Enantiomerically pure tetrahydroisoquinolines by enzyme catalysis and gold-catalyzed phenol synthesis

Article abstract of DOI:10.1016/j.tet.2008.12.058

Five different furfural derivatives were converted to chiral cyanohydrins by enzyme catalysis in good enantiomeric excess. After a sequence of silyl protection, nitrile reduction, tosylation and propargylation, substrates for the gold(I) catalyzed cyclois

Full text of DOI:10.1016/j.tet.2008.12.058

Tetrahedron 65 (2009) 1919–1927
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Enantiomerically pure tetrahydroisoquinolines by enzyme catalysis and
gold-catalyzed phenol synthesis
*
A. Stephen K. Hashmi , Filiz Ata, Patrick Haufe, Frank Rominger
Organisch-Chemisches Institut, Universita¨t Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Five different furfural derivatives were converted to chiral cyanohydrins by enzyme catalysis in good
enantiomeric excess. After a sequence of silyl protection, nitrile reduction, tosylation and propargylation,
Received 5 November 2008
Received in revised form 6 December 2008
Accepted 7 December 2008
Available online 24 December 2008
substrates for the gold(I) catalyzed cycloisomerization of
d-alkynyl furans delivered good yields of
enantiomerically pure dihydroxytetrahydroisoquinoline building blocks. Neither racemization nor
elimination to quinolines was observed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
product cyanohydrin 4 (for example: from almonds, Prunus amyg-
dalus, (R)-PaHNL; from manihot, Manihot esculenta, (S)-MeHNL).4
Over the past eight years, gold catalysis has become a highly
useful tool for organic synthesis.1 One of the new reactions de-
veloped, is the gold-catalyzed phenol synthesis, which has a very
broad synthetic scope, especially for the synthesis of benzo-anel-
lated heterocycles.2 Such heterocycles are often found as sub-
structures in natural products, but then in most cases possess
stereocenters, for example, in the benzylic position of the hetero-
cycle. These stereocenters cannot be set in the gold-catalyzed
cyclization of 1 to 2, thus for enantiomerically pure building blocks
these stereocenters have to be implemented during the synthesis
of 1 (Scheme 1).
The aim of this investigation was to extend the use of these en-
zymes to different furylic substrates and to explore the scope and
limitations in the subsequent functional group modifications and
the gold-catalyzed synthesis of tetrahydroisoquinoline building
blocks with benzylic stereocenters bearing a hydroxy group. Re-
garding the gold-catalyzed step, the presence of this benzylic
stereocenters will be of interest, since it would be important to
avoid an elimination or an even elimination/aromatization pro-
cesses, what is, in principle, possible in gold catalysis.5
We report herein our findings with regard of this synthesis of
enantiomerically pure dihydroxytetrahydroisoquinolines.
For setting a furylic stereocenter in 1, we were inspired by the
work of Effenberger, who developed a beautiful and simple en-
zyme-catalyzed asymmetric formation of cyanohydrins from al-
dehydes (Scheme 2).3
Different enzymes, the hydroxynitrile lyases (HNL), are available
for the selective synthesis of each of the enantiomeric form of the
2. Results and discussion
For the investigation of the first, enzyme-catalyzed step, we
chose a series of furfural derivatives 5a–e possessing a various
substitution patterns (Scheme 3). For analytical purposes, in
R3
R3
R4
X
R2
R1
X = O, OCR2, NR, CR2NR', CR2, CR2CR'2 ...
R1 = H, alkyl, aryl, alkynyl
R2 = H, alkyl, Br
R4
X
R2
R1
[Au]
phenol
synthesis
O
R3 = H, alkyl
R4, R5 = H, alkyl, aryl
H
R5
R5
OH
2
1
Scheme 1. The gold-catalyzed phenol synthesis.
* Corresponding author.
E-mail address: hashmi@hashmi.de (A.S.K. Hashmi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.058

1920
A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
Table 1
OH
CN
Synthesis of furfural-derived and protected cyanohydrins 7
(R)-HNL
from almonds
R
Entry
Furfural
Methoda
Productb (yield)
Enantiomeric
H
excess of 7 (ee)
(R)-4
O
H
NaCN/H+
R
1
2
3
4
5
6
7
8
9
10
5a: R1, R2¼H
A
B
A
B
A
B
A
B
A
B
(S)-7a (81%)
rac-7a (93%)
(S)-7b (64%)
rac-7b (82%)
(S)-7c (15%)
rac-7c (76%)
(S)-7d (93%)
rac-7d (93%)
(S)-7e (32%)
rac-7e (83%)
98%
d
5a: R1, R2¼H
CN
OH
5b: R1¼Me, R2¼H
5b: R1¼Me, R2¼H
5c: R1¼Ph, R2¼H
5c: R1¼Ph, R2¼H
5d: R1¼Et, R2¼H
5d: R1¼Et, R2¼H
5e: R1¼Me, R2¼Me
5e: R1¼Me, R2¼Me
98%
d
R
3
(S)-HNL
from manihot
H
95%
d
(S)-4
99%
d
Scheme 2. Enzymes for both enantiomers of the cyanohydrin are available.
99%
d
addition to the enzyme-catalyzed enantioselective conversions, an
uncatalyzed cyanohydrin formation was also investigated for each
case. This synthetic sequence delivered racemic samples as refer-
ence material for the determination of the enantiomeric excess of
the product obtained from enzyme catalysis and gold catalysis. In
one case, namely 5d, both the non-racemic and the racemic ma-
terials were carried through the whole sequence, in order to proof
thatdas expecteddthe stereocenter does neither racemize in any
of the subsequent functional group manipulations nor in the gold-
catalyzed step. It is important to note, that due to the CIP
nomenclature system, for the same steric arrangement of the four
substituents at the chiral centre, the opposite stereodiscriptor is
obtained (the furan oxygen atom has a higher priority than the
nitrile nitrogen atom), thus the (R)-HNL in the case of furyl-sub-
stituents delivers the (S)- and not the (R)-product.
a
Method A: Pa-HNL/KCN/H2O/DIPE; Method B: KCN/HOAc.
b
Due to the sensitivity of the unprotected cyanohydrin, 6 is not purified; the
crude product 6 is directly silylated to 7, which is stable and allows the de-
termination of the ee value.
The results are summarized in Table 1. Since the stability of the
unprotected cyanohydrin 6 is limited and especially an enantiomer
analysis is difficult for this substrate, the crude material was di-
rectly engaged in the silylation step to furnish the silyl-protected
derivative 7, which is completely stable and easy to handle. Since
the yields in the silylation step usually are excellent and the ster-
eocenter in 6 is not changed during the protection, the ee values
and yields of 7 are good indicators for the efficiency of the step from
5 to 6. For the unsubstituted furfural 5a as well as for the methyl
substituted 5b, the ethyl substituted 5d and the dimethyl derivative
5e, excellent ee values were obtained (entries 1, 3, 7 and 9). The
reaction conditions for the catalyzed and uncatalyzed reaction are
quite different: in the case of enzyme catalysis the undesired,
uncatalyzed cyanohydrin formation must be suppressed. Thus in
the case of the sterically more demanding phenyl group in 5c and
5e with a methyl group in 4-position of the furan ring, much lower
yields were obtained in enzyme catalysis (entries 5 and 9); in the
case of 5a, 5b and 5d, the enzyme-catalyzed and the uncatalyzed
cyanohydrin formation provide similar yields. This clearly indicates
that for these two substrates there is a steric problem in the active
centre of the enzyme, which significantly reduces the rate of re-
action. For rac-7c a crystal structure analysis was obtained (Fig. 1).6
The structure shows a typical dihedral angle for O–C–C–O.
Figure 1. Solid state structure of rac-7c.
A subsequent reduction of the nitrile to amine 8, followed by
a tosylation to sulfonamide 9 and a propargylation to alkyne 10
provided the substrates for the gold catalysis. From previous
work2a,7 it was known that a purification of 8 does not deliver good
yields, it was preferable to use the crude material for the sub-
sequent tosylation, the purification of 9 did not cause any difficulty.
In the case of 7d, the racemic sample was also converted to rac-10d;
the comparison of (S)-10d and rac-10d proofed that, as one would
expect for these steps, the stereocenter was not harmeddby HPLC
still the 99% ee were detected for (S)-10d. Figure 2 shows the results
of a crystal structure analysis of (S)-10a. The conformation of the
tether between the furan ring and the alkyne is oriented in a way
R2
R1
R2
R2
Pa-HNL/HCN
or HCN
CN
OH
TBDMSCl
DMF, rt
CN
OTBDMS
O
R1
R1
DIPE, rt
O
O
O
H
H
H
5
(S)-6
(S)-7
DIBAL-H
Et2O
-70°C
R2
R2
R1
R2
R1
TsCl, Et3N
cat. DMAP
DCM, rt
C3H3Br
Cs2CO3
OTBDMS acetone,
rt
NTs
NH2
OTBDMS
NHTs
OTBDMS
R1
O
O
O
H
H
H
(S)-10
(S)-9
(S)-8
Scheme 3. Enzyme-catalyzed asymmetric cyanohydrin formation and conversion to protected N-propargyl tosylamides 10.

A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
1921
phophane-based gold(I) precatalysts 13 was used.8 With substrate
(S)-10a two constitutional isomers, namely (R)-11a and (R)-12a
(Fig. 3), were obtained (Table 3, entry 1), which is in agreement
with our previous observations for reactions of furans without
substituents in the 5-position.2a The other four substrates (S)-10b–
e gave good yields of (R)-11b–e, as one would expect for furans with
a substituent in the 5-position (entries 2–6). Most important is the
observation that no elimination to the isoquinoline was observed.
