopdopee@lg.ehu.es.
(1) (a) Minor, D. L.; Wyrick, S. D.; Charifson, P. S.; Wats, W. J .;
Nichols, D. E.; Mailman, R. B. J . Med. Chem. 1994, 37, 4317-4328.
(b) Hodgkiss, J . P.; Sherriffs, H. J .; Cottrell, D. A.; Shirakawa, K.; Kelly,
J . S.; Kuno, A.; Ohkubo, M.; Butchr, S. P.; Olverman, H. J . Eur. J .
Pharmacol. 1993, 240, 219-227. (c) Lezama, E. J .; Konkar, A. A.;
Salazar-Bookaman, M. M.; Miller, D. D.; Feller, D. R. Eur. J . Phar-
macol. 1996, 308, 69-80. (d) Cho, W. J .; Yoo, S. J .; Park, M. J .; Chung,
B. H.; Lee, C. O. Arch. Pharmacal Res. 1997, 20, 264-268.
(2) (a) Matulenko, M. A.; Meyers, A. I. J . Org. Chem. 1996, 61, 573-
580. (b) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1996, 61, 4607-
4610. (c) Yamazaki, N.; Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetra-
hedron Lett. 1996, 37, 6161-6164. (d) Kitamura, M.; Hisao, Y.; Ohta,
M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J . Org. Chem.
1994, 59, 297-310. (e) Chan, W.; Lee, A. W. M.; J iang, L. Tetrahedron
Lett. 1995, 36, 715-718. (f) Wu¨nsch, B.; Nerdinger, S. Tetrahedron
Lett. 1995, 36, 8003-8006. (g) Rein, K. S.; Gawley, R. E. Tetrahedron
Lett. 1990, 31, 3711-3714.
(3) (a) Gossmann, G.; Guillaume, D.; Husson, H. Tetrahedron Lett.
1996, 37, 4369-4372. (b) Bringmann, G.; Weirich, R.; Reuscher, H.;
J ansen, J . R.; Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993,
877-888. (c) Coote, S. J .; Davies, S. G.; Sutton, K. H. J . Chem. Soc.,
Perkin Trans. 1 1988, 1481-1487.
(4) Tellitu, I.; Bad´ıa, D.; Dom´ınguez, E.; Garc´ıa, F. J . Tetrahedron:
Asymmetry 1994, 5, 1567-1578.
Resu lts a n d Discu ssion
To accomplish the enantioselective preparation of the
(3S)-3-aryl-tetrahydroisoquinoline 3d , amine 2a , which
is easily obtained by removal (H2, Pd-C) of the chiral
appendage of the corresponding (+)-â-amino alcohol 1a ,5b
was made to react with formaldehyde in acidic medium
(see Scheme 1), thus, affording the target heterocycle 3d
in high yield (80%) without racemization. When acet-
aldehyde was used instead of formaldehyde under similar
(5) (a) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Ortega, F.; Tellitu, I.
Tetrahedron: Asymmetry 1998, 9, 151-155. (b) Carrillo, L.; Bad´ıa, D.;
Dom´ınguez, E.; Vicario, J . L.; Tellitu, I. J . Org. Chem. 1997, 62, 6716-
6721. (c) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Tellitu, I.; Vicario, J .
L. Tetrahedron: Asymmetry 1998, 9, 1809-1816.
10.1021/jo981326h CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/27/1999

1116 J . Org. Chem., Vol. 64, No. 4, 1999
Carrillo et al.
Ta ble 1. Red u ctive Assa ys Ca r r ied ou t on
Dih yd r oisoqu in olin e 5
Sch em e 1
reagent and conditions
yielda (%)
3a :6
H2, Pd/C, EtOH, rt
NaBH4, MeOH, rt
NaBH(OAc)3, CH2Cl2, reflux
LAH, THF, reflux
95
70
88
b
>95:5
73:27
>95:5
LAH/AlCl3, THF, reflux
LAH/AlMe3, THF, -78 °C f rt
b
90
80:20
a
b
Combined yield for both stereoisomers. No reaction was
observed.
Sch em e 2
cyclization conditions, a series of (1S,3S)-1-methyl-3-
aryltetrahydroisoquinolines 3a -c was obtained from
amines 2a -c, respectively, in good yield (70-82%), as a
single enantiomer in each case. Extensive NMR studies
(NOE experiments) proved the 1,3-cis relationship be-
tween the substituents at both stereogenic centers. This
result can be explained by assuming that, in the transi-
tion state, the iminium salt is stabilized in a chairlike
conformation, with the aryl substituent in an equatorial
position and where the CdN bond adopts the (E) config-
uration, as has been previously rationalized for the
cyclization of related compounds.6 In this preferred
conformation, the attack of the aryl ring leads to the
observed stereochemistry in isoquinolines 3a -c. More-
over, since the unique stereoisomer obtained is the less
sterically hindered one, the corresponding heterocycliza-
tion reaction seems to be a thermodynamically controlled
process.3b
NaBH(OAc)3 in refluxing CH2Cl2 afforded the corre-
sponding 1,3-cis-tetrahydroisoquinoline 3a with very high
diastereoselection. Besides, whereas the use of LAH or
LAH/AlCl3 in refluxing THF10 only afforded unreacted
starting material, other nucleophilic reducing systems
such as NaBH4/MeOH led to mixtures of both epimers
at C-1, where the desired 1,3-trans epimer 6 was obtained
as the minor stereoisomer (27% of the reaction mixture
1
by H NMR). Finally, and according to previous reports
by Bringmann,3b we expected the pair LAH/AlMe3 to
afford the 1,3-trans-tetrahydroisoquinoline 6, but unfor-
tunately, in the present case the 1,3-cis derivative 3a was
the one obtained as the major stereoisomer, probably due
to an electrostatic repulsive interaction between the
incoming hydride and the electron-enriched aryl ring.
