Chiral aziridine-2-carboxylates: Versatile precursors for functionalized tetrahydroisoquinoline (THIQ) containing heterocycles

Article abstract of DOI:10.1016/j.tet.2011.11.031

Preparation of functionalized 3,4-dihydroisoquinolines 17a-j from (S)-N-methoxy-N-methyl-1-[(R)-1-phenylethyl]aziridine-2-carboxamide 4 is an effective route for the synthesis of 3-(hydroxymethyl)-1,2,3,4- tetrahydroisoquinolin-4-ols. Stereoselective redu

Full text of DOI:10.1016/j.tet.2011.11.031

Tetrahedron 68 (2012) 883e893
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Chiral aziridine-2-carboxylates: versatile precursors for functionalized
tetrahydroisoquinoline (THIQ) containing heterocycles
,
b
b,
*
Kyu Myung Lee a, Jong Chan Kim a, Philjun Kang a, Won Koo Lee a , Heesung Eum , Hyun-Joon Ha
*
a Department of Chemistry, Sogang University, Shinsu-dong 1, Mapo-gu, Seoul 121-742, Republic of Korea
b Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Preparation of functionalized 3,4-dihydroisoquinolines 17aej from (S)-N-methoxy-N-methyl-1-[(R)-
1-phenylethyl]aziridine-2-carboxamide 4 is an effective route for the synthesis of 3-(hydroxymethyl)-
1,2,3,4-tetrahydroisoquinolin-4-ols. Stereoselective reduction of the cyclic imines 17aej resulted
in (1S,3S,4R)-4-(tert-butyldimethylsilyl-oxy)-3-[(tert-butyldimethylsilyloxy)methyl]-6,7-dimethoxy-1,2-
disubstituted-1,2,3,4-tetrahydroisoquinolines and the desilylation of the TBS groups afforded (1S,3S,4R)-
3-(hydroxymethyl)-6,7-dimethoxy-1,2-disubstituted-1,2,3,4-tetrahydroisoquinolin-4-ols 19aei in good
yields. Also, an asymmetric synthesis of novel tetracyclic 3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-
4-ols 23 and 25 was successfully achieved via Pd-catalyzed N-arylation and CeC coupling reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 September 2011
Received in revised form 10 November 2011
Accepted 10 November 2011
Available online 18 November 2011
Keywords:
Chiral aziridine
Modified BischlereNapieralski cyclization
Stereoselective reduction
Tetrahydroisoquinoline
1. Introduction
substituted-1,2,3,4-tetrahydroisoquinolin-4-ol structure, as a po-
tent anticancer agent (Fig. 1). Therefore, we were interested in the
Many tetrahydroisoquinoline (THIQ) derivatives, including sev-
eral alkaloids, show pharmacologically important properties.1 Also,
some natural products containing THIQ moiety have been used as
antitumor antibiotics,2 antimalarial,3 and ionotropic glutamate re-
ceptor antagonist4 for central nervous system (CNS). Recently,
(þ)-tetrabenazine5 (TBZ) 1 and (þ)-dihydrotetrabenazine6 (DTBZ) 2
were reported as therapeutic agents for imagining VMAT-2 in brain.
Therefore, the synthesis of tetrahydroquinoline (THIQ) containing
molecules has attracted much attention due to the importance of the
compounds as pharmacophore.7 The syntheses of functionalized
tetrahydroisoquinolines, which have substituents at C-1, C-3, C-4
positions have been reported previously and the asymmetric syn-
thesis of 1-substituted tetrahydroisoquinolines takes most of the
cases.8 Moreover, the introduction of substituents at 1-position
provides variously substituted (aryl and aliphatic group) tetrahy-
droisoquinolines.9 Though substitution at C-3, C-1, 3,8f,10 as well as
C-1 has been reported, there has not been many examples for
the preparation of chiral 1,3,4-trisubstituted tetrahydroisoquino-
lines. Therefore, the synthesis of 1-substituted-3-hydroxymethyl-
4-hydroxy-1,2,3,4-tetrahydroisoquinolines is a rare case except for
some examples.11 Koga et al. reported the asymmetric synthesis of
2-azapo-dophyllotoxins 312 containing 3-(hydroxymethyl)-1-
synthesis of enantiomerically pure substituted 1,2,3,4-
tetrahydroisoquinolines starting from chiral aziridines and we re-
port herein an efficient synthesis of enantiopure 3-(hydrox-
ylmethyl)-1-substituted-1,2,3,4-tetrahydroisoquinolin-4-ols
and
also THIQ containing heterocycles from the readily available chiral
aziridine-2-carboxamide 4.
Fig. 1. Some examples of biologically active THIQs.
Chiral aziridines have been used as important chiral building
blocks for the synthesis of various natural and unnatural amino acid
derivatives,13 andalsobiologicallyactiveheterocycles in asymmetric
manners. Starting from chiral aziridines, we recently reported the
synthesis of enantiomerically pure functionalized oxazolidinones,14
imidazolidinones,15 piperidines,16 bicyclic triazoles,17 and also phy-
tosphingosine derivatives.18 Furthermore, the synthesis of enan-
tiomerically pure benzofused bicyclic heterocycles, such as 2-
* Corresponding authors. Tel.: þ82 2 705 8449; fax: þ82 2 701 0967; e-mail
addresses: wonkoo@sogang.ac.kr, wonkoo62@gmail.com (W.K. Lee), hjha@hufs.ac.kr
(H.-J. Ha).
hydroxymethyl-1,2,3,4-tetrahydroquinolines,
3,4-dihydro-2H-
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.031

884
K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
benzo[b][1,4]-oxazine, and 1,2,3,4-tetrahydroquinoxalines from
chiral aziridine-2-methanol was reported.19 The above results show
that a variety of nitrogen containing heterocycles can be prepared
from chiral aziridines stereoselectively using functional group
elaboration and simple organic transformations.
2. Results and discussion
The chiral aziridine-2-carboxamide can be converted to various
acylaziridines via organometallic additions. (S)-N-Methoxy-N-
methyl-1-[(R)-1-phenylethyl]aziridine-2-carboxamide 4 was reac-
ted with ortho-lithiated styrene to provide the corresponding acy-
laziridine 5 in 91% yield. The reduction of the ketone by chelation-
controlled reaction provided benzyl alcohol 7 in 90% yield (dr
>99/1). The secondary benzylic alcohol of 7 was protected using
TBSOTf and 2,6-lutidine at 0 ꢀC to give 86% yield of the silyl ether 9.
Ozonolysis20 of the styrene 9 in CH2Cl2/MeOH (1/1) at ꢁ78 ꢀC pro-
vided the corresponding aldehyde and in situ reduction of the al-
dehyde with NaBH4 at ꢁ78 ꢀC provided the benzylic alcohol 10 in
77% yield (two steps). The aziridine-2-carboxamide 4, obtained from
the corresponding carboxylate and Weinreb’s amine, and the lithi-
ated 4-bromoveratrole were reacted to provide the corresponding
ketone 6 in 89%. Tetrahydroisoquinolines have been prepared from
phenylethanamine derivatives using the BischlereNapieralski cy-
clization.21 Therefore, we prepared the phenylethanamine de-
rivative 11 via stereoselective reduction of the ketone, regioselective
aziridine ring-opening followed by alcohol protection with TBS
group for further ring cyclization reactions (Scheme 1).
Scheme 2. Synthesis of 3-(hydroxymethyl)-3,4-dihydroisoquinolin-4-ol 15a via for-
mation and regioselective ring-opening of the aziridinium salt 12.
and the acetate was hydrolyzed with LiOH$H2O in aqueous EtOH
(EtOH/H2O¼2/1, v/v) under refluxing for 8 h to provide the diol 14a
in 86% yield. The nitrogen protecting group of 14a was also removed
by successive catalytic hydrogenation with atmospheric pressure of
H2 in MeOH in the presence of Boc2O to provide the N-Boc protected
3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol 15a in 90%
yield, which is a novel method for the synthesis of enantiomerically
pure 3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol.23
The 1-a-methylbenzyl group of the chiral phenylethanamine 11
was removed by catalytic hydrogenation with Pd(OH)2 to give the
free amine and the following reaction with various acyl chlorides
provided N-acylated products 16aej under basic aqueous THF in
72e99% yields.
Each of the N-acylated product 16aej underwent dehydrative
cyclization24 using a modified BischlereNapieralski cyclization
with Tf2O and 2-ClPyr in CH2Cl2 to provide (3S,4R)-1-substituted-
3,4-dihydroisoquinolines 17aej in 50e95% yields (Scheme 3).
Scheme 1. Preparation of substrate 10, 11 for the synthesis of THIQ.
The reaction of the primary benzyl alcohol 10 with MsCl forms
the corresponding mesylate and the nucleophilic aziridine nitrogen
initiates the intramolecular cyclization reaction to form the azir-
idinium ion intermediate 12.22 Regioselective aziridine ring-
opening reaction by the chloride liberated from the MsCl provided
the corresponding chloride 120, which was isolated and confirmed
using HRMS and 1H NMR. Therefore, the reaction mixture was di-
rectly treated with an additional nucleophile, acetate or azide, to
provide the acetate 13a (when the nucleophile was acetate) and the
azidomethyl compound 13b (when the nucleophile was azide) in
reasonable yields (Scheme 2). The TBS group of 13a was deprotected
Scheme 3. The preparation of 1,2,3,4-substituted THIQs 19aei by a modified Bisch-
lereNapieralski cyclization and the following reduction.

K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
885
N-Methyl-1-substituted-3,4-dihydroisoquinolinium iodide in-
termediates were formed from the reaction of 17 and CH3I in CH2Cl2 at
35 ꢀC. The reduction of the iminium salt using NaBH(OAc)3 in MeOH at
absolute configurations of C-1 of the corresponding desilylated
products 19 were determined by 1He1H NOEexperiments, suggesting
that (1R)-1-substituted 2-methyl-1,2,3,4-tetrahydroisoquinoline was
the major product (Fig. 2).
0
ꢀC provided 1-substituted-N-methyl-1,2,3,4-tetrahydroisoquino-
lines 18aei in 55e82% yields (Table 1). While 1-aryl substituted-3,4-
dihydroisoquinolines 17fei formed 3,4-dihydroisoquinolinium in-
termediate rapidly, 1-alkyl substituted-3,4-dihydroisoquinolines
17aee were not as reactive as 1-aryl substituted compounds. After
stereoselective reduction of the 1-substituted-3,4-dihydroiso
quinolinium iodide, the alcohol protecting groups of 18aei were
cleaved by LiOH in aqueous EtOH (EtOH/H2O¼2/1, v/v) under reflux to
give the corresponding diols 19aei in 51e87% yields (Table 1). The
We also synthesized tetracyclic structures 23 and 25 containing
3-hydroxymethyl-4-hydroxy tetrahydroisoquinoline moiety using
Pd-catalyzed intramolecular CeN and CeC bond formation. Indolo
[2,1-a]isoquinolines26 have been known for their biological activi-
ties27 and the synthesis was accomplished by an intramolecular
coupling of the aryl bromide with an amine nitrogen of 1-(2-
bromobenzyl)-1,2,3,4-tetrahydroisoquinoline 20, which was pre-
pared by the stereoselective reduction of the imine obtained from
Table 1
Synthesis of 3-(hydroxymethyl)-1-substituted-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ols 19aei
Entry
Substrate 17
Product 18
Product 19
Timeb (h)
Yieldc (%)
55
Yield (%)
1
40
2
3
34
36
63
73
19c;
19d;
4
5
72
40
68
62
19e;
19f;
6
4.5
61
7
19g;
4
78
(continued on next page)

886
K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
Table 1 (continued )
Entry
Substrate 17
Product 18
Product 19
Timeb (h)
Yieldc (%)
Yield (%)
8
3.5
82
19h;
9
7
69
19i;
10
NDd
NDd
NDd
aIsolated three steps yield. The cyclization reaction was carried out in the presence of Tf2O (1.1 equiv) and 2-ClPyr (1.1 equiv) in anhydrous CH2Cl2 at ꢁ78 ꢀC to rt.
b
Reaction time of N-methylation step.
c
Isolated yield. The stereoselective reduction was carried out in the presence of NaBH(OAc)3 (2.0 equiv) in MeOH at 0 ꢀC via N-methyl-tetrahydroisoquinolinium iodide
intermediate.
d
The reactions of the corresponding substrate were not carried out. No Data.
