Synthesis, antitubulin, and antiproliferative sar of c3/c1-substituted tetrahydroisoquinolines

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DOI: 10.1002/cmdc.201300412

Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1-

Substituted Tetrahydroisoquinolines

Wolfgang Dohle,^[a]Mathew P. Leese,^[a]Fabrice L. Jourdan,^[a]Meriel R. Major,^[a]Ruoli Bai,^[b]

Ernest Hamel,^[b]Eric Ferrandis,^[c]Philip G. Kasprzyk,^[d]Ann Fiore,^[d]Simon P. Newman,^[e]

Atul Purohit,^[e]and Barry V. L. Potter*^[a]

The syntheses and antiproliferative activities of novel substitut-

ed tetrahydroisoquinoline derivatives and their sulfamates are

discussed. Biasing of conformational populations through sub-

stitution on the tetrahydroisoquinoline core at C1 and C3 has

a profound effect on the antiproliferative activity against vari-

ous cancer cell lines. The C3 methyl-substituted sulfamate (ꢀ)-

7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6b), for example, was found to

be ~10-fold more potent than the corresponding non-methy-

lated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoy-

loxy-1,2,3,4-tetrahydroisoquinoline (4b) against DU-145 pros-

tate cancer cells (GI₅₀values: 220 nm and 2.1 mm, respectively).

Such compounds were also found to be active against a drug-

resistant MCF breast cancer cell line. The position and nature

of substitution of the N-benzyl group in the C3-substituted

series was found to have a significant effect on activity. Where-

as C1 methylation has little effect on activity, introduction of

C1 phenyl and C3-gem-dimethyl substituents greatly decreases

antiproliferative activity. The ability of these compounds to in-

hibit microtubule polymerisation and to bind tubulin in a com-

petitive manner versus colchicine confirms the mechanism of

action. The therapeutic potential of a representative com-

pound was confirmed in an in vivo multiple myeloma xeno-

graft study.

Introduction

In previous work, we described our discovery of N-benzyl tetra-

hydroisoquinolines (THIQs) as novel microtubule disruptors

with potential therapeutic application for the treatment of

cancer.^[1]The THIQs were designed to mimic the 2-substituted

estratriene class of microtubule disruptors (e.g., 1e and 2a)^[2]

in which incorporation of a 3-O-sulfamate group is observed to

be highly beneficial for both activity and oral bioavailability

(Figure 1). The THIQ core was used as a mimic of the steroidal

A,B-ring system from which steroidomimetics could be con-

structed. Substitution of the THIQ at C6 and C7, with those

groups requisite for activity in the steroidal series (correspond-

ing to the C3 and C2 positions, respectively, of the latter com-

pounds), was thus required. Attachment at N2 of a group pro-

jecting into the area of space occupied by the steroidal D-ring

and bearing the H-bond acceptor required for optimal activity

[a] Dr. W. Dohle, Dr. M. P. Leese, Dr. F. L. Jourdan, Dr. M. R. Major,

Prof. B. V. L. Potter

Figure 1. Design of THIQ-based microtubule disruptors 3 and 4 and their

modification into conformationally restricted analogues 5 and 6.

Medicinal Chemistry, Department of Pharmacy and Pharmacology

University of Bath, Claverton Down, Bath, BA27AY (UK)

E-mail: B.V.L.Potter@bath.ac.uk

[b] Dr. R. Bai, Dr. E. Hamel

completed our prototypical steroidomimetic design. A generic

THIQ-based compound set 4 bearing the three key elements

of the steroidal pharmacophore was thus elaborated, with en-

couraging results obtained for compounds bearing a methoxy

group at C7, an O-sulfamate group at C6, and an N2-benzyl

group substituted with an H-bond acceptor at the C3’ position.

Supporting the hypothesis that such a compound class could

mimic its steroidal parents is the finding that removal of any of

Screening Technologies Branch

National Cancer Institute, Frederick, MD 21702 (USA)

[c] Dr. E. Ferrandis

Institut de Recherche Henri Beaufour, 91966 Les Ulis Cedex (France)

[d] Dr. P. G. Kasprzyk, Dr. A. Fiore

IPSEN, 27 Maple Street, Milford, MA 01757 (USA)

[e] Dr. S. P. Newman, Dr. A. Purohit

Diabetes, Endocrinology & Metabolism

Imperial College London, Hammersmith Hospital, London, W120NN (UK)

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the three key pharmacophore elements (at C6 and

C7 of the THIQ moiety and at C3’ of the N1-benzyl

group) results in biologically inactive compounds.

Furthermore, the THIQ derivatives, like the steroids,

were found to disrupt the polymerisation of tubulin

and inhibit the binding of [³H]colchicine to tubulin.

Like the steroid sulfamates, the THIQ compounds in-

hibit carbonic anhydrase,^[3]an interaction believed to

contribute to the high oral bioavailability observed

for the steroid derivatives.^[4]In addition, once more

reflecting observations made in the steroidal series,

the THIQ compounds proved capable of inhibiting

the growth of taxane-resistant cancer cells^[5]and

HUVEC cell proliferation (a commonly used marker

for anti-angiogenic activity),^[6]thus supporting the

idea that these small-molecule microtubule disrup-

tors work in a similar manner to the 2-substituted es-

tradiol 3-O-sulfamates (e.g., 2a).

Scheme 1. Synthesis of C3-substituted THIQs. Reagents and conditions: a) RCH₂NO₂,

NH₄OAc, reflux; b) NaBH₄, EtOH, 08C; c) Raney Ni, N₂H₄·H₂O, MeOH, 508C; d) Ac₂O, Et₃N,

CH₂Cl₂, 0!258C; e) (CH₂O)_n, p-TsOH, toluene, 1208C; f) KOH, EtOH/H₂O, reflux; g) Pd/C

(10%, 140 mg cartridge), full H₂, H-cube, THF/MeOH at 1.0 mLmin^ꢁ1, 258C; h) TIPSCl, imi-

dazole, CH₂Cl₂, 258C.

To investigate conformational effects, we needed to access

In the present work our goal was to achieve enhanced anti-

cancer effects through optimisation of the THIQ-based lead

compounds. We reasoned that the rotational freedom enjoyed

by the N-benzyl group would likely lead to a small population

of the conformer in which the H-bond acceptor is projected

into the region of space occupied by the corresponding group

in the steroid series, and that substitution on the THIQ core

with groups that could hamper, to some extent, the free rota-

tion of the N-benzyl group to favour the postulated active con-

formations might deliver compounds with improved activity.

The likely sites of modification were thus the C1 and C3 posi-

tions of the THIQ core (Figure 1), with C3 substitution likely fa-

vouring a “steroid-like” conformation and C1 substitution likely

forcing the N2 substituent away from the presumed “steroid-

like” optimal conformation. Herein we report our full optimisa-

tion studies, in vitro biological evaluation, and preliminary in

vivo studies to demonstrate the potential of this new com-

pound class.

C1- and C3-substituted THIQs. Installation of the C3 substituent

required a simple modification of the synthetic approach we

had previously applied to synthesise the THIQ core system

(Scheme 1).^[3]Thus, commercially available 3-benzyloxy-4-me-

thoxybenzaldehyde 7 was subjected to a Henry aldol reaction^[9]

with nitroethane and 1-nitropropane to afford requisite nitro-

styrenes 8a,b in good yield. Reduction of the styrene double

bonds of 8a,b with sodium borohydride furnished the racemic

secondary nitroalkanes, the nitro groups of which were then

reduced with hydrazine hydrate and Raney nickel to afford the

corresponding phenethylamines 10a,b. Although the phene-

thylamines could be directly transformed into the correspond-

ing THIQ derivatives by Pictet–Spengler annulation,^[10]it

proved expeditious first to acylate, as this facilitated separation

of the THIQ reaction products from impurities and thus afford-

ed an improved yield. The Pictet–Spengler reaction of the N-

acyl phenethylamines was carried out with paraformaldehyde

under acid catalysis in toluene at reflux. Hydrolysis of the

amides 12a,b with potassium hydroxide in aqueous ethanol

delivered the key intermediate THIQs 13a,b. As there was

some degree of incompatibility expected between conditions

for the benzyl deprotection procedure and some of the func-

tional groups we wished to evaluate, a quantity of 13a was

debenzylated and then reprotected with TIPSCl to give 15. The

debenzylation step proved much more effective if a flow hy-

drogenator system (H-cube) was used, as the product of the

hydrogenation 14a proved prone to precipitation on removal

of catalyst, with only moderate product recovery (~45%) when

conventional hydrogenation was performed.

Results and Discussion

Chemistry

Our previous structure–activity relationship (SAR) studies on N-

benzyl-7-methoxy-6-O-sulfamoyl THIQs indicated that these

compounds are good leads for optimisation as anticancer

agents.^[7]Of the compounds bearing a single H-bond acceptor

on the N-benzyl group (steroidal D-ring mimic), the 3’-methoxy

derivative 4b and other 3’-substituted compounds proved

most active in vitro (micromolar antiproliferative GI₅₀values).

We also reported that the 3’,4’,5’-trimethoxybenzyl derivative

had greatly improved activity, although the observed SAR is di-

vergent from that exhibited by the monosubstituted N-benzyl

derivatives 4.^[3]We proposed that this compound is best con-

sidered a chimera of the steroid and the class of microtubule

disruptors bearing a trimethoxybenzene ring that bind at the

colchicine site, including combretastatins, the colchicinoids,

and podophyllotoxins.^[8]

The C3-substituted THIQs 13a,b and 15 were then convert-

ed into the desired N-benzyl derivatives, either under various

direct N-benzylation conditions or by first forming the amide

from the appropriate benzoic acid, using an N’-(3-dimethylami-

nopropyl)-N-ethylcarbodiimide (EDCI) coupling followed by re-

duction with lithium aluminum hydride, to give 16a–h and

17a–l (Scheme 2). The C6 hydroxy groups were unmasked

with hydrogen and palladium on carbon (for 16a–h) or tetra-

n-butylammonium fluoride (TBAF; for 17a–l) to deliver good

yields of 5a–t. Sulfamoylation of 5a–t in N,N-dimethylaceta-

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with sodium borohydride in eth-

anol at reflux to give the C1-sub-

stituted THIQs 26a and 26b,

which were elaborated to deliver

the desired phenols 5w–z and

sulfamates 6w–z using condi-

tions analogous to those de-

scribed for the synthesis of C3-

substituted THIQs above.

