A convergent and stereoselective total synthesis of (-)-crispine A, (-)-benzo[a]quinolizidine and (-)-salsolidine

Article abstract of DOI:10.1016/j.tetlet.2013.05.132

A novel strategy has been developed for the syntheses of (-)-crispine, (-)-benzo[a]quinolizidine, and (-)-salsolidine using (R)-tert-butanesulfinamide as a source of chirality. The approach involves the stereoselective addition of Grignard reagent to chiral N-sulfinyl imine followed by cyclization of the secondary amide with a tethered halide as key steps.

Full text of DOI:10.1016/j.tetlet.2013.05.132

Accepted Manuscript
A convergent and stereoselective total synthesis of (-)-crispine A, (-)-ben‐
zo[a]quinolizidine and (-)-salsolidine
N. Siva Senkar Reddy, B. Jaganmohan Reddy, B.V. Subba Reddy
PII:
S0040-4039(13)00923-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.132
TETL 43032
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 March 2013
27 May 2013
29 May 2013
Please cite this article as: Siva Senkar Reddy, N., Jaganmohan Reddy, B., Subba Reddy, B.V., A convergent and
stereoselective total synthesis of (-)-crispine A, (-)-benzo[a]quinolizidine and (-)-salsolidine, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.132
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Graphical Abstract
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A convergent and stereoselective total synthesis of
(-)-crispine A, (-)-benzo[a]quinolizidine and (-)-salsolidine
N. Siva Senkar Reddy, B. Jaganmohan Reddy and B. V. Subba Reddy*

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
A convergent and stereoselective total synthesis of (-)-crispine A, (-)-
benzo[a]quinolizidine and (-)-salsolidine
N. Siva Senkar Reddy,a,b B. Jaganmohan Reddyb and B. V. Subba Reddya*
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad –500 007, India.
bDepartment of Organic Chemistry, Adikavi Nannaya University, Rajahmundry, 533105, India.
E-mail:basireddy@iict.res.in
Abstract: A novel strategy has been developed for the syntheses of (-)-crispine, (-)-benzo[a]quinolizidine and (-)-salsolidine
using (R)-tert-butanesulfinamide as a source of chirality. The approach involves the stereoselective addition of Grignard
reagent to chiral N-sulfinyl imine followed by cyclization of the secondary amide with a tethered halide as key steps.
Keywords: Asymmetric synthesis, (R)-tert-butanesulfinamide, allylation of N-sulfinyl imine, isoquinoline alkaloids
Crispine A was isolated from Carduus crispus plant
along with crispine B and three other bicyclic
isoquinoline alkaloids (Figure 1). It belongs to a
family of pyrroloisoquinoline alkaloids and is used in
folk medicine for the treatment of bronchitis,
stenocardia, gastroenteritis and rheumatism. It also
shows a promising biological activity against human
cancer cell lines.1 Therefore, crispine A has attracted
many synthetic chemists to take up its total synthesis.
As a result, various approaches have appeared in the
literature for the synthesis of racemic crispine A.2-4
Subsequently, stereoselective syntheses of (+)-
Figure 1. Examples of crispine, salsolidine and
benzo[a]quinolizidine
crispine A have been reported using approaches such
as asymmetric Strecker reaction,5 asymmetric transfer
hydrogenation,6,7 asymmetric allylation of cyclic
imines,8 diastereoselective cyclization of N-
N-tert-Butanesulfinamide is
a
versatile chiral
acyliminium,9 chemo-enzymatic deracemization,10 α-
auxiliary for the preparation of synthetically useful
chiral amines.15 Addition of an organometallic reagent
onto enantiopure sulfinimine is one of the most
elegant methods for the synthesis of chiral secondary
amines. The sulfinyl group is highly stereodirecting
and activates the C=N bond effectively in
nucleophilic addition reactions and can easily be
removed under mild conditions to afford the
enantiopure amines.16 However, the use of this useful
chiral auxiliary to the total synthesis of isoquinoline
alkaloids is still unexplored.
amidoalkylation
alkylmagnesium halide,11 and Pictet−Spengler
stereodirected Recently, an
cyclization.12
of
tricyclic
lactam
with
electrochemical approach has also been reported for
the asymmetric synthesis of crispine A.13 However,
only a few methods have been reported for the
synthesis of (-)-benzo[a]quinolizidine and (-)-
salsolidine.14

2
Tetrahedron Letters
Inspired by its potential application in natural
products synthesis,16a we wish to report the total
syntheses of (-)-crispine, (-)-benzo[a]quinolizidine
and (-)-salsolidine using N-tert-butanesulfinamide as
a chiral source.
