A novel straightforward synthesis of enantiopure tetrahydroisoquinoline alkaloids

Article abstract of DOI:10.1021/jo001397s

A novel, direct, and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.

Full text of DOI:10.1021/jo001397s

J . Org. Chem. 2001, 66, 243-250
243
A Novel Str a igh tfor w a r d Syn th esis of En a n tiop u r e
Tetr a h yd r oisoqu in olin e Alk a loid s
Rafael Pedrosa,* Celia Andre´s,* and J esu´s M. Iglesias
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011-Valladolid, Spain
pedrosa@qo.uva.es
Received September 20, 2000
A novel, direct, and high-yielding stereoselective method for enantiopure 1-substituted tetrahydro-
isoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during
the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-
1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring
opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen
atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The
starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different
aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The
method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different
substituents at C-1, by changing the nature of the starting aldehydes.
In tr od u ction
reaction creates the stereogenic carbon at C-1 simulta-
neous with the ring closure.
We have recently reported9 that the diastereoselective
ring opening of the N,O-acetal moiety in perhydrobenz-
oxazines derived from (-)-8-aminomenthol affords enan-
tiopure amines. In this way, the perhydrobenzoxazine
acts as chiral inductor and as a source of the nitrogen
atom, and both the stereochemistry of the final amines
and the stereochemical course of the reactions depend
on the nature of the organometallic nucleophile.
These facts intrigued us to develop a novel, direct way
to enantiopure 1-substituted THIQ, including some al-
kaloids, by diastereoselective intramolecular ring opening
of perhydrobenzoxazines derived from (-)-8-aminomen-
thol. THIQ could be prepared from 2-substituted perhy-
dro-1,3-benzoxazines bearing the aryl group attached to
the nitrogen through an ethylene tether. The saturated
heterocycle of the THIQ nucleus could be created by
intramolecular nucleophilic attack of the o-arylmetal to
C-2, while the stereochemistry and the nature of the
substituent at C-1 in the final heterocycle were deter-
mined by the stereochemical outcome of the reaction and
the nature of the substituent at C-2 in the starting
perhydrobenzoxazine (Figure 1).
1,2,3,4-Tetrahydroisoquinolines (THIQ), specially 1-sub-
stituted-THIQ, are compounds of great interest due to
their biological and pharmacological properties. For
instance, 1-methyl- and 1-phenyl-THIQ are involved in
the treatment of Parkinson’s and other nervous diseases,1
and derivatives with alkoxy substituents at the aromatic
rings comprise the widest group of naturally occurring
alkaloids. Preparation of these compounds has received
much attention, especially efforts directed to the enan-
tioselective synthesis.2 The most remarkable synthetic
methods are the Pictet-Spengler cyclization,3 the reduc-
tion of 3,4-dihydroisoquinolines,4 the Pomeranz-Fristch
reaction,5 and more recently, R-alkylation of chiral for-
mamidines,6 organolithium additions to imines followed
by condensation,7 and metal-catalyzed cyclization reac-
tions.8 These methods allow the synthesis of enantiopure
1-substituted-THIQ in two steps: cyclization and creation
of the stereocenter, although only the Pictet-Spengler
* To whom correspondence should be addressed. Phone: Int+ 983-
423211, Fax: Int+ 983423013.
(1) (a) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron:
Asymmetry 1999, 10, 221 and references therein. (b) Gray, N. M.;
Cheng, B. K.; Mick. S. J .; Lair, C. M.; Contreras, P. C. J . Med. Chem.
1989, 32, 1242. (c) Wanner, K. Th.; Beer, H.; Ho¨fner, G.; Ludwig, M.
Eur. J . Org. Chem. 1998, 2019.
(2) Rozwadowska, M. D. Heterocycles 1994, 39, 903 and references
therein.
(3) Whaley, W. M.; Govindachari, T. R. Organic Reactions; J ohn
Wiley & Sons: New York, 1951; Vol. 6, p 151.
(4) (a) Polniaszek, R. P.; Kaufman, C. R. J . Am. Chem. Soc. 1989,
111, 4859. (b) Polniaszek, R. P.; Dillard, L. W. Tetrahedron Lett. 1990,
31, 797. (c) Comins, D. L.; Badawi, M. M. Heterocycles 1991, 32, 1869.
(5) (a) Kaufman, T. S. J . Chem. Soc., Perkin Trans. 1 1996, 2497.
(b) Schlosser, M.; Simig, G.; Geneste, H. Tetrahedron 1998, 54, 9023.
(6) (a) Meyers, A. I.; Dickman, D. A. J . Am. Chem. Soc. 1987, 109,
1263. (b) Meyers, A. I.; Warmus, J . S.; Gonza´lez, M. A.; Guiles, J .;
Akahane, A. Tetrahedron Lett. 1991, 32, 5509. (c) Meyers, A. I.
Tetrahedron 1992, 48, 2589.
This strategy afforded different enantiopure 1-substi-
tuted THIQ simply by changing both the nature of the
aryl nucleus on the substituent at the nitrogen atom, and
the substituent at C-2 of the initial chiral N,O-acetal.
Resu lts a n d Discu ssion
The preparation of the starting perhydrobenzoxazines
7a ,b and 8a -f was carried out in three steps in 82-90%
overall yield as shown in Scheme 1. Condensation of (-)-
8-aminomenthol with 2-bromophenylacetaldehyde (1) or
2-bromo-4,5-dimethoxyphenyl acetaldehyde (2), in me-
(7) Wu¨nsch, B.; Nerdinger, S. Eur. J . Org. Chem. 1998, 711.
(8) (a) Richter-Addo, G. B.; Knight, D. A.; Dewey, M. A.; Arif, A.
M.; Gladysz, J . A. J . Am. Chem. Soc. 1993, 115, 11863. (b) Wirth, T.;
Fragale, G. Synthesis 1998, 162.
(9) (a) Andre´s, C.; Nieto, J .; Pedrosa, R.; Villaman˜a´n, N. J . Org.
Chem. 1996, 61, 4130 and references therein. (b) Alberola, A.; Andre´s,
C.; Pedrosa, R. Synlett 1990, 763.
10.1021/jo001397s CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

244 J . Org. Chem., Vol. 66, No. 1, 2001
Pedrosa et al.
Sch em e 2
F igu r e 1.
Sch em e 1
Ta ble 1. Ster eoselective In tr a m olecu la r Rin g Op en in g
of P er h yd r oben zoxa zin es 7a n d 8
Lewis acid
(equiv)
yield,
%
entry compd
products (ratio)a
H-7a
H-7a
H-5
1
7a
7a
7a
7a
7a
7a
7a
7b
8a
8b
8c
8d
8e
8f
none
ZnCl2 (2)
100b
100b
100b
100b
2
3
4
5
BF3‚OEt2 (1)
BF3‚OEt2 (2)
H-5
MgBr2‚OEt2 (1) H-7a (40) 9a (48) 9′a (12) 100b
6
7
8
9
MgBr2‚OEt2 (2) H-7a (25) 9a (60) 9′a (15) 100b
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (1)
9a
9b
80c
78c
83c
83c
77c
81c
79c
77c
10a
10b
10c
10d
10e
10f
10
11
12
13
14
Determined by integration of the 1H NMR signals in the crude
a
reaction. The referred compounds were the only detected by 1H
NMR in the crude of the reaction. c Yield of isolated pure product
after flash chromatography.
b
thylene chloride at rt afforded quantitatively perhy-
drobenzoxazines 3 or 4, respectively. These compounds
were transformed into phenethylaminomenthols 5 or 6
by reduction10 with sodium borohydride and boron trif-
luoride etherate in THF at rt. Perhydrobenzoxazines 7a ,b
and 8a -f were obtained in excellent overall yields by
heating, in a sealed tube at 120 °C, a mixture of 5 or 6
with the corresponding aldehyde, prepared by homolo-
gation11 of benzaldehyde derivatives or by oxidation12 of
the corresponding alcohols with PCC.
The formation of the arylmetal was tested by treatment
of 7a with t-BuLi (2.2 equiv) in dry, degassed diethyl
ether at -90 °C and then warming the reaction mixture
to rt. Under these conditions, the debromination product
H-7a was detected as the only product, indicating that
the aryllithium intermediate was formed but the in-
tramolecular ring opening did not take place13 even after
stirring at rt for 24 h. Then, we turned our attention to
probe other arylmetals prepared from the intermediate
aryllithium by transmetalation. To this end, 7a was
treated with 2.2 equiv of t-BuLi at -90 °C in dry diethyl
ether, and after 10 min, 1 or 2 equiv of the corresponding
Lewis acid were added at -90 °C, and the reaction
mixture was allowed to reach room temperature. The
results are summarized in Scheme 2 and Table 1.
The dehalogenation product H-7a was the only one
detected in the reaction with ZnCl2, whereas the reaction
with boron trifluoride etherate (entries 3, 4) afforded the
debrominated amino alcohol H-5 and acetaldehyde re-
sulting from the hydrolysis of the N,O-acetal. The addi-
tion of 1 equiv of MgBr2‚OEt2 to the preformed aryllith-
ium intermediate gave a mixture of debrominated
perhydrobenzoxazine H-7a (40%) and the aminomenthol
derivative resulting from the intramolecular nucleophilic
ring opening as a mixture (4:1) of diastereomers 9a and
(10) Meyers, A. I.; Elworthy, T. R. J . Org. Chem. 1992, 57, 4732.