Fig. 2. NOE experiment for the determination of the absolute stereochemistry at C-1
position of 19g, 19g0.25
the intramolecular dehydrative cyclization product 17j with NaBH4
in MeOH at 0 ꢀC in 87% yield (dr >9/1). The major diastereomer of
the reduction product 20 was easily separated by flash column
chromatography in high purity and Pd-catalyzed N-arylation28 of
20 with 5 mol % Pd2(dba)3, 10 mol % X-Phos ligand, and NaOtBu in
toluene at 110 ꢀC was completed within 1.5 h to give the tetracyclic
5,6-dihydroindoloisoquinolinol 22 in 90% yield. During the desi-
lylation of the TBS group, the oxidation of the C(12)eC(12a) bond
was also proceeded to provide 6-(hydroxymethyl)-5,6-
dihydroindoloisoquinolin-5-ol 23 in 96% yield (Scheme 4). The
synthesis and application of nuciferine alkaloid29 containing tet-
rahydroisoquinoline (THIQ) motif are well known. Especially, direct
CeH arylation30 of unactivated substrates is an important key
protocol for the synthesis of tetrahydro-4H-dibenzo[de,g]-quino-
line. Following the recently reported method, substrate 21 pro-
tected by N-acetyl group was reacted with 20 mol % Pd(OAc)2,
30 mol % X-Phos ligand, and Cs2CO3 in refluxing DMA to yield the
cyclized product 24 in 65% yield (two steps).31 The TBS groups of the
cyclized product 24 were removed by LiOH in aqueous EtOH (EtOH/
H2O¼2/1, v/v) to yield 5-(hydroxymethyl)-5,6,6a,7-tetrahydro-4H-
Scheme 4. Synthesis of tetracyclic 3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-
4-ols 23 and 25.
dibenzo-[de,g]-quinolin-4-ol 25 in 77% yield (Scheme 4) (Fig. 3).

K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
887
solution at ꢁ78 ꢀC. The reaction mixture was continuously stirred for
30 min, and allowed to warm to room temperature. The reaction
mixture was diluted with EtOAc and treated with aqueous NH4Cl
solution. The aqueous layer was extracted with CH2Cl2. The combined
extracts were dried over anhydrous MgSO4 and filtered then the
solvent was removed in vacuo. The crude product was purified by
silicagelflashcolumnchromatographyusingEtOAc/hexane(15/85)to
give 3.23 g of product 5 as a colorless oil (91%); ½a D24
ꢂ
ꢁ55.3 (c 0.70,
Fig. 3. Some examples of nuciferine alkaloids.
CH3OH); 1H NMR (300 MHz, CDCl3)
d 7.50e7.13 (m, 9H), 6.79 (dd, 1H,
3. Conclusion
J¼10.8, 17.4 Hz), 5.56 (d, 1H, J¼17.4 Hz), 5.10 (d, 1H, J¼10.8 Hz),
2.70e2.67(m,1H), 2.67(q,1H,J¼6.6 Hz)2.53e2.51(m,1H),1.92(d,1H,
In conclusion, enantiomerically pure functionalized tetrahy-
droisoquinolines (THIQs) were efficiently prepared starting from
chiral aziridines using simple organic transformations. Enantiopure
3-(hydroxymethyl)-1-functionalized-1,2,3,4-tetrahydroisoquinolin-
4-ols were synthesized from chiral phenylethanamine 11 derived
from chiral aziridine-2-carboxaimde 4 via modified Bischlere
Napieralski cyclization and stereoselective reduction of the corre-
sponding cyclized imines in moderate yields. Also, asymmetric
synthesis of novel tetracyclic 3-(hydroxymethyl)-1,2,3,4-tetra-
hydroisoquinolin-4-ols was successfully achieved via Pd-catalyzed
N-arylation and also CeC coupling reaction.
J¼4.8 Hz), 1.50 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz, CDCl3)
d 201.2,
144.3, 137.7, 137.0, 134.8, 131.3, 128.7, 128.3, 127.5, 127.4, 127.0, 126.7,
117.2, 70.7, 43.3, 38.2, 23.7; HRMS m/z calcd for C19H19NO [MþNa]þ
300.1365, found 300.1362.
4.1.2. (3,4-Dimethoxyphenyl)[(S)-1-(R)-1-phenylethylaziridin-2-yl]
methanone (6). Colorless oil (89%); ½a D24
ꢂ
ꢁ0.7 (c 1.14, CHCl3); 1H
NMR (300 MHz, CDCl3) d 7.42e7.38 (m, 3H), 7.32e7.20 (m, 4H), 6.71
(d, 1H, J¼8.4 Hz), 3.90 (s, 3H), 3.82 (s, 3H), 2.87 (q, 1H, J¼3.0 Hz),
2.72 (q,1H, J¼6.3 Hz), 2.56 (dd,1H, J¼1.5, 3.0 Hz),1.92 (dd,1H, J¼1.5,
6.3 Hz), 1.52 (d, 3H, J¼6.3 Hz); 13C NMR (125 MHz, CDCl3)
d 194.7,
153.5, 149.1, 144.3, 130.3, 128.7, 127.3, 126.8, 123.2, 110.5, 110.0, 70.9,
56.2, 56.1, 40.2, 36.9, 23.8; HRMS m/z calcd for C19H21NO3 [MþNa]þ
334.1419, found 334.1419.
4. Experimental section
4.1. Remarks
4.1.3. (R)-(S)-1-[(R)-1-Phenylethylaziridin-2-yl](2-vinylphenyl)
methanol (7). To a 0.20 M solution of 5 (3.00 g, 10.82 mmol) in
MeOH (54.0 mL) was added ZnCl2 (2.21 g, 16.22 mmol) at ꢁ78 ꢀC.
After stirring for an additional 30 min, NaBH4 (0.82 g, 21.63 mmol)
was added to the resulting solution at ꢁ78 ꢀC. Stirring was con-
tinued for 3 h at ꢁ78 ꢀC and the reaction mixture was allowed to
warm to room temperature. The solvent was concentrated under
reduced pressure and the resulting white sticky residue was diluted
with CH2Cl2, then quenched with H2O. The aqueous layer was
extracted with CH2Cl2. The combined extracts were dried over
anhydrous MgSO4, filtered, and then the solvent was removed in
vacuo. The crude product was purified by silica gel flash column
chromatography using EtOAc/hexane (30/70) to give 2.72 g of
All reactions were carried out under an atmosphere of nitrogen in
oven-dried glasswares with magnetic stirring. Air sensitive reagents
and solutions were transferred via syringe and were introduced to the
apparatus through rubber septa. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium/benzophenone ketyl.
Dichloro-methane (CH2Cl2) was distilled from calcium hydride. Re-
actions were monitored by thin layer chromatography (TLC) with
0.25 mm E. Merck pre-coated silica gel plates (60 F254). Visualization
was accomplished with either UV light, or by immersion in solutions
of ninhydrin, p-anisaldehyde, or phosphomolybdic acid (PMA) fol-
lowed by heating on a hot plate for about 10 s. Purification of reaction
products was carried out by flash chromatography using Kieselgel 60
Art 9385 (230e400 mesh). 1H NMR and 13C NMR spectra were ob-
tained using a Varian Gemini-300 (300 MHz for 1H, and 75 MHz for
13C), oraVarian400(400 MHzfor1H, and100 MHz for 13C), oraVarian
Inova-500 (500 MHz for 1H, and 125 MHz for 13C) spectrometers.
product 7 as a colorless oil (90%); ½a D24
ꢂ
þ40.5 (c 0.96, CH2Cl2); 1H
NMR (300 MHz, CDCl3)
d
7.42e7.22 (m, 9H), 6.83 (dd, 1H, J¼10.8,
17.1 Hz), 5.55 (d, 1H, J¼17.1 Hz), 5.20 (d, 1H, J¼10.8 Hz), 5.00e4.98
(m, 1H), 3.01 (br, 1H), 2.66 (q, 1H, J¼6.6 Hz), 2.08e2.07 (m, 1H),
1.88e1.85 (m, 1H), 1.43 (d, 3H, J¼6.6 Hz), 1.41e1.39 (m, 1H); 13C
Chemical shifts are reported relative to chloroform (
d
¼7.26) for 1H
NMR and chloroform (
d
¼77.2) for 13C NMR. Data are reported as
NMR (125 MHz, CDCl3) d 144.4, 138.8, 136.0, 134.2, 128.6, 128.0,
(br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet).
Coupling constants are given in hertz. Ambiguous assignments were
resolved on the basis of standard one dimensional proton decoupling
experiments. Optical rotations were obtained using a Rudolph Auto-
pol III digital polarimeter and optical rotation data were reported as
127.6, 127.4, 126.7, 126.0, 125.8, 116.5, 69.2, 66.3, 42.0, 29.8, 23.2; FT-
IR: v 3354 cmꢁ1 (br, OH); HRMS m/z calcd for C19H21NO [MþNa]þ
302.1521, found 302.1524.
4.1.4. (R)-(3,4-Dimethoxyphenyl)[(S)-1-(R)-1-phenylethylaziridin-2-
follows: ½a 2D4
ꢂ
(concentration c¼g/100 mL, solvent). Elemental analy-
yl]methanol (8). White solid (94%); ½a D24
ꢂ
þ41.7 (c 0.77, CHCl3); 1H
ses were performed by the Organic Chemistry Research Center at
Sogang Universityusinga Carlo Erba EA 1180elemental analyzer. High
resolution mass spectra were recorded on a 4.7 T IonSpec ESI-FTMS or
aMicromassLCTESI-TOFmassspectrometer. IRspectrawererecorded
neat on Nicolet Avatar 330 FT-IR. Melting points were recorded on an
Electrothermal-9100 and are uncorrected. All commercially available
compounds were used as received unless stated otherwise.
NMR (300 MHz, CDCl3) d 7.31e7.25 (m, 5H), 6.81e6.75 (m, 3H), 4.58
(d, 1H, J¼3.6 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 2.96 (br, 1H), 2.66 (q, 1H,
J¼6.6 Hz), 2.13 (d, 1H, J¼3.6 Hz), 1.83e1.79 (m, 1H), 1.63 (s, 1H), 1.43
(d, 3H, J¼6.6 Hz); 13C NMR (100 MHz, CDCl3)
d 148.7, 148.3, 144.2,
134.3, 128.4, 127.1, 126.5, 118.4, 110.7, 109.2, 70.3, 69.1, 55.9, 55.7,
43.1, 29.8, 23.4; FT-IR: v 3363 cmꢁ1 (br, OH); mp 131e133 ꢀC; HRMS
m/z calcd for C19H23NO3 [MþNa]þ 336.1576, found 336.1577.
