Stereoselective synthesis of 1,3-substituted tetrahydroisoquinolines through palladium-catalyzed three-component reaction

Article abstract of DOI:10.1016/j.tetasy.2007.05.031

Chiral 1,3-substituted 1,2,3,4-tetrahydroisoquinolines have been synthesized in acceptable yield and diastereoselectivity through a three component reaction, starting from aromatic halides, enantiopure bromoalkyl derivatives and methyl acrylate, under pal

Full text of DOI:10.1016/j.tetasy.2007.05.031

Tetrahedron: Asymmetry 18 (2007) 1475–1480
Stereoselective synthesis of 1,3-substituted tetrahydroisoquinolines
through palladium-catalyzed three-component reaction
Raffaella Ferraccioli,a,* Clelia Gianninib and Giorgio Moltenib
aCNR—Istituto di Scienze e Tecnologie Molecolari (ISTM), Via C. Golgi 19, 20133 Milano, Italy
`
Dipartimento di Chimica Organica e Industriale dell’Universita, Via Venezian 21, 20133 Milano, Italy
b
Received 10 May 2007; accepted 29 May 2007
Available online 5 July 2007
Abstract—Chiral 1,3-substituted 1,2,3,4-tetrahydroisoquinolines have been synthesized in acceptable yield and diastereoselectivity
through a three component reaction, starting from aromatic halides, enantiopure bromoalkyl derivatives and methyl acrylate, under pal-
ladium catalysis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
R1
I
CO2Me
a
CO2Me
Cbz
CO2Me
Cbz
Multicomponent reactions (MCRs) are powerful tools for
the rapid and efficient assembly of complex structures from
simple starting materials with minimal production of
waste.1 For the synthesis of heterocycles, palladium-cata-
lyzed MCRs turn out to be of great interest due to their
functional group tolerability and the versatility of palla-
dium in cross coupling reactions.2
R1
R1
+
1 N
1 N
1
3
+
3
3
R2
+
R2
NHCbz
R2
cis-4
trans-4
R1 = Me, Et, i-Pr
R2 = (S)-Me, (R)-Et, (S)-Bn, (S)-i-Bu
Br
2
The 1,2,3,4-tetrahydroisoquinoline nucleus has recently
attracted significant attention, as it is the structural motif
of many alkaloids.3 In a preliminary communication, we
disclosed a novel palladium-catalyzed three-component
synthesis of 1-substituted tetrahydroisoquinolines 4 (R2 =
H) (Scheme 1), assembled from a pool of simple molecules
1, 2, and 3 through the formation of two carbon–carbon
and one carbon–nitrogen bonds in a single operation.4
Herein, we explore the possibility of obtaining chiral tetra-
hydroisoquinolines 4 starting from enantiomerically pure
Br-derivatives 2 (Scheme 1). The 1,3-substituted derivatives
represent an important subclass of tetrahydroisoquinolines
and only a few stereoselective syntheses have been reported
so far.3c–e A key point in the synthesis of these compounds
is the control of stereochemistry at the C-1 and C-3 carbon
atoms. We wonder whether the use of enantiopure
Br-derivatives 2 in the reaction outlined in Scheme 1 could
Scheme 1. Reagents and condition: (a) Pd(OAc)2/tri-2-furylphosphine,
norbornene, Cs2CO3, DMF, 80 ꢁC.
address the formation of the new stereogenic center C-1
in 4.1b
2. Results and discussion
Compounds 2 can be easily prepared from the correspond-
ing commercially available, enantiopure alcohols by OH/
Br exchange (CBr4, PPh3 in THF). The reaction of 1, 2,
and 3 in the presence of Pd(OAc)2/tri-2-furylphosphine
and norbornene as catalysts, Cs2CO3 as a base, in anhy-
drous DMF at 80 ꢁC leads to 4 in acceptable yield and dia-
stereoselectivity (Table 1).
