Synthesis of tyrosine-derived tetrahydroisoquinolines by Lewis acid catalyzed cyclization of N-(phenylsulfonyl)alkyloxazolidinones

Article abstract of DOI:10.1002/ejoc.200700443

N-Boc-protected tyrosine esters 5a,b were converted into tetrahydroisoquinolines 13 and 14 in four steps by reduction and ring closure to oxazolidinones 9 and 10, addition of benzenesulfinic acid and aldehydes to sulfones 11 and 12 and subsequent Lewis ac

Full text of DOI:10.1002/ejoc.200700443

FULL PAPER
DOI: 10.1002/ejoc.200700443
Synthesis of Tyrosine-Derived Tetrahydroisoquinolines by Lewis Acid
Catalyzed Cyclization of N-(Phenylsulfonyl)alkyloxazolidinones
Stefan Tussetschläger,[a] Angelika Baro,[a] Sabine Laschat,*[a] and Wolfgang Frey[a]
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 75th birthday
Keywords: Amino acids / Bromine / Protecting groups / Debromination / Oxazolidinones / Regioselectivity
N-Boc-protected tyrosine esters 5a,b were converted into
tetrahydroisoquinolines 13 and 14 in four steps by reduction
radical reduction conditions by using Bu3SnH/AIBN. Tetra-
hydroisoquinolines 13 and 14 were isolated as single dia-
and ring closure to oxazolidinones 9 and 10, addition of ben- stereomers whose trans configuration was confirmed by X-
zenesulfinic acid and aldehydes to sulfones 11 and 12 and
subsequent Lewis acid catalyzed cyclization. In the case of
m-tyrosine derivative 5a, selective protection with bromine
prevented the formation of undesired regioisomers. Debro-
mination of target compounds 13 was readily achieved under
ray crystal structure analysis. Partial epimerization of trans-
13i and trans-21 to the corresponding cis diastereomers was
achieved under basic conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
attracted by the conversion of benzyl-substituted oxazol-
idinones with aldehydes and benzenesulfinic acid to the cor-
responding N-[1-(phenylsulfonyl)alkyl]oxazolidinones and
their Lewis acid mediated ring closure to tricyclic tetra-
hydroisoquinoline derivatives published by Petrini.[13] This
approach was used for the synthesis of azapodophyllo-
toxin[14] starting from DOPA.[13b] To the best of our knowl-
edge, however, in no case was either p- or m-tyrosine consid-
ered as a starting material. Thus, we investigated the cycli-
zation of tyrosine-derived N-[(phenylsulfonyl)alkyl]oxazol-
idinones as an extension of Petrini’s methodology. The re-
sults are reported below.
Introduction
Tetrahydroisoquinoline alkaloids have received much
interest because of their tremendous structural diversity
and broad spectrum of biological and pharmaceutical ac-
tivities.[1] The most popular synthetic approaches towards
tetrahydroisoquinolines are the Pictet–Spengler reaction,[2,3]
the Bischler–Napieralski reaction,[4,5] and the Pomeranz–
Fritsch reaction.[6–8] However, concerning m-tyrosine-de-
rived precursors 1, the above-mentioned cyclizations are
hampered by the formation of regioisomers 2 and 3
(Scheme 1) or undesired byproducts such as oxazoles.[9]
Results and Discussion
The synthesis of cyclization precursors 9 and 10 com-
menced with the conversion of tyrosines 4a,b to the corre-
sponding Boc-protected amino acids[15] in 90 and 81%
Scheme 1. Possible regioisomers 2 and 3.
A typical example for these regioisomers was reported yield, respectively, following the method used by Jung[15a]
by Myers in the total synthesis of (–)-quinocarcin.[10] To (Scheme 2). The N-Boc derivatives were subsequently meth-
overcome the regioselectivity problem, Fukuyama intro- ylated with iodomethane in acetone in the presence of
duced a bromine protecting group at C-6 of cyclization pre- K2CO3 according to the protocol by Reddy[16a] to give com-
cursor 1, and subjected these bromo-substituted m-tyro- pounds 5a,b[16] in 97 and 76% yield, respectively.
sines to Pictet–Spengler reactions.[11] Hashmi used substi-
Prior to reduction with LiBH4 in Et2O/MeOH to alcohol
tuted furylalanine derivatives in Au-catalyzed cycloisomer- 7 (95%), m-tyrosine 5a was brominated at the C-6 position
izations.[12] Upon searching for suitable methods we were with NBS in CH2Cl2 at room temperature to compound 6
(86%) (Scheme 2) to suppress cyclization to the undesired
[a] Institut für Organische Chemie der Universität Stuttgart,
regioisomer. Tyrosine derivative 5b was directly reduced to
Pfaffenwaldring 55, 70569 Stuttgart, Germany,
corresponding Boc-protected amino alcohol 8[16a] in 80%
Fax: +49-711-68564285
E-mail: sabine.laschat@oc.uni-stuttgart.de
yield.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
Treatment of amino alcohols 7 and 8 with thionyl chlo-
ride at 0 °C[13b] yielded oxazolidinones 9 and 10 in 83 and
89% yield, respectively. Crystallization of derivative 10 from
Et2O gave single crystals that were suitable for X-ray crystal
structure analysis (Figure 1).[17]
Figure 1. Molecular structure of 4-(4-methoxybenzyl)-1,3-oxazol-
idin-2-one (10) in the solid state (ORTEP presentation).
Following the protocol of Petrini,[13] compounds 9 and
10 were treated with benzenesulfinic acid and various alde-
hydes to give corresponding α-amidoalkylphenyl sulfones
11 and 12 as diastereomeric mixtures. The results are sum-
marized in Table 1.
Whereas the addition reaction worked for aliphatic alde-
hydes and croton- and 2-benzyloxyacetaldehyde (Table 1,
Entries 1–5, 9–13), benzaldehyde and glyoxal did not give
sulfones 11f,g and 12f,g (Table 1, Entries 6, 7, 14, 15). In
the reaction of tyrosine-based oxazolidinone 10 and gly-
oxal, hemiaminal 15 was isolated instead (Table 1). Under
the conditions of the addition reaction, m-tyrosine-derived
9 afforded directly tricyclic tetrahydroisoquinoline 13f in
4% yield. As derivative 11e was difficult to isolate, the alter-
Scheme 2. Preparation of m- and p-tyrosine-derived oxazolidinones
9 and 10 and subsequent cyclization to corresponding tetrahydro-
isoquinolines 13 and 14.
Table 1. Reaction of oxazolidinones 9 and 10 with aldehydes and PhSO2H to form N-[1-(phenylsulfonyl)alkyl]oxazolidinones 11 and 12
followed by cyclization to tetrahydroisoquinolines 13 and 14[a]
.
Entry Compound RCHO
R =
Oxazolidinones
Yield [%]
Time
[h]
Isoquinolines
Yield [%]
dr
1
2
3
4
5
6
7
8
9
Pr
C5H11
iPr
CH=CHCH3
CH2OBn
Ph
CO2Et
CH2OPMB
Pr
C5H11
iPr
CH=CHCH3
CH2OBn
Ph
11a
11b
11c
11d
11e
11f
11g
11h
12a
12b
12c
12d
12e
12f
12g
78
41
37
52
38
–
51:49
51:49
58:42
67:33
55:45
–
0.75
2.25
2.5
1.0
6.5
36
13a
13b
13c
13d
13e
13f
13g
13h
14a
14b
14c
14d
14e
14f
14g
56
80
80
9
9
9
19
[b]
9
–
9
4[c]
9
–
–
–
–
[d]
9
40
31
11
52
44
22
56:44
89:11
57:43
51:49
70:30
68:32
–
1.0
1.0
2.0
2.5
1.0
0.75
–
–
9
10
10
10
10
10
10
10
68
73
28
10
11
12
13
14
15
[e]
–
30
–
–
[f]
–
–
[g]
CO2Et
–
–
[a] Reaction conditions according to Scheme 2. [b] Starting material 11e was reisolated in 36% yield. [c] Under the reaction conditions
starting material 9 was directly converted into 13f (4%) and reisolated in 37%. [d] Oxazolidinone 16 was isolated in 50% (dr 52:48). [e]
Starting material 12d was reisolated in 68% yield. [f] Starting material 10 was reisolated in 37% yield. [g] Hemiaminal 15 was isolated in
51% yield (dr 71:29).
Eur. J. Org. Chem. 2007, 5590–5602
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Tussetschläger, A. Baro, S. Laschat, W. Frey
FULL PAPER
native paramethoxybenzyl (PMB) protecting group was to the corresponding amido sulfones.[18] In our case, how-
used; addition product 11h was obtained in 40% yield ever, sulfinic acid partially reduced the aldehydes to the cor-
(Table 1, Entry 8).
responding primary alcohols, RCH2OH, which were found
in all crude mixtures as byproducts.
The failure of ring closure in the case of crotyl-substi-
tuted oxazolidinone 12d might be explained by the influ-
ence of the methoxy group. Although the charge delocaliza-
tion through conjugation with R should be operative in
both acyliminium ions 17 and 19, presumably the +M effect
of the methoxy substituent in m-tyrosine derivative 17 in-
creases the nucleophilicity of the aromatic ring relative to
tyrosine derivative 19 where such mesomeric activation is
not possible (Scheme 3).
N-[1-(Phenylsulfonyl)alkyl]oxazolidinones 11 and 12
were then cyclized in the presence of TiCl4 in CH2Cl2 at
–78 °C[13] to afford target compounds 13 and 14
(Scheme 2). As can be seen from Table 1, the ring closure
of starting sulfones 11a–c and 12a–c proceeded uneventfully
(Table 1, Entries 1–3, 9–11). Crotyl-substituted compound
12d, however, did not react and was reisolated in 68% yield,
whereas analogous m-tyrosine-based derivative 11d gave the
product in 19% yield (Table 1, Entries 4, 12). In contrast,
from benzyloxymethyl-substituted oxazolidinones 11e and
12e, the reaction of tyrosine derivative 12e afforded tricyclic
compound 14e, whereas 13e was not formed (Table 1, En-
tries 5, 13). Under the cyclization conditions, the PMB pro-
tecting group in compound 11h was removed and sulfone
derivative 16 was isolated instead of desired tetrahydroiso-
quinoline 13h (Table 1, Entry 8).
Scheme 3.
It should be noted that in all cases tetrahydroisoquinol-
ines 13 and 14 were obtained as single diastereomers inde-
pendent of the diastereomeric ratio of intermediate adducts
11 and 12. The trans configuration was assigned according
to NOE experiments for tyrosine-based tetrahydroisoquino-
line 14e. This assignment was further supported by X-ray
crystal structure analysis of m-tyrosine derivative 13a (Fig-
ure 2).[17]
As shown in Scheme 4 for one example, alternative pro-
cedures were investigated for comparison. Following the
benzotriazole method by Katritzky[14a] (A), tricyclic prod-
ucts 13a and 14a could be isolated in 64 and 54% yield,
respectively.
In contrast, the direct Pictet–Spengler reaction (B) could
not be applied to starting materials 23a,b. Under the used
conditions, condensation products 24a,b were obtained in-
stead of the desired bicycles. Derivatives 24 might be
formed by an aldol-type condensation in analogy to a for-
mer publication by Ishii.[19] It should be noted that Tourwé
and Hruby reported the failure of tetrahydroisoquinoline
formation from tyrosine derivatives and formaldehyde by
the Pictet–Spengler reaction.[20] It thus seems that the
limitations of the Pictet–Spengler cyclization with regard
to aliphatic aldehydes can be overcome by the Petrini and
Katritzky methods.
m-Tyrosine-derived tetrahydroisoquinolines 13a,b were
debrominated under radical reduction conditions by using
Bu3SnH in the presence of catalytic amounts of AIBN in
refluxing benzene according to the method of Fuku-
yama[11,21] to afford the corresponding tricyclic products in
88 and 51% yield, respectively.
Next, the utilization of crotyl-substituted tetrahydroiso-
quinoline 13d as a possible precursor to the AB system of
the antitumor alkaloid quinocarcin[10,22,23] was investigated.
Thus, derivative 13d was ozonized in MeOH in the presence
of NaOH at –78 °C to derivative 13i, which was isolated in
69% yield (Scheme 5).
Figure 2. Molecular structure of 9-bromo-6-methoxy-5-propyl-
1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquinolin-3-one (13a) in
the solid state (ORTEP presentation).
The failure of initial adduct formation of benzaldehyde
Its trans configuration was confirmed by X-ray crystal
and glyoxal might be due to the oxazolidinone because Pe- structure analysis (Figure 3).[17] It should be noted that cor-
trini reported the successful conversion of both aldehydes responding ethyl ester 13g could not be obtained by the
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Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
epimerized to cis configured analogues cis-13i and cis-25 in
a trans:cis ratio of 85:15. The isomers of 13i could be sepa-
rated by preparative HPLC [tR(cis) = 6.59 min and tR(trans)
= 10.05 min] to afford trans- and cis-13i in 93 and 5% yield,
respectively.
Figure 3. Molecular structure of methyl 9-bromo-6-methoxy-3-
oxo-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquinoline-5-carbox-
ylate (13i) (ORTEP presentation).
Scheme 4. Cyclization by (A) benzotriazole and (B) the Pictet–
Spengler reaction. Reaction conditions: (a) 1. butyraldehyde
(1.6 equiv.), molecular sieves 4 Å, CH2Cl2, r.t., 24 h; 2. TFA
(3.2 equiv.), 0 °C, 16 h, 27% (24a), 32% (24b); (b) p-TsOH
(0.1 equiv.), nPrCHO (1 equiv.), Dean–Stark trap, 16 h, 18% (24a),
14% (24b).
Conclusions
It could be demonstrated that N-[1-(phenylsulfonyl)-
alkyl]oxazolidinones 11 and 12 are valuable intermediates
for the synthesis of tyrosine-derived tetrahydroisoquinolines
13 and 14. Butyraldehyde was used to compare Petrini’s
method with Katritzky’s benzotriazoles and the Pictet–
Spengler cyclization. Whereas the latter completely failed,
the methods by Petrini and Katritzky gave similar results.
Thus, the used Petrini method complements the Pictet–
Spengler reaction. In particular, m-tyrosine 4a can be con-
verted regioselectively via the N-[1-(phenylsulfonyl)alkyl]-
oxazolidinones to the corresponding tetrahydroisoquinol-
ines by employing bromine as a protecting group. This may
open synthetic access to tetrahydroisoquinoline alkaloids.
Experimental Section
General: Melting points were determined with a Büchi SMP 20 and
are uncorrected. NMR spectra were recorded with a Bruker Avance
300 or a Bruker Avance 500 (1H: 300 or 500 MHz, 13C: 75 or
125 MHz) with TMS as an internal standard. Signal assignments
were made on the basis of DEPT experiments. IR spectra were
recorded with a Bruker Vector 22 FTIR. Mass spectrometry was
performed with a Finnigan MAT 95, Varian MAT 711, or Bruker
Daltonics micrOTOF_Q. Chromatography was performed on silica
gel 60 (230–400 mesh) (Macherey–Nagel). GC was performed with
a Hewlett–Packard HP 6890, column HP 5TA (30 mϫ0.32 mm),
temperature program 16 °Cmin–1, gradient from 80 to 300 °C.
Scheme 5.
sulfinic acid route (Table 1). Radical-induced debromina-
tion of trans-13i gave derivative trans-25 in 69% yield. Epi-
merization with NaOMe in MeOH heated at reflux led to
complete decomposition of trans-25. In contrast, bromo de-
rivative trans-13i epimerized partially under these condi-
tions to yield a trans:cis mixture of 13i in a 90:10 ratio. By
using DBU in boiling toluene, however, both 13i and 25 Commercial reagents were used without further purification. Bu-
Eur. J. Org. Chem. 2007, 5590–5602
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S. Tussetschläger, A. Baro, S. Laschat, W. Frey
FULL PAPER
tyraldehyde, isobutyraldehyde, crotonaldehyde, and hexanal, as well
as all solvents, were distilled prior to use. Reactions were performed
in oven-dried glassware under a N2 atmosphere. The following
compounds were prepared according to literature procedures: N-
Boc protected tyrosines,[15a] 5a,b,[16a] 8,[16a] [(4-methoxybenzyl)oxy]-
acetaldehyde,[24] and benzenesulfinic acid.[25]
C15H22BrNO4 (360.24): calcd. C 50.01, H 6.16, N 3.89; found C
50.09, H 6.23, N 3.86.
