Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides

Article abstract of DOI:10.1039/c8ob02007h

The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquinolines 12 as single diastereomers.

Full text of DOI:10.1039/c8ob02007h

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Carter, M. J. González-Soria, M. wasinska, D. Gill, B. Macia and V. Caprio, Org. Biomol. Chem., 2018, DOI:
10.1039/C8OB02007H.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Stereoselective Synthesis of 1,3-Disubstituted
Dihydroisoquinolines via L-Phenylalanine-Derived
Dihydroisoquinoline N-Oxides
Received 00th January 20xx,
Accepted 00th January 20xx
Jesús Flores-Ferrándiz,a Nicholas Carter,a Maria José González-Soria,a Malgorzata Wasinska,a
Daniel Gill,a Beatriz Maciáa,* and Vittorio Caprioa,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a
range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-
disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this
nitrone
provided
access
to
3-(2-hydroxyalkyl)isoquinolines
12
as
single
diastereomers.
and reductive coupling with electrophiles,11 confers wide scope to
this system (Scheme 1). Furthermore, the hydroxymethyl group
functions as a readily removable stereocontrol element.12
Introduction
Tetrahydroisoquinoline (THIQ) systems occur in a wide range of
natural products and therapeutic drugs1 and have been highlighted
both as privileged scaffolds2 and as useful moieties in fragment-
based drug discovery.3 Moreover, there is interest in the use of
tetrahydroisoquinolines as ligands in asymmetric catalysis4 and as
chiral bases.5 The methods for accessing 1,3-disubstituted THIQ’s,
can be broadly grouped into two strategies, based on either
cyclisations of suitably substituted aromatic precursors6 or
functionalisation of isoquinoline-based scaffolds.7 In an effort to
develop a strategy towards enantiodefined tetrahydroisoquinolines,
of general use, we became interested in an approach of the latter
Removable
RMgX/RLi,
via
cycloaddition
decarboxylation
or reductive coupling
OH
OH
N
NH
O
3
then reduction of
R
4
hydroxylamine group
Pictet/Spengler
L-Phenylalanine
type utilizing
a chiral pool-derived isoquinoline unit with a
potentially broad reactivity profile. The only previous approaches
with these criteria utilize either 1-lithiated derivative 18 or imine 25
Scheme 1. Synthetic approaches to 1,3-disubstituted
tetrahydroisoquinolines utilising nitrone 3.
–
with reactivity restricted to additions to electrophiles or
nucleophiles respectively (Figure 1).
Results and discussion
OTBS
OTBS
N
N
Boc
Preparation of nitrone 3. Our approach to nitrone 3 centred on the
oxidation of the known amine 5 (Scheme 2), accessed by Pictet-
Spengler reaction of L-phenylalanine,13 followed by borane-
mediated reduction of the resulting acid.5 Trialing a range of
methods for the direct oxidative conversion of amines to nitrones,
Li
2
1
Figure 1. Previous chiral pool-derived THIQ precursors.
We envisaged that nitrone 3 would exhibit much utility in this
regard. The core scaffold is readily accessible, in enantioenriched
form from L-phenylalanine, and the reactivity of the nitrone group,
functionalised via 1,3-dipolar cycloaddition,9 nucleophilic addition10
revealed that the corresponding isoquinoline N-oxide was
a
significant byproduct. Best results were achieved using Oxone as
oxidant, providing dihydroisoquinoline derived nitrone 3 cleanly, in
moderate yield (58%), with no evidence of overoxidation to the
corresponding isoquinoline N-oxide.14
Oxone, Na2EDTA,
CH3CN-THF (4:1)
OH
OH
NH
N
58%
O
5
3
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Scheme 2. Synthesis of nitrone 3.
2
3
4
5
EtMgBr
6b/7b
6c/7c
6d/7d
6e/7e
6.5/1
5.9/1
2.8/1
10/1
87
85
90
96
iPrMgBr
AllylMgBr
PhMgBr
Addition of organometallic reagents to nitrone 3. With nitrone 3 in
hand, the nucleophilic addition of organometallic reagents was
initially investigated by screening of a range of solvents and
temperatures, using methylmagnesium bromide and methyllithium
as test reagents (Table 1). In all cases, full conversion was achieved
using 3 equivalents of nucleophile, with the 1,3-trans isomer 6a as
the major product. THF provided the best diastereomeric ratios and
no advantage was conferred by performing the reaction under
cryogenic conditions see (entries 7-9). It is noteworthy that, while
the addition of the more reactive methyllithium proceeded with full
conversion, stereoselectivity was lower than that obtained with the
corresponding Grignard reagent (entry 10 vs entry 7).
Consequently, subsequent studies were performed using Grignard
species under the conditions outlined in entry 7.
a Reaction conditions: 3 (0.3 mmol), RMgBr (3 eq), THF, 0 oC to r.t.
Ratio determined by analysis of crude H-NMR spectra. Relative
stereochemistry determined by 2D–NOESY studies, see Fig. 2 and
SI for further details. Isolated combined yield after column
b
1
c
chromatography.
The addition of different Grignard reagents to nitrone 3 provided, in
all cases, the trans-isomer 6 as the major product (Table 2). No
discernable trends are evident in Table 2, although the best levels
of selectivity were obtained with the larger phenylmagnesium
bromide (entry 5). Cis/trans stereochemistry of products 6 and 7
was assigned by 2D NOESY analysis (see Fig. 2 for an example).
Strong correlations between the protons of the C1-substituent and
H3 were observed in the trans-adduct, while the trans-diaxial
correlations between H1 and H3 revealed the cis-diequatorial
substitution pattern of the minor adduct, as illustrated on the ethyl-
adduct 6b/7b.
Table 1. Optimization of the addition of organometallic reagents
to nitrone 3.a
Entry
RM
Solvent
T (ºC)
6a/7ab
Conv
(%)c
1
2
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeLi
CH2Cl2
PhMe
Dioxane
tBuOMe
Et2O
0
0
4.5/1
7.1/1
3.0/1
3.5/1
5.5/1
6.0/1
7.5/1
7.5/1
7.5/1
3.8/1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
3
0
4
0
Figure 2. Selected correlations observed in the 2D-NOESY spectra of
tetrahydroisoquinolines 6b and 7b.