At this point in the research, a new approach to the
stereoselective synthesis of 1,3-trans disubstituted tet-
rahydroisoquinolines was envisaged as depicted in Scheme
2. Oxazolidines 7a ,b, quantitatively prepared from the
common precursor 1a by reaction with aqueous formal-
dehyde and acetaldehyde, respectively, were heated in 1
N HCl to attempt heterocyclization. In the former case,
oxazolidine 7a yielded the expected tetrahydroisoquino-
line 8, but unfortunately, analogous behavior was not
observed for oxazolidine 7b since, under the same reac-
tion conditions, unreacted starting material and amine
2a were the only products found in the crude reaction
mixture.
Once the stereocontrolled synthesis of 1,3-cis disubsti-
tuted tetrahydroisoquinolines 3a -c had been optimized,
a second synthetic alternative was evaluated and opti-
mized for the transformation of 2a into 6. For that
purpose, (see Scheme 1) dihydroisoquinoline 5 was
prepared from the common precursor, amine 2a , via
heterocyclization of the acetamide intermediate 4,7 and
then the reduction of the azomethine function in dihy-
droisoquinoline 5 was studied under different conditions
(see Table 1).
As shown in Table 1, catalytic hydrogenation8 of
dihydroisoquinoline 5 or the use of the bulky reagent9
(6) See ref 3b. See also: Ungemach, F.; DiPierro, M.; Weber, R.;
Cook, J . M. J . Org. Chem. 1981, 46, 164-168, and Dom´ınguez, E.; Lete,
E.; Bad´ıa, D.; Villa, M. J .; Castedo, L.; Dom´ınguez, D. Tetrahedron
1987, 43, 1943-1948.
(7) Dom´ınguez, E.; Lete, E. Heterocycles 1983, 20, 1247-1254.
(8) Eleveld, M. B.; Hogeveen, H.; Schudde, E. P. J . Org. Chem. 1986,
51, 3635-3642.
(9) Cimarelli, C.; Palmieri G. Tetrahedron: Asymmetry 1994, 5,
1455-1458.
(10) Ashby, E. C.; Sanders, J . R.; Clavely, P.; Schwartz, R. J . Am.
Chem. Soc. 1973, 95, 6485-6486.

Chiral Amino Alcohols as Intermediates
J . Org. Chem., Vol. 64, No. 4, 1999 1117
Sch em e 3
Sch em e 4
To circumvent the difficulties found during the prepa-
ration of the target 1,3-trans disubstituted heterocycle
6, a modified synthetic route was evaluated (see Scheme
2). Thus, after oxidation of isoquinoline 8 and the
subsequent treatment of it with the base, the 5,10b-trans-
oxazolotetrahydroisoquinoline 9 (no NOE was observed
between the protons at C-10b and C-5 or C-3) was
obtained as a single diastereoisomer. To conclude the
projected synthesis, the stereoselective methylation of 9
was performed, affording the target tetrahydroisoquino-
line 10, which, under treatment with H2 (Pd-C), pro-
duced the (1R,3S)-6,7-dimethoxy-3-(3,4-dimethoxyphenyl)-
1-methyl-1,2,3,4-tetrahydroisoquinoline 6 (de>95% by 1H
NMR). The observed stereocontrol at C-1 during the
formation of tetrahydroisoquinoline 10 can be attributed
to the nucleophilic attack on the less hindered face of the
developing iminium intermediate formed with simulta-
neous opening of the oxazolidine ring.11 This stereochem-
ical proposal was confirmed a posteriori by measure-
ments of NOE experiments carried out on the target
heterocycle 6.
Once the feasibility of the proposed strategies for the
preparation of different nonracemic tetrahydroisoquino-
line derivatives had been demonstrated, we moved to our
second synthetic goal, which was the stereoselective
synthesis of protoberberine derivatives of type 12 (see
Scheme 3). This protocol illustrates the possible stereo-
selection that the presence of the adjacent asymmetric
carbon would induce in the generation of the new
stereogenic center.
Thereby, the already available isoquinoline 8 was
oxidized under Swern conditions12 to give the labile
aldehyde 11. As already anticipated,5c when treated with
an acetone solution of aqueous HCl, the latter derivative
11 was diastereoselectively transformed into (5S,6S,14S)-
5-hydroxy-6-phenyl-2,3,10,11-tetramethoxyprotober-
berine (12) as a result of a 1,2-induction due to the
presence of an adjacent stereogenic center (de > 95% by
1H NMR). The relative configuration at the newly created
stereogenic center accounts for the observation of an
intense NOE between H-5 and H-6. Besides, since no
chromatographic resolution could be achieved for the
signals attributed to each enantiomer, the ee determi-
nation (95%) had to be performed on its acetylated
derivative 13.
To demonstrate that the presence of a substituent (i.e.,
a phenyl) adjacent to the new stereogenic center was
required to get stereoselection in the above-mentioned
synthesis of protoberberine 12, the following experiment
was designed (see Scheme 4). Acetal 14, prepared from
tetrahydroisoquinoline 3d (KOH, BADA (bromoacetal-
dehydediethylacetal)-, DMSO), was submitted to the
same cyclization conditions as mentioned above. In this
case, the acidic treatment13 of acetal 14 yielded proto-
berberine 15, a hydroxylated analogue of the naturally
occurring protoberberine (-)-xylopinine,14 as a separable
1:1 diastereomeric mixture of protoberberines (5R,14S)-
15a and (5S,14S)-15b. The relative configuration at C-5
was elucidated by means of extensive NMR studies. Thus,
the observation sand the absences of NOE between
H-14 and H-5 was used as a diagnosis for the stereo-
structure assignments of 15a and 15b, respectively. In
both cases, the ee (95%) was determined by chiral HPLC
analysis after chromatographic separation of both dia-
stereoisomers.