General Procedure for the Cyclization to Oxazolidinones 9 and 10:
To an ice-cold solution of either 7 or 8 in absolute THF in a
Schlenk flask under inert gas was added dropwise thionyl chloride
(8 equiv.), and the reaction mixture was stirred at 0 °C for a further
3 h. After warming to room temperature, all volatile materials were
removed and crude product 9 or 10 was chromatographed on SiO2
(CH2Cl2/EtOAc, 3:1).
Methyl 2-Bromo-N-(tert-butoxycarbonyl)-5-methoxyphenylalaninate
(6): N-Bromosuccinimide (790 g, 4.44 mmol) was added portion-
wise to a solution of 5a (1.25 g, 4.04 mmol) in absolute DMF
(40 mL), and the reaction mixture was stirred at room temperature
for 6 h. The solvent was removed, and the residue was chromato-
graphed on SiO2 (hexanes/EtOAc, 6:1) to give 6 as a colorless solid
(1.36 g, 86%). M.p. 106–108 °C. Rf = 0.23 (hexanes/EtOAc, 6:1).
1H NMR (300 MHz, CDCl3): δ = 1.39 [s, 9 H, C(CH3)3], 3.05 (dd,
J = 8.3, 13.8 Hz, 1 H, 3-HA), 3.27 (dd, J = 5.7, 13.8 Hz, 1 H, 3-
HB), 3.72 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.60–4.67 (m, 1 H,
2-H), 5.07 (d, J = 8.3 Hz, 1 H, NH), 6.68 (dd, J = 2.9, 8.7 Hz, 1
H, 4Ј-H), 6.75 (d, J = 2.9 Hz, 1 H, 2Ј-H), 7.42 (d, J = 8.7 Hz, 1 H,
5Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.3 [C(CH3)3], 38.8
(C-3), 52.4 (OCH3), 53.5 (C-2), 55.4 (OCH3), 79.9 [C(CH3)3], 114.5
(C-2Ј, C-4Ј), 115.4 (C-6Ј), 116.7 (C-2Ј, C-4Ј), 133.4 (C-5Ј), 136.9
(C-1Ј), 155.0, 158.9 (C-3Ј, CO2tBu), 172.4 (CO2CH3) ppm. FTIR
4-(2-Bromo-5-methoxybenzyl)-1,3-oxazolidin-2-one (9): From
7
(1.84 g, 5.12 mmol) in THF (100 mL) was obtained 9 as a colorless
solid (1.21 g, 83%). M.p. 87–88 °C. Rf = 0.31 (CH2Cl2/EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): δ = 2.94 (dd, J = 7.4, 13.5 Hz, 1 H,
3-HA), 3.02 (dd, J = 5.6, 13.5 Hz, 1 H, 3-HB), 3.79 (s, 3 H, OCH3),
4.16–4.27 (m, 2 H, 1-H, 2-H), 4.43–4.52 (m, 1 H, 1-H), 5.73 (br. s,
1 H, NH), 6.71 (dd, J = 3.0, 8.7 Hz, 1 H, 4Ј-H), 6.77 (d, J = 3.0 Hz,
1 H, 2Ј-H), 7.45 (d, J = 8.7 Hz, 1 H, 5Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 41.6 (C-3), 52.0 (C-2), 55.5 (OCH3), 69.5
(C-1), 114.4 (C-4Ј), 114.7 (C-6Ј), 117.2 (C-2Ј), 133.9 (C-5Ј), 136.4
(C-1Ј), 159.2, 159.3 (C-5Ј, C=O) ppm. FTIR (ATR): ν = 1766 (vs),
˜
1592 (m), 1579 (m), 1480 (m), 1470 (m), 1436 (m), 1404 (m), 1310
(m), 1239 (s), 1221 (s), 1177 (s), 1120 (m), 1114 (m), 1075 (m), 1007
(s), 948 (m), 937 (s), 889 (m), 822 (m), 812 (s), 762 (m), 705 (s), 657
(br., m) cm–1. MS (EI, 70 eV): m/z (%) = 287, 285 (22) [M]+, 207
(12), 206 (100) [M – Br]+, 202 (97) [H3COC6H4BrCH2 + H]+, 200
(98) [MeOC6H4BrCH2 + H]+, 160, 158 (4), 171, 169 (3), 162 (13),
147 (1), 132 (1), 121 (29), 105 (3), 91 (9), 86 (86) [M – Me-
OC6H4BrCH2]+, 77 (9), 63 (3), 58 (5), 42 (20), 28 (2). C11H12BrNO3
(286.12): calcd. C 46.18, H 4.23, N 4.90; found C 46.25, H 4.26, N
4.82.
(ATR): ν = 1739 (s), 1689 (s), 1521 (s), 1480 (m), 1463 (m), 1440
˜
(m), 1276 (br., m), 1240 (s), 1218 (s), 1157 (vs), 1041 (m), 1013 (m),
994 (m), 847 (m), 825 (m), 599 (br., m) cm–1. MS (EI, 70 eV): m/z
(%) = 389 (7) [M]+, 387 (7) [M]+, 333 (13), 331 (13), 316 (10) [M –
OC(CH3)3]+, 314 (10) [M – OC(CH3)3]+, 288 (2) [M – CO2C-
(CH3)3]+, 286 (2) [M – CO2C(CH3)3]+, 272 (35), 270 (29), 252 (43),
230 (11), 228 (11), 208 (22), 200 (10), 191 (30), 175 (2), 148 (9), 132
(3), 121 (6), 91 (3), 88 (20), 77 (2), 57 (100) [C(CH3)3]+, 41 (7).
C16H22BrNO5 (388.25): calcd. C 49.50, H 5.71, N 3.61, Br 20.58;
found C 49.71, H 5.79, N 3.61, Br 20.62.
(4S)-4-(4-Methoxybenzyl)-1,3-oxazolidin-2-one (10): From
8
(959 mg, 3.41 mmol) in THF (60 mL) was obtained 10 as colorless
crystals (632 mg, 89%). M.p. 75 °C. Rf = 0.20 (CH2Cl2/EtOAc,
3:1). [α]2D2 = –55.9 (c = 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ = 2.80 (dd, J = 6.6, 13.8 Hz, 1 H, 3-HA), 2.83 (dd, J = 7.2,
13.8 Hz, 1 H, 3-HB), 3.79 (s, 3 H, OCH3), 4.02–4.07 (m, 1 H, 2-
H), 4.13 (dd, J = 5.5, 8.7 Hz, 1 H, 1-HA), 4.43 (dd, J = 8.0, 8.7 Hz,
1 H, 1-HB), 5.72 (br. s, 1 H, NH), 6.85–6.88 (m, 2 H, 3Ј-H, 5Ј-H),
7.09–7.10 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 40.5 (C-3), 53.9 (C-2), 55.3 (OCH3), 69.6 (C-1), 114.4 (C-3Ј, C-
5Ј), 127.9 (C-1Ј), 130.0 (C-2Ј,C-6Ј), 158.8, 159.4 (C-4Ј, C=O) ppm.
tert-Butyl 1-(2-Bromo-5-methoxybenzyl)-2-hydroxyethylcarbamate
(7): To a solution of 6 (2.10 g, 5.41 mol) in absolute Et2O (100 mL)
in a Schlenk flask under inert gas at 0 °C was added lithiumborohy-
dride (470 mg, 21.6 mmol) and absolute MeOH (10 mL), and the
reaction mixture was stirred at 0 °C for a further 30 min. After
warming to room temperature, the reaction mixture was heated at
reflux for 16 h. Then a saturated solution of NH4Cl (50 mL) was
added, and the reaction mixture was stirred for 15 min. The layers
were separated, and the aqueous layer was extracted with EtOAc
(3ϫ20 mL). The combined organic layers were washed with brine
(3ϫ100 mL), dried (Na2SO4), and concentrated. The residue was
chromatographed on SiO2 (hexanes/EtOAc, 2:1) to give 7 as a col-
orless solid (1.84 mg, 95%). M.p. 109–110 °C. Rf = 0.24 (hexanes/
EtOAc, 2:1) 1H NMR (500 MHz, CDCl3): δ = 1.40 [s, 9 H,
C(CH3)3], 2.17 (br. s, 1 H, OH), 2.74–2.96 (m, 1 H, 3-HA), 2.99
(dd, J = 6.8, 13.7 Hz, 1 H, 3-HB), 3.61 (dd, J = 4.6, 11.2 Hz, 1 H,
1-HA), 3.70 (dd, J = 3.6, 11.2 Hz, 1 H, 1-HB), 3.77 (s, 3 H, OCH3),
3.87–3.94 (m, 1 H, 2-H), 4.91 (d, J = 7.8 Hz, 1 H, NH), 6.67 (dd,
J = 3.0, 8.8 Hz, 1 H, 4Ј-H), 6.75 (br. s, 1 H, 2Ј-H), 7.42 (d, J =
8.8 Hz, 1 H, 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 28.3
[C(CH3)3], 37.5 (C-3), 53.1 (C-2), 55.5 (OCH3), 64.5 (C-1), 79.7
[C(CH3)3], 114.1 (C-2Ј), 115.3 (C-6Ј), 116.7 (C-4Ј), 133.3 (C-5Ј),
FTIR (ATR): ν = 1740 (vs), 1512 (s), 1243 (s), 1178 (m), 1026 (m)
˜
cm–1. MS (EI, 70 eV): m/z (%) = 208 (1) [M + H]+, 207 (10) [M]+,
123 (2), 122 (26), 121 (100) [CH2C6H5OMe]+, 107 (2), 91 (3), 78
(4), 65 (3), 51 (1), 42 (4), 32 (3), 28 (30), 18 (24). C11H13NO3
(207.23): calcd. C 63.76, H 6.32, N 6.76; found C 63.73, H 6.34, N
6.66.
General Procedure for the Preparation of Sulfones 11 and 12: To a
solution of either 9 or 10 (100–150 mg, 1 equiv.) in CH2Cl2 (5–
7 mL) in a Schlenk flask under inert gas were successively added
benzenesulfinic acid (2 equiv.), the respective aldehyde (1.5 equiv.),
and MgSO4 (100–150 mg), and the reaction mixture was stirred for
36 h at room temperature. Then, the mixture was filtered through
a sintered-glass frit (bottom layer: 1 cm sand, top layer: 1 cm Flori-
sil) with CH2Cl2. The filtrate was concentrated and crude sulfone
10 or 11 was chromatographed on SiO2.
138.6 (C-1Ј), 156.0, 159.0 (C-3Ј, C=O) ppm. FTIR (ATR): ν = 1687
˜
(vs), 1670 (m), 1573 (m), 1520 (s), 1475 (m), 1445 (m), 1418 (m),
1391 (m), 1366 (m), 1356 (m), 1318 (m), 1303 (m), 1280 (m), 1241
(s), 1166 (s), 1145 (m), 1091 (m), 1065 (m), 1015 (m), 1004 (s), 822 4-(2-Bromo-5-methoxybenzyl)-3-[1-(phenylsulfonyl)butyl]-1,3-oxazol-
(m), 807 (m) cm–1. MS (EI, 70 eV): m/z (%) = 361, 359 (1) [M]+, idin-2-one (11a): Yield: 132 mg (78%), colorless foam. Rf = 0.13
330, 328 (1), 305, 303 (1), 274, 272 (4), 230, 228 (10), 224 (12), 203,
(hexanes/EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ = 0.94–1.04
201 (7), 202, 200 (7) [M + H – HOCH2CHNHC(O)OC(CH3)3]+, (m, 3 H, 4ЈЈ-H), 1.30–1.57 (m, 2 H, 3ЈЈ-H), 2.06–2.18 (m, 0.5 H,
180 (6), 161 (2), 160 (26) [HOCH2CHNHC(O)OC(CH3)3]+, 121 (4), 2ЈЈ-H), 2.22–2.35 (m, 1 H, 2ЈЈ-H), 2.39–2.52 (m, 0.5 H, 2ЈЈ-H), 2.81
104 (34), 60 (78), 57 (100) [C(CH3)3]+, 42 (2), 41 (11), 28 (11). (dd, J = 11.2, 13.1 Hz, 0.5 H, 3-HA), 2.85 (dd, J = 11.2, 13.4 Hz,
5594
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
0.5 H, 3-HA), 3.31 (dd, J = 3.6, 13.1 Hz, 0.5 H, 3-HB), 3.70 (br. d,
J = 13.4 Hz, 0.5 H, 3-HB), 3.80 (2 s, 3 H, OCH3), 3.90–3.95 (m,
0.5 H, 1-H), 4.08–4.18 (m, 1.5 H, 1-H), 4.24–4.33 (m, 0.5 H, 2-H),
J = 3.7, 13.0 Hz, 1 H, 3-HB), 3.64–3.72 (m, 1 H, 1-HA), 3.80 (s, 3
H, OCH3), 4.06 (dd, J = 3.4, 8.8 Hz, 1 H, 1-HB), 4.59 (br. s, 1 H,
2-H), 5.04 (br. d, J = 10.8 Hz, 1 H, CHSO2C6H5), 6.72 (dd, J =
4.64–4.76 (m, 0.5 H, 2-H), 4.93 (br. d, J = 9.2 Hz, 0.5 H, 1ЈЈ-H), 3.0, 8.8 Hz, 1 H, 4Ј-H), 6.78 (d, J = 3.0 Hz, 1 H, 2Ј-H), 7.60 (d, J
5.15 (t, J = 7.4 Hz, 0.5 H, 1ЈЈ-H), 6.73 (ddd, J = 1.8, 2.9, 8.7 Hz, = 8.8 Hz, 1 H, 5Ј-H), 7.55–7.58 (m, 2 H, m-SO2C6H5), 7.64–7.67
1 H, 4Ј-H), 6.78 (dd, J = 2.4, 2.9 Hz, 1 H, 2Ј-H), 7.47 (dd, J = 3.8, (m, 1 H, p-SO2C6H5), 7.94 (br. d, J = 7.3 Hz, 2 H, o-SO2C6H5)
8.7 Hz, 1 H, 5Ј-H), 7.55–7.63 (m, 2 H, m-C6H5), 7.66–7.73 (m, 1
H, p-C6H5), 7.92–7.96 (m, 1 H, o-C6H5), 7.99–8.03 (m, 1 H, o-
ppm. 13C NMR (125 MHz, CDCl3): δ = 20.4 [CH(CH3)2], 21.4
[CH(CH3)2], 28.5 (C-3), 53.8 (C-2), 55.6 (OCH3), 67.1 (C-1), 81.2
C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.45, 13.50 (C-4ЈЈ), (CHSO2C6H5), 114.6 (C-4Ј), 115.0 (C-6Ј), 117.5 (C-2Ј), 127.9 (o-
19.3, 19.7 (C-3ЈЈ), 26.8, 27.4 (C-2ЈЈ), 40.0, 40.3 (C-3), 53.4 (C-2),
SO2C6H5), 129.3 (m-SO2C6H5), 134.0 (C-5Ј), 134.1 (p-SO2C6H5),
55.6 (OCH3), 66.9, 67.0 (C-1), 74.6, 75.7 (C-1ЈЈ), 114.5, 114.6 (C- 135.2, 135.9 (C-1Ј, i-SO2C6H5), 159.2 (C=O, C-3Ј) ppm. FTIR
4Ј), 114.8, 115.1 (C-6Ј), 117.7, 117.8 (C-2Ј), 128.7 (o-C6H5), 129.28,
(ATR): ν = 1751 (vs), 1474 (m), 1407 (m), 1302 (m), 1241 (m),
˜
129.32, 129.5 (o-, m-C6H5), 134.0 (C-5Ј), 134.3, 134.5 (p-C6H5), 1142 (m), 1075 (m), 599 (m), 585 (m), 561 (m) cm–1. MS (FAB, 3-
135.8, 135.9, 136.9, 137.4 (C-1Ј, C-6Ј, i-C6H5), 157.1, 159.2 (C=O, nitrobenzyl alcohol + NaI): m/z (%) = 538 (1), 506 (100) [M +
C-3Ј) ppm. FTIR (ATR): ν = 1753 (vs), 1473 (m), 1446 (m), 1403
Na]+, 504 (96) [M + Na]+, 479 (5), 418 (1), 395 (1), 364 (79) [M +
˜
(m), 1305 (m), 1240 (m), 1199 (m), 1163 (m), 1143 (s), 1079 (m), Na – PhSO2H]+, 362 (80) [M + Na – PhSO2H]+, 342 (52) [M –
1044 (m), 1012 (m), 722 (m), 687 (m), 600 (m), 577 (m), 555 (m), PhSO2]+, 340 (52) [M – PhSO2]+, 329 (13), 296 (2), 284 (5), 245 (2),
540 (m), 522 (m) cm–1. MS (FAB, 3-nitrobenzyl alcohol + NaI):
m/z (%) = 506 (48) [M + Na]+, 504 (46) [M + Na]+, 479 (2), 477
(2), 413 (2), 364 (27) [M + Na – PhSO2H]+, 362 (27) [M + Na –
PhSO2H]+, 342 (22) [M – SO2Ph]+, 340 (23) [M – SO2Ph]+, 329
(15), 327 (13), 284 (3), 218 (1), 199 (16) [H3COC6H3BrCH2]+, 176
(100) [3-NO2C6H5 + Na]+, 172 (21), 136 (9), 95 (7), 92 (11), 69
(11), 55 (15). HRMS (FAB): calcd. for C21H24BrNNaO5S+ [M +
Na]+ 504.0451; found 504.0452.
