Stereoselective isoquinoline alkaloid synthesis with new diselenides

Article abstract of DOI:10.1055/s-1998-2011

The synthesis of improved optically active selenium compounds for electrophilic additions to C=C double bonds is described. These reagents allow the formation of methoxyselenenylated products with high diastereoselectivities (up to 93% de). Intramolecular aminoselenenylations with chiral selenium electrophiles provide a short route to tetrahydroisoquinoline alkaloids.

Full text of DOI:10.1055/s-1998-2011

162
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SYNTHESIS
Stereoselective Isoquinoline Alkaloid Synthesis with New Diselenides
Thomas Wirth,* Gianfranco Fragale
Institut für Organische Chemie, Universität Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Fax: + 41(61)267-1105; E-mail:wirth@ubaclu.unibas.ch
Received 30 June 1997; revised 8 August 1997
Abstract: The synthesis of improved optically active selenium com- bility are less selective in the addition reactions. There-
pounds for electrophilic additions to C=C double bonds is described.
These reagents allow the formation of methoxyselenenylated prod-
ucts with high diastereoselectivities (up to 93% de). Intramolecular
aminoselenenylations with chiral selenium electrophiles provide a
fore, diselenide 1c with increased rigidity was synthesized
from optically active tetralol via ortho-lithiation10 in only
one step.
short route to tetrahydroisoquinoline alkaloids.
Key words: asymmetric synthesis, chiral diselenides, chirality, iso-
quinoline alkaloids, selenium
Synthetic approaches towards the isoquinoline system are
almost as old as the discovery of the isoquinoline system
itself1. Since that time there have been many improve-
ments in the synthesis of these N-heterocycles, as a great
number of alkaloids are based on 1-substituted tetrahy-
droisoquinolines. The introduction of a substituent in the
1-position leads to an asymmetric center and is the key
problem in the synthesis of these compounds. Some of
these compounds exhibit important physiological activi-
ties.2 Therefore, many synthetic methods have been em-
ployed to date for the synthesis of either racemic3 or
chiral4 isoquinolines. An important enantioselective route
is performed by asymmetric reduction of 3,4-dihydroiso-
quinolines with chiral transition metal catalysts yielding
the products with high selectivities.5
Recently we,6 and also other research groups,7 have inves-
tigated the use of chiral selenium compounds for the acti-
vation of C=C double bonds to perform inter- as well as
intramolecular additions. Substrates bearing an internal
nucleophile can cyclize to chiral heterocyclic compounds.
Many reports describe the selective formation of O-het-
erocycles from unsaturated alcohols or acids. Due to the
poor nucleophilicity of the nitrogen atom, only few selec-
tive cyclizations of unsaturated amines have been report-
ed to date.7a,b The products of intramolecular amino-
selenenylation reactions are nitrogen containing heterocy-
cles and, therefore, interesting building blocks for alka-
loid synthesis. The selenium functionality is still present
in the addition products and can be used for further func-
tionalizations. We applied this strategy to the synthesis of
tetrahydroisoquinoline alkaloids and describe herein this
new approach in the form of a synthesis of salsolidine
(14), which was chosen as the synthetic target.
Scheme 1
As a test reaction we first investigated the addition of se-
lenium electrophiles 2 to styrene using methanol as nu-
cleophile. The diastereoselectivities of the addition
products 4 resulting from this reaction were determined
by NMR spectroscopy as well as by GC analysis of the
cleavage product 5. Selenium electrophiles with electron-
withdrawing substituents, such as in 2b or the more rigid
bicyclic system in 2c, show enhanced diastereoselectivi-
ties in additions to double bonds compared with the cation
2a.
Scheme 2
For the synthesis of salsolidine an appropriate precursor
had to be synthesized. The synthetic sequence started with
6,7-dimethoxy-3,4-dihydroisoquinoline (6) which is
readily accessible via either a Bischler–Napieralski11 or a
Pictet–Spengler12 reaction. Compound 6 was converted to
the aldehyde 7 by reaction with acetyl chloride.13 Differ-
ent methods for the subsequent methylenation were
screened because Wittig olefination afforded the styrene
derivative 8 in only very low yields. The highest yields in
the synthesis of 8 were obtained with Lombardo’s re-
agent.14
Recently we showed that diselenide 1a is accessible by a
short synthetic sequence and is a versatile reagent for the
synthesis of other natural products.8 It is converted into
the selenium cation 2a, which is used for additions to dou-
ble bonds. Attachment of substituents at the aromatic ring
should change the electrophilicity of the selenium cations
and have an influence on reactivity as well as upon the dia-
stereoselectivity of the reaction. Therefore, nitro-substi-
tuted diselenide 1b was prepared from precursor 3 by Efforts to cyclize 8 with the electrophilic selenium reagent
reaction with sodium diselenide.9 We have already shown 2a to the corresponding tetrahydroisoquinoline derivative
that selenium cations with greater conformational flexi-
were not successful. This property coincides with earlier

February 1998
SYNTHESIS
163
contrast to other examples, in which higher selectivities
have been achieved with tetrafluoroborate as a counter-
ion,7b we found triflate to be the most suitable counterion.