(11) Gibson, S. E.; Guillo, N.; Middleton, R. J .; Thuilliez, A.; Tozer,
M. J . J . Chem. Soc., Perkin Trans. 1 1997, 447.
(12) For experimental details of preparation and analytical and
spectroscopical data for aldehydes, see Supporting Information.
(13) This result contrasts with the easy ring opening of oxazolidines;
see: Takahashi, H.; Suzuki, Y.; Kametani, F. Heterocycles 1983, 20,
607.

Synthesis of Tetrahydroisoquinoline Alkaloids
J . Org. Chem., Vol. 66, No. 1, 2001 245
Sch em e 3
Sch em e 4
Ta ble 2. Exp er im en ta l Con d ition s a n d Reten tion Tim es
for Ch ir a l-HP LC of Ra cem a tes 11, 12, a n d 13
tR (min)
eluent
(i-PrOH/hex)
flow rate
(mL/min)
compd
R
S
11a
11b
12a
12b
13b
12c
12d
13d
13e
12f
13f
5/95
30/70
20/80
20/80
20/80
30/70
20/80
20/80
30/70
30/70
20/80
0.3
0.7
0.7
0.3
0.2
0.7
0.9
0.5
0.7
1
33.48
9.99
32.20a
6.96
14.88
23.21
23.24
12.04
25.77
22.34
19.30
16.63
23.59
11.83
25.35
20.42
15.72
17.91
12.43
9.38
9′a . When the ratio of the magnesium salt increased to
2 equiv, tetrahydroisoquinoline derivatives 9a and 9′a
(4:1 ratio) were isolated in 75% yield and the amount of
H-7a decreased to 25% yield.
The best results were obtained when 2 equiv of
diethylaluminum chloride were added (entry 7). In this
case, the transmetalation and subsequent N,O-acetal
opening with concomitant formation of the tetrahydroiso-
quinoline nucleus is the only process observed. This
protocol was then applied to perhydrobenzoxazines 7b
and 8a -e directed to the synthesis of enantiopure
tetrahydroisoquinoline alkaloids. Thus, a solution of the
substrate in dry ether was treated with t-BuLi (2.2 equiv)
at -90 °C, and after 5 min, 2 equiv of diethylaluminum
chloride were added, the mixture was allowed to reach
room temperature and stirred for 16 h. Isolation and
purification by flash chromatography, after the corre-
sponding hydrolysis, afforded tetrahydroisoquinoline de-
rivatives 9a ,b and 10a -e in 77-83% yield as single
diastereomers (entries 8-14 in Table 1 and Scheme 3).
The only exception to this general method was for
compound 8f. In this case, only 1 equiv of t-BuLi was
used in the aryllithium formation because the reaction
with 2 equiv of t-BuLi yielded the reductive ring opening
as major product.
The final tetrahydroisoquinolines 11a ,b and 12a -f
were obtained in 55-82% yield from 9a ,b and 10a -f by
removal of the menthol appendage using a two-step
procedure. 9a ,b and 10a -f were oxidized to the corre-
sponding 8-aminomenthone derivatives by a modified
published procedure.14 In this case the oxidation of
aminomenthol derivatives must be carried out with PCC
and molecular sieves in a solution buffered with NaOAc;
otherwise the formation of 3,4-dihydroisoquinoline de-
rivative was observed. The crude 8-aminomenthones,
without isolation, were then transformed into enan-
tiopure 11a ,b or 12a -f by treatment with a KOH
solution in MeOH/THF (Scheme 3).
10.79
16.18
0.5
a
Peaks not completely resolved at the baseline.
assigned as R and 12c19 as S by comparison of the sign
of the optical rotations with those previously described.
However, compounds 12d , 12e, and 12f were trans-
formed into the enantiopure known alkaloids (R)-O-
methylarmepavine20 (13d ), (R)-laudanosine20 (13e), and
(R)-homolaudanosine21 (13f) respectively, by methylation
with dimethylpyrocarbonate followed by carbamate re-
duction with LiAlH4 (Scheme 4). This method allowed the
first preparation of enantiopure (R)-O-methyllophocerine
(13b) from 12b. In this case the assignment of R
configuration at C-1 was made by generalization of the
stereochemical outcome of the intramolecular ring open-
ing. (S)-Calycotomine19 (13c) was obtained from 12c by
debenzylation with Pearlmann’s catalyst.
The enantiomeric purity of the final compounds was
studied by HPLC on a chiral stationary phase using
mixtures of i-PrOH/hexane as eluent. To this end, race-
mates of the tetrahydroisoquinolines were prepared by
Bischler-Napieralski cyclization4a of the intermediate
amides followed by NaBH4 reduction of the dihydroiso-
quinolines. Our synthetic products were studied by HPLC
and coinjected with the corresponding racemate showing
ee >99% in all the cases. Table 2 summarizes the
experimental conditions for the resolution of racemates
and the retention times for both enantiomers of com-
pounds 11, 12, and 13.
It is noteworthy that, in the experimental conditions
used, the S enantiomer eluted before than R except for
compound 12b, although O-methyllophocerine 13b, re-
sulting from the methylation of 12b, fits in with the
The absolute configuration at C-1 in the tetrahydroiso-
quinolines 11a ,15 11b,7,16 12a ,4a,15,17 and 12e4a,18 was
(17) Battersby, A. R.; Edwards, T. P. J . Chem. Soc. 1960, 1214.
(18) Corrodi, H.; Hardegger, E. Chem. Ber. 1956, 107, 889.
(19) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry
1998, 9, 183.
(14) Andre´s, C.; Nieto, J .; Pedrosa, R.; Vicente, M. J . Org. Chem.
1998, 63, 8570.
(15) Meyers, A. I.; Boes, M.; Dickmann, D. A. Angew. Chem., Int.
Ed. Engl. 1984, 23, 458.
(16) Ludwig, M.; Beer, H.; Lotter, H.; Wanner, K. Th. Tetrahedron:
Asymmetry 1997, 8, 2693.
(20) Southon, I. W.; Buckingham, J . Dictionary of Alkaloids; Chap-
man, Hall, Eds.; London: New York, 1989.
(21) Aladesamm, A. J .; Kelley, C. J .; Leary, J . D. J . Nat. Prod. 1983,
46, 127.

246 J . Org. Chem., Vol. 66, No. 1, 2001
Pedrosa et al.
methylene signals in 1H NMR and 13C NMR for 9a ,b and
10a -f appeared unresolved at 298 K, and then the spectra
for these compounds were registered at 333 K. Analytical
HPLC was done on a Chiralcel OD column (0.46 × 25 cm)
equipped with a precolumn (0.46 × 5 cm) using a UV detector
at 220 nm wavelength. The eluents were mixtures 2-propanol/
n-hexane, as indicated in Table 2. Mass spectra were obtained
by chemical ionization (MSCI), and infrared spectra were
registered neat or as Nujol dispersion.
Sch em e 5
Syn th esis of P er h yd r oben zoxa zin es 3 a n d 4. A mixture
of (-)-8-aminomenthol (5 g, 29.2 mmol) and the corresponding
aldehyde (32 mmol) in CH2Cl2 (50 mL) was stirred at room
temperature until disappearance of the amino alcohol (TLC).
Then, anhydrous MgSO4 (2 g) was added and the mixture
stirred for 10 min. The solid was filtered off and the solvent
removed under vacuo. The oily residue was purified by flash
chromatography (silica gel ethyl acetate/hexanes 1:15 v/v).
2r-(2′-Br om op h en ylm eth yl)-4,4,7r-tr im eth yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e 3. 97%. White solid, mp 61-62 °C
(from ethanol). [R]25 ) -18.6 (c ) 0.9, CHCl3). 1H NMR δ:
D
0.80-1.10 (4H, m); 0.88 (3H, d, J ) 6.5); 1.03 (3H, s); 1.05
(3H, s); 1.30-1.50 (2H, m); 1.55-1.70 (2H, m); 1.79-1.89 (1H,
m); 2.89 (1H, dd, J ) 6.6, 14.2); 2.98 (1H, dd, J ) 4.8, 14.2);
3.30 (1H, dt, J ) 4.1 Hz, 10.4); 4.56-4.60 (1H, m); 6.97-7.49
(4H, m). 13C NMR δ: 19.7; 22.3; 25.5; 29.9; 31.3; 35.0; 41.6;
42.4; 51.3; 51.6; 74.9; 81.9; 125.0; 126.9; 127.7; 131.7; 132.4;
137.4. IR (neat): 3050, 2940 cm-1. MSCI (m/z, %): 352 (M +
1, 100), 354 (M + 3, 95). Anal. Calcd for C18H26BrNO: C, 61.36;
H, 7.44; N, 3.98. Found C, 61.25; H, 7.35; N, 4.15.
general tendency. 12c was not an exception to this
behavior because the priority of the substituents is
different.
The stereochemical outcome of the intramolecular ring
opening for 1,3-perhydrobenzoxazine system is in agree-
ment with that previously described for intermolecular
reactions.9a The stereodiscrimination is better for orga-
noaluminum derivatives because they have a greater
nucleophilic character than magnesium derivatives.22
Taking into account the configuration of the stereocenter
created in the reaction, we can rationalize the results as
summarized in Scheme 5.