Configurational assessment of each diastereomer has been
carried out on compounds 4 (R2 = Et). Flash chromato-
graphy of the diastereomeric mixture of 4 gave the major
diastereomer as a pure compound and the minor as an
*
Corresponding author. Fax: +39 (0) 2 50314139; e-mail: Raffaella.
Ferraccioli@istm.cnr.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.031

1476
R. Ferraccioli et al. / Tetrahedron: Asymmetry 18 (2007) 1475–1480
Table 1. Stereoselective palladium-catalyzed three-component synthesis of 4a
Entry
R1
R2
Time (h)
4b (%)
c/t ratioc
1
2
3
4
5
6
Me
Me
Et
i-Pr
Me
Me
(S)-Me
(R)-Et
(R)-Et
(R)-Et
(S)-Bn
(S)-i-Bu
15
9
15
15
12
13
49
78:22
79:21e
80:20
84:16
76:24
77:23
56d
52f
60f
48
45
a Unless otherwise indicated, reactions were run with 1 (1 mol equiv), 2 (2 mol equiv), 3 (2 mol equiv), norbornene (2 mol equiv), Pd(OAc)2 (10 mol %), tri-
2-furylphosphine (TFP) (20 mol %), Cs2CO3 (2 mol equiv) in DMF at 80 ꢁC, [1] = 0.05 M.
b Yields after column chromatography.
c cis/trans diastereomeric ratio was determined by 1H NMR and/or GC analysis of the crude.
d Compound 11 (R1 = Me) was also isolated in 5% yield.
CO2Me
R1
R1
11
e With t-butyl acrylate a 4c/4t ratio of 80:20 was obtained.
f With 4 mol equiv of norbornene.
80% enriched mixture. NMR studies allowed us to estab-
lish a cis relationship between the substituents bonded to
R1
R1
C-1 and C-3 carbon atoms for the major diastereomer 4c,
and a trans relationship for the minor 4t (Fig. 1). In the
case of 4c, NOE interactions between (a) Ha (2.60 ppm)
and Hb (1.61 ppm), (b) Ha and the methyl group at
0.93 ppm were noteworthy. The assignment of the trans
configuration to 4t is supported by the observation of an
NOE between Ha (2.70 ppm) and H-3 (4.00 ppm). Mini-
mum energy geometries of the structures assigned to the
products showed that in 4c the heterocyclic ring adopts a
boat-like conformation, wherein the C-1 and C-3 substitu-
ents are in a pseudo-axial position and the calculated dis-
PdIL2
Pd(0)L2
, Cs2CO3
2
1
Pd
-CsI, -CsHCO3
L
L
5
6
R1
R1
-
R2
L
PdBrL2
Pd
Br
R2
L
NHCbz
7
8
NHCbz
˚
tance between Ha and Hb is 2.19 A. The C-1 and C-3
R1
CO2Me
R1
substituents of 4t are pseudo-axial and equatorial, respec-
˚
PdBrL2
tively, and the Ha–H3 distance is 2.63 A. In both cases
3
˚
the calculated distance between H1 and H3 is 4.46 A, thus
4
- Pd(0)L2
- CsHCO3
- CsBr
precluding any NOE effect.
R2
R2
10
NHCbz
NHCbz
9
CO2Me ax
Ha'
CO2Me ax
Ha
Ha'
H1
Ha
H1
Scheme 2. Proposed mechanism of 4.
NOE
NOE
N-Cbz
H3
N-Cbz
mide 2 then reacts with 6 giving palladium(IV) metallacycle
7. Reductive elimination forms 8, which readily undergoes
norbornene expulsion because of the steric hindrance of the
two ortho alkyl substituents leading to 9. Alkyl acrylate
insertion completes the catalytic cycle with formation of
the key-intermediate (E)-10, CsHCO3, and CsBr. At this
stage, 10 undergoes intramolecular aza-Michael addition,
which determines the relative stereochemistry between sub-
stituents at positions 1 and 3 of 4.7
Hb
Me ax
H3
Hb'
Me eq
4c
4t
Figure 1. NOE interactions of 4c and 4t (R1 = Me; R2 = Et).