8 in 76% yield.20 Removal of the sulfinyl group with
ethanolic HCl gave the tetrahydroisoquinoline in 85%
yield.21 The resulting free amine was then protected as
a Boc derivative 9 in 80% yield by treatment with an
excess of TEA in CH2Cl2 followed by addition of Boc
anhydride.18 Hydroboration of the terminal olefin 9
with BH3.DMS in THF followed by oxidation with
H2O2 in the presence of NaOH gave the primary
alcohol 10 in 89% yield. Protection of 10 with mesyl
chloride in the presence of Et3N gave the mesylate
which was subsequently converted into the target
molecule, (-)-crispine A (1) in 69% yield over two
steps using TMSOTf in CH2Cl2 (Scheme 2). The
spectral data of synthetic (-)-crispine A (1) was in
good agreement with the natural product.1,24
At the outset, we attempted the stereoselective total
synthesis of (-)-crispine (1) via the addition of
allylmagnesium bromide to enantiopure sulfinyl
imine. Our retrosynthetic approach for the synthesis
of (-)-crispine (1) is outlined in Scheme 1.
Accordingly, we envisioned that (-)-crispine (1) could
be accessed from primary alcohol 10 which in turn
could be prepared by hydroboration of the olefin 9.
The key intermediate 9 was proposed to be obtained
through allylation of enantiopure N-sulfinyl imine 6.
Aldimine 6 could be prepared by condensation of (R)-
tert-butanesulfinamide with aldehyde 5 which could
be derived from 2-(3,4-dimethoxyphenyl)ethanol 4.
Scheme 1. Retrosynthetic approach of (-)-crispine
Accordingly, we began the synthesis of (-)-crispine
Scheme 2. Synthesis of crispine A (1)
(1)
from
commercially
available
2-(3,4-
dimethoxyphenyl)ethanol 4, which was converted into
the corresponding aldehyde 5 in 70% yield using a
known procedure.17 Treatment of the aldehyde 5 with
(R)-tert-butanesulfinamide in the presence of
anhydrous CuSO4 afforded the corresponding N-
sulfinyl imine 6 in 81% yield.18 Addition of
allylmagnesium bromide to aldimine 6 at -78 ˚C in
CH2Cl2 gave the homoallylic sulfinamide 7 in 80%
yield with 9:1 ratio of diastereomers.19 The
diastereomeric mixture could easily be separated by
column chromatography. An intramolecular ring
closure of a major isomer 7 in the presence of NaH in
DMF at room temperature gave the cyclized product
Reagents
and
conditions:
a)
(R)-tert-
Butanesulfinamide, CuSO4, CH2Cl2, 25 °C, 24h, 81%;
b) AllylMgBr, CH2Cl2, -78 °C, 1h, 80%; c) NaH,
DMF, 0 °C to r.t., 6h, 76%; d) (i) EtOH-HCl, 1,4-
dioxane, 0 °C to r.t., 5h; (ii) Boc2O, Et3N, CH2Cl2, r.t.,
1h, 75% (over two steps); e) (i) BH3.DMS, THF, 0
°C, 3h; (ii) H2O2, NaOH, r.t., 24h, 89%; (f) MsCl,
Et3N, CH2Cl2, r.t., 4h; (ii) TMSOTf, CH2Cl2, r.t., 4h,
69% (over two steps).
After successful synthesis of crispine A, we
attempted
benzo[a]quinolizidine (2) following the above
the
total
synthesis
of
(-)-

Tetrahedron Letters
3
sequence of reactions to prepare the key fragment 9.