The lithiated intermediate A formed by reaction of the
initial bromo derivative with t-BuLi will be transformed
into the arylaluminum reagent B by transmetalation
with Et2AlCl. The tetrahydroisoquinoline derivative should
be formed by both intramolecular transfer of the aryl
group from the aluminum atom while complexed to the
oxygen in B′ to the si face of the incipient iminium ion
or by synchronous intramolecular arylation in the early
transition state B′. The formation of the minor diaste-
reomer with the arylmagnesium is a consequence of the
lesser reactivity of this organometallic and can be inter-
preted by intramolecular arylation of the late iminium
ion to the re face.
In conclusion, the described method allows prepara-
tion, in a short, highly efficient way, enantiopure 1-sub-
stituted tetrahydroisoquinolines from two different al-
dehydes by using (-)-8-aminomenthol as chiral template.
The general method allows alkyl, aryl, benzyl, or homo-
benzyl substituents to be introduced at C-1 in the final
THIQ by changing the structure of the aldehyde em-
ployed in the formation of the starting perhydrobenzox-
azine.
2r-(2′-Br om o-3′,4′-d im eth oxyp h en ylm eth yl)-4,4,7r-tr i-
m eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e 4. 95%. Colorless
oil. [R]25D ) -9.6 (c ) 0.4, CHCl3). 1H NMR δ: 0.80-1.05 (4H,
m); 0.87 (3H, d, J ) 6.5); 1.04 (3H, s); 1.05 (3H, s); 1.32-1.52
(1H, m); 1.55-1.70 (3H, m); 1.80-1.89 (1H, m); 2.80 (1H, dd,
J ) 6.5, 14.3); 2.91 (1H, dd, J ) 4.8, 14.3); 3.32 (1H, dt, J )
4.1 Hz, 10.6); 3.82 (6H, s); 4.52 (1H, dd, J ) 4.8, 6.5); 6.93
(1H, s); 6.96 (1H, s). 13C NMR δ: 19.7; 22.2; 25.4; 29.9; 31.2;
34.9; 41.5; 41.7; 51.3; 51.5; 55.8; 55.9; 74.8; 82.1; 114.3; 114.6;
114.9; 129.3; 147.7; 147.8. IR (neat): 3050, 2940 cm-1. MSCI
(m/z, %): 412 (M + 1, 100), 414 (M + 3, 94). Anal. Calcd for
C
20H30BrNO3: C, 58.25; H, 7.33; N, 3.40. Found C, 58.39; H,
7.36; N, 3.28.
Red u ction of 3 a n d 4 to 8-Am in om en th ols 5 a n d 6. To
a cooled (0 °C) mixture of NaBH4 (2.85 g, 75 mmol) and BF3‚
OEt2 (150 mL of 1 M solution, 15 mmol) in THF (80 mL) was
added a solution of the corresponding perhydrobenzoxazine (35
mmol) in THF (40 mL). The mixture was allowed to reach rt,
stirred for 2 h, and then quenched by slow addition of methanol
(30 mL), and the sttirring was continued for additional 30 min.
The solvents were eliminated under vacuo, the residue was
treated with 20% solution of NaOH (30 mL) and solid NaOH
(2 g), and the mixture was refluxed for 1 h. The reaction
mixture was cooled and extracted with CHCl3 (5 × 75 mL),
the organic layer washed with brine and dried over anhydrous
Na2SO4, and the solvent was eliminated under vacuo. The
amino alcohols were purified by flash chromatography (silica
gel ethyl acetate/hexanes 1/3).
N-[(2′-Br om oph en yl)eth yl]-8-am in om en th ol 5. 90% from
3. Colorless oil. [R]25 ) -15.8 (c ) 0.8, CHCl3). 1H NMR δ:
D
0.80-1.05 (3H, m); 0.90 (3H, d, J ) 6.5); 1.04 (3H, s); 1.08
(3H, s); 1.22-1.31 (1H, m); 1.32-1.51 (1H, m); 1.57-1.68 (2H,
m); 1.91-2.01 (1H, m); 2.81-2.88 (4H, m), 3.60 (1H, dt, J )
3.8, 10.1), 7.03-7.53 (4H, m). 13C NMR δ: 21.5; 22.1; 25.7;
26.1; 30.9; 34.9; 37.1; 40.7; 44.4; 49.5; 56.6; 72.5; 124.4; 127.4;
Exp er im en ta l Section
All solvents employed were dried and distilled prior to use.
t-BuLi was used as 1.5 M solution in pentane and Et2AlCl as
1 M solution in hexanes. TLC was performed with silica gel
60 F254 plates, and flash chromatography using 240-300
mesh silica gel. Melting points were measured in a capillary
tube and are uncorrected. Optical rotation measurements are
obtained on a digital polarimeter with a sodium lamp (254 nm).
The 1H NMR and 13C NMR were recorded at 300 MHz and
75.2 MHz using CDCl3 as solvent; chemical shifts (δ) are given
in ppm related to tetramethylsilane (TMS) as internal refer-
ence (δ ) 0 for TMS) and J values are given in hertz. Some
128.0; 130.8; 132.8; 138.7. IR (neat): 3320, 3050, 2940 cm-1
.
MSCI (m/z, %): 354 (M + 1, 100), 356 (M + 3, 94). Anal. Calcd
for C18H28BrNO: C, 61.02; H, 7.97; N, 3.95. Found C, 60.88;
H, 8.06; N, 3.99.
N-[(2′-Br om o-4′,5′-d im et h oxyp h en yl)et h yl]-8-a m in o-
m en th ol 6. 90% from 4. Colorless oil. [R]25 ) -9.2 (c ) 0.6,
D
1
CHCl3). H NMR δ: 0.80-1.10 (3H, m); 0.91 (3H, d, J ) 6.5);
1.07 (3H, s); 1.10 (3H, s); 1.18-1.47 (2H, m); 1.6-1.59 (2H,
m); 1.88-1.97 (1H, m); 2.74-2.90 (4H, m); 3.61 (1H, dt, J )
3.9, 10.2); 3.84 (3H, s); 3.87 (3H, s); 6.75 (1H, s); 6.99 (1H, s).
13C NMR δ: 21.4; 22.0; 25.6; 25.9; 30.9; 34.8; 36.6; 40.8; 44.3;
(22) Hagen, G.; Mayr, H. J . Am. Chem. Soc. 1991, 113, 4954.

Synthesis of Tetrahydroisoquinoline Alkaloids
J . Org. Chem., Vol. 66, No. 1, 2001 247
49.3; 56.0 (2C); 56.7; 72.4; 113.3; 113.9; 115.4; 130.4; 148.0;
148.2. IR (neat): 3320, 3050, 2940 cm-1. MSCI (m/z, %): 414
(M + 1, 100), 416 (M + 3, 96). Anal. Calcd for C20H32BrNO3:
C, 57.97; H, 7.78; N, 3.38. Found C, 58.02; H, 7.61; N, 3.56.
Syn th esis of P er h yd r oben zoxa zin es 7 a n d 8. Gen er a l
P r oced u r e. A mixture of (-)-8-aminomenthol derivative 5 or
6 (1.5 mmol) and the corresponding aldehyde (3 mmol) was
heated, without solvent, in a sealed tube at 120 °C in an oil
bath. When the reaction was finished (TLC), the mixture was
diluted with EtOH (50 mL), and the solvents were evaporated
under vacuum. The residue was purified by flash chromatog-
raphy (silica gel, EtOAc/hexane).
(1H, t, J ) 5.0); 6.59 (1H, s); 6.94 (1H, s); 7.22-7.37 (5H, m).
13C NMR δ: 20.7; 22.3; 25.0; 26.5; 31.2; 35.0; 39.7; 41.3; 43.7;
46.1; 55.8; 56.0; 56.9; 71.9; 73.5; 75.8; 86.0; 113.7; 113.9; 115.1;
127.6; 127.9 (2C); 128.3 (2C); 131.9; 138.0; 147.8; 148.1. IR
(neat): 3020, 2920 cm-1. MSCI (m/z, %): 546 (M + 1, 100),
548 (M + 3, 94). Anal. Calcd for C29H40BrNO4: C, 63.73; H,
7.38; N, 2.56. Found C, 63.86; H, 7.47; N, 2.37.
3-[(2′-Br om o-4′,5′-d im eth oxyp h en yl)eth yl]-2r-(p-m eth -
oxyben zyl)-4,4,7r-tr im eth yl-tr a n s-octa h yd r o-1,3-ben zox-
a zin e 8d . 83% from 6 and 4-methoxyphenylacetaldehyde.
Colorless oil. [R]25D ) -26.4 (c ) 0.3, CHCl3). 1H NMR δ: 0.85-
1.10 (3H, m); 0.88 (3H, d, J ) 6.5); 1.25 (3H, s); 1.30 (3H, s);
1.30-1.50 (2H, m); 1.55-1.75 (2H, m); 1.79-1.89 (1H, m);
2.75-3.20 (6H, m); 3.37 (1H, dt, J ) 4.0, 10.5); 3.77 (3H, s);
3.82 (3H, s); 3.84 (3H, s); 4.76-4.79 (1H, m); 6.69 (1H, s); 6.83
(2H, d, J ) 8.6); 6.98 (1H, s); 7.25 (2H, d, J ) 8.6). 13C NMR
δ: 20.4; 22.1; 24.8; 26.4; 31.2; 34.8; 39.2; 39.4; 41.1; 43.9; 45.6;
55.1; 56.1 (2C); 58.6; 76.0; 88.4; 113.5 (3C); 113.9; 115.4; 130.3
(2C); 130.6; 131.7; 148.0; 148.3; 158.0. IR (neat): 3020, 2930
cm-1. MSCI (m/z, %): 546 (M + 1, 100), 548 (M + 3, 95). Anal.