Biology

To assess their potential as anti-

cancer agents, the new THIQ de-

rivatives were assayed for their

ability to inhibit the proliferation

of DU-145 (androgen-receptor-

negative) prostate cancer cells

and MDA MB-231 (estrogen-re-

Scheme 2. Synthesis of N-benzyl-substituted THIQs. Reagents and conditions: a) BnCl, Et₃N, EtOH, 1308C, MW;

b) BnBr, DIPEA, DMF, 808C; c) Benzoic acid, EDCI, CH₂Cl₂/THF, 258C; d) LiAlH₄, THF, reflux; e) H₂, Pd/C, THF/MeOH,

258C; f) TBAF, THF, 258C; g) H₂NSO₂Cl, DMA, 258C.

ceptor-negative) breast cancer cells in vitro. The assay results

obtained for these compounds are listed in Table 1 alongside

selected comparator compounds from our earlier studies.^[7]

Most of the compounds had similar antiproliferative activity

against both the DU-145 and MDA MB-231 cells and thus, to

simplify the SAR discussion, only the DU-145 data are used for

comparison of relative activities. In our earlier study^[7]we

showed that in the C3-unsubstituted series an H-bond accept-

or at the meta position of the N-benzyl group delivers the

greatest antiproliferative activity. In the current series, of the

mono-methoxybenzyl C3-methyl derivatives (6a, 6b, and 6d)

the meta-methoxy compound 6b was most active, as was also

the case in the C3-unsubstituted series. In contrast to the un-

substituted series, however, 6a, 6b, and 6d all had sub-micro-

molar GI₅₀values against the DU-145 cells. Activity enhance-

ment was most pronounced in the case of the para-methoxy

compound 6d, which was >50-fold more active than 4c. The

high activity obtained by incorporation of the methyl group at

C3 with 6b (GI₅₀: 222 nm) was also observed in a congener

with a C3-ethyl group (6c has a GI₅₀value of 286 nm). It is thus

clear that at least a small C3-alkyl substituent is desirable. This

may indicate that the C3-alkyl group contributes a positive lip-

Scheme 3. Synthesis of 3,3-gem-dimethyl THIQs. Reagents and conditions:

a) KCN, AcOH, H₂SO₄, 0!258C; b) NaBH₄, EtOH, 0!258C; c) TIPSCl, imida-

zole, CH₂Cl₂, 258C; d) BnCl, Et₃N, EtOH, 1308C, MW; e) TBAF, THF, 0!258C;

f) H₂NSO₂Cl, DMA, 258C.

mide (DMA)^[11]gave the corresponding sulfamate derivatives

6a–t (Scheme 2).

To establish whether di-substitution at C3 would be advanta-

geous, we prepared the gem-dimethyl THIQ 20 and used it to

elaborate the 6-O-sulfamate derivatives 6u and 6v with 3’-me-

thoxy- or 3’,4’,5’-trimethoxy-substituted benzyl groups, respec-

tively (Scheme 3). Ritter reaction^[12]of 5-(2-hydroxy-2-methyl-

propyl)-2-methoxyphenol 18^[13]with potassium cya-

nide under strong acidic conditions delivered the 3,4-

dihydroisoquinoline 19 in low yield. Borohydride re-

duction of the imine, followed by triisopropylsilyl

(TIPS) protection was then carried out to give the

silyl-protected THIQ 21. N-Benzylation of 21 using

the appropriate benzyl chloride with triethylamine in

ethanol at 1308C under microwave irradiation afford-

ed 22a and 22b, which were converted into the C3-

dimethyl-substituted target sulfamates 6u and 6v by

TBAF deprotection and sulfamoylation (Scheme 3).

Access to the C1-substituted THIQs was carried out

by treating phenethylamine 23 with the appropriate

acid chloride or anhydride and then performing the

Scheme 4. Synthesis of C1-substituted THIQs. Reagents and conditions: a) BzCl, Et₃N,

CHCl₃, 08C; b) Ac₂O, Et₃N, CH₂Cl₂, 08C; c) POCl₃, toluene, reflux; d) NaBH₄, EtOH, reflux;

ring closure with phosphorus oxychloride (Scheme 4).

The cyclic imines 25a and 25b were then reduced e) BnCl, Et₃N, EtOH, 1308C, MW; f) H₂, Pd/C, THF/MeOH, 258C; g) H₂NSO₂Cl, DMA, 258C.

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Our original plan involved addressing the three

key pharmacophore elements required for high activ-

ity in the steroidal series, and these three elements

had proven essential for activity in the prototypical

THIQ series previously prepared.^[7]The finding that

the unsubstituted benzyl derivative 6e retains low

micromolar antiproliferative activity was consistent

with the SAR findings obtained in the steroidal

series; 2-methoxyestrone-3-O-sulfamate is ~10-fold

more active than 2-methoxy-17-deoxyestrone-3-O-

sulfamate, which lacks an H-bond acceptor in the D-

ring.^[14]This supports the hypothesis that the C3-

methyl THIQs are good mimics of the steroidal series

and that the C3-methyl group favours a conforma-

tional population in which the N-benzyl group occu-

pies the D-ring space in the steroidal series.^[1]The

positive lipophilic interactions resulting from this

conformational biasing thus, in themselves, appear to

deliver a reasonable degree of antiproliferative activi-

ty. The results obtained with the ortho-substituted

compounds 6g and especially 6 f reinforce this hy-

pothesis. In fact, the ortho-methyl compound 6g is

more than threefold more active than the ortho-me-

thoxy compound 6a. It thus appears that small ortho

substituents can contribute a greater positive lipo-

philic interaction than the methoxy group, and sub-

stitution with chlorine at C2’ (6 f GI₅₀: 0.2 mm) affords

a further improvement in activity relative to the

methyl substituent (6g GI₅₀: 1 mm). Clearly, a further

exploration of similarly sized ortho substituents is

merited.

In contrast to the C3-unsubstituted lead series,^[7]it

was found that, with a C3-methyl group, an H-bond

acceptor was not required for optimal activity. Ethyl

(6h), ethoxy (6i), nitro (6j), chloro (6k), and acetyl

(6l) derivatives all exhibited GI₅₀values in the 0.2–

0.3 mm range and were thus of similar activity to the

3’-methoxy analogue 6b. The lack of a substantial

difference between electron donating and withdraw-

ing substitution suggests that, as observed for the

C2’ substituents, the C3’ substituents likely contribute

a positive lipophilic interaction that delivers a 10-fold

improvement in activity relative to the unsubstituted

N-benzyl analogue 6e or the C3-unsubstituted lead

4b. We also assessed the activity of four dimethoxy

benzyl derivatives 6m–p. Three are moderately less

active than 6b, but the 2’,5’-dimethoxy derivative 6p

is slightly more active. The 2’,5’-substitution pattern

of 6p was explored further with fluorine (6q) and

Table 1. Antiproliferative activity of polymethoxylated THIQs against DU-145 human

prostate cancer cells and MDA MB-231 human breast cancer cells in vitro.

Compd^[a]

R¹

X

R²

R³

R⁴

R⁵

GI₅₀[mm]^[b]

DU-145

MDA MB-231

3a

4a

5a

6a

3b

4b

5b

6b

5c

6c

3c

4c

5d

6d

5e

6e

5 f

6 f

5g

6g

3d

4d

5h

6h

5i

H

SO₂NH₂

H

OMe

H

>100

ND

>100

2.9

ND

1.53

0.234

ND

0.281

ND

99.8

0.7

7.8

>100

3.4

>100

2.1

Me OMe

SO₂NH₂Me OMe

H

SO₂NH₂

H

Me

H

Cl

Me

H

OMe

H

Et

3.73

0.222

SO₂NH₂Me

H

SO₂NH₂

H

SO₂NH₂

H

Et

H

Me

ND

0.286

>100

57.2

>100

1.1

>100

2.2

H

OMe

H

SO₂NH₂Me

Me

SO₂NH₂Me

Me

SO₂NH₂Me

Me

SO₂NH₂Me

H

>100

1.4

H

9

0.2

10

9

0.2

7

0.5

H

1

>100

35

H

SO₂NH₂

H

Me

>100

8.0

39

9.63

0.368

8.1

0.2

9.4

0.2

9.3

0.1

94

0.2

84

0.4

86

SO₂NH₂Me

Me

SO₂NH₂Me

Me

SO₂NH₂Me

Me

SO₂NH₂Me

Me

SO₂NH₂Me

Et

0.324

20

0.3

19

0.3

H

OEt

NO₂

Cl

Ac

6i

5j

6j

5k

6k

5l

H

9.9

0.3

H

56

0.2

98

0.6

30

0.9

15.3

0.73

54.3

0.189

6l

5m

6m

5n

6n

5o

6o

5p

6p

5q

6q

5r

H

Me OMe OMe

SO₂NH₂Me OMe OMe

H

Me

SO₂NH₂Me

Me

SO₂NH₂Me

H

OMe OMe

OMe

H

0.7

3.2

0.49

>100

0.16

1

H

OMe

H

Me OMe

SO₂NH₂Me OMe

H

Me

SO₂NH₂Me

Me

SO₂NH₂Me

F

Cl

2

0.299

0.265

0.4

0.269

0.173

0.4

H

6r

H

[a] All compounds of type 5 and 6 are racemic mixtures; data for 3a–d, 4a–d, 5a–b,

5d, 6a–b, and 6d are taken from the literature.^[1,7][b] Data are the mean of three de-

terminations; ND: not determined.

ophilic interaction, as well as creating a desirable bias in the

conformational population with the benzyl group projected

into the region of space occupied by the D-ring in the steroi-

dal series. With these preliminary results, we focused on explo-

ration of the SAR at the meta-benzyl position. However, we

also made several additional control compounds worthy of

mention.

chlorine (6r) substituents at C2’. Both compounds are slightly

less active than 6p. Evidently, placing an electron-withdrawing

group at the para position does not significantly modulate the

H-bond acceptor capability of the 5’-methoxy group. However,

in the absence of the sulfamate substituent, using 5b with

a 2’-methoxy substituent for comparison, the 2’-chloro-5’-me-

thoxy phenol compound 5r displays a 14-fold increase in activ-

ity. In contrast, the 2’-fluoro-5’-methoxy phenol compound 5q

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is only about twice as active as 5b. In the phenol

series, the combination of a 5’-methoxy group with

a second substituent at C2’ reveals that Cl@F, H @

MeO in terms of antiproliferative activity. Moreover,

5r is more potent than 6r, the only example in

which the phenol is more potent than the corre-

sponding sulfamate derivative. The origins of this un-

expected reversal in potency remain to be deter-

mined. When combined with the observations on the

activities of the 2’-substituted series, it appears that

chloro substitution provides considerable benefit at

the site of action and/or enhances the postulated

conformational biasing.