The three-component synthesis of 4 starts with a Pd-cata-
lyzed aromatic substitution, made possible by sequential
activation of two adjacent C–I and C–H bonds of an
aromatic iodide, as discovered by Catellani.5 The catalytic
cycle begins with 1, which oxidatively adds to palladium(0)
affording 5 (Scheme 2, TFP as a ligand). Norbornene inser-
tion and subsequent ring closure through C–H activation6
give palladacycle 6, CsHCO3, and CsI. The aliphatic bro-
As shown in Scheme 3, compound 10 can assume a and b
conformations. We hypothesize that the cis- and trans-iso-
mers form through the less hindered nucleophilic attack
of the nitrogen atom (–NHCbz) to the carbon–carbon
double bond, according to path-a and -b, respectively.

R. Ferraccioli et al. / Tetrahedron: Asymmetry 18 (2007) 1475–1480
1477
R1
R1
H
CO2Me
N-Cbz
H
R1
H
CO2Me
CO2Me
path-a
H
H
H
NH-Cbz
NH-Cbz
Et
TS1
H
Et
H
Et
(S,R)-4c
(E)-(R)-10-a
R1
H
R1
CO2Me
H
N-Cbz
R1
path-b
H
CO2Me
NH-Cbz
CO2Me
NH-Cbz
Et
H
H
H
Et
(R,R)-4t
H
H
Et
(E)-(R)-10-b
TS2
Scheme 3. Proposed mechanism of the stereoselective intramolecular aza-Michael addition reaction.
AM1 calculations of the two diastereomeric transition
compounds, isolated in one case (entry 2), originate from
the reaction of the aromatic halide 1 with palladacycle 6,
according to a related catalytic sequence.8 Two molar
equivalents of 2 were needed9 to counteract the competitive
oxidative addition of 1 to 6, thus minimizing the formation
of 11. With aryl iodides 1 bearing bulky groups in the ortho
position (R1 = Et, i-Pr), the reaction leads to 4 in low selec-
tivity, when run under the conditions of Table 1. In both
cases the use of 4 mol equiv of norbornene10 improved
yields significantly (20–25%), probably favoring the forma-
tion of palladacycle 6.
states TS1 and TS2 showed a dDEz ¼ DEtzrans ꢀ DEczis
¼
5045 J=mol, which implies a predicted 4c/4t ratio of
84:16. This finding agrees with the experimental results
(Table 1). Apparently, the stereoselectivity is not affected
by the encumbrance of R1 and R2substituents, the cis/trans
ratio being nearly the same when varying their steric size.
The reaction of 1, 2, and 3, run in DMF at 80 ꢁC for a
shorter time (1 h) gave intermediate 10 (R1 = Me;
R2 = Et). Unexpectedly, treatment of 10 with Cs2CO3
(1 equiv) at 80 ꢁC in DMF for 10 h in the absence of the
catalyst gave an equimolar diastereomeric mixture of 4.
The involvement of palladium catalysis in the stereoselec-
tive carbon–nitrogen bond formation was ruled out after
checking the stability of tetrahydroisoquinoline derivative
4c under the aforementioned conditions. We observed that
4c was transformed into a 1:1 mixture of cis/trans isomers.
Apparently, the kinetically controlled product 4c can equil-
ibrate into 4t through a base-catalyzed retro-Michael addi-
tion reaction. In the one-pot procedure, the cyclization
occurs under less basic conditions (CsHCO3) and C-1 epi-
merization is less favored. We also verified that diastereo-
selectivity is scarcely time-dependent. When prolonging
the reaction time up to 20 h, the cis/trans ratio changed
from 79:21 to 77:23.