218 (4), 201 (5), 187 (18), 154 (11), 107 (6), 79 (4), 55 (4), 28 (2).
HRMS (FAB): calcd. for C21H24BrNNaO5S+ [M + Na]+ 504.0451;
found 504.0438.
4-(2-Bromo-5-methoxybenzyl)-3-[(2E)-1-(phenylsulfonyl)but-2-enyl]-
1,3-oxazolidin-2-one (11d): Yield: 88 mg (52%), colorless foam. Rf
= 0.13 (hexanes/EtOAc, 5:2). 1H NMR (300 MHz, CDCl3): δ =
1.43 (d, J = 6.9 Hz, 1.98 H, 4ЈЈ-H), 1.51 (d, J = 6.9 Hz, 1.02 H,
4ЈЈ-H), 2.61 (dd, J = 9.6, 13.7 Hz, 0.33 H, 3-H), 2.67 (dd, J = 9.6,
4-(2-Bromo-5-methoxybenzyl)-3-[1-(phenylsulfonyl)hexyl]-1,3- 13.7 Hz, 0.67 H, 3-H), 3.38–3.46 (m, 1 H, 3-H), 3.68–3.77 (m, 1 H,
oxazolidin-2-one (11b): Yield: 74 mg (41%), colorless foam. Rf =
0.25 (hexanes/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 0.82–
0.96 (m, 3 H, 6ЈЈ-H), 1.21–1.61 (m, 6 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 2.09–
3ЈЈ-H), 3.79, 3.80 (2 s, 3 H, OCH3), 4.11–4.27 (m, 2 H, 1-H), 4.26–
4.46 (m, 1 H, 2-H), 5.23 (dd, J = 8.3, 14.6 Hz, 0.66 H, 2ЈЈ-H), 5.24
(dd, J = 8.7, 14.6 Hz, 0.34 H, 2ЈЈ-H), 6.57 (d, J = 14.6 Hz, 0.33 H,
2.23 (m, 0.56 H, 2ЈЈ-H), 2.24–2.35 (m, 1.01 H, 2ЈЈ-H), 2.35–2.52 1ЈЈ-H), 6.60 (d, J = 14.6 Hz, 0.67 H, 1ЈЈ-H), 6.70–6.76 (m, 2 H, 3Ј-
(m, 0.53 H, 2ЈЈ-H), 2.81 (dd, J = 7.8, 13.1 Hz, 0.5 H, 3-H), 2.85 H, 4Ј-H), 7.43–7.49 (m, 1 H, 5Ј-H), 7.51–7.55 (m, 2 H, m-
(dd, J = 7.6, 13.1 Hz, 0.5 H, 3-H), 3.31 (dd, J = 3.5, 13.1 Hz, 0.52
SO2C6H5), 7.56–7.69 (m, 1 H, p-SO2C6H5), 7.85–7.91 (m, 2 H, o-
H, 3-H), 3.70–3.76 (m, 0.53 H, 3-H), 3.80 (2 s, 1.5 H, OCH3), 3.88– SO2C6H5) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.0, 14.2 (C-
3.98 (m, 0.56 H, 1-H), 4.05–4.23 (m, 1.69 H, 1-H), 4.22–4.35 (m,
0.56 H, 2-H), 4.63–4.77 (m, 0.52 H, 2-H), 4.92 (br. d, J = 9.8 Hz,
0.49 H, 1ЈЈ-H), 5.09–5.19 (m, 0.48 H, 1ЈЈ-H), 6.73 (dd, J = 2.9,
8.8 Hz, 1 H, 4Ј-H), 6.78 (dd, J = 1.8, 2.9 Hz, 1 H, 2Ј-H), 7.45 (dd,
J = 4.2, 8.8 Hz, 1 H, 5Ј-H), 7.55–7.63 (m, 2 H, m-SO2C6H5), 7.66–
4ЈЈ), 36.3, 36.8 (C-3), 53.1, 53.2 (C-2), 55.59, 55.63 (OCH3), 62.2,
62.5 (C-3ЈЈ), 65.9, 66.2 (C-1), 103.5, 104.1 (C-2ЈЈ), 114.66, 114.73
(C-3Ј, C-4Ј), 114.8 (C-6Ј), 117.8, 118.0 (C-3Ј, C-4Ј), 128.2, 128.4
(C-1ЈЈ), 129.0, 129.05, 129.11, 129.2 (o-, m-SO2C6H5), 133.9, 134.0
(C-5Ј, p-SO2C6H5), 135.4, 135.6, 136.9, 137.2 (C-1Ј, i-SO2C6H5),
7.73 (m, 1 H, p-SO2C6H5), 7.92–7.95 (m, 1 H, o-SO2C6H5), 7.99– 154.7, 159.2 (C=O, C-3Ј) ppm. FTIR (ATR): ν = 1753 (vs), 1663
˜
8.01 (m, 1 H, o-SO2C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = (m), 1475 (m), 1446 (m), 1408 (s), 1291 (m), 1224 (m), 1135 (s),
13.89, 13.90 (C-6ЈЈ), 22.3 (C-4ЈЈ, C-5ЈЈ), 24.8, 25.4 (C-2ЈЈ), 25.6, 1082 (s), 1012 (m), 951 (m), 757 (m), 728 (s), 690 (s), 666 (m), 599
26.6 (C-3ЈЈ), 31.09, 31.13 (C-4ЈЈ, C-5ЈЈ), 40.0, 40.3 (C-3), 53.13, (m), 586 (m), 570 (m), 547 (m) cm–1. MS (ESI): m/z (%) = 983 (6)
53.20 (C-2), 55.9 (OCH3), 66.8, 67.0 (C-1), 74.9, 75.9 (C-1ЈЈ), [2 M + Na]+, 520 (21) [M + K]+, 518 (18) [M + K]+, 504 (100) [M
114.49, 114.54 (C-4Ј), 114.8, 115.1 (C-6Ј), 117.7, 117.8 (C-2Ј), + Na]+ , 502 (95) [M + Na]+ . HRMS (ESI): calcd. for
128.7, 129.27 (o-SO2C6H5), 129.31, 129.4 (m-SO2C6H5), 134.0 (C-
5Ј), 134.3, 134.5 (p-SO2C6H5), 135.8, 135.9, 136.9, 137.4 (C-1Ј, i-
C21H22BrNNaO5S+ [M + Na]+ 502.0300; found 502.0303.
3-[2-(Benzyloxy)-1-(phenylsulfonyl)ethyl]-4-(2-bromo-5-methoxyben-
SO C H ), 158.1, 159.2 (C-3Ј) ppm. FTIR (ATR): ν = 1755 (vs),
˜
2
6
5
zyl)-1,3-oxazolidin-2-one (11e): Yield: 75 mg (38%), colorless foam.
1471 (m), 1446 (m), 1403 (m), 1304 (m), 1241 (m), 1217 (m), 1144
(s), 1081 (m), 1044 (m), 1013 (m), 724 (m), 688 (m), 620 (m), 601
(m), 579 (m) cm–1. MS (FAB, 3-nitrobenzyl alcohol + NaI): m/z
(%) = 684 (5), 682 (5), 649 (3), 545 (2), 534 (100) [M + Na]+, 532
(94) [M + Na]+, 499 (9), 476 (9), 474 (8), 413 (2), 392 (82) [M +
Na – PhSO2H]+, 390 (81) [M + Na – PhSO2H]+, 370 (32) [M –
PhSO2]+, 368 (37) [M – PhSO2]+, 349 (7), 323 (19), 259 (1), 214 (5),
205 (10), 187 (27), 176 (12), 133 (10), 119 (14), 109 (11), 105 (14).
HRMS (FAB): calcd. for C23H28BrNNaO5S+ [M + Na]+ 532.0764;
found 532.0768.
1
Rf = 0.10 (hexanes/EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ =
2.79 (dd, J = 10.7, 13.7 Hz, 0.5 H, 3-HA), 2.87 (dd, J = 10.7,
13.7 Hz, 0.5 H, 3-HA), 3.29 (dd, J = 3.7, 13.7 Hz, 0.5 H, 3-HB),
3.62 (dd, J = 3.7, 13.7 Hz, 0.5 H, 3-HB), 3.73, 3.74 (2 s, 3 H,
OCH3), 3.77–3.88 (m, 2 H, CHCH2OCH2C6H5), 4.06–4.39 (m, 3
H, 2-H, 1-H, CHCH2OCH2C6H5), 4.50–4.61 (m, 2 H, 1-H,
CHCH2OCH2C6H5), 5.14–5.18 (m, 0.5 H, CHCH2OCH2C6H5),
5.38–5.43 (m, 0.5 H, CHCH2OCH2C6H5), 6.70 (ddd, J = 1.0, 3.0,
8.8 Hz, 1 H, 4Ј-H), 6.75 (dd, J = 1.0, 3.0 Hz, 1 H, 2-H), 7.18–7.36
(m, 5 H, o-, m-, p-CH2C6H5), 7.44 (dd, J = 1.6, 8.8 Hz, 1 H, 5Ј-
4-(2-Bromo-5-methoxybenzyl)-3-[2-methyl-1-(phenylsulfonyl)- H), 7.52–7.60 (m, 2 H, m-SO2C6H5), 7.65–7.72 (m, 1 H, p-
propyl]-1,3-oxazolidin-2-one (11c): Yield: 62 mg (37 %), colorless
foam. Rf = 0.24 and 0.27 (hexanes/EtOAc, 3:1). Major dia-
stereomer: 1H NMR (500 MHz, CDCl3): δ = 1.19 [br. d, J = 6.5 Hz,
3 H, CH(CH3)2], 1.27 [d, J = 6.5 Hz, 3 H, CH(CH3)2], 2.73–2.84
[m, 1 H, CH(CH3)2], 2.89 (br. t, J = 13.0 Hz, 1 H, 3-HA), 3.39 (dd,
SO2C6H5), 7.89–7.98 (m, 2 H, o-SO2C6H5) ppm. 13C NMR
(75 MHz, CDCl3): δ = 34.3, 39.6 (C-3), 48.3 (C-2), 50.0
(CHCH2OCH2C6H5), 55.49, 55.50 (OCH3), 68.9 (C-1), 70.2
(CHCH2OCH2C6H5), 72.6 (CHCH2OCH2C6H5), 110.0 (C-2Ј),
116.0 (C-6Ј), 117.5, 117.7 (C-4Ј), 127.6, 127.8, 127.9, 128.0, 128.1
Eur. J. Org. Chem. 2007, 5590–5602
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5595

S. Tussetschläger, A. Baro, S. Laschat, W. Frey
(o-, m-, p-CH2C6H5), 128.5, 129.1 (o-SO2C6H5), 129.3, 129.4 (m- CDCl3): δ = 13.4 (C-4ЈЈ), 19.1 (C-3ЈЈ), 27.7 (C-2ЈЈ), 38.9 (C-3), 55.3
FULL PAPER
SO2C6H5), 131.8 (C-5Ј), 134.4 (p-SO2C6H5), 155.1, 156.3, 156.7,
159.1 (C-3Ј, C=O) ppm. FTIR (ATR): ν = 1746 (vs), 1460 (m),
(OCH3), 67.6 (C-1), 74.4 (C-1ЈЈ), 114.5 (C-3Ј, C-5Ј), 127.2 (C-1Ј),
128.6 (o-C6H5), 129.5 (m-C6H5), 130.2 (C-2Ј, C-6Ј), 134.6 (p-C6H5),
˜
1438 (m), 1409 (m), 1289 (m), 1241 (m), 1216 (m), 1145 (m), 1079 136.9 (i-C H ), 158.2, 158.9 (C=O, C-5Ј) ppm. FTIR (ATR): ν =
˜
6
5
(s), 1011 (m), 984 (m), 806 (m), 737 (s), 697 (s), 688 (s), 600 (m), 1749 (vs), 1512 (s), 1446 (m), 1403 (m), 1304 (m), 1289 (m), 1246
581 (s), 553 (m), 523 (m) cm–1. MS (ESI): m/z (%) = 600 (6) [M +
K]+, 598 (6) [M + K]+, 584 (86) [M + Na]+, 582 (100) [M + Na]+,
560 (4), 558 (4), 487 (2), 473 (3), 458 (4), 456 (4), 442 (89) [M + H
+ Na – SO2Ph]+, 440 (87) [M + H + Na – SO2Ph]+, 420 (2), 418
(2), 387 (3), 362 (7). HRMS (ESI): calcd. for C26H26BrNNaO6S+
[M + Na]+ 582.0556; found 582.0549.
(s), 1195 (m), 1178 (m), 1143 (s), 1079 (m), 1029 (m), 999 (m), 758
(m), 722 (m), 714 (m), 687 (m), 614 (m), 576 (s), 549 (m), 535 (m),
524 (m) cm–1. MS (CI, 70 eV): m/z (%) = 523 (9) [2 (M –
C6H5SO2) – H]+, 474 (1), 469 (13), 458 (3), 415 (6), 375 (4), 350
(4), 332 (13), 258 (2), 278 (7), 267 (25), 262 (80) [M – C6H5SO2]+,
251 (15), 218 (7), 208 (46), 178 (3), 159 (6), 147 (11), 143 (71), 125
(100), 121 (33) [CH2C6H5OCH3]+, 94 (7), 78 (21), 55 (16).
C21H25NO5S (403.49): calcd. C 62.51, H 6.25, N 3.47; found C
62.31, H 6.23, N 3.37.