A diastereomeric excess of 79% in the addition product
12a was obtained. Although the cyclization product 12b
with the nitro-substituted electrophile 2b was isolated in
64% yield, it was not possible to determine the diastereo-
meric excess by NMR and the radical cleavage of the
carbon–selenium bond was not possible. A further im-
provement in the selectivity of the cyclization was
achieved with the selenium cation 2c. Cyclization product
12c was obtained in 40% yield with a diastereoselectivity
of 90%.
Scheme 3
Reagents and Conditions: a) AcCl, sat. NaHCO3, CH2Cl2, 1.5 h, 90%.
b) Zn, CH2Br2, TiCl4, THF, 30 min, 33%. c) DMAP, (Boc)2O,
CH2Cl2, 15 h, 79%. d) N2H4. H2O . MeOH, 1 h, 98%.
observations of cyclizations using acetamides as nucleo-
philes.15 Even in the presence of methanol, which was
necessary for selenolactonizations,6,7a the cyclization
product could not be detected. Probably due to the poor
nucleophilicity of the acetamide group the intermolecular
methoxyselenenylation is preferred yielding the addition
product 11 in 49% yield and a diastereomeric ratio of
about 10:1.16
Scheme 5
Reagents and Conditions: a) 2, Et2O, –100°C, 36–66%. b) Ph3SnH,
AIBN, toluene, 120°C, 1 h, 93%. c) TFA, CH2Cl2, 3 h, 99%.
The last steps on the way to salsolidine were a radical
cleavage of the selenium moiety to Boc-protected salsoli-
dine 13,19 which could be converted almost quantitatively
into salsolidine (14) by treatment with trifluoroacetic
acid.20 The absolute configuration of the stereocenter of
salsolidine was confirmed to be S by comparison with the
optical rotation of the natural product.21
In conclusion, the addition to double bonds with chiral se-
lenium electrophiles 2 was further optimized. Electronic
as well as steric variations lead to diastereomeric excesses
up to 93% in the methoxyselenenylation products 4. In-
tramolecular cyclizations of the e-unsaturated carbamate
10 gave b-amino selenides 12 with tetrahydroisoquinoline
structure. By this approach a representative member of the
family of isoquinoline alkaloids, (–)-(S)-salsolidine (14),
has been synthesized with an enantiomeric excess of 90%.
Scheme 4
A different precursor for cyclization with an increased nu-
cleophilicity of the nitrogen atom was synthesized. Com-
pound 8 was, therefore, transformed into the carbamate 10
via a sequence of Boc-protection17 and deacetylation.18
Now cyclizations using this e-unsaturated carbamate 10
with different selenium electrophiles (2a–c) yielding the
tetrahydroisoquinolines 12 are possible. The results are
summarized in the Table.
All reactions were performed under anhyd Ar atmosphere. [a]D: Per-
kin–Elmer-141 polarimeter. IR spectra: Perkin–Elmer-781 spectro-
photometer.1H and 13C NMR spectra: Varian–Gemini-300
spectrometer (300 and 75 MHz respectively), chemical shifts d in
ppm relative to TMS as internal standard, 13C multiplicities assigned
via APT pulse sequence. MS spectra: Finnigan-MAT-312 apparatus.
Melting points are uncorrected. Et2O and THF were distilled from so-
dium/benzophenone, MeCN was distilled from P2O5 prior to use.