Oxidative cleavage of the terminal olefin of 9 using
OsO4, 2,6-lutidine and NaIO4 gave the aldehyde in
78% yield which when subjected to Wittig olefination
with a two carbon stable ylide gave the corresponding
α,β-unsaturated ester 11 in 84% yield (Scheme 3).22
Reduction of conjugated olefin 11 using
NiCl2.6H2O/NaBH4 afforded the saturated ester 12 in
81% yield. Removal of the Boc group from
compound 12 with TMSOTf in CH2Cl2 followed by
cyclization of the resulting secondary amine with a
tethered ester in the presence of K2CO3 and 18-crown-
6 in MeOH gave the lactam 13 in 79% yield (over two
steps).23 Reduction of the lactam 13 with lithium
aluminum hydride (LAH) in THF afforded the (-)-
benzo[a]quinolizidine (2) in 71% yield [α]D= -54.5, c
= 0.6, MeOH] (Scheme 3).6b The optical rotation and
spectral data of the (-)-benzo[a]quinolizidine (2) are
in good agreement with the data reported in the
literature.14a,24
79% yield (95:5 ratio of diastereomers).19 An
intramolecular ring closure of 14 in the presence of
NaH in DMF at room temperature gave the cyclized
product 15 in 76% yield.20 Removal of the sulfinyl
group with ethanolic HCl gave the (-)-salsolidine 3 in
86% yield (Scheme 4). The optical rotation and
spectral data of the (-)-salsolidine (3) are in good
agreement with the data reported in literature.14,24
Scheme 4. Synthesis of (-)-salsolidine
Reagents and conditions: (a) MeMgBr, CH2Cl2, -78
oC, 2h, 79%; b) NaH, DMF, 0 °C to r.t., 6h, 76%; c)
EtOH-HCl, 1,4-dioxane, 0 °C to r.t., 5h, 86%.
In summary, an efficient approach has been devised
for the enantioselective syntheses of (-)-crispine, (-)-
benzo[a]quinolizidine and (-)-salsolidine using (R)-
tert-butanesulfinamide as a chiral source. The use of a
readily available chiral auxilliary makes this synthesis
simple, quite efficient and attractive.
References and Notes
1. Zhang, Q.; Tu, G.; Zhao,Y.; Cheng, T. Tetrahedron
2002, 58, 6795.
2. Knolker, H.-J.; Agarwal, S. Tetrahedron Lett. 2005,
46, 1173.
3. Meyer, N.; Opatz, T. Eur. J. Org. Chem. 2006, 3997.
4. (a) King, F. D. Tetrahedron 2007, 63, 2053. (b) Chiou,
W.-H.; Lin, G.-H.; Hsu, C.-C.; Chaterpaul, S. J.;
Ojima, I. Org. Lett. 2009, 11, 2659. (c) Saha, S.;
Reddy, Ch. V. R.; Patro, B. Tetrahedron Lett. 2011, 52,
4014. (d) Coldham, I.; Jana, S.; Watson, L.; Martin, N.
G. Org. Biomol. Chem. 2009, 7, 1674.
Scheme 3. Synthesis of (-)-benzo[a]quinolizidine
Reagents and conditions: a) (i) OsO4, 2,6-lutidine,
NaIO4, 1,4-dioxane, 2h, 78%; (ii) PPh3CHCO2Et, C6H6,
80 °C, 2h, 84%; b) NiCl2.6H2O/NaBH4, MeOH, 0 °C
to r.t., 2h, 81%; c) (i) TMSOTf, CH2Cl2, r.t., 5h, (ii)
K2CO3, 18-crown-6, MeOH, r.t., 1d, 79%; (over two
steps); d) LAH, THF, 70 °C, 2h, 71%.
5. Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T.
Heterocycles 2007, 74, 199.
6. (a) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J.
Am. Chem. Soc. 2009, 131, 1366. (b) Szawkało, J.;
Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.;
Leniewski, A.; Maurin, J. K.; Czarnocki, Z.;
Drabowicz, J. Tetrahedron: Asym. 2007, 18, 406.
7. (a) Evanno, L.; Ormala, J.; Pihko, P. M. Chem. Eur. J.