Table 3. Negligible antiproliferative activity of C3-dimethyl-substituted THIQs against

DU-145 human prostate cancer cells and MDA MB-231 human breast cancer cells in

vitro.

Compd

R¹

R²

R³

R⁴

R⁵

GI₅₀[mm]^[a]

MDA MB-231

DU-145

5u

6u

5v

6v

H

OMe

H

OMe

H

OMe

>100

SO₂NH₂

H

SO₂NH₂

We recently reported 3’,4’,5’-trimethoxybenzyl-sub-

stituted compounds 3e and 4e to show excellent

sub-micromolar in vitro antiproliferative activities

against the DU-145 and MDA MB-231 cancer cell

lines.^[3]We consider that these compounds are best

described as chimeras composed of the key pharma-

cophore elements of two series of colchicine site

binders, namely 2-methoxyestradiol and the trime-

thoxyaryl family of colchicine site binders, such as

the colchinoids and combretastatins.^[3]To establish

effects of various C3 monosubstitution patterns, we

synthesised compounds 5s,t and 6s,t. In the phenol

series, incorporation of a C3-methyl group causes

a slight decrease in activity (cf. 5s and 3e), whereas

the ethyl derivative 5t is <20% as active as 3e

(Table 2). In contrast, in the sulfamate series the C3-

methyl derivative 6s is moderately more active than

the unsubstituted 4e, but it is threefold more active

than the ethyl compound 6t. Thus, any conforma-

tional biasing affected by the C3 substituent does

not enhance interaction with tubulin significantly in

the presence of the 3’,4’,5’-trimethoxy benzyl group.

We also synthesised C3-dimethyl-substituted com-

[a] Data are the mean of three determinations.

Table 4. Antiproliferative activity of C1-substituted THIQs against DU-145 human

prostate cancer cells and MDA MB-231 human breast cancer cells in vitro.

Compd^[a]

R¹

X

R³

R⁴

R⁵

GI₅₀[mm]^[b]

MDA MB-231

DU-145

5w

6w

5x

6x

5y

6y

5z

6z

H

SO₂NH₂

H

SO₂NH₂

H

SO₂NH₂

H

SO₂NH₂

Me

Ph

OMe

H

OMe

H

OMe

H

OMe

H

OMe

>100

1.3

>100

0.97

>100

0.3

>100

63

>100

0.36

>100

16

>100

41

>100

58

[a] All compounds of type 5 and 6 are racemic mixtures. [b] Results are the mean of

three determinations.

pounds 5u,v and 6u,v, but, as the data listed in Table 3 dem-

onstrate, the additional C3 substituent results in uniformly in-

active compounds. The 3,3-gem-dimethyl group could simply

be too large to be accommodated at the site of action, and

thus compounds with this substitution pattern are inactive; al-

ternately, this substitution could interfere with cell uptake,

thus rendering the compounds inactive in these assays.

Table 2. Antiproliferative activity of 3’,4’,5’-trimethoxy-substituted THIQs

against DU-145 human prostate cancer cells and MDA MB-231 human

breast cancer cells in vitro.

We also investigated incorporating a substituent at the C1

position, which on steric grounds would logically disfavour

conformers in which the benzyl group projects into the re-

gions occupied by the steroidal D-ring. The C1-methyl and

phenyl THIQ core structure with N-3’-methoxybenzyl and N-

3’,4’,5’-trimethoxybenzyl substituents attached to it were syn-

thesised and evaluated (Table 4). None of phenols 5w–z exhib-

its significant activity. However, the sulfamates 6w–z display

micromolar to sub-micromolar activity, with C1-methyl-substi-

tuted derivatives proving more active than their C1-phenyl-

substituted congeners. Clearly C1 phenyl substitution is poorly

tolerated either at the site of action or in terms of cellular

uptake. Comparison of compounds 6w and 6x with 4b and

4e reveals that C1 methylation has little effect on antiprolifera-

tive activity, with a slight improvement and a slight decrease

Compd^[a]

R¹

X

GI₅₀[mm]^[b]

MDA MB-231

DU-145

3e

4e

5s

6s

5t

6t

H

Me

Et

0.65

0.297

0.79

0.196

3.38

0.735

0.62

0.329

0.67

0.24

2.61

0.626

SO₂NH₂

H

SO₂NH₂

H

SO₂NH₂

Et

[a] All compounds of type 5 and 6 are racemic mixtures; data for com-

pounds 3e and 4e are taken from the literature.^[3][b] Results are the

mean of three determinations.

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Our preliminary studies had shown that the initial

lead compound 6b inhibits tubulin polymerisation.^[1]

To establish a SAR for these compounds as microtu-

bule disruptors, we selected a number of them with

good antiproliferative activity for evaluation as inhibi-

tors of tubulin assembly, as well as inhibitors of the

binding of [³H]colchicine to tubulin alongside the es-

tablished potent microtubule disruptor combretasta-

tin A-4 (CA-4) and the 3’,4’,5’-trimethoxybenzyl THIQ

derivatives 3e and 4e (Table 7). The majority of our

steroidomimetic derivatives bearing a substituent at

C3 proved more active than the chimeras 3e and 4e

as inhibitors of tubulin assembly and colchicine bind-

ing to tubulin. 3’-Chlorobenzyl 6k, 2’-fluoro-5’-me-

thoxybenzyl 6q, and 2’-chloro-5’-methoxybenzyl 6r

derivatives all display assembly IC₅₀values <10 mm

and >25% inhibition of [³H]colchicine binding.

Table 5. Antiproliferative activity of selected compounds against various cancer cell

lines from the NCI-60 cell line panel.

Compd^[a]

GI₅₀[mm]^[b]

Melanoma

UACC-62

Lung

Colon

CNS

Ovarian

Renal

MGM

HOP-62 HCT-116 SF-539

OVCAR-3 SN-12-C

1e

2a

5b

6b

6 f

6l

6p

6q

6r

0.7

0.051

5.17

0.47

0.045

2.82

0.051

0.436

0.221

0.446

0.066

0.048

0.267

0.32

0.036

5.31

0.032

0.392

0.12

0.331

0.091

0.042

0.018

0.36

<0.01

5.5

0.033

0.324

0.53

0.584

0.074

0.069

0.04

0.21

<0.01

4.72

0.039

0.124

0.101

0.298

0.043

0.039

0.028

0.95

0.126

9.11

0.188

0.971

0.612

1.64

0.559

0.372

0.628

1.3

0.087

6.76

0.109

0.447

0.437

0.562

0.145

0.102

0.204

0.07

0.217

0.364

0.504

0.122

0.075

0.236

6s

[a] All compounds of type 5 and 6 are racemic mixtures; data for compounds 1 and

2a are taken from the literature.^[2d,15][b] Results are the mean of three determina-

tions.

Although not quite as active as CA-4, compound

6r shows very encouraging results, disrupting the

in activity obtained in the monomethoxy- and trimethoxy-sub-

stituted benzyl derivatives, respectively.

Table 6. Antiproliferative activity of selected compounds against wild-

type and resistant MCF-7 breast cancer cells and HUVECs.

All compounds were submitted to the US National Cancer

Institute (NCI) for preliminary screening, and some of them

were selected for evaluation in the full 60-cell-line assay

(Table 5) across a wide range of cancer types. Data from six

cancer cell lines are presented, along with the mean activity

across the whole panel (MGM value). Screening is conducted

at concentrations ranging from 10 nm to 100 mm. The data ob-

tained in the assay are consistent with those obtained in our

antiproliferative screens and demonstrate the potential of

these compounds against multiple cancer phenotypes. The sul-

famate derivatives 6b, 6l, 6q, 6r, and 6s are more active than

2-methoxyestradiol 1e and, in the best cases, 6b and 6r dis-

play activities equivalent to that of 2-methoxyestradiol-3,17-

O,O-bis-sulfamate 2a.

Compd^[a]

GI₅₀[mm]^[b]

MCF-7_WT

MCF-7_Dox

HUVEC

2a

4b

6b

6s

0.25

2.85

0.35

0.45

0.38

1.4

0.09

0.3

0.05

1.16

0.16

0.2

[a] All compounds of type 6 are racemic mixtures. [b] Results are the

mean of three determinations.

Table 7. Activity of selected THIQs as inhibitors of tubulin polymerisation

and [³H]colchicine binding (5 mm inhibitor) to tubulin.^[a]

In addition to their antiproliferative activity against wild-type

cancer cells, the steroidal sulfamates (e.g., 2a) inhibit the pro-

liferation of taxane-resistant cancer cells and inhibit angiogen-

esis.^[5,6]The MCF-7_Doxcell line is a multidrug-resistant breast

cancer cell line that expresses P-glycoprotein (P-gp) and is re-

sistant to taxanes and a range of other anticancer agents.^[5c]

Compounds 4b, 6b, and 6s were thus evaluated for their abili-

ty to inhibit wild-type MCF-7 cells (MCF-7_WT) and its resistant

subline MCF-7_Dox. As a preliminary assessment of potential

anti-angiogenic activity, the compounds were also assayed for

their ability to inhibit the proliferation of human umbilical vein

endothelial cells (HUVECs), a commonly used marker of anti-

angiogenic potential (Table 6). The C3-methylated derivatives

6b and 6s exhibit good activity against both the wild-type

and multidrug-resistant MCF-7 lines, with activity similar to

that of 2a. These compounds thus do not appear to be sub-

strates for the P-gp efflux pump and have potential for the

treatment of taxane-resistant tumours. Good activity was also

observed for 6b and 6s against the proliferation of HUVECs;

therefore, these compounds, like the steroids that inspired

their design, may have a complementary anti-angiogenic

mechanism of action.