Based on recent findings in the synthesis of benzofurans by a gold-
catalyzed cyclization/elimination reaction,5 one could have sur-
mised that such an elimination might occur. Again, comparison of
the racemic sample of 11d with (R)-11d proved that, as one could
expect on the basis of previous conversion of substrates with
stereocenters in the tether,9 the ee-value remained unchanged in
the gold-catalyzed step. For 10b we also tested an other successful
precatalysts, with 5 mol % of [(Ph3PAu)2Cl]BF4 only 90% of (R)-11b
were obtained (Scheme 4).
Figure 2. Solid state structure of (S)-10a.
OTBDMS
R2
R2
R1
NTs
Au(I) cat.
R1
OTBDMS
CDCl3 or
CD2Cl2
NTs
O
H
Table 2
Further conversion of chiral 7 to substrate 10
OH
rt
(R)-11
(S)-10
Entry
7
9 (Yield, ee)a
10 (Yield, ee)
Scheme 4. Gold-catalyzed conversion of 10.
1
2
3
4
5
6
(S)-7a: R1, R2¼H
(S)-9a (23%)
(S)-9b (47%)
(S)-9c (32%)
(S)-9d (93%)
rac-9d (93%)
(S)-9e (54%)
(S)-10a (80%)
(S)-10b (99%)
(S)-10c (79%)
(S)-10d (80%, 99%)
rac-10d (80%)
(S)-10e (92%)
(S)-7b: R1¼Me, R2¼H
(S)-7c: R1¼Ph, R2¼H
(S)-7d: R1¼Et, R2¼H
rac-7d: R1¼Et, R2¼H
(S)-7e: R1¼Me, R2¼Me
3. Conclusion
A sequence including the enzyme-catalyzed asymmetric addi-
tion of HCN to furfurals and a gold-catalyzed cycloisomerization
delivers chiral derivatives of 4,8-dihydroxytetrahydroisoquinolines.
The stereocenter formed by enzyme catalysis suffers no racemiza-
tion in this sequence.
a
Compound 8 is not purified and directly engaged in the tosylation step to
obtain 9 as a stable, easy to handle material.
suitable for a cyclization reaction, similar conformers have been
discussed previously (Table 2).7
An advantage of this sequence is the availability of enzymes for
both series of enantiomers, a limitation is a low conversion in the
enzyme-catalyzed step for furfurals with substituents in the 4-
position of the furan ring or bulky substituents in the 5-position. In
the gold-catalyzed step no undesired elimination is observed.
The gold-catalyzed cycloisomerization to hydroxytetrahydro-
isoquinolines 11. The stereodescriptor switches again, since the
oxygen atom from the furan is more remote now, without a change
of the steric arrangement of the substituents, the (R)-configuration
is now obtained in product 11. For this investigation the biaryl
4. Experimental
4.1. General
1H NMR spectra were recorded at room temperature on the
following spectrometers: Bruker ARX 250, Bruker AC 300 or Bruker
Avance DRX-300, Bruker Avance DRX-500. 13C NMR spectra were
recorded at room temperature on the following spectrometers:
Bruker AC 300 (75.5 MHz), Bruker Avance DRX-300 (75.5 MHz),
Bruker Avance DRX-500 (125.6 MHz). The multiplicity of signals
refers to the DEPT 135- and DEPT 90-spectra. IR spectra (IR) were
measured on a Bruker Vector 22 FT-IR. The substances were
employed as film or KBr pressed disk. Flash column chromatogra-
phy was accomplished using silica gel (0.032–0.062 mm) pur-
chased from Macherey–Nagel as stationary phase. Mass spectra
(MS) and high-resolution mass spectra (HRMS) were determined
on the following instruments: Vakuum Generators ZAB-2F, Fin-
nigan MAT TSQ 700, JEOL JMS-700. Elemental analyses were carried
out on an Elementar Vario EL.
OTBDMS
NTs
HO
(R)-12a
Figure 3. (R)-12a as an expected second product in the conversion of (S)-10a.
Table 3
Results of the gold-catalyzed conversions of 10a
Entry
Substrate 10
(S)-10a: R1, R2¼H
Product 11 (yield, ee)
1
2
3
4
4
4
(R)-11a (45%)þ12a (20%)
(R)-11b (99%)
(R)-11c (82%)
(R)-11d (85%, 99%)
rac-11d (85%)
(R)-11e (81%)
(S)-10b: R1¼Me, R2¼H
(S)-10c: R1¼Ph, R2¼H
(S)-10d: R1¼Et, R2¼H
rac-10d: R1¼Et, R2¼H
(S)-10e: R1¼Me, R2¼Me
All ee determinations were carried out on an Agilent 1100 Series
instrument with a Daicel Chiralpak AS-H (250ꢀ4 mm) column.
In all cases the mobile phase was 99% n-hexane and 1% iso-
propanol, an UV-detector was used, flow rate of 0.5 ml/min, tem-
perature 25 ꢁC.
a
Catalyst loadings: 7 mol % for 10a, 5 mol % for 10b–e.

1922
A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
4.2. Synthesis of (S)-furan-2-yl-hydroxyacetonitrile ((S)-6a,
FA-334)
4.6. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
furan-2-ylethyl]-4-methylphenylsulfonamide ((S)-9a, FA-110)
Citric acid (23.8 g) was dissolved in 32 ml water and 130 ml DIPE
was added. A solution of 5.42 g (104 mmol) KCN in 13 ml water was
added slowly. After 30 min the aqueous layer was separated and
added to a mixture of 25.8 g of powdered almonds with 130 ml
buffer, 32 ml DIPE and 5.00 g (52.0 mmol) of the furfural was
added. After 30 min the organic layer was quickly filtered from the
powdered almonds, dried over MgSO4, filtered and the solvent
removed in vacuo. Thus 2.78 g of (S)-6a as a yellow liquid was
Crude (S)-8a (1.35 g, 5.56 mmol) was dissolved in 50 ml DCM,
1.16 ml (8.34 mmol) NEt3, 68.0 mg (556 mmol) DMAP and finally
1.06 g (5.56 mmol) tosyl chloride were added slowly at room
temperature. After stirring over night, 20 ml H2O was added, the
aqueous phase was extracted with 3ꢀ20 ml DCM. The organic
phase was dried over MgSO4, filtered and the solvent was removed
in vacuo. After column chromatography (silica gel; PE/EE, 20:1)
1.35 g (23% over two steps) of (S)-9a was obtained as a yellow oil. Rf
obtained. 1H NMR (CDCl3, 300 MHz):
d
¼4.25 (br s, 1H), 5.53 (s, 1H),
(PE/EE, 20:1)¼0.30. IR (film):
n
¼3287, 2953, 2929, 2886, 2856,1599,
6.41 (d, J¼1.8 Hz, J¼3.4 Hz 1H), 6.58 (d, J¼3.4 Hz, 1H), 7.47 (d,
J¼1.9 Hz, 1H).
1463, 1406, 1329, 1252, 1159, 1085 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
d
¼ꢂ0.14 (s, 3H), 0.00 (s, 3H), 0.82 (s, 9H), 2.42 (s, 3H), 3.22
(t, J¼6.2 Hz, 2H), 4.64 (t, J¼6.1 Hz, 1H), 4.73 (t, J¼6.1 Hz, 1H), 6.20
(d, J¼3.2 Hz, 1H), 6.29 (d, J¼3.2 Hz, 1H), 6.30 (d, J¼3.2 Hz, 1H), 7.30
(d, J¼8.1 Hz, 2H), 7.72 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
4.3. Synthesis of rac-furan-2-yl-hydroxyacetonitrile (rac-6a,
FA-107)
d
¼ꢂ5.09 (q), 18.10 (s), 21.53 (q), 25.72 (q), 47.92 (t), 67.15 (d), 107.63
(d), 110.25 (d), 127.11 (d), 129.76 (d), 136.96 (s), 142.17 (d), 143.48 (s),
153.49 (s). MS (EI, 70 eV): m/z (%): 395 (6) [Mþ], 340 (8), 339 (14),
338 (62), 212 (18), 211 (100), 155 (12), 91 (17), 75 (17), 73 (36), 28
(22). C19H29NO4SSi (395.59): calcd C 57.69, H 7.39, N 3.54; found C
58.12, H 7.42, N 3.53. HRMS (70 eV): C19H29NO4SSi: calcd 395.1587;
found 395.1605.
Furfural (5.08 g, 52.0 mmol) was dissolved in 26 ml glacial
acetic acid and cooled to 0 ꢁC. Then a solution of 8.14 mg
(156 mmol) KCN in 16 ml H2O was added dropwise and the mix-
ture was stirred over night at room temperature. Then 26 ml H2O
was added, the product was extracted with Et2O (3ꢀ20 ml) and
dried over MgSO4. After filtration and addition of toluene, the
solvent was removed. Crude rac-6a (6.94 g) was obtained and
directly used in the next step without further purification. 1H NMR
data identical to (S)-6a.
4.7. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
furan-2-ylethyl]-4-methyl-N-prop-2-ynylphenylsulfonamide
((S)-10a, FA-111)
Compound (S)-9a (1.18 g, 2.99 mmol) was dissolved in 20 ml
acetone; 2.92 g (8.96 mmol) Cs2CO3 and 1.00 ml (8.96 mmol)
propargyl bromide (80 wt % in toluene) were added. After stirring
over night, the solvent was removed in vacuo and the residue was
taken up in 20 ml H2O. After three extractions with 20 ml DCM each
the organic layer was dried over MgSO4, filtered and the solvent
removed in vacuo. After column chromatography (silica gel; PE/EE,
20:1) 1.04 g (S)-10a (80%) was obtained as a yellow solid. Mp: 59 ꢁC.