5
0
6
THF
20
0
The effect of protection of the 3-hydroxymethyl group, in
combination with increasing size of the 3-substituent, was
investigated by studying the addition of different Grignard reagents
to the TBS-protected nitrone 8 (Table 3), prepared by sodium
tungstate-catalysed-oxidation of the known TBS-derivative of
hydroxymethyl-THIQ 5.5,15 The addition of both ethyl- and
phenylmagnesium bromide to 8 proceeded in favour of the trans-
adducts 9, but with much lower selectivities than those obtained
with the unprotected nitrone 3 (compare Table 3, entries 1-2 with
Table 2, entries 2 and 5, respectively).
7
THF
8
THF
−20
−40
0
9
THF
10
THF
a
b
Reaction conditions: 3 (0.1 mmol), RM (3 eq), T, solvent.
Ratio determined by analysis of 1H-NMR spectra of crude
products. Relative stereochemistry determined by 2D–NOESY
Table 3. Addition of organometallic reagents to nitrone 8.a
studies; see SI for further details. Determined by 1H-NMR
c
analysis of crude products.
Table 2. Addition of organometallic reagents to nitrone 3.a
Entry
RM
Product
9a/10a
9b/10b
9/10b
2.5/1
3/1
Yield (%)c
1
2
EtMgBr
PhMgBr
56
53
Entry
RM
Products
6a/7a
6:7a,b
Yield (%)c
a Reaction conditions: 8 (0.3 mmol), RMgBr (3 eq), THF, 0 oC to
1
MeMgBr
7.5/1
75
2 | J. Name., 2012, 00, 1-3
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b
r.t. Ratio determined by 1H-NMR on the reaction crude.
Entry
R
Product
11a/12a
11b/12b
11c/12c
11d/12d
11 (% yield)b
12 (% yield)b
c
Relative stereochemistry determined by 2D–NOESY studies.
Isolated combined yield after column chromatography.
1
2
3
4
Ph
86
74
61
64
33
90
51
47
(CH2)3CH3
(CH2)2OBn
(CH2)2SPh
These results indicate that, in addition to the metal, (see Table 1,
entries
7 and 10, for the addition of MeMgBr and MeLi,
respectively), the nitrone oxygen and the free hydroxyl group play
an important role in determining the mode and level of
diastereoselectivity in the addition to 3. This hypothesis is
supported by the results obtained with imine 2, where the
selectivities of the addition of organolithium species are generally
lower than those reported in Table 2 for all but the largest
nucleophiles.5 We propose the model depicted in Fig. 3 to account
for this selectivity, which involves a cyclic magnesium chelate
similar to that hypothesized during additions to N-glycosyl
nitrones.16 In our model, the syn addition is hindered by the pseudo-
axial proton at C4.
a
Reaction conditions: (i) CH2=CH2R (5 eq), toluene, 110 oC; (ii)
b
AcOH, Zn, reflux.
Relative stereochemistry determined by 2D–NOESY studies, see Fig.
4 and SI for further details.
Isolated yield after flash chromatography.
H
OH
H
H
5
6
H
N
10b
H
H
H
O
2
Ph H
Figure 4. Selected correlations observed in the 2D-NOESY spectrum
of 11a.
The subsequent reductive N-O bond cleavage of isoxazolidine 11,
with zinc powder in AcOH, proceeded with no stereochemical
degradation,17 providing the corresponding 1,3-THIQ 12a-d in good
to moderate yields (Table 2).
Figure 3. Proposed mode of addition of Grignard reagents to
nitrone 3.
Conclusions
In conclusion, we have developed an approach to the synthesis of a
range of optically active 1,3-disubstituted tetrahydroisoquinolines
from (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline 2-oxide 3. The
addition of Grignard reagents to 3 proceeded with good yields and
stereoselectivities, and unprecedented levels of stereoselection
were found for the dipolar cycloaddition reaction of alkenes to
nitrone 3. This strategy allows the direct assembly of highly
functionalized tetrahydroisoquinoline units with up to three
stereogenic centres in a simple and effective manner, starting from
a readily available chiral substrate.
Cycloaddition reactions of nitrone 3. Next, the preparation of more
functionalized, stereodefined 1,3-THIQ systems was investigated via
1,3-dipolar cycloaddition of 3 with a range of alkenes, followed by
reduction of the resulting isoxazolidines 11 (Table 4). Styrene and
hex-1-ene were chosen as the prototypical model dipolarophiles
(entries 1 and 2), alongside functionalized butenes, selected to
access products of subsequent synthetic utility (entries 3 and 4).
Optimum yields/selectivity were obtained in toluene under reflux
conditions. The stereochemistry of the cycloaddition was readily
deduced by analysis of 2D-NOESY spectra of cycloadducts 11 (see
an example in Fig. 4), which revealed strong correlations between
H2/H6 and H10b/CH2(OH). In all cases, the exo-1,3-trans-
isoxazolidine was exclusively obtained in moderate to good yield
and no traces of any other isomers were detected in the 1H NMR
spectra of crude products. The cycloaddition reactions of nitrone 3
with a range of electron deficient systems, including acrylates, were
trialed but, unfortunately, failed to provide the corresponding
cycloadducts.
Experimental
General. 1H NMR and 13C NMR have been recorded on a JEOL® ECS-
400 (400 and 100.6 MHz, respectively) using CDCl3 as solvent.
Chemical shift values are reported in ppm with TMS as internal
1
standard (CDCl3: δ 7.26 for H-NMR, δ 77.0 for 13C-NMR). Data are
reported as follows: chemical shifts, multiplicity (s = singlet, quint =
quintuplet, m = multiplet), coupling constants (Hz), and integration.
IR spectra were recorded on Nicolet® 380 FT/IR – Fourier Transform
Infrared Spectrometer. Only the most significant frequencies have
been considered during the characterization, and have been
reported in cm-1. High resolution mass spectra were measured on
an Agilent Technologies® 6540 Ultra-High-Definition (UHD)
Accurate-Mass equipped with a time of flight (Q-TOF) analyzer and
the samples were ionized by ESI techniques and introduced through
Table 4. Cycloaddition of nitrone 3 and reduction of cycloadducts
11.a
a
high pressure liquid chromatography (HPLC) model Agilent
Technologies® 1260 Infinity Quaternary LC system. Optical rotations
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were measured on a Bellingham + Stanley® ADP 440+ Polarimeter ν = 3257, 2981, 2930, 2880 cm-1; 1H NMR (400 MHz, CDCl3): δH
=
with a 0.5 cm cell (c given in g/100 mL).