4.1.1. ((S)-1-((R)-1-phenylethyl)aziridin-2-yl)(2-vinylphenyl)meth-
anone (5). To a 0.30 M solution of 2-bromostyrene (2.31 mL,
17.93 mmol)inanhydrousTHF(42.70 mL)wasaddedn-BuLi(8.32 mL,
2.00 M in hexane) in dropwise at ꢁ78 ꢀC under nitrogen atmosphere.
The reaction mixture was stirred for 1 h atꢁ78ꢀC and (S)-N-methoxy-
N-methyl-1-[(R)-1-phenylethyl]-aziridine-2-carboxamide 4 (3.00 g,
12.81 mmol) in anhydrous THF was slowly added to the resulting
4.1.5. (S)-2-[(R)-(tert-Butyldimethylsilyloxy)(2-vinylphenyl)methyl]-
1-[(R)-1-phenylethyl]aziridine (9). To a 0.20 M solution of 7 (0.64 g,
2.29 mmol) in CH2Cl2 (11.50 mL) was added 2,6-lutidine (0.53 mL,
4.58 mmol) at 0 ꢀC. To the reaction mixture was added TBSOTf
(0.58 mL, 2.52 mmol) at 0 ꢀC. After stirring for additional 15 min,
the reaction mixture was allowed to warm to room temperature
and diluted with CH2Cl2, treated with aqueous NH4Cl solution. The

888
K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
aqueous layer was extracted with CH2Cl2. The combined extracts
were dried over anhydrous MgSO4, filtered, and then the solvent
was removed in vacuo. The crude product was purified by silica gel
flash column chromatography using EtOAc/hexane (5/95) to give
1H),1.17 (d, 3H, J¼7.0 Hz), 0.95 (s, 9H), 0.81 (s, 9H), 0.10 (s, 3H), 0.08 (s,
3H), ꢁ0.02 (s, 3H), ꢁ0.26 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 148.6,
148.1, 146.0, 135.9, 128.1, 126.9, 126.6, 120.2, 110.2, 110.0, 75.1, 62.2,
61.2, 56.0, 55.8, 55.6, 26.2, 25.9, 25.1,18.5,18.3, ꢁ4.5, ꢁ4.9, ꢁ5.1, ꢁ5.3;
mp 68e69 ꢀC; HRMS m/z calcd for C31H53NO4Si2 [MþNa]þ 582.3411,
found 582.3410.
773 mg of product 9 as a colorless oil (86%); ½a D24
ꢁ47.6 (c 0.44,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.26e7.23 (m, 2H), 7.12e7.09
(m, 2H), 7.06 (s, 5H), 6.99 (dd, 1H, J¼11.0, 17.5 Hz), 5.38 (d, 1H,
J¼17.5 Hz), 5.13 (d, 1H, J¼11.0 Hz), 4.47 (d, 1H, J¼6.5 Hz), 2.37 (q, 1H,
J¼6.5 Hz), 1.98 (d, 1H, J¼3.5 Hz), 1.82e1.79 (m, 1H), 1.43 (d, 1H,
J¼6.5 Hz), 1.36 (d, 3H, J¼6.5 Hz), 0.84 (s, 9H), 0.01 (s, 3H), ꢁ0.16 (s,
4.1.8. [(3S,4R)-4-(tert-Butyldimethylsilyloxy)-2-(R)-1-phenylethyl-
1,2,3,4-tetrahydroisoquinolin-3-yl]methyl acetate (13a). To a 0.10 M
solution of 10 (186 mg, 0.47 mmol) in CH3CN (4.70 mL) was treated
with MsCl (0.043 mL, 0.56 mmol) and Et3N (0.13 mL, 0.94 mmol) at
room temperature. After stirring for 5 min at room temperature,
KOAc (92 mg, 0.94 mmol) was added to the reaction mixture. The
resulting reaction mixture was stirred for 4 h at 45 ꢀC and cooled to
room temperature. The mixture was diluted with CH2Cl2 and
treated with H2O. The aqueous layer was extracted with CH2Cl2. The
combined organic layer was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by silica
gel flash column chromatography using EtOAc/hexane (10/90) to
3H); 13C NMR (125 MHz, CDCl3)
d 143.9, 140.5, 135.7, 135.3, 127.9,
127.4, 127.3, 127.2, 126.9, 126.7, 125.9, 115.5, 74.3 70.2, 44.7, 32.8,
25.9, 22.8, 18.3, ꢁ4.7, ꢁ4.8; HRMS m/z calcd for C25H35NOSi
[MþNa]þ 416.2386, found 416.2383.
4.1.6. (2-((R)-(tert-butyldimethylsilyloxy)((S)-1-((R)-1-phenylethyl)
aziridin-2-yl)methyl)phenyl)methanol (10). To a 0.20 M solution of 9
(675 mg, 1.72 mmol) in MeOH/CH2Cl2 (1/1) (8.60 mL) was added O3
(g) at ꢁ78 ꢀC using ozone gas generator. Stirring was continued
30 min under O3 (g) at ꢁ78 ꢀC. To the reaction mixture was added
Me2S and stirred for 1 h and then the solvent was removed under
reduced pressure. To a 0.20 M solution of the crude product in MeOH
(8.60 mL) was added NaBH4 (130 mg, 3.43 mmol) at 0 ꢀC and the
reaction mixture was stirred for 1 h. The mixture was diluted with
CH2Cl2 and treated with H2O. The aqueous layer was extracted with
CH2Cl2 and the combined extracts were dried over anhydrous
MgSO4, filtered, and then the solvent was removed in vacuo. The
crude product was purified by silica gel flash column chromatogra-
phy using EtOAc/hexane (10/90) to give 526 mg of the product 10 as
give 139 mg of product 13a as a colorless oil (67%); ½a D24
þ9.2 (c
ꢂ
0.13, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.66 (d, 2H, J¼7.2 Hz), 7.58
(t, 2H, J¼7.2 Hz), 7.53e7.44 (m, 4H), 7.30e7.28 (m, 1H), 4.91 (d, 1H,
J¼2.0 Hz), 4.48 (dd, 1H, J¼4.4, 11.2 Hz), 4.29 (d, 1H, J¼15.2 Hz), 4.21
(q, 1H, 6.8 Hz), 3.92 (d, 1H, J¼15.2 Hz), 3.87 (t, 1H, J¼11.2 Hz),
3.59e3.57 (m, 1H), 2.24 (s, 3H), 1.74 (d, 3H, J¼6.8 Hz), 1.12 (s, 9H),
0.26 (s, 3H), 0.21 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.9, 144.8,
136.0, 135.2, 129.4, 128.6, 127.9, 127.7, 127.1, 126.8, 126.7, 69.6, 62.4,
62.0, 59.7, 48.0, 26.1, 22.0, 21.0, 18.4, ꢁ4.3, ꢁ4.5; HRMS m/z calcd for
C26H37NO3Si [MþNa]þ 462.2441, found 462.2443.
a colorless oil (77%); ½a D24
ꢂ
þ6.9 (c 0.08, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
7.16e7.12 (m, 2H), 7.03 (t, 1H, J¼7.5 Hz), 6.99e6.96 (m, 1H),
4.1.9. (3S,4R)-3-(Azidomethyl)-4-(tert-butyldimethylsilyloxy)-2-[(R)-
6.94 (t,1H, J¼6.0 Hz), 6.89 (t, 2H, J¼7.5 Hz), 6.76 (d, 2H, J¼7.5 Hz), 4.60
(d, 1H, J¼12.0 Hz), 4.33 (d, 1H, J¼12.0 Hz), 4.28 (d, 1H, J¼8.0 Hz), 2.41
(q,1H, J¼6.5 Hz), 2.09 (d,1H, J¼3.5 Hz),1.88e1.84 (m,1H),1.73 (d,1H,
J¼6.5 Hz), 1.28 (d, 3H, J¼6.5 Hz), 0.82 (s, 9H), ꢁ0.03 (s, 3H), ꢁ0.17 (s,
1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline (13b). Colorless oil
(72%); ½a 2D4
ꢂ
ꢁ13.8 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.40e7.32 (m, 4H), 7.31e7.26 (m, 2H), 7.24e7.22 (m, 2H),
7.02e7.00 (m, 1H), 4.66 (d, 1H, J¼2.8 Hz), 3.96 (d, 1H, J¼14.8 Hz),
3.84 (q, 1H, J¼6.4 Hz), 3.63 (d, 1H, J¼14.8 Hz), 3.28 (dd, 1H, J¼4.4,
12.0 Hz), 3.23e3.20 (m, 1H), 2.83 (dd, 1H, J¼8.0, 12.0 Hz), 1.46 (d,
3H, J¼6.4 Hz), 0.90 (s, 9H), 0.07 (s, 3H), ꢁ0.01 (s, 3H); 13C NMR
3H); 13C NMR (125 MHz, CDCl3)
d 141.9, 141.3, 137.0, 129.9, 128.5,
128.1, 127.5, 127.0, 126.8, 126.1, 73.1, 69.9, 63.3, 44.1, 37.3, 25.8, 22.0,
18.2, ꢁ4.6, ꢁ4.7; FT-IR: v 3349 cmꢁ1 (br, OH); HRMS m/z calcd for
C24H35NO2Si [MþNa]þ 420.2335, found 420.2333.
(100 MHz, CDCl3)
d 144.7, 135.8, 135.8, 128.7, 128.4, 127.8, 127.6,
127.3, 126.8, 126.7, 69.5, 62.4, 60.7, 50.7, 48.4, 26.1, 21.3, 18.3, ꢁ4.4,
ꢁ4.4; FT-IR: v 2097 cmꢁ1 (N3); HRMS m/z calcd for C24H34N4OSi
[MþNa]þ 423.2581, found 423.2577.
4.1.7. (5R,6S)-5-(3,4-Dimethoxyphenyl)-2,2,3,3,9,9,10,10-octamethyl-
N-[(R)-1-phenylethyl]-4,8-dioxa-3,9-disilaundcan-6-amine (11). To
a 0.20 M solution of 8 (6.26 g, 19.97 mmol) in CH2Cl2 (99.80 mL) was
added AcOH (6.85 mL, 0.12 mol) at room temperature. After addi-
tional stirring for 8 h, the reaction was quenched with aqueous
NaHCO3 solution at 0 ꢀC, and the aqueous layer was extracted with
CH2Cl2, dried over anhydrous MgSO4, concentrated under reduced
pressure. The crude product was dissolved in EtOH (66.50 mL,
0.30 M) and KOH (3.36 g, 59.91 mmol) was added at room temper-
ature. After additional stirring for 20 min, the solvent was removed
under reduced pressure to give the 1,3-diol. The crude product was
diluted with CH2Cl2, and treated with H2O. The aqueous layer was
extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was dissolved in
CH2Cl2 (99.80 mL) and added TBSCl (6.62 g, 43.93 mmol) at 0 ꢀC. To
the reaction mixture were added Et3N (9.74 mL, 69.89 mmol) and
DMAP (732 mg, 5.99 mmol) and stirred for 20 h at refluxing tem-
perature. The reaction was quenched with H2O and the aqueous layer
was extracted with CH2Cl2. The combined extracts were dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by silica gel flash column chromatography us-
ing EtOAc/hexane (3/97) to give 10.41 g of 11 as a white solid (93%);
4.1.10. (3S,4R)-3-(Hydroxymethyl)-2-[(R)-1-phenylethyl]-1,2,3,4-
tetrahydroisoquinolin-4-ol
(14a). Compound
13a
(119 mg,
0.27 mmol) was dissolved in EtOH/H2O (2/1) (2.70 mL, 0.10 M) and
lithium hydroxide monohydrate (114 mg, 2.71 mmol) was added at
room temperature. The reaction mixture was heated to refluxing
temperature and stirred for 8 h. The mixture was cooled to room
temperature, and thesolvent wasremovedunderreduced pressureto
give a crude sticky product. The crude product was diluted with
CH2Cl2, and treated with H2O. The aqueous layer was extracted with
CH2Cl2 and dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel flash column chro-
matography using EtOAc/hexane(50/50) to give 66 mgofproduct 14a
as a yellow oil (86%); ½a D24
ꢂ
þ26.2 (c 0.25, CHCl3); 1H NMR (400 MHz,
CDCl3)
d 7.36e7.33 (m, 5H), 7.29e7.27 (m, 1H), 7.25e7.23 (m, 2H),
7.07e7.05 (m, 1H), 4.43 (s, 1H), 4.08 (d, 1H, J¼16.0 Hz), 4.07e4.04 (m,
1H), 3.77 (d, 1H, J¼16.0 Hz), 3.72e3.70 (m, 1H), 3.40e3.36 (m, 1H),
3.22e3.21 (m, 1H), 1.48 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d
144.7, 135.9, 134.3, 129.7, 128.9, 127.8, 127.6, 127.5, 127.1, 126.6, 67.8,
61.5, 60.8, 58.7, 47.4, 22.1;FT-IR:v3389 cmꢁ1 (br, OH);HRMSm/zcalcd
for C18H21NO2 [MþNa]þ 306.1470, found 306.1472.