In summary, the first enantioselective synthesis of
3-aryltetrahydroisoquinolines from optically active (95%
ee) amino alcohols 1 is reported. Besides, the diastereo-
divergent synthesis of the pair that is epimeric at C-1,
1-methyl-3-aryl-1,2,3,4-tetrahydroisoquinolines 3a and 6,
has been achieved with great success. At the same time,
the same type of precursor, 1, led to the obtaining of
isoquinoline 8 and then (5S,6S,14S)-6-phenylprotober-
berin-5-ol 12, a new kind of protoberberine derivative.
In this case, the high overall and optical yields, the small
number of steps, and the chemical economy (the chiral
auxiliary is included in the skeleton of the target
molecule) feature the described synthesis. Ee determina-
tions (95% by chiral HPLC) were carried out on isoquino-
lines 3a -d and 6 and also on protoberberines 13 and
15a ,b, indicating that no racemization took place in any
of the performed transformations.
Exp er im en ta l Section 15
Typ ica l P r oced u r e for Syn th esis of Tetr a h yd r oiso-
qu in olin es 3a -c. Syn th esis of (-)-(1S,3S)-6,7-Dim eth oxy-
3-(3,4-d im eth oxyp h en yl)-1-m eth yl-1,2,3,4-tetr a h yd r oiso-
(13) Tellitu, I.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo, L. Heterocycles
1996, 43, 2099-2112.
(14) For
a stereocontrolled synthesis of (-)-xylopinine, see, for
(11) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994,
50, 1083-1092.
(12) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
example: Comins, D. L.; Thakker, P. M.; Baevsky, M. F. Tetrahedron
1997, 53, 16327-16340.
(15) For general procedures, see ref 5a.

1118 J . Org. Chem., Vol. 64, No. 4, 1999
Carrillo et al.
qu in olin e (3a ). Over a suspension of amine 2a (0.65 g, 2.05
mmol) in 6 N H2SO4 (1 mL) was added acetaldehyde (0.27 g,
6.15 mmol) in three portions. After the first addition the
mixture was heated to reflux for 24 h. Then, the mixture was
allowed to reach room temperature, a new portion of acetal-
dehyde was added, and the suspension was stirred for 24 h.
Finally, the third portion was added and the mixture was
stirred at reflux for 5 h. Then, after cooling with an ice bath,
the mixture was basified with NaOH (10%) and extracted with
Et2O (3 × 20 mL). The combined organic extracts were dried
over Na2SO4, the solvent was distilled under vacuum, and the
resulting oil was crystallized from Et2O to afford tetrahy-
droisoquinoline 3a as a white solid (0.49 g, 1.43 mmol, 70%)
8.2, 1H), 6.92 (dd, J ) 8.3, 1.8, 1H), 7.00 (d, J ) 1.8, 1H). 13C
NMR (δ, ppm): 37.1, 48.7, 55.2, 58.2, 109.0, 109.5, 110.9, 111.5,
118.5, 126.5, 126.6, 136.8, 147.2, 147.4, 148.1, 148.9. IR
(KBr): 3350-3275. EI-MS m/z: 330 (M+ + 1, 2), 329 (M+, 7).
(-)-(1S)-N-[1,2-Bis(3,4-d im et h oxyp h en yl)et h yl]a cet -
a m id e (4). Over a solution of amine 2a (0.45 g, 1.42 mmol) in
20 mL of CH2Cl2 were added catalytic amounts of DMAP and
Et3N (0.30 mL, 2.13 mmol). The mixture was cooled with an
ice bath, AcCl (0.13 mL 1.78 mmol) was added via syringe,
and the new solution was stirred overnight at room temper-
ature. Then, the crude was poured onto ice and extracted with
CH2Cl2 (3 × 25 mL). The combined organic extracts were dried
over Na2SO4 and the solvent distilled under vacuum. The
resulting oil was purified by flash column chromatography
(CH2Cl2/EtOAc, 6:4) and then crystallized from Et2O to afford
1
[R]20D: -1.7 (c ) 1.0, CH2Cl2). Mp: 130-133 °C. H NMR (δ,
ppm): 1.50 (d, J ) 6.5, 3H), 1.74 (br s, 1H), 2.82 (dd, J ) 15.6,
3.8, 1H), 2.96 (dd, J ) 15.6, 10.8, 1H), 3.85 (s, 3H), 3.87 (s,
3H), 3.88 (s, 3H), 3.90 (s, 3H), 3.97 (dd, J ) 10.8, 3.8, 1H),
4.23 (q, J ) 6.5, 1H), 6.57 (s, 1H), 6.72 (s, 1H), 6.86 (d, J )
8.2, 1H), 6.97 (dd, J ) 8.2, 1.8, 1H), 7.02 (d, J ) 1.8, 1H). 13C
NMR (δ, ppm). 22.4, 38.3, 53.2, 55.9, 56.0, 58.6, 108.5, 109.7,
111.1, 111.5, 118.7, 127.2, 131.7, 137.2, 147.4, 147.5, 148.2,
149.1. IR (KBr): 3320-3280. EI-MS m/z: 339 (M+ - 4, 100).
Anal. Calcd for C20H25NO4: C, 69.94; H, 7.34; N, 4.08. Found:
C, 69.65; H, 7.33, 3.71.
acetamide 4 as a white solid (0.40 g, 1.11 mmol, 79%). [R]20
:
D
-4.8 (c ) 0.3, EtOH). Mp: 148-150 °C. 1H NMR (δ, ppm):
1.97 (s, 3H), 3.03-3.07 (m, 2H), 3.75 (s, 3H), 3.82 (s, 3H), 3.83
(s, 3H), 3.85 (s, 3H), 5.15-5.18 (m, 1H), 5.70 (br d, 1H), 6.50-
6.82 (m, 6H). 13C NMR (δ, ppm): 23.3, 42.0, 54.1, 55.6, 55.7,
55.8, 110.4, 110.8, 111.0, 112.4, 118.5, 121.3, 129.7, 134.0,
147.5, 148.1, 148.5, 148.8, 169.2. IR (KBr): 3297, 1641. EI-
MS m/z: 300 (M+ - 57, 12).