7.22-7.11 (m, 3H), 7.10-7.04 (m, 1H), 4.06 (q, J = 6.6 Hz, 1H), 3.82-
3.78 (m, 2H), 3.16 (brs, 1H), 3.03 (dd, J = 16.2, 12.1 Hz, 1H), 2.65 (d,
J = 14.8 Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (101 MHz,
CDCl3): δC = 137.2, 133.0, 128.2, 126.6, 126.4, 126.0, 64.3, 64.0,
62.6, 29.7, 18.4 ppm; HRMS (ESI-MeOH): m/z calcd for C11H16NO2
[M+H]+: 194.1176 found 194.1177.
All reactions were monitored by thin-layer chromatography using
precoated sheets of silica gel 60, 0.25 mm thick (F254 Merck
KGaA®). The components were visualized by UV light (254 nm) and
phosphomolybdic acid. Flash column chromatography was done
using Geduran® Silica gel 60, 40-63 microns RE. The eluent used is
mentioned in each particular case. All glassware employed during (1R,3S)-1-ethyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol
inert atmosphere experiments was flame-dried under a stream of (6b) and (1S,3S)-1-ethyl-3-(hydroxymethyl)-3,4-
dry argon. Alkenes reagents were purchased from Sigma-Aldrich or dihydroisoquinolin-2(1H)-ol (7b): Following the general procedure,
Fisher Scientific and used without further purification. Grignard and
organolithium reagents were purchased from Sigma-Aldrich.
Anhydrous THF was obtained from a Pure Solv™ Solvent Purification
Systems.
the reaction of ethylmagnesium bromide (3.0 M in Et2O, 300 ꢀL)
with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-
25
ol 6b (47 mg, 76% yield) as a yellow oil. [α]D +3 (c = 1, CHCl3); IR
1
(ATR): ν = 3285, 3062, 2931, 2873 cm-1; H NMR (400 MHz, CDCl3):
δH = 7.20-7.12 (m, 2H), 7.10-7.07 (m, 2H), 4.07 (t, J = 7.5 Hz, 1H),
3.84 (dd, J = 10.2, 9.0 Hz, 1H), 3.68 (dd, J = 11.0, 3.5 Hz, 1H), 3.40-
3.33 (m, 1H), 2.90 (dd, J = 16.7, 11.7 Hz, 1H), 2.52 (dd, J = 16.7, 5.0
Hz, 1H), 1.76-1.63 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H) ppm; 13C NMR
(101 MHz, CDCl3): δC = 136.7, 132.4, 128.8, 127.8, 126.4, 126.0,
68.9, 63.1, 56.2, 29.4, 24.6, 11.9 ppm; HRMS (ESI-MeOH): m/z calcd
for C12H18NO2 [M+H]+: 208.1332 found 208.1334. 7b (7 mg, 11%
(S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2-oxide
NaHCO3 (6.72 g, 80.0 mmol) was added to
(3):
solution of
a
tetrahydroisoquinoline 5 (2.6 g, 16.0 mmol) in THF-CH3CN 1:4 (28
mL) and 0.01 M aqueous EDTA solution (22.4 mL) at 5 °C. Oxone
(10.3 g, 16.8 mmol) was then added portionwise over 2 h, and the
mixture stirred for 20 min, at 5 °C. Ethyl acetate (80 mL) was added
and the aqueous layer further extracted with ethyl acetate (2 × 80
mL). The combined organic extracts were dried over anhydrous
MgSO4 and concentrated under reduced pressure to give nitrone 3
(1.66 g, 59%) as a pale yellow solid. m.p decomposes T > 145 °C;
[α]D25 174 (c = 3.3, CHCl3); IR (ATR): ν = 3242, 3054, 2945, 2897 cm-1;
1H NMR (400 MHz, CDCl3): δH = 7.80 (s, 1H), 7.35-7.25 (m, 2H), 7.25-
7.20 (m, 1H), 7.18-7.14 (m, 1H), 4.51 (br s, 1H), 4.26-4.16 (m, 1H),
4.04 (dd, J = 12.0, 6.9 Hz, 1H), 3.94 (dd, J = 12.0, 3.6 Hz, 1H), 3.22-
3.07 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3): δC = 135.4, 130.0,
129.8, 127.6, 127.5, 127.2, 125.6, 67.2, 62.7, 29.8 ppm; MS (EI, 70
25
yield) as a yellow oil. [α]D –29 (c = 1, CHCl3); IR (ATR): ν = 3279,
2961, 2931, 2873 cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.22-7.11
(m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 4.00 (t, J = 4.6 Hz, 1H), 3.81 (d, J =
4.9 Hz, 2H), 3.17-3.09 (m, 1H), 2.96 (dd, J = 16.1, 12.0 Hz, 1H), 2.64
(dd, J = 16.1, 4.0 Hz, 1H), 2.29-2.17 (m, 1H), 2.01-1.89 (m, 1H), 0.92
(t, J = 7.3 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3): δC = 136.0, 133.9,
128.2, 126.3, 126.3, 125.9, 67.7, 64.9, 63.4, 29.7, 24.1, 9.2 ppm;
HRMS (ESI-MeOH): m/z calcd for C12H18NO2 [M+H]+: 208.1332 found
208.1334.
ev): m/z (%) = 177 (M+, 8), 130 (100), 115 (34), 103 (22), 77 (26); (1R,3S)-3-(hydroxymethyl)-1-isopropyl-3,4-dihydroisoquinolin-
HRMS (ESI-MeOH): m/z calcd for C10H12NO2 [M+H]+: 178.0863 found 2(1H)-ol (6c) and (1S,3S)-3-(hydroxymethyl)-1-isopropyl-3,4-
178.0862.
dihydroisoquinolin-2(1H)-ol (7c): Following the general procedure,
the reaction of isopropylmagnesium bromide (0.75 M in THF, 1.2
General Procedure for the Diastereoselective Addition of Grignard
Reagents: A solution of RMgBr (0.9 mmol, 3 eq) was added to a
solution of nitrone 3 (53.1 mg, 0.3 mmol) in THF (1.5 mL). The
mixture was stirred at 0 ºC for 1 h and then warmed to room
temperature and quenched with water. The mixture was extracted
with EtOAc (3 x 10 mL) and the combined organic phases dried over
MgSO4, and concentrated under reduced pressure. The crude
product, was purified by flash column chromatography eluting with
n-hexane/EtOAc (gradient from 10 to 60%) to give the
corresponding 1,3-disubstituted tetrahydroisoquinoline-2-ol as a
yellow oil.
mL)
with
nitrone
3
gave
the
1,3-disubstituted
tetrahydroisoquinoline-2-ol 6c (48 mg, 73% yield) as a yellow oil.