4-(2-Bromo-5-methoxybenzyl)-3-[2-[(4-methoxybenzyl)oxy]-1-(phen-
ylsulfonyl)ethyl]-1,3-oxazolidin-2-one (11h): Yield: 79 mg (40%),
1
colorless solid. M.p. 37–40 °C. Rf = 0.33 (hexanes/EtOAc, 2:1). H
NMR (300 MHz, CDCl3): δ = 2.77 (dd, J = 10.6, 13.6 Hz, 1 H, 3- (4S)-4-(4-Methoxybenzyl)-3-[1-(phenylsulfonyl)hexyl]-1,3-oxazol-
H), 2.86 (dd, J = 10.9, 13.6 Hz, 1 H, 3-H), 3.24 (dd, J = 3.8, idin-2-one (12b): With hexanal. Yield: 147 mg (11 %). Colorless
13.6 Hz, 0.55 H, 3-H), 3.61 (dd, J = 3.6, 13.6 Hz, 0.48 H, 3-H), foam. Rf = 0.13 and 0.17 (hexanes/EtOAc, 7:2). 1H NMR
3.74, 3.77, 3.78, 3.79 (4 s, 6 H, OCH3), 4.08 (q, J = 8.1 Hz, 0.67 (500 MHz, CDCl3): δ = 0.85–0.88 (m, 3 H, 6ЈЈ-H), 1.26–1.61 (m, 6
H, 1-H), 4.11–4.17 (m, 1.9 H, 1-H, CHCH2OCH2C6H5OCH3), 4.19 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 2.09–2.23 (m, 1 H, 2ЈЈ-HA), 2.23–2.30 (m,
(dd, J = 5.3, 11.2 Hz, 0.62 H, CHCH2OCH2C6H5OCH3), 4.24– 1 H, 2ЈЈ-HB), 2.59 (dd, J = 11.4, 13.1 Hz, 0.56 H, 3-H), 2.68 (dd,
4.35 (m, 1.5 H, 2-H, CHCH2OBn), 4.41 (d, J = 11.4 Hz, 0.46 H,
J = 10.3, 13.5 Hz, 0.42 H, 3-H), 3.30 (dd, J = 3.7, 13.1 Hz, 0.55 H,
OCH2C6H5OCH3), 4.46 (d, J = 11.4 Hz, 0.47 H, OCH2C6H5- 3-H), 3.46–3.55 (m, 0.45 H, 3-H), 3.80 (2 s, 3 H, OCH3), 3.88 (dd,
OCH3), 4.47 (d, J = 11.4 Hz, 0.54 H, OCH2C6H5OCH3), 4.53 (d,
J = 11.4 Hz, 0.57 H, OCH2C6H5OCH3), 4.60–4.65 (m, 0.58 H, 2-
J = 8.1, 8.8 Hz, 0.56 H, 1-H), 3.99 (dd, J = 4.4, 8.8 Hz, 0.56 H, 1-
H), 4.06–4.16 (m, 1.32 H, 1-H, 2-H), 4.52–4.56 (m, 0.53 H, 2-H),
H), 5.15 (dd, J = 5.1, 8.7 Hz, 0.47 H, CHCH2OCH2C6H5OCH3), 4.84 (br. d, J = 6.6 Hz, 0.38 H, 1ЈЈ-H), 5.17 (br. d, J = 9.1 Hz, 0.51
5.38 (dd, J = 5.5, 7.5 Hz, 0.53 H, CHCH2OCH2C6H5OCH3), 6.70
(dd, J = 1.2, 3.1 Hz, 1 H, 4Ј-H), 6.71 (dd, J = 1.2, 3.1 Hz, 0.5 H,
H, 1ЈЈ-H), 6.86–6.88 (m, 1 H, 3Ј-H, 5Ј-H), 6.88–6.90 (m, 1 H, 3Ј-
H, 5Ј-H), 7.12–7.15 (m, 1 H, 2Ј-H, 6Ј-H), 7.14 (m, 1 H, 2Ј-H, 6Ј-
4Ј-H), 6.74 (dd, J = 3.0, 4.5 Hz, 1 H, 2Ј-H), 6.81–6.85 (m, 2 H, o- H), 7.57–7.61 (m, 2 H, m-SO2C6H5), 7.70–7.71 (m, 1 H, p-
C6H5OCH3), 7.14–7.20 (m, 2 H, m-C6H5OCH3), 7.44 (dd, J = 2.5,
8.8 Hz, 1 H, 5Ј-H), 7.52–7.60 (m, 2 H, m-SO2C6H5), 7.65–7.72 (m,
SO2C6H5), 7.93 (d, J = 7.3 Hz, 1 H, o-SO2C6H5), 7.97 (d, J =
7.3 Hz, 1 H, o-SO2C6H5) ppm. 13C NMR (125 MHz, CDCl3): δ =
1 H, p-SO2C6H5), 7.89–7.91 (m, 1 H, o-SO2C6H5), 7.96–7.98 (m, 1 13.88, 13.90 (C-6ЈЈ), 22.27, 22.30, 24.8, 25.4, 25.7, 25.9, 31.05, 31.10
H, o-SO2C6H5) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 39.5, 40.3 (C-2ЈЈ, C-3ЈЈ, C-4ЈЈ, C-5ЈЈ), 38.9, 39.0 (C-3), 55.29, 55.31 (C-2,
(C-3), 53.5 (C-2), 55.26, 55.28, 55.50, 55.54 (OCH3), 62.9, 63.7 OCH3), 55.9 (C-2), 67.57, 67.60 (C-1), 74.6, 75.9 (C-1ЈЈ), 114.5 (C-
(CHCH2OCH2C6H5OCH3), 67.16, 67.22 (C-1), 73.0, 73.1
3Ј, C-5Ј), 127.2 (C-1Ј), 128.6, 129.27 (o-SO2C6H5), 129.30, 129.5
(OCH2C6H5), 73.6, 74.6 (CHCH2OCH2C6H5OCH3), 113.9, 114.0 (m-SO2C6H5), 130.1, 130.2 (C-2Ј, C-6Ј), 134.3, 134.6 (p-SO2C6H5),
(o-C6H5OCH3), 114.4, 114.6 (C-4Ј), 114.8, 115.1 (C-6Ј), 117.5, 136.9, 137.1 (i-SO2C6H5), 158.2, 158.8, 158.9 (C-4Ј, C=O) ppm.
117.7 (C-2Ј), 128.3, 128.5 (C-1Ј, i-SO2C6H5, p-C6H5OCH3), 128.7, FTIR (ATR): ν = 1752 (vs), 1512 (m), 1404 (m), 1303 (m), 1247
˜
129.1 (o-SO2C6H5), 129.3, 129.4 (m-SO2C6H5), 129.6, 129.8 (m-
C6H5OCH3), 134.4, 134.5 (p-SO2C6H5), 135.9, 136.0 (C-1Ј, i-
SO2C6H5, p-C6H5OCH3), 137.6, 137.8 (C-1Ј, i-SO2C6H5, p-
C6H5OCH3), 159.12, 159.16, 159.55, 159.57, 157.5, 157.9 (C-3Ј, i-
(s), 1178 (m), 1144 (s), 1080 (m), 1030 (m), 751 (m), 722 (m), 715
(m), 688 (m), 578 (s), 550 (m) cm–1. MS (FAB, 3-nitrobenzyl
alcohol + NaI): m/z (%) = 885 (2) [2 M + Na]+, 604 (7), 454 (100)
[M + Na]+, 413 (2), 328 (2), 312 (1) [M + Na – PhSO2H]+, 290
C H OCH , C=O) ppm. FTIR (ATR): ν = 1754 (vs), 1513 (m), (56) [M – PhSO2 ]+ , 197 (2), 187 (13), 165 (5), 121 (14)
˜
6
5
3
1473 (m), 1446 (m), 1405 (m), 1304 (m), 1242 (s), 1210 (m), 1174 [H3 COC6 H5 CH2 ]+ , 55 (1 9) . H RM S ( FA B) : c al cd . for
(m), 1144 (s), 1080 (m), 1062 (m), 1031 (m), 1012 (m), 815 (m), 756 C23H29NNaO5S [M + Na]+ 454.1659; found 454.1670.
(m), 724 (m), 687 (m), 584 (s), 552 (m), 522 (m) cm–1. MS (FAB,
(4S)-4-(4-Methoxybenzyl)-3-[2-methyl-1-(phenylsulfonyl)propyl]-1,3-
3-nitrobenzyl alcohol + NaI): m/z (%) = 764 (2), 686 (1), 614 (96)
oxazolidin-2-one (12c): With isobutyraldehyde. Yield: 102 mg
[M + Na]+, 612 (89) [M + Na]+, 472 (11) [M + H + Na – SO2Ph]+,
(52%). Colorless foam. Rf = 0.22 (hexanes/EtOAc, 7:2). Major dia-
470 (11) [M + H + Na – SO2Ph]+, 352 (4), 329 (48), 307 (4), 245
1
stereomer: H NMR (300 MHz, CDCl3): δ = 1.18 [d, J = 6.5 Hz,
(2), 187 (3), 177 (5), 154 (38), 121 (100) [CH2C6H5OCH3]+, 83 (11),
3 H, CH(CH3)2], 1.28 [d, J = 6.5 Hz, 3 H, CH(CH3)2], 2.63 (dd, J
= 11.7, 13.0 Hz, 1 H, 3-HA), 2.66–2.76 [m, 1 H, CH(CH3)2], 3.36
(dd, J = 3.3, 13.0 Hz, 1 H, 3-HB), 3.53–3.75 (m, 1 H, 1-HA), 3.80
81 (9), 69 (16), 57 (16), 43 (7). HRMS (FAB): calcd. for
C27H28BrNNaO7S+ [M + Na]+ 612.0662; found 612.0661.
(4S)-4-(4-Methoxybenzyl)-3-[1-(phenylsulfonyl)butyl]-1,3-oxazol- (s, 3 H, OCH3), 3.94 (dd, J = 4.4, 8.8 Hz, 1 H, 1-HB), 4.33–4.49
idin-2-one (12a): With butyraldehyde. Yield: 90 mg (31%), colorless
solid. M.p. 94–96 °C. Rf = 0.27 and 0.22 (hexanes/EtOAc, 3:1).
[α]2D2 = +97.35 (c = 1.0, CH2Cl2). Major diastereomer: 1H NMR
(m, 1 H, 2-H), 5.05 (br. d, J = 10.4 Hz, 1 H, CHSO2C6H5), 6.85–
6.90 (m, 2 H, 3Ј-H, 5Ј-H), 7.10–7.15 (m, 2 H, 2Ј-H, 6Ј-H), 7.53–
7.59 (m, 2 H, m-SO2C6H5), 7.63–7.69 (m, 1 H, p-SO2C6H5), 7.94 (d,
(300 MHz, CDCl3): δ = 0.99 (t, J = 7.4 Hz, 2 H, 4ЈЈ-H), 1.43–1.66 J = 7.3 Hz, 2 H, o-SO2C6H5) ppm. 13C NMR (125 MHz, CDCl3): δ
(m, 2 H, 3ЈЈ-H), 2.08–2.30 (m, 1 H, 2ЈЈ-H), 2.60 (dd, J = 11.3,
13.1 Hz, 1 H, 3-HA), 3.30 (dd, J = 3.6, 13.1 Hz, 1 H, 3-HB), 3.81
(s, 3 H, OCH3), 3.88 (dd, J = 8.0, 8.8 Hz, 1 H, 1-HA), 3.99 (dd, J
= 4.3, 8.8 Hz, 1 H, 1-HB), 4.50–4.59 (m, 1 H, 2-H), 5.19 (dd, J =
4.3, 10.9 Hz, 1 H, 1ЈЈ-H), 6.85–6.91 (m, 2 H, 3Ј-H, 5Ј-H), 7.11–7.16
= 20.4, 21.2 [CH(CH3)2], 28.6 [CH(CH3)2], 39.0 (C-3), 55.3
(OCH3), 55.7 (C-2), 67.6 (C-1), 80.7 (CHSO2C6H5), 114.5 (C-3Ј,
C-5Ј), 127.2 (C-1Ј), 127.8 (o-SO2C6H5), 129.3 (m-SO2C6H5), 130.2
(C-2Ј, C-6Ј), 134.2 (p-SO2C6H5), 139.2 (i-SO2C6H5), 158.9 (C=O,
C-4Ј) ppm. FTIR (ATR): ν = 1748 (vs), 1512 (s), 1446 (m), 1301
˜
(m, 2 H, 2Ј-H, 6Ј-H), 7.56–7.61 (m, 2 H, m-C6H5), 7.67–7.72 (m, 1 (m), 1247 (s), 1178 (m), 1141 (s), 1073 (m), 1029 (m), 759 (m), 729
H, p-C6H5), 7.92–7.95 (m, 2 H, o-C6H5) ppm. 13C NMR (75 MHz, (m), 712 (m), 689 (m), 608 (m), 578 (s), 546 (m), 523 (m) cm–1. MS
5596
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
(FAB, 3-nitrobenzyl alcohol + NaI): m/z (%) = 487 (2), 449 (1),
Ethyl Hydroxy[4-(4-methoxybenzyl)-2-oxo-1,3-oxazolidin-3-yl]acet-
434 (2), 426 (100) [M + Na]+, 402 (1), 363 (4), 337 (1), 300 (1), 285
ate (15): Yield: 77 mg (51%). Colorless oil. Rf = 0.15 (hexanes/
(14), 284 (81) [M + Na – PhSO2H]+, 262 (82) [M – PhSO2]+, 230 EtOAc, 2:1). H NMR (500 MHz, CDCl3): δ = 1.35, 1.36 (t, J =
1
(1), 189 (1), 187 (18), 165 (1), 147 (7), 133 (7), 121 (18)
[H3COC6H5CH2]+, 92 (10), 72 (9), 63 (18), 51 (1), 27 (1). HRMS
(FAB): calcd. for C21H25NNaO5S [M + Na]+ 426.1346; found
426.1340.
7.1 Hz, 3 H, CH2CH3), 2.63 (dd, J = 9.5, 13.8 Hz, 0.29 H, 3-HA),
2.79 (dd, J = 8.7, 13.8 Hz, 0.75 H, 3-HA), 3.06 (dd, J = 4.2, 13.9 Hz,
0.27 H, 3-HB), 3.17 (dd, J = 4.7, 13.9 Hz, 0.75 H, 3-HB), 3.80 (s, 3
H, OCH3), 4.05 (dd, J = 6.1, 8.2 Hz, 1 H, 1-HA), 4.10–4.18 (m, 1
H, 2-H), 4.21 (dd, J = 8.2, 16.4 Hz, 1 H, 1-HB), 4.37 (q, J = 7.2 Hz,
2 H, CH2CH3), 5.31 (s, 0.7 H, 1ЈЈ-H), 5.41 (s, 0.23 H, 1ЈЈ-H), 6.83–
(4S)-4-(4-Methoxybenzyl)-3-[(2E)-1-(phenylsulfonyl)but-2-enyl]-1,3-
oxazolidin-2-one (12d): With crotonaldehyde. Yield: 86 mg (44%).