4.4. Synthesis of (S)-(tert-butyldimethylsilanyloxy)furan-2-yl-
acetonitrile ((S)-7a, FA-335)
Crude rac-6a (2.78 g, 22.6 mmol) was dissolved in 14 ml DMF,
6.80 g (45.1 mmol) imidazole and 3.84 g (56.4 mmol) TBDMSCl
were added and the mixture was stirred over night at room tem-
perature. After column chromatography (silica; PE/EE, 20:1) 4.40 g
(81% over two steps) of the yellow liquid (S)-7a was obtained. Rf
Rf (PE/EE, 20:1)¼0.40. IR (film):
2118, 2023, 1737, 1598, 1472, 1161, 1094 cmꢂ1
500 MHz):
n
¼3297, 2929, 2857, 2363, 2214,
(PE/EE, 20:1)¼0.28. IR (film):
n
¼2956, 2931, 2888, 2859, 1500, 1472,
1H NMR (CDCl3,
1391, 1363, 1304, 1255, 1147, 1071 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
.
d
¼ꢂ0.06 (s, 3H), 0.09 (s, 3H), 0.87 (s, 9H), 1.99 (t,
d
¼0.14 (s, 3H), 0.17 (s, 3H), 0.91 (s, 9H), 5.55 (s, 1H), 6.40 (d,
J¼3.2 Hz, 1H), 6.53 (d, J¼3.2 Hz, 1H), 7.44 (d, J¼3.2 Hz, 1H). 13C NMR
J¼2.5 Hz, 1H), 2.41 (s, 3H), 3.44 (d, J¼6.6 Hz, 2H), 4.01 (dd, J¼2.4,
18.4 Hz, 1H), 4.20 (dd, J¼2.5, 18.5 Hz, 1H), 5.01 (t, J¼6.5 Hz, 1H), 6.28
(d, J¼3.2 Hz, 1H), 6.32 (d, J¼1.9 Hz, 1H), 7.28 (d, J¼8.3 Hz, 2H), 7.37
(d, J¼1.9 Hz, 1H), 7.73 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
(CDCl3, 125 MHz):
d¼ꢂ5.21 (q), 18.19 (s), 25.48 (q), 58.10 (d), 109.46
(d), 110.79 (d), 117.27 (s), 143.80 (s), 148.54 (s). MS (ESI (þ), 70 eV):
m/z (%): 260 (100) [MþNa]þ. C12H19NO2Si (237.37): calcd C 60.72, H
8.07, N 5.90; found C 60.93, H 8.06, N 5.92. HRMS (ESI (þ), 70 eV):
d
¼ꢂ5.09 (q), 14.18 (s), 18.08 (d), 21.52 (q), 25.72 (q), 38.76 (t), 51.33
578
546
(t), 68.73 (d), 73.44 (s), 107.57 (d), 110.26 (d), 127.78 (d), 129.40 (d),
136.08 (s), 142.01 (d), 143.47 (s), 153.14 (s). MS (EI, 70 eV): m/z (%):
433 (7) [Mþ], 377 (10), 376 (36), 222 (9), 212 (18), 211 (100), 155
(10), 91 (17), 73 (36), 28 (16). C22H31NO4SSi (433.6374): calcd C
60.93, H 7.21, N 3.23; found C 61.61, H 7.23, N 3.16. HRMS (70 eV):
C12H19NO2Si: calcd 237.1075; found 237.1072. [
a]
17.8; [a]
436
20.4; [
a
]
37.1.
4.5. Synthesis of (S)-2-(tert-butyldimethylsilanyloxy)-2-
furan-2-ylethylamine ((S)-8a, FA-109)
578
546
C22H31NO4SSi: calcd 433.1743; found 433.1750. [
a
]
ꢂ47.2; [
a]
436
ꢂ54.1; [
a]
ꢂ98.6.
Compound (S)-7a (3.50 g, 14.7 mmol) was dissolved in
100 ml Et2O and cooled to ꢂ70 ꢁC. Then 29.4 ml DIBAL-H (1.0 M
solution in hexane) was added dropwise and the solution was
warmed to ꢂ20 ꢁC. After cooling to ꢂ70 ꢁC again, 45 ml MeOH
and 1.11 g (29.4 mmol) NaBH4 were added and the solution was
allowed to warm to room temperature over night. Et2O (50 ml)
was added and the organic layer was washed with 50 ml 2 N
NaOH, 50 ml H2O, 50 ml brine and then dried over MgSO4. After
filtration and removal of the solvent in vacuo, 4.01 g (S)-8a was
obtained as a yellow oil, which was used in the next step di-
4.8. Synthesis of (R)-4-(tert-butyldimethylsilanyloxy)-7-
phenyl-2-(toluol-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-
8-ol ((R)-11a, FA-347)
Compound (R)-10a (100 mg, 230
mmol) was dissolved in an
NMR tube in 500 l CD2Cl2, then 8.20 mg (16.3
m
m
mol, 7 mol %) of di-
tert-butyl-{3,4,5,6-tetramethyl-2-[2,4,6-(triisopropyl)phenyl]phenyl}-
phosphingold chloride (13) the gold complex and 5.00 mg
(16.3 mmol) Ag[SbF6] in CD2Cl2 were added. The reaction was
rectly. 1H NMR (CDCl3, 300 MHz):
d
¼0.01 (s, 3H), 0.08 (s, 3H),
monitored by 1H NMR spectroscopy. When complete, the solvent
was removed in vacuo and the residue purified by column chro-
matography (silica gel; PE/EE, 3:1), delivering 45 mg (45%) of (R)-
11a and 20 mg (20%) of (R)-12a, both as colourless solids. In the
0.88 (s, 9H), 1.77 (m, 1H), 3.01 (m, 2H), 4.74 (dd, J¼4.7, 6.1 Hz,
1H), 6.24 (d, J¼3.3 Hz, 1H), 6.32 (dd, J¼1.9, 3.3 Hz, 1H), 7.36 (d,
J¼1.8 Hz, 1H).

A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
1923
crude material the ratio of (R)-11a/(R)-12a was determined to be
71:29 by 1H NMR spectroscopy.
C13H21NO2Si (251.40): calcd C 62.11, H 8.42, N 5.57; found C 62.15, H
20
8.38, N 5.53. [
a
]
ꢂ24.4 (c 0.52 g/100 ml, CHCl3).
D
Compound 11a: Mp: 142 ꢁC. Rf (PE/EE, 3:1)¼0.19. IR (film):
n
¼3485, 2956, 2929, 1597, 1470 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
4.12. (S)-(tert-Butyldimethylsilyloxy)-2-(5-methylfuran-2-yl)-
ethylamine ((S)-8b, PH-310)
d
¼0.00 (s, 6H), 0.753 (s, 9H), 2.59 (dd, J¼5.2, 11.4 Hz, 1H), 3.63 (dd,
J¼6.3, 11.4 Hz, 1H), 3.69 (d, J¼15.9 Hz, 1H), 4.35 (d, J¼15.8 Hz, 1H),
4.64 (dd, J¼5.2, 8.2 Hz, 1H), 4.77 (br s, 1H), 6.43 (t, J¼7.8 Hz, 1H),
6.80 (d, J¼7.8 Hz, 1H), 6.91 (t, J¼7.8, Hz, 1H), 7.13 (d, J¼7.9 Hz, 2H),
Compound (S)-7b (1.10 g, 4.38 mmol) was dissolved in 40 ml
Et2O and cooled to ꢂ70 ꢁC; 5.26 ml DIBALH (1.0 M in hexane) added
slowly, then the mixture is allowed to warm to ꢂ20 ꢁC. After
cooling to ꢂ70 ꢁC, 14 ml MeOH and then 331 mg (8.76 mmol)
NaBH4 was added and the solution was slowly warmed to room
temperature. Et2O (20 ml) was added, the organic layer is washed
with 75 ml 2 N NaOH, 75 ml H2O, and 75 ml brine and then dried
over MgSO4. Removal of the solvent in vacuo delivered 975 mg of
amine (S)-8b as a colourless oil, which is directly used in the next
step.
7.55 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 76 MHz):
¼ꢂ4.75 (q),
d
ꢂ4.30 (q), 21.51 (q), 25.82 (q), 43.37 (t), 49.61 (t), 67.08 (d), 113.55
(d), 118.70 (d), 127.43 (d), 127.83 (d), 129.80 (d), 133.72 (s), 139.03
(s), 143.73 (s), 151.56 (s). MS (ESI, eV): m/z (%): 456 (100) [MþNaþ].
HRESI (eV): C22H31NNaO4SSi: calcd 456.1633 [MþNa]þ; found
456.1638 [MþNa]þ. [
a
]
33.3; [
a
]
546 35.3; [
a
]
45.5.
578
436
Compound 12a: Mp: 142 ꢁC. Rf (PE/EE, 3:1)¼0.15. IR (film):
n
¼3485, 2956, 2929, 1597, 1470 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
¼0.00 (s, 6H), 0.75 (s, 9H), 2.23 (s, 3H), 2.59 (dd, J¼5.2, 11.4 Hz,1H),
d
3.62 (dd, J¼5.3, 8.2 Hz, 1H), 3.72 (d, J¼15.9 Hz, 1H), 4.35 (d,
J¼15.8 Hz, 1H), 4.63 (dd, J¼5.2, 11.4 Hz, 1H), 5.53 (br s, 1H), 6.43 (d,
J¼7.8 Hz, 1H), 6.80 (d, J¼7.8 Hz, 1H), 7.08 (s, 1H), 7.13 (d, J¼7.9 Hz,
4.13. N-[(S)-(tert-Butyldimethylsilyloxy)-2-(5-methylfuran-2-
yl)ethyl]-4-methyl-benzenesulfonamide ((S)-9b, PH-311A)
2H), 7.55 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 76 MHz):
d¼ꢂ4.75 (q),
Compound (S)-8b (975 mg) was dissolved in 20 ml DCM and
916 ml (665 mg, 6.57 mmol) NEt3, 53.8 mg (440 mmol) DMAP and
ꢂ4.30 (q), 21.07 (q), 25.64 (q), 43.37 (t), 49.61 (t), 67.08 (d), 113.49
(d), 118.66 (d), 127.38 (d), 127.60 (d), 129.80 (d), 133.72 (s), 138.99
(s), 143.73 (s), 151.56 (s). MS (ESI, eV): m/z (%): 456 (100) [MþNaþ].