Table. Results of the Cyclization Reaction 10 ® 12 Using Different
Selenium Electrophiles 2
Entry
Se Electrophile
Product
Yield (%)
eea (%)
of 12
of 13
1
2
3
4
2a (X=OTf)
2a (X=BF4)
2b (X=OTf)
2c (X=OTf)
12a
12a
12b
12c
66
36
64
40
79
59
–
b
Addition of Selenium Cations to Alkenes; General Procedures 1
and 2:
90
The diselenide (0.1 mmol) was dissolved in anhyd Et2O (4 mL) under
Ar, cooled to –78°C and treated with 1 M bromme in CCl4 (0.11 mL,
0.11 mmol). After 10 min a solution of silver triflate (72 mg,
0.28 mmol) in MeOH (0.1 mL, General Procedure 1) or THF (0.1
mL, General Procedure 2) was added and stirred for 10 min at
–78 C. The reaction mixture was cooled to –100°C and treated with
styrene (0.4 mmol, 0.046 mL). After stirring for 3–4 h at –100°C,
sym-collidine (0.3 mmol, 0.04 mL) was added followed by 0.3 M aq
citric acid (4 mL). After extraction of the reaction mixture with t-
a Determined by HPLC (Regis Whelk-O1, i-PrOH/hexane 1:5) af-
ter cleavage of the Se moiety.
b Not determined.
These results show clearly that the counterion of the elec-
trophilic organoselenium species plays a non-negligible
role in the addition reaction, having a dramatic influence
on yield as well as on selectivity (see entries 1 and 2). In BuOMe (3 ´ 10 mL), drying of the combined organic phases

164
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SYNTHESIS
(MgSO4) and removal of the solvent under reduced pressure the res-
idue was purified by flash chromatography on silica gel.
the organic layer was washed with 1 M KHSO4 (2 ´ 10 mL) and sat.
NaHCO3 (2 ´ 10 mL), dried (MgSO4) and the solvent evaporated in
vacuo. The residue was purified by flash chromatography on silica gel
(CH2Cl2/acetone 50:1) and recrystallized (t-BuOMe) to yield 9
(273 mg, 79%) as colorless needles; mp 93–94 °C.
Preparation and characterization of diselenide 1a see lit.8a The di-
selenides 1b and 1c, compound 3 and the addition products 4a–c are
described in lit.6b Spectroscopic data are given only for the major dia-
stereomers of 11, 12a, 12b, and 12c. The Boc-protected tetrahy-
droisoquinoline derivatives 12a, 12b, 12c, and 13 show some broad
signals in the 1H NMR which are due to rotamers of these compounds
as described in lit.20
1H NMR (CDCl3): d = 1.50 [s, 9H, C(CH3)3], 2.48 (s, 3H, COCH3),
2.84 (m, 2H, ArCH2), 3.81 (m, 2H, CH2N), 3.87 (s, 3H, OCH3),
3.89 (s, 3H, OCH3), 5.23 (dd, J = 10.9 Hz, J = 1.2 Hz, 1H, CH=CHcis
Htrans), 5.58 (dd, J = 17.2 Hz, J = 1.2 Hz, 1H, CH=CHcisHtrans), 6.66
(s, 1H, arom H-6), 7.03 (s, 1H, arom H-3), 7.03 (dd, J = 17.3 Hz,
J = 11.0 Hz, 1H, CH=CH2).
13C NMR (CDCl3): d = 27.0 (q, COCH3), 27.8 [q, 3C, C(CH3)3], 31.7
(t, ArCH2), 45.4 (t, CH2N), 55.87 (q, OCH3), 55.91 (q, OCH3), 83.0
[s, C(CH3)3], 108.1 (d, arom C-3/6), 113.0 (d, arom C-3/6), 113.4 (t,
CH= CH2), 129.03 (s, arom C-1/2), 129.06 (s, arom C-1/2), 133.7 (d,
CH=CH2), 147.9 (s, arom C-4/5), 148.9 (s, arom C-4/5), 153.0 [s,
COC(CH3)3], 173.1 (s, COCH3).
N-[2-(2-Formyl-4,5-dimethoxyphenyl)ethyl]acetamide (7):
Compound 622 (1.75 g, 9.16 mmol) was dissolved in a mixture of
CH2Cl2 (15 mL) and sat. NaHCO3 (15 mL). After the addition of
AcCl (1.44 mL, 20 mmol) in CH2Cl2 (2 mL) the mixture was stirred
at r.t. for 90 min. The layers were separated and the aqueous layer ex-
tracted with CH2Cl2 (3 ´ 5 mL). The organic layer was dried
(MgSO4) and evaporated to leave a residue which was purified by
flash chromatography on silica gel (CH2Cl2/acetone 4:1) to afford 7
(2.08 g, 90%) as a colorless solid.
IR (CHCl3): n = 3006, 2981, 1730, 1687, 1512, 1370, 1147, 1104,
1049, 909 cm–1.
MS (EI, 70 eV): m/z (%) = 349 (39) [M+], 276 (10), 249 (6), 234 (25),
190 (100), 177 (45), 175 (25), 159 (14), 146 (19), 131 (11), 57 (31).