Colorless foam. Rf = 0.12 (hexanes/EtOAc, 2:1). 1H NMR
(500 MHz, CDCl3): δ = 1.48 (d, J = 7.0 Hz, 2.1 H, 4ЈЈ-H), 1.52 (d,
J = 7.0 Hz, 0.9 H, 4ЈЈ-H), 2.70–2.80 (m, 1 H, 3-HA), 3.00 (dd, J =
3.1, 14.1 Hz, 0.3 H, 3-HB), 3.05 (dd, J = 3.1, 14.1 Hz, 0.7 H, 3-
HB), 3.77–3.81 (m, 1 H, 3ЈЈ-H), 3.80 (s, 3 H, OCH3), 4.17–4.27 (m,
3 H, 1-H, 2-H), 5.00 (dd, J = 9.0, 14.7 Hz, 0.2 H, 1ЈЈ-H), 5.05 (dd,
J = 8.0, 14.7 Hz, 0.8 H, 1ЈЈ-H), 6.58 (dd, J = 0.8, 14.7 Hz, 0.3 H,
2ЈЈ-H), 6.60 (dd, J = 0.8, 14.7 Hz, 0.7 H, 2ЈЈ-H), 6.85 (d, J = 8.7 Hz,
0.3 H, 3Ј-H, 5Ј-H), 6.84–6.88 (m, 2 H, 3Ј-H, 5Ј-H), 6.98–7.01 (m,
0.6 H, 2Ј-H, 6Ј-H), 7.03–7.06 (m, 1.4 H, 2Ј-H, 6Ј-H), 7.52–7.56 (m,
2 H, m-SO2C6H5), 7.63–7.69 (m, 1 H, p-SO2C6H5), 7.86–7.89 (m,
2 H, o-SO2C6H5) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.9,
14.3 (C-4ЈЈ), 34.9, 35.3 (C-3), 54.6, 54.9 (C-2), 55.3 (OCH3), 62.1,
62.5 (C-3ЈЈ), 66.4, 66.7 (C-1), 102.7, 103.5 (C-1ЈЈ), 114.4, 114.5 (C-
2Ј, C-6Ј), 126.3, 126.5 (C-1Ј), 128.5, 128.6 (C-2ЈЈ), 128.9, 129.1,
129.2 (o-, m-SO2C6H5), 130.37, 130.42 (C-3Ј, C-5Ј), 133.89, 133.91
(p-SO2C6H5), 136.9, 137.2 (i-SO2C6H5), 154.8, 159.0 (C-4Ј, C=O)
6.88 (m, 2 H, 3Ј-H, 5Ј-H), 7.07–7.14 (m, 2 H, 2Ј-H, 6Ј-H) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 14.07, 14.13 (CH2CH3), 38.1, 38.8
(C-3), 55.2, 55.8 (C-2), 55.3 (OCH3), 63.16, 63.27 (CH2CH3), 67.60,
67.63 (C-1), 74.8, 74.9 (C-1ЈЈ), 114.38, 114.39 (C-3Ј, C-5Ј), 126.95,
127.05 (C-1Ј), 130.08, 130.16 (C-2Ј, C-6Ј), 157.4, 157.6 (COH),
158.8 (C-4Ј), 169.1, 170.3 (COO) ppm. FTIR (ATR): ν = 1734 (vs),
˜
1512 (s), 1418 (br., m), 1299 (m), 1243 (br., s), 1178 (s), 1113 (m),
1067 (br., m), 1023 (br., s) cm–1. MS (FAB, 3-nitrobenzyl alcohol):
m/z (%) = 332 (6) [M + Na]+, 310 (12) [M + H]+, 309 (14) [M]+,
292 (40) [M + OH]+, 259 (4), 236 (9), 218 (100) [M – H – CO2-
C2H5]+, 208 (5), 188 (5), 174 (7), 151 (6), 147 (14), 121 (21)
[CH2C6H5OCH3]+, 107 (7), 91 (9), 83 (8), 69 (10), 57 (12), 43 (13).
HRMS (FAB): calcd. for C15H19NO6 [M]+ 309.1212; found
309.1220.
4-(2-Bromo-5-methoxybenzyl)-3-[2-hydroxy-1-(phenylsulfonyl)ethyl]-
1,3-oxazolidin-2-one (16): Yield: 19 mg (50%). Colorless crystalline
solid. M.p. 124–125 °C. Rf = 0.12 and 0.17 (hexanes/EtOAc, 2:1).
Major diastereomer: 1H NMR (300 MHz, CDCl3): δ = 2.74 (t, J =
6.7 Hz, 1 H, OH), 2.92 (dd, J = 10.8, 13.4 Hz, 1 H, 3-HA), 3.41
(dd, J = 3.7, 13.4 Hz, 1 H, 3-HB), 3.79 (s, 3 H, OCH3), 4.10 (dd, J
= 7.7, 8.8 Hz, 1 H, 1-HA), 4.22 (dd, J = 2.7, 8.8 Hz, 1 H, 1-HB),
4.44 (dd, J = 5.6, 6.7 Hz, 1 H, CH2OH), 4.64–4.72 (m, 1 H, 2-H),
5.25 (t, J = 5.6 Hz, 1 H, CHCH2OH), 6.72 (dd, J = 3.0, 8.8 Hz, 1
H, 4Ј-H), 6.83 (d, J = 3.0 Hz, 1 H, 2Ј-H), 7.47 (d, J = 8.8 Hz, 1
H, 5Ј-H), 7.57–7.69 (m, 2 H, m-SO2C6H5), 7.71–7.74 (m, 1 H, p-
SO2C6H5), 7.93–7.99 (m, 2 H, o-SO2C6H5) ppm. 13C NMR
(75 MHz, CDCl3): δ = 39.6 (C-3), 54.4 (C-2), 55.6 (OCH3), 58.7
(CH2OH), 67.5 (C-1), 75.1 (CHCH2OH), 114.6 (C-4Ј), 115.2 (C-
6Ј), 117.5 (C-2Ј), 128.6 (o-SO2C6H5), 129.6 (m-SO2C6H5), 133.9 (C-
5Ј), 134.8 (p-SO2C6H5), 136.1, 137.4 (C-1Ј, i-SO2C6H5), 158.2,
ppm. FTIR (ATR): ν = 1750 (vs), 1661 (m), 1512 (m), 1410 (s),
˜
1301 (m), 1247 (s), 1179 (m), 1138 (s), 1115 (m), 1083 (m), 1068
(m), 1026 (m), 1000 (m), 952 (m), 818 (m), 754 (m), 728 (s), 690
(m), 666 (m), 587 (m), 547 (m) cm–1. MS (ESI): m/z (%) = 825 (4)
[2 M + Na]+, 440 (27) [M + K]+, 425 (27) [M + Na + H]+, 424
(100) [M + Na]+. HRMS (ESI): calcd. for C21H23NNaO5S+ [M +
Na]+ 424.1189; found 424.1188.
(4S)-3-[2-(Benzyloxy)-1-(phenylsulfonyl)ethyl]-4-(4-methoxybenzyl)-
1,3-oxazolidin-2-one (12e): With benzyloxyacetaldehyde. Yield:
1
78 mg (22%). Colorless foam. Rf = 0.17 (hexanes/EtOAc, 3:1). H
NMR (300 MHz, CDCl3): δ = 2.58 (dd, J = 10.5, 13.5 Hz, 0.7 H,
3-H), 2.69 (dd, J = 10.5, 14.0 Hz, 0.3 H, 3-H), 3.15 (dd, J = 3.8,
13.5 Hz, 0.7 H, 3-H), 3.41 (dd, J = 3.8, 14.0 Hz, 0.3 H, 3-H), 3.78
(s, 3 H, OCH3), 4.02–4.27 (m, 4.5 H, 2-H, 2ЈЈ-H, OCH2C6H5),
4.40–4.62 (m, 2.9 H, 1-H, 2-H), 5.14 (dd, J = 5.1, 8.9 Hz, 0.3 H,
1ЈЈ-H), 5.38 (dd, J = 5.4, 6.7 Hz, 0.6 H, 1ЈЈ-H), 6.78–6.83 (m, 2 H,
3Ј-H, 5Ј-H), 6.92–6.97 (m, 0.6 H, 2Ј-H, 6Ј-H), 7.00–7.05 (m, 1.4 H,
2Ј-H, 6Ј-H), 7.24–7.38 (m, 5 H, o-, m-, p-OCH2C6H5), 7.52–7.60
(m, 2 H, m-C6H5SO2), 7.64–7.72 (m, 2 H, p-C6H5SO2), 7.88–7.98
(m, 2 H, o-C6H5SO2) ppm. 13C NMR (75 MHz, CDCl3): δ = 38.6,
39.1 (C-3), 55.3 (OCH3), 55.4, 55.8 (C-2), 63.1, 64.8 (C-2ЈЈ), 67.7,
67.9 (OCH2C6H5), 73.4, 73.6 (C-1ЈЈ), 74.6 (C-1ЈЈ), 114.28, 114.34
(C-3Ј, C-5Ј), 127.2, 127.3 (C-1Ј), 128.1, 128.2 (o-, m-, p-
OCH2C6H5), 128.3 (o-OCH2C6H5), 128.5, 128.65, 128.68, 129.1 (o-
C6H5SO2), 129.3, 129.4 (m-C6H5SO2), 130.0, 130.3 (C-2Ј, C-6Ј),
134.4, 134.5 (p-C6H5SO2), 136.5, 136.7, 137.6, 137.7 (i-OCH2C6H5,
i-C6H5SO2), 157.6, 158.0, 158.7, 158.8 (C-4Ј, C=O) ppm. FTIR
159.2 (C-3Ј, C=O) ppm. FTIR (ATR): ν = 1717 (vs), 1470 (m),
˜
1415 (m), 1322 (m), 1308 (m), 1281 (m), 1252 (m), 1233 (m), 1218
(m), 1197 (m), 1183 (m), 1162 (m), 1145 (m), 1133 (m), 1116 (m),
1085 (m), 1069 (m), 1055 (m), 1000 (m), 806 (m), 774 (m), 766 (m),
727 (m), 686 (m), 609 (m), 598 (m), 576 (m) cm–1. MS (ESI): m/z
(%) = 963 (9) [2 M + Na]+, 510 (15) [M + K]+, 508 (13) [M + K]+,
494 (100) [M + Na]+, 492 (93) [M + Na]+, 352 (42), 350 (45).
HRMS (ESI): calcd. for C19H20BrNNaO6S+ [M + Na]+ 492.0087;
found 492.0088.
General Procedure for the Preparation of Tetrahydroisoquinolines 13
and 14: To a solution of either 11 or 12 (1 equiv.) in CH2Cl2 (3–
5 mL) in a Schlenk flask under inert gas at –78 °C was added TiCl4
(ca. 3.5 equiv.) by syringe, and the reaction mixture was stirred for
the given time (Table 1). After the addition of brine (10 mL), the
reaction mixture was warmed to room temperature. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ10 mL). The combined organic layer was dried (Na2SO4) and
concentrated. Crude product 13 or 14 was chromatographed on
SiO2 with hexanes/EtOAc.
(ATR): ν = 1752 (vs), 1512 (s), 1405 (m), 1304 (m), 1247 (s), 1214
˜
(m), 1178 (m), 1144 (s), 1114 (m), 1079 (m), 1029 (m), 736 (m), 698
(m), 687 (s) 578 (s) cm–1. MS (CI, 70 eV): m/z (%) = 697 (1) [2
(M – C6H5SO2) + C2H5]+, 679 (10) [2 (M – C6H5SO2) + H]+, 589
(6), 550 (1), 499 (5), 460 (6), 430 (10), 390 (1), 368 (4), 340 (100)
[M – C6H5SO2]+, 322 (3), 262 (3), 250 (48), 218 (31), 176 (5), 147 9-Bromo-6-methoxy-5-propyl-1,5,10,10a-tetrahydro[1,3]oxazolo-
(17), 121 (65) [H3COC6H5CH2]+, 91 (33) [C7H7]+, 77 (5), 65 (3). [3,4-b]isoquinolin-3-one (13a): Yield: 22 mg (56%). Colorless crys-
C26H27NO6S (481.56): calcd. C 64.85, H 5.65, N 2.91; found C
64.94, H 5.70, N 2.79.
talline solid. M.p. 137 °C. Rf = 0.33 (hexanes/EtOAc, 5:1). 1H
NMR (300 MHz, CDCl3 ): δ = 0.98 (t, J = 7.2 Hz, 3 H,
Eur. J. Org. Chem. 2007, 5590–5602
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5597

S. Tussetschläger, A. Baro, S. Laschat, W. Frey
FULL PAPER
CH2CH2CH3), 1.28–1.59 (m, 3 H, CH2CH2CH3), 1.92–1.93 (m, 1 9-Bromo-6-methoxy-5-[(1E)-prop-1-enyl]-1,5,10,10a-tetrahydro[1,3]-
H, CH2CH2CH3), 2.64 (dd, J = 10.4, 17.0 Hz, 1 H, 10-HA), 3.12 oxazolo[3,4-b]isoquinolin-3-one (13d): Yield: 5 mg (19%). Colorless
(dd, J = 5.5, 17.0 Hz, 1 H, 10-HB), 3.83 (s, 3 H, OCH3), 4.07–4.16
(m, 1 H, 10a-H), 4.19 (dd, J = 3.3, 8.6 Hz, 1 H, 1-H), 4.55 (dd, J EtOAc, 3:1). H NMR (300 MHz, CDCl3): δ = 1.66 (s, 1.5 H, 3Ј-
= 7.8, 8.6 Hz, 1 H, 1-H), 5.03 (dd, J = 2.5, 10.1 Hz, 1 H, 5-H), H), 1.68 (t, J = 1.5 Hz, 1.5 H, 3Ј-H), 2.64 (dd, J = 10.2, 16.9 Hz,
crystalline solid. M.p. 132–133 °C (Et2O). Rf = 0.20 (hexanes/
1
6.68 (d, J = 8.8 Hz, 1 H, 7-H), 7.42 (d, J = 8.8 Hz, 1 H, 8-H) 1 H, 10-HA), 3.14 (dd, J = 5.2, 16.9 Hz, 1 H, 10-HB), 3.81 (s, 3 H,
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6 (CH2CH2CH3), 19.7 OCH3), 4.05–4.18 (m, 2 H, 10a-H, 1-H), 4.61 (dd, J = 7.6, 8.3 Hz,
(CH2CH2CH3), 34.2 (C-10), 36.0 (CH2CH2CH3), 47.0 (C-10a), 1 H, 1-H), 5.34–5.46 (m, 1 H, 2Ј-H), 5.55–5.64 (m, 2 H, 5-H, 1Ј-
48.8 (C-5), 55.6 (OCH3), 68.7 (C-1), 110.1 (C-7), 115.8 (C-9), 128.5
(C-9a, C-5a), 131.2 (C-8), 131.6 (C-9a, C-5a), 155.0, 156.8 (C-6, C-
H), 6.68 (d, J = 8.8 Hz, 1 H, 7-H), 7.46 (d, J = 8.8 Hz, 1 H, 8-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6 (C-3Ј), 34.5 (C-10),
47.3 (C-10a), 49.5 (C-5), 55.7 (OCH3), 69.0 (C-1), 110.2 (C-7),
3) ppm. FTIR (ATR): ν = 1739 (vs), 1460 (m), 1425 (m), 1289 (m),
˜
1273 (m), 1255 (s), 1230 (m), 1079 (s), 1044 (m), 1014 (m), 993 (m), 115.8 (C-9), 126.1 (C-5a), 127.3 (C-2Ј), 127.8 (C-1Ј), 131.6 (C-8),
966 (m), 820 (m), 756 (m), 619 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 341 (4) [M]+, 339 (4) [M]+, 298 (99) [M – (CH2)2CH3]+, 296 (100)
[M – (CH2)2CH3]+, 281 (1), 254 (2), 252 (2), 239 (7), 237 (7), 225
132.2 (C-9a), 155.4, 156.4 (C-6, C-3) ppm. FTIR (ATR): ν = 1742
˜
(vs), 1459 (m), 1436 (m), 1412 (m), 1288 (m), 1258 (m), 1218 (m),
1081 (m), 1023 (m), 966 (m), 803 (m), 744 (m) cm–1. MS (EI,
(9), 217 (6), 196 (2), 173 (24), 158 (6), 146 (10), 130 (10), 103 (5), 70 eV): m/z (%) = 339 (47) [M]+, 337 (46) [M]+, 324 (7), 322 (6),
77 (3), 63 (1), 36 (2). C15H18BrNO3 (340.21): calcd. C 52.96, H 308 (30), 306 (30), 298 (45) [M – CH=CHCH3]+, 296 (100) [M –
5.33, N 4.12; found C 52.89, H 5.31, N 4.11.