Calcd for C29H40BrNO4: C, 63.73; H, 7.38; N, 2.56. Found C,
63.58; H, 7.51; N, 2.51.
3-[(2′-Br om op h en yl)eth yl]-2r,4,4,7r-tetr a m eth yl-tr a n s-
octa h yd r o-1,3-ben zoxa zin e 7a . 88% from 5 and acetalde-
1
hyde. Colorless oil. [R]25 ) -34.7 (c ) 1.3, CHCl3). H NMR
D
δ: 0.80-1.08 (3H, m); 0.89 (3H, d, J ) 6.5); 1.11 (3H, s); 1.20-
1.51 (2H, m); 1.22 (3H, s); 1.37 (3H, d, J ) 5.9); 1.53-1.71
(2H, m); 1.81-1.91 (1H, m); 2.54-2.64 (1H, m); 2.78-2.97 (3H,
m); 3.41 (1H, dt, J ) 4.0, 10.5); 4.68 (1H, q, J ) 5.9); 7.00-
7.53 (4H, m). 13C NMR δ: 19.1; 20.9; 22.2; 25.1; 26.8; 31.3;
34.9; 40.8; 41.4; 43.6; 46.6; 57.0; 75.5; 83.1; 124.2; 127.3; 127.6;
131.0; 132.6; 140.1. IR (neat): 3050, 2940, 745 cm-1. MSCI
(m/z, %): 380 (M + 1, 100), 382 (M + 3, 95). Anal. Calcd for
3-[(2′-Br om o-4′,5′-d im eth oxyp h en yl)eth yl]-2r-(3′,4′-d i-
m et h oxyb en zyl)-4,4,7r-t r im et h yl-tr a n s-oct a h yd r o-1,3-
ben zoxa zin e 8e. 82% from 6 and 3,4-dimethoxyphenylace-
C
20H30BrNO: C, 63.15; H, 7.95; N, 3.68. Found C, 63.26; H,
8.08; N, 3.77.
3-[(2′-Br om op h en yl)eth yl]-2r-p h en yl-4,4,7r-tr im eth yl-
taldehyde. Colorless oil. [R]25 ) -28.7 (c ) 0.6, CHCl3). 1H
D
tr a n s-octa h yd r o-1,3-ben zoxa zin e 7b. 85% from 5 and ben-
NMR δ: 0.88 (3H, d, J ) 6.5); 0.90-1.10 (3H, m); 1.18 (3H, s);
1.25 (3H, s); 1.32-1.48 (2H, m); 1.52-1.71 (2H, m); 1.79-1.88
(1H, m); 2.70-3.10 (6H, m); 3.36 (1H, dt, J ) 3.9, 10.6); 3.84
(3H, s); 3.85 (3H, s); 3.86 (3H, s); 3.88 (3H, s); 4.70-4.73 (1H,
m); 6.67 (1H, s); 6.80-6.99 (4H, m). 13C NMR δ: 20.8; 22.2;
25.0; 26.8; 31.2; 35.0; 40.1; 40.3; 41.4; 43.7; 45.8; 55.7; 56.0
(2C); 57.3 (2C); 75.9; 88.2; 110.7; 112.7; 113.5; 114.0; 115.3;
121.1; 131.8; 132.1; 147.2; 147.9; 148.2; 148.4. IR (neat): 3020,
2930 cm-1. MSCI (m/z, %): 576 (M + 1, 100), 578 (M + 3, 90).
Anal. Calcd for C30H42BrNO5: C, 62.49; H, 7.34; N, 2.43. Found
C, 62.71; H, 7.41; N, 2.32.
1
zaldehyde. Colorless oil. [R]25 ) + 11.0 (c ) 1.2, CHCl3). H
D
NMR δ: 0.90-1.05 (2H, m); 0.92 (3H, d, J ) 6,4); 1.05-1.16
(1H, m); 1.26 (3H, s); 1.30 (3H, s); 1.40-1.55 (2H, m); 1.60-
1.72 (2H, m); 1.92-2.00 (1H, m); 2.25 (1H, m); 2.37-2.53 (2H,
m); 2.64-2.75 (1H, m); 3.57 (1H, dt, J ) 4.0, 10.5); 5.56 (1H,
s); 6.35 (1H, d, J ) 7.4); 6.88-7.56 (8H, m). 13C NMR δ: 19.7;
22.4; 25.2; 27.0; 31.4; 35.1; 39.9; 41.5; 44.4; 46.5; 57.1; 75.9;
87.9; 124.1; 127.2; 127.4; 127.6; 127.7 (2C); 127.9 (2C); 130.9;
132.3; 140.3; 140.9. IR (neat): 3020, 2920, 750 cm-1. MSCI
(m/z, %): 442 (M + 1, 100), 444 (M + 3, 93). Anal. Calcd for
C
25H32BrNO: C, 67.87; H, 7.29; N, 3.17. Found C, 67.69; H,
3-[(2′-Br om o-4′,5′-d im eth oxyp h en yl)eth yl]-2r-(3′,4′-d i-
m et h oxyp h en et h yl)-4,4,7r-t r im et h yl-tr a n s-oct a h yd r o-
1,3-ben zoxazin e 8f. 86% from 6 and 3-(3′,4′-dimethoxyphenyl)-
propionaldehyde. White solid, mp 113-114 °C (from ethanol).
7.26; N, 3.27.
3-[(2′-Br om o-4′,5′-d im et h oxyp h en yl)et h yl]-2r,4,4,7r-
tetr a m eth yl-tr a n s-octa h yd r o-1,3-ben zoxa zin e 8a . 86%
from 6 and acetaldehyde. Colorless oil. [R]25D ) -32.3 (c ) 0.2,
25
1
[R]D ) - 29.1 (c ) 0.3, CHCl3). H NMR δ: 0.88-1.10 (3H,
m); 0.90 (3H, d, J ) 6.5); 1.11 (3H, s); 1.22 (3H, s); 1.30-1.55
(2H, m); 1.55-1.70 (2H, m); 1.80-2.01 (3H, m); 2.58-2.90 (5H,
m); 2.92-3.00 (1H, m); 3.38 (1H, dt, J ) 4.0; 10.6); 3.76 (3H,
s); 3.80 (3H, s); 3.84 (3H, s); 3.85 (3H, s); 4.51 (1H, dd, J )
4.9; 7.1); 6.64 (1H, s); 6.72-6.80 (3H, m); 6.95 (1H, s). 13C NMR
δ: 20.7; 22.0; 25.1; 26.8; 31.4; 31.7; 35.1; 35.8; 40.3; 41.6; 43.7;
46.3; 55.9; 56.0; 56.1; 56.2; 57.0; 76.1; 86.6; 111.9; 112.5; 114.1;
114.2; 116.1; 120.4; 132.5; 135.1; 147.4; 148.3; 148.6; 149,1.
IR (neat): 3020, 2940 cm-1. MSCI (m/z, %): 590 (M + 1, 100),
592 (M + 3, 94). Anal. Calcd for C31H44BrNO5: C, 63.04; H,
7.51; N, 2.37. Found C, 63.19; H, 7.53; N, 2.49.
1
CHCl3). H NMR δ: 0.83-1.09 (3H, m); 0.90 (3H, d, J ) 6.5);
1.12 (3H, s); 1.22 (3H, s); 1.23-1.55 (2H, m); 1.37 (3H, d, J )
5.8); 1.57-1.73 (2H, m); 1.80-1.90 (1H, m); 2.54-2.63 (1H,
m); 2.69-2.97 (3H, m); 3.42 (1H, dt, J ) 4.0, 10.5); 3.83 (3H,
s); 3.85 (3H, s); 4.69 (1H, q, J ) 5.8); 6.69 (1H, s); 6.98 (1H, s).
13C NMR δ: 19.2; 20.9; 22.2; 25.0; 26.8; 31.2; 34.9; 40.4; 41.4;
43.5; 46.5; 55.9; 56.0; 56.9; 75.4; 83.0; 113.5; 113.9; 115.3; 132.0;
147.8; 148.2. IR (neat): 3020, 2920, 745 cm-1. MSCI (m/z, %):
440 (M + 1, 100), 442 (M + 3, 94). Anal. Calcd for C22H34
-
BrNO3: C, 60.00; H, 7.78; N, 3.18. Found C, 60.12; H, 7.69;
N, 3.36.