Compd

Tubulin assembly IC₅₀[mm]

Colchicine binding [% inhib]

CA-4

3e

4e

5r

6b

6c

6e

6 f

6g

6h

6i

6j

6k

6l

6p

6q

6r

1.2ꢀ0.1

>20 (no act.)

>20 (partial act.)

14ꢀ1

98ꢀ0.7

4.1ꢀ2

10ꢀ0.9

14ꢀ1

16ꢀ2

0ꢀ3

12ꢀ0.6

>20 (no act.)

>20 (weak act.)

9.7ꢀ1

6.7ꢀ1

15ꢀ4

13ꢀ2

4.1ꢀ0.7

12ꢀ2

21ꢀ3

26ꢀ2

11ꢀ2

>20 (weak act.)

>20 (partial act.)

19ꢀ0.4

11 ꢀ1

9.2ꢀ0.2

13ꢀ1

>20 (partial act.)

7.0ꢀ0.4

8.2ꢀ2

26ꢀ2

47ꢀ3

9.3ꢀ0.6

3.2ꢀ0.3

6s

16ꢀ2

[a] Values are the mean ꢀSD of at least two determinations. Compounds

4e, 6e, 6g, 6h, and 6p inhibited tubulin assembly at 20 mm, whereas 3e

and 6c are inactive at this concentration. All compounds of type 5 and 6

are racemic mixtures. Data for CA-4, 3e, and 4e are taken from the litera-

ture.^[7]

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polymerisation of tubulin with an IC₅₀value of 3.2ꢀ0.3 mm

and inhibiting colchicine binding to tubulin by 47% at 5 mm.

Its phenol 5r and sulfamates 6b, 6 f, 6l, 6p, and 6s, which are

the most active antiproliferative compounds in vitro (Tables 1

and 2) and are all about twice as active as 6r, display IC₅₀

values of 9.7–14 mm or >20 mm (for the most active compound

in vitro 6p), and inhibition of [³H]colchicine binding to tubulin

is not better than 16% at 5 mm (6b). Comparison of phenol 5r

and sulfamate 6r particularly illustrates the relevance of the

sulfamate group at C6 for the ability to inhibit tubulin poly-

merisation and the binding of [³H]colchicine to tubulin effec-

tively. Overall, these data (Table 7) do not exactly correlate with

the in vitro data (Tables 1 and 2) and for the 2’-X-5’-methoxy-

substituted sulfamates 6b (X=H), 6p (X=MeO), 6q (X=F),

and 6r (X=Cl), the observed trend in terms of activity is oppo-

site (X=Cl>F>H>MeO) to the in vitro data for DU-145 and

MDA MB-231 (X=Cl<F<H<MeO) and correlates better with

the in vitro data of their phenols 5b (X=H), 5p (X=MeO), 5q

(X=F), and 5r (X=Cl), but the differences are not of the same

magnitude (X=Cl@F>H@MeO).

Having established in vitro activity and confirmed activity at

the postulated site of action, we wished to establish the in

vivo activity of this compound series. Compound 6b was as-

sessed for its ability to inhibit the growth of RPMI-8226 multi-

ple myeloma xenografts in female nude athymic mice. Daily

dosing of 6b at 40 mgkg^ꢁ1, formulated as a solution in 5%

aqueous citric acid, for 28 days was compared with vehicle

and 2a at its optimal dose of 20 mgkg^ꢁ1. As can be seen in

Figure 2a, a substantial 39% inhibition of growth was achieved

by 6b at this non-optimised dose level at cessation of dosing.

Furthermore, a prolonged inhibition of tumour growth was ob-

served in the 6b-treated cohort (48% growth inhibition 18

days after cessation of dosing). In addition, no evidence of tox-

icity was found in this treatment group, as mouse body weight

increased in line with the vehicle group over the course of

treatment (Figure 2b). This experiment confirms the potential

of THIQ derivatives such as 6b as antitumour agents in vivo,

and suggests that with optimisation of dose, they could well

match or even better the activity observed for the steroidal

compounds.

Figure 2. a) The activity of 6b (40 mgkg^ꢁ1day^ꢁ1, 28 d, p.o. in 5% aqueous

citric acid) against the growth of RPMI-8226 (multiple myeloma) xenografts

in athymic nude mice was assessed alongside the benchmark steroid deriva-

tive, 2-methoxyestradiol-3,17-O,O-bis-sulfamate 2a (20 mgkg^ꢁ1day^ꢁ1, 28 d,

p.o.). After 28-day dosing, significant inhibition of tumour growth was ob-

served for both cohorts of treated animals. b) No significant weight loss was

observed in either cohort, indicating that 6b is well tolerated. Data are the

meanꢀSEM of n=6.

also far less toxic. In the hollow fiber assay compound 6l

shows good activity, good tissue distribution, and the activity

surpasses normal criteria (score >20) for further investigations

at the NCI, but it was not selected for additional study to fur-

ther develop this class of compounds as in vivo agents. A

COMPARE analysis^[18]of data obtained for 6l against the pub-

licly available NCI screening data afforded only two positive

correlations, with the highest Pearson correlation coefficient

being 0.725 (>0.6 is considered a positive correlation), which

was obtained for the well-known microtubule disruptor vincris-

tine. Significantly, there was no correlation found with any of

the steroidal derivatives 2a–d. Compound 6b, on the other

hand, did not deliver any positive correlations in the COMPARE

analysis.

Compound 6l was also selected for in vivo evaluation at the

NCI in the hollow fiber assay that involves assessment of activi-

ty against the proliferation of various cancer lines in sealed

polyvinylidine fluoride fibers implanted i.p. or s.c. in mice.^[16]

A

50% net cell growth inhibition is awarded a score of 2, and

with over 48 fibers (12 cell lines ꢁ 2 sites ꢁ 2 dose levels)

a

maximum score of 96 is possible. Dosing of 6l at

150 mgkg^ꢁ1results in 50% inhibition of cell growth in ten

fibers i.p. and five fibers s.c., and thus delivers a score of 30

(20 for i.p. fibers and 10 for s.c. fibers). Similar scores were ob-

tained for tested steroid derivatives, although at a much lower

dose level. Compound 2d, for example, displaying an excellent

MGM value of 28 nm in the NCI 60-cell line assay,^[17]was award-

ed a score of 32 (18 for i.p. and 14 for s.c. fibers) when dosed

at 37.5 and 18.75 mgkg^ꢁ1. Although THIQ derivative 6l shows

far less activity in vitro (MGM=0.437 mm) than most of the

steroidal compounds 2a–d, in vivo it is nearly equipotent and

Conclusions

This study was aimed at identifying requirements to enhance

the level of antiproliferative activity of the tetrahydroisoquino-

line derivatives 4b and 4e by modification of the C1 and C3

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with 10% fetal bovine serum, l-glutamine (2 mm), 1% nonessential

amino acids, and 0.075% sodium bicarbonate (Sigma). Human um-

bilical vein endothelial cells (HUVECs) were obtained from TCS Cell-

works (Claydon, UK) and maintained in large-vessel endothelial

medium supplemented with basic fibroblast growth factor/heparin,

epidermal growth factor and cortisol in the presence of amphoteri-

cin/gentamycin (TCS Cellworks). Human adult dermal fibroblasts

(TCS Cellworks) were maintained in fibroblast growth medium (TCS

Cellworks) with the same supplements as used in the HUVEC

media. HUVECs and dermal fibroblasts were used up to passage

10. To ascertain IC₅₀values, 5000–10000 cells in their appropriate

growth medium were added to each well of a 96-well microtitre

plate (Falcon; BD Biosciences, Cowley, UK). Plates were incubated

for 4–5 h at 378C in a 5% CO₂humidified atmosphere before addi-

tion of compounds at a final concentration of 10^ꢁ10–10^ꢁ2m.

positions. As described above, incorporation of a methyl or

ethyl group at C3 has a dramatic effect on antiproliferative ac-

tivity. It appears reasonable to suggest that the increased activ-

ity derives at least in part from the C3 substituent favouring

populations of “steroid-like” conformers. In contrast, C1 meth-

ylation has little effect on antiproliferative activity, whereas in-

troduction of a larger C1 phenyl group is deleterious to activi-

ty. A short summary of the in vitro SAR of these compounds as

antiproliferative agents is presented in Figure 3. The potential

Antiproliferative assays: DU-145 and MDA-MB-231 cells were

seeded into 96-well microtitre plates (5000 cells per well) and treat-

ed with compound at 10^ꢁ9–10^ꢁ4m or with vehicle control. At 96 h

post-treatment, live cell counts were determined by WST-1 cell pro-

liferation assay (Roche, Penzberg, Germany), as per the manufac-

turer’s instructions. Viability results were expressed as a percentage

of mean control values resulting in the calculation of the 50%

growth inhibition (GI₅₀). MCF-7_WT, MCF-7_Dox, and HUVECs were treat-

ed with 10^ꢁ10–10^ꢁ2m compound or with vehicle control for 96 h.

All compounds were dissolved at 10^ꢁ2m in tetrahydrofuran (THF)

for in vitro experiments (10^ꢁ6–10^ꢁ1% final THF concentration). Cells

were grown in the absence or presence of the compounds for

5 days. At the end of this period, MTS (20 mL per well; Promega,

Southampton, UK) was added and incubated for a further 2 h. Ab-

sorbance was recorded at l 490 nm with a 96-well plate reader

(FLUOSTAR; BMG, Aylesbury, UK). All experiments were performed

in triplicate.