HRESI (eV): C22H31NNaO4SSi: calcd 456.1633 [MþNa]þ; found
456.1638 [MþNa]þ.
919 mg (4.82 mmol) tosyl chloride were added at room tempera-
ture. After complete conversion of the substrate, 20 ml H2O was
added, the organic layer was extracted with 20 ml DCM. The or-
ganic layer was dried over Na2SO4, filtered, the solvent removed in
vacuo. After column chromatography (SiO2, PE/EE¼10:1) 842 mg
(2.06 mmol, 47% over two steps) of (S)-9b was obtained as a pale
4.9. Synthesis of (S)-5-methylfuran-2-yl-hydroxyacetonitrile
((S)-6b)
yellow oil. Rf (PE/EE, 5:1)¼0.34. IR (neat):
1405, 1331, 1253, 1160, 1087, 1017, 965, 837, 781 cmꢂ1
(CDCl3, 500 MHz):
n
¼2931, 2891, 2857, 1461,
.
1H NMR
Citric acid (23.8 g) was dissolved in 32 ml water and 50 ml DIPE
was added. A solution of 5.42 g (104 mmol) KCN in 13 ml water was
added slowly. After 30 min the aqueous layer was separated and
added to a mixture of 25.8 g of powdered almonds with 130 ml
buffer, 32 ml DIPE and 1.10 g (10.0 mmol) of 5b was added. After
30 min the organic layer was quickly filtered from the powdered
almonds, dried over MgSO4, filtered and the solvent removed in
vacuo. Thus 1.38 g of (S)-6b was obtained as a yellow liquid.
d
¼ꢂ0.13 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H), 2.21 (d,
J¼1.0 Hz, 3H), 2.42 (s, 3H), 3.18–3.26 (m, 2H), 4.62–4.67 (m, 2H),
5.86 (dq, J¼3.1, 1.0 Hz, 1H), 6.04 (d, J¼3.1 Hz, 1H), 7.30 (d, J¼8.2 Hz,
2H), 7.72 (d, J¼8.2 Hz, 2H). 13C NMR (CDCl3, 125.8 MHz):
¼ꢂ5.19
d
(q), ꢂ5.00 (q), 13.50 (q), 18.13 (s), 21.54 (q), 25.77 (q, 3C), 47.88 (t),
67.18 (d), 106.13 (d), 108.51 (d), 127.13 (d, 2C), 129.74 (d, 2C), 137.05
(s), 143.43 (s), 151.52 (s), 151.98 (s). MS (EI (þ), 70 eV): m/z (%): 409
(1) [Mþ], 394 (1), 352 (20), 225 (100). EA: C20H31NO4SSi (409.61):
20
calcd C 58.64, H 7.63, N 3.42; found C 58.92, H 7.71, N 3.44. [a]
D
4.10. Synthesis of rac-5-methylfuran-2-yl-hydroxyacetonitrile
(rac-6b)
þ110.2 (c 0.48 g/100 ml, CHCl3).
4.14. N-[(S)-(tert-Butyldimethylsilyloxy)-2-(5-methylfuran-2-
yl)ethyl]-4-methyl-N-prop-2-ynylbenzenesulfonamide ((S)-
10b, PH-312A)
Compound 5b (1.10 g, 10.0 mmol) was dissolved in 15 ml glacial
acetic acid and cooled to 0 ꢁC. Then a solution of 4.07 g (78.0 mmol)
KCN in 16 ml H2O was added dropwise and the mixture was stirred
over night at room temperature. Then 20 ml H2O was added, the
product was extracted with Et2O (3ꢀ20 ml) and dried over MgSO4.
After filtration and addition of toluene, the solvent was removed.
Crude rac-6b (940 mg) was obtained.
Compound (S)-9b (778 mg,1.90 mmol) was dissolved in 10 ml of
acetone; 1.86 g (5.70 mmol) Cs2CO3 and 633 (678 mg,
ml
5.70 mmol) propargyl bromide (80 wt % in toluene) were added.
After stirring over night, the solvent was removed in vacuo and the
residue was taken up in 10 ml H2O. After three extractions with
10 ml DCM each the organic layer was dried over MgSO4, filtered
and the solvent removed in vacuo. After column chromatography
(silica gel; PE/EE, 10:1) 848 mg (1.89 mmol, 99%) of (S)-10b was
obtained as a colourless solid. Mp 58–60 ꢁC. Rf (PE/EE, 5:1)¼0.29. IR
4.11. (S)-(L)-(tert-Butyldimethylsilyloxy)-(5-methylfuran-2-
yl)acetonitrile ((S)-7b, PH-300A)
Crude cyanohydrin (S)-6b (1.38 g, 10.0 mmol) was dissolved in
6 ml DMF and at room temperature 1.70 g (25.0 mmol) imidazole
and 3.01 g (20.0 mmol) TBDMSCl were added and the mixture was
stirred over night. After the usual work up and purification by
column chromatography (SiO2, PE/EE¼10:1) 1.62 g (64%) (S)-7b
was obtained as a colourless solid. Mp 36–38 ꢁC. Rf (PE/EE,
(neat):
1188, 1154, 1086, 1006, 937, 832, 786, 716, 652, 591 cmꢂ1. 1H NMR
(CDCl3, 500 MHz):
n
¼3279, 2936, 2891, 2855, 1598, 1558, 1437, 1343, 1253,
d¼ꢂ0.06 (s, 3H), 0.08 (s, 3H), 0.86 (s, 9H), 1.99 (t,
J¼2.4 Hz, 1H), 2.26 (d, J¼1.0 Hz, 3H), 2.41 (s, 3H), 3.43 (d, J¼6.6 Hz,
2H), 4.02 (dd, J¼18.4, 2.4 Hz, 1H), 4.21 (dd, J¼18.4, 2.4 Hz, 1H), 4.92
(sichtbares t, J¼6.6 Hz, 1H), 5.89 (dq, J¼3.0, 1.0 Hz, 1H), 6.12 (d,
J¼3.0 Hz, 1H), 7.27 (d, J¼8.3 Hz, 2H), 7.74 (d, J¼8.3 Hz, 2H). 13C NMR
5:1)¼0.54. IR (neat):
n
¼2932, 2891, 2857, 1465, 1360, 1322, 1251,
1086, 1013, 963, 925, 837, 775 cmꢂ1
.
1H NMR (CDCl3, 500 MHz):
d
¼0.13 (s, 3H), 0.15 (s, 3H), 0.91 (s, 9H), 2.31 (s, 3H), 5.49 (s,1H), 5.97
(CDCl3, 125.8 MHz):
d¼ꢂ5.07 (q), ꢂ4.99 (q), 13.56 (q), 18.14 (s),
(d, J¼3.1 Hz,1H), 6.38 (s, J¼3.1 Hz,1H). 13C NMR (CDCl3,125.8 MHz):
21.55 (q), 25.80 (q, 3C), 38.70 (t), 51.29 (t), 68.78 (d), 73.41 (d), 77.31
(s), 106.12 (d), 108.45 (d), 127.81 (d, 2C), 129.41 (d, 2C), 136.27 (s),
143.44 (s), 151.80 (s), 152.26 (s). MS (EI (þ), 70 eV): m/z (%): 447 (2)
[Mþ], 432 (1), 390 (16), 225 (100). EA: C23H33NO4SSi (447.66): calcd
d
¼ꢂ5.21 (q), ꢂ5.12 (q), 13.54 (q), 18.17 (s), 25.48 (q, 3C), 58.10 (d),
106.69 (d), 110.38 (d), 117.43 (s), 146.60 (s), 153.90 (s). MS (EI (þ),
70 eV): m/z (%): 251 (1) [Mþ], 194 (97), 75 (100). Elemental analysis:

1924
A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
20
C 61.71, H 7.43, N 3.13; found C 61.59, H 7.41, 3.10. [
0.50 g/100 ml, CHCl3).
a
]
D
þ265.0 (c
(s, 9H), 0.21 (s, 3H), 0.20 (s, 3H). 13C NMR (CDCl3, 76 MHz):
d¼ꢂ5.16
(q), 18.16 (q), 25.44 (q), 58.20 (d), 105.73 (d), 114.44 (d), 117.19 (s),
123.94 (d), 128.05 (d), 128.74 (d), 129.55 (s), 147.73 (s), 155.23 (s).
MS (EI, 70 eV): m/z (%): 313 (8) [Mþ], 298 (5), 256 (100), 251 (3), 201
(4), 182 (89), 151 (9), 113 (8). C18H23NO2Si (313.15): calcd C 68.97, H
7.40, N 4.47; found C 69.08, H 7.45, N 4.47. HRMS (70 eV):
4.15. (R)-(tert-Butyldimethylsilyloxy)-7-methyl-2-(toluol-4-
sulfonyl)-1,2,3,4-tetrahydroisoquinolin-8-ol ((R)-11b, PH-
314A)
C18H23NO2Si: calcd 313.1498; found 313.1495. [
[a]
a] a]
578 3.6; [ 546 4.0;
From 58.7 mg (131
m
mol) (S)-10b was dissolved in an NMR tube
436 7.4.
in 600 L CD2Cl2 and 8.48 mg (6.56
m
mmol, 5 mol %) 13 and 2.25 mg
(6.56 mmol) Ag[SbF6] in CD2Cl2 were added. The reaction was
monitored by 1H NMR spectroscopy, when complete the solvent
was removed in vacuo and the residue purified by column chro-
4.19. Synthesis of (S)-2-(tert-butyldimethylsilanyloxy)-2-(4,5-
dimethylfuran-2-yl)ethylamine ((S)-8c, FA-278)
matography (silica gel; PE/EE, 10:1), delivered 20.1 mg (44.9
m
mol,
Compound (S)-7c (1.88 g, 10.9 mmol) was dissolved in 30 ml
Et2O and cooled to ꢂ70 ꢁC. Then 21.9 ml DIBAL-H (1.0 M solution in
hexane) was added dropwise and the solution was warmed to
ꢂ20 ꢁC. After cooling to ꢂ70 ꢁC again, 8 ml MeOH and 825 mg
(21.9 mmol) NaBH4 were added and the solution was allowed to
warm to room temperature over night. Et2O (30 ml) was added and
the organic layer was washed with 30 ml 2 N NaOH, 30 ml H2O and
30 ml brine, then dried over MgSO4. After filtration and removal of
the solvent in vacuo, 1.86 g (S)-8c was obtained as a yellow oil,
which was used in the next step directly.