3-[(2′-Br om o-4′,5′-d im eth oxyp h en yl)eth yl]-2r-isobu tyl-
Gen er a l Meth od for In tr a m olecu la r Op en in g of P er -
h yd r oben zoxa zin es 7a ,b a n d 8a -f. A solution of the cor-
responding perhydrobenzoxazine 7a ,b or 8a -f (3.5 mmol) in
anhydrous Et2O (35 mL) under argon and cooled to -90 °C
was treated with 1.5 M solution of t-BuLi in pentane (4.12 mL,
7.7 mmol) for 10 min and then was added 1 M solution of Et2-
AlCl in hexane (7 mL, 7 mmol) at that temperature. The
cooling bath was removed, and the reaction was allowed to
reach rt and stirred overnight. The reaction was quenched by
addition of 2 M NaOH solution (4 mL) and extracted first with
EtOAc (3 × 25 mL) and then with CHCl3 (3 × 25 mL). The
organics were washed with brine and water and dried over
anhydrous Na2SO4. The solvents were removed, and the
residue was purified by flash chromatography (silica gel,
EtOAc/hexane).
4,4,7r-tr im eth yl-tr a n s-octah ydr o-1,3-ben zoxazin e 8b. 87%
from 6 and isovaleraldehyde. Colorless oil. [R]25 ) -37.1 (c
D
) 0.1, CHCl3). 1H NMR δ: 0.89 (3H, d, J ) 6.5); 0.90-1.10
(3H, m); 0.94 (3H, d, J ) 6.5); 0.95 (3H, d, J ) 6.5); 1.19 (3H,
s); 1.24 (3H, s); 1.30-1.40 (1H, m); 1.42-1.75 (5H, m); 1.78-
1.90 (2H, m); 2.62-2.99 (4H, m); 3.41 (1H, dt, J ) 3.9, 10.6);
3.83 (3H, s); 3.85 (3H, s); 4.64 (1H, s); 6.68 (1H, s); 6.98 (1H,
s). 13C NMR δ: 21.3; 22.2; 22.6; 23.1; 24.9; 25.1; 26.8; 31.3;
35.0; 40.3; 41.5; 42.9; 43.6; 45.7; 55.9; 56.0; 57.0; 76.1; 85.6;
113.3; 113.9; 115.3; 132.3; 147.8; 148.2. IR (neat): 3040, 2940,
750 cm-1. MSCI (m/z, %): 482 (M + 1, 100), 484 (M + 3, 89).
Anal. Calcd for C25H40BrNO3: C, 62.23; H, 8.36; N, 2.90. Found
C, 62.29; H, 8.45; N, 2.74.
2r-Be n zyloxym e t h yl-3-[(2′-b r om o-4′,5′-d im e t h oxy-
p h en yl)eth yl]-4,4,7r-tr im eth yl-tr a n s-octa h yd r o-1,3-ben z-
(1R)-N-(8-Men th yl)-1-m eth yl-1,2,3,4-tetr ah ydr oisoqu in -
oxa zin e 8c. 90% from 6 and benzyloxy acetaldehyde. Colorless
olin e 9a . 80% from 7a . White solid, mp 138-139 °C (from
1
1
oil. [R]25 ) -20.8 (c ) 0.1, CHCl3). H NMR δ: 0.88 (3H, d, J
EtOAc/hexane). [R]25 ) -6.4 (c ) 0.8, CHCl3). H NMR (333
D
D
) 6.4); 0.85-1.10 (3H, m); 1.16 (6H, s); 1.22-1.48 (2H, m);
1.53-1.70 (2H, m); 1.85-1.96 (1H, m); 2.67-2.88 (4H, m); 3.47
(1H, dt, J ) 3.5, 10.4); 3.61-3.64 (2H, m); 3.71 (3H, s); 3.78
(3H, s); 4.55 (1H, d, J ) 12.1); 4.64 (1H, d, J ) 12.1); 4.83
K) δ: 0.85-1.05 (3H, m); 0.92 (3H, d, J ) 6.5); 0.95 (3H, s);
1.34 (3H, s); 1.40-1.50 (1H, m); 1.44 (3H, d, J ) 6.8); 1.53-
1.75 (3H, m); 1.88-1.97 (1H, m); 2.63-2.70 (1H, m); 2.89-
3.18 (2H, m); 3.20-3.26 (1H, m); 3.61 (1H, dt, J ) 4.0, 10.0);

248 J . Org. Chem., Vol. 66, No. 1, 2001
Pedrosa et al.
4.37 (1H, q, J ) 6.8); 6.99-7.12 (4H, m). 13C NMR (333 K) δ:
19.6; 21.9 (2C); 23.7; 25.9; 28.0; 31.0; 35.4; 37.2; 45.2; 48.6;
51.6; 60.8; 72.4; 125.6; 125.8; 126.8; 128.7; 133.9; 141.6. IR
(Nujol): 3240, 2920 cm-1. MSCI (m/z, %): 302 (M + 1, 100).
Anal. Calcd for C20H31NO: C, 79.68; H, 10.36; N, 4.65. Found
C, 79.77; H, 10.40; N, 4.63.
(1R)-N-(8-Men t h yl)-1-(3′,4′-d im et h oxyp h en ylm et h yl)-
6,7-d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e 10e. 79%
from 8e. Colorless oil. [R]25D ) -44.3 (c ) 0.5, CHCl3). 1H NMR
(333 K) δ: 0.80-1.10 (3H, m); 0.90 (3H, s); 0.93 (3H, d, J )
6.5); 1.36 (3H, s); 1.40-1.50 (1H, m); 1.60-1.75 (3H, m); 1.95-
2.05 (1H, m); 2.55-2.62 (1H, m); 2.75-2.86 (2H, m); 3.10-
3.22 (2H, m); 3.30 (1H, dd, J ) 3.5, 12.9); 3.47 (3H, s); 3.64
(1H, dt, J ) 4.0, 10.2); 3.73 (3H, s); 3.80 (3H, s); 3.82 (3H, s);
4.16-4.20 (1H, m); 5.80 (1H, s); 6.54-6.58 (2H, m); 6.75 (2H,
d, J ) 8.1). 13C NMR (333 K) δ: 20.0; 21.9; 23.8; 26.0; 27.0;
30.9; 35.4; 39.1; 43.3; 45.4; 48.7; 55.4; 55.8 (2C); 56.0; 58.1;
61.4; 72.5; 111.6; 111.7; 111.8; 114.0; 122.1; 126.3; 130.7; 132.4;
146.2; 147.6; 147.8; 148.9. IR (neat): 3200, 2920 cm-1. MSCI
(m/z, %): 498 (M + 1, 100). Anal. Calcd for C30H43NO5: C,
72.40; H, 8.71; N, 2.81. Found C, 72.59; H, 8.77; N, 2.69.
(1R)-N-(8-Men th yl)-1-(3′,4′-d im eth oxyp h en yleth yl)-6,7-
d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e 10f. 77% from
8f. Colorless oil. [R]25D ) -30.2 (c ) 0.1, CHCl3). 1H NMR (333
K) δ: 0.79 (3H, s); 0.86-1.12 (3H, m); 0.93 (3H, d, J ) 6.4);
1.28 (3H, s); 1.37-1.48 (1H, m); 1.50-1.62 (2H, m); 1.64-1.73
(1H, m); 1.90-2.05 (2H, m); 2.23-2.38 (1H, m); 2.55-2.83 (4H,
m); 3.12-3.28 (2H, m); 3.60 (1H, dt, J ) 4.0, 10.3); 3.81 (3H,
s); 3.82 (3H, s); 3.84 (3H, s); 3.86 (3H, s); 3.95-3.99 (1H, m);
6.46 (1H, s); 6.57 (1H, s); 6.78 (1H, s); 6.81 (2H, s); 13C NMR
(333 K) δ: 20.1; 21.9; 23.8; 26.0; 26.9; 30.9; 32.9; 35.3; 39.6
(2C); 45.2; 48.3; 54.9; 55.8; 56.0 (2C); 56.1; 61.4; 72.8; 111.1;
112.0 (2C); 112.8; 120.5; 126.9; 132.4; 134.8; 147.2; 147.5;
147.8; 149.3. IR (neat): 3200, 2940 cm-1. MSCI (m/z, %): 512
(M + 1, 100). Anal. Calcd for C31H45NO5: C, 72.76; H, 8.86;
N, 2.74. Found C, 72.88; H, 8.98; N, 2.68.
(1R)-N-(8-Men th yl)-1-ph en yl-1,2,3,4-tetr ah ydr oisoqu in -
olin e 9b. 78% from 7b. White solid, mp 184-185 °C (from
1
EtOAc). [R]25 ) -124.5 (c ) 0.7, CHCl3). H NMR (333 K) δ:
D
0.74 (3H, s); 0.92-1.14 (3H, m); 0.93 (3H, d, J ) 6.9); 1.38-
1.55 (1H, m); 1.44 (3H, s); 1.56-1.78 (2H, m); 1.80-1.92 (1H,
m); 1.93-2.03 (1H, m); 2.75-2.80 (1H, m); 3.00-3.12 (1H, m);
3.25-3.35 (2H, m); 3.63 (1H, dt, J ) 4.1, 10.5); 5.37 (1H, s);
6.81-7.22 (9H, m); 7.55 (1H, broad s). 13C NMR (333 K) δ:
20.2; 21.9; 24.2; 26.2; 27.1; 31.0; 35.4; 37.4; 45.4; 48.8; 59.7;
61.8; 72.6; 125.9; 126.3; 126.9; 127.8 (2C); 128.2; 128.7; 130.2
(2C); 134.3; 138.3; 143.4. IR (Nujol): 3200, 2940 cm-1. MSCI
(m/z, %): 364 (M + 1, 100). Anal. Calcd for C25H33NO: C, 82.60;
H, 9.15; N, 3.85. Found C, 82.71; H, 9.23; N, 3.88.