Figure 3. In vitro SAR of C3/C1-substituted THIQs as antiproliferative agents.

of this series of compounds was confirmed by their broad-

spectrum activity across the NCI-60 cell line panel and their

ability to inhibit proliferation of a taxane-resistant cancer cell

line.

In addition, the ability of selected compounds to inhibit

HUVEC proliferation and microtubule polymerisation indicates

a common mechanism and profile of action as those of the

steroidal derivatives (e.g., 2a) that inspired their design. Finally,

the inhibitory activity of 6b against the growth of an RPMI-

8226 multiple myeloma xenograft model at a non-optimised

dose confirms the potential of this series of THIQ derivatives as

orally active anticancer agents. We have thus established the

use of the N-benzyl THIQs as steroidomimetics and have eluci-

dated how substitution at C3, through conformational biasing,

can be used to enhance activity. All compounds were studied

as racemic mixtures, and clearly for exploring potential devel-

opment compounds for the work, it will be necessary to sepa-

rate enantiomers. We are currently exploring further optimisa-

tion of these compounds as anticancer agents and the applica-

tion of THIQ-based steroidomimetics to alternate therapeutic

targets.

Tubulin assays: Bovine brain tubulin, prepared as described previ-

ously,^[19]was used in studies presented herein. Assembly IC₅₀values

were determined as described in detail elsewhere.^[20]Briefly,

1.0 mgmL^ꢁ1(10 mm) tubulin was pre-incubated without GTP with

varying compound concentrations for 15 min at 308C. Reaction

mixtures were placed on ice, and GTP (0.4 mm final concentration)

was added. The reaction mixtures were transferred to cuvettes,

held at 08C in a recording spectrophotometer. Baselines were es-

tablished at 08C, and increase in turbidity was followed for 20 min

following a rapid (<30 s) jump to 308C. Compound concentrations

required to decrease the turbidity increase by 50% were deter-

mined. The method for measuring inhibition of the binding of

[³H]colchicine to tubulin was described in detail previously.^[21]Reac-

tion mixtures contained 0.1 mgmL^ꢁ1(1.0 mm) tubulin, 5.0 mm

[³H]colchicine, and potential inhibitor at 5.0 mm. Compounds were

compared with CA-4, a particularly potent inhibitor of the binding

of colchicine to tubulin.^[22]Reaction mixtures were incubated for

10 min at 378C, a time point at which the binding of colchicine in

control reaction mixtures is generally 40–60% complete. A mini-

mum of two experiments were performed with each compound.

Experimental Section

Biology

In vitro studies, cell lines: DU-145 (brain metastasis carcinoma of the

prostate) and MDA-MB-231 (metastatic pleural effusion of breast

adenocarcinoma) established human cell lines were obtained from

ATCC Global Bioresource Center. Cells were maintained in a 5%

CO₂humidified atmosphere at 378C in RPMI-1640 medium, supple-

mented with 10% fetal bovine serum, penicillin (100 UmL^ꢁ1), and

streptomycin (0.1 mgmL^ꢁ1). MCF-7 (estrogen-receptor-positive)

breast cancer cells were obtained from the ATCC (LGC Promochem)

and MCF-7_Doxcells were kindly donated by Dr. G. L. Scheffer (De-

partment of Pathology, Free University Hospital, Amsterdam, Neth-

erlands). Cells were maintained in a 5% CO₂humidified atmos-

phere at 378C in DMEM containing phenol red, supplemented

In vivo studies: Female NCr-nude mice, 4–6 weeks of age (acquired

from Harlan Labs), were fed ad libitum water and an autoclaved

standard rodent diet consisting of 18% protein, 5% fat, 5% fiber,

8% ash, and 3% minerals. Mice were housed in isolators on a 12 h

life cycle at 228C and 40–60% humidity. Animal care was in ac-

cordance with IPSEN institutional guidelines. Tumour cells (6ꢁ10⁶

cells per animal) were implanted subcutaneously into the left flank.

Multiple myeloma cancer cells were implanted with an equal

volume of Matrigel to increase take rate. Tumours were monitored

initially twice weekly, and then daily as the neoplasms reached the

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desired size, ~100 mm³(100 mg). When the tumours attained this

predetermined size, the animals were randomised into three

groups with six animals per group. Estimated tumour weight (TW)

was calculated according to the formula: TW(mg)=(w²ꢁl)/2, in

which w=width and l=length (mm) of the multiple myeloma

tumour.

2-Benzyloxy-1-methoxy-4-((E)-2-nitrobut-1-enyl)benzene

(8b):

Method as for 8a using compound 7 (24.23 g, 100 mmol) and am-

monium acetate (7.73 g, 100 mmol) in 1-nitropropane (90 mL, 1.01

mol) at 1608C for 22 h. Crystallisation from hot EtOH afforded com-

pound 8b as a yellow powder (14.07 g, 44%); mp: 97–998C;

¹H NMR (270 MHz, CDCl₃): d=1.14 (3H, t, J=7.3 Hz), 2.71 (2H, q,

J=7.4 Hz), 3.93 (3H, s), 5.19 (2H, s), 6.91 (1H, d, J=1.9 Hz), 6.94

(1H, d, J=8.5 Hz), 7.05 (1H, dd, J=8.4, 1.9 Hz), 7.25–7.48 (5H, m),

7.91 ppm (1H, s); LC–MS (ES+): m/z 314.2 [M+H]⁺.

(ꢀ)-2-Benzyloxy-1-methoxy-4-(2-nitropropyl)benzene (9a): Finely

powdered NaBH₄(1.52 g, 40.2 mmol) was covered with EtOH

(20 mL) and a solution of compound 8a (6.0 g, 20.1 mmol) in THF

(40 mL) was added at 08C over 0.5 h. The reaction mixture was

stirred at 08C for 1 h and at room temperature for 0.5 h. HCl (2m,

20 mL) was added very carefully and the reaction mixture was

then extracted with EtOAc (3ꢁ100 mL). The combined organics

were washed with H₂O (60 mL) and brine (60 mL), then dried

(MgSO₄) and evaporated. Flash column chromatography (hexane/

EtOAc 4:1) afforded compound 9a as a pale-green solid (3.35 g,

55%); ¹H NMR (270 MHz, CDCl₃): d=1.44 (3H, d, J=6.7 Hz), 2.87

(1H, dd, J=14.1, 6.9 Hz), 3.19 (1H, dd, J=14.1, 7.4 Hz), 3.85 (3H, s),

4.65 (1H, sept, J=6.9 Hz), 5.12 (2H, s), 6.65–6.71 (2H, m), 6.81 (1H,

d, J=8.2 Hz), 7.25–7.43 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=18.7, 40.8, 56.1, 71.2, 84.6, 112.0, 115.2, 121.9, 127.5, 127.9,

128.0, 128.7, 137.0, 148.1, 149.1 ppm; LC–MS (APCIꢁ): m/z 300.01

[MꢁH]^ꢁ.

Chemistry

All chemicals were either purchased from Aldrich Chemical Co. (Gil-

lingham, UK) or Alfa Aesar (Heysham, UK). Organic solvents of A.R.

grade were supplied by Fisher Scientific (Loughborough, UK) and

used as supplied. CH₃Cl, CH₂Cl₂, DMA and THF were purchased

from Aldrich and stored under a positive pressure of N₂after use.

Sulfamoyl chloride was prepared by an adaptation of the method

of Appel and Berger^[23]and was stored in the refrigerator under

positive pressure of N₂as a solution in toluene as described by

Woo et al.^[24]An appropriate volume of this solution was freshly

concentrated in vacuo immediately before use. Reactions were car-

ried out at room temperature unless stated otherwise. Compounds

23 and 24a were prepared according to literature procedure.^[7]

Thin-layer chromatography (TLC) was performed on precoated alu-

minum plates (Merck, silica gel 60 F₂₅₄). Product spots were visual-

ised either by UV irradiation at l 254 nm or by staining with either

alkaline KMnO₄solution or 5% dodecamolybdophosphoric acid in

EtOH, followed by heating. All final compounds of type 5 and 6

were synthesised as racemic mixtures. Separation of enantiomers

was not pursued. Flash column chromatography was performed

using gradient elution (solvents indicated in text) on either pre-

packed columns (Isolute) on a Flashmaster II system (Biotage, Up-

psala, Sweden) or on a CombiFlash R_fAutomated Flash Chroma-

tography System (Teledyne Isco, Lincoln, NE, USA) with RediSep R_f

(ꢀ)-2-Benzyloxy-1-methoxy-4-(2-nitrobutyl)benzene

(9b):

Method as for 9a using compound 8b (13.95 g, 44.5 mmol) and

finely powdered NaBH₄(3.38 g, 89.3 mmol) in EtOH (40 mL) and

THF (160 mL) at 08C over 2 h via dropping funnel, at 08C for 4 h

and at room temperature for 60 h. Flash column chromatography

(hexane/EtOAc 9:1) afforded compound 9b as a yellow solid

(8.83 g, 62%); mp: 62–648C; ¹H NMR (270 MHz, CDCl₃): d=0.91

(3H, t, J=7.4 Hz), 1.62–1.79 (1H, m), 1.81–2.00 (1H, m), 2.88 (1H,

dd, J=14.3, 6.0 Hz), 3.12 (1H, dd, J=14.3, 8.3 Hz), 3.84 (3H, s),

4.42–4.55 (1H, m), 5.11 (2H, s), 6.65 (1H, d, J=1.9 Hz), 6.69 (1H,

dd, J=8.2, 1.9 Hz), 6.80 (1H, d, J=8.0 Hz), 7.25–7.45 ppm (5H, m);

LC–MS (ES+): m/z 338.3 [M+Na]⁺.

disposable flash columns. H and ¹³C NMR spectra were recorded

1

with either a Delta JMN-GX 270 (Jeol, Peabody, MA, USA) at 270

and 67.5 MHz, respectively, or a Mercury VX 400 NMR spectrometer

(Varian, Paolo Alto, CA, USA) at 400 and 100 MHz, respectively.