2009, 15, 12963. (b) Szawkało, J.; Zawadzka, A.;
Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.;
Czarnocki, Z. Tetrahedron: Asym. 2005, 16, 3619. (c)
Eventually, we extended this approach to the total
synthesis of (-)-salsolidine. Accordingly, treatment of
N-sulfinyl aldimine 6 with methylmagnesium bromide
at -78 ˚C in CH2Cl2 gave the methyl sulfinamide 14 in

4
Tetrahedron Letters
(3H, m); 13C NMR (75 MHz, CDCl3): δ 147.1, 130.5,
126.0, 111.2, 108.7, 62.6, 55.9, 55.7, 52.9, 48.0, 30.5,
27.7. IR (KBr): vmax 3423, 2935, 1612, 1519, 1256,
1008, 755 cm-1; MS (ESI): m/z 234 [M+H]+.
Werner, F.; Blank, N.; Opatz, T. Eur. J. Org. Chem.
2007, 3911.
8. (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006,
128, 9646. (b) Miyazaki, M.; Ando, N.; Sugai, K.;
Seito, Y.; Fukuoka, H.; Kanemitsu, T.; Nagata, K.;
Odanaka, Y.; Nakamura, K; T.; Itoh, T. J. Org. Chem.
2011, 76, 534.
9. Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.; Page, P.
C. B.; Saha, B.; McKenzie, M. J.; Martin, W. P. J. Org.
Chem. 2007, 72, 8972.
10. Bailey, K. R.; Ellis, A. J.; Reiss, R.; Snape, T. J.;
Turner, N. J. Chem. Commun. 2007, 3640.
11. (a) Taniyama, D.; Hasegawa, M.; Tomioka, K.
Tetrahedron Lett. 2000, 41, 5533. (b) Amat, M.; Elias,
V.; Llor, N.; Subrizi, F.; Molins, E.; Bosch, J. Eur. J.
Org. Chem. 2010, 4017.
12. Gurram, M.; Gyimothy, B.; Wang, R.; Lam, S. Q.;
Ahmed, F.; Herr, R. J. J. Org. Chem. 2011, 76, 1605.
13. Louafi, F.; Moreau, J.; Shahane, S.; Golhen, S.;
Roisnel, T.; Sinbandhit, S.; Hurvois, J.-P. J. Org.
Chem. 2011, 76, 9720.
14. (a) Williams, G. D.; Wade, C. E.; Wills, M. Chem.
Commun. 2005, 4735. (b) Grajewska, A.;
Rozwadowska, M. D. Tetrahedron: Asym. 2007, 18,
557. (c) Gremmen, C.; Wanner, M. J.; Koomen, G.-J.
Tetrahedron Lett. 2001, 42, 8885.
15. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984. (b) Sun, X. W.; Xu, M. H.; Lin, G.
Q. Org. Lett. 2006, 8, 4979. (c) Lin, G. Q.; Xu, M. H.;
Zhong, Y. W.; Sun, X. W. Acc. Chem. Res. 2008, 41,
831.
(S)-9,10-Dimethoxy-2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinoline (2):
1
[α]20 – 62 (c = 0.5, MeOH); H NMR (600 MHz,
D
CDCl3): δ 6.66 (1H, s), 6.58 (1H, s), 3.84 (3H, s), 3.84
(3H, s), 3.56-3.46 (1H, m), 3.31-3.10 (3H, m), 2.82-
2.69 (1H, m), 2.66-2.52 (1H, m), 2.35-2.24 (1H, m),
2.08-1.50 (6H, m); 13C NMR (75 MHz, CDCl3): δ
148.0, 147.5, 126.3, 124.7, 111.2, 108.0, 61.7, 55.8,
55.7, 50.3, 29.5, 29.3, 26.6, 23.2. IR (KBr): vmax 3415,
2927, 2855, 1608, 1516, 1259, 1028, 764 cm-1; MS
(ESI): m/z 248 [M+H]+.
(-)-Salsolidine (3):
1
[α]20 – 54 (c = 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.62 (1H, s), 6.57 (1H, s), 4.06 (1H, q, J =
6.7 Hz), 3.85 (3H, s), 3.84 (3H, s), 3.31-3.20 (1H, m),
3.07-2.94 (1H, m), 2.87-2.73 (1H, m), 2.72-2.60 (2H,
m), 1.45 (3H, d, J = 6.7 Hz); 13C NMR (75 MHz,
CDCl3): δ 147.3, 147.2, 132.0, 126.4, 111.6, 109.0,
55.8, 55.7, 51.0, 41.4, 29.5, 22.5. IR (KBr): vmax 3415,
2924, 2853, 1610, 1515, 1030, 759 cm-1; MS (ESI):
m/z 208 [M+H]+.