CH=CHCH3]+, 294 (51), 264 (8), 239 (10), 237 (11), 225 (13), 207
(7), 183 (5), 173 (35), 158 (27), 146 (14), 130 (15), 128 (10), 89 (4),
+
9-Bromo-6-methoxy-5-pentyl-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (13b): Yield: 29 mg (80%). Colorless crys-
talline solid. M.p. 86–87 °C. Rf = 0.23 (hexanes/EtOAc, 6:1). 1H
NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3 H, 5Ј-H), 1.22–
1.55 (m, 7 H, 1Ј-H, 2Ј-H, 3Ј-H, 4Ј-H), 1.83–1.96 (m, 1 H, 1Ј-H),
2.64 (dd, J = 10.4, 17.0 Hz, 1 H, 10-HA), 3.11 (dd, J = 5.6, 17.0 Hz,
1 H, 10-HB), 3.82 (s, 3 H, OCH3), 4.06–4.16 (m, 1 H, 10a-H), 4.19
(dd, J = 3.2, 8.6 Hz, 1 H, 1-H), 4.58 (dd, J = 7.8, 8.6 Hz, 1 H, 1-
H), 4.99–5.02 (m, 1 H, 5-H), 6.66 (d, J = 8.8 Hz, 1 H, 7-H), 7.42
(d, J = 8.8 Hz, 1 H, 8-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.0 (C-5Ј), 22.5, 26.1, 31.2 (C-2Ј, C-3Ј, C-4Ј), 33.7 (C-1Ј), 34.2 (C-
10), 47.0 (C-10a), 49.1 (C-5), 55.6 (OCH3), 68.7 (C-1), 110.1 (C-7),
115.8 (C-9), 128.6 (C-9a, C-5a), 131.2 (C-8), 131.6 (C-9a, C-5a),
77 (7), 73 (2), 39 (3). HRMS (ESI): calcd. for C15H16BrNNaO3
[M + Na]+ 360.0206; found 360.0189.
9-Bromo-6-methoxy-5-phenyl-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (13f): Yield: 5 mg (4 %). Colorless solid.
M.p. 200–201 °C. Rf = 0.23 (hexanes/EtOAc, 5:1). 1H NMR
(500 MHz, CDCl3): δ = 2.73 (dd, J = 10.6, 17.0 Hz, 1 H, 10-HA),
3.23 (dd, J = 5.3, 17.0 Hz, 1 H, 10-HB), 3.60 (s, 3 H, OCH3), 3.91–
3.96 (m, 1 H, 10a-H), 4.14 (dd, J = 4.8, 8.7 Hz, 1 H, 1-H), 4.47
(dd, J = 8.0, 8.7 Hz, 1 H, 1-H), 6.21 (s, 1 H, 5-H), 6.68 (d, J =
8.8 Hz, 1 H, 7-H), 7.15–7.17 (m, 2 H, 3Ј-H), 7.25–7.30 (m, 3 H, 2Ј-
H, 4Ј-H), 7.54 (d, J = 8.8 Hz, 1 H, 8-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 34.7 (C-10), 46.9 (C-10a), 52.0 (C-5), 55.7 (OCH3),
68.9 (C-1), 110.4 (C-7), 115.8 (C-9), 125.4 (C-9a), 127.6 (C-3Ј),
127.7 (C-4Ј), 128.4 (C-2Ј), 132.1 (C-8), 133.0 (C-1Ј, C-5a), 140.6
155.0, 156.8 (C-6, C-3) ppm. FTIR (ATR): ν = 2958 (m), 2920 (m),
˜
1735 (vs), 1700 (m), 1291 (m), 1267 (m), 1246 (m), 1230 (m), 1200
(m), 1169 (m), 1134 (m), 1111 (m), 1082 (s), 1070 (s), 1052 (m),
1002 (m), 976 (m), 965 (m), 877 (m), 810 (m), 762 (m), 621 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 369 (3) [M]+, 367 (3) [M]+, 299
(1), 298 (99) [M – C5H11]+, 296 (100) [M – C5H11]+, 254 (1), 252
(1), 239 (3), 237 (3), 225 (5), 217 (2), 173 (12), 146 (4), 115 (2).
C17H22BrNO3 (368.27): calcd. C 55.44, H 6.02, N 3.80; found C
55.23, H 5.93, N 3.65.
(C-1Ј, C-5a), 155.6, 156.1 (C-6, C-3) ppm. FTIR (ATR): ν = 1733
˜
(vs), 1455 (m), 1411 (m), 1386 (m), 1287 (s), 1259 (s), 1223 (m),
1083 (m), 1068 (s), 1014 (m), 983 (m), 809 (m), 754 (m), 602 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 376 (18) [M + H]+, 375 (100)
[M]+, 374 (18) [M + H]+, 373 (100) [M]+, 358 (1), 330 (4), 328 (4),
314 (9), 298 (75) [M – C6H5]+, 296 (76) [M – C6H5]+, 252 (2), 239
(5), 237 (5), 226 (37), 224 (37), 209 (13), 194 (7), 178 (9), 173 (19),
146 (10), 130 (6), 104 (6), 77 (5), 51 (2), 39 (1). HRMS (ESI): calcd.
for C18H16BrNNaO3 [M + Na]+ 396.0206; found 396.0205.
+
9-Bromo-5-isopropyl-6-methoxy-1,5,10,10a-tetrahydro[1,3]oxazolo-
[3,4-b]isoquinolin-3-one (13c): Yield: 18 mg (80%). Colorless crys-
talline solid. M.p. 161 °C. Rf = 0.39 (hexanes/EtOAc, 3:1). 1H
Methyl 9-Bromo-6-methoxy-3-oxo-1,5,10,10a-tetrahydro[1,3]-
oxazolo[3,4-b]isoquinoline-5-carboxylate (13i): To a solution of 13d
NMR (300 MHz, CDCl3): δ = 0.82 [d, J = 7.1 Hz, 3 H, CH- (42 mg, 0.124 mmol) in CH2Cl2 (5 mL) at –78 °C was added a solu-
(CH3)2], 1.06 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 2.36 [sept.d, Jd
5.2, Jsept. = 6.9 Hz, 1 H, CH(CH3)2], 2.64 (dd, J = 9.6, 17.1 Hz, 1
H, 10-HA), 3.15 (dd, J = 6.2, 17.1 Hz, 1 H, 10-HB), 3.81 (s, 3 H,
=
tion of NaOH (2.5  in MeOH, 248 µL, 24.8 mg, 620 µmol
NaOH). Then, O3 was passed through the mixture for 10 min fol-
lowed by oxygen for 5 min. Et2O and H2O (4 mL each) were added,
OCH3), 4.12 (dd, J = 3.6, 8.6 Hz, 1 H, 1-H), 4.24–4.33 (m, 1 H, and the reaction mixture was warmed to room temperature. The
10a-H), 4.59 (dd, J = 7.9, 8.6 Hz, 1 H, 1-H), 4.98 (d, J = 5.2 Hz,
1 H, 5-H), 6.67 (d, J = 8.8 Hz, 1 H, 7-H), 7.44 (d, J = 8.8 Hz, 1
H, 8-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.1, 19.9
layers were separated, and the aqueous layer was extracted with
Et2O (3 ϫ 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated to give 13i as a colorless solid. Yield:
[CH(CH3)2], 32.0 [CH(CH3)2], 33.8 (C-10), 49.1 (C-10a), 53.8 (C- 34 mg (69 %). M.p. 157–158 °C (Et2O). 1H NMR (500 MHz,
5), 55.5 (OCH3), 68.8 (C-1), 110.1 (C-7), 115.8 (C-9), 127.3 (C-5a), CDCl3): δ = 2.64 (dd, J = 10.7, 16.6 Hz, 1 H, 10-HA), 3.19 (dd, J
131.3 (C-8), 132.3 (C-9a), 155.4, 157.7 (C-3, C-6) ppm. FTIR
(ATR): ν = 1734 (vs), 1458 (m), 1434 (m), 1421 (m), 1412 (m), 1384
= 4.7, 16.6 Hz, 1 H, 10-HB), 3.78 (s, 3 H, CO2CH3), 3.81 (s, 3 H,
OCH3), 4.17–4.21 (m, 1 H, 10a-H), 4.23 (dd, J = 3.7, 8.6 Hz, 1 H,
˜
(m), 1290 (m), 1252 (m), 1224 (m), 1069 (s), 1009 (m), 980 (m), 880 1-H), 4.60 (dd, J = 7.6, 8.6 Hz, 1 H, 1-H), 5.60 (s, 1 H, 5-H), 6.70
(m), 802 (m), 756 (m), 703 (m), 629 (m) cm–1. MS (EI, 70 eV): m/z
(%) = 341 (22) [M]+, 339 (21) [M]+, 298 (99) [M – CH(CH3)2]+,
(d, J = 8.8 Hz, 1 H, 7-H), 7.52 (d, J = 8.8 Hz, 1 H, 8-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 33.5 (C-10), 48.6 (C-10a), 52.2 (C-
296 (100) [M – CH(CH3)2]+, 254 (2), 239 (5), 237 (5), 224 (7), 173 5), 52.8 (CO2CH3), 55.9 (OCH3), 68.5 (C-1), 110.1 (C-7), 115.9 (C-
(19), 158 (3), 146 (7), 130 (5), 103 (2), 77 (1), 41 (1), 28 (3). 9), 121.6 (C-5a), 132.6 (C-8), 133.0 (C-9a), 155.7, 156.3 (C-3, C-6),
C15H18BrNO3 (340.21): calcd. C 52.96, H 5.33, N 4.12; found C
53.00, H 5.40, N 4.02.
170.2 (CO CH ) ppm. FTIR (ATR): ν = 1750 (vs), 1731 (vs), 1578
˜
2 3
(m), 1464 (m), 1436 (m), 1416 (m), 1287 (s), 1245 (s), 1217 (m),
5598
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
1201 (m), 1191 (m), 1080 (s), 1001 (m), 968 (m), 811 (m), 763 (m), 5-(Benzyloxy)methyl-7-methoxy-1,5,10,10a-tetrahydro[1,3]oxazolo-
753 (m), 615 (m) cm–1. MS (ESI): m/z (%) = 735 (7) [2 M + Na]+,
[3,4-b]isoquinolin-3-one (14e): Yield: 9 mg (30%). Colorless oil. Rf
= 0.21 (hexanes/EtOAc, 2:1). 1H NMR (500 MHz, CDCl3): δ =
2.79 (dd, J = 11.0, 15.3 Hz, 1 H, 10-HA), 2.87 (dd, J = 4.7, 15.3 Hz,
1 H, 10-HB), 3.75 (s, 3 H, OCH3), 3.80 (dd, J = 5.3, 10.2 Hz, 1 H,
C H C H 2 O C H 2 P h ) , 3 . 8 9 ( d d , J = 3 . 7 , 1 0 . 2 H z , 1 H ,
CHCH2OCH2Ph), 4.11 (dd, J = 4.1, 8.6 Hz, 1 H, 1-H), 4.16–4.22
(m, 1 H, 10a-H), 4.43 (d, J = 12.2 Hz, 1 H, OCH2Ph), 4.53 (dd, J
= 7.9, 8.6 Hz, 1 H, 1-H), 4.61 (d, J = 12.2 Hz, 1 H, OCH2Ph), 5.03
(t, J = 4.4 Hz, 1 H, 5-H), 6.71 (d, J = 2.6 Hz, 1 H, 6-H), 6.79 (dd,
J = 2.6, 8.4 Hz, 1 H, 8-H), 7.05 (d, J = 8.4 Hz, 1 H, 9-H), 7.19–
7.21 (m, 1 H, p-PhCH2O), 7.25–7.35 (m, 4 H, o-, m-PhCH2O) ppm.
13C NMR (125 MHz, CDCl3): δ = 33.4 (C-10), 49.7 (C-10a), 52.5
(C-5), 55.3 (OCH3), 68.5 (C-1), 72.98 (CH2OCH2Ph), 73.04
(PhCH2O), 111.6 (C-6), 113.6 (C-8), 124.5 (C-9a, C-5a, i-PhCH2O),
127.67 (o-, m-PhCH2O), 127.71 (p-PhCH2O), 128.4 (o-, m-
PhCH2O), 130.3 (C-9), 133.7, 137.9 (C-9a, C-5a, i-PhCH2O), 157.0,
396 (5), 394 (5), 380 (92) [M + Na]+, 378 (100) [M + Na]+, 272
+
(100) [M + H]+. HRMS (ESI): calcd. for C14H14BrNNaO5 [M +
Na]+ 377.9948; found 377.9950.
7-Methoxy-5-propyl-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquin-
olin-3-one (14a): Yield: 19 mg (68%). Colorless oil. Rf = 0.32 (hex-
anes/EtOAc, 2:1). 1H NMR (300 MHz, CDCl3): δ = 0.98 [t, J =
7.3 Hz, 3 H, (CH2)2CH3], 1.40–1.58 (m, 2 H, CH2CH2CH3), 1.67–
1.79 (m, 1 H, CH2CH2CH3), 1.82–1.93 (m, 1 H, CH2CH2CH3),
2.82–2.85 (m, 2 H, 10-H), 3.80 (s, 3 H, OCH3), 3.99–4.08 (m, 1 H,
10a-H), 4.14 (dd, J = 3.1, 8.6 Hz, 1 H, 1-H), 4.53 (dd, J = 7.8,
8.6 Hz, 1 H, 1-H), 4.87 (dd, J = 3.8, 9.7 Hz, 1 H, 5-H), 6.70 (d, J
= 2.6 Hz, 1 H, 6-H), 6.76 (dd, J = 2.6, 8.4 Hz, 1 H, 8-H), 7.02 (d,
J = 8.4 Hz, 1 H, 9-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9
[ ( CH2 )2 CH3 ] , 1 9. 4 ( C H2 CH2 CH3 ) , 3 3 . 2 ( C- 10 ), 39 . 4
(CH2CH2CH3), 48.6 (C-10a), 52.7 (C-5), 55.4 (OCH3), 68.3 (C-1),
111.9 (C-6), 113.1 (C-8), 123.4 (C-9a), 130.2 (C-9), 137.5 (C-5a),
158.4 (C-3, C-7) ppm. FTIR (ATR): ν = 1741 (s), 1424 (m), 1222
˜
(m), 1103 (m), 1068 (m), 1027 (m), 742 (m), 697 (m) cm–1. MS (EI,
70 eV): m/z (%) = 339 (11) [M]+, 233 (1), 219 (11), 218 (100) [M –
CH(CH3)2]+, 207 (2), 174 (8), 159 (2), 147 (7), 131 (5), 130 (2), 91
157.2, 158.4 (C-3, C-7) ppm. FTIR (ATR): ν = 1738 (vs), 1502 (m),
˜
1415 (m), 1271 (m), 1226 (m), 1203 (m), 1177 (m), 1068 (m), 1034
(m), 1003 (m), 991 (m), 961 (m), 887 (m), 763 (m) cm–1. MS (EI,
70 eV): m/z (%) = 261 (13) [M]+, 219 (13), 218 (100) [M – C3H7]+,
174 (14), 159 (5), 147 (16), 131 (9), 115 (3), 91 (3), 77 (2), 65 (1),
51 (1), 27 (1). C15H19NO3 (261.32): calcd. C 68.94, H 7.33, N 5.36;
found C 69.06, H 7.43, N 5.09.
+
(7), 32 (1), 28 (7). HRMS (ESI): calcd. for C20H21NNaO4 [M +
Na]+ 362.1363; found 362.1359.
General Procedure for the Debromination of 13: To a solution of 13
(1 equiv.) in benzene was added Bu3SnH (ca. 1.1 equiv.) and AIBN
(ca. 0.1 equiv.), and the reaction mixture was heated at reflux for
3.5–4.5 h. After cooling to room temperature, H2O (10 mL) was
added. The layers were separated, and the organic layer was washed
with brine (3ϫ10 mL) and dried (Na2SO4). The solvent was re-
moved, and the residue was chromatographed on SiO2 with hex-
anes/EtOAc.