C19H27NO5: calcd C 65.31, H 7.79, N 4.01, O 22.89; found: C 65.29,
H 7.59, N 3.98, O 22.92.
1H NMR (CDCl3): d = 1.93 (s, 3H, COCH3), 3.19 (t, J = 7.2 Hz, 2H,
ArCH2), 3.48 (q, J = 7.0 Hz, 2H, CH2NH), 3.93 (s, 3H, OCH3), 3.95
(s, 3H, OCH3), 5.88 (s, br, 1H, NH), 6.76 (s, 1H, arom H-6), 7,31 (s,
1H, arom H-3), 10.07 (s, 1H, CHO).
13C NMR (CDCl3): d = 23.1 (q, COCH3), 31.5 (t, ArCH2), 41.4 (t,
CH2NH), 56.0(q, OCH3), 56.1(q, OCH3), 113.3(d, arom C-3/6), 113.5
(d, arom C-3/6), 127.1 (s, arom C-2), 136.6 (s, arom C-1), 147.8 (s,
arom C-4), 153.7 (s, arom C-5), 170.2 (s, COCH3), 190.7 (d, CHO).
IR (CHCl3): v = 3451, 3368, 3006, 2847, 1672, 1600, 1517, 1464,
1360, 1117, 1049, 1002, 870 cm–1.
N-(tert-Butoxycarbonyl)-2-(4,5-dimethoxy-2-vinylphenyl)ethyl-
amine (10):
Hydrazine hydrate (26 mg, 0.45 mmol) was added to a solution of 9
(35 mg, 0.1 mmol) in MeOH (0.5 mL) and allowed to stir for 1 h at
r.t.. After addition of CH2Cl2 (5 mL) the organic layer was washed
with 1 M KHSO4 (2 ´ 5 mL) and sat. NaHCO3 (2 ´ 5 mL), dried
(MgSO4) and the solvent evaporated in vacuo. The residue was re-
crystallized from MeOH and gave 10 (30 mg, 98%) as colorless crys-
tals; mp 127–129 °C.
MS (EI, 70 eV): m/z (%) = 251 (19) [M+], 234 (5), 207 (5), 192 (100),
180 (50), 164 (40), 151(13), 43 (30).
C13H17NO4: calcd C 62.14, H 6.82, N 5.57, O 25.47; found: C 62.15,
H 6.99, N 5.52, O 25.52.
1H NMR (CDCl3): d = 1.46 [s, 9H, C(CH3)3], 2.84 (m, 2H, ArCH2),
3.30 (m, 2H, CH2NH), 3.89 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
4.56 (s, br, 1H, NH), 5.24 (dd, J = 10.9 Hz, J = 1.2 Hz, 1H, CH=CHcis
Htrans), 5.57 (dd, J = 17.3 Hz, J = 1.2 Hz, 1H, CH=CHcisHtrans), 6.65
(s, 1H, arom H-6), 7.03 (dd, J = 17.3 Hz, J = 10.9 Hz, 1H, CH=CH2),
7.04 (s, 1H, arom H-3).
N-[2-(4,5-Dimethoxy-2-vinylphenyl)ethyl]acetamide (8):
CH2Br2 (2.02 mL, 29 mmol) was added to a suspension of activated zinc
dust(5.89g, 89mmol)inanhydTHF(100mL).Aftercoolingto–40°C,
TiCl4 (2.4 mL, 22 mmol) was added dropwise over a period of 15 min
and the reaction mixture was allowed to stir for 3 d at 5°C. The resulting
slurry was diluted with THF (20 mL) and cooled to 0°C. Compound 7
(317 mg, 1.26 mmol) in THF (1 mL) was added over a period of 15 min.
The reaction mixture was stirred 30 min at r.t.. After addition of pentane
(20 mL), sat. Na2CO3 (80 mL) was added carefully over 1 h. The organic
layer was separated and the residue extracted with CH2Cl2 (3 x 50 mL).
The organic layer was dried (MgSO4) and evaporated to leave a residue
whichwaspurifiedbyflashchromatographyonsilicagel(CH2Cl2/ace-
tone 4:1). Further recrystallization from t-BuOMe afforded 8 (105 mg,
33%) as colorless crystals; mp 123–125°C.
13C NMR (CDCl3): d = 28.4 [q, 3C, C(CH3)3], 33.0 (t, ArCH2), 41.6
(t, CH2NH), 55.9 (s, 2C, OCH3), 79.2 [s, C(CH3)3], 108.6 (d, arom C-
3/6), 112.8 (t, CH= CH2), 113.8 (d, arom C-3/6), 129.03 (s, arom C-1/
2), 129.06 (s, arom C-1/2), 133.7 (d, CH=CH2), 147.8 (s, arom C-4/
5), 148.8 (s, arom C-4/5), 155.8 [s, COC(CH3)3].