3. Conclusion
In conclusion, we have developed a straightforward entry
to optically active 1,3-substituted tetrahydroisoquinolines
4 in fair yield and reasonable diastereoselectivity through
an asymmetric three-component reaction starting from 1,
2, and 3. Our approach couples Pd-catalyzed alkyl/vinyl
aromatic substitution and a stereoselective aza-Michael
addition. This methodology is complementary to the
reported ones.
4. Experimental
4.1. General
Attempts to improve the stereoselectivity of the intramole-
cular aza-Michael reaction by running the cyclization of 10
at lower temperature and in the presence of a stronger base
(kinetic control) did not produce better results. The crude
containing 10 (R2 = Et) was treated with t-BuOK (0.3
mol equiv) at room temperature. Under these conditions,
cyclization occurred rapidly (5 min) giving 4 in a 62:38 dia-
stereomeric ratio, which increased to 80:20 when the ring
closure was carried out at ꢀ30 ꢁC.
All reagents and solvents were purchased from commercial
suppliers and used without further purification. The palla-
dium-catalyzed reactions were run under nitrogen using
standard Schlenk and vacuum line techniques. Melting
points are uncorrected. IR spectra were recorded with a
Perkin–Elmer FT-IR 1725X spectrophotometer.
1
As shown in Scheme 2, compounds 4 result from a complex
multistep mechanism. Tuning reagent and catalyst ratio is
crucial to obtain satisfactory selectivity in terms of yield,
as competitive side-reactions can occur and lead to several
byproducts.5 The crude of the reactions revealed the pres-
ence of compounds of type-11 (Table 1, entry 2), as unde-
Unless otherwise specified, H and 13C NMR spectra were
recorded at room temperature on a Bruker 300-AMX spec-
trometer at 300 and 75 MHz, respectively. Phase sensitive
ROESY spectra were measured on a 500 MHz with a mix-
ing time tm of 400 ms, while HMQC and HMBC were opti-
1
2,3
mized for JC–H = 135 Hz and
J
= 8 and 10 Hz,
C–H
1
sired products (4/11 ratio ffi10:1, H NMR analysis). Such
respectively.

1478
R. Ferraccioli et al. / Tetrahedron: Asymmetry 18 (2007) 1475–1480
4.2. Synthesis of enantiopure (1-alkyl-2-bromo)ethyl
carbamic acid benzyl esters 2 (adapted from a reported
procedure)11
DMF (2.1 mL). The mixture was heated at 80 ꢁC under
stirring for the time reported in Table 1, then cooled to
rt. After addition of a saturated aqueous n-Bu4NCl
(50 mL) and extraction with AcOEt (2 · 10 mL), the com-
bined organic phases were dried (Na2SO4) and evaporated
under vacuum. The residue was purified by flash chroma-
tography on silica gel (eluent: hexane/AcOEt 8.5:1.5).
A solution of tetrabromomethane (647 mg, 1.95 mmol) in
anhydrous THF (5 mL) was added dropwise to a solution
of PPh3 (511 mg, 1.95 mmol) in THF (5 mL), kept at 0 ꢁC.
After the addition, the mixture was left at 0 ꢁC under stir-
ring for 15 min. Then, it was treated with a solution of the
proper commercial N-Cbz protected 2-aminoalcohol
(0.975 mmol) in THF (10 mL). The mixture was left under
stirring at 0 ꢁC for 10 min, then at rt for 2.0 h. The solid
precipitate was filtered and washed with AcOEt
(2 · 10 mL). The combined organic phases were washed
with brine (70 mL), separated, and dried over Na2SO4.
The crude residue was purified by chromatography on
silica gel (eluent: hexane/AcOEt, 9:1).