(-)-(3S)-6,7-Dim eth oxy-3-(3,4-dim eth oxyph en yl)-1-m eth -
yl-3,4-d ih yd r oisoqu in olin e (5). Over a solution of acetamide
4 (0.54 g, 1.49 mmol) in 25 mL of MeCN was added PCl5 (2.48
g, 11.9 mmol) under argon in three portions at 0 °C, and after
each addition the mixture was allowed to reach room temper-
ature. When the starting material was completely consumed
(TLC) the solution was cooled with an ice bath and basified
using NaOH (20%), and the stirring was continued for 1 h.
Then, the crude reaction mixture was extracted with CH2Cl2
(3 × 50 mL). The combined organic extracts were dried over
Na2SO4, the solvent distilled under vacuum, and the resulting
oil was purified by flash column chromatography (hexanes/
EtOAc/TEA, 6:3.5:0.5) to afford 3,4-dihydroisoquinoline 5 (0.46
g, 1.34 mmol, 90%). [R]20D: -2.9 (c ) 1.0, CH2Cl2). 1H NMR (δ,
ppm): 2.45 (d, J ) 2.0, 3H), 2.81-2.87 (m, 2H), 3.84 (s, 3H),
3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 4.25 (ddd, J ) 12.6, 6.6,
2.0, 1H), 6.67 (s, 1H), 6.82 (d, J ) 8.2, 1H), 6.91 (dd, J ) 8.2,
1.8, 1H), 7.01 (d, J ) 1.8, 1H), 7.03 (s, 1H). 13C NMR (δ, ppm):
23.3, 34.1, 55.7, 55.8, 55.9, 56.1, 60.4, 109.0, 110.1, 110.4, 111.0,
118.9, 122.1, 130.7, 136.9, 147.6, 147.9, 148.8, 151.1, 163.8.
IR (neat): 1625. EI-MS m/z: 341 (M+, 100).
(+)-(1S,3S)-5,6-Dim eth oxy-3-(3,4-d im eth oxyp h en yl)-1-
m eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e (3b). According to
the typical procedure, the reaction of (+)-amine 2b (0.20 g,
0.63 mmol) with acetaldehyde (1.38 g, 31.50 mmol) afforded,
after chromatographic purification, the tetrahydroisoquinoline
3b as a colorless oil (0.17 g, 0.50 mmol, 80%). [R]20D: +35.0 (c
1
) 0.8, CH2Cl2). H NMR (δ, ppm): 1.49 (d, J ) 6.5, 3H), 2.39
(br s, 1H), 2.78 (dd, J ) 16.8, 11.4, 1H), 3.12 (dd, J ) 16.8,
3.5, 1H), 3.77 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 3.90-3.96 (m,
4H), 4.22 (q, J ) 6.5, 1H), 6.79 (d, J ) 8.5, 1H), 6.85 (d, J )
8.5, 1H), 6.92-7.04 (m, 3H). 13C NMR (δ, ppm): 22.1, 33.3,
53.2, 55.7, 55.9, 58.5, 59.9, 109.7, 110.2, 111.1, 118.7, 120.4,
129.6, 133.0, 137.2, 146.2, 148.2, 149.1, 150.5. IR (neat): 3500-
3400. EI-MS m/z: 343 (M+, 14).
(-)-(1S,3S)-3-(3,4-Dim eth oxyph en yl)-6-m eth oxy-1-m eth -
yl-1,2,3,4-tetr a h yd r oisoqu in olin e (3c). According to the
typical procedure, the reaction of (+)-amine 2c (0.20 g, 0.69
mmol) with acetaldehyde (1.53 g, 34.80 mmol) afforded the
tetrahydroisoquinoline 3c which was purified by crystallization
from Et2O (0.18 g, 0.57 mmol, 82%). [R]20D: -46.8 (c ) 1.0,
Typ ica l P r oced u r e for th e Syn th esis of Oxa zolid in es
7. Syn th esis of (+)-(4S,1′S)-3-[1,2-Bis(3,4-d im eth oxy-
ph en yl)eth yl]-4-ph en yloxazolidin e (7a). A solution of â-ami-
no alcohol 1a (1.6 g, 3.80 mmol), HCHO (1.5 mL, 35% aq, 19.0
mmol), and molecular sieves (4 Å) in 10 mL of CH2Cl2 was
stirred at room temperature until there was total consumption
of starting material (TLC, CH2Cl2/AcOEt, 6:4). Then, the
molecular sieves were filtered, the solvent was distilled at
reduced pressure, and the resulting mixture was purified by
flash column chromatography (hexanes/EtOAc, 7:3) to afford
oxazolidine 7a as a colorless oil (1.70 g, 3.80 mmol, quantita-
1
CH2Cl2). Mp: 218-221 °C (HCl salt). H NMR (δ, ppm): 1.49
(d, J ) 6.4, 3H), 2.87 (dd, J ) 16.1, 3.8, 1H), 3.03 (dd, J )
16.1, 11.0, 1H), 3.77 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 3.99
(dd, J ) 11.0, 3.8, 1H), 4.23 (q, J ) 6.4, 1H), 6.61 (d, J ) 2.6,
1H), 6.76 (dd, J ) 8.5, 2.6, 1H), 6.84 (d, J ) 8.2, 1H), 6.97 (dd,
J ) 8.2, 2.0, 1H), 7.01 (d, J ) 2.0, 1H), 7.14 (d, J ) 8.5, 1H).