Chemical shifts (d) are reported in ppm relative to tetramethylsi-

lane (TMS) as internal standard. Coupling constants (J) are recorded

to the nearest 0.1 Hz. Mass spectra were recorded at the Mass

Spectrometry Service Centre, University of Bath (UK). FAB-MS was

carried out using m-nitrobenzyl alcohol (NBA) as the matrix. Melt-

ing points were determined using a Stuart SMP3 or a Stanford re-

search systems Optimelt MPA100 melting point apparatus (Stan-

ford Research Systems, Sunnyvale, CA, USA), and are uncorrected.

All compounds were ꢂ98% pure by reversed-phase HPLC carried

out with CH₃CN/H₂O or MeOH/H₂O (Sunfire C₁₈reversed-phase

column, 4.6ꢁ150 mm, 3.5 mm pore size).

(ꢀ)-1-(3-Benzyloxy-4-methoxyphenyl)propan-2-amine

(10a):

Raney Ni (50% slurry in H₂O, 3.0 g) was washed in presence of

a magnetic stirring bar with MeOH (3ꢁ5 mL). Compound 9a

(3.05 g, 10.1 mmol) in MeOH (70 mL) was then introduced, and the

reaction mixture was cooled to 08C. N₂H₄·H₂O (2.53 g, 50.5 mmol)

was added in a dropwise manner at which stage the reaction was

brought to 408C for 18 h. After cooling to room temperature the

reaction mixture was filtered through Celite, washed with MeOH

(4ꢁ50 mL) and concentrated in vacuo. Flash column chromatogra-

phy (EtOAc/MeOH gradient) afforded compound 10a as a pale-

1

yellow oil (2.074 g, 76%); H NMR (270 MHz, CDCl₃): d=1.04 (3H,

2-Benzyloxy-1-methoxy-4-((E)-2-nitroprop-1-enyl)benzene (8a):

Compound

d, J=6.4 Hz), 2.36 (1H, dd, J=13.3, 8.2 Hz), 2.58 (1H, dd, J=13.3,

5.2 Hz), 2.98–3.10 (1H, m), 3.86 (3H, s), 5.13 (2H, s), 6.67–6.83 (3H,

m), 7.25–7.43 ppm (5H, m); LC–MS (ES+): m/z 272.19 [M+H]⁺.

7 (8.0 g, 33.1 mmol), ammonium acetate (2.55 g,

33.1 mmol) and nitroethane (120 mL, 1.67 mol) were stirred at

1208C for 22 h. The reaction mixture was cooled to room tempera-

ture and concentrated in vacuo. The residue was dissolved in

EtOAc (200 mL), washed with H₂O (40 mL) and brine (2ꢁ40 mL),

then dried (MgSO₄), filtered and concentrated in vacuo. Crystallisa-

tion from hot EtOH afforded compound 8a as yellow crystals

(ꢀ)-N-(1-(3-Benzyloxy-4-methoxyphenyl)propan-2-yl)acetamide

(11a): Compound 10a (2.07 g, 7.6 mmol) was dissolved in CH₂Cl₂

(20 mL) and Et₃N (1.6 mL, 11.4 mmol). Ac₂O was then added drop-

wise at 08C. The reaction mixture was stirred at 08C for 1 h and at

room temperature for 23 h. H₂O (30 mL) was added carefully and

the mixture extracted with CH₂Cl₂(4ꢁ30 mL). The combined or-

ganics were washed with brine (30 mL), then dried (MgSO₄), fil-

tered and concentrated in vacuo to afford compound 11 a as

1

(6.19 g, 63%); mp: 102–1048C; H NMR (270 MHz, CDCl₃): d=2.27

(3H, s), 3.94 (3H, s), 5.19 (2H, s), 6.91 (1H, d, J=2.0 Hz), 6.94 (1H,

d, J=8.4 Hz), 7.05 (1H, dd, J=8.4, 2.0 Hz), 7.30–7.43 (4H, m),

7.97 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=14.0, 56.2, 71.3,

111.7, 115.8, 124.9, 124.9, 127.2, 128.2, 128.8, 133.8, 136.7, 145.9,

148.0, 151.5 ppm; LC–MS (APCIꢁ): m/z 297.93 [MꢁH]^ꢁ.

1

a white powder (2.268 g, 95%); mp: 139–1428C; H NMR (270 MHz,

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CDCl₃): d=0.99 (3H, d, J=6.7 Hz), 1.91 (3H, s), 2.57 (1H, dd, J=

13.6, 7.2 Hz), 2.70 (1H, dd, J=13.6, 5.7 Hz), 3.85 (3H, s), 4.08–4.22

(1H, m), 5.12 (2H, s), 5.17–5.23 (1H, m), 6.68–6.71 (2H, m), 6.79–

6.82 (1H, m), 7.24–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=19.9, 23.6, 41.8, 46.1, 56.1, 71.1, 111.8, 115.6, 122.2, 127.4, 127.9,

128.6, 130.4, 137.2, 147.9, 148.5, 169.3 ppm; LC–MS (APCIꢁ): m/z

312.29 [MꢁH]^ꢁ.

(ꢀ)-N-(1-(3-(Benzyloxy)-4-methoxyphenyl)butan-2-yl)acetamide

(11b): Method as for 10a using compound 9b (7.88 g, 25.0 mmol),

Raney Ni (50% slurry in H₂O, 3.82 g) and N₂H₄·H₂O (6.30 g,

126 mmol) in MeOH (100 mL) were reacted at 08C for 1 h and at

508C for 7 h as described for the synthesis of 10a. The crude

amine 10b, a brown–green oil (7.72 g), was used without further

purification. Acylation was then carried out as described for the

synthesis of 11 a with 10b (7.41 g, max. 24.0 mmol), Et₃N (3.68 g,

36.4 mmol) and Ac₂O (2.96 g, 29.0 mmol) in CH₂Cl₂(80 mL) at 08C

for 4 h. The work-up, carried out using HCl (1m, 50 mL), CH₂Cl₂(2ꢁ

100 mL) and brine (80 mL), afforded compound 11 b as a beige

solid (8.73 g, 99%); ¹H NMR (270 MHz, CDCl₃): d=0.83 (3H, t, J=

7.4 Hz), 1.09–1.27 (1H, m), 1.32–1.50 (1H, m), 1.87 (3H, s), 2.64 (2H,

d, J=6.3 Hz), 3.85 (3H, s), 3.89–4.07 (1H, m), 5.08 (1H, d, br, J=

8.8 Hz), 5.13 (2H, s), 6.63–6.72 (2H, m), 6.77–6.82 (1H, m), 7.24–

7.44 ppm (5H, m); LC–MS (ES+): m/z 328.2 [M+H]⁺.

15.6 Hz), 4.03 (1H, d, J=15.6 Hz), 5.09 (2H, s), 6.53 (1H, s), 6.56

(1H, s), 7.23–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

22.6, 36.8, 48.4, 49.4, 56.2, 71.2, 109.5, 114.8, 126.8, 127.4, 127.8,

128.1, 128.6, 137.4, 146.6, 148.0 ppm; LC–MS (ES+): m/z 284.13

[M+H]⁺.

(ꢀ)-3-Ethyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquino-

line (13b): Compound 12b (6.281 g, 18.5 mmol) and KOH (10.14 g,

181 mmol) in EtOH (69 mL) and H₂O (23 mL) were reacted at

1208C for 88 h following the method described for the synthesis of

13a. A further aliquot of KOH (10.12 g, 180 mmol) in H₂O (23 mL)

was then added and heating was continued at 1408C for a further

80 h. Flash column chromatography (EtOAc and 0.5% Et₃N to

EtOAc/MeOH 4:1 and 0.5% Et₃N) afforded 13b as a beige solid

(4.23 g, 76%); mp: 83–858C; ¹H NMR (270 MHz, CDCl₃): d=0.98

(3H, t, J=7.4 Hz), 1.39–1.63 (2H, m), 1.72 (1H, s, br), 2.34 (1H, dd,

J=16.0, 10.2 Hz), 2.63 (1H, dd, J=15.8, 3.8 Hz), 2.65–2.78 (1H, m),

3.82 (3H, s), 3.93 (1H, d, J=15.7 Hz), 4.01 (1H, d, J=15.7 Hz), 5.09

(2H, s), 6.53 (1H, s), 6.58 (1H, s), 7.23–7.45 ppm (5H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=10.4, 29.5, 34.4, 48.3, 55.2, 56.0, 71.0, 109.3,

114.6, 126.6, 127.2, 127.7, 128.1, 128.4, 137.2, 146.5, 147.8 ppm;

LC–MS (ES+): m/z 298.3 [M+H]⁺.

(ꢀ)-6-Hydroxy-7-methoxy-3-methyl-1,2,3,4-tetrahydroisoquino-

line (14a): Pd/C (10%, 2.02 g) was covered with MeOH (20 mL)

and then treated with 13a (20.68 g, 73.0 mmol) in MeOH (180 mL).

The reaction mixture was degassed then stirred under an atmos-

phere of H₂at room temperature for 24 h. The mixture was filtered

through Celite which was washed with hot MeOH (10ꢁ20 mL). The

filtrate was evaporated to afford the desired product 14a as

a white solid (7.90 g, 56%); mp: 206–2098C; ¹H NMR (270 MHz,

CD₃OD): d=1.24 (3H, d, J=6.3 Hz), 2.44 (1H, dd, J=16.2, 10.7 Hz),

2.66 (1H, dd, J=16.3, 3.9 Hz), 2.86–3.02 (1H, m), 3.82 and 3.82 (3H,

2s), 3.89 (1H, d, J=15.4 Hz), 3.97 (1H, d, J=15.7 Hz), 6.53 (1H, s,

CH), 6.61 ppm (1H, s, CH); LC–MS (ES+): m/z 194.0 [M+H]⁺.