[
a
]D24 ꢁ5.2 (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.15e7.12 (m,
3H), 6.87e6.86 (m, 2H), 6.55 (q, 2H, J¼8.0 Hz), 6.64 (s,1H), 4.48 (d,1H,
J¼8.0 Hz), 3.91 (s, 3H), 3.81 (q, 1H, J¼7.0 Hz), 3.78 (dd, 1H, J¼4.0,
10.0 Hz), 3.71e3.69 (m, 1H), 3.68 (s, 3H), 2.55e2.52 (m, 1H), 1.44 (br,
4.1.11. (3S,4R)-tert-Butyl-4-hydroxy-3-(hydroxymethyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate
(15a). Compound
14a

K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
889
(29 mg, 0.10 mmol) was dissolved in MeOH (0.50 mL) and 10 wt %
Pd(OH)2 (2.5 mg) and (Boc)2O (22 mg, 0.10 mmol) were added. Then,
the reaction mixture was stirred for 4 h under atmospheric pressure
of H2 (g). The reaction mixture was filtered to remove Pd catalyst and
the solvent was removed under reduced pressure. The residue was
purified by silica gel flash column chromatography using EtOAc/
hexane (40/60) to give 23 mg of product 15a as a colorless oil (90%);
1H), 1.69e1.64 (m, 2H), 1.36e1.32 (m, 4H), 0.90 (t, 3H, J¼10.0 Hz),
0.88 (s, 9H), 0.86 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), ꢁ0.01
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 165.9, 150.9, 148.5, 131.6, 120.6,
110.1, 108.6, 66.5, 65.5, 61.9, 56.3, 56.1, 36.1, 31.6, 27.2, 26.1, 26.0,
22.7, 18.5, 18.3, 14.2, ꢁ4.1, ꢁ4.2, ꢁ5.1, ꢁ5.2; HRMS m/z calcd for
C29H53NO4Si2 [MþNa]þ 558.3411, found 558.3411.
½
a 2D4
ꢂ
þ0.10 (c 0.17, CH3OH); 1H NMR (400 MHz, CD3OD)
d
7.35 (d, 1H,
4.1.15. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-1-iso propyl- 6, 7-dimethoxy-3, 4-
J¼6.8 Hz), 7.33e7.24 (m, 2H), 7.20e7.18 (m, 1H), 4.85e4.75 (m, 2H),
4.50e4.49 (m, 1H), 4.29 (dd, 1H, J¼12.0, 16.8 Hz), 3.44e3.39 (m, 1H),
dihydroisoquinoline (17d). Yellow oil, (95%); ½a D24
ꢁ94.4 (c 0.75,
ꢂ
3.26e3.19 (m, 1H), 1.52 (s, 9H); 13C NMR (100 MHz, CD3OD)
d
157.7,
CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.03 (s,1H), 6.89 (s,1H), 4.77 (d,
135.0,134.0,130.9,129.4,128.0,127.2, 81.4, 68.0, 61.5, 60.2, 59.0, 44.8,
43.8, 28.7; FT-IR: v 3378 cmꢁ1 (br, OH); HRMS m/z calcd for
C15H21NO4 [MþNa]þ 302.1369, found 302.1365.
1H, J¼4.8 Hz), 3.92 (s, 3H), 3.91 (s, 3H), 3.89e3.85 (m, 1H), 3.82 (dd,
1H, J¼4.8, 10.0 Hz), 3.26e3.22 (m, 1H), 3.20e3.18 (m, 1H), 1.21 (d,
3H, J¼2.8 Hz),1.20 (d, 3H, J¼2.8 Hz), 0.88 (s, 9H), 0.86 (s, 9H), 0.16 (s,
3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
4.1.12. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline
(17a). To a 0.20 M solution of 11 (740 mg, 1.32 mmol) in MeOH
(6.60 mL) was added 10 wt % Pd(OH)2 (74 mg) and the mixture was
stirred for 3 h under atmospheric pressure of H2 (g). The mixture
was filtered and the solvent was removed under reduced pressure.
The crude product was dissolved in THF (4.40 mL, 0.30 M) and
added aqueous 3 N NaOH solution (0.66 mL) at 0 ꢀC. Then, acetic
anhydride (0.15 mL, 1.59 mmol) was slowly added to the reaction
mixture. The reaction mixture was stirred for 5 min and warmed to
room temperature, neutralized with aqueous NaHCO3 solution. The
reaction mixture was diluted with EtOAc and the aqueous layer was
extracted with EtOAc and dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The crude product 16a was dissolved in
anhydrous CH2Cl2 (6.60 mL, 0.20 M) and added 2-ClPyr (0.14 mL,
1.45 mmol) and Tf2O (0.24 mL, 1.45 mmol) at ꢁ78 ꢀC. After 5 min,
the reaction mixture was placed in an ice-water bath and warmed
to 0 ꢀC. After 5 min, the resulting solution was allowed to room
temperature and then aqueous 3 N NaOH solution (0.66 mL) was
added to neutralize the trifluoromethanesulfonate salts. The
aqueous layer was extracted with CH2Cl2 and dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by silica gel flash column chromatography using EtOAc/
CDCl3) d 169.4, 150.6, 148.3, 132.5, 120.6, 110.5, 108.2, 66.5, 65.0,
62.0, 56.3, 56.1, 31.8, 26.0, 26.0, 21.0, 20.9,18.4,18.3, ꢁ4.1, ꢁ4.3, ꢁ5.1,
ꢁ5.2; HRMS m/z calcd for C27H49NO4Si2 [MþNa]þ 530.3098, found
530.3094.
4.1.16. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldimethylsi-
lyloxy)methyl]-1-cyclohexyl-6,7-dimethoxy-3,4-dihydroisoquinoline
(17e). Colorless oil, (80%); ½a D24
ꢂ
ꢁ74.8 (c 0.70, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
7.02 (s, 1H), 6.87 (s, 1H), 4.75 (d, 1H, J¼5.2 Hz),
3.92 (s, 6H), 3.90e3.87 (m, 1H), 3.80 (dd, 1H, J¼5.2, 10.0 Hz), 3.19
(dd, 1H, J¼7.2, 10.0 Hz), 2.84 (t, 1H, J¼10.0 Hz), 1.89e1.83 (m, 3H),
1.75e1.67 (m, 2H),1.52e1.14 (m, 4H),1.28e1.22 (m,1H), 0.88 (s, 9H),
0.86 (s, 9H), 0.16 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d 168.8, 150.6, 148.3, 132.4, 120.6, 110.7,
108.3, 65.2, 62.0, 56.4, 56.1, 42.2, 31.4, 26.8, 26.5, 26.1, 26.0, 25.8,
18.5, 18.3, ꢁ4.1, ꢁ4.2, ꢁ5.1, ꢁ5.1; HRMS m/z calcd for C30H53NO4Si2
[MþNa]þ 570.3411, found 570.3410.
4.1.17. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
t h y l s i l y l o x y ) m e t h y l ] - 6 , 7 - d i m e t h o x y - 1 - p h e n y l - 3 , 4 -
dihydroisoquinoline (17f). White solid, (72%); ½a D24
ꢁ36.8 (c 0.27,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.64e7.62 (m, 2H), 7.44e7.42
(m, 3H), 6.96 (s, 1H), 6.81 (s, 1H), 4.87 (d, 1H, J¼5.0 Hz), 4.10e4.07
(m, 1H), 3.95 (s, 3H), 3.92 (dd, 1H, J¼5.0, 10.5 Hz), 3.73 (s, 3H), 3.38
(dd, 1H, J¼7.0, 10.5 Hz), 0.92 (s, 9H), 0.86 (s, 9H), 0.18 (s, 3H), 0.12 (s,
hexane (40/60) to give 507 mg of 17a as a brown oil (80%); ½a D24
ꢂ
ꢁ52.2 (c 0.34, CHCl3); 1H NMR (300 MHz, CDCl3)
d 6.98 (s, 1H), 6.87
(s, 1H), 4.82 (d, 1H, J¼6.0 Hz), 3.91 (s, 6H), 3.88e3.79 (m, 2H), 3.23
(dd, 1H, J¼6.0, 9.9 Hz), 2.38 (s, 3H), 0.89 (s, 9H), 0.85 (s, 9H), 0.15 (s,
3H), 0.08 (s, 3H), 0.03 (s, 3H), ꢁ0.01 (s, 3H); 13C NMR (125 MHz,
3H), 0.05 (s, 3H), ꢁ0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 165.5,
150.1, 148.0, 139.1, 132.9, 129.3, 128.9, 128.2, 120.5, 111.3, 110.3, 66.7,
66.1, 62.0, 56.2, 56.2, 26.1, 26.0, 18.5, 18.4, ꢁ4.0, ꢁ4.2, ꢁ5.1, ꢁ5.1; mp
114e116 ꢀC; HRMS m/z calcd for C30H47NO4Si2 [MþNa]þ 564.2942,
found 564.2941.
CDCl3) d 162.4, 151.1, 148.4, 131.3, 121.2, 110.6, 108.7, 66.4, 65.7, 62.2,
56.3, 56.1, 26.1, 26.0, 23.4, 18.5, 18.4, ꢁ4.1, ꢁ4.1, ꢁ5.1, ꢁ5.1; HRMS m/
z calcd for C25H45NO4Si2 [MþNa]þ 502.2785, found 502.2783.
4.1.18. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1-(2-methoxyphenyl)-3,4-
4.1.13. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)-methyl]-6,7-dimethoxy-1-propyl-3,4-dihydroisoquinoline
dihydroisoquinoline (17g). White solid, (86%); ½a D24
ꢁ54.7 (c 0.40,
ꢂ
(17b). Yellow solid (95%); ½a D24
ꢂ
ꢁ58.1 (c 0.52, CHCl3); 1H NMR
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.38 (t, 1H, J¼8.0 Hz), 7.32 (d,
(500 MHz, CDCl3)
d
6.99 (s, 1H), 6.85 (s, 1H), 4.79 (d, 1H, J¼3.0 Hz),
1H, J¼8.0 Hz), 7.03 (t, 1H, J¼8.0 Hz), 6.95 (d, 1H, J¼8.0 Hz), 6.87 (br,
1H), 6.52 (s, 1H), 4.93 (d, 1H, J¼4.0 Hz), 4.23 (br, 1H), 3.93 (s, 3H),
3.91e3.89 (m, 1H), 3.68 (br, 3H), 3.67 (s, 1H), 3.66 (s, 3H), 0.89 (br,
9H), 0.87 (s, 9H), 0.17 (s, 3H), 0.09 (br, 3H), 0.04 (s, 3H), 0.00 (s, 3H);
3.98e3.96 (m, 1H), 3.92 (s, 6H), 3.79 (dd, 1H, J¼3.0, 6.0 Hz), 3.13 (t,
1H, J¼9.5 Hz), 2.82e2.77 (m, 1H), 2.64e2.58 (m, 1H), 1.71e1.69 (m,
2H), 0.97 (t, 3H, J¼6.0 Hz), 0.88 (s, 9H), 0.86 (s, 9H), 0.16 (s, 3H), 0.07
(s, 3H), 0.03 (s, 3H), ꢁ0.01 (s, 3H); 13C NMR (125 MHz, CDCl3)
13C NMR (125 MHz, CDCl3)
d 157.4, 150.9, 150.0, 148.3, 138.8, 130.4,
d
165.6, 150.9, 148.5, 131.6, 120.7, 111.0, 108.6, 66.6, 65.6, 61.8, 56.3,
130.1, 129.1, 124.6, 122.4, 121.5, 121.1, 110.9, 66.6, 66.5, 56.1, 56.1,
55.9, 26.1, 26.0, 25.8, 18.4, 18.3, ꢁ4.0, ꢁ4.1, ꢁ5.1, ꢁ5.1; mp 77e78 ꢀC;
HRMS m/z calcd for C31H49NO5Si2 [MþNa]þ 594.3047, found
594.3047.