[α]D +15 (c = 1, CHCl3); IR (ATR): ν = 3308, 3020, 2956, 2871 cm-1;
25
1H NMR (400 MHz, CDCl3): δH = 7.20-7.12 (m, 2H), 7.12-7.05 (m, 2H),
3.85 (dd, J = 11.3, 8.6 Hz, 1H), 3.79 (d, J = 8.7 Hz, 1H), 3.64 (dd, J =
11.3, 3.6 Hz, 1H), 3.46-3.35 (m, 1H), 2.81 (dd, J = 17.1, 11.3 Hz, 1H),
2.57 (dd, J = 17.1, 6.1 Hz, 1H), 1.85-1.70 (m, 1H), 1.09 (d, J = 6.7 Hz,
3H), 0.97 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): δC
=
135.0, 132.8, 129.3, 128.8, 126.5, 125.2, 73.3, 63.2, 56.2, 33.2, 24.5,
21.2, 20.8 ppm; HRMS (ESI-MeOH): m/z calcd for C13H20NO2 [M+H]+:
25
222.1489 found 222.1483. 7c (8 mg, 12% yield) as a yellow oil. [α]D
+88 (c = 1, CHCl3); IR (ATR): ν = 3311, 3020, 2956, 2871 cm-1; 1H
NMR (400 MHz, CDCl3): δH = 7.22-7.07 (m, 4H), 4.12 (d, J = 3.7 Hz,
1H), 3.93 (dd, J = 11.1, 3.0 Hz, 1H), 3.72 (dd, J = 11.1, 4.5 Hz, 1H),
3.11-3.01 (m, 1H), 2.88 (dd, J = 15.6, 12.4 Hz, 1H), 2.59 (dd, J = 15.6,
3.2 Hz, 1H), 2.29-2.12 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.87 (d, J =
6.8 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): δC = 136.8, 134.9,
127.5, 126.8, 126.1, 126.0, 73.8, 64.9, 63.7, 34.6, 30.9, 20.6, 17.9
ppm; HRMS (ESI-MeOH): m/z calcd for C13H20NO2 [M+H]+: 222.1489
found 222.1482.
(1R,3S)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-
ol
(6a)
and
(1S,3S)-3-(hydroxymethyl)-1-methyl-3,4-
dihydroisoquinolin-2(1H)-ol (7a): Following the general procedure,
the reaction of methylmagnesium bromide (3.0 M in Et2O, 300 ꢀL)
with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-
25
ol 6a (38 mg, 66% yield) as a yellow oil. [α]D –15 (c = 1, CHCl3); IR
1
(ATR): ν = 3240, 3019, 2973, 2932 cm-1; H NMR (400 MHz, CDCl3):
δH = 7.17-7.10 (m, 2H), 7.10-7.01 (m, 2H), 4.32 (q, J = 7.1, 1H), 3.82
(dd, J = 11.5, 7.6 Hz, 1H), 3.72 (br s, 1H), 3.41-3.34 (m, 1H), 2.93 (dd,
J = 16.7, 11.5 Hz, 1H), 2.53 (d, J = 14.8 Hz, 1H), 1.41 (d, J = 7.1 Hz,
3H) ppm; 13C NMR (101 MHz, CDCl3): δC = 137.6, 132.2, 128.7,
127.3, 126.4, 126.2, 63.2, 62.4, 56.5, 25.8, 21.0 ppm; HRMS (ESI-
MeOH): m/z calcd for C11H16NO2 [M+H]+: 194.1176 found 194.1778.
7a (5 mg, 9% yield) as a yellow oil. [α]D25 –27 (c = 1, CHCl3); IR (ATR):
(1R,3S)-1-allyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol
(6d) and (1S,3S)-1-allyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-
2(1H)-ol (7d): Following the general procedure, the reaction of
allylmagnesium bromide (1.0 M in Et2O, 900 ꢀL) with nitrone 3 gave
the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6d (44 mg, 67%
4 | J. Name., 2012, 00, 1-3
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25
yield) as a yellow oil. [α]D –51 (c = 1, CHCl3); IR (ATR): ν = 3302, 68.8, 61.8, 29.2, 25.5, 18.0, –5.7, –5.78 ppm; HRMS (ESI-MeOH):
1
3076, 3021, 2928, 2044 cm-1; H NMR (400 MHz, CDCl3): δH = 7.21- m/z calcd for C16H26NO2Si [M+H]+: 292.1727 found 292.1734.