7-Methoxy-5-pentyl-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquin-
olin-3-one (14b): Yield: 59 mg (73%). Colorless oil. Rf = 0.25 (hex-
anes/EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J =
7.0 Hz, 3 H, 5Ј-H), 1.26–1.52 (m, 6 H, 2Ј-H, 3Ј-H, 4Ј-H), 1.66–1.79
(m, 1 H, 1Ј-H), 1.84–1.96 (m, 1 H, 1Ј-H), 2.82–2.85 (m, 2 H, 10-
H), 3.79 (s, 3 H, OCH3), 3.98–4.07 (m, 1 H, 10a-H), 4.14 (dd, J =
3.0, 8.6 Hz, 1 H, 1-H), 4.54 (dd, J = 7.8, 8.6 Hz, 1 H, 1-H), 4.86
(dd, J = 3.7, 9.6 Hz, 1 H, 5-H), 6.70 (d, J = 2.6 Hz, 1 H, 6-H), 6.76
(dd, J = 2.6, 8.4 Hz, 1 H, 8-H), 7.01 (d, J = 8.4 Hz, 1 H, 9-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1 (C-5Ј), 22.6, 25.7, 31.6 (C-
2Ј, C-3Ј, C-4Ј), 33.2 (C-10), 37.2 (C-1Ј), 48.7 (C-10a), 53.0 (C-5),
55.4 (OCH3), 68.3 (C-1), 111.9 (C-6), 113.0 (C-8), 123.7 (C-9a),
130.2 (C-9), 137.5 (C-5a), 157.2, 158.4 (C-7, C-3) ppm. FTIR
6-Methoxy-5-propyl-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquin-
olin-3-one: From 13a (7.40 mg, 21.7 µmol) in benzene (1 mL).
Yield: 5 mg (88%). Colorless solid. M.p. 93–95 °C. Rf = 0.18 (hex-
anes/EtOAc, 3:1). 1H NMR (500 MHz, CDCl3): δ = 0.98 (t, J =
7.2 Hz, 3 H, 3Ј-H), 1.44–1.55 (m, 3 H, 1Ј-HA, 2Ј-H), 1.91–1.99 (m,
1 H, 1Ј-HB), 2.87 (dd, J = 10.3, 16.1 Hz, 1 H, 10-HA), 2.94 (dd, J
= 5.3, 16.1 Hz, 1 H, 10-HB), 3.83 (s, 3 H, OCH3), 4.10–4.15 (m, 2
H, 10a-H, 1-H), 4.52–4.56 (m, 1 H, 1-H), 5.03–5.05 (m, 1 H, 5-H),
6.70 (d, J = 7.7 Hz, 1 H, 9-H), 6.73 (d, J = 8.2 Hz, 1 H, 7-H), 7.15
(dd, J = 7.7, 8.2 Hz, 1 H, 8-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 13.7 (C-3Ј), 19.8 (C-2Ј), 33.3 (C-10), 36.3 (C-1Ј), 47.2 (C-10a),
49.1 (C-5), 55.3 (OCH3), 68.5 (C-1), 108.5 (C-7), 121.3 (C-9), 126.0
(C-5a), 127.5 (C-8), 132.3 (C-9a), 155.9, 157.0 (C-6, C-3) ppm.
(ATR): ν = 1740 (vs), 1502 (m), 1414 (m), 1269 (m), 1244 (m), 1222
˜
(s), 1176 (m), 1098 (m), 1067 (m), 1037 (m), 1007 (m), 970 (m), 760
(m) cm–1. MS (EI, 70 eV): m/z (%) = 289 (7) [M]+, 219 (13), 218
(100) [M – C5H11]+, 174 (9), 159 (2), 147 (6), 131 (3), 115 (1), 91
(1), 28 (1). HRMS (ESI): calcd. for C17H23NNaO3 [M + Na]+
+
312.1570; found 312.1568.
5-Isopropyl-7-methoxy-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]iso-
quinolin-3-one (14c): Yield: 9 mg (28%). Colorless oil. Rf = 0.11
FTIR (ATR): ν = 1726 (vs), 1471 (m), 1459 (m), 1441 (m), 1430
˜
(m), 1420 (m), 1269 (m), 1253 (m), 1237 (s), 1098 (m), 1086 (m),
1065 (m), 1005 (m), 968 (m), 780 (m), 759 (m) cm–1. MS (EI,
70 eV): m/z (%) = 261 (2) [M]+, 219 (13), 218 (100) [M – C3H7]+,
203 (1), 174 (3), 160 (1), 159 (7), 147 (7), 131 (3), 115 (2), 103 (1),
1
(hexanes/EtOAc, 6:1). H NMR (300 MHz, CDCl3): δ = 0.78 [d, J
= 6.9 Hz, 3 H, CH(CH3)2], 1.16 [d, J = 6.8 Hz, 3 H, CH(CH3)2],
2.36 [sept.d, Jd = 4.0, Jsept. = 6.8 Hz, 1 H, CH(CH3)2], 2.79–2.82
(m, 2 H, 10-H), 3.80 (s, 3 H, OCH3), 4.01–4.09 (m, 1 H, 10a-H),
4.12 (dd, J = 2.4, 8.6 Hz, 1 H, 1-H), 4.54 (dd, J = 7.6, 8.6 Hz, 1
H, 1-H), 4.79 (d, J = 4.0 Hz, 1 H, 5-H), 6.75–6.89 (m, 2 H, 6-H,
8-H), 7.01–7.04 (m, 1 H, 9-H) ppm. 13C NMR (75 MHz, CDCl3):
91 (1), 77 (1). HRMS (ESI): calcd. for C15H19NNaO3 [M + Na]+
+
284.1257; found 284.1251.
6-Methoxy-5-pentyl-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]isoquin-
δ = 17.6, 20.3 [CH(CH3)2], 32.9 (C-10), 35.0 [CH(CH3)2], 51.0 (C- olin-3-one: From 13b (21 mg, 57.0 µmol) in benzene (6 mL). Yield:
10a), 55.3 (OCH3), 58.0 (C-5), 67.9 (C-1), 111.9, 113.0 (C-6, C-8), 9 mg (51%). Colorless solid. M.p. 82–84 °C. Rf = 0.18 (hexanes/
124.3 (C-9a), 130.2 (C-9), 136.4 (C-5a), 158.3, 158.4 (C-7, C-3) EtOAc, 3:1). H NMR (300 MHz, CDCl3): δ = 0.83–0.95 (m, 3 H,
1
ppm. FTIR (ATR): ν = 1729 (vs), 1501 (m), 1407 (m), 1276 (m), 5Ј-H), 1.19–1.56 (m, 6 H, 2Ј-H, 3Ј-H, 4Ј-H), 1.61–1.75 (m, 1 H, 1Ј-
˜
1258 (m), 1245 (m), 1222 (m), 1176 (m), 1154 (m), 1065 (m), 1037 H), 1.92–2.05 (m, 1 H, 1Ј-H), 2.82–2.98 (m, 2 H, 10-H), 3.83 (s, 3
(m), 1008 (m), 763 (m), 594 (m) cm–1. MS (EI, 70 eV): m/z (%) = H, OCH3), 4.07–4.16 (m, 2 H, 3-H, 1-H), 4.51–4.57 (m, 1 H, 1-H),
262 (1) [M + H]+, 261 [M]+, 219 (12), 218 (100) [M – CH-
5.00–5.03 (m, 1 H, 5-H), 6.70 (d, J = 7.7 Hz, 1 H, 9-H), 6.73 (d, J
(CH3)2]+, 174 (12), 159 (3), 147 (10), 145 (7), 131 (5), 115 (1), 91 = 8.1 Hz, 1 H, 7-H), 7.15 (dd, J = 7.7, 8.1 Hz, 1 H, 8-H) ppm. 13C
+
(1), 77 (1), 28 (2). HRMS (ESI): calcd. for C15H19NNaO3 [M +
NMR (125 MHz, CDCl3): δ = 14.1 (C-5Ј), 22.5, 26.2, 31.4 (C-2Ј,
C-3Ј, C-4Ј), 33.3 (C-10), 34.0 (C-1Ј), 47.2 (C-10a), 49.4 (C-5), 55.3
Na]+ 284.1257; found 284.1263.
Eur. J. Org. Chem. 2007, 5590–5602
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5599

S. Tussetschläger, A. Baro, S. Laschat, W. Frey
(OCH3), 68.5 (C-1), 108.5 (C-7), 121.3 (C-9), 126.0 (C-5a), 127.5 H), 6.81 (d, J = 8.7 Hz, 0.72 H, 3Ј-H), 6.90 (d, J = 8.7 Hz, 1.28 H,
FULL PAPER
(C-8), 132.3 (C-9a), 155.9, 157.0 (C-3, C-6) ppm. FTIR (ATR): ν
2Ј-H), 7.04 (d, J = 8.7 Hz, 0.72 H, 2Ј-H), 7.39–7.44 (m, 1 H, 3ЈЈ-
H, 4ЈЈ-H), 7.52–7.57 (m, 1 H, 3ЈЈ-H, 4ЈЈ-H), 7.76 (d, J = 8.4 Hz,
0.72 H, 2ЈЈ-H, 5ЈЈ-H), 8.01 (d, J = 8.4 Hz, 1.28 H, 2ЈЈ-H, 5ЈЈ-H),
8.07 (d, J = 8.4 Hz, 1.28 H, 2ЈЈ-H, 5ЈЈ-H), 8.11 (d, J = 8.4 Hz, 0.72
˜
= 1734 (vs), 1469 (m), 1434 (m), 1422 (m), 1261 (m), 1238 (m),
1074 (m), 1010 (m), 778 (m), 753 (m), 731 (m), 708 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 289 (12) [M]+, 219 (14), 218 (100) [M –
C5H11]+, 203 (1), 174 (4), 159 (7), 147 (13), 131 (3), 115 (2), 91 (1). H, 2ЈЈ-H, 5ЈЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.4,
+
HRMS (ESI): calcd. for C17H23NNaO3 [M + Na]+ 312.1576; 13.5 (CHCH2CH2CH3), 19.1, 19.3 (CHCH2CH2CH3), 32.0, 35.0
found 312.1574.
(CHCH2CH2CH3), 37.7, 39.4 (C-3), 54.2 (C-2), 55.2 (OCH3), 66.5,
67.3 (CHCH2CH2CH3), 67.4, 67.5 (C-1), 110.2, 110.9 (C-2ЈЈ, C-
5ЈЈ), 114.27, 114.35 (C-3Ј), 119.8, 119.9 (C-2ЈЈ, C-5ЈЈ), 124.6, 124.8
(C-3ЈЈ, C-4ЈЈ), 127.0, 127.1 (C-1Ј), 128.2, 128.4 (C-3ЈЈ, C-4ЈЈ), 130.9
(C-2Ј), 132.86, 132.91 (C-1ЈЈ, C-6ЈЈ), 145.8, 146.1 (C-1ЈЈ, C-6ЈЈ),
3-[1-(1H-1,2,3-Benzotriazol-1-yl)butyl]-4-(2-bromo-5-methoxy-
benzyl)-1,3-oxazolidin-2-one (21): Butyraldehyde (15.4 µL, 12.6 mg,
175 µmol) was added to a suspension of rac-9 (50.0 mg, 175 µmol),
1H-benzotriazole (20.8 mg, 175 µmol) and p-toluenesulfonic acid
(3.33 mg, 17.5 µmol) in absolute toluene (10 mL), and the reaction
mixture was heated at reflux with a Dean–Stark trap for 10 h. After
dilution with toluene (20 mL), the reaction mixture was washed
with a NaOH solution (2 ; 2ϫ40 mL) and a saturated NH4Cl
solution (2ϫ40 mL), dried (Na2SO4), and concentrated. The resi-
due (79 mg) was chromatographed on SiO2 (hexanes/EtOAc, 4.5:1)
to give a diastereomeric mixture of 21 (dr 83:17 by 1H NMR spec-
troscopy). Yield: 47 mg (58%). Colorless foam. Rf = 0.18 (hexanes/
EtOAc, 4.5:1). 1H NMR (500 MHz, CDCl3): δ = 1.05 (t, J =
7.4 Hz, 0.5 H, CHCH2CH2CH3), 1.09 (t, J = 7.4 Hz, 2.5 H,
CHCH2CH2CH3), 1.51 (sext, J = 7.4 Hz, 2 H, CHCH2CH2CH3),
1.99 (dd, J = 10.9, 13.3 Hz, 2.5 H, 3-HA), 2.32 (dd, J = 10.5,
13.5 Hz, 0.5 H, 3-HA), 2.79–2.87 (m, 1 H, CHCH2CH2CH3), 2.90–
2.99 (m, 1 H, CHCH2CH2CH3), 3.08 (dd, J = 4.0, 13.4 Hz, 1 H,
3-HB), 3.69 (s, 2.5 H, OCH3), 3.73 (s, 0.5 H, OCH3), 4.03–4.14 (m,
2 H, 1-H), 4.37–4.43 (m, 0.5 H, 2-H), 4.43–4.49 (m, 2.5 H, 2-H),
6.48 (d, J = 3.0 Hz, 0.83 H, 2Ј-H), 6.56 (d, J = 3.0 Hz, 0.17 H, 2Ј-
H), 6.61–6.74 (m, 2 H, CHCH2CH2CH3, 4Ј-H), 7.38–7.44 (m, 2 H,
5Ј-H, 3ЈЈ-H, 4ЈЈ-H), 7.52–7.57 (m, 2 H, 3ЈЈ-H, 4ЈЈ-H), 8.02 (d, J =
8.4 Hz, 1 H, 2ЈЈ-H, 5ЈЈ-H), 8.07 (d, J = 8.4 Hz, 1 H, 2ЈЈ-H, 5ЈЈ-H)
p p m . 1 3 C N M R ( 1 2 5 M H z , C D C l 3 ) : δ = 1 3 . 4 , 1 3 . 5
(CHCH2CH2CH3), 19.1, 19.3 (CHCH2CH2CH3), 32.1, 32.7
(CHCH2CH2CH3), 38.9, 40.0 (C-3), 52.1, 52.5 (C-2), 55.4, 55.5
(OCH3), 66.5, 66.6 (CHCH2CH2CH3), 66.7, 66.9 (C-1), 110.2,
110.9 (C-2ЈЈ, C-5ЈЈ), 114.4, 114.6 (C-4Ј), 114.75, 114.84 (C-6Ј),
117.0, 117.4 (C-2Ј), 119.8, 119.9 (C-2ЈЈ, C-5ЈЈ), 124.6, 124.7 (C-3ЈЈ,
C-4ЈЈ), 128.1, 128.3 (C-3ЈЈ, C-4ЈЈ), 132.9 (C-1ЈЈ, C-6ЈЈ), 133.9 (C-
5Ј), 135.7 (C-1Ј), 145.9, 146.1 (C-1ЈЈ, C-6ЈЈ), 157.8, 158.5, 158.98,
157.8, 158.6, 158.7, 158.8 (C=O, C-4Ј) ppm. FTIR (ATR): ν = 1745
˜
(s), 1512 (m), 1410 (m), 1245 (s), 1178 (m), 1155 (m), 1076 (m),
1030 (m), 1002 (m), 780 (m), 769 (m), 747 (s) cm–1. MS (ESI): m/z
(%) = 403 (100) [M + Na]+, 338 (19) [M + H – CH2CH2-
CH3]+, 284 (19) [M – H – benzotriazolyl]+. HRMS (ESI): calcd.
for C21H24N4NaO3 [M + Na]+ 403.1741; found 403.1722.
+
General Procedure for the Preparation of Compounds 13a,14a by
Benzotriazole: To a solution of 23 or 24 (1 equiv.) in absolute aceto-
nitrile (5 mL) was added TiCl4 (1.5 equiv.) by syringe, and the reac-
tion mixture was heated at 60 °C for 8 h. After the addition of H2O
(10 mL), the reaction mixture was extracted with Et2O (2ϫ30 mL).