56.1, 38.0, 26.1, 26.0, 20.7, 18.5, 18.3, 13.9, ꢁ4.1, ꢁ4.2, ꢁ5.1, ꢁ5.2; mp
62e64 ꢀC; HRMS m/z calcd for C27H49NO4Si2 [MþNa]þ 530.3098,
found 530.3099.
4.1.14. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1-pentyl-3,4-dihydroisoquinoline
4.1.19. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1-(3-(trifluoromethyl)phenyl)-
(17c). Yellow oil, (94%); ½a D24
ꢂ
ꢁ76.2 (c 0.72, CHCl3); 1H NMR
3,4-dihydroisoquinoline (17h). Pale yellow oil, (50%); ½a D24
ꢁ25.8 (c
ꢂ
(500 MHz, CDCl3)
d
7.00 (s, 1H), 6.85 (s, 1H), 4.79 (d, 1H, J¼4.5 Hz),
0.39, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.94 (s, 1H), 7.83 (d, 1H,
3.99e3.96 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.80 (dd, 1H, J¼4.5,
10.0 Hz), 3.13 (t, 1H, J¼8.5 Hz), 2.82e2.76 (m, 1H), 2.66e2.60 (m,
J¼8.0 Hz), 7.71 (d, 1H, J¼8.0 Hz), 7.56 (t, 1H, J¼8.0 Hz), 6.99 (s, 1H),
6.72 (s, 1H), 4.88 (d, 1H, J¼6.4 Hz), 4.08e4.03 (m, 1H), 3.96 (s, 3H),

890
K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
3.94e3.91 (m, 1H), 3.73 (s, 3H), 3.45 (dd, 1H, J¼6.4, 10.0 Hz), 0.93
(s, 9H), 0.85 (s, 9H), 0.19 (s, 3H), 0.13 (s, 3H), 0.05 (s, 3H), ꢁ0.03 (s,
0.86 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) 148.0, 147.3, 132.2, 128.7, 111.8, 109.6, 67.7,
66.1, 61.8, 61.2, 56.0, 55.9, 39.4, 35.0, 26.1, 26.0, 19.0, 18.4, 18.2, 14.5,
ꢁ3.7, ꢁ4.0, ꢁ5.2, ꢁ5.3; HRMS m/z calcd for C28H53NO4Si2 [MþNa]þ
546.3411, found 546.3410.
d
3H); 13C NMR (125 MHz, CDCl3)
d
164.3, 151.3, 148.1, 139.7, 133.4,
132.2, 128.7, 126.1, 126.0, 125.9, 125.9, 119.8, 110.7, 110.3, 66.6,
66.3, 62.0, 56.2, 56.2, 26.1, 26.0, 18.5, 18.4, ꢁ4.0, ꢁ4.2, ꢁ5.1, ꢁ5.1;
HRMS m/z calcd for C31H46F3NO4Si2 [MþNa]þ 632.2815, found
632.2813.
4.1.24. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-2-methyl-1-pentyl-1,2,3,4-
4.1.20. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldimethylsi-
lyloxy)methyl]-1-(furan-2-yl)-6,7-dimethoxy-3,4-dihydroisoquinoline
tetrahydroisoquinoline (18c). Yellow oil. See Table 1 (73%); ½a D24
ꢂ
ꢁ13.7 (c 0.26, CHCl3); 1H NMR (500 MHz, CDCl3)
d 6.78 (s, 1H), 6.58
(17i). Dark brown oil, (74%); ½a D24
ꢂ
ꢁ10.5 (c 0.27, CHCl3); 1H NMR
(s, 1H), 4.68 (d, 1H, J¼5.0 Hz), 3.86 (s, 6H), 3.74 (q, 1H, J¼5.0 Hz),
3.54 (t, 1H, J¼5.0 Hz), 3.39e3.36 (m, 1H), 2.95e2.91 (m, 1H), 2.45 (s,
3H), 1.89e1.84 (m, 1H), 1.79e1.74 (m, 1H), 1.42e1.39 (m, 1H),
1.30e1.25 (m, 5H), 0.90 (s, 9H), 0.89 (s, 9H), 0.85 (t, 3H, J¼6.5 Hz),
0.13 (s, 3H), 0.11 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR
(300 MHz, CDCl3) d 7.58 (s, 1H),7.34 (s, 1H), 6.96 (s, 1H), 6.91 (d, 1H,
J¼2.1 Hz), 6.53 (q, 1H, J¼2.1 Hz), 4.86 (d, 1H, J¼6.3 Hz), 4.06e4.02
(m, 1H), 3.95 (s, 3H), 3.92e3.91 (m, 1H), 3.89 (s, 3H), 3.38 (dd, 1H,
J¼6.3, 10.2 Hz), 0.92 (s, 9H), 0.86 (s, 9H), 0.18 (s, 3H), 0.10 (s, 3H),
0.06 (s, 3H), ꢁ0.02 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
155.2, 152.0,
(125 MHz, CDCl3) d 148.0, 147.3, 132.0, 128.8, 111.8, 109.5, 67.7, 66.1,
151.2, 148.1, 143.8, 133.1, 119.3, 112.9, 111.4, 110.6, 110.3, 66.3, 65.5,
62.0, 56.3, 56.2, 26.1, 26.1, 18.5, 18.4, ꢁ4.1, ꢁ4.2, ꢁ5.0, ꢁ5.1; HRMS
m/z calcd for C28H45NO5Si2 [MþNa]þ 554.2734, found 554.2733.
61.7, 61.2, 56.0, 55.9, 39.4, 32.8, 32.4, 26.1, 26.0, 25.3, 22.9, 18.4, 18.2,
14.3, ꢁ3.7, ꢁ3.9, ꢁ5.2, ꢁ5.3; HRMS m/z calcd for C30H57NO4Si2
[MþNa]þ 574.3724, found 574.3723.
4.1.21. (3S,4R)-1-(2-Bromobenzyl)-4-(tert-butyldimethylsilyloxy)-3-
[(tert-butyldimethylsilyloxy)methyl]-6,7-dimethoxy-3,4-
4.1.25. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-1-isopropyl-6,7-dimethoxy-2-methyl-1,2,3,4-
dihydroisoquinoline (17j). Brown oil, (79%); ½a D24
ꢂ
ꢁ22.2 (c 0.17,
tetrahydroisoquinoline (18d). Yellow oil. See Table 1 (68%); ½a D24
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d
7.55 (d, 1H, J¼8.0 Hz), 7.27
ꢁ27.7 (c 0.46, CHCl3); 1H NMR (500 MHz, CDCl3)
d 6.85 (s, 1H), 6.58
(d, 1H, J¼8.0 Hz), 7.09 (t, 1H, J¼8.0 Hz), 7.02 (t, 1H, J¼8.0 Hz), 6.87 (s,
1H), 6.76 (s, 1H), 4.83 (d, 1H, J¼3.5 Hz), 4.45 (d, 1H, J¼16.0 Hz),
4.22e4.19 (m, 1H), 4.00 (d, 1H, J¼16.0 Hz), 3.88 (s, 3H), 3.84 (dd, 1H,
J¼3.5, 10.0 Hz), 3.79 (s, 3H), 3.13e3.09 (m, 1H), 0.90 (s, 9H), 0.88 (s,
9H), 0.20 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), ꢁ0.01 (s, 3H); 13C NMR
(s, 1H), 4.70 (d, 1H, J¼7.0 Hz), 3.86 (s, 6H), 3.79 (q, 1H, J¼5.5 Hz),
3.53 (q, 1H, J¼5.5 Hz), 3.10 (d, 1H, J¼7.0 Hz), 2.95e2.92 (m, 1H), 2.32
(s, 3H), 2.13e2.08 (m,1H),1.09 (d, 3H, J¼6.5 Hz), 0.92 (s, 9H), 0.89 (s,
9H), 0.86 (d, 3H, J¼6.5 Hz), 0.15 (s, 3H), 0.12 (s, 3H), 0.04 (s, 3H), 0.03
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 147.3, 147.1, 130.6, 129.8, 111.2,
(125 MHz, CDCl3)
d
164.2, 150.8, 148.6, 137.6, 132.7, 131.1, 130.4,
110.9, 68.8, 66.8, 64.5, 61.6, 56.0, 55.9, 39.2, 31.7, 26.1, 26.0, 20.9,
20.7, 18.3, ꢁ3.4, ꢁ3.8, ꢁ5.2, ꢁ5.3; HRMS m/z calcd for C28H53NO4Si2
[MþNa]þ 546.3411, found 546.3410.
128.3, 127.8,124.5,120.0,111.1,109.0, 66.6, 66.2, 61.4, 56.3, 56.1, 42.7,
26.0, 26.0, 18.4, 18.3, ꢁ4.1, ꢁ4.2, ꢁ5.1, ꢁ5.2; HRMS m/z calcd for
C31H48BrNO4Si2 [MþH]þ 634.2384, found 634.2385.
4.1.26. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-1-cyclohexyl-6,7-dimethoxy-2-methyl-1,2,3,4-
4.1.22. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1,2-dimethyl-1,2,3,4-
tetrahydroisoquinoline (18a). To a 0.50 M solution of 17a (520 mg,
1.08 mmol) in CH2Cl2 (2.20 mL) was treated with MeI (0.67 mL,
10.84 mmol) at room temperature and the mixture was stirred for
40 h at 35 ꢀC. The reaction mixture was concentrated under re-
duced pressure, dissolved in MeOH (5.40 mL, 0.20 M). After the
tetrahydroisoquinoline (18e). Colorless oil. See Table 1 (62%); ½a D24
ꢂ
ꢁ9.4 (c 0.16, CHCl3); 1H NMR (500 MHz, CDCl3)
d 6.84 (s, 1H), 6.54
(s, 1H), 4.70 (d, 1H, J¼7.0 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.79 (dd, 1H,
J¼6.5, 10.5 Hz), 3.58 (dd, 1H, J¼5.0, 10.5 Hz), 3.10 (d, 1H, J¼7.0 Hz),
3.01 (q, 1H, J¼6.5 Hz), 2.33 (s, 3H), 2.14 (d, 1H, J¼12.5 Hz), 1.84 (d,
1H, J¼12.5 Hz), 1.77e1.72 (m, 2H), 1.71e1.68 (m, 1H), 1.65e1.63 (m,
1H), 1.25e1.01 (m, 5H), 0.92 (s, 9H), 0.89 (s, 9H), 0.14 (s, 3H), 0.11 (s,
reaction mixture was cooled to
0
ꢀC, NaBH(OAc)3 (459 mg,
2.17 mmol) was added. After stirring for 30 min at 0 ꢀC, the reaction
mixture was warmed to room temperature and concentrated under
reduced pressure. The sticky crude product was diluted in CH2Cl2
and neutralized with aqueous NaHCO3 solution. The aqueous layer
was extracted with CH2Cl2 and the combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by silica gel flash column chromatog-
raphy using EtOAc/hexane (20/80) to give 295 mg of product 18a as
3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 147.3,
147.1, 130.7, 129.7, 111.4, 105.1, 68.6, 66.7, 63.5, 61.7, 56.1, 55.9, 41.9,
38.8, 31.2, 27.0, 26.9, 26.8, 26.1, 26.1, 18.4, ꢁ3.3, ꢁ3.7, ꢁ5.2, ꢁ5.2;
HRMS m/z calcd for C31H57NO4Si2 [MþNa]þ 586.3724, found
586.3723.