4.3.1. (1R,3S)-1-Methoxycarbonylmethyl-3,8-dimethyl-1,2,
3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester
20
(4c, R1 = R2 = Me). Dense oil; ½aŠ ¼ þ18:1 (c 0.93,
D
MeOH). IR (neat, cmꢀ1): 3030, 2950, 1739, 1695. 1H
NMR (DMSO-d6, 80 ꢁC): d = 1.44 (d, J = 6.0 Hz, 3H),
2.30 (s, 3H), 2.62 (dd, J = 14.2, 5.5 Hz, 1H), 2.81 (dd,
J = 14.2, 9.6 Hz, 1H), 2.86 (dd, J = 15.9, 11.3 Hz, 1H),
3.05 (dd, J = 15.9, 7.13 Hz, 1H), 3.56 (s, 3H), 3.9 (m,
1H), 5.03–5.18 (m, 2H), 5.98 (dd, J = 9.6, 5.5 Hz, 1H),
7.06–7.13 (m, 3H), 7.36–7.38 (m, 5H). 13C NMR
(DMSO-d6): d = 17.8, 22.2, 34.2, 38.8, 48.7, 49.8, 51.3,
66.4, 125.6, 127.3, 127.4, 127.8, 128.2, 128.3, 132.5, 134.5,
136.5, 136.8, 152.2, 170.4. HRMS (ESI) m/z: [M+Na]+
calcd for C22H25NO4Na, 390.16758; found, 390.16700.
4.2.1. Compound 2 (R2 = (S)-Me). Yield 66%; white solid;
20
mp 50–51 ꢁC (hexane/AcOEt 9.5:0.5); ½aŠ ¼ ꢀ24:6 (c 0.9,
D
1
CHCl3). IR (Nujol, cmꢀ1): 3341, 1686. H NMR (CDCl3):
d = 1.31 (d, J = 6.6 Hz, 3H), 3.44 (dd, J = 10.2, 3.4 Hz,
1H), 3.56 (br dd, J = 10.0, 4.2 Hz, 1H), 4.02 (br s, 1H),
5.00–5.14 (m, 3H), 7.31–7.36 (m, 5H).13C NMR (CDCl3):
d = 19.1, 39.1, 46.7, 66.6, 127.9, 128.0, 128.4, 136.2,
155.3. Anal. Calcd for C11H14BrNO2: C, 48.55; H, 5.19;
N, 5.15. Found: C, 48.45; H, 5.23; N, 5.15.
4.3.2. (1S,3R)-3-Ethyl-1-methoxycarbonylmethyl-8-methyl-
1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester
20
(4c, R1 = Me; R2 = Et). Dense oil; ½aŠ ¼ ꢀ0:8 (c 1.16,
D
MeOH). IR (neat, cmꢀ1): 3030, 2960, 2874, 1740, 1696.
1H NMR (DMSO-d6): d = 0.93 (t, J = 7.5 Hz, 3H, CH2–
CH3), 1.61 (m, 1H, Hb), 1.96 (m, 1H, Hb0), 2.28 (s, 3H,
8-CH3), 2.60 (dd, J = 14.5, 4.7 Hz, 1H, Ha), 2.78 (m, 1H,
Ha0), 2.80 (m, 1H, H-4), 3.12 (dd, J = 15.9, 7.43 Hz, 1H,
H-40), 3.54 (s, 3H, O–CH3), 3.75 (m, 1H, H-3), 5.07 (m,
2H, CH2–Ph), 5.95 (dd, J = 10.2, 4.7 Hz, 1H, H-1), 7.04
(m, 2H, H-6, Hpara), 7.05 (m, 2H, Hmeta), 7.08 (m, 1H, H-
5), 7.12 (m, 2H, Hortho), 7.36 (m, 1H, H-7). 13C NMR
(DMSO-d6): d = 10.5 (CH2–CH3), 18.3 (8-CH3), 30.7
(CH2–CH3), 32.0 (C-4), 39.2 (CH2–CO2–), 50.3 (C-1),
51.9 (O–CH3), 54.3 (C-3), 67.0 (CH2–Ph), 126.4 (C-5),
127.8 (C-7), 127.9 (2Cortho), 128.4 (2Cmeta, 1Cpara), 128.5
(C-6), 132.9 (C-8), 134.6 (C-4a), 137.1 (Cipso), 137.3 (C-
8a), 156.5 (N–CO), 170.9 (CO2). HRMS (ESI) m/z:
[M+Na]+ calcd for C23H27NO4Na, 404.18323; found,
404.18357.