7.13 (m, 2H), 7.13-7.04 (m, 2H), 6.01-5.85 (m, 1H), 5.09-5.05 (m,
(1R,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethyl-3,4-
dihydroisoquinolin-2(1H)-ol (9a) and (1S,3S)-3-(((tert-
2H), 4.26 (t, J = 7.4 Hz, 1H), 3.83 (dd, J = 11.2, 8.4 Hz, 1H), 3.68 (dd, J
= 11.2, 3.4 Hz, 1H), 3.44-3.35 (m, 1H), 2.92 (dd, J = 16.7, 11.7 Hz,
1H), 2.53 (dd, J = 16.7, 4.7 Hz, 1H), 2.49-2.39 (m, 2H) ppm; 13C NMR
(101 MHz, CDCl3): δC = 135.8, 135.5, 132.5, 128.8, 127.7, 126.6,
126.0, 117.1, 66.8, 63.1, 56.3, 40.6, 24.7 ppm; HRMS (ESI-MeOH):
m/z calcd for C13H18NO2 [M+H]+: 220.1332 found 220.1325. 7d (15
butyldimethylsilyl)oxy)methyl)-1-ethyl-3,4-dihydroisoquinolin-
2(1H)-ol (10a): Following the general procedure, the reaction of
ethylmagnesium bromide (3.0 M in Et2O, 300 ꢀL) with nitrone 8
gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 9a (38 mg,
25
25
40% yield) as a yellow solid. m.p. 50-51 °C;.[α]D –12 (c = 1.2,
mg, 23% yield) as a yellow oil. [α]D –41 (c = 1, CHCl3); IR (ATR): ν =
1
3280, 3075, 3021, 2927, 2042 cm-1; H NMR (400 MHz, CDCl3): δH
=
CHCl3); IR (ATR): ν = 3229, 3063, 2954, 2928, 2856, 1462, 1252,
1
1100, 834, 774, 748 cm-1; H NMR (400 MHz, CDCl3): δH = 7.18-7.09
7.26-7.14 (m, 3H), 7.14-7.06 (m, 1H), 6.02-5.87 (m, 1H), 5.16 (dd, J =
17.2, 1.6 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.15 (t, J = 5.7 Hz, 1H),
3.85-3.74 (m, 2H), 3.21-3.12 (m, 1H), 3.02-2.95 (m, 2H), 2.78-2.69
(m, 1H), 2.63 (dd, J = 16.3, 3.8 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): δC = 136.3, 135.8, 133.8, 128.4, 126.5, 126.4, 126.1, 116.4,
66.1, 64.6, 63.3, 36.8, 28.9 ppm; HRMS (ESI-MeOH): m/z calcd for
C13H18NO2 [M+H]+: 220.1332 found 220.1326.
(m, 4H), 6.42 (br s, 1H), 4.05 (dd, J = 8.3, 6.3 Hz, 1H), 3.99 (dd, J =
10.0, 5.6 Hz, 1H), 3.79 (dd, J = 10.0, 6.1 Hz, 1H ), 3.31 (td, J = 11.1,
5.6 Hz, 1H), 2.98 (dd, J = 16.7, 11.0 Hz, 1H), 2.66 (dd, J = 16.7, 5.2
Hz, 1H), 1.76-1.67 (m, 2H), 1.09 (t, J = 7.4Hz, 3H), 0.92 (s, 9H), 0.11
(s, 3H), 0.10 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3): δC = 137.4,
133.3, 128.9, 127.8, 126.3, 126.0, 68.7, 65.5, 56.6, 29.7, 26.1, 25.6,
18.5, 11.9, –5.1, –5.2 ppm; HRMS (ESI-EtOAc): m/z calcd for
C18H31NO2Si [M+H]+ 322.2202 found 322.2197. 10a (16 mg, 16%
(1R,3S)-3-(hydroxymethyl)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-
25
ol
(6e)
and
(1S,3S)-3-(hydroxymethyl)-1-phenyl-3,4-
yield) as a yellow oil. [α]D –7 (c = 1.5, CHCl3); IR (ATR): ν = 3263,
1
3066, 2954, 2928, 2855, 1462, 1252, 1103, 834, 775, 739 cm-1; H
dihydroisoquinolin-2(1H)-ol (7e): Following the general procedure,
reaction of phenylmagnesium bromide (3.0 M in Et2O, 300 ꢀL) with NMR (400 MHz, CDCl3): δH = 7.19-7.11 (m, 4H),5.05 (br s, 1H), 4.03
nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6e (dd, J = 10.0, 4.9 Hz, 1H), 3.96 (t, J = 4.6 Hz, 1H), 3.77 (dd, J = 10.0,
(67 mg, 87% yield) as a yellow oil. [α]D25 –84 (c = 1, CHCl3); IR (ATR): 6.2 Hz, 1H ), 3.09 (m, 1H), 2.93-2.86 (m 1H), 2.79 (dd, J = 16.2, 4.2
ν = 3240, 3061, 3026, 2889 cm-1; 1H NMR (400 MHz, CDCl3): δH
=
Hz, 1H), 2.28-2.17 (m, 1H), 1.98-187 (m, 1H), 0.92 (s, 9H), 0.89 (t, J =
7.29-7.24 (m, 3H), 7.23-7.18 (m, 2H), 7.18-7.12 (m, 1H), 7.12-7.06 7.2 Hz, 1H ), 0.11 (s, 3H), 0.10 (s, 3H) ppm; 13C NMR (101 MHz,
(m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 5.33 (s, 1H), 3.77 (dd, J = 11.4, 7.6 CDCl3): δC = 136.6, 134.6, 128.3, 126.3, 126.2, 126.0, 68.1, 66.1,
Hz, 1H), 3.55 (d, J = 9.2 Hz, 1H), 3.36-3.26 (m, 1H), 2.96 (dd, J = 16.9, 63.6, 29.9, 26.1, 24.6, 18.5, 9.2, –5.1, –5.2 ppm; HRMS (ESI-EtOAc):
10.1 Hz, 1H), 2.70 (dd, J = 16.9, 5.1 Hz, 1H) ppm; 13C NMR (101 MHz, m/z calcd for C18H31NO2Si [M+H]+ 322.2202 found 322.2197.