IR (CHCl3): n = 3455, 3006, 2937, 1706, 1511, 1464, 1367, 1134,
1103, 1049, 1016 cm–1.
MS (EI, 70 eV): m/z (%) = 307 (55) [M+], 251 (39), 234 (17), 206 (8),
190 (76), 177 (100), 146 (22), 57 (57).
1H NMR (CDCl3): d = 1.93 (s, 3H, COCH3), 2.85 (t, J = 7.1 Hz, 2H,
ArCH2), 3.42 (q, J = 6.6 Hz, 2H, CH2NH), 3.87 (s, 3H, OCH3), 3.90
(s, 3H, OCH3), 5.23 (d, J = 11.0 Hz, 1H, CH=CHcisHtraa), 5.56 (d, J
= 17.5 Hz, 1H, CH=CHcisHtrans), 5.71 (s, br, 1H, NH), 6.64 (s, 1H,
arom H-6), 6.93 (dd, J = 17.3 Hz, J = 10.9 Hz, 1H, CH=CH2), 7.02 (s,
1H, arom H-3).
C17H25NO4: calcd C 66.43, H 8.20, N 4.56; found C 66.18, H 7.97, N
4.60.
[2-(2-Acetamidoethyl-4,5-dimethoxyphenyl)-2-methoxyethyl]
{2-[(S)-1-Hydroxypropyl]phenyl} Selenide (11):
Using General Procedure 1 with 1a (68 mg, 0.15 mmol) and 8 (37 mg,
0.15 mmol). Purification by flash chromatography on silica gel (ace-
tone/CH2Cl2 1:4) afforded 11 (36 mg, 49%) as a yellowish oil;
[a]D25 –25.4 (c = 0.74, CHCl3).
13C NMR (CDCl3): d = 23.2 (q, COCH3), 32.3 (t, ArCH2), 40.7 (t,
CH2NH), 55.8 (q, OCH3), 55.9 (q, OCH3), 108.5 (d, arom C-3/6),
112.7 (d, arom C-3/6), 113.8 (t, CH= CH2), 129.0 (s, 2C, arom C-1, C-
2), 133.7 (d, CH=CH2), 147.8 (s, arom C-4/5), 148.9 (s, arom C-4/5),
170.1 (s, COCH3).
1H NMR (CDCl3): d = 0.97 (t, J = 7.3 Hz, 3H, CH2CH3), 1.77 (quint,
J = 7.2 Hz, 2H, CH2CH3), 1.90 (s, 3H, COCH3), 2.51–2.63 (m, 2H,
ArCH2), 3.00–3.30 (m, 5H, CH2Se, CH2NH, OH), 3.21 (s, 3H,
CHOCH3), 3.84 (s, 3H, ArOCH3), 3.86 (s, 3H, ArOCH3), 4.48 (dd, J
= 8.5 Hz, J = 4.5 Hz, 1H, CHOCH3), 5.06 (t, J = 5.0 Hz, 1H, CHOH),
5.72 (s, br, 1H, NH), 6.59 (s, 1H, arom H-6), 6.91 (s, 1H, arom H-3),
7.17 (td, J = 7.4 Hz, J = 1.5 Hz, 1H, arom H-5¢), 7.32 (td, J = 7.5 Hz,
J = 1.2 Hz, 1H, arom H-4¢), 7.51 (dd, J= 7.7 Hz, J = 1.6 Hz, 1H, arom
H-3¢), 7.59 (dd, J = 7.7 Hz, J = 1.3 Hz, 1H, arom H-6¢).
IR (CHCl3): n = 3451, 3006, 2938, 1666, 1604, 1512, 1464, 1134,
1049, 1016, 910 cm–1.
MS (EI, 70 eV): m/z (%) = 249 (35) [M+], 190 (100), 177 (35), 146 (33).
C14H19NO3: calcd C 67.45, H 7.68, N 5.62, O 19.25; found: C 67.27,
H 7.53, N 5.47, O 19.24.