13C NMR (δ, ppm): 22.1, 39.0, 52.9, 55.1, 55.8, 58.5, 109.6,
110.9, 112.0, 113.3, 118.6, 126.1, 131.9, 136.3, 137.2, 148.1,
149.0, 158.3 (quaternary Carom). IR (KBr): 3310-3300. EI-
MS m/z: 313 (M+, 3). Anal. Calcd for C19H23NO3: C, 72.82; H,
7.39; N, 4.47. Found: C, 72.71; H, 7.27; N, 4.40.
tive yield). [R]20
:
+173.5 (c ) 1.0, CH2Cl2). 1H NMR (δ,
D
(-)-(3S)-6,7-Dim eth oxy-3-(3,4-dim eth oxyph en yl)-1,2,3,4-
tetr a h yd r oisoqu in olin e (3d ). Over a suspension of amine
2a (0.44 g, 1.38 mmol) in 8 mL of 1 N HCl was added 35%
aqueous formaldehyde (1.08 mL, 13.8 mmol), and the mixture
was heated to 60 °C until total consumption of the starting
material (TLC, CH2Cl2/MeOH, 9.5:0.5). After cooling, the
solution was basified with NH4OH and extracted with CH2Cl2
(3 × 25 mL). The combined organic extracts were washed with
water and dried over Na2SO4, and the solvent was evaporated.
The so-obtained oil was purified by crystallization from EtOH
to afford tetrahydroisoquinoline 3d as a white solid (0.36 g,
1.10 mmol, 80%). [R]20D: -67.3 (c ) 0.2, CH2Cl2). Mp: 97-98
ppm): 2.82 (dd, J ) 13.1, 9.6, 1H), 3.11 (dd, J ) 13.1, 4.0,
1H), 3.46 (s, 3H), 3.63 (s, 3H), 3.68 (dd, J ) 7.9, 4.7, 1H), 3.78
(s, 3H), 3.79 (s, 3H), 3.78-3.82 (m, 1H), 4.03 (dd, J ) 7.2, 4.8,
1H), 4.15 (t, J ) 7.7, 1H), 4.72 (d, J ) 5.1, 1H), 4.87 (d, J )
5.1, 1H), 6.20 (d, J ) 1.8, 1H), 6.37-6.45 (m, 2H), 6.54-6.64
(m, 3H), 7.14-7.24 (m, 5H). 13C NMR (δ, ppm): 42.7, 55.3,
55.5, 55.7, 64.8, 69.2, 72.7, 85.2, 109.8, 110.6, 111.3, 112.7,
121.2, 121.5, 126.7, 126.9, 128.1, 130.8, 133.7, 143.5, 147.1,
147.9, 148.1, 148.3. IR (neat): 1520. EI-MS m/z: 449 (M+,
<1). Anal. Calcd for C27H31NO5: C, 72.14; H, 6.95; N, 3.11.
Found: C, 71.98; H, 6.94; N, 3.00.
(+)-(2S,4S,1′S)-3-[1,2-Bis(3,4-d im eth oxyp h en yl)eth yl]-
2-m eth yl-4-p h en yloxa zolid in e (7b). According to the typical
procedure the reaction between (+)-amine 1a (0.8 g, 1.9 mmol)
and CH3CHO (0.51 mL, 9.1 mmol) afforded, after 5 h, oxazol-
idine 7b as a 92:8 cis-trans mixture of diastereoisomers (0.70
1
°C (lit.16 mp 104-105 °C, racemic MeOH). H NMR (δ, ppm):
2.11 (s, 1H), 2.84-2.87 (m, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 3.85
(s, 3H), 3.86 (s, 3H), 3.89-3.92 (m, 1H), 4.04 (d, J ) 15.1, 1H),
4.14 (d, J ) 15.1, 1H), 6.54 (s, 1H), 6.56 (s, 1H), 6.82 (d, J )
1
g, 1.52 mmol, 80%). [R]20D: +94.5 (c ) 0.2, CH2Cl2). H NMR
(δ, ppm): 1.46 (d, J ) 5.3, 3H), 2.78 (dd, J ) 13.5, 9.5, 1H),
3.02 (dd, J ) 13.5, 5.2, 1H), 3.58 (s, 3H), 3.66 (s, 3H), 3.72 (dd,
(16) Vicente, T.; Mart´ınez de Marigorta, E.; Domı´nguez, E.; Carrillo,
L.; Bad´ıa, D. Heterocycles 1993, 36, 2067-2072.

Chiral Amino Alcohols as Intermediates
J . Org. Chem., Vol. 64, No. 4, 1999 1119
J ) 6.5, 3.6, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.89 (dd, J ) 9.5,
5.2, 1H), 3.93-4.02 (m, 2H), 4.91 (q, J ) 5.3, 1H), 6.51 (d, J )
1.9, 1H), 6.59-6.65 (m, 5H), 7.16-7.13 (m, 5H). 13C NMR (δ,
ppm): 22.3, 41.4, 55.6, 55.8, 64.9, 68.1, 73.1, 92.3, 110.0, 110.6,
112.0, 112.6, 121.3, 121.5, 126.8, 127.3, 128.1, 131.6, 132.8,
143.9, 147.1, 148.0, 148.2, 148.3. IR (neat): 1520. EI-MS
m/z: 462 (M+ - 1, <1). Anal. Calcd for C28H33NO5: C, 72.55;
H, 7.17; N, 3.02. Found: C, 72.88; H, 7.29; N, 2.73.
7.05 (m, 8H). 13C NMR (δ, ppm): 24.9, 28.9, 51.7, 53.4, 55.7,
55.9, 56.0, 56.1, 61.2, 62.2, 109.4, 110.9, 111.4, 111.5, 119.8,
127.4, 127.7, 128.5, 126.4, 131.9, 133.8, 140.1, 147.1, 147.4,
148.4, 149.2. IR (neat): 3600-3300. EI-MS m/z: 446 (M+
-
17, 100). Anal. Calcd for C28H33NO5: C, 72.55; H, 7.17; N, 3.02.
Found: C, 72.76; H, 7.07; N, 2.78.
(-)-(1R,3S)-6,7-Dim eth oxy-3-(3,4-d im eth oxyp h en yl)-1-
m eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e (6). A solution of
tetrahydroisoquinolines 10 (0.45 g, 1.10 mmol) in a mixture
of 10 mL of EtOH and 5 mL of HCl (10%) was hydrogenated
at 2 atm in the presence of catalytic amounts of Pd-C (10%).