16. (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem.
Rev. 2010, 110, 3600. (b) Davis, F. A.; Yang, B.; Deng,
J.; Zhang, J. ARKIVOC 2006 (vii) 120. (c) Bosque, I.
(R,E)-N-(2-(2-Chloroethyl)-4,5-
dimethoxybenzylidene)-2-methylpropane-2-
-
, J. C.; Foubelo, F.; Yus, M. J. Org.
sulfinamide (6):
Chem. 2012, 77, 4190.
1
[α]20 – 52 (c = 0.5, CHCl3); H NMR (500 MHz,
D
17. (a) Yamato, M.; Washigaki, K.; Qais, N.; Ishikawa, S.
Tetrahedron 1990, 46, 5909. (b) Coldham, I.; Jana, S.;
Watson, L.; Martin, N. G. Org. Biomol. Chem. 2009, 7,
1674.
CDCl3): δ 8.69 (1H, s), 7.41 (1H, s), 6.78 (1H, s), 3.96
(3H, s), 3.92 (3H, s), 3.76-3.65 (2H, m), 3.46-3.33
(2H, m), 1.27 (9H, s); 13C NMR (75 MHz, CDCl3): δ
160.4, 152.0, 148.0, 133.4, 124.6, 113.7, 112.6, 57.4,
56.0, 55.8, 44.7, 35.7, 22.4. IR (KBr): vmax 3444,
2923, 2853, 1460, 1271, 770 cm-1; MS (ESI): m/z 233
(M+H)+.
18. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (b)
Harried, S. S.; Croghan, M. D.; Kaller, M. R.; Lopez,
P.; Zhong, W.; Hungate, R.; Reider, P. J. J. Org. Chem.
2009, 74, 5975.
19. (a) Nishikawa, Y.; Kitajima, M.; Kogure, N.;
Takayama, H. Tetrahedron 2009, 65, 1608. (b) Lin, S.;
Zhao. G. Eur. J. Org. Chem. 2010, 1660.
20. (a) Natsume, M.; Wada, M. Chem. Pharm. Bull. 1972,
20, 1589. (b) Reddy, L. R.; Das, S. G.; Liu, Y.;
Prashad, M. J. Org. Chem. 2010, 75, 2236.
(R,N)-((S)-1-(2-(2-Chloroethyl)-4,5-
dimethoxyphenyl)but-3-enyl)-2-methylpropane-2-
sulfinamide (7):
1
[α]28 –29 (c = 0.7, CHCl3); H NMR (500 MHz,
D
CDCl3): δ 6.80 (1H, s), 6.61 (1H, s), 5.73-5.60 (1H,
m), 5.19-5.06 (2H, m), 4.60-4.51 (1H, m), 3.81 (3H,
s), 3.76 (3H, s), 3.73-3.66 (2H, m), 3.64-3.55 (1H, m),
3.10-2.99 (2H, m), 2.53-2.44 (1H, m), 2.43-2.32 (1H,
m), 1.13 (9H, s); 13C NMR (75 MHz, CDCl3): δ 148.2,
148.1 134.1, 131.2, 128.7, 119.2, 112.9, 110.3, 55.8,
55.4, 51.8, 44.6, 43.1, 35.7, 22.5; IR (KBr): vmax 3425,
2927, 1518, 1213, 1030 cm-1; MS (ESI): m/z 374
[M+H]+.
21. (a) Liu, M.; Sun, X.; Xu, M.; Lin, G. Chem. Eur. J.
2009, 15, 10217. (b) Sun, X.; Liu, M.; Xu, M.; Lin, G.
Org. Lett. 2008, 10, 1259.
22. Chandrasekhar, S.; Mahipal, M.; Kavitha, M. J. Org.
Chem. 2009, 74, 9531.
23. Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka,
H.; Kanemitsu, T.; Nagata, K.; Odanaka, Y.;
Nakamura, K. T.; Itoh, T. J. Org. Chem. 2011, 76, 534.