N-(tert-Butoxycarbonyl)-N-[2-(4,5-dimethoxy-2-vinylphenyl)eth-
yl]acetamide (9):
Compound 8 (247 mg, 0.99 mmol) and DMAP (30 mg, 0.1 mmol)
were dissolved in MeCN (7 mL), treated with Boc2O (273 mg, 1.25
mmol) and stirred for 15 h at r.t.. After addition of CH2Cl2 (20 mL)
13C NMR (CDCl3): d = 10.4 (q, CH2CH3), 23.1 (q, COCH3), 31.4 (t,
CH2Se), 31.7 (t, CH2CH3), 35.4 (t, ArCH2), 40.4 (t, CH2NH), 55.99
(q, ArOCH3), 56.03 (q, ArOCH3), 56.7 (q, CHOCH3), 74.2 (d,
CHOH), 78.0 (d, CHOCH3), 109.7 (d, arom C-3/6), 112.5 (d, arom C-

February 1998
SYNTHESIS
165
3/6), 126.7 (d, arom C-5¢), 127.7 (d, arom C-3¢), 128.1 (d, arom C-4¢),
128.4 (s, arom C-1¢), 128.9 (s, arom C-2), 131.0 (s, arom C-1), 135.3
(d, arom C-6¢), 147.1 (s, arom C-2¢), 148.2 (s, arom C-4/5), 148.5 (s,
arom C-4/5), 170.3 (s, COCH3).
1H NMR (CDCl3): d = 1.46 [s, 9H, C(CH3)3], 1.70–1.80 (m, 2H,
CH2CH2CH2), 1.90–2.05 (m, 1H), 2.10–2.20 (m, 1H), 2.50–2.90 (m,
5H), 3.25–3.40 (m, 3H, CH2N, CHHSe), 3,86 (s, 6H, 2 ´ OCH3),
3.80–3.90 (m, 1H, CHHSe), 5.00–5.10 (m, 1H, CHOH), 5.25–5.45
(m, 1H, CHN), 6.59 (s, 1H, arom H-5/8), 6.65 (s, 1H, arom H-5/8),
7.00 (d, J = 7.4 Hz, 1H, arom H-4¢), 7.09 (t, J = 7.5 Hz, 1H, arom H-
3¢), 7.30–7.55 (m, 1H, arom H-2¢).
IR (CHCl3): n = 3449, 3005, 2936, 1663, 1514, 1464, 1135, 1105,
1049, 1016 cm–1.
MS (EI, 70 eV): m/z (%) = 495 (5) [M+], 266 (100), 192 (51).
13C NMR (CDCl3): d = 28.0 (t, C-6¢), 28.4 [q, 3C, C(CH3)3], 29.7 (t,
CH2), 30.1 (t, CH2), 31.4 (t, CH2), 34.1 (t, CH2), 37.3 (t, CH2), 53.9
(d, CHN), 55.9 (q, OCH3), 56.1 (q, OCH3), 66.0 (d, CHOH), 80.0 [s,
C(CH3)3], 110.2 (d, arom C-5/8), 111.5 (d, arom C-5/8), 126.5 (s, 2C,
arom C-4a, C-8a), 127.9 (d, arom C-2¢/3¢/4¢), 128.4 (d, arom C-2¢/3¢/
4¢), 130.5 (d, arom C-2¢/3¢/4¢), 133.3 (s, arom C-l¢), 138.6 (s, arom C-
4a¢/8a¢), 139.0 (s, arom C-4a¢/8a¢), 147.5 (s, arom C-6/7), 148.1 (s,
arom C-6/7), 154.5 [s, COC(CH3)3)].
(1R)-2-(tert-Butoxycarbonyl)-1-{[(S)-2-(1-hydroxypropyl)phen-
yl]selenomethyl}-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(12a):
Using General Procedure 2 with 1a (64 mg, 0.15 mmol) and 10
(26 mg, 0.085 mmol). Purification by flash chromatography on silica
gel (t-BuOMe/pentane 1:1) afforded 12a (29 mg, 66%) as a yellowish
oil; [a]D25 + 20.3 (c= 1.3, CHCl3).
1H NMR (CDCl3): d = 0.90 (m, 3H, CH2CH3), 1.53 [s, 9H, C(CH3)3],
1.57–1.83 (m, 3H, CH2CH3, OH), 2.45–3.00 (m, 3H, ArCH2,
CHHN), 3.25–3.48 (m, 2H, CHHN, CHHSe), 3.80–3.90 (m, 1H,
CHHSe), 3.83 (s, 6H, 2 x OCH3), 5.10 (m, 1H, CHOH), 5.20–5.30
(m, br, 0.7H, CHN), 5.40–5.50 (m, br, 0.3H, CHN), 6.60 (s, 2H, arom
H-5, H-8), 7.12 (t, J = 8.4 Hz, 1H, arom H-5¢), 7.28 (t, J = 8.4 Hz, 1H,
arom H-4¢), 7.46–7.57 (m, 2H, arom H-3¢, H-6¢).