CDCl3): δC = 140.6, 134.0, 133.3, 130.2, 129.0, 128.6, 128.2, 127.7,
(1R,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-phenyl-3,4-
dihydroisoquinolin-2(1H)-ol (9b) and (1S,3S)-3-(((tert-
127.0, 126.2, 70.3, 62.8, 56.7, 26.2 ppm; HRMS (ESI-MeOH): m/z
calcd for C16H18NO2 [M+H]+: 256.1332 found 256.1336. 7e (6 mg, 9%
yield) as a yellow oil. [α]D +4.5 (c = 1, CHCl3); IR (ATR): ν = 3238,
25
butyldimethylsilyl)oxy)methyl)-1-phenyl-3,4-dihydroisoquinolin-
2(1H)- (10b): Following the general procedure, the reaction of
phenylmagnesium bromide (3.0 M in Et2O, 300 ꢀL) with nitrone 8
gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 9b (44 mg,
40% yield) as a yellow oil. [α]D25 –4 (c = 1, CHCl3); IR (ATR): ν = 3213,
3062, 2927, 2855 cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.39-7.31
(m, 3H), 7.29-7.28 (m, 2H), 7.25-7.17 (m, 3H), 6.96 (d, J = 7.7 Hz,
1H), 6.92 (s, 1H), 5.28 (s, 1H), 4.06 (dd, J = 10.0, 5.2 Hz, 1H), 3.82
(dd, J = 10.0, 6.7 Hz, 1H), 3.48-3.40 (m, 1H), 3.14 (dd, J = 16.8, 8.3
Hz, 1H), 2.98 (dd, J = 16.8, 5.3 Hz, 1H), 0.92 (s, 9H), 0.08 (s, 3H), 0.06
(s, 3H) ppm; 13C NMR (101 MHz, CDCl3): δC = 141.8, 134.9, 133.7,
130.0, 128.9, 128.7, 128.1, 127.4, 126.7, 125.9, 70.0, 63.4, 57.5,
27.2, 25.8, 18.2, –5.4, –5.5 ppm; HRMS (ESI-MeOH): m/z calcd for
C22H32NO2Si [M+H]+ 370.2197 found 370.2205. 10b (15 mg, 13%
3061, 3025, 2890 cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.35-7.30
(m, 2H), 7.29-7.23 (m, 2H), 7.15-7.08 (m, 2H), 7.03-6.95 (m, 1H),
6.54 (d, J = 7.8 Hz, 1H), 5.35 (br s, 1H), 4.88 (s, 1H), 3.95-3.82 (m,
1H), 3.77 (dd, J = 11.8, 5.3 Hz, 1H), 3.21 (d, J = 11.8 Hz, 1H), 3.14
(dd, J = 27.5, 11.8 Hz, 2H), 2.82 (d, J = 15.6 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3): δC = 141.9, 136.6, 133.2, 130.3, 128.3, 128.2,
127.8, 127.7, 126.7, 125.9, 75.1, 64.8, 64.6, 31.6 ppm; HRMS (CI-
CH4): m/z calcd for C16H18NO2 [M+H]+: 256.1332 found 256.1337.
(S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-
dihydroisoquinoline 2-oxide (8):
butyldimethylsilyl)oxy)methyl)-3,4-dihydroisoquinoline
A solution of (S)-3-(((tert-
5,15
(0.76 g,
2.77 mmol) was added to a solution of sodium tungstate (0.14 g,
0.046 mmol) in methanol (1 mL). A 30% aqueous solution of H2O2
(1.0 mL, 8.31 mmol) was added at 0 °C over a period of 30 min. and
the reaction mixture was warmed to room temperature and stirred
overnight. The mixture was concentrated under reduced pressure,
25
yield) as a yellow oil. [α]D –55 (c = 1, CHCl3); IR (ATR): ν = 3306,
3028, 2927, 2854 cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.39-7.34
(m, 5H), 7.16-7.11 (m, 2H), 7.04-6.97 (m, 1H), 6.59 (d, J = 7.8 Hz,
1H), 4.89 (s, 2H), 4.16 (dd, J = 9.9, 4.4 Hz, 1H), 3.79 (dd, J = 9.9, 6.9
diluted with brine and extracted with CH2Cl2 (2 × 15 mL). The Hz, 1H), 3.29-3.18 (m, 1H), 3.09 (s, 1H), 3.07 (s, 1H), 0.93 (s, 9H),
combined organic layers were dried over anhydrous MgSO4, and 0.10 (s, 3H), 0.10 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3): δC
=
concentrated under reduced pressure. The residue was purified by 142.9, 137.3, 133.5, 129.9, 128.4, 128.1, 127.8, 127.5, 126.5, 125.8,
column chromatography, using CHCl3-CH3OH (10:1) as eluent, to 74.7, 65.3, 64.1, 25.9, 22.7, 18.3, –5.2, –5.3 ppm; HRMS (ESI-
25
give nitrone 10 (0.46 g, 57%) as a viscous oil. [α]D –36 (c = 1, MeOH): m/z calcd for C22H32NO2Si [M+H]+ 370.2197 found
CHCl3); IR (ATR): ν = 2952, 2927, 2883, 2855 cm-1; 1H NMR (400 370.2203.
MHz, CDCl3): δH = 7.73 (s, 1H), 7.28-7.18 (m, 3H), 7.08 (d, J = 6.9 Hz,
General Procedure for the Cycloaddition Reactions of Nitrone 3: A
solution of nitrone 3 (0.1 g, 0.56 mmol) in dry toluene (5 mL) was
heated to 80 ºC. A solution of the corresponding alkene (5 eq.) in
dry toluene (5 mL) was added dropwise and the reaction was
1H), 4.16-4.08 (m, 1H), 3.96 (dd, J = 9.9, 3.8 Hz, 1H), 3.84 (dd, J =
9.9, 7.7 Hz, 1H), 3.42 (dd, J = 16.7, 7.3 Hz, 1H), 3.25 (dd, J = 16.8, 3.2
Hz, 1H), 0.79 (s, 9H), –0.01 (s, 3H), –0.03 (s, 3H) ppm; 13C NMR (101
MHz, CDCl3): δC = 134.8, 129.6, 129.2, 127.7, 127.6, 127.2, 125.1,
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heated at 110 ºC overnight. Removal of the solvent under reduced 2.30 (m, 2H), 2.08-1.91 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3): δC
pressure yielded the crude product as a dark brown oil. Purification = 135.8, 134.8, 132.1, 129.2, 128.9,128.1, 126.9, 126.8, 126.3,
by flash chromatography eluting with EtOAc/cyclohexane (1:1) gave 126.1, 75.7, 66.1, 63.7, 56.7, 42.1, 34.7, 31.4, 29.9 ppm; HRMS (ESI-
the corresponding products 11.
EtOAc): m/z calcd for C20H23NO2S [M+H]+: 342.1528 found
342.1522.