4.1.27. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-2-methyl-1-phenyl-1,2,3,4-tetra-
a yellow oil, (55%); ½a D24
ꢂ
ꢁ9.4 (c 0.14, CHCl3); 1H NMR (500 MHz,
hydroisoquinoline (18f). Colorless oil. See Table 1 (61%); [
a
]
24þ9.6
D
CDCl3)
d
6.82 (s, 1H), 6.58 (s, 1H), 4.71 (d, 1H, J¼4.0 Hz), 3.86 (s, 6H),
(c 0.16, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.38 (d, 2H, J ¼ 6.6 Hz),
3.80e3.76 (m, 2H), 3.51e3.48 (m, 1H), 2.93e2.91 (m, 1H), 2.50 (s,
3H), 1.41 (d, 3H, J¼6.5 Hz), 0.91 (s, 9H), 0.89 (s, 9H), 0.11 (s, 3H), 0.10
7.24e7.12 (m, 3H), 6.63 (s, 1H), 6.15 (s, 1H), 4.75 (d, 1H, J ¼ 2.1 Hz),
4.40 (s, 1H), 3.86 (dd, 1H, J ¼ 3.6, 9.0 Hz), 3.80 (s, 3H), 3.56 (s, 3H),
3.26e3.20 (m, 1H), 3.13 (td, 1H, J ¼ 3.6, 9.0 Hz), 2.33 (s, 3H), 0.90
(s, 9H), 0.82 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H), ꢁ0.06 (s, 3H), ꢁ0.10
(s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 148.2,
147.5, 132.9, 128.4, 111.9, 109.1, 68.3, 66.2, 62.0, 56.2, 56.0, 55.9, 39.8,
26.1, 26.0, 18.6, 18.4, 18.3, ꢁ3.5, ꢁ3.7, ꢁ5.1, ꢁ5.2; HRMS m/z calcd for
C26H49NO4Si2 [MþNa]þ 518.3098, found 518.3099.
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 148.3, 147.4, 145.6,131.2,129.1,
128.2, 127.1, 126.6, 112.5, 110.6, 68.6, 67.0, 65.9, 58.3, 55.9, 55.7,
40.8, 26.1, 26.0, 18.3, 18.3, ꢁ3.8, ꢁ4.1, ꢁ5.2, ꢁ5.4; HRMS m/z calcd
for C31H51NO4Si2 [MþNa]þ 580.3255, found 580.3253.
4.1.23. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-2-methyl-1-propyl-1,2,3,4-
tetrahydroisoquinoline (18b). Yellow oil. See Table 1, (63%); ½a D24
ꢂ
4.1.28. (1R,3S,4R)-4-(tert-butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-1-(2-methoxyphenyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline (18g). Colorless oil. See Table 1 (78%);
ꢁ4.9 (c 0.31, CHCl3); 1H NMR (300 MHz, CDCl3)
d 6.78 (s, 1H), 6.58
(s, 1H), 4.69 (d, 1H, J¼4.8 Hz), 3.86 (s, 6H), 3.74 (q, 1H, J¼5.4 Hz),
3.55 (t, 1H, J¼5.4 Hz), 3.40e3.35 (m, 1H), 2.96e2.90 (m, 2H), 2.46 (s,
3H), 1.90e1.69 (m, 3H), 1.45e1.21 (m, 3H), 0.90 (s, 9H), 0.89 (s, 9H),
[
a
]
2D4þ108.0 (c 0.96, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.64 (d, 1H,
J ¼ 8.0 Hz), 7.16 (t, 1H, J ¼ 8.0 Hz), 6.91e6.85 (m, 2H), 6.65 (s, 1H),

K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
891
6.45 (s, 1H), 5.17 (s, 1H), 4.81 (d, 1H, J ¼ 2.4 Hz), 3.96e3.95 (m, 1H),
3.93 (s, 3H), 3.84 (s, 3H), 3.65 (s, 3H), 3.30-3.25 (m, 1H), 3.21 (td, 1H,
J ¼ 2.4, 8.0 Hz), 2.38 (s, 3H), 0.96 (s, 9H), 0.88 (s, 9H), 0.22 (s, 3H),
0.18 (s, 3H), ꢁ0.01 (s, 3H), ꢁ0.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
66.1, 62.4, 61.8, 60.0, 56.1, 56.0, 37.5, 36.9, 19.2, 14.2; FT-IR: v
3383 cmꢁ1 (br, OH); HRMS m/z calcd for C16H25NO4 [MþNa]þ
318.1682, found 318.1682.
d
157.4, 148.4, 147.2, 134.2, 132.1, 130.5, 127.5, 126.4, 121.5, 112.4,
4.1.33. (1S,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-2-methyl-1-
110.4, 110.0, 68.8, 67.0, 58.4, 56.2, 55.8, 55.7, 55.6, 40.3, 26.1, 26.0,
18.3, 18.3, ꢁ3.8, ꢁ4.1, ꢁ5.2, ꢁ5.4; HRMS m/z calcd for C32H53NO5Si2
[MþNa]þ 610.3360, found 610.3463.
pentyl-1,2,3,4-tetrahydroisoquinolin-4-ol (19c). Colorless oil, (87%);
½
a 2D4
ꢂ
þ15.8 (c 0.54, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.95 (s, 1H),
6.56 (s, 1H), 4.47 (d, 1H, J¼7.6 Hz), 3.86 (s, 6H), 3.77e3.74 (m, 2H),
3.54 (dd, 1H, J¼5.2, 7.6 Hz), 3.09 (q, 1H, J¼7.6 Hz), 2.81 (br, 2H), 2.41
(s, 3H), 1.83e1.68 (m, 2H), 1.44e1.37 (m, 1H), 1.33e1.22 (m, 5H),
4.1.29. (1S,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-6,7-dimethoxy-2-methyl-1-(3-(trifluoromethyl)
phenyl)-1,2,3,4-tetrahydroisoquinoline (18h). Yellow oil. See Table 1
0.87 (t, 3H, J¼6.4 Hz); 13C NMR (125 MHz, CDCl3)
d 148.7, 147.9,
130.6, 128.7, 110.2, 109.4, 66.1, 62.4, 61.7, 60.0, 56.0, 55.9, 37.6, 34.5,
31.9, 25.4, 22.7, 14.1; FT-IR: v 3388 cmꢁ1 (br, OH); HRMS m/z calcd
for C18H29NO4 [MþNa]þ 346.1995, found 346.1994.
(82%); ½a 2D4
ꢂ
þ43.9 (c 0.86, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.71
(s, 1H), 7.65 (d, 1H, J¼7.6 Hz), 7.47 (d, 1H, J¼7.6 Hz), 7.37 (t, 1H,
J¼7.6 Hz), 6.67 (s, 1H), 6.17 (s, 1H), 4.80 (d, 1H, J¼2.8 Hz), 4.53 (s,
1H), 3.90e3.87 (m, 1H), 3.85 (s, 3H), 3.63 (s, 3H), 3.28e3.23 (m, 1H),
3.19 (td, 1H, J¼2.8, 8.8 Hz), 2.38 (s, 3H), 0.95 (s, 9H), 0.87 (s, 9H),
0.20 (s, 3H), 0.17 (s, 3H), ꢁ0.02 (s, 3H), ꢁ0.06 (s, 3H); 13C NMR
4.1.34. (1S,3S,4R)-3-(Hydroxymethyl)-1-isopropyl-6,7-dimethoxy-2-
methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (19d). Yellow oil, (70%);
½
a 2D4
ꢂ
þ35.1 (c 0.54, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.02 (s, 1H),
(100 MHz, CDCl3)
d
148.5, 147.7, 147.1, 132.5, 130.1, 128.7, 126.6,
6.58 (s, 1H), 4.45 (d, 1H, J¼9.2 Hz), 3.94 (q, 1H, J¼6.4 Hz), 3.88 (s,
3H), 3.86 (s, 3H), 3.72 (t, 1H, J¼8.8 Hz), 3.21e3.15 (m, 1H), 3.08 (d,
1H, J¼8.8 Hz), 2.60 (br, 2H), 2.30 (s, 3H), 2.06e1.97 (m, 1H), 1.08 (d,
3H, J¼6.4 Hz), 1.00 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
125.6, 124.1, 124.0, 115.4, 112.6, 110.4, 68.6, 67.0, 65.7, 58.4, 55.9,
55.8, 40.7, 26.1, 26.0, 18.3, 18.3, ꢁ3.9, ꢁ4.2, ꢁ5.3, ꢁ5.4; HRMS m/z
calcd for C32H50F3NO4Si2 [MþNa]þ 648.3128, found 648.3125.
d
148.2, 147.8, 129.3, 129.0, 111.8, 110.1, 70.3, 66.0, 61.0, 60.4, 56.0,
4.1.30. (1R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldime-
thylsilyloxy)methyl]-1-(furan-2-yl)-6,7-dimethoxy-2-methyl-1,2,3,4-
56.0, 36.6, 32.4, 21.1; FT-IR: v 3359 cmꢁ1 (br, OH); HRMS m/z calcd
for C16H25NO4 [MþNa]þ 318.1682, found 318.1680.
tetrahydroisoquinoline (18i). Brown oil. See Table 1 (69%); ½a D24
ꢂ
þ8.7 (c 0.66, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.35 (d, 1H,
4.1.35. (1S,3S,4R)-1-Cyclohexyl-3-(hydroxymethyl)-6,7-dimethoxy-
2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (19e). Colorless oil,
J¼3.2 Hz), 6.85 (s, 1H), 6.42 (s, 1H), 6.31 (t, 1H, J¼3.2 Hz), 6.14 (d, 1H,
J¼3.2 Hz), 4.81 (d, 1H, J¼5.2 Hz), 4.77 (s, 1H), 3.89 (dd, 1H, J¼5.2,
10.4 Hz), 3.86 (s, 3H), 3.74 (s, 3H), 3.62 (dd, 1H, J¼5.2, 10.4 Hz),
3.07e3.03 (m,1H), 2.49 (s, 3H), 0.93 (s, 9H), 0.86 (s, 9H), 0.15 (s, 3H),
0.07 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
(76%); ½a 2D4
ꢂ
þ15.0 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.02
(s, 1H), 6.54 (s, 1H), 4.46 (d, 1H, J¼6.0 Hz), 4.99 (dd, 1H, J¼6.0,
10.0 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.75 (t, 1H, J¼10.0 Hz), 3.25e3.19
(m, 1H), 3.15 (d, 1H, J¼8.4 Hz), 2.80 (br, 2H), 2.30 (s, 3H), 2.10 (d, 1H,
J¼12.4 Hz), 1.78e1.70 (m, 3H), 1.67e1.63 (m, 2H), 1.20e1.12 (m, 3H),
d
155.8, 148.2,148.0,141.9,128.8, 127.9,111.8,110.1,109.6,109.0, 68.1,
64.7, 60.5, 60.0, 55.9, 55.9, 40.2, 26.1, 26.0, 18.4, 18.3, ꢁ3.2, ꢁ3.6,
ꢁ5.2, ꢁ5.3; HRMS m/z calcd for C29H49NO5Si2 [MþNa]þ 570.3047,
found 570.3045.