(ꢀ)-2-Acetyl-6-benzyloxy-7-methoxy-3-methyl-1,2,3,4-tetrahy-

droisoquinoline (12a): Compound 11 a (2.21 g, 7.04 mmol) was

treated with paraformaldehyde (6.32 g, 210 mmol) and p-TsOH

(120 mg, 0.64 mmol) in toluene (55 mL) at 1208C for 22 h. The re-

action mixture was cooled to room temperature, filtered and

evaporated. EtOAc (60 mL) was added, and the organic layer was

washed with H₂O (3ꢁ50 mL), brine (50 mL) then dried (MgSO₄) and

evaporated to afford compound 12a as a colourless oil (2.15 g,

1

94%); H NMR (270 MHz, CDCl₃): d=1.04 and 1.12 (3H, 2d, J=7.2

and 6.7 Hz), 2.14 and 2.17 (3H, 2 s), 2.38–2.51 (1H, m), 2.89–3.06

(1H, m), 3.84 and 3.85 (3H, 2 s), 4.06–4.60 (2H, m), 4.96–5.14 (1H,

m), 5.08 and 5.10 (2H, 2s), 6.61 and 6.64 (1H, 2s), 6.62 and 6.67

(1H, 2s), 7.28–7.44 ppm (5H, m); LC–MS (ES+): m/z 348.19 [M+

Na]⁺.

(ꢀ)-7-Methoxy-3-methyl-6-(triisopropylsilyloxy)-1,2,3,4-tetrahy-

dro-isoquinoline (15): 14a (7.904 g, 40.9 mmol) and imidazole

(8.181 g, 121 mmol) in CH₂Cl₂(200 mL) were treated with chlorotrii-

sopropylsilane (9.496 g, 49.3 mmol) in a dropwise manner. After

22 h stirring at room temperature H₂O (400 mL) was added, and

the layers separated. The aqueous layer was extracted with CH₂Cl₂

(3ꢁ200 mL) and the combined organics were then washed with

brine (200 mL), dried (NaCl), and evaporated. Flash column chro-

matography (hexane/EtOAc 4:1 to 1:1 to 1:1 and 2% Et₃N) afforded

15 as a beige solid (6.81 g, 47%); ¹H NMR (270 MHz, CDCl₃): d=

1.06 (18H, d, J=6.9 Hz), 1.11–1.31 (3H, m), 1.19 (3H, d, J=6.0 Hz),

1.56 (1H, s, br), 2.35 (1H, dd, J=16.0, 10.7 Hz), 2.61 (1H, dd, J=

16.1, 3.7 Hz), 2.86–3.02 (1H, m), 3.72 (3H, s), 3.90 (1H, d, J=15.7),

4.02 (1H, d, J=16.0 Hz), 6.45 (1H, s), 6.54 ppm (1H, s); HRMS

(ES+): m/z found 350.2514, C₂₀H₃₆NO₂Si⁺[M+H]⁺requires

350.2510.

(ꢀ)-2-Acetyl-6-benzyloxy-3-ethyl-7-methoxy-1,2,3,4-tetrahydroi-

soquinoline (12b): 11 b (8.70 g, 23.0 mmol), paraformaldehyde

(4.25 g, 141 mmol) and p-TsOH (220 mg, 1.2 mmol) in toluene

(140 mL) were reacted at 1208C for 16 h as described for the syn-

thesis of 12a. The reaction was worked-up with H₂O (100 mL),

EtOAc (3ꢁ100 mL), H₂O (50 mL) and brine (2ꢁ20 mL) to afford

compound 12b as a viscous orange oil (6.33 g, 81%); ¹H NMR

(270 MHz, CDCl₃): d=0.86 (3H, t, J=7.5 Hz), 1.23–1.64 (2H, m),

2.16 (3H, s), 2.44–2.61 (1H, m), 2.80–3.06 (1H, m), 3.82 (3H, s),

3.92–4.03 (1H, m), 4.33 (1H, d, J=16.2 Hz), 4.55 (1H, d, J=16.2 Hz),

5.08 (2H, s), 6.53–6.64 (2H, m), 7.18–7.44 ppm (5H, m); HRMS

+

(ES+): m/z found 340.1903, C₂₁H₂₆NO₃

[M+H]⁺requires

340.1907.

(ꢀ)-6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-3-methyl-

1,2,3,4-tetrahydroisoquinoline (16a): Compound 13a (300 mg,

1.1 mmol) was treated with 3-methoxybenzyl chloride (0.18 mL,

1.3 mmol) and Et₃N (0.30 mL, 2.1 mmol) in EtOH (3.0 mL) at 1308C

for 1.5 h under microwave irradiation. The mixture was then

evaporated and the residues dissolved in EtOAc (30 mL). The solu-

tion was then washed with brine (30 mL), dried, and evaporated.

Flash column chromatography (hexane/EtOAc gradient) afforded

16a as a colourless oil (357 mg, 84%); ¹H NMR (270 MHz, CDCl₃):

d=1.12 (3H, d, J=6.4 Hz), 2.47 (1H, dd, J=16.1, 5.7 Hz), 2.86 (1H,

dd, J=16.1, 4.9 Hz), 3.01–3.11 (1H, m), 3.55 (2H, t, J=13.4 Hz),

3.76–3.81 (2H, m), 3.80 (6H, s), 5.10 (2H, s), 6.47 (1H, s), 6.60 (1H,

(ꢀ)-6-Benzyloxy-7-methoxy-3-methyl-1,2,3,4-tetrahydroisoquino-

line (13a): Compound 12a (3.16 g, 9.7 mmol) was treated with

KOH (5.44 g, 97.0 mmol) in EtOH (36 mL) and H₂O (12 mL) at 1208C

for 66 h. The reaction mixture was then cooled to room tempera-

ture and concentrated. H₂O (30 mL) was then added, and the mix-

ture was then extracted with CH₂Cl₂(3ꢁ50 mL). The combined or-

ganics were washed with brine (50 mL), then dried (MgSO₄) and

evaporated to afford compound 13a as a beige solid (2.51 g,

91%); mp: 110–1128C; ¹H NMR (270 MHz, CDCl₃): d=1.20 (3H, d,

J=6.4 Hz), 1.78 (1H, s, br), 2.35 (1H, dd, J=15.8, 10.6 Hz), 2.60 (1H,

dd, J=15.8, 3.7 Hz), 2.88–3.01 (1H, m), 3.82 (3H, s), 3.93 (1H, d, J=

ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2014, 9, 350 – 370 359

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+

s), 6.79 (1H, ddd, J=8.2, 2.5, 1.0 Hz), 6.94–6.97 (2H, m), 7.15–

7.45 ppm (6H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.3, 35.0, 51.5,

52.3, 55.3, 56.1, 57.2, 71.2, 110.0, 112.5, 114.4, 114.6, 121.3, 125.8,

127.0, 127.4, 127.8, 128.6, 129.3, 137.5, 141.4, 146.7, 147.9,

159.8 ppm; LC–MS (ES+): m/z 404.25 [M+H]⁺.

7.46 ppm (6H, m); HRMS (ES+): m/z found 432.2175, C₂₇H₃₀NO₄

[M+H]⁺requires 432.2169. The amide (432 mg, 1.0 mmol) was

then reacted with LiAlH₄(117 mg, 3.0 mmol) in THF (4.0 mL) at 08C

for 0.5 h, then at room temperature for 18 h. Flash column chroma-

tography (hexane to hexane/EtOAc 3:2) afforded 16d as a colour-

less sticky oil (314 mg, 74%); ¹H NMR (270 MHz, CDCl₃): d=1.12

(3H, d, J=6.3 Hz), 1.40 (3H, t, J=6.9 Hz), 2.47 (1H, dd, J=16.1,

5.9 Hz), 2.86 (1H, dd, J=16.0, 4.7 Hz), 3.06 (1H, sext, J=6.1 Hz),

3.47–3.68 (3H, m), 3.74–3.83 (1H, m), 3.79 (3H, s), 4.02 (2H, q, J=

7.0 Hz), 5.10 (2H, s), 6.47 (1H, s), 6.60 (1H, s), 6.75–6.84 (1H, m),

6.88–6.97 (2H, m), 7.22 (1H, t, J=8.1 Hz), 7.24–7.47 ppm (5H, m);

(ꢀ)-6-Benzyloxy-3-ethyl-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (16b): Compound 13b (297 mg,

1.0 mmol) was treated with 3-methoxybenzyl bromide (222 mg,

1.1 mmol) and DIPEA (263 mg, 2.0 mmol) in DMF (3.0 mL) at 808C

for 18 h. After cooling to room temperature the reaction mixture

was evaporated then treated with H₂O (100 mL) and NH₄Cl (satu-

rated, 10 mL) before extracting into EtOAc (2ꢁ100 mL). The com-

bined organics were dried (NaCl), and evaporated. Flash column

chromatography (hexane to hexane/EtOAc 7:3) afforded com-

HRMS (ES+): m/z found 418.2379, C₂₇H₃₂NO₃[M+H]⁺requires

+

418.2377.

(ꢀ)-6-Benzyloxy-2-(3,5-dimethoxybenzyl)-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (16e): Method as for 16a using

compound 13a (300 mg, 1.1 mmol), 3,5-dimethoxybenzyl bromide

(294 mg, 1.3 mmol) and Et₃N (0.30 mL, 2.1 mmol) in EtOH (3.0 mL)

in the microwave at 1308C for 2.5 h. Flash column chromatography

(hexane/EtOAc gradient) afforded 16e as a colourless oil (222 mg,

46%); ¹H NMR (270 MHz, CDCl₃): d=1.10 (3H, d, J=6.4 Hz), 2.45

(1H, dd, J=15.9, 5.8 Hz), 2.86 (1H, dd, J=15.9, 4.7 Hz), 3.02–3.11

(1H, m), 3.45–3.71 (4H, m), 3.77 (6H, s), 3.79 (3H, s), 5.09 (2H, s),

6.35 (1H, t, J=2.2 Hz), 6.48 (1H, s), 6.54 (2H, d, J=2.2 Hz), 6.60

(1H, s), 7.28–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

15.2, 34.9, 51.5, 52.2, 55.4, 56.1, 57.4, 71.2, 99.0, 106.7, 110.0, 114.5,

125.8, 126.9, 127.4, 127.8, 128.6, 137.5, 142.2, 146.7, 147.9,

160.8 ppm; LC–MS (ES+): m/z 434.36 [M+H]⁺; HRMS (ES+): m/z

1

pound 16b as a pale-yellow oil (323 mg, 77%); H NMR (270 MHz,

CDCl₃): d=1.02 (3H, t, J=7.4 Hz), 1.46 (1H, sept, J=7.2 Hz), 1.73

(1H, sept, J=6.8 Hz), 2.55 (1H, dd, J=16.2, 6.1 Hz), 2.82 (1H, dd,

J=16.2, 5.0 Hz), 2.85–2.98 (1H, m), 3.61–3.77 (4H, m), 3.84 (6H, s),

5.16 (2H, s), 6.52 (1H, s), 6.67 (1H, s), 6.81–6.87 (1H, m), 6.95–7.02

(2H, m), 7.23–7.52 (5H, m), 7.27 ppm (1H, t, J=6.9); HRMS (ES+):

m/z found 418.2381, C₂₇H₃₂NO₃[M+H]⁺requires 418.2377.