4.2.2. Compound 2 (R2 = (R)-Et). Yield 62%; white solid;
20
mp 60–62 ꢁC (iPr2O); ½aŠ ¼ þ28:6 (c 1.2, CHCl3). IR
D
1
(Nujol, cmꢀ1): 3301, 1708, 1685. H NMR (CDCl3): d =
0.97 (t, J = 7.45 Hz, 3H), 1.50–1.75 (m, 2H), 3.51–3.64
(m, 2H), 3.80 (br s, 1H), 4.90 (br s, 1H), 5.14 (br s, 2H),
7.33–7.39 (m, 5H). 13C NMR (CDCl3): d = 10.2, 26.0,
37.7, 52.2, 66.7, 127.9, 128.0, 128.4, 136.2, 155.7. Anal.
Calcd for C12H16BrNO2: C, 50.37; H, 5.64; N, 4.89. Found:
C, 50.29; H, 5.66; 4.91.
4.2.3. Compound 2 (R2 = (S)-Bn). Yield 85%; white solid;
20
mp 70 ꢁC (iPr2O) (lit12 69–70 ꢁC); ½aŠ ¼ ꢀ10:1 (c 1.00,
D
CH2Cl2).
4.2.4. Compound 2 (R2 = (S)-i-Bu). Yield 50%; Dense oil;
20
½aŠ ¼ ꢀ23:8 (c 2.1, CH2Cl2). IR (neat, cmꢀ1): 3322, 2957,
D
1
2932, 2869, 1699, 1530. H NMR (CDCl3): d = 0.91–0.95
(m, 6H), 1.40–1.46 (m, 2H), 1.60–1.70 (m, 1H), 3.45 (dd,
J = 10.4, 3.4 Hz, 1H), 3.60 (dd, J = 10.4, 4.0 Hz, 1H),
3.95 (m, 1H), 4.80 (br d, J = 8.4 Hz, 1H), 5.10 (s, 2H),
7.30–7.40 (m, 5H). 13C NMR (CDCl3): d = 22.2, 22.6,
24.6, 38.7, 42.1, 49.0, 66.7, 127.9, 128.0, 128.4, 136.3,
155.6. Anal. Calcd for C14H20BrNO2: C, 53.51; H, 6.42;
N, 4.46. Found: C, 53.56; H, 6.46; N, 4.46.
4.3.2.1. Characteristic NMR data of (1R,3R)-4t. 1H
NMR (DMSO-d6, 4c/4t = 20:80): d = 0.67 (t, J = 7.0 Hz,
3H, CH2–CH3), 1.39 (m, 2H, Hb, Hb0), 2.28 (s, 3H, 8-
CH3), 2.50 (dd, J = 13.3, 6.4 Hz, 1H, Ha), 2.70 (dd,
J = 13.3, 6.4 Hz, 1H, Ha0), 2.80 (dd, J = 15.5, 2.0 Hz,
1H, H-4), 3.09 (dd, J = 15.5, 4.5 Hz, 1H, H-40), 3.47 (s,
3H, O–CH3), 4.00 (m, 1H, H-3), 5.14 (m, 2H, CH2–Ph),
5.47 (t, J = 6.4 Hz, 1H, H-1), 7.04–7.37 (m, 8H). 13C
NMR (DMSO-d6): d = 10.5 (CH2–CH3), 18.2 (8-CH3),
30.7 (CH2–CH3), 32.0 (C-4), 39.2 (CH2–CO2–), 50.1 (C-
1), 51.9 (O–CH3), 53.8 (C-3), 67.1 (CH2–Ph), 126.4 (C-5),
127.9 (2Cortho), 128.4 (2Cmeta), 134.6 (C-4a), 137.1 (Cipso),
156.5 (N–CO), 170.9 (CO2).