1.12e1.03 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 148.3, 147.8, 129.0,
128.9, 112.1, 110.2, 69.7, 66.1, 61.1, 60.1, 56.1, 56.0, 41.9, 36.4, 31.6,
31.4, 26.6; FT-IR: v 3337 cmꢁ1 (br, OH); HRMS m/z calcd for
C19H29NO4 [MþH]þ 336.2176, found 336.2175.
4.1.31. (1S,3S,4R)-3-(hydroxymethyl)-6,7-dimethoxy-1,2-dimethyl-
1,2,3,4-tetrahydroisoquinolin-4-ol (19a). Substrate 18a (172 mg,
0.35 mmol) was dissolved in EtOH/H2O (2/1) (3.50 mL, 0.10 M) and
lithium hydroxide monohydrate (145 mg, 3.46 mmol) was added at
room temperature. The reaction mixture was heated to refluxing
temperature and stirred for 5 h. The solution was cooled to room
temperature and the solvent was removed under reduced pressure
to give a crude sticky product. The crude product was diluted with
CH2Cl2, and treated with H2O. The aqueous layer was extracted
with CH2Cl2 and the combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel flash column chromatography using
MeOH/CH2Cl2 (10/90) to give 74 mg of product 19a as a colorless oil,
4.1.36. (1S,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-2-methyl-1-
phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (19f). Colorless oil, (82%);
½
a 2D4
ꢂ
þ57.8 (c 0.45, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.31e7.23
(m, 3H), 7.21e7.20 (m, 2H), 6.89 (s, 1H), 6.18 (s, 1H), 4.65 (d, 1H,
J¼4.0 Hz), 4.55 (s, 1H), 3.93 (dd,1H, J¼5.5,10.5 Hz), 3.85 (s, 3H), 3.61
(s, 3H), 3.53 (dd, 1H, J¼7.5, 10.5 Hz), 3.22e3.18 (m, 1H), 2.40 (s, 3H);
13C NMR (125 MHz, CDCl3)
d 148.7, 148.2, 143.0, 129.6, 129.2, 128.5,
127.9, 127.6, 111.5, 110.8, 67.5, 66.3, 65.5, 58.5, 55.9, 55.8, 40.4; FT-IR:
v 3349 cmꢁ1 (br, OH); HRMS m/z calcd for C19H23NO4 [MþNa]þ
352.1525, found 352.1526.
4.1.37. (1R,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-1-(2-
methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol
(80%); [
a
]
2D4þ10.0 (c 0.22, CHCl3); 1H NMR (400 MHz, CD3OD)
d 7.03
(s, 1H), 6.67 (s, 1H), 4.57 (d, 1H, J ¼ 8.0 Hz), 3.89 (dd, 1H, J ¼ 5.2, 11.6
Hz), 3.83 (dd, 1H, J ¼ 5.2, 11.6 Hz), 3.82 (s, 3H), 3.80 (s, 3H),
3.29e3.31 (m, 1H), 2.95e2.91 (m, 1H), 2.51 (s, 3H), 1.38 (d, 3H, J ¼
(19g). Pale yellow oil, (76%); ½a D24
ꢂ
þ27.4 (c 0.17, CHCl3); 1H NMR
(500 MHz, CDCl3)
d
7.28e7.24 (m, 1H), 7.12 (d, 1H, J¼7.0 Hz),
6.92e6.89 (m, 2H), 6.88 (s, 1H), 6.23 (s, 1H), 4.95 (s, 1H), 4.64 (d, 1H,
J¼4.0 Hz), 3.97 (dd, 1H, J¼4.0,11.0 Hz), 3.88 (s, 3H), 3.71 (s, 3H), 3.63
(s, 3H), 3.55 (dd,1H, J¼7.0, 11.0 Hz), 3.30e3.27 (m, 1H), 3.01 (br, 2H),
6.8 Hz) ; 13C NMR (100 MHz, CD3OD)
d 149.9, 149.4, 133.3, 129.7,
112.1, 110.6, 66.8, 62.7, 60.1, 59.8, 56.4, 56.4, 38.8, 18.4; FTeIR: v
3378 cmꢁ1 (br, OH); HRMS m/z calcd for C14H21NO4 [MþNa]þ
290.1369, found 290.1367.
2.45 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 157.8, 148.7, 147.9, 131.1,
131.0, 129.8, 128.9, 127.6, 120.9, 111.9, 111.3, 110.0, 67.8, 65.8, 61.2,
58.6, 55.9, 55.8, 55.8, 40.4; FT-IR: v 3352 cmꢁ1 (br, OH); HRMS m/z
calcd for C20H25NO5 [MþH]þ 360.1812, found 360.1812.
4.1.32. (1S,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-2-methyl-1-
propyl-1,2,3,4-tetrahydroisoquinolin-4-ol (19b). Yellow oil, (70%);
½
a 2D4
ꢂ
þ2.0 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3)
d
6.97 (s, 1H),
4.1.38. (1S,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-1-(2-
methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol
(19g0). To a 0.50 M solution of 17g (388 mg, 0.68 mmol) in CH2Cl2
(1.40 mL) was treated with MeI (0.21 mL, 3.40 mmol) at room
temperature and stirred for 4 h at 35 ꢀC. The reaction mixture was
6.57 (s, 1H), 4.50 (d, 1H, J¼8.0 Hz), 3.88 (s, 3H), 3.87 (s, 3H),
3.83e3.75 (m, 2H), 3.57 (t, 1H, J¼5.6 Hz), 3.12 (q, 1H, J¼7.2 Hz), 2.43
(s, 3H), 1.85e1.60 (m, 2H), 1.51e1.33 (m, 2H), 0.93 (t, 3H, J¼7.2 Hz);
13C NMR (100 MHz, CDCl3)
d 148.8, 148.1, 130.6, 128.7, 110.2, 109.6,

892
K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
concentrated under reduced pressure, dissolved in MeOH (3.40 mL,
0.30 M). After the reaction mixture was cooled to 0 ꢀC, NaBH4
(51 mg, 1.36 mmol) was added. After stirring for 30 min at 0 ꢀC, the
reaction mixture was warmed to room temperature and concen-
trated under reduced pressure. The sticky crude product was di-
luted in CH2Cl2 and aqueous NaHCO3 solution. The aqueous layer
was extracted with CH2Cl2 and the combined extract was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture
of two diastereomersy (dr 2/1) was purified by silica gel flash col-
umn chromatography using EtOAc/hexane (5/95) to give 51 mg of
the reduced product. The desilylation of the reduced product gave
4.08 (dd, 1H, J¼3.0, 9.0 Hz), 3.90 (s, 3H), 3.87 (s, 3H), 3.57 (t, 1H,
J¼9.0 Hz), 3.29 (td, 1H, J¼3.0, 9.0 Hz), 3.24 (dd, 1H, J¼3.0, 13.5 Hz),
3.15 (dd, 1H, J¼9.0, 13.5 Hz), 2.31 (br, 1H), 1.03 (s, 9H), 0.93 (s, 9H),
0.27 (s, 3H), 0.18 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 147.9, 147.7, 139.0, 133.1, 132.1, 131.1, 130.5, 128.2, 127.6,
125.1, 109.6, 109.5, 69.9, 65.4, 55.9, 55.9, 55.9, 54.8, 43.1, 26.2, 26.1,
18.6, 18.3, ꢁ3.3, ꢁ3.6, ꢁ5.2, ꢁ5.2; HRMS m/z calcd for
C31H50BrNO4Si2 [MþNa]þ 658.2360, found 658.2362.
4.1.42. (5R,6S)-6-(Hydroxymethyl)-2,3-dimethoxy-5,6-dihydro-in-
dolo[2,1-a]isoquinolin-5-ol (23). To a 0.10 M solution of 20 (552 mg,
0.82 mmol) in anhydrous toluene (8.20 mL) was added NaOBut
(197 mg, 2.05 mmol) at room temperature under nitrogen atmo-
sphere. The reaction mixture was degassed for 5 min and were
added 5 mol % Pd2(dba)3 (28 mg) and 10 mol % X-Phos (55 mg). The
reaction mixture was refluxed at 110 ꢀC and stirred for 1.5 h under
nitrogen atmosphere. After the reaction was completed, the re-
action mixture was cooled to room temperature, filtered with
a glass filter on a pad of Celite. The residue was concentrated in
vacuo to give a crude product. The crude product was purified by
silica gel flash column chromatography using EtOAc/hexane (5/95)
to give 410 mg of product 22 (90%). The substrate 22 was dissolved
in EtOH/H2O (2/1) (7.40 mL, 0.10 M) and lithium hydroxide mono-
hydrate (306 mg, 7.38 mmol) was added at room temperature. The
mixture was heated to refluxing temperature and stirred for 24 h.
The solution was cooled to room temperature and the solvent was
removed under reduced pressure to give a crude sticky product.
The crude product was diluted with CH2Cl2 and treated with H2O.
The aqueous layer was extracted with CH2Cl2, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel flash column chromatography using MeOH/CH2Cl2
(5/95) to give 232 mg of product 23 as a yellowish brown solid,
19g0 as a yellow oil (21%);z
(400 MHz, CDCl3)
½
a 2D4
ꢂ
ꢁ6.2 (c 0.12, CHCl3); 1H NMR
d
7.25 (t, 1H, J¼10.0 Hz), 7.17 (d, 1H, J¼7.6 Hz), 7.05
(s, 1H), 6.95e6.87 (m, 2H), 6.17 (s, 1H), 5.07 (s, 1H), 4.96 (d, 1H,
J¼7.6 Hz), 3.94e3.90 (m, 2H), 3.86 (s, 6H), 3.59 (s, 3H), 3.05 (br, 2H),
2.58e2.56 (m, 1H), 2.31 (s, 3H); 13C NMR (MHz, CDCl3)
d 157.9,
148.4,148.0,132.9, 130.2, 130.1, 129.7,128.6, 121.4,111.0, 110.4, 108.5,
67.9, 67.8, 62.2, 60.6, 56.1, 55.9, 55.8, 40.5; FT-IR: v 3358 cmꢁ1 (br,
OH); HRMS m/z calcd for C20H25NO5 [MþH]þ 360.1812, found
360.1812.
4.1.39. (1S,3S,4R)-3-(Hydroxymethyl)-6,7-dimethoxy-2-methyl-1-
(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-4-ol
(19h). Pale yellow oil, (77%); ½a D24
ꢂ
þ37.5 (c 0.32, CHCl3); 1H NMR
(500 MHz, CDCl3)
d
7.56e7.53 (m, 2H), 7.43 (t, 1H, J¼7.5 Hz), 7.39 (d,
1H, J¼7.5 Hz), 6.92 (s, 1H), 6.14 (s, 1H), 4.66e4.65 (m, 2H), 3.96 (dd,
1H, J¼5.5, 10.5 Hz), 3.89 (s, 3H), 3.63 (s, 3H), 3.62e3.58 (m, 1H),
3.24e3.21 (m, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 148.9,
148.5, 144.4, 132.5, 129.2, 128.5, 128.0, 125.9, 125.9, 124.7, 124.7,
111.7, 110.7, 67.5, 66.1, 65.6, 58.8, 56.0, 55.9, 40.5; FT-IR: v 3361 cmꢁ1
(br, OH); HRMS m/z calcd for C20H22F3NO4 [MþNa]þ 420.1399,
found 420.1396.