After total consumption of the starting material (TLC, hex-
anes/EtOAc, 6:4, 20 h) the solution was filtered, basified with
a saturated solution of NaHCO3, and extracted with CH2Cl2
(3 × 25 mL). The combined organic extracts were dried over
Na2SO4, the solvent was evaporated under reduced pressure,
and the resulting colorless oil was purified by flash column
chromatography to afford tetrahydroisoquinoline 6 (0.31 g, 0.90
(+)-(3S,1′S)-6,7-Dim eth oxy-3-(3,4-d im eth oxyp h en yl)-2-
(2-h yd r oxy-1-p h en ylet h yl)-1,2,3,4-t et r a h yd r oisoq u in o-
lin e (8). A suspension of oxazolidine 7a (0.56 g, 1.25 mmol)
in 5 mL of 1 N HCl was heated under argon at 50-60 °C for
5 h. Then, the mixture was cooled at 0 °C, basified with 1 M
NaOH, and extracted with CH2Cl2 (3 × 25 mL). The combined
organic extracts were dried over Na2SO4, the solvent was
distilled under vacuum, and the resulting oil was purified by
flash column chromatography (hexanes/EtOAc, 1:1) to afford
tetrahydroisoquinoline 8 as a colorless oil (0.39 g, 0.87 mmol,
1
1
70%). [R]20D: +35.8 (c ) 1.0, CH2Cl2). H NMR (δ, ppm): 2.86
mmol, 82%). [R]20D: -2.4 (c ) 0.5, CH2Cl2). H NMR (δ, ppm):
(dd, J ) 16.5, 4.5, 1H), 3.11 (dd, J ) 16.5, 5.9, 1H), 3.82 (s,
3H), 3.82 (s, 3H), 3.83-3.99 (m, 11H), 4.23 (dd, J ) 5.9, 4.5,
1H), 6.50 (s, 1H), 6.59 (s, 1H), 6.64-6.82 (m, 3H), 7.23-7.39
(m, 5H). 13C NMR (δ, ppm): 32.7, 47.2, 55.6, 55.8, 55.9, 58.1,
62,4, 64.9, 109.1, 110.7, 111.1, 111.2, 119.9, 127.5, 128.4, 125.8,
128.1, 134.9, 139.9, 147.3, 147.6, 148.1, 148.7. IR (neat): 3600-
3300. EI-MS m/z: 449 (M+, 2). Anal. Calcd for C27H31NO5:
C, 72.14; H, 6.95; N, 3.11. Found: C, 71.96; H, 6.83; N, 3.25.
(+)-(3S ,5S ,10b R )-8,9-Dim e t h oxy-5-(3,4-d im e t h oxy-
ph en yl)-3-ph en yl-2,3,5,6-tetr ah ydr o-10bH-oxazolo-[2,3-a]-
isoqu in olin e (9). Over a solution of tetrahydroisoquinoline
8 (0.38 g, 0.85 mmol) in 30 mL of EtOH were added iodine
(0.43 g, 1.7 mmol) and NaOAc (0.09 g, 1.1 mmol) the resulting
mixture was refluxed for 1 h, and after cooling, an aqueous
solution of sodium thiosulfate (10%) was added dropwise. The
mixture was extracted with CH2Cl2 (3 × 50 mL), the combined
organic extracts were washed with brine and dried over
Na2SO4, and after the solvent was distilled under vacuum, the
so-obtained solid was dissolved in 15 mL of CH2Cl2 and cooled
at -78 °C. Then, triethylamine (0.24 mL, 1.7 mmol) was added,
the mixture was stirred under argon for 1 h, and the temper-
ature was raised to room temperature. Water was added, the
organic phase was decanted and dried over Na2SO4, and the
solvent was distilled at reduced pressure to afford an oil that
was purified by flash column chromatography (hexanes/EtOAc,
1:1) yielding oxazoloisoquinoline 9 as a colorless oil (0.26 g,
1.52 (d, J ) 6.8, 3H), 1.73 (br s, 1H), 2.87 (d, J ) 7.1, 2H),
3.85 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.21 (t, J
) 7.1, 1H), 4.30 (q, J ) 6.8, 1H), 6.57 (s, 1H), 6.60 (s, 1H),
6.84 (d, J ) 8.2, 1H), 6.95 (dd, J ) 8.2, 1.9, 1H), 7.02 (d, J )
1.9, 1H). 13C NMR (δ, ppm): 24.1, 37.5, 51.2, 51.6, 55.8, 55.9,
109.7, 110.9, 111.3, 118.7, 126.3, 131.4, 137.1, 147.2, 147.4,
148.1, 148.9. IR (neat): 3350-3200. EI-MS m/z: 343 (M+, 16).
Anal. Calcd for C20H25NO4: C, 69.94; H, 7.34; N, 4.08. Found:
C, 69.84; H, 7.48; N, 4.45.
(-)-(5S ,6S ,14S )-6-P h e n y l-2,3,10,11-t e t r a m e t h o x y -
7,8,13,14-tetr a h yd r op r otober ber in -5-ol (12). Over a cooled
(-60 °C) solution of oxalyl chloride (0.13 mL, 1.40 mmol) in 6
mL of CH2Cl2 was added dropwise a solution of DMSO (0.20
mL, 2.90 mmol) in 4 mL of the same solvent, and the mixture
was stirred for 15 min. Then, a solution of tetrahydroisoquino-
line 8 (0.58 g, 1.30 mmol) in 10 mL of CH2Cl2 was added
dropwise, and the stirring was continued for 30 min. Working
at the same low temperature, diisopropylethylamine (1.13 mL,
6.50 mmol) was added slowly, and after being stirred for 15
min, the solution was allowed to reach ambient temperature.