+

(ꢀ)-6-Benzyloxy-2-(3-ethylbenzyl)-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (16c): Compound 13a (425 mg, 1.5 mmol)

and 3-ethylbenzoic acid (339 mg, 2.25 mmol) were dissolved in

CH₂Cl₂(4.5 mL) and THF (1.5 mL). EDCI (578 mg, 3.0 mmol) was

then added, and the reaction mixture was stirred at room tempera-

ture for 20 h. The reaction mixture was then diluted with HCl (1m,

50 mL), extracted with CH₂Cl₂/EtOAc (~9:1, 2ꢁ50 mL) and the com-

bined organics were dried and evaporated. Flash column chroma-

tography (hexane to hexane/EtOAc 7:3) afforded the desired amide

as a colourless sticky foam (534 mg, 85%); ¹H NMR (270 MHz,

CDCl₃): d=1.14 (3H, s, br), 1.24 (3H, t, J=7.6 Hz), 2.36 and 2.41

(1H, 2 s, br), 2.67 (2H, q, J=7.5 Hz), 3.04 and 3.08 (1H, 2 s, br), 3.85

(3H, s, br), 4.25, 4.30 and 4.43 (2H, 3 s, br), 5.06–5.44 (1H, m), 5.11

(2H, s), 6.44 and 6.68 (1H, 2 s, br), 6.63 (1H, s, br), 7.16–7.47 ppm

found 434.2330, C₂₇H₃₂NO₄[M+H]⁺requires 434.2326.

+

(ꢀ)-6-Benzyloxy-2-(2,5-dimethoxybenzyl)-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (16 f): Method as for 16b using

compound 13a (338 mg, 1.2 mmol), 2,5-dimethoxybenzyl chloride

(279 mg, 1.5 mmol) and DIPEA (314 mg, 2.4 mmol) in DMF (3.6 mL)

at 808C for 20 h. Flash column chromatography (hexane to

hexane/EtOAc 1:1) afforded 16 f as an orange oil (395 mg, 76%);

¹H NMR (270 MHz, CDCl₃): d=1.14 (3H, d, J=6.3 Hz), 2.48 (1H, dd,

J=16.3, 6.0 Hz), 2.86 (1H, dd, J=16.1, 4.8 Hz), 3.11 (1H, sext, J=

6.1 Hz), 3.58–3.77 (4H, m), 3.76 (3H, s), 3.77 (3H, s), 3.81 (3H, s),

5.11 (2H, s), 6.50 (1H, s), 6.61 (1H, s), 6.74 (1H, dd, J=8.8, 3.0 Hz),

6.80 (1H, d, J=8.8 Hz), 7.07 (1H, d, J=2.8 Hz), 7.24–7.47 ppm (5H,

m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.5, 34.5, 50.0, 51.4, 52.4, 55.7,

56.0, 56.0, 71.0, 109.9, 111.3, 111.9, 114.4, 116.0, 125.8, 127.0, 127.2,

(9H, m); HRMS (ES+): m/z found 416.2223, C₂₇H₃₀NO₃[M+H]⁺re-

+

quires 416.2220. A suspension of LiAlH₄(114 mg, 3.0 mmol) in THF

(1.0 mL) was then treated with a solution of the amide (250 mg,

0.6 mmol) in THF (3.0 mL) in a dropwise manner. After 0.5 h the re-

action mixture was carefully diluted with EtOAc (100 mL), then left

to stand for 0.5 h. The reaction mixture was then filtered through

Celite, the residues washed with EtOAc (4ꢁ10 mL), and the com-

bined filtrates were evaporated to afford compound 16c as a col-

127.7, 128.4, 128.9, 137.3, 146.5, 147.7, 151.9, 153.6 ppm; HRMS

+

(ES+): m/z found 434.2332, C₂₇H₃₂NO₄

[M+H]⁺requires

1

ourless oil (240 mg, 99%); H NMR (270 MHz, CDCl₃): d=1.13 (3H,

434.2326.

d, J=6.6 Hz), 1.23 (3H, t, J=7.6 Hz), 2.48 (1H, dd, J=16.1, 5.9 Hz),

2.64 (2H, q, J=7.6 Hz), 2.86 (1H, dd, J=16.0, 4.7 Hz), 3.06 (1H,

sext, J=6.1 Hz), 3.44–3.71 (3H, m), 3.73–3.88 (1H, m), 3.79 (3H, s),

5.10 (2H, s), 6.47 (1H, s), 6.60 (1H, s), 7.06–7.51 ppm (9H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=15.2, 15.6, 28.8, 34.8, 51.4, 52.1,

56.0, 57.1, 71.1, 109.8, 114.4, 125.7, 126.2, 126.4, 126.8, 127.2, 127.7,

128.4, 128.5, 137.3, 139.3, 144.2, 146.6, 147.8 ppm; HRMS (ES+): m/

(ꢀ)-6-Benzyloxy-2-(2-fluoro-5-methoxybenzyl)-7-methoxy-3-

methyl-1,2,3,4-tetrahydroisoquinoline (16g): Method as for 16b

using compound 13a (339 mg, 1.2 mmol), 2-fluoro-5-methoxyben-

zyl bromide (401 mg, 74 wt%, 1.35 mmol) and DIPEA (314 mg,

2.4 mmol) in DMF (3.6 mL) at 808C for 20 h. Flash column chroma-

tography (hexane to hexane/EtOAc 3:2) afforded 16g as an orange

oil (363 mg, 71%); ¹H NMR (270 MHz, CDCl₃): d=1.14 (3H, d, J=

6.3 Hz), 2.47 (1H, dd, J=16.2, 6.1 Hz), 2.86 (1H, dd, J=16.2, 5.0 Hz),

3.09 (1H, sext, J=6.1 Hz), 3.54–3.68 (3H, m), 3.69–3.81 (1H, m),

3.75 (3H, s), 3.80 (3H, s), 5.09 (2H, s), 6.49 (1H, s), 6.59 (1H, s), 6.72

(1H, dt, J=9.1, 3.7 Hz), 6.94 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=5.9,

3.2 Hz), 7.23–7.45 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

15.2, 34.8, 49.5 (d, J 1.5), 51.3, 52.4, 55.7, 56.0, 71.0, 109.8, 113.4 (d,

J 8.2), 114.4, 115.6 (dd, J 14.2, 9.5), 125.6, 126.5, 126.7, 127.0, 127.2,

127.7, 128.4, 137.3, 146.6, 147.8, 154.0, 155.6 ppm (d, J 2.1); LC–MS

(ES⁺): m/z 422.3 [M+H]⁺.

z found 402.2429, C₂₇H₃₂NO₂[M+H]⁺requires 402.2428.

+

(ꢀ)-6-Benzyloxy-2-(3-ethoxybenzyl)-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (16d): Method as for 16c using com-

pound 13a (424 mg, 1.5 mmol), 3-ethoxybenzoic acid (374 mg,

2.25 mmol) and EDCI (578 mg, 2.0 mmol) in CH₂Cl₂(4.5 mL) and

THF (1.5 mL) at room temperature for 20 h. Flash column chroma-

tography (hexane to hexane/EtOAc 1:1) afforded the desired amide

1

as a colourless sticky oil (608 mg, 94%); H NMR (270 MHz, CDCl₃):

d=1.06–1.28 (3H, m), 1.40 (3H, t, J=7.0 Hz), 2.30–2.53 (1H, m),

2.96–3.15 (1H, m), 3.85 (3H, s), 4.03 (2H, q, J=7.0 Hz), 4.17–4.37

(2H, m), 5.10 (2H, s), 6.36–6.74 (2H, m), 6.88–6.97 (3H, m), 7.23–

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(ꢀ)-6-Benzyloxy-7-methoxy-3-methyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (16h): Method as for 16a using

compound 13a (227 mg, 0.8 mmol), 3,4,5-trimethoxybenzyl chlo-

ride (208 mg, 0.96 mmol) and Et₃N (0.22 mL, 1.6 mmol) in EtOH

(3.0 mL) in the microwave at 1508C for 0.5 h. Flash column chro-

matography (hexane/EtOAc gradient) afforded compound 16h as

d=1.08 (18H, d, J=6.6 Hz), 1.13 (3H, d, J=6.6 Hz), 1.15–1.32 (3H,

m), 2.47 (1H, dd, J=16.0, 6.0 Hz), 2.86 (1H, dd, J=16.0, 4.9 Hz),

3.05 (1H, sext, J=6.1 Hz), 3.42–3.86 (4H, m), 3.69 (3H, s), 6.39 (1H,

s), 6.57 (1H, s), 7.20–7.41 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=12.9, 15.2, 17.9, 34.8, 51.5, 52.2, 55.5, 57.2, 110.0, 120.4, 125.7,

126.6, 126.8, 128.2, 129.0, 139.4, 143.7, 148.9 ppm; HRMS (ES+): m/

z found 440.2970, C₂₇H₄₂NO₂Si