(1R)-N-(8-Men th yl)-1-m eth yl-6,7-d im eth oxy-1,2,3,4-tet-
r a h yd r oisoqu in olin e 10a . 83% from 8a . White solid, mp 66-
67 °C (from EtOAc/hexane). [R]25 ) -24.2 (c ) 1.0, CHCl3).
D
1H NMR (333 K) δ: 0.85-1.10 (6H, m); 0.93 (3H, d, J ) 6.5);
1.34 (3H, s); 1.40-1.53 (1H, m); 1.44 (3H, d, J ) 6.7); 1.55-
1.75 (3H, m); 1.89-1.99 (1H, m); 2.51-2.61 (1H, m); 2.82-
3.18 (2H, m); 3.21-3.31 (1H, m); 3.61 (1H, dt, J ) 4.0, 10.2);
3.81 (3H, s); 3.83 (3H, s); 4.30 (1H, q, J ) 6.7); 6.54 (2H, s);
8.10 (1H, broad s). 13C NMR (333 K) δ: 19.5; 21.9 (2C); 23.7;
25.8; 27.2; 30.9; 35.3; 37.6; 45.2; 48.5; 53.2; 55.8; 56.0; 60.7;
72.3; 110.5; 112.0; 125.9; 133.7; 147.5; 147.7. IR (Nujol): 3200,
2920 cm-1. MSCI (m/z, %): 362 (M + 1, 100). Anal. Calcd for
Elim in a tion of th e Ch ir a l Au xilia r y. To a stirred solution
of the corresponding aminomenthol (0.55 mmol) in dichlo-
romethane (15 mL) were added PCC (2.1 mmol), NaOAc (0.55
mmol), and 3 Å molecular sieves, and the mixture was stirred
at room temperature for 2 h. The reaction was quenched with
C
22H35NO3: C, 73.09; H, 9.76; N, 3.87. Found C, 73.22; H, 9.64;
N, 3.91.
(1R)-N-(8-Men t h yl)-1-isob u t yl-6,7-d im et h oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e 10b 83% from 8b. Colorless oil.
1
o
[R]25 ) -18.2 (c ) 1.1, CHCl3). H NMR (333 K) δ: 0.92 (3H,
2 M NaOH solution (20 mL) in an ice bath and stirred at 0 C
D
s); 0.97-1.09 (3H, m); 0.99 (3H, d, J ) 2.7); 1.01 (3H, d, J )
2.4); 1.15 (3H, d, J ) 6.1); 1.37 (3H, s); 1.40-1.72 (4H, m);
1.75-1.95 (3H, m); 2.00-2.08 (1H, m); 2.63-2.72 (1H, m);
2.78-2.89 (1H, m); 3.23-3.37 (2H, m); 3.67 (1H, dt, J ) 4.0,
10.3); 3.90 (3H, s); 3.91 (3H, s); 4.10 (1H, dd, J ) 4.8, 8.5);
6.61 (1H, s); 6.63 (1H, s). 13C NMR (333 K) δ: 20.0; 21.9; 22.2;
23.5; 24.1; 24.9; 26.1; 26.8; 31.0; 35.5; 38.9; 45.3; 47.5; 48.5;
53.6; 55.8; 56.1; 61.4; 72.7; 111.0; 112.1; 126.6; 133.2; 147.2;
147.7. IR (Nujol): 3200, 2940 cm-1. MSCI (m/z, %): 404 (M +
1, 100). Anal. Calcd for C25H41NO3: C, 74.40; H, 10.24; N, 3.47.
Found C, 74.27; H, 10.28; N, 3.59.
for 15 min. The organic layer was decanted and the aqueous
phase extracted with chloroform (5 × 25 mL). The organic
extracts were washed with brine and dried over anhydrous
Na2SO4, and the solvent was removed. The residue was
redissolved in THF (6 mL), MeOH (2 mL), and 2.5 M KOH
solution (2 mL), and the mixture was stirred overnight. The
volatiles were eliminated, and the residue was acidified with
1 N solution of HCl and extracted with ether (2 × 25 mL).
The aqueous layer was then made alkaline by careful addition
of 2 M NaOH solution and extracted with chloroform (5 × 25
mL). The organic phase were washed, dried, and concentrated,
and the residue was purified by flash chromatography (silica
gel, CHCl3/EtOH) to give enantiopure THIQ.
(1S)-N-(8-Men th yl)-1-(ben zyloxym eth yl)-6,7-dim eth oxy-
1,2,3,4-tetr a h yd r oisoqu in olin e 10c. 77% from 8c. Colorless
oil. [R]25D ) -36.5 (c ) 0.5, CHCl3). 1H NMR (333 K) δ: 0.85-
1.10 (9H, m); 1.31 (3H, s); 1.33-1.50 (1H, m); 1.55-1.70 (3H,
m); 1.88-1.95 (1H, m); 2.49-2.59 (1H, m); 2.71-2.86 (1H, m);
3.08-3.21 (2H, m); 3.54-3.62 (2H, m); 3.74 (3H, s); 3.81 (3H,
s); 3.96 (1H, dd, J ) 5.2, 9.2); 4.20-4.25 (1H, m); 4.41 (1H, d,
J ) 11.8); 4.46 (1H, d, J ) 11.8); 6.54 (1H, s); 6.70 (1H, s);
7.21-7.27 (5H, m). 13C NMR (333 K) δ: 19.9; 21.9; 23.7; 26.1;
27.7; 31.0; 35.3; 39.8; 45.2; 48.5; 55.5; 55.8 (2C); 61.3; 72.7;
73.3; 74.3; 111.6; 111.7; 127.2; 127.3; 127.5 (2C); 128.1 (2C);
129.7; 138.3; 147.2; 148.0. IR (neat): 3200, 2920 cm-1. MSCI
(m/z, %): 468 (M + 1, 100). Anal. Calcd for C29H41NO4: C,
74.48; H, 8.84; N, 3.00. Found C, 74.53; H, 8.77; N, 3.08.
(1R)-N-(8-Men th yl)-1-(p-m eth oxyben zyl)-6,7-dim eth oxy-
1,2,3,4-tetr a h yd r oisoqu in olin e 10d . 81% from 8d . Colorless
oil. [R]25D ) -48.2 (c ) 0.5, CHCl3). 1H NMR (333 K) δ: 0.89-
1.10 (9H, m); 1.35-1.60 (1H, m); 1.36 (3H, s); 1.65-1.80 (3H,
m); 1.95-2.05 (1H, m); 2.55-2.63 (1H, m); 2.75-2.85 (2H, m);
3.14-3.22 (2H, m); 3.31 (1H, dd, J ) 3.7, 12.8); 3.40 (3H, s);
3.63 (1H, dt, J ) 4.0, 10.1); 3.73 (3H, s); 3.78 (3H, s); 4.17 (1H,
dd, J ) 3.2, 9.8); 5.68 (1H, s); 6,52 (1H, s); 6.77 (2H, d, J )
8.6); 6.86 (2H, d, J ) 8.6). 13C NMR (333 K) δ: 20.0; 21.9; 23.9;
26.0; 27.2; 30.9; 35.4; 39.0; 42.8; 45.3; 48.7; 55.1; 55.2; 55.7;
58.1; 61.4; 72.6; 111.5; 113.7 (2C); 126.2; 127.5; 130.6; 130.8
(R)-1-Meth yl-1,2,3,4-tetr a h yd r oisoqu in olin e 11a . 71%
from 9a . Colorless oil. [R]25 ) +72.2 (c ) 1.1, CHCl3). Lit.15
D
[R]25 ) -71.3 (c ) 0.6, CHCl3) for the S enantiomer. tR: 33,-
D
48 min (i-PrOH/hexane 5/95; 0,3 mL/min). 1H NMR δ: 1.42
(3H, d, J ) 6.6); 2.41 (1H, broad s); 2.68 (1H, dt, J ) 4.0, 16.0);
2.78-2.88 (1H, m); 2.92-3.00 (1H, m); 3.20 (1H, dt, J ) 5.0,
12.2); 4.05 (1H, q, J ) 6.6); 7.03-7.11 (4H, m). 13C NMR δ:
22.7; 30.0; 41.8; 51.5; 125.8 (2C); 125.9; 129.2; 134.7; 140.5.
IR (Nujol): 3300 cm-1. MSCI (m/z, %): 148 (M + 1, 100). Anal.
Calcd for C10H13N: C, 81.59; H, 8.90; N, 9.51. Found C, 81.62;
H, 8.96; N, 9.39.
(R)-1-P h en yl-1,2,3,4-tetr a h yd r oisoqu in olin e 11b. 82%
from 9b. White solid, mp 78-79 °C (from EtOAc/hexane). [R]25
D
) - 10.9 (c ) 1.1, CHCl3). lit.16 [R]25 ) -12.3 (c ) 1.5, CH2-
D
Cl2); lit.7 [R]25 ) -10.2 (c ) 0.2, CHCl3); [R]25 ) +12.7 (c )
D
D
0.5, CHCl3) for the S enantiomer.16 tR: 9.99 min (i-PrOH/
hexane 30/70; 0.7 mL/min). 1H NMR δ: 2.10 (1H, broad s);
2.79-2.89 (1H, m); 2.99-3.14 (2H, m); 3.23-3.31(1H, m); 5.11
(1H, s); 6.74-7.35 (9H, m). 13C NMR δ: 29.7; 42.2; 62.0; 125.6;
126.2; 127.4; 128.1; 128.4 (2C); 129.0 (3C); 135.4; 138.2; 144.8.