((2R,5S,10bR)-2-phenyl-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-
a]isoquinolin-5-yl)methanol (11a): Following the general General Procedure for the Reduction of Cycloadducts 11:17
procedure, reaction of styrene (2.8 mmol, 322 ꢀL) with nitrone 3
25
Zinc dust (5.0 eq) was added to a solution of cycloadduct 11 (1 eq)
in 50% acetic acid:water at room temperature. The mixture was
stirred under reflux for 3 h. After cooling, the mixture was
neutralized with saturated aqueous NaHCO3 and the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
phases were dried over MgSO4, concentrated under reduced and
the residue purified by column chromatography.
gave the cycloadduct 11a (26 mg, 86% yield) as a yellow oil; [α]D
–
29 (c = 3.6, CHCl3); IR (ATR): ν = 3372, 3027, 2937, 2886, 1733, 1241,
1047, 927, 794, 699 cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.46-7.43
(m, 2H), 7.42-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.21-7.14 (m, 3H),
7.09-7.07 (m, 1H), 5.44 (dd, J = 9.5, 4.5 Hz, 1H), 4.88 (dd, J = 10.3,
8.2 Hz, 1H), 3.94-3.93 (m, 2H), 3.35-3.30 (m, 1H), 2.97 (dd, J = 16.4,
11.5 Hz, 1H), 2.82-2.72 (m, 2H), 2.68-2.62 (m, 1H) ppm; 13C NMR
(101 MHz, CDCl3): δC = 141.1, 134.7, 132.2, 128.6, 128.2, 128.0,
127.0, 126.9, 126.4, 79.1, 66.2, 64.1, 56.9, 45.5, 31.5 ppm; HRMS
(ESI- EtOAc): m/z calcd for C18H19NO2 [M+H]+: 282.1494 found
282.1489.
(R)-2-((1R,3S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl)-1-phenylethanol (12a): Following the general procedure,
reduction of cycloadduct 11a (50 mg, 0.18 mmol) gave 1,3-
25
disubstituted THIQ 12a (17 mg, 33% yield) as a yellow oil. [α]D
–
0.42 (c = 2.4, CHCl3); IR (ATR): ν = 3300, 3060, 3024, 2918, 1655,
1450, 1057, 1028, 743, 700 cm-1; 1H NMR (400 MHz, CDCl3): δH
((2S,5S,10bR)-2-butyl-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-
a]isoquinolin-5-yl)methanol (11b): Following the general procedure
reaction of 1-hexene (2.8 mmol, 350 ꢀL) with nitrone 3 gave the
=
7.45 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.27-7.23 (m, 1H),
7.12-7.03 (m, 3H), 6.82-6.80 (m, 1H), 5.09 (t, J = 4.3 Hz, 1H), 4.4 (br
s, 2H), 4.17 (dd, J = 11.2, 2.2 Hz, 1H), 3.76 (dd, J = 11.1, 3.8 Hz, 1H),
3.59 (dd, J = 11.2, 6.3 Hz, 1H), 3.30-3.24 (m, 1H), 2.69 (dd, J = 16.5,
4.2 Hz, 1H), 2.56 (dd, J = 16.4, 10.7 Hz, 1H), 2.44 (ddd, J = 14.8, 11.4,
3.6 Hz, 1H), 1.98 (ddd, J = 14.7, 5.2, 2.8 Hz, 1H), ppm; 13C NMR (101
MHz, CDCl3): δC = 144.7, 138.0, 134.0, 129.4, 128.2, 126.7, 126.2,
125.9, 125.4, 72.3, 65.1, 51.5, 48.6, 41.8, 30.4 ppm; HRMS (ESI-
EtOAc): m/z calcd for C18H21NO2 [M+H]+: 284.1651 found 284.1645.
25
cycloadduct 11b (17 mg, 74% yield) as a yellow oil; [α]D –6 (c = 1,
CHCl3); IR (ATR): ν = 3405, 2953, 2858, 1454, 1050, 944, 748, 713
cm-1; 1H NMR (400 MHz, CDCl3): δH = 7.20-7.14 (m, 2H), 7.10-7.09
(m, 2H), 4.60 (t, J = 9.2, 1H), 4.41 (dq, J = 12.6, 6.1 Hz, 1H), 3.86-3.85
(m, 2H), 3.29 (br s, 1H), 3.20-3.14 (m, 1H), 2.85 (dd, J = 16.3, 11.6
Hz, 1H), 2.70 (dd, J = 16.4, 3.6 Hz, 1H), 2.40-2.31 (m, 2H), 1.72-1.66
(m, 1H), 1.64 (m, 1H), 1.44-1.30 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (101 MHz, CDCl3): δC = 135.3, 132.2, 128.3, 127.1, 126.8,
126.4, 77.6, 66.7, 63.9, 56.5, 42.4, 35.0, 31.6, 28.2, 22.8, 14.1 ppm;
HRMS (ESI- EtOAc): m/z calcd for C16H23NO2 [M+H]+: 262.1807
found 262.1802.
(S)-1-((1R,3S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl)hexan-2-ol (12b): Following the general procedure, reduction of
cycloadduct 11b (17 mg, 0.07 mmol) gave 1,3-disubstituted THIQ
12b (16 mg, 90% yield) as a yellow oil. [α]D25 –0.21 (c = 4.7, CHCl3);
IR (ATR): ν = 3310, 3062, 2926, 2857, 1452, 1123, 1035, 743 cm-1; 1H
NMR (400 MHz, CDCl3): δH = 7.14-7.01 (m, 4H), 4.43 (dd, J = 10.8,
2.4 Hz, 1H), 3.82 (br s, 3H), 3.70 (dd, J = 11.1, 3.7 Hz, 1H), 3.54 (dd, J
= 11.0. 7.3 Hz, 1H), 3.26-3.20 (m, 1H), 2.73 (dd, J = 16.4, 4.1 Hz, 1H),
2.56 (dd, J = 16.4, 10.2 Hz, 1H), 2.10 (ddd, J = 14.2, 11.3, 3.0 Hz, 1H),
1.73-1.61 (m, 2H), 1.56-1.1.25 (m, 6H), 0.91 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (101 MHz, CDCl3): δC = 138.3, 133.8, 129.4, 126.3, 126.2,
126.0, 69.4, 64.8, 51.3, 48.9, 40.3, 36.8, 30.5, 28.3, 22.8, 14.1 ppm;
HRMS (ESI-EtOAc): m/z calcd for C16H25NO2 [M+H]+: 264.1964 found
264.1958.