The reaction was quenched with water (10 mL) and extracted
with CH2Cl2 (3 × 25 mL). The combined organic extracts were
dried over Na2SO4, and the solvent was distilled under reduced
pressure to afford aldehyde 11. Crude aldehyde 11 was quickly
dissolved in acetone (18 mL), and after cooling with an ice bath,
concd HCl (6 mL) was added, and the mixture was stirred for
2 h at room temperature. Then, the crude was cooled again,
basified with 1 M NaOH, and extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried over Na2SO4,
the solvent was distilled under vacuum, and the resulting oil
was purified by flash column chromatography (CH2Cl2/EtOAc,
6:4). The resulting colorless oil was crystallized from Et2O to
afford protoberberine 12 as a white solid (0.40 g, 0.91 mmol,
yield ) 70%, two steps). [R]20D: -94.5 (c ) 0.5, CH2Cl2). Mp
1
0.60 mmol, 70%). [R]20D: +33.4 (c ) 1.0, CH2Cl2). H NMR (δ,
ppm): 2.80 (dd, J ) 16.0, 3.2, 1H), 3.03 (dd, J ) 16.0, 11.3,
1H), 3.55 (s, 3H), 3.79 (dd, J ) 7.8, 5.2, 1H), 3.84 (s, 3H), 3.87
(s, 3H), 3.89 (s, 3H), 4.01 (dd, J ) 11.3, 3.2, 1H), 4.30 (dd, J )
7.8, 5.2, 1H), 4.41 (t, J ) 7.8, 1H), 5.53 (s, 1H), 6.60 (s, 1H),
6.76 (d, J ) 8.2, 1H), 6.88 (dd, J ) 8.2, 1.8, 1H), 6.94 (s, 1H),
6.97 (d, J ) 1.8, 1H), 7.15-7.28 (m, 5H). 13C NMR (δ, ppm):
39.9, 55.4, 55.8, 55.9, 60.5, 66.4, 70.7, 90.9, 109.9, 110.3, 110.6,
120.0, 126.5, 126.8, 128.3, 123.8, 127.5, 135.5, 142.9, 147.8,
1
122-124 °C. H NMR (δ, ppm): 2.86 (dd, J ) 15.8, 11.1, 1H),
148.1, 148.8, 149.1. IR (neat): 1520. EI-MS m/z: 446 (M+
-
3.18 (dd, J ) 15.8, 3.6, 1H), 3.66 (d, J ) 15.1, 1H), 3.71-3.94
(m, 2H), 3.77 (s, 3H), 3.82 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H),
4.41 (d, J ) 5.5, 1H), 5.26 (apparent d, 1H), 6.44 (s, 1H), 6.74
(s, 1H), 6.60 (s, 1H), 7.02-7.24 (m, 5H), 7.16 (s, 1H). 13C NMR
(δ, ppm): 36.5, 53.8, 54.9, 55.7, 55.9, 67.3, 68.7, 107.5, 108.6,
108.7, 111.0, 125.6, 126.1, 129.4, 129.8, 134.5, 128.1, 128.4,
130.4, 147.2, 147.3, 148.0, 148.2. IR (KBr): 3600-3200. EI-
MS m/z: 447 (M+, 15).
1, 100). Anal. Calcd for C27H29NO5: C, 72.14; H, 6.53; N, 3.13.
Found: C, 72.06; H, 6.35; N, 2.97.
(+)-(1R,3S,1′S)-3-(3,4-Dim eth oxyp h en yl)-2-(2-h yd r oxy-
1-p h e n yle t h yl)-1-m e t h yl-1,2,3,4-t e t r a h yd r oisoq u in o-
lin e (10). Over a stirred and cold (0 °C) solution of MeMgI
(0.7 mL of a 3M solution in ether, 2.0 mmol) in 5 mL of THF
was added a solution of tetrahydroisoquinoline 9 (0.18 g, 0.40
mmol) in 10 mL of the same solvent. Then, the solution was
allowed to reach room temperature, 15 mL of a saturated
solution of NH4Cl was added, the organic phase was decanted,
and the aqueous layer was extracted with CH2Cl2 (3 × 25 mL).
The combined organic extracts were washed with brine and
dried over Na2SO4, and the so-obtained crude was purified by
flash column chromatography (hexanes/EtOAc, 6:4) to afford
tetrahydroisoquinoline 10 as a colorless oil (0.19 g, 0.38 mmol,
(-)-(5S ,6S ,14S )-5-Ac e t o x y -6-p h e n y l-2,3,10,11-t e t -
r a m eth oxy-7,8,13,14-tetr a h ydr opr otober ber in e (13). Over
a solution of protoberberin-5-ol 12 (0.45 g, 1.01 mmol) in 15
mL of CH2Cl2 were added TEA (0.20 mL, 1.50 mmol) and a
catalytic amount of DMAP. The solution was cooled at 0 °C,
Ac2O (0.12 mL, 1.25 mmol) was added, and the new solution
was stirred for 4 h. For the workup, the mixture was poured
onto ice and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with brine and dried with
Na2SO4, and the solvent was evaporated under vacuum. The
resulting crude was purified by flash column chromatography
(hexanes/EtOAc, 3:7) to afford an oil which was crystallized
from Et2O to yield acetate 13 as a white solid (0.3 g, 0.6 mmol,
1
97%). [R]20D: +21.0 (c ) 1.0, CH2Cl2). H NMR (δ, ppm): 1.66
(d, J ) 6.9, 3H), 2.65 (dd, J ) 16.0, 4.3, 1H), 2.86 (dd, J )
16.0, 11.8, 1H), 3.27 (dd, J ) 9.0, 3.7, 1H), 3.74 (s, 3H), 3.77-
3.86 (m, 2H), 3.86 (s, 3H), 3.93 (s, 6H), 4.50 (q, J ) 6.9, 1H),
4.63 (dd, J ) 11.8, 4.3, 1H), 6.28 (s, 1H), 6.53 (s, 1H), 6.92-

1120 J . Org. Chem., Vol. 64, No. 4, 1999
Carrillo et al.