IR (Nujol): 3300 cm-1. MSCI (m/z, %): 210 (M + 1, 100). Anal.
Calcd for C15H15N: C, 86.08; H, 7.22; N, 6.69. Found C, 86.19;
H, 7.12; N, 6.73.
(2C); 131.7; 146.0; 147.5; 158.2. IR (neat): 3200, 2920 cm-1
.
(R)-1-Meth yl-6,7-d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in -
MSCI (m/z, %): 468 (M + 1, 100). Anal. Calcd for C29H41NO4:
C, 74.48; H, 8.84; N, 3.00. Found C, 74.51; H, 8.89; N, 2.89.
olin e (R)-Sa lsolid in e 12a . 60% from 10a . Colorless oil. [R]25
D
) +59.5 (c ) 0.9, EtOH). lit.17 [R]25 ) -59.5 (c ) 4.4, EtOH);
D

Synthesis of Tetrahydroisoquinoline Alkaloids
J . Org. Chem., Vol. 66, No. 1, 2001 249
lit.4a [R]25 ) -58 (c ) 2.4, EtOH); lit.15 [R]25 ) -56.5 (c )
at room temperature. The solvent was removed by evaporation
and the residue redissolved in anhydrous diethyl ether (10 mL)
and slowly added to a suspension of LiAlH4 (0.14 g., 3.6 mmol)
in the same solvent at 0 °C. After stirring at that temperature
for 20 min., the reaction was quenched by addition of H2O (0.14
mL), 20% NaOH solution (0.14 mL) and H2O (0.42 mL), and
the mixture was stirred for 1 h. The mixture was filtered off.
The solids were washed with EtOAc and the solution was dried
over anhydrous Na2SO4. The solvents were evaporated and the
mixture was purified by flash chromatography (silica gel,
EtOAc/hexane).
D
D
4.1, EtOH), all of them referred to the S enantiomer. tR: 14.88
min (i-PrOH/hexane 20/80; 0.7 mL/min). 1H NMR δ: 1.46 (3H,
d, J ) 6.7); 2.10 (1H, broad s); 2.64-2.70 (1H, m); 2.71-2.86
(1H, m); 2.97-3.05 (1H, m); 3.23-3.28 (1H, m); 3.84 (3H, s);
3.85 (3H, s); 4.07 (1H, q, J ) 6.7); 6.57 (1H, s); 6.62 (1H, s).
13C NMR δ: 22.5; 29.1; 41.4; 51.1; 55.8; 55.9; 108.9; 111.6;
126.4; 131.8; 147.2; 147.3. IR (neat): 3300 cm-1. MSCI (m/z,
%): 208 (M + 1, 100). Anal. Calcd for C12H17NO2: C, 69.54;
H, 8.27; N, 6.76. Found C, 69.66; H, 8.32; N, 6.63.
(R)-1-Isobu tyl-6,7-dim eth oxy-1,2,3,4-tetr ah ydr oisoqu in -
olin e 12b. 61% from 10b. Colorless oil. [R]25 ) +45.4 (c )
D
(R)-1-Isobu tyl-2-m eth yl-6,7-d im eth oxy-1,2,3,4-tetr a h y-
d r oisoqu in olin e. (R)-O-Meth yllop h ocer in e. 13b. 77% from
12b. Colorless oil [R]25D ) +0.7 (c ) 0.9, CHCl3); [R]25D ) -5.4
(c ) 0.7, EtOH). tR: 23.24 min (i-PrOH/hexane 20/80; 0.2 mL/
1.0, CHCl3). tR: 23.21 min (i-PrOH/hexane 20/80; 0.3 mL/min).
1H NMR δ: 0.98 (3H, d, J ) 6.6); 1.02 (3H, d, J ) 6.5); 1.52
(1H, ddd, J ) 3.6, 10.3, 13.9); 1.66 (1H, ddd, J ) 3.8, 10.3,
13.9); 1.83-1.94 (1H, m); 2.05 (1H, broad s); 2.62-2.79 (2H,
m); 2.92-3.00 (1H, m); 3.17-3.25 (1H, m); 3.84 (3H, s); 3.86
(3H, s); 3.91-3.96 (1H, m); 6.56 (1H, s); 6.58 (1H, s). 13C NMR
δ: 21.3; 24.0; 24.7; 29.4; 40.6; 46.0; 53.0; 55.7; 55.9; 109.1;
111.7; 126.9; 132.1; 147.0; 147.1. IR (neat): 3300 cm-1. MSCI
(m/z, %): 250 (M + 1, 100). Anal. Calcd for C15H23NO2: C,
72.25; H, 9.30; N, 5.62. Found C, 72.36; H, 9.38; N, 5.55.
(S)-1-Ben zyloxym eth yl-6,7-d im eth oxy-1,2,3,4-tetr a h y-
1
min). H NMR δ: 0.92 (3H, d, J ) 6.6); 0.99 (3H, d, J ) 6.6);
1.37 (1H, ddd, J ) 4.8, 8.8, 14.0); 1.70 (1H, ddd, J ) 5.2, 8.8,
14.0); 1.81-1.92 (1H, m); 2.44 (3H, s); 2.45-2.53 (1H, m);
2.74-2.91 (2H, m); 3.14-3.25 (1H, m); 3.45 (1H, dd, J ) 4.8,
8.6); 3.84 (3H, s); 3.85 (3H, s); 6.53 (1H, s); 6.55 (1H, s). 13C
NMR δ: 22.2; 23.0; 23.4; 25.1; 41.8; 45.4; 45.5; 55.7; 55.8; 60.6;
110.5; 111.3; 125.5; 130.8; 147.1 (2C). IR (neat): 3020, 2940
cm-1. MSCI (m/z, %): 264 (M + 1, 100%). Anal. Calcd for
d r oisoqu in olin e 12c. 59% from 10c. Colorless oil. [R]25
)
D
+20.2 (c ) 0.6, EtOH). lit.19 [R]25D ) +19.3 (c ) 1.2, EtOH). tR:
15.72 min (iPrOH/hexane 30/70; 0.7 mL/min). 1H NMR δ: 2.50
(1H, broad s); 2.70-2.73 (2H, m); 2.90-2.97 (1H, m); 3.10-
3.18 (1H, m); 3.63-3.75 (2H, m); 3.78 (3H, s); 3.82 (3H, s); 4.14
(1H, dd, J ) 3.8, 8.1); 4.55 (1H, d, J ) 11.9); 4.60 (1H, d, J )
11.9); 6.57 (1H, s); 6.59 (1H, s); 7.26-7.34 (5H, m). 13C NMR
δ: 29.2; 40.1; 55.1; 55.7; 55.9; 73.1; 73.2; 109.3; 111.8; 127.1;
127.6; 127.7 (2C); 127.9; 128.3 (2C); 138.1; 147.0; 147.5. IR
(neat): 3300 cm-1. MSCI (m/z, %): 314 (M + 1, 100). Anal.
Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found C,
72.97; H, 7.37; N, 4.58.
C
16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found C, 72.87; H, 9.45;
N, 5.28.
(R)-1-(4′-Meth oxyben zyl)-2-m eth yl-6,7-dim eth oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e. (R)-O-Meth yla r m ep a vin e 13d .
78% from 12d . Colorless oil. [R]25 ) -69.9 (c ) 0.8, CHCl3).
D
Lit.20 [R]25 ) -81 (c ) 1.2, CHCl3); [R]25 ) +85.0 for the S
D
D
enantiomer. tR: 22.34 min (i-PrOH/hexane 20/80; 0.5 mL/min).
1H NMR δ: 2.53 (3H, s); 2.53-2.62 (1H, m); 2.72-2.89 (3H,
m); 3.11-3.22 (2H, m); 3.55 (3H, s); 3.68 (1H, dd, J ) 5.2, 7.7);
3.77 (3H, s); 3.83 (3H, s); 6.00 (1H, s); 6.55 (1H, s); 6.80 (2H,
d, J ) 8.5); 7.00 (2H, d, J ) 8.5). 13C NMR δ: 25.4; 40.3; 42.6;
46.7; 55.2; 55.4; 55.7; 64.9; 110.9; 111.0; 113.5 (2C); 125.8;
129.1; 130.7 (2C); 131.9; 146.1; 147.1; 157.8. IR (neat): 3020,
2920 cm-1. MSCI (m/z, %): 328 (M + 1, 100). Anal. Calcd for
(R)-1-(4′-Meth oxyben zyl)-6,7-dim eth oxy-1,2,3,4-tetr ah y-
d r oisoqu in olin e 12d . 55% from 10d . Colorless oil. [R]25
)
D
+15.7 (c ) 0.4, CHCl3). tR: 25.77 min (i-PrOH/Hexane 20/80;
1
0.9 mL/min). H NMR δ: 2.22 (1H, broad s); 2.70-2.76 (2H,
C
20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found C, 73.48; H, 7.77;
N, 4.39.