IR (CHCl3): n = 3671, 3460, 3006, 2935, 2856, 1683, 1516, 1465,
1367, 1134, 1050, 1015, 859 cm–1.
MS (FAB+KCl): m/z (%) = 572 (8) [M++K], 516 (3), 460 (5), 416 (5),
292 (45), 236 (100), 57 (98).
(S)-N-(tert-Butoxycarbouyl)salsolidine (13):
Compound 12a (29 mg, 0.056 mmol), triphenyltin hydride (45 mg,
0.128 mmol) and AIBN (10 mg, 0.061 mmol) were dissolved in tolu-
ene (0.4 mL) and refluxed for 1 h. The reaction mixture was separated
via preparative TLC (t-BuOMe/pentane 1:1) to give 13 (16 mg, 93%);
[a]D25 + 72.1 (c = 0.69, CHCl3).
13C NMR (CDCl3): d = 10.4 (q, CH2CH3), 27.9 (t, CH2Se), 28.5 [q,
3C, C(CH3)3], 29.7 (t, ArCH2), 31.9 (t, CH2CH3), 36.5 (t, CH2N),
54.2 (d, CHN), 55.9 (q, OCH3), 56.1 (q, OCH3), 73.7 (d, CHOH), 80.8
[s, C(CH3)3], 110.0 (d, arom C-5/8), 110.3 (d, arom C-5/8), 126.4 (d,
arom C-5¢), 127.6 (d, arom C-3¢), 127.8 (d, arom C-4¢), 128.3 (s, arom
C-1¢), 130.0 (s, 2C, arom C-4a, C-8a), 133.7 (d, arom C-6¢), 147.4 (s,
arom C-2¢), 148.0 (s, arom C-6/7), 148.1 (s, arom C-6/7), 155.1 [s,
COC(CH3)3].
1H NMR (CDCl3): d = 1.42 (d, J = 6.7 Hz, 3H, CHCH3), 1.49 [s, 9H,
C(CH3)3], 2.58–2.70 (m, 1H, ArCHH), 2.77–2.90 (m, 1H, ArCHH),
3.07–3.25 (m, 1H, CHHN), 3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
3.95–4.25 (m, 1H, CHHN), 5.06–5.23 (m, 1H, CHN), 6.59 (s, 2H,
arom H-5, H-8).
IR (CHCl3): n – 3438, 3063, 3006, 2967, 1682, 1517, 1464, 1367,
13C NMR (CDCl3): d = 21.8 (q, CHCH3), 28.5 [q, 3C, C(CH3)3], 28.8
(t, 2C, ArCH2, CH2N), 50.2 (d, CHN), 55.9 (q, OCH3), 56.0 (q,
OCH3), 79.6 [s, C(CH3)3], 109.8 (d, arom C-5/8), 111.4 (d, arom C-
5/8), 126.2 (s, 2C, arom C-4a, C-8a), 147.5 (s, 2C, arom C-6, C-7),
154.5 [s, COC(CH3)3].
1099, 858 cm–1
.
MS (FAB, NBA): m/z (%) = 520 (2) [M+–H], 464 (2), 446 (5), 420
(1), 292 (39), 248 (35), 236 (100), 192 (16), 57 (81); (FAB, NBA+
KCl): m/z = 560 [M++K]; (electron spray) m/z = 544 [M++Na].
IR (CHCl3): n = 3006, 2978, 2935, 1681, 1518, 1421, 1366, 1106,
(1R)-2-(tert-Butoxycarbonyl)-1-{[(S)-2-(1-hydroxypropyl)-4-
nitrophenyl]selenomethyl}-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (12b):
1053, 992, 859 cm–1.
MS (EI, 70 eV): m/z (%) = 307 (9) [M+], 292 (4), 250 (78), 236 (100),
234 (20), 192 (45), 57 (50).
Using General Procedure 2 with 1b (28 mg, 0.054 mmol) and 10
(22 mg, 0.072 mmol). Purification by flash chromatography on silica
gel (t-BuOMe/pentane 1:1) afforded 12b (26 mg, 64%) as a yellowish
oil; [a]D25 + 8.3 (c = 0.19, CHCl3).
(–)-(S)-Salsolidine (14):
To a solution of 13 (12 mg, 0.039 mmol) in CH2Cl2 (0.4 mL) was add-
ed,I.FA (0.04 mL, 0.53 mmol). The reaction mixture was allowed to
stir for 3 h at r.t.. After addition of 1 N NaOH (5 mL) the aqueous lay-
er was extracted with CH2Cl2. The organic layer was dried (MgSO4)
and evaporated to afford salsolidine 14 (7 mg, 99%); [a]D25 – 29.5 (c
= 0.325, EtOH).