The combined extracts were washed with a NaOH solution (2 ;
2 ϫ 20 mL) and a saturated NH4Cl solution (2 ϫ30 mL), dried
(Na2SO4), and concentrated. The residue was chromatographed on
SiO2 (hexanes/EtOAc, 3:1) to give product 13a [64%, Rf = 0.26
(hexanes/EtOAc, 3:1)] as colorless crystals or 14a [54%, Rf = 0.13
(hexanes/EtOAc, 3:1)] as a colorless oil.
Cyclization of Derivatives 23a,b by the Pictet–Spengler Reaction
Method A: To a solution of 23a (72 mg, 250 µmol) or 23b (76 mg,
363 µmol) in absolute CH2Cl2 (5 mL) were added molecular sieves
4 Å (100 mg) and butyraldehyde (35.3 µL, 28.8 mg, 400 µmol for
23a, 51.3 µL, 41.9 mg, 581 µmol for 23b), and the reaction mixture
was stirred at room temperature for 24 h. Then, the reaction mix-
ture was cooled to 0 °C and trifluoroacetic acid (59.4 µL, 91.2 mg,
800 µmol for 23a, 86.0 µL, 132 mg, 1.16 mmol for 23b) was added
dropwise by syringe, and the mixture was stirred at 0 °C for a fur-
ther 16 h. After filtration, the filtrate was concentrated and the resi-
due chromatographed on basic Al2O3 (hexanes/EtOAc, 20:1) to
159.04 (C=O, C-3Ј) ppm. FTIR (ATR): ν = 1747 (s), 1473 (m),
˜
1
give 24a or 24b (E/Z, 90:10 by H NMR spectroscopy).
1453 (m), 1411 (m), 1239 (m), 1157 (m), 1078 (m), 1046 (m), 1012
(m), 747 (s) cm–1. MS (ESI): m/z (%) = 483 (75) [M + Na]+, 481
(83) [M + Na]+, 364 (92) [M – benzotriazolyl + H + Na]+, 362 (92)
[M – benzotriazole + H + Na]+, 342 (27) [M + H]+, 340 (30) [M
+ H]+, 149 (4), 132 (7), 104 (2). HRMS (ESI): calcd. for
Methyl 2-Bromo-N-[2-ethylhex-2-enylidene]-5-methoxyphenylalanin-
ate (24a): Yield: 27 mg (27%). Light yellow oil. Rf = 0.29 (hexanes/
1
EtOAc, 4.5:1). Major diastereomer: H NMR (500 MHz, CDCl3):
δ = 0.91 (t, J = 7.4 Hz, 3 H, 4ЈЈЈ-H), 0.97 (t, J = 7.5 Hz, 3 H, 4ЈЈ-
H), 1.42 (sext, J = 7.4 Hz, 2 H, 3ЈЈЈ-H), 2.17 (ddd, J = 1.7, 7.4,
C21H23BrN4NaO3 [M + Na]+ 481.0846; found 481.0853.
+
3-[1-(1H-1,2,3-Benzotriazol-1-yl)butyl]-4-(4-methoxybenzyl)-1,3- 14.8 Hz, 2 H, 2ЈЈЈ-H), 2.29–2.42 (m, 2 H, 3ЈЈ-H), 3.09 (dd, J = 9.0,
oxazolidin-2-one (22): As described above from (S)-10 (50.0 mg,
241 µmol), 1H-benzotriazole (28.7 mg, 241 µmol), and p-TsOH
(4.58 mg, 24.1 µmol) in absolute toluene (10 mL) and butyral-
dehyde (21.3 µL, 17.4 mg, 241 µmol) to give a diastereomeric mix-
ture of 22 (dr = 64:36). Yield: 34 mg (37%). Colorless foam. Rf =
0.16 (hexanes/EtOAc, 4.5:1). [α]2D2 = –112.9 (c = 0.036, CHCl3). 1H
13.5 Hz, 1 H, 3-HA), 3.49 (dd, J = 5.2, 13.5 Hz, 1 H, 3-HB), 3.71,
3.74 (2 s, 3 H, OCH3), 4.15 (dd, J = 5.2, 9.0 Hz, 1 H, 2-H), 5.69
(t, J = 7.4 Hz, 3 H, 1ЈЈЈ-H), 6.63 (dd, J = 3.1, 8.8 Hz, 1 H, 4Ј-H),
6.71 (d, J = 3.1 Hz, 1 H, 3Ј-H), 7.39 (d, J = 8.8 Hz, 1 H, 5Ј-H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 13.6 (C-4ЈЈ), 13.9 (C-4ЈЈЈ),
19.0 (C-3ЈЈ), 22.3 (C-3ЈЈЈ), 30.3 (C-2ЈЈЈ), 40.0 (C-3), 52.2, 55.4 (2 x
NMR (500 MHz, CDCl3): δ = 1.04 (t, J = 7.4 Hz, 1.7 H, OCH3), 72.1 (C-2), 114.6 (C-4Ј), 115.1 (C-6Ј), 117.2 (C-2Ј), 133.2
CHCH2CH2CH3), 1.09 (t, J = 7.4 Hz, 1.3 H, CHCH2CH2CH3), (C-5Ј), 137.9 (C-1Ј), 141.7 (C-2ЈЈ), 143.6 (C-1ЈЈЈ), 158.5 (C-3Ј),
1.42–1.54 (m, 2 H, CHCH2CH2CH3), 1.89 (dd, J = 10.5, 13.5 Hz, 167.8 (C-1ЈЈ), 172.3 (CO CH ) ppm. FTIR (ATR): ν = 2958 (m),
˜
2
3
0.64 H, 3-HA), 2.56–2.63 (m, 0.36 H, CHCH2CH2CH3), 2.66–2.76
1738 (m), 1613 (m), 1512 (s), 1245 (s), 1201 (m), 1175 (m), 1162
(m, 1.64 H, CHCH2CH2CH3, 3-HA, 3-HB), 2.85–2.96 (m, 1 H, (m), 1034 (m), 823 (m) cm–1. MS (EI, 70 eV): m/z (%) = 397 (7)
CHCH2CH2CH3), 3.68 (dd, J = 3.9, 13.1 Hz, 0.36 H, 3-HB), 3.75 [M]+, 395 (7) [M]+, 368 (2), 366 (2), 338 (5) [M – CO2Me]+, 336
(s, 1.7 H, OCH3), 3.77 (s, 1.3 H, OCH3), 3.93–4.00 (m, 1 H, 1-HA), (5) [M – CO2Me]+, 316 (100) [M – Br]+, 300 (7), 284 (14), 260 (12),
4.08–4.13 (m, 1 H, 1-HB), 4.14–4.19 (m, 1 H, 2-H), 6.61 (d, J = 244 (3), 228 (5), 218 (9), 196 (25) [M – CH2C6H4(OMe)Br]+, 186
7.6 Hz, 0.64 H, CHCH2CH2CH3), 6.77 (d, J = 8.7 Hz, 1.28 H, 3Ј-
(9), 158 (7), 136 (9), 109 (3), 91 (1), 69 (3). C19H26BrNO3 (396.32):
5600
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602

Synthesis of Tyrosine-Derived Tetrahydroisoquinolines
calcd. C 57.58, H 6.61, N 3.53; found C 57.83, H 6.71, N 3.37.
680 µg, 12.6 µmol) was added, and the reaction mixture was heated
at reflux for 2 d (trans:cis, 90:10 by GC). HCl-saturated MeOH
(2 mL) was added, and the reaction mixture was concentrated. The
residue was taken up in CHCl3 (10 mL), washed with a saturated
NaHCO3 solution (3 ϫ 10 mL) and brine (2 ϫ 20 mL), dried
(Na2SO4), and concentrated. The residue was chromatographed on
SiO2 (hexanes/EtOAc, 2:1) to give a mixture of cis/trans-13i as a
colorless solid (4 mg, trans/cis, 90:10). The isomers were separated
by preparative HPLC on a column Kromasil (250ϫ20 mm, 100 Sil
5 µm) (MZ-Analysentechnik) with 2-PrOH in hexane (gradient
from 0–10%, flow 7 mLmin–1).
HRMS (ESI): calcd. for C19H26BrNNaO3 [M + Na]+ 418.0988;
+
found 418.0969.
Methyl N-(2-Ethylhex-2-enylidene)-O-methyl-L-tyrosinate (24b):
Yield: 37 mg (32%). Light yellow oil. Rf = 0.27 (hexanes/EtOAc,
4.5:1). Major diastereomer: 1H NMR (500 MHz, CDCl3): δ = 0.92
(t, J = 7.4 Hz, 3 H, 4ЈЈЈ-H), 0.98 (t, J = 7.5 Hz, 3 H, 4ЈЈ-H), 1.36–
1.48 (m, 2 H, 3ЈЈЈ-H), 2.14–2.21 (m, 2 H, 2ЈЈЈ-H), 2.28–2.47 (m, 2
H, 3ЈЈ-H), 3.00 (dd, J = 8.9, 13.6 Hz, 1 H, 3-HA), 3.24 (dd, J =
5.2, 13.6 Hz, 1 H, 3-HB), 3.71, 3.77 (2 s, 3 H, OCH3), 3.94 (dd, J
= 5.2, 8.9 Hz, 1 H, 2-H), 5.67 (t, J = 7.4 Hz, 3 H, 1ЈЈЈ-H), 6.78 (d,
J = 8.8 Hz, 2 H, 3Ј-H, 5Ј-H), 7.06 (d, J = 8.8 Hz, 2 H, 2Ј-H, 6Ј-
H), 7.37 (s, 1 H, 1ЈЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
13.7 (C-4ЈЈ), 13.9 (C-4ЈЈЈ), 19.0 (C-3ЈЈ), 22.4 (C-3ЈЈЈ), 30.2 (C-2ЈЈЈ),
39.0 (C-3), 52.1, 55.2 (2 x OCH3), 75.2 (C-2), 113.6 (C-3Ј, C-5Ј),
129.8 (C-1Ј), 130.7 (C-2Ј, C-6Ј), 141.7 (C-2ЈЈ), 143.3 (C-1ЈЈЈ), 158.2
Method B: To a solution of trans-13i (5.00 mg, 14.7 µmol) in tolu-
ene (3 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.23 µL,
2.27 mg, 14.7 µmol) by syringe, and the reaction mixture was
heated at reflux for 24 h. After the addition of more DBU (20.1 µL,
132 µmol), the reaction mixture was heated at reflux for 24 h (7%
conversion to cis-13i), which resulted in a mixture of cis/trans-13i
in a trans/cis ratio of 85:15 (by GC).
(C-4Ј), 167.3 (C-1ЈЈ), 172.7 (CO CH ) ppm. FTIR (ATR): ν = 2958
˜
2
3
(m), 1738 (m), 1612 (m), 1512 (s), 1245 (s), 1201 (m), 1168 (m),
1110 (m), 1034 (m), 823 (m) cm–1. MS (EI, 70 eV): m/z (%) = 317
(69) [M]+, 302 (1), 288 (4), 274 (4), 258 (14) [M – CO2Me]+, 242
(1), 214 (3), 196 (100) [M – CH2C6H4OMe]+, 186 (1), 165 (2), 164
(20), 151 (3), 136 (28), 121 (85) [CH2C6H4OMe]+, 108 (6), 91 (3),
77 (3), 55 (2), 41 (2). C19H27NO3 (317.42): calcd. C 71.89, H 8.57,
N 4.41; found C 71.79, H 8.76, N 4.32. HRMS (ESI): calcd. for
Methyl 6-Methoxy-3-oxo-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]-
isoquinoline-5-carboxylate (cis-25): As described above under
method b to give a mixture of cis/trans-25 in a trans/cis ratio of
85:15 (by GC).
+
C19H27NNaO3 [M + Na]+ 340.1883; found 340.1872.
Acknowledgments
Method B: To a solution of 23a or 23b (1 equiv.) in absolute toluene
(10 mL) was added p-TsOH (0.1 equiv.) and butyraldehyde
(1 equiv.), and the reaction mixture was heated at reflux with a
Dean–Stark trap for 16 h. After dilution with toluene (10 mL), the
reaction mixture was poured into a saturated NaHCO3 solution
(25 mL). The layers were separated, and the organic layer was
washed with a NaOH solution (0.5 ; 2ϫ25 mL) and a saturated
NaHCO3 solution (2ϫ20 mL), dried (Na2SO4), and concentrated.
The residue was chromatographed on basic Al2O3 (hexanes/EtOAc,
20:1) to give 24a [18%, Rf = 0.19 (hexanes/EtOAc, 20:1)] or 24b
[14%, Rf = 0.15 (hexanes/EtOAc, 20:1)] as colorless oils.
Generous financial support by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the Ministerium
für Wissenschaft, Forschung und Kunst des Landes Baden-
Württemberg is gratefully acknowledged.
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Methyl 6-Methoxy-3-oxo-1,5,10,10a-tetrahydro[1,3]oxazolo[3,4-b]-
isoquinoline-5-carboxylate (25): From 13i (15 mg, 41.1 µmol) in
benzene (4 mL). Yield: 8 mg (69 %). Colorless solid. M.p. 111–
112 °C. Rf = 0.07 (hexanes/EtOAc, 2:1). 1H NMR (300 MHz,
CDCl3): δ = 2.87 (dd, J = 10.6, 15.8 Hz, 1 H, 10-HA), 2.96 (dd, J
= 4.8, 15.8 Hz, 1 H, 10-HB), 3.78 (s, 3 H, CO2CH3), 3.81 (s, 3 H,
OCH3), 4.16 (dd, J = 3.6, 8.5 Hz, 1 H, 1-H), 4.19–4.28 (m, 1 H,
10a-H), 4.57 (dd, J = 7.6, 8.5 Hz, 1 H, 1-H), 5.59 (s, 1 H, 5-H),
6.77 (d, J = 7.8 Hz, 1 H, 7-H), 6.78 (d, J = 8.2 Hz, 1 H, 9-H), 7.25
(dd, J = 7.8, 8.2 Hz, 1 H, 8-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 32.9 (C-10), 48.8 (C-10a), 52.4 (C-5), 52.6 (CO2CH3), 55.6
(OCH3), 68.4 (C-1), 108.6 (C-7), 119.1 (C-5a), 121.6 (C-9), 129.0
(C-8), 133.5 (C-9a), 156.47, 156.53 (C-3, C-6), 170.8 (CO2CH3)
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ppm. FTIR (ATR): ν = 1739 (vs), 1585 (m), 1472 (m), 1443 (m),
˜
1412 (m), 1381 (m), 1337 (m), 1263 (m), 1238 (m), 1194 (m), 1167
(s), 1076 (m), 1007 (m), 987 (m), 959 (m), 781 (m), 768 (m), 741
(m), 727 (m), 707 (m), 665 (m), 620 (m) cm–1. MS (ESI): m/z (%)
= 577 (2) [2 M + Na]+, 365 (28), 316 (6), 300 (100) [M + Na]+,
278 (2), 244 (1), 218 (1) [M – CO2CH3]+. HRMS (ESI): calcd. for
+
C14H15NNaO5 [M + Na]+ 300.0842; found 300.0839.
Methyl 9-Bromo-6-methoxy-3-oxo-1,5,10,10a-tetrahydro[1,3]-
oxazolo[3,4-b]isoquinoline-5-carboxylate (cis-13i)
Method A: To a solution of trans-13i (5.00 mg, 14.0 µmol) in abso-
lute MeOH (2 mL) was added 3 % NaOMe/MeOH (2.63 µL,
75.6 µg, 1.40 µmol), and the reaction mixture was stirred at room
temperature for 2 d. Additional 3 % NaOMe/MeOH (23.7 µL,
Eur. J. Org. Chem. 2007, 5590–5602
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5601

S. Tussetschläger, A. Baro, S. Laschat, W. Frey
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Received: May 16, 2007
Published Online: September 25, 2007
5602
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5590–5602