24. Spectral data for selected compounds
(-)-Crispine A (1):
1
[α]20 – 91 (c = 1.0, CHCl3); H NMR (300 MHz,
(S)-1-Allyl-2-((R)-tert-Butylsulfinyl)-6,7-
D
dimethoxy-1,2,3,4-tetrahydroisoquinoline (8):
CDCl3): δ 6.61 (1H, s), 6.57 (1H, s), 3.85 (6H, s),
3.53-3.44 (1H, m), 3.23-3.13 (1H, m), 3.12-2.94 (2H,
m), 2.80-2.55 (3H, m), 2.40-2.27 (1H, m), 1.96-1.67
1
[α]20 + 62 (c = 0.55, CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.55 (1H, s), 6.52 (1H, s), 6.0-5.83 (1H, m),

Tetrahedron Letters
5
5.15-5.04 (2H, m), 4.30 (1H, t, J = 6.7 Hz), 3.82-3.79
(6H, m), 3.50-2.91 (1H, dd, J = 6.7, 6.0 Hz), 3.33-
3.20 (1H, m), 3.05-2.91 (1H, m), 2.77-2.46 (3H, m),
1.15 (9H, s); 13C NMR (75 MHz, CDCl3,): δ 147.4,
146.7, 135.0, 129.3, 125.3, 117.7, 111.4, 109.7, 58.1,
55.6, 55.5, 41.1, 27.5, 22.7. IR (KBr): vmax 3450,
2929, 1636, 1516, 1118, 763 cm-1; MS (ESI): m/z 338
[M+H]+.
14.1. IR (KBr): vmax 2931, 1732, 1688, 1418, 1251,
1166, 1033, 769 cm-1; MS (ESI): m/z 430 [M+Na]+.
(S)-9,10-Dimethoxy-2,3,6,7-tetrahydro-1H-
pyrido[2,1-a]isoquinolin-4-(11bH)-one (13):
[α]20 – 38.8 (c = 0.9, CHCl3); 1H NMR (300 MHz,
D
CDCl3): δ 6.68 (1H, s), 6.62 (1H, s), 4.93-4.83 (1H,
m), 4.66-4.57 (1H, m), 3.87 (6H, s), 2.99-2.75 (2H,
m), 2.69-2.47 (3H, m), 2.46-2.31 (1H, m), 2.01-1.76
(2H, m), 1.75-1.59 (1H, m); 13C NMR (75 MHz,
CDCl3): δ 169.6, 147.6, 147.5, 128.8, 127.0, 111.3,
108.0, 56.5, 56.0, 55.7, 39.6, 32.0, 30.7, 28.2, 19.3. IR
(KBr): vmax 3422, 2931, 1612, 1514, 1260, 1222, 768
cm-1; MS (ESI): m/z 262 [M+H]+.
(S)-tert-Butyl-1-allyl-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate (9):
1
[α]20 + 109 (c = 0.3, CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.63-6.55 (2H, m), 5.95-5.57 (1H, m), 5.21-
4.94 (3H, m), 4.28-3.92 (1H, m), 3.85 (6H, s), 3.34-
3.0 (1H, m), 2.97-2.73 (1H, m), 2.69-2.48 (3H, m),
1.48 (9H, s); 13C NMR (75 MHz, CDCl3): δ 154.6,
147.6, 147.2, 135.1, 128.9, 126.4, 117.1, 111.4, 109.8,
79.7, 55.9, 55.8. IR (KBr): vmax 2972, 2926, 1691,
1517, 1166, 770 cm-1; MS (ESI): m/z 334 [M+H]+.