1H NMR (CDCl3): d = 0.98 (t, J = 7.4 Hz, 3H, CH2CH3), 1.52 [s, 9H,
C(CH3)3], 1.50–1.80 (m, 3H, CH2CH3, OH), 2.60–2.85 (m, 3H,
ArCH2, CHHN), 3.30–3.50 (m, 3H, CHHN, CH2Se), 3.87 (s, 6H, 2 ´
OCH3), 5.06 (t, 5.8 Hz, 1H, CHOH), 5.22–5.35 (m, 0.7H, CHN),
5.35–5.47 (m, 0.3H, CHN), 6.60 (s, 2H, arom H-5, H-8), 7.55 (m, 1H,
arom H-6¢), 7.95 (dd, J = 8.6 Hz, J = 2.7 Hz, 1H, arom H-5¢), 8.38 (m,
1H, arom H-3¢).
1H NMR (CDCl3): d = 1.44 (dd, J = 6.5 Hz, J = 1.8 Hz, 3H, CHCH3),
1.78 (s, br, 1H, NH), 2.60–2.83 (m, 2H, ArCH2), 2.85–3.03 (m, 1H,
CHHNH), 3.20–3.50 (m, 1H, CHHNH), 3.848 (s, 3H, OCH3), 3.853
(s, 3H, OCH3), 4.05 (q, J = 6.4 Hz, 1H, CHNH), 6.57 (s, 1H, arom H-
8), 6.63 (s, 1H, arom H-5).
13C NMR (CDCl3): d = 10.7 (q, CH2CH3), 28.0 (t, CH2Se), 28.4 [q,
3C, C(CH3)3], 31.2 (t, CH2CH3), 36.3 (t, ArCH2), 39.3 (t, CH2N),
53.8 (d, CHN), 55.9 (q, O CH3), 56.1 (q, OCH3), 72.9 (d, CHOH), 80.5
[s, C(CH3)3], 110.7 (d, arom C-5/8), 111.7 (d, arom C-5/8), 121.1 (d,
arom C-5¢), 126.5 (d, arom C-3¢), 127.5 (s, arom C-4a/8a), 131.0 (s,
arom C-4a/8a), 131.4 (d, arom C-6¢), 140.0 (s, arom C-1¢), 146.0 (s,
2C, arom C-6, C-7), 147.6 (s, arom C-4¢), 148.7 (s, arom C-2¢), 155.2
[s, COC(CH3)3].
13C NMR (CDCl3): d = 22.9 (q, CHCH3), 29.6 (t, ArCH2), 41.9 (t,
CH2N), 51.3 (d, CHNH), 55.9 (q, OCH3), 56.1 (q, OCH3), 109.2 (d,
arom C-5), 111.9 (d, arom C-8), 126.8 (s, arom C-8a), 132.5 (s, arom
C-4a), 147.3 (s, arom C-6/7), 147.4 (s, arom C-6/7).
IR (CHCl3): n = 3685, 3009, 2931, 2855, 1682, 1601, 1573, 1464,
This work was supported by the Stipendienfonds der Basler Chemi-
schen Industrie (scholarship for G. F.), by the Deutschen For-
schungsgemeinschaft, by the Schweizer Nationalfonds and by the
Treubel-Fonds (scholarship for T. W.). We thank Prof. B. Giese for
his continuous generous support.
1366, 1342, 1134, 1050, 1036, 858 cm–1.
MS (FAB+KCl): m/z (%) = 605 (2) [M++K], 493 (3), 292 (16), 236
(65), 57 (100).
(1R)-2-(tert-Butoxycarbonyl)-1-{[(S)-8-hydroxy-5,6,7,8-tetrahy-
dro-1-naphthyl]selenomethyl}-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (12c):
(1) a) Claret, P. A. In Comprehensive Organic Synthesis, Burton,
D.; Ollis, W. D. Eds.; Pergamon: Oxford, 1979; Vol. 4, p 205-
232.
Using General Procedure 2 with 1c (39 mg, 0.086 mmol) and 10 (20
mg, 0.065 mmol). Purification by flash chromatography on silica gel
(t-BuOMe/pentane 1:1) afforded 12c (14 mg, 40%) as a yellowish oil;
[a]D25 + 21.0 (c = 0.70, CHCl3).
b) Bentley, K. W. Nat. Prod. Rep. 1996, 13, 127.

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