34%) of (R)-11b as a colourless solid (NMR-yield 90%). Mp 159–
161 ꢁC. Rf (PE/EE, 10:1)¼0.20. IR (neat):
¼3496, 2932, 2856, 1593,
n
1462, 1336, 1244, 1158, 1081, 954, 897, 818, 780, 652 cmꢂ1. 1H NMR
(CDCl3, 500 MHz):
d
¼0.17 (s, 6H), 0.93 (s 9H), 2.20 (s, 3H), 2.42 (s,
3H), 2.78 (dd, J¼11.4, 8.4 Hz, 1H), 3.79 (ddd, J¼11.4, 5.1, 1.0 Hz, 1H),
3.93 (d, J¼15.8 Hz, 1H), 4.56 (d, J¼15.8 Hz, 1H), 4.83 (dd, J¼8.4,
5.1 Hz, 1H), 4.87 (br s, 1H), 6.90 (d, J¼7.9 Hz, 1H), 7.00 (d, J¼7.9 Hz,
1H), 7.32 (d, J¼8.3 Hz, 2H), 7.75 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3,
125.8 MHz):
d
¼ꢂ4.76 (q), ꢂ4.31 (q), 15.33 (q), 18.11 (s), 21.50 (q),
25.81 (q, 3C), 43.51 (t), 49.60 (t), 66.94 (d), 118.52 (d), 118.78 (s),
120.79 (s), 127.62 (d, 2C), 128.83 (d), 129.73 (d, 2C), 133.84 (s),
136.83 (s), 143.62 (s), 149.59 (s). MS (CI (þ), 70 eV): m/z (%): 446 (5)
4.20. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
(5-phenylfuran-2-yl)-ethyl]-4-methylphenylulfonamide ((S)-
9c, FA-281)
[MꢂH]þ, 432 (9), 390 (100), 316 (70). HRMS (CI (þ)): C23H33NO4SSi:
[MꢂH]þ calcd 446.1821; found 446.1825. [
a]
¼ꢂ24.5 (c 0.82 g/
20
D
100 ml, CHCl3).
Crude (S)-8c (620 mg, 1.19 mmol) was dissolved in 10 ml DCM,
160 ml (1.19 mmol) NEt3,14.5 mg (119 mmol) DMAP and finally 227 g
4.16. Synthesis of (S)-hydroxy(5-phenylfuran-2-yl)acetonitrile
((S)-6c, FA-ER-26)
(119 mmol) tosyl chloride were added slowly at room temperature.
After stirring over night, 20 ml H2O was added, the aqueous phase
was extracted with 3ꢀ10 ml DCM. The organic phase was dried
over MgSO4, filtered and the solvent was removed in vacuo. After
column chromatography (silica gel; PE/EE, 10:1) 1.69 g (32% over
three steps) of (S)-9c was obtained as a yellow oil. Rf (PE/EE,
Citric acid (21.1 g) was dissolved in 30 ml water and 30 ml DIPE
were added. A solution of 4.81 g (92.3 mmol) in 12 ml water was
added slowly. After 30 min the aqueous layer was separated and
added to a mixture of 22.9 g of powdered almonds with 110 ml
buffer, 115 ml DIPE and 7.94 g (46.1 mmol) of 5-phenylfurfural was
added. After 30 min the organic layer was quickly filtered from the
powdered almonds, dried over MgSO4, filtered and the solvent
removed in vacuo. Thus 4.93 g of crude (S)-6c was obtained as
a greenish liquid.
10:1)¼0.14. IR (film):
n
¼2954, 2930, 2857, 1486, 1470, 1448, 1406,
1361, 1332, 1254 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
d
¼ꢂ0.03 (s, 3H),
0.11 (s, 3H), 0.88 (s, 9H), 2.33 (s, 3H), 3.33–3.21 (m, 3H), 4.71 (t,
J¼5.8 Hz, 1H), 4.79 (dd, J¼5.0, 6.5 Hz, 1H), 6.34 (d, J¼3.3 Hz, 1H),
6.58 (d, J¼3.3 Hz, 1H), 7.39–7.33 (m, 3H), 7.59 (d, J¼10.0 Hz, 2H),
7.61 (d, J¼8.5 Hz, 2H), 7.68 (d, J¼10.0 Hz, 2H). 13C NMR (CDCl3,
76 MHz):
d
¼ꢂ5.20 (q), ꢂ5.00 (q), 25.6 (q), 53.20 (t), 105.50 (d),
4.17. Synthesis of rac-hydroxy(5-phenylfuran-2-
yl)acetonitrile (rac-6c, FA-217)
110.10 (d), 123.60 (d), 123.80 (d), 127.00 (d), 127.80 (d), 128.60 (d),
128.70 (d), 136.80 (s), 143.40 (s), 152.00 (s), 153.00 (s). MS (FABþ):
m/z (%): 471 (9) [Mþ], 470 (12), 456 (23), 414 (57), 387 (14), 340
(100). HRMS (HRFABþ): C25H33NO4SSi: calcd 471.1967; found
471.1967.
5-Phenylfurfural (500 mg, 2.90 mmol) was dissolved in 3.5 ml
glacial acetic acid and cooled to 0 ꢁC. Then a solution of 457 mg
(8.71 mmol) KCN in 3.5 ml H2O was added dropwise and the mix-
ture was stirred over night at room temperature. Then 3.5 ml H2O
was added, the product was extracted with Et2O (3ꢀ10 ml) and
dried over MgSO4. After filtration and addition of toluene, the sol-
vent was removed. Crude rac-6c (560 mg) was obtained and di-
rectly used in the next step without further purification.
4.21. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
furan-2-ylethyl]-4-methyl-N-prop-2-ynylphenylsulfonamide
((S)-10c, FA-283)
Compound (S)-9c (561 mg, 1.19 mmol) was dissolved in 20 ml
acetone; 1.16 g (3.57 mmol) Cs2CO3 and 3.57 ml (3.57 mmol)
propargyl bromide (80 wt % in toluene) were added. After stirring
over night, the solvent was removed in vacuo and the residue was
taken up in 10 ml H2O. After three extractions with 10 ml DCM each
the organic layer was dried over MgSO4, filtered and the solvent
removed in vacuo. After column chromatography (silica gel; PE/EE,
5:1) 478 g (79%) (S)-10c was obtained as a yellow solid. Rf (PE/EE,
4.18. Synthesis of (S)-(tert-butyldimethylsilanyloxy)-(5-
phenylfuran-2-yl)acetonitrile ((S)-7c, FA-219)
Crude (S)-6c (560 mg, 2.83 mmol) was dissolved in 10 ml DMF,
385 mg (5.66 mmol) imidazole and 639 mg (168 mmol) TBDMSCl
were added and the mixture was stirred over night at room tem-
perature. After column chromatography (silica; PE/EE, 10:1) 677 mg
(76% over two steps) of the yellow solid (S)-7c was obtained. Mp:
5:1)¼0.30. IR (film):
n
¼3297, 2929, 2857, 2363, 2214, 2118, 2023,
1737, 1598, 1472, 1161, 1094 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
54 ꢁC. Rf (PE/EE, 3:1)¼0.27. IR (film):
n
¼2958, 2949, 2931, 2858,
d
¼0.20 (d, J¼3.0 Hz, 3H), 0.94 (s, 9H), 2.41 (s, 3H), 2.77 (dd, J¼3.0,
1470, 1335, 1264, 1256, 1215, 1074 cmꢂ1. 1H NMR (CDCl3, 300 MHz):
6.0 Hz, 1H), 3.90 (d, J¼18.0 Hz, 1H), 4.60 (d, J¼15.0 Hz, 1H), 4.89 (dd,
J¼6.0, 9.0 Hz, 1H), 5.28 (s, 1H), 7.03 (d, J¼6.0 Hz, 1H), 7.12 (d,
J¼9.0 Hz, 1H), 7.30–7.73 (m, 7H), 7.75 (d, J¼6.0 Hz, 2H). 13C NMR
d
¼9.64 (s, 1H), 7.85 (d, J¼8.1 Hz, 1H), 7.70 (d, J¼7.2 Hz, 1H), 7.39 (m,
3H), 6.86 (d, J¼3.7 Hz, 1H), 6.68 (d, J¼3.4 Hz, 1H), 5.6 (s, 1H), 0.90

A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
1925
(CDCl3, 125 MHz):
d
¼18.11 (q), 21.51 (q), 25.77 (q), 38.78 (t), 51.44
(93% over two steps) of liquid (S)-7d was obtained. Rf (PE/EE,
20:1)¼0.37. IR (film): ¼2930, 2886, 2858, 1556, 1464, 1363, 1255,
1204, 1086, 1015, 911, 839 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
(t), 68.82 (d), 73.53 (s), 105.65 (d), 109.59 (d), 123.74 (d), 127.38 (d),
127.79 (d), 129.44 (d), 130.71 (s), 136.12 (s), 143.50 (s), 153.42 (s),
153.86 (s). MS (EI, 70 eV): m/z (%): 509 (38) [Mþ], 508 (22), 452
(100), 404 (9). HRMS (70 eV): C28H35NO4SSi: calcd 509.2056; found
509.2018.
n
d
¼0.01
(s, 6H), 0.78 (s, 9H), 1.10 (t, J¼7.6 Hz, 3H), 2.52 (q, J¼7.6 Hz, 2H), 5.37
(s,1H), 5.85 (d, J¼3.2 Hz,1H), 6.28 (d, J¼3.2 Hz,1H). 13C NMR (CDCl3,
125 MHz):
d
¼ꢂ5.28 (q),12.02 (q),18.17 (s), 21.37 (t), 25.46 (q), 58.13
(d), 105.15 (d), 110.19 (d), 117.44 (s), 146.43 (s), 159.50 (s). MS (EI,
70 eV): m/z (%): 265 (12) [Mþ], 250 (74), 239 (11), 209 (16), 208
(100), 194 (4), 181 (5), 134 (11), 119 (4), 75 (47). C14H23NO2Si
(265.42): calcd C 63.35, H 8.73, N 5.28; found C 63.43, H 8.98, N 5.07.