((2R,5S,10bR)-2-(2-(benzyloxy)ethyl)-1,5,6,10b-tetrahydro-2H-
isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11c): Following the
general procedure, reaction of 4-benzyloxybut-1-ene18 (2.8 mmol,
454 mg) with nitrone 3 gave the cycloadduct 11c (42 mg, 61% yield)
as a yellow oil. [α]D25 –1.21 (c = 9.9, CHCl3); IR (ATR): ν = 3421, 3027,
2916, 2882, 1454, 1361, 1096, 910, 733, 697 cm-1; 1H NMR (400
MHz, CDCl3): δH = 7.38-7.27 (m, 5H), 7.21-7.15 (m, 2H), 7.12-7.07
(m, 2H), 4.64-4.55 (m, 2H), 4.52 (s, 2H), 3.86 (d, 4.2 Hz, 2H), 3.65-
3.60 (m, 2H), 3.24 (br s, 1H), 3.17 (ddd, J = 11.7, 7.9, 4.0 Hz, 1H),
2.88 (dd, J = 16.3, 11.6 Hz, 1H), 2.72 (dd, J = 16.4, 3.6 Hz, 1H), 2.48-
2.36 (m, 2H), 2.05-1.92 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3): δC
= 138.1, 135.0, 132.1, 128.3, 128.1, 127.6, 127.5, 126.9, 126.7,
126.2, 77.2, 74.8, 73.1, 66.9, 66.1, 63.6, 56.5, 42.2, 35.2, 31.4 ppm;
HRMS (ESI- EtOAc): m/z calcd for C21H25NO3 [M+H]+: 340.1913
found 340.1907.
(R)-4-(benzyloxy)-1-((1R,3S)-3-(hydroxymethyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)butan-2-ol (12c): Following the general
procedure, reduction of cycloadduct 11c (27 mg, 0.08 mmol) gave
25
1,3-disubstituted THIQ 12c (14 mg, 51% yield) as a yellow oil. [α]D
–0.31 (c = 3.2, CHCl3); IR (ATR): ν = 3298, 3061, 3028, 2916, 2857,
((2R,5S,10bR)-2-(2-(phenylthio)ethyl)-1,5,6,10b-tetrahydro-2H-
isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11d):
1
1452, 1362, 1090, 1027, 740, 697 cm-1; H NMR (400 MHz, CDCl3):
δH = 7.28-7.18 (m, 5H), 7.06-6.89 (m, 4H), 4.43 (s, 2H), 4.36 (dd, J =
10.9, 2.5 Hz, 1H), 4.01-3.92 (m, 4H), 3.64 (dd, J = 11.2, 3.8 Hz, 1H),
3.53 (t, J = 6.1 Hz, 2H), 3.45 (dd, J = 11.1, 7.4 Hz, 1H), 3.20-3.14 (m,
1H), 2.64 (dd, J = 16.5, 4.3 Hz, 1H), 2.49 (dd, J = 16.5, 10.4 Hz, 1H),
2.02-1.95 (m, 1H), 1.88-1.81 (m, 1H), 1.78-1.64 (m, 2H) ppm; 13C
NMR (101 MHz, CDCl3): δC = 138.4, 138.2, 133.7, 129.5, 128.5,
127.9, 127.8, 126.6, 126.5, 126.2, 73.4, 68.5, 67.8, 64.9, 51.4, 49.1,
41.1, 36.8, 30.6 ppm; HRMS (ESI- EtOAc): m/z calcd for C21H27NO3
[M+H]+: 342.2069 found 342.2064.
Following the general procedure, reaction of but-3-en-1-
yl(phenyl)sulfane19 (2.8 mmol, 459 mg) with nitrone 3 gave the
cycloadduct 11d (50 mg, 64% yield) as a yellow oil. [α]D25 –91 (c = 1,
CHCl3); IR (ATR): ν = 3408, 3058, 2930, 2884, 1582, 1438, 1051,
1
1024, 944, 736, 690cm-1; H NMR (400 MHz, CDCl3): δH = 7.37-7.35
(m, 2H), 7.32-7.28 (m, 2H), 7.21-7.06 (m, 5H), 4.63-4.54 (m, 2H),
3.86 (s, 2H), 3.19-3.07 (m, 3H), 2.99 (ddd, J = 13.1, 8.3, 7.2 Hz, 1H),
2.88 (dd, J = 16.2, 11.6 Hz, 1H), 2.72 (dd, J = 16.4, 3.6 Hz, 1H), 2.45-
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(R)-1-((1R,3S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl)-4-(phenylthio)butan-2-ol (12d): Following the general
procedure, reduction of cycloadduct 11d (47 mg, 0.13 mmol) gave
1,3-disubstituted THIQ 12d (22 mg, 47% yield) as a white solid; m.p.
25
60-62 °C; [α]D –6 (c = 2, CHCl3); IR (ATR): ν = 3369, 3070, 2919,
1581, 1479, 1437, 1090, 1027, 735, 689 cm-1; 1H NMR (400 MHz,
CDCl3): δH = 7.25 (d, J = 7.4 Hz, 2H), 7.18 (t, J = 7.6 Hz, 2H), 7.09-7.02
(m, 31h), 7.00-6.97 (m, 1H), 6.92-6.90 (m, 1H), 4.31 (dd, J = 10.8, 2.6
Hz, 1H), 3.94-3.88 (m, 1H), 3.71 (br s, 3H), 3.61 (dd, J = 11.1, 3.8 Hz,
1H), 3.44 (dd, J = 11.1, 7.2 Hz, 1H), 3.16-3.03 (m, 2H), 2.95-2.88 (m,
1H), 2.64 (dd, J = 16.5, 4.3 Hz, 1H), 2.46 (d, J = 16.4, 101 Hz, 1H),
2.02 (ddd, J = 14.2, 11.2, 3.1), 1.96-1.87 (m, 1H), 1.75-1.67 (m, 1H),
1.62 (ddd, J =14.7, 6.6, 3.1 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3):
δC = 128.3, 136.6, 133.9, 129.7, 129.0, 128.9, 126.5, 126.4, 126.2,
125.9, 68.6, 65.1, 51.6, 49.0, 40.4, 36.5, 30.7, 30.3 ppm; HRMS (ESI-
EtOAc): m/z calcd for C20H25NO2S [M+H]+: 344.1684 found
344.1679.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
JF-F thanks the University of Alicante for
a placement
studentship. MW thanks the Erasmus+ programme for funding
her internship. BM thanks the European Commission for a
Marie Curie Career Integration Grant, the EPSRC for a First
Grant and the RS for a travel grant.
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