(S)-N-((S)-1-(2-(2-Chloroethyl)-4,5-
dimethoxyphenyl)ethyl)-2-methylpropane-2-
sulfinamide (14):
1
[α]20 – 10 (c = 0.3 CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.89 (1H, s), 6.62 (1H, s), 4.82-4.70 (1H,
m), 3.86 (3H, s), 3.82 (3H, s), 3.78-3.58 (2H, m),
3.14-3.06 (2H, m), 1.48 (3H, d, J = 6.7 Hz), 1.19 (9H,
s); 13C NMR (75 MHz, CDCl3): δ 148.8, 148.7, 133.0,
128.0, 112.8, 109.6, 55.8, 55.7, 49.0, 44.6, 35.6, 25.0,
22.5. IR (KBr): vmax 3448, 2923, 2853, 1612, 1519,
(S)-tert-Butyl-1-(3-hydroxypropyl)-6,7-dimethoxy-
3,4-dihydroisoquinoline-2(1H)-carboxylate (10):
1
[α]20 + 84 (c = 0.25, CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.63-6.56 (2H, m), 5.16 (1H, br.s), 4.22
(1H, br.s), 3.91-3.64 (8H, m), 3.31-3.05 (1H, m),
2.94-2.74 (1H, m), 2.69-2.56 (1H, m), 1.90-1.78 (2H,
m), 1.74-1.58 (2H, m), 1.47 (9H, s); 13C NMR (75
MHz, CDCl3): δ 155.1, 147.3, 129.8, 126.0, 111.3,
110.1, 79.7, 62.7, 56.0, 55.8, 54.1, 42.6, 38.2, 33.3,
29.6, 28.4, 28.1, 22.6. IR (KBr): vmax 3446, 2930,
2853, 1684, 1516, 1423, 1163, 935, 762 cm-1; MS
(ESI): m/z 374 [M+Na]+.
1217, 1028, 692 cm-1; MS (ESI): m/z 348 [M+H]+
.
(S)-2-((S)-tert-Butylsulfinyl)-6,7-dimethoxy-1-
methyl-1,2,3,4-tetrahydroisoquinoline (15):
1
[α]20 + 28 (c = 0.3 CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.56 (1H, s), 6.50 (1H, s), 4.44 (1H, q, J =
7.5 Hz), 3.83 (6H, s), 3.50-3.38 (1H, m), 3.31-3.17
(1H, m), 3.08-2.92 (1H, m), 2.69-2.57 (1H, m), 1.54
(3H, d, J = 6.7 Hz), 1.19 (9H, s); 13C NMR (75 MHz,
CDCl3): δ 147.4, 147.2, 131.0, 125.4, 111.4, 109.4,
58.0, 55.8, 55.7, 52.3, 38.0, 28.0, 23.0, 21.7. IR
(KBr): vmax 3449, 2927, 2855, 1613, 1517, 1122,
1029, 753 cm-1; MS (ESI): m/z 312 [M+H]+.
(S,E)-tert-Butyl-1-(4-ethoxy-4-oxobut-2-enyl)-6,7-
dimethoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (11):
[α]20 + 51.5 (c = 0.75, CHCl3); 1H NMR (500 MHz,
D
CDCl3): δ 7.06-6.95 (1H, m), 6.62-6.56 (2H, m), 5.88-
5.77 (1H, m), 5.12-5.06 (1H, m), 4.27-4.12 (2H, m),
3.85 (6H, s), 3.30-3.06 (2H, m), 2.92-2.76 (1H, m),
2.72-2.60 (3H, m), 1.47 (9H, s), 1.31-1.24 (3H, m);
13C NMR (75 MHz, CDCl3): δ 166.0, 154.2, 147.8,
147.4, 145.1, 128.0, 126.5, 123.4, 111.5, 109.5, 80.2,
60.2, 56.0, 55.8, 39.8, 36.6, 29.6, 28.2, 14.2. IR
(KBr): vmax 2974, 2931, 1716, 1690, 1517, 1416,
1164, 1099, 770 cm-1; MS (ESI): m/z 428 [M+Na]+.
(S)-tert-Butyl-1-(4-ethoxy-4-oxobutyl)-6,7-
dimethoxy-3,4-dihydroisoquinoline-2(1H)-
carboxylate (12):
1
[α]20 + 54 (c = 0.5, CHCl3); H NMR (300 MHz,
D
CDCl3): δ 6.62-6.54 (2H, m), 5.01-4.91 (1H, m), 4.18-
4.06 (2H, m), 3.89-3.83 (6H, m), 3.30-3.01 (2H, m),
2.97-2.74 (1H, m), 2.67-2.55 (1H, m), 2.48-2.28 (2H,
m), 1.85-1.68 (4H, m), 1.48 (9H, s), 1.25 (3H, t, J =
6.7 Hz); 13C NMR (75 MHz, CDCl3): δ 173.2, 154.7,
147.5F, 147.2, 129.5, 126.2, 111.4, 109.7, 79.9, 60.2,
55.9, 55.8, 53.9, 38.0, 36.4, 34.0, 28.3, 27.8, 21.9,