4.22. Synthesis of (R)-4-(tert-butyldimethylsilanyloxy)-7-
phenyl-2-(toluol-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-
8-ol ((R)-11c, FA-ER-35)
578
546
[a
]
4.8; [
a
]
5.5; [a]
436 9.8.
Compound (S)-10c (181 mg, 355
tube in 500 l CD2Cl2, then 12.7 mg (17.7
7.71 mg (17.7 mol) Ag[SbF6] in CD2Cl2 were added. The reaction
m
mol) was dissolved in an NMR
m
m
mmol, 5 mol %) 13 and
4.26. Synthesis of (S)-2-(tert-butyldimethylsilanyloxy)-2-(5-
ethylfuran-2-yl)ethylamine ((S)-8d, FA-292)
was monitored by 1H NMR spectroscopy, when complete the solvent
was removed in vacuo and the residue purified by column chro-
matography (silica gel; PE/EE, 10:1), delivering 149 mg (82%) of (R)-
11c as colourless oil, which solidifies in the freezer but melts at room
Compound (S)-7d (4.44 g, 16.7 mmol) was dissolved in 50 ml
Et2O and cooled to ꢂ70 ꢁC. Then 33.4 ml DIBAL-H (1.0 M solution in
hexane) was added dropwise and the solution was warmed to
ꢂ20 ꢁC. After cooling to ꢂ70 ꢁC again, 20 ml MeOH and 1.26 g
(33.4 mmol) NaBH4 were added and the solution was allowed to
warm to room temperature over night. Et2O (50 ml) was added and
the organic layer was washed with 50 ml 2 N NaOH, 50 ml H2O and
50 ml brine, then dried over MgSO4. After filtration and removal of
the solvent in vacuo, 4.09 g (S)-8d was obtained as a yellow oil,
which was used in the next step directly. 1H NMR (CDCl3, MHz):
temperature. Rf (PE/EE, 8:1)¼0.10. IR (film):
1344, 1255, 1233, 1167, 1127, 1091, 1074, 991 cmꢂ1. 1H NMR (CDCl3,
300 MHz):
n
¼3500, 2954, 2929,
d
¼0.20 (d, J¼3.0 Hz, 3H), 0.94 (s, 9H), 2.41 (s, 3H), 2.77
(dd, J¼3.0, 6.0 Hz, 1H), 3.90 (d, J¼18.0 Hz, 1H), 4.60 (d, J¼15.0 Hz,
1H), 4.89 (dd, J¼6.0, 9.0 Hz, 1H), 5.28 (s, 1H), 7.03 (d, J¼6.0 Hz, 1H),
7.12 (d, J¼9.0 Hz, 1H), 7.30–7.73 (m, 7H), 7.75 (d, J¼6.0 Hz, 2H). 13C
NMR (CDCl3, 125 MHz):
d
¼ꢂ4.74 (q), ꢂ4.26 (q), 21.54 (q), 25.85 (q),
43.67 (t), 49.53 (t), 67.04 (d), 118.49 (d), 119.18 (s), 127.66 (d), 128.17
(d),128.22 (d),128.96 (d),129.66 (d),129.76 (d),127.80 (s),133.91 (s),
136.37 (s),138.69 (s),143.63 (s),148.06 (s). MS (ESI, eV): m/z (%): 508
(31) [M]þ, 494 (11), 452 (58), 436 (9), 434 (7), 378 (100), 352 (22).
HRESI (eV): C28H35NO4SSi: calcd 508.2056 [M]þ; found 508.1972
d
¼ꢂ0.07 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 1.18 (t, J¼6.0 Hz, 2H), 1.44
(br s, 2H), 2.59 (q, J¼6.0 Hz,1H), 2.99–2.82 (m, 2H), 4.57 (t, J¼6.0 Hz,
1H), 5.87 (d, J¼3.0 Hz, 1H), 6.05 (d, J¼3.0 Hz, 1H).
4.27. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
(5-ethylfuran-2-yl)ethyl]-4-methylphenylsulfonamide ((S)-9d,
FA-294)
[M]þ. [ 578 17.1; [ 546 18.7; [ 436 31.0.
a] a] a]
4.23. Synthesis of (S)-5-ethylfuran-2-yl-hydroxyacetonitrile
((S)-6d, FA-307)
Crude (S)-8d (2.00 g, 5.08 mmol) was dissolved in 20 ml DCM,
700 ml (5.08 mmol) NEt3, 62.0 mg (508 mmol) DMAP and finally
Citric acid (3.68 g) was dissolved in 20 ml water and 75 ml DIPE
was added. A solution of 3.20 g (61.2 mmol) KCN in 13 ml water was
added slowly. After 30 min the aqueous layer was separated and
added to a mixture of 15.2 g of powdered almonds with 76 ml
buffer, 30 ml DIPE and 3.80 g (30.6 mmol) of 5d was added. After
30 min the organic layer was quickly filtered from the powdered
almonds, dried over MgSO4, filtered and the solvent removed in
vacuo. Thus 2.72 g of crude (S)-6d was obtained as a yellow liquid.
968 mg (5.08 mmol) tosyl chloride were added slowly at room
temperature. After stirring over night, 20 ml H2O was added, the
aqueous phase was extracted with 3ꢀ10 ml DCM. The organic
phase was dried over MgSO4, filtered and the solvent was removed
in vacuo. After column chromatography (silica gel; PE/EE, 10:1)
2.30 g (93% over two steps) of (S)-9d was obtained as a yellow oil. Rf
(PE/EE, 10:1)¼0.30. IR (film):
n
¼3055, 2955, 2931, 2858, 1462, 1421,
1334, 1265, 1162, 1091 cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼ꢂ0.16 (s,
1H NMR (CDCl3, 250 MHz):
d
¼1.29 (t, J¼7.6 Hz, 3H), 2.71 (q,
3H), ꢂ0.02 (s, 3H), 0.80 (s, 9H), 0.88 (d, J¼7.5 Hz, 3H), 2.41 (s, 3H),
2.54 (q, J¼7.6 Hz, 2H), 3.21 (t, J¼6.2 Hz, 3H), 4.62 (q, J¼6.2 Hz, 2H),
5.84 (d, J¼3.1 Hz, 1H), 6.03 (d, J¼3.1 Hz, 1H), 7.25 (d, J¼8.1 Hz, 2H),
J¼7.6 Hz, 2H), 3.42 (br s, 1H), 5.48 (s, 1H), 6.04 (d, J¼3.1 Hz, 1H), 6.52
(d, J¼3.3 Hz, 1H).
7.70 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 76 MHz):
¼ꢂ5.23 (q),
d
4.24. Synthesis of rac-(5-ethylfuran-2-yl)hydroxyacetonitrile
(rac-6d, FA-288)
ꢂ5.06 (q), 12.20 (q), 21.36 (q), 25.66 (q), 47.82 (t), 67.12 (d), 104.35
(d), 108.23 (d), 127.10 (d), 129.72 (d), 137.03 (s), 143.41 (s), 151.32 (s),
157.68 (s). MS (FABþ): m/z (%): 423 (2) [Mþ], 408 (11), 390 (6), 366
(46), 316 (8), 292 (66), 258 (4), 239 (100). C21H23NO4Si (423.64):
calcd C 59.54, H 7.85, N 3.31; found C 59.67, H 8.36, N 3.25. HRMS
(HRFABþ): C21H33NO4SSiNa: calcd 423.1900; found 446.1783.
Compound 5d (2.00 g, 16.1 mmol) was dissolved in 8 ml glacial
acetic acid and cooled to 0 ꢁC. Then a solution of 2.52 mg
(48.3 mmol) KCN in 16 ml H2O was added dropwise and the mix-
ture was stirred over night at room temperature. Then 8 ml H2O
was added, the product was extracted with Et2O (3ꢀ10 ml) and
dried over MgSO4. After filtration and addition of toluene, the sol-
vent was removed. Crude rac-6d (2.70 g) was obtained and directly
used in the next step without further purification.