4.3. Synthesis of 1,3-substituted tetrahydroisoquinolines 4
A Schlenk-type flask was charged under nitrogen with
anhydrous Cs2CO3 (98 mg, 0.30 mmol), Pd(OAc)2
(3.4 mg, 0.015 mmol), tri-2-furylphosphine (7.0 mg,
0.03 mmol), norbornene (28 mg, 0.30 mmol), and anhy-
drous DMF (1.0 mL). The mixture was stirred at rt for
10 min, then treated with 1 (0.15 mmol), 3 (26 mg, 27 lL,
0.30 mmol), and a solution of 2 (0.30 mmol) in anhydrous
4.3.3. (1S,3R)-3,8-Ethyl-1-methoxycarbonylmethyl-1,2,3,4-
tetrahydroisoquinoline-2-carboxylic acid benzyl ester (4c,
20
R1 = R2 = Et). Dense oil; ½aŠ ¼ ꢀ9:8 (c 1.0, MeOH). IR
D
(neat, cmꢀ1): 3032, 2964, 2875, 1741, 1695. 1H NMR

R. Ferraccioli et al. / Tetrahedron: Asymmetry 18 (2007) 1475–1480
1479
(DMSO-d6, 80 ꢁC): d = 0.97 (t, J = 7.4 Hz, 3H), 1.16 (t,
4.4. Computational details
J = 7.5 Hz, 3H), 1.60–1.73 (m, 1H), 1.94–2.44 (m, 1H),
2.53–2.88 (m, 5H), 3.13 (dd, J = 16.0, 7.3 Hz, 1H), 3.58
(s, 3H), 3.72–3.83 (m, 1H), 5.05 (d, J = 12.6 Hz, 1H),
5.13 (d, J = 12.6 Hz, 1H), 6.05 (dd, J = 12.0, 4.9 Hz, 1H),
7.06–7.10 (m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.34–7.37
(m, 5H). 13C NMR (DMSO-d6): d = 10.2, 15.5, 24.3,
30.0, 31.6, 39.0, 49.1, 51.4, 53.6, 66.5, 125.9, 126.6, 127.4,
127.7, 128.3, 134.5, 136.0, 136.7, 138.6, 156.1, 170.4.
HRMS (ESI) m/z: [M+Na]+ calcd for C24H29NO4Na,
418.19888; found, 418.19855.
The geometry of 4c and 4t was fully optimized at the AM1
level.13 It was verified that structures 4c and 4t correspond
to energy minima by the absence of negative eigenvalues of
the Hessian matrix. The geometry of TS1 and TS2 was
fully optimized at the AM1 level. Transition states TS1
and TS2 were confirmed by harmonic analysis, each one
having a negative eigenvalue. All computations were car-
ried out by the HYPERCHEM suite implemented in the
Hyperchem 7.04 Professional package of programs, Hyper-
cube, 2002.
4.3.4.
methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic
(1S,3R)-3-Ethyl-8-isopropyl-1-methoxycarbonyl-
acid
20
benzyl ester (4c, R1 = i-Pr; R2 = Et). Dense oil; ½aŠ
¼
D
Acknowledgments
ꢀ9:2 (c 1.2, MeOH). IR (neat, cmꢀ1): 3031, 2962, 2929,
1739, 1695. 1H NMR (DMSO-d6, 80 ꢁC): d = 0.92 (t,
J = 7.5 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.21 (d,
J = 6.8 Hz, 3H), 1.59–1.75 (m, 1H), 1.95–2.07 (m, 1H),
2.55 (dd, J = 15.8, 7.5 Hz, 1H), 2.77–2.90 (m, 2H), 3.10–
3.22 (m, 2H), 3.58 (s, 3H), 3.72–3.82 (m, 1H), 5.02–5.15
(m, 2H), 6.15 (dd, J = 9.0, 5.0 Hz, 1H), 7.06 (br d, 1H),
7.16–7.24 (m, 2H), 7.31–7.37 (m, 5H). 13C NMR
(DMSO-d6): d = 10.0, 22.6, 24.7, 27.8, 30.7, 31.7, 39.3,
48.7, 51.3, 53.6, 66.5, 123.2, 125.7, 127.5, 127.6, 127.7,
128.2, 134.4, 135.7, 136.6, 143.1, 156.4, 170.3. HRMS
(ESI) m/z: [M+Na]+calcd for C25H31NO4Na, 432.21453;
found, 432.21378.