(96%); ½a 2D4
ꢂ
ꢁ40.2 (c 0.28, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.60
4.1.40. (1R,3S,4R)-1-(Furan-2-yl)-3-(hydroxymethyl)-6,7-
dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol
(d, 1H, J¼8.0 Hz), 7.37 (d, 1H, J¼8.0 Hz), 7.21 (s, 1H), 7.18 (td, 1H,
J¼1.2, 7.2 Hz), 7.10 (td, 1H, J¼1.2, 7.2 Hz), 6.87 (s, 1H), 6.78 (s, 1H),
4.84 (d, 1H, J¼6.0 Hz), 4.76 (td, 1H, J¼2.0, 6.0 Hz), 3.97 (s, 3H), 3.89
(s, 3H), 3.56e3.52 (m, 1H), 3.43e3.37 (m, 1H), 2.31 (br, 1H), 1.85 (br,
(19i). Colorless oil, (51%); ½a D24
ꢂ
þ30.5 (c 0.21, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
7.34 (d, 1H, J¼0.8 Hz), 6.96 (s, 1H), 6.42 (s, 1H),
6.29 (dd, 1H, J¼0.8, 3.2 Hz), 6.10 (d, 1H, J¼3.2 Hz), 4.77 (s, 1H), 4.66
(d, 1H, J¼6.0 Hz), 3.91 (dd, 1H, J¼6.0, 10.8 Hz), 3.87 (s, 3H), 3.74 (s,
3H), 3.69 (dd, 1H, J¼6.0, 10.8 Hz), 3.09 (q, 1H, 6.0 Hz), 2.46 (s, 3H);
1H); 13C NMR (100 MHz, CDCl3)
d 150.2, 149.4, 137.5, 133.3, 129.2,
124.5, 122.2, 120.8, 120.6, 120.4, 112.6, 109.4, 107.1, 96.6, 68.5, 63.0,
59.8, 56.2, 26.2; FT-IR: v 3382 cmꢁ1 (br, OH); mp 102e104 ꢀC;
HRMS m/z calcd for C19H19NO4 [MþNa]þ 348.1212, found 348.1216.
13C NMR (125 MHz, CDCl3)
d 154.7, 148.8, 148.6, 142.6, 128.7, 126.6,
110.7, 110.1, 109.9, 109.6, 67.3, 63.6, 60.6, 59.9, 56.0, 55.9, 39.3; FT-IR:
v 3345 cmꢁ1 (br, OH); HRMS m/z calcd for C17H21NO5 [MþNa]þ
342.1318, found 342.1317.
4.1.43. 1-((4R,5S,6aS)-4-(tert-butyldimethylsilyloxy)-5-((tert-bu-
tyldimethylsilyloxy)methyl)-1,2-dimethoxy-6a,7-dihydro-4H-dibenzo
[de,g]quinolin-6(5H)-yl)ethanone (24). To a 0.20 M solution of 20
(463 mg, 0.73 mmol) in DMF (3.60 mL) was added NaH (44 mg,
1.82 mmol) at 0 ꢀC. After stirring for an additional 20 min, acetic
anhydride (0.10 mL, 1.09 mmol) was slowly added to the reaction
mixture at room temperature. Stirring was continued for 1 h and
the reaction mixture was diluted with EtOAc and treated with H2O.
The aqueous layer was extracted with EtOAc and the combined
extracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The N-acetyl protected product 21 was dissolved in
DMA (14.5 mL, 0.05 M) and 20 mol % Pd(OAc) (33 mg), 30 mol % X-
Phos (104 mg), and Cs2CO3 (710 mg, 2.18 mmol) were added at
room temperature. The reaction mixture was heated to 110 ꢀC for
5 h in preheated oil bath. And the reaction mixture was concen-
trated in vacuo to give a crude product. The crude product was
purified by silica gel flash column chromatography using EtOAc/
hexane (10/90) to give 282 mg of product 24 as a yellow solid,
4.1.41. (1S,3S,4R)-1-(2-Bromobenzyl)-4-(tert-butyldimethylsilyloxy)-
3[(tert-butyldimethylsilyloxy)methyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (20). To a 0.20 M solution of 17j (1.33 g,
2.10 mmol) in MeOH (10.48 mL) was added NaBH4 (159 mg,
4.19 mmol) at 0 ꢀC. After stirring for 1 h, the reaction mixture was
allowed to warm to room temperature. The reaction solvent was
concentrated under reduced pressure and the resulting white
sticky residue was diluted with CH2Cl2, quenched with H2O. The
aqueous layer was extracted with CH2Cl2. The combined extracts
were dried over anhydrous MgSO4, filtered, and then the solvent
was removed in vacuo. The crude product was purified by silica gel
flash column chromatography using EtOAc/hexane (15/85) to give
1.16 g of product 20 as a colorless oil, (87%); ½a D24
þ14.9 (c 1.10,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3)
d
7.62 (d, 1H, J¼7.5 Hz), 7.32 (d,
1H, J¼7.5 Hz), 7.27 (t, 1H, J¼7.5 Hz), 7.14 (t, 1H, J¼7.5 Hz), 6.95 (s,
1H), 6.80 (s, 1H), 4.51 (d, 1H, J¼9.0 Hz), 4.26 (dd, 1H, J¼3.0, 9.0 Hz),
(65%); ½a 2D4
ꢂ
ꢁ6.6 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.33
(d, 1H, J¼7.6 Hz), 7.34 (d, 1H, J¼7.6 Hz), 7.31 (d, 1H, J¼7.6 Hz),
7.27e7.23 (m, 1H), 6.69 (s, 1H), 4.77 (d, 1H, J¼2.4 Hz), 4.30 (dd, 1H,
J¼2.4, 12.8 Hz), 4.25e4.22 (m, 1H), 4.13e4.08 (m, 1H), 3.90 (s, 3H),
3.67 (s, 3H), 3.46e3.42 (m, 1H), 3.39e3.36 (m, 1H), 2.47 (t, 1H,
J¼12.8 Hz), 2.28 (s, 3H), 0.86 (s, 9H), 0.84 (s, 9H), 0.19 (s, 3H), 0.10 (s,
y
The ratio of each diastereomers was determined by 1H NMR of the crude re-
duction product.
z
Yield was not optimized.

K.M. Lee et al. / Tetrahedron 68 (2012) 883e893
893
3H), -0.07 (s, 3H), ꢁ0.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 152.2,
8. (a) Vicario, J. L.; Badía, D.; Carrillo, L.; Anakabe, E. Tetrahedron: Asymmetry 2003,
14, 347e353; (b) Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.; Potier, P. J. Org.
Chem. 1998, 63, 1767e1772; (c) Corey, E. J.; Gin, D. Y. Tetrahedron Lett. 1996, 37,
7163e7166; (d) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64,
8627e8634; (e) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W.
Org. Lett. 2000, 2, 3901e3903; (f) Gosmann, G.; Guillaume, D.; Husson, H.-P.
Tetrahedron Lett. 1996, 37, 4369e4372; (g) Monsees, A.; Laschat, S.; Dix, I.; Jones,
P. G. J. Org. Chem. 1998, 63, 10018e10021; (h) Ohba, M.; Nishimura, Y.; Kato, M.;
Fujii, T. Tetrahedron 1999, 55, 4999e5016; (i) Vicario, J. L.; Badia, D.; Dominguez,
E.; Carrillo, L. J. Org. Chem. 1999, 64, 4610e4616.
147.0, 138.8, 131.5, 129.9, 128.6, 128.3, 128.0, 127.5, 126.9, 126.5,
120.6, 111.9, 67.8, 62.7, 60.1, 56.1, 51.7, 34.9, 25.9, 25.8, 24.3, 23.9,
18.2, 18.1, ꢁ4.1, ꢁ4.3, ꢁ5.4, ꢁ5.6; mp 117e119 ꢀC; HRMS m/z calcd
for C33H51NO5Si2 [MþNa]þ 620.3204, found 620.3202.
4.1.44. (4R,5S,6aS)-5-(Hydroxymethyl)-1,2-dimethoxy-5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinolin-4-ol
(25). Substrate
24
9. (a) Wang, S.; Onaran, M. B.; Seto, C. T. Org. Lett. 2010, 12, 2690e2693; (b)
Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.;
Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18,
406e413; (c) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org. Chem. 1999, 64,
6724e6729; (d) Chan, W.; Lee, A. W. M.; Jiang, L. Tetrahedron Lett. 1995, 36,
715e718; (e) Kitamura, M.; Hisao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya,
H.; Noyori, R. J. Org. Chem. 1994, 59, 297e310; (f) Matulenko, M. A.; Meyers, A. I.
J. Org. Chem. 1996, 61, 573e580; (g) Munchhof, M. J.; Meyers, A. I. J. Org. Chem.
1996, 61, 4607e4610; (h) Rein, K. S.; Gawley, R. E. Tetrahedron Lett. 1990, 31,
(49 mg, 0.082 mmol) was dissolved in EtOH/H2O (2/1) (0.80 mL,
0.10 M) and lithium hydroxide monohydrate (34 mg, 0.82 mmol)
was added at room temperature. The reaction mixture was heated
to refluxing temperature and stirred for 1.5 h. The solution was
cooled to room temperature and the solvent was removed under
reduced pressure to give a crude sticky product. The crude product
was diluted with CH2Cl2 and treated with H2O. The aqueous layer
was extracted with CH2Cl2 and dried over anhydrous Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by silica
gel flash column chromatography using MeOH/CH2Cl2 (10/90) to
€
3711e3714; (i) Wunsch, B.; Nerdinger, S. Tetrahedron Lett. 1995, 36, 8003e8006;
(j) Yamazaki, N.; Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1996, 37,
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1990, 46, 5909e5920.
10. (a) Carrillo, L.; Badia, D.; Dominguez, E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vi-
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Reuscher, H.; Jansen, J. R.; Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993,
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11. Aubry, S.; Pellet-Rostaing, S.; Lemaire, M. Eur. J. Org. Chem. 2007, 5212e5225.
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Lee, W. K.; Ha, H.-J. Tetrahedron: Asymmetry 2000, 11, 3283e3292.
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Chang, J.-W.; Ha, H.-J. J. Org. Chem. 2002, 68, 43e49; (b) Sim, T. B.; Kang, S. H.;
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give 21 mg of product 25 as a light brown oil, (77%); ½a D24
þ2.4 (c
ꢂ
0.14, CHCl3); 1H NMR (500 MHz, CDCl3)
d
8.36 (d, 1H, J¼8.0 Hz), 7.30
(t, 1H, J¼8.0 Hz), 7.23e7.19 (m, 2H), 6.94 (s, 1H), 4.43 (s, 1H), 3.93
(br, 2H), 3.91 (s, 3H), 3.66 (dd, 1H, J¼4.5, 10.0 Hz), 3.62 (s, 3H),
3.59e3.57 (m, 1H), 3.56e3.54 (m, 1H), 2.81 (dd, 1H, J¼4.5, 13.5 Hz),
2.73 (t, 1H, J¼13.5 Hz), 2.04e2.00 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d 153.2, 147.1, 135.8, 131.9, 129.4, 128.6, 128.1, 127.9, 127.5,
126.8, 126.6, 112.5, 66.3, 60.3, 59.7, 56.1, 47.5, 36.6, 29.8; FT-IR: v
3400 cmꢁ1 (br, OH); HRMS m/z calcd for C19H21NO4 [MþNa]þ
350.1369, found 350.1367.
Acknowledgements
The authors are grateful for the financial support from the Na-
tional Research Foundation of Korea (NRF-2010-0005538 and NRF-
2009-0081956 for W.K.L. and NRF-2010-0008424 and Centre for
Bioactive Molecular Hybrids for H.J.H.)
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