4.28. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
(5-ethylfuran-2-ylethyl)ethyl]-4-methyl-N-prop-2-
ynylphenylsulfonamide ((S)-10d, FA-295)
Compound (S)-9d (2.15 g, 5.09 mmol) was dissolved in 10 ml
acetone; 5.00 g (15.3 mmol) Cs2CO3 and 1.40 ml (15.3 mmol)
propargyl bromide (80 wt % in toluene) were added. After stirring
over night, the solvent was removed in vacuo and the residue was
taken up in 10 ml H2O. After three extractions with 10 ml DCM each
the organic layer was dried over MgSO4, filtered and the solvent
removed in vacuo. After column chromatography (silica gel; PE/EE,
50:1) 1.46 g (80%) (S)-10d was obtained as a colourless oil, which
4.25. Synthesis of (S)-(tert-butyldimethylsilanyloxy)(5-
ethylfuran-2-yl)acetonitrile ((S)-7d, FA-315)
Crude (S)-6d (1.36 g, 9.06 mmol) was dissolved in 5 ml DMF,
1.54 g (22.7 mmol) imidazole and 2.73 g (18.1 mmol) TBDMSCl
were added and the mixture was stirred over night at room tem-
perature. After column chromatography (silica; PE/EE, 20:1) 2.23 g

1926
A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
solidifies in the fridge. Rf (PE/EE, 50:1)¼0.10. IR (film):
2931, 2856, 1461, 1350, 1255, 1185, 1161, 1092, 1011 cmꢂ1. 1H NMR
(CDCl3, 500 MHz):
J¼7.5 Hz, 3H), 2.39 (s, 3H), 2.59 (q, J¼7.6 Hz, 2H), 3.41 (d, J¼6.7 Hz,
2H), 3.95 (dd, J¼2.4, 18.5 Hz, 1H), 4.18 (dd, J¼2.5, 18.5 Hz, 1H), 4.90
(t, J¼6.6 Hz, 1H), 5.87 (d, J¼3.1 Hz, 1H), 6.12 (d, J¼3.1 Hz, 1H), 7.25
(d, J¼8.0 Hz, 1H), 7.71 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
n
¼2995,
4.32. Synthesis of (S)-(tert-butyldimethylsilanyloxy)-(4,5-
dimethylfuran-2-yl)acetonitrile ((S)-7e, FA-232)
d
¼ꢂ0.08 (s, 3H), 0.06 (s, 3H), 0.84 (s, 9H), 1.19 (t,
Crude (S)-6e (1.50 g, 9.92 mmol) was dissolved in 20 ml DMF,
1.35 g (19.8 mmol) imidazole and 2.24 g (14.9 mmol) TBDMSCl
were added and the mixture was stirred over night at room tem-
perature. After column chromatography (silica; PE/EE, 10:1) 2.18 g
(83% over two steps) of the yellow solid (S)-7e was obtained. Mp:
d
¼ꢂ5.11 (q), 12.28 (s), 21.36 (t), 21.52 (q), 25.78 (q), 38.62 (t), 51.19
(t), 68.73 (d), 73.38 (s), 104.55 (d), 108.23 (d), 127.78 (d), 129.39 (d),
136.28 (s), 143.41 (s), 152.08 (s), 157.52 (s). MS (FABþ, eV): m/z (%):
461 (11) [Mþ], 466 (9), 404 (36), 330 (100), 305 (4). C24H35NO4SSi
(461.6905): calcd C 62.44, H 7.64, N 3.03; found C 62.14, H 7.79, N
2.92. HR FABþ (eV): C22H31NO4SSi: calcd 461.2056; found 461.2065.
30 ꢁC. Rf (PE/EE, 10:1)¼0.43. IR (film):
¼2960, 2929, 2887, 2859,
n
1636, 1570, 1472, 1464, 1362, 1292 cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼6.26 (s, 1H), 5.42 (s, 1H), 2.18 (s, 3H), 1.91 (s, 3H), 0.90 (s, 3H), 0.13
(s, 3H), 0.11 (s, 3H). 13C NMR (CDCl3, 76 MHz):
d
¼ꢂ5.14 (q), 9.72 (q),
11.36 (q), 25.49 (q), 58.09 (d), 112.63 (d), 115.15 (s), 117.53 (s), 145.34
(s), 149.14 (s). MS (EI, 70 eV): m/z (%): 265 (3) [Mþ], 250 (6), 210 (6),
208 (100), 181 (4), 134 (20), 75 (40). C14H23NO2Si (265.15): calcd C
63.35, H 8.73, N 5.28; found C 62.98, H 8.72, N 5.20. HRMS (70 eV):
C14H23NO2Si: calcd 265.1498; found 265.1467. [
22.5; [
578
546
[
a
]
ꢂ50.5; [
a
]
ꢂ57.9.
4.29. Synthesis of (R)-4-(tert-butyldimethylsilanyloxy)-7-
ethyl-2-(toluol-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-8-
ol ((R)-11d, FA-350)
578
546
a
]
19.6; [a]
436
a]
40.8.
Compound (S)-10d (143 mg, 310
tube in 500 l CD2Cl2, then 11.0 mg (15.3
6.70 mg (15.3 mol) Ag[SbF6] in CD2Cl2 were added. The reaction
m
mol) was dissolved in an NMR
4.33. Synthesis of (S)-2-(tert-butyldimethylsilanyloxy)-2-(4,5-
dimethylfuran-2-yl)ethylamine ((S)-8e, FA-236)
m
mmol, 5 mol %) 13 and
m
was monitored by 1H NMR spectroscopy, when complete the sol-
vent was removed in vacuo and the residue purified by column
chromatography (silica gel; PE/EE, 20:1), delivering 95 mg (85%) of
(R)-11d as colourless solid. Mp: 113 ꢁC. Rf (PE/EE, 20:1)¼0.15. IR
Compound (S)-7e (200 mg, 753 mmol) was dissolved in 10 ml
Et2O and cooled to ꢂ70 ꢁC. Then 1.51 ml DIBAL-H (1.0 M solution in
hexane) was added dropwise and the solution was warmed to
ꢂ20 ꢁC. After cooling to ꢂ70 ꢁC again, 2 ml MeOH and 57.0 g
(1.51 mmol) NaBH4 were added and the solution was allowed to
warm to room temperature over night. Et2O (10 ml) was added and
the organic layer was washed with 5 ml 2 N NaOH, 5 ml H2O and
5 ml brine, then dried over MgSO4. After filtration and removal of
the solvent in vacuo, 166 mg (S)-8e was obtained as a yellow oil,
which was used in the next step directly. 1H NMR (CDCl3,
300 MHz): 6.29 (s, 1H), 4.79 (t, 2H), 3.26 (s, 3H), 2.43 (s, 3H), 2.53
(br s, 2H).
(film):
n
¼2954, 2928, 2857, 1494, 1447, 1341, 1254, 1223, 1163, 1163,
1126, 1090 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
d
¼0.61 (s, 6H), 0.91 (s,
9H), 1.19 (t, J¼9.0 Hz, 2H), 2.40 (s, 3H), 2.53 (q, J¼9.0 Hz, 2H), 2.47
(dd, J¼9.0, 12.0 Hz, 1H), 3.79 (dd, J¼6.0, 12.0 Hz, 1H), 3.87 (d,
J¼15.0 Hz, 1H), 4.54 (d, J¼18.0 Hz, 1H), 4.83 (dd, J¼6.0, 9.0 Hz, 1H),
6.93 (d, J¼9.0 Hz, 1H), 7.01 (d, J¼6.0 Hz, 1H), 7.31 (d, J¼9.0 Hz, 2H),
7.73 (d, J¼9.0 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
¼ꢂ4.77 (q),
d
ꢂ4.30 (q), 8.30 (q), 13.78 (q), 21.52 (q), 22.42 (t), 25.83 (q), 43.54 (t),
49.58 (t), 66.97 (d), 118.75 (d), 118.93 (s), 127.05 (d), 127.64 (d),
129.73 (d), 133.90 (s), 136.80 (s), 143.60 (s), 149.00 (s). MS (FABþ,
eV): m/z (%): 461 (37) [Mþ], 460 (100), 459 (13), 404 (49), 393 (7),
362 (2), 330 (83), 307 (14), 304 (13), 289 (18). HR FABþ (eV):
C24H35NO4SSi: calcd 462.2136 [MþH]þ; found 426.2068 [MþH]þ.
4.34. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
(4,5-dimethylfuran-2-yl)ethyl]-4-methylbenzenesulfonamide
((S)-9e, FA-238)
578
546
436
[
a]
ꢂ8,2; [
a]
ꢂ10.5; [
a
]
ꢂ12.5.
Crude (S)-8e (500 g, 1.86 mmol) was dissolved in 10 ml DCM,
260 ml (1.86 mmol) NEt3, 22.7 mg (168 mmol) DMAP and finally
4.30. Synthesis of (S)-(4,5-dimethylfuran-2-yl)hydroxy-
acetonitrile ((S)-6e, FA-336)
345 mg (1.86 mmol) tosyl chloride were added slowly at room
temperature. After stirring over night, 20 ml H2O was added, the
aqueous phase was extracted with 3ꢀ10 ml DCM. The organic
phase was dried over MgSO4, filtered and the solvent was removed
in vacuo. After column chromatography (silica gel; PE/EE, 10:1)
230 mg (54% over two steps) of (S)-9e was obtained as a yellow oil.
Citric acid (18.4 g) was dissolved in 25 ml water and 100 ml DIPE
was added. A solution of 4.20 g (80.6 mmol) in 10 ml water was
added slowly. After 30 min the aqueous layer was separated and
added to a mixture of 20.0 g of powdered almonds with 100 ml
buffer, 25 ml DIPE and 5.00 g (40.7 mmol) of 5e was added. After
30 min the organic layer was quickly filtered from the powdered
almonds, dried over MgSO4, filtered and the solvent removed in
vacuo. Thus 4.42 g of crude (S)-6e was obtained as a yellow liquid.