60%). [R]20D: -54.2 (c ) 0.1, CH2Cl2). Mp 96-98 °C. H NMR
(δ, ppm): 1.90 (s, 3H), 2.93 (m, 1H), 3.08 (dd, J ) 16.2, 4.36,
1H), 3.76 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 3.95 (s, 3H), 3.65-
3.95 (m, 14H), 4.13 (dd, J ) 10.5, 4.3, 1H), 4.58 (d, J ) 5.2,
1H), 6.26 (apparent d, 1H), 6.36 (s, 1H), 6.58 (s, 1H), 6.74 (s,
1H), 6.83 (s, 1H), 7.10-7.31 (m, 5H). 13C NMR (δ, ppm): 21.1,
35.0, 52.9, 55.1, 55.8. 55.9, 56.0, 62.7, 70.7, 107.9, 108.9, 109.6,
110.9, 124.3, 125.5, 125.7, 131.5, 135.3, 127.9, 130.1, 147.3,
148.8, 170.7. IR (KBr): 1733. EI-MS m/z: 167 (40), 149 (100).
(+)-(3S)-2-(2,2-Die t h oxye t h yl)-6,7-d im e t h oxy-3-(3,4-
d im et h oxyp h en yl)-1,2,3,4-t et r a h yd r oisoq u in olin e (14).
Over a suspension of K2CO3 (1.10 g, 8.20 mmol) in 25 mL of
dry MeCN was added a solution of tetrahydroisoquinoline 3d
(0.83 g, 2.50 mmol) in 15 mL of the same solvent, and the
mixture was heated to reflux for 2 h. After cooling, BADA (1.50
mL, 10.1 mmol) was added, and the reflux was continued until
there was total consumption of the starting material (TLC,
CH2Cl2/EtOAc, 8:2). The mixture was cooled, water (25 mL)
was added, and then the mixture was extracted with CH2Cl2
(3 × 25 mL). The combined organic extracts were washed with
brine and dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The resulting crude reaction was
purified by flash column chromatography to afford tetrahy-
droisoquinoline 14 as a colorless oil (0.90 g, 2.02 mmol, 81%).
solution was cooled again, basified with 1 M NaOH solution,
and extracted with CH2Cl2 (3 × 15 mL). The combined organic
extracts were washed with water and dried over Na2SO4, and
the solvent was evaporated under vacuum. The resulting oil
was purified by PTLC to afford protoberberines 15a and 15b
in a 70% combined yield.
1
15a . [R]20D: -93.2 (c ) 0.1, MeOH). 1H NMR (δ, ppm): 2.59
(dd, J ) 11.1, 7.5, 1H), 2.82 (m, 1H), 3.09 (dd, J ) 15.8, 3.9,
1H), 3.35 (dd, J ) 11.1, 4.8, 1H), 3.79-3.93 (m, 1H), 3.85 (s,
3H), 3.86 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 4.87 (apparent t,
1H), 6.58 (s, 1H), 6.62 (s, 1H), 6.70 (s, 1H), 7.07 (s, 1H). 13C
NMR (δ, ppm): 34.2, 55.8, 55.9, 57.1, 57.5, 58.5, 66.7, 107.8,
108.8, 109.3, 111.1, 125.6, 129.8, 130.4, 147.4, 147.5, 147.9,
148.4.
15b. [R]20D: -73.3 (c ) 0.1, MeOH). 1H NMR (δ, ppm): 2.77-
2.79 (m, 2H), 3.20-3.31 (m, 2H), 3.57 (dd, J ) 11.0, 3.8, 1H),
3.73 (d, J ) 16.2, 1H), 3.85-3.95 (m, 1H), 3.87 (s, 3H), 3.88 (s,
3H), 3.90 (s, 3H), 3.91 (s, 3H), 4.52 (m, 1H), 6.60 (s, 3H), 6.68
(s, 1H), 6.75 (s, 1H), 6.87 (s, 1H). 13C NMR (δ, ppm): 36.5,
55.9, 58.7, 59.6, 60.1, 66.7, 107.8, 108.7, 111.1, 111.7, 125.8,
126.0, 128.8, 129.1, 147.4, 147.6, 148.9.
Ack n ow led gm en t . Financial support from the
Basque Government (Project GV PI 96/53 and fellow-
ships to J .L.V. and to E.A.) and from the University of
the Basque Country (Project UPV 170.310-E.A.154/96)
is gratefully acknowledged. The authors gratefully
acknowledge PETRONOR, S. A. (Muskiz, Bizkaia) for
the generous gift of solvents.
1
[R]20D: +28.0 (c ) 0.1, CH2Cl2). H NMR (δ, ppm): 1.15 (t, J
) 6.9, 3H), 1.20 (t, J ) 6.9, 3H), 2.36 (dd, J ) 13.5, 5.1, 1H),
2.73 (dd, J ) 13.5, 5.3, 1H), 3.05 (dd, J ) 16.4, 8.9, 1H), 3.65
(m, 6H), 3.84 (s, 3H), 3.86 (s, 6H), 3.88 (s, 3H), 4.12 (d, J )
15.3, 1H), 4.61 (t, J ) 5.1, 1H), 6.56 (s, 2H), 6.80-6.97 (m,
3H). 13C NMR (δ, ppm): 15.7, 36.4, 55.7, 56.2, 56.3, 61.7, 62.5,
64.1, 102.6, 109.5, 110.6, 111.0, 111.2, 120.6, 126.4, 126.8,
135.5, 147.7, 147.9, 148.5. IR (neat): 1270. EI-MS m/z: 445
(M+, 3).
(-)-(5R,14S)- a n d (-)-(5S,14S)-2,3,10,11-Tetr a m eth oxy-
7,8,13,14-t et r a h yd r op r ot ob er b er in -5-ol (15a a n d 15b ).
Concentrated HCl (4 mL) was added over a cold (0 °C) solution
of acetal 14a (0.50 g, 1.10 mmol) in 12 mL of acetone, and the
mixture was allowed to reach room temperature slowly. The
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and/or 13C NMR spectra of compounds 3b,d , 4, 5, 12-14, and
15a ,b (14 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 O981326H