We thank Professor M. Catellani, University of Parma, for
helpful discussion. We are grateful to Consiglio Nazionale
delle Ricerche (CNR) and MIUR for financial support.
References
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4.3.5. (1R,3S)-3-Benzyl-1-methoxycarbonylmethyl-8-meth-
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20
ester (4c, R1 = Me; R2 = Bn). Dense oil; ½aŠ ¼ ꢀ40:9 (c
D
1.00, MeOH). IR (neat, cmꢀ1): 3062, 3026, 2958, 2855,
1739, 1696. 1H NMR (DMSO-d6, 80 ꢁC): d = 2.30 (s,
3H), 2.57 (dd, J = 14.0, 6.0 Hz, 1H), 2.74–2.95 (m, 4H),
3.36 (dd, J = 13.0, 3.1 Hz, 1H), 3.60 (s, 3H), 4.00 (m,
1H), 5.12 (d, J = 12.0 Hz, 1H), 5.15 (d, J = 12.0 Hz, 1H),
6.03 (dd, J = 9.2, 5.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H),
7.00–7.11 (m, 2H), 7.24–7.44 (m, 10H). 13C NMR
(DMSO-d6): d = 18.3, 32.1, 39.2, 50.2, 51.9, 54.9, 67.4,
126.2, 126.8, 127.8, 128.4, 128.7, 128.9, 129.6, 133.1,
134.6, 137.2, 138.9, 155.6, 171.0. HRMS (ESI) m/z:
[M+Na]+ calcd for C28H29NO4Na, 446.19888; found,
446.19892.
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4.3.6.
methyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic
(1R,3S)-3-Isobutyl-1-methoxycarbonylmethyl-8-
acid
benzyl ester (4c, R1 = Me; R2 = i-Bu). Dense oil;
20
½aŠ ¼ þ15:3 (c 0.98, MeOH). IR (neat, cmꢀ1): 2954,
D
1
2870, 1740, 1696. H NMR (DMSO-d6, 80 ꢁC): d = 0.88
(d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H), 1.50–1.60
(m, 1H), 1.75–1.85 (m, 2H), 2.3 (s, 3H), 2.62 (dd,
J = 14.4, 5.4 Hz, 1H), 2.76–2.84 (m, 2H), 3.14 (dd,
J = 15.9, 7.5 Hz, 1H), 3.57 (s, 3H), 3.50–4.04 (m, 1H),
5.03 (d, J = 12.6 Hz, 1H), 5.14 (d, J = 12.6 Hz, 1H), 5.98
(dd, J = 9.6, 5.4 Hz, 1H), 7.04–7.15 (m, 3H), 7.32–7.36
(m, 5 H). 13C NMR (DMSO-d6): d = 17.7, 20.9, 23.9,
24.1, 32.2, 38.4, 49.5, 50.3, 51.3, 66.5, 125.9, 127.1, 127.8,
128.0, 128.2, 132.5, 134.2, 136.8, 157.6, 170.4. HRMS
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found, 432.21404.
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7460–7461.

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7. The absolute configuration of the new stereocenter C-1
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behaves as a catalyst. Only a small amount of norbornene
was consumed in side-reactions.
is determined on the basis of the known configuration of
2.
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