Rf (PE/EE, 10:1)¼0.21. IR (film):
n
¼2956, 2928, 2906, 2886, 2857,
2241, 1730, 1671, 1601, 1330 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼7.68 (d, J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz, 2H), 5.95 (s, 1H), 4.70 (t,
J¼5.9 Hz, 1H), 2.94 (d, J¼7.2 Hz, 1H), 2.85 (d, J¼6.8 Hz, 1H), 2.15 (s,
3H), 1.89 (s, 3H), 0.84 (s, 9H), 0.02 (s, 3H), ꢂ0.09 (s, 3H). 13C NMR
1H NMR (CDCl3, 500 MHz):
9H), 1.77 (s, 3H), 2.05 (s, 3H), 5.29 (s, 1H), 6.12 (s, 1H).
d
¼ꢂ0.19 (s, 3H), 0.00 (s, 3H), 0.76 (s,
(CDCl3, 76 MHz):
d
¼ꢂ5.28 (q), ꢂ5.03 (q), 9.72 (q),11.19 (q),18.04 (s),
21.43 (q), 25.77 (q), 47.76 (t), 67.03 (d), 110.76 (d), 114.37 (s), 127.03
(d), 129.56 (d), 136.97 (s), 143.29 (s), 147.02 (s), 150.10 (s). MS
(FABþ): m/z (%): 423 (11) [Mþ], 408 (25), 406 (9), 366 (74), 365 (5),
292 (100), 290 (11). HRMS (HRFABþ): C21H33NO4SSi: calcd
423.1900; found423.1868.
4.31. Synthesis of rac-(4,5-dimethylfuran-2-yl)hydroxy-
acetonitrile (rac-6e, FA-231)
Compound 5e (3.00 g, 24.2 mmol) was dissolved in 24 ml glacial
acetic acid and cooled to 0 ꢁC. Then a solution of 3.78 mg
(72.5 mmol) KCN in 24 ml H2O was added dropwise and the mix-
ture was stirred over night at room temperature. Then 24 ml H2O
was added, the product was extracted with Et2O (3ꢀ10 ml) and
dried over MgSO4. After filtration and addition of toluene, the sol-
vent was removed. Crude rac-6e (3.34 g) was obtained and directly
used in the next step without further purification.
4.35. Synthesis of (S)-N-[2-(tert-butyldimethylsilanyloxy)-2-
(4,5-dimethylfuran-2-yl)ethyl]-4-methyl-N-prop-2-
ynylbenzenesulfonamide ((S)-10e, FA-239)
Compound (S)-9e (100 mg, 236
acetone; 231 mg (708 mol) Cs2CO3 and 660
argyl bromide (80 wt % in toluene) were added. After stirring over
mmol) was dissolved in 10 ml
m
m
l (708 mol) prop-
m

A.S.K. Hashmi et al. / Tetrahedron 65 (2009) 1919–1927
1927
night, the solvent was removed in vacuo and the residue was taken
up in 10 ml H2O. After three extractions with 10 ml DCM each the
organic layer was dried over MgSO4, filtered and the solvent re-
moved in vacuo. After column chromatography (silica gel; PE/EE,
10:1) 39 mg (92%) (S)-10e was obtained as a yellow solid. Mp: 32 ꢁC.
6.79 (s, 1H), 7.30 (d, J¼9.0 Hz, 2H), 7.73 (d, J¼9.0 Hz, 2H). 13C NMR
(CDCl3, 125 MHz):
d
¼ꢂ4.72 (q), ꢂ4.27 (q), 11.29 (q), 20.39 (q), 21.50
(q), 25.84 (t), 43.53 (t), 49.67 (t), 66.91 (d), 116.45 (s), 119.59 (s),
120.12 (d), 127.62 (d), 129.71 (d), 134.02 (s), 135.66 (s), 143.55 (s),
149.34 (s). MS (ESI, eV): m/z (%): 484 (100) [MþNaþ], 351 (5), 297
Rf (PE/EE, 10:1)¼0.28. IR (film):
n
¼3307, 2957, 2929, 2885, 2857,
(10), 216 (7). HRESI (eV): C24H35NNaO4SSi: calcd 484.1954 [MþH]þ;
1601, 1482, 1347, 1257, 1223 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
found 484.19483 [MþH]þ. [
a
]
578 36.3; [
a
]
546 39.8; [
a
]
67.6.
436
d
¼7.73 (d, J¼8.6 Hz, 2H), 7.27 (d, J¼8.6 Hz, 2H), 6.01 (s, 1H), 4.88 (t,
J¼6.6 Hz, 1H), 4.20 (dd, J¼18.6, 2.6 Hz, 1H), 4.00 (dd, J¼18.6, 2.4 Hz,
1H), 3.40 (d, J¼6.8 Hz, 2H), 2.41 (s, 3H), 2.16 (s, 3H), 1.98 (t, J¼2.2 Hz,
1H), 1.90 (s, 3H), 0.86 (s, 9H), 0.08 (s, 3H), ꢂ0.05 (s, 3H). 13C NMR
References and notes
1. (a) Dyker, G. Angew. Chem. 2000, 112, 4407–4409; Angew. Chem., Int. Ed. 2000, 39,
4237–4239; (b) Hashmi, A. S. K. Gold Bull. 2003, 36, 3–9; (c) Hashmi, A. S. K. Gold
Bull. 2004, 37, 51–65; (d) Krause, N.; Hoffmann-Ro¨der, A. Org. Biomol. Chem.
2005, 3, 387–391; (e) Hashmi, A. S. K. Angew. Chem. 2005, 117, 7150–7154; An-
gew. Chem., Int. Ed. 2005, 44, 6990–6993; (f) Hashmi, A. S. K.; Hutchings, G.
Angew. Chem. 2006, 118, 8064–8105; Angew. Chem., Int. Ed. 2006, 45, 7896–7936;
(g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211.
2. (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553–
11554; (b) Hashmi, A. S. K.; Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.;
Bats, J. W. Angew. Chem. 2005, 117, 2858–2861; Angew. Chem., Int. Ed. 2005, 44,
2798–2801; (c) Hashmi, A. S. K.; Rudolph, M.; Siehl, H.-U.; Tanaka, M.; Bats, J. W.;
Frey, W. Chem.dEur. J. 2008, 14, 3703–3708.
(CDCl3, 76 MHz):
d
¼ꢂ5.01 (q), 9.84 (q),11.29 (q), 21.51 (q), 25.80 (q),
38.65 (t), 51.23 (t), 68.69 (s), 73.32 (d), 110.82 (d), 127.79 (d), 129.36
(d), 136.28 (s), 143.36 (s), 146.91 (s), 150.89 (s). MS (FABþ, eV): m/z
(%): 461 (56) [Mþ], 460 (68), 446 (34), 405 (36), 404 (100), 366 (11),
330 (100). HRMS (HRFABþ): C24H35NO4SSi: calcd 461.2056; found
578
546
436
461.2075. [
a]
ꢂ64.6; [
a
]
ꢂ74.0; [
a
]
ꢂ134.6.
4.36. Synthesis of (R)-4-(tert-butyldimethylsilanyloxy)-6,7-
dimethyl-2-(toluol-4-sulfonyl)-1,2,3,4-tetrahydro-
isoquinoline-8-ol ((R)-11e, FA-351)
3. (a) Effenberger, F. Angew. Chem. 1994, 106, 1609–1619; Angew. Chem., Int. Ed. Engl.
1994, 33, 1555–1564, see also; (b) Schmidt, M.; Gringl, H. Top. Curr. Chem. 1999,
200, 193–226.
4. (a) Wajant, H.; Effenberger, F. Biol. Chem. 1996, 377, 611–617; (b) Gregory, R. J. H.
Chem. Rev. 1999, 99, 3649–3682.
5. (a) Grise´, C. M.; Rodrigue, E. M.; Barriault, L. Tetrahedron 2008, 64, 797–808; (b)
Compound (S)-10e (344 mg, 745
tube in 500 l CD2Cl2, then 26.6 mg (37.3
16.2 mg (37.7 mol) Ag[SbF6] in CD2Cl2 were added. The reaction
m
mol) was dissolved in an NMR
m
mmol, 5 mol %) 13 and
´
Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905–5908.
m
6. CCDC 706502 (7c) and 706503 (10a) contain the supplementary crystallographic
data for this paper. These data can be obtained online free of charge (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336 033; or deposit@ccdc.cam.ac.uk).
was monitored by 1H NMR spectroscopy, when complete the sol-
vent was removed in vacuo and the residue purified by column
chromatography (silica gel; PE/EE, 10:1), delivering 280 mg (81%) of
(R)-11e as colourless solid. Mp: 58 ꢁC. Rf (PE/EE, 10:1)¼0.27. IR
7. Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost, T. M.; Miehlich, B.; Frey, W.;
Bats, J. W. Chem.dEur. J. 2006, 12, 5806–5814.
(film):
n
¼3500, 2955, 2930, 2857, 1461, 1341, 1253, 1202, 1166,
8. Partyka, D. V.; Robilotto, T. J.; Zeller, M.; Hunter, A. D.; Gray, T. G. Organometallics
2008, 27, 28–32.
9. (a) Hashmi, A. S. K.; Scha¨fer, S.; Bats, J. W.; Frey, W.; Rominger, F. Eur. J. Org. Chem.
2008, 4891–4899; (b) Hashmi, A. S. K.; Ata, F.; Kurpejovic, E.; Huck, J.; Rudolph,
M. Top. Catal. 2007, 44, 245–251; (c) Hashmi, A. S. K.; Haufe, P.; Schmid, C.; Rivas
Nass, A.; Frey, W. Chem.dEur. J. 2006, 12, 5376–5382.
1090 cmꢂ1. 1H NMR (CDCl3, 500 MHz):
d
¼0.15 (s, 3H), 0.16 (s, 3H),
0.93 (s, 9H), 2.08 (s, 3H), 2.40 (s, 3H), 2.74 (dd, J¼9.0, 12.0 Hz, 1H),
3.77 (dd, J¼9.0, 12.0 Hz, 1H), 3.85 (d, J¼15.0 Hz, 1H), 4.49 (d,
J¼18.0 Hz, 1H), 4.79 (d, J¼18.0 Hz, 1H), 4.79 (dd, J¼6.0, 9.0 Hz, 1H),