(R)-1-(3′,4′-Dim eth oxyben zyl)-2-m eth yl-6,7-d im eth oxy-
m); 2.80-2.96 (2H, m); 3.12-3.25 (2H, m); 3.80 (3H, s); 3.82
(3H, s); 3.86 (3H, s); 4.11 (1H, dd, J ) 4.2, 9.3); 6.59 (1H, s);
6.63 (1H, s); 6.87 (2H, d, J ) 8.5); 7.16 (2H, d, J ) 8.5). 13C
NMR δ: 29.4; 40.6; 41.7; 55.2; 55.8; 55.9; 56.8; 109.3; 111.7;
113.9 (2C); 127.2; 130.3 (2C); 130.9; 145.8; 146.9; 147.3; 158.2.
IR (neat): 3300 cm-1. MSCI (m/z, %): 314 (M + 1, 100). Anal.
Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found C,
72.96; H, 7.36; N, 4.57.
1,2,3,4-tetr ah ydr oisoqu in olin e. (R)-Lau dan osin e 13e. 77%
from 12e. White solid, mp 114-115 °C, (from EtOAc/hexane).
[R]25 ) -45.2 (c ) 0.6, CHCl3); [R]D ) -85 (c ) 0.4, EtOH).
D
Lit.20 [R]D ) +103 (EtOH); [R]D ) +52 (CHCl3) for the S
enantiomer. tR: 19.30 min (i-PrOH/hexane 30/70; 0.7 mL/min).
1H NMR δ: 2.55 (3H, s); 2.55-2.62 (1H, m); 2.73-2.88 (3H,
m); 3.11-3.23 (2H, m); 3.57 (3H, s); 3.70 (1H, dd, J ) 4.9, 7.7);
3.79 (3H, s); 3.84 (3H, s); 3.85 (3H, s); 6.05 (1H, s); 6.56 (1H,
s); 6.60-6.65 (2H, m); 6.76 (1H, d, J ) 8.1). 13C NMR δ: 25.4;
40.8; 42.6; 46.9; 55.5; 55.7 (2C); 55.8; 64.8; 110.8; 110.9; 111.0;
112.9; 121.8; 125.9; 129.1; 132.4; 146.0; 146.2; 147.2; 148.4.
IR (Nujol): 3040 cm-1. MSCI (m/z, %): 358 (M + 1, 100). Anal.
Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found C,
70.68; H, 7.71; N, 3.85.
(R)-1-(3′,4′-Dim et h oxyb en zyl)-6,7-d im et h oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e. (R)-Nor la u d a n osin e 12e. 58%
from 10e. Colorless oil. [R]25 ) +21.5 (c ) 0.6, CHCl3). lit.4a
D
[R]25 ) -28.8 (c ) 1.1, CHCl3); lit.18 [R]25 ) -21 (c ) 1,
D
D
1
CHCl3), both of them for the S enantiomer. H NMR δ: 2.59
(1H, broad s); 2.62-2.83 (2H, m); 2.84-2.96 (2H, m); 3.14-
3.25 (2H, m); 3.83 (3H, s); 3.85 (3H, s); 3.86 (3H, s); 3.87 (3H,
s); 4.15 (1H, dd, J ) 4.5, 9.1); 6.59 (1H, s); 6.65 (1H, s); 6.76
(1H, s); 6.77-6.85 (2H, m). 13C NMR δ: 29.3; 40.8; 42.1; 55.8
(2C); 55.9; 56.0; 56.7; 109.3; 111.2; 111.7; 112.3; 121.4; 127.3;
(R)-1-(3′,4′-Dim eth oxyp h en eth yl)-2-m eth yl-6,7-d im eth -
oxy-1,2,3,4-tetr ah ydr oisoqu in olin e. (R)-Hom olau dan osin e
13f. 75% from 12f. Colorless oil. [R]25D ) -3.2 (c ) 1.0, CHCl3);
[R]25 ) -10.9 (c ) 1.0, EtOH). lit.21 [R]25 ) +11 (c ) 0.2,
130.2; 131.2; 146.9; 147.4; 147.6; 148.8. IR (neat): 3300 cm-1
.
MSCI (m/z, %): 344 (M + 1, 100). Anal. Calcd for C20H25NO4:
C, 69.95; H, 7.34; N, 4.08. Found C, 70.09; H, 7.46; N, 4.14.
(R)-1-(3′,4′-Dim eth oxyph en eth yl)-6,7-dim eth oxy-1,2,3,4-
tetr a h yd r oisoqu in olin e 12f. 57% from 10f. Colorless oil.
[R]25D ) +13.0 (c ) 0.4, CHCl3). tR: 16.63 min (i-PrOH/hexane
D
D
EtOH) for the S enantiomer. tR: 23.59 min (i-PrOH/hexane
1
20/80; 0.5 mL/min). H NMR δ: 2.00-2.08 (2H, m); 2.48 (3H,
s); 2.50-2.57 (1H, m); 2.63-2.84 (4H, m); 3.11-3.22 (1H, m);
3.43 (1H, t, J ) 5.4); 3.83 (3H, s); 3.84 (3H, s); 3.85 (3H, s);
3.86 (3H, s); 6.54 (1H, s); 6.58 (1H, s); 6.71 (1H, s); 6.72-6.80
(2H, m). 13C NMR δ: 25.3; 31.2; 37.0; 42.6; 47.9; 55.7 (2C);
55.8; 55.9; 62.5; 109.9; 111.1; 111.2; 111.7; 120.1; 126.6; 129.7;
1
30/70; 1 mL/min). H NMR δ: 1.84 (1H, broad s); 1.91-2.18
(2H, m); 2.62-2.84 (4H, m); 2.94-3.03 (1H, m); 3.19-3.27 (1H,
m); 3.82 (3H, s); 3.83 (3H, s); 3.84 (3H, s); 3.86 (3H, s); 3.89-
3.96 (1H, m); 6.57 (1H, s); 6.59 (1H, s); 6.76-6.82 (3H, m). 13
C
NMR δ: 29.4; 32.0; 38.4; 41.0; 55.0; 55.7 (2C); 55.8; 55.9; 109.1;
111.2; 111.7 (2C); 120.1; 127.2; 131.2; 134.9; 147.1(2C); 147.2;
148.7. IR (neat): 3300 cm-1. MSCI (m/z, %): 358 (M + 1, 100).
Anal. Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found
C, 70.68; H, 7.69; N, 3.84.
135.5; 146.9; 147.1; 147.2; 148.6. IR (neat): 3020, 2900 cm-1
.
MSCI (m/z, %): 372 (M + 1, 100). Anal. Calcd for C22H29NO4:
C, 71.13; H, 7.87; N, 3.77. Found C, 71.17; H, 7.96; N, 3.89.
(S)-1-Hydr oxym eth yl-6,7-dim eth oxy-1,2,3,4-tetr ah ydr o-
isoqu in olin e. (S)-Ca lycotom in e 13c. Debenzylation of 12c19
afforded S-calycotomine in 90% yield. White solid, mp 140 °C
N-Meth yla tion of THIQ. To a solution of the correspond-
ing THIQ (0.6 mmol) in CH2Cl2 (10 mL) was added dimeth-
ylpyrocarbonate (0.9 mmol) and the mixture stirred for 20 min.
(dec) (from toluene) [R]25 ) +37.9 (c ) 0.2, H2O); [R]25
)
D
D

250 J . Org. Chem., Vol. 66, No. 1, 2001
Pedrosa et al.
-13.1 (c ) 0.38, CHCl3); lit.23 [R]25 ) +33.7 (c ) 1.1, H2O);
Ack n ow led gm en t. The financial support provided
by the Spanish DGESIC (project PB98-0361) and J unta
de Castilla y Leo´n (Project VA79/99) is gratefully
acknowledged. One of us (J . M. I.) also thanks the
Ministerio de Educacio´n y Cultura for a predoctoral
fellowship (F.P.U.).
D
[R]25 ) +36 (c ) 1, H2O). 1H NMR δ: 2.66-2.75 (2H, m);
D
2.94-3.02 (1H. m); 3.07-3.14 (1H, m); 3.24 (2H, broad s);
3.60-3.67 (1H, m); 3.77 (1H, dd, J ) 3.9, 10.9); 3.82 (3H, s);
3.83 (3H, s); 3.96 (1H, dd, J ) 3.8, 8.8); 6.57 (1H, s); 6.58 (1H,
s). 13C NMR δ: 28.9; 39.0; 55.7; 55.9; 56.3; 64.1; 109.1; 111.8;
126.9; 127.5; 147.2; 147.6. IR (Nujol): 3300 cm-1. MSCI (m/z,
%): 224 (M + 1, 100). Anal. Calcd for C12H17NO3: C, 64.55;
H, 7.67; N, 6.27. Found C, 64.63; H, 7.76; N, 6.31.
Su p p or tin g In for m a tion Ava ila ble: Synthesis and spec-
troscopic data for starting aldehydes, and 13C NMR spectra
for compounds 7a ,b, 8a -f, 9a ,b, and 10a -f.
(23) (a) Brossi, A.; Burkhardt, F. Helv. Chim. Acta 1961, 44, 1588.
(b) Morimoto, T.; Suzuki, N.; Achiva, K. Tetrahedron: Asymmetry 1998,
9, 183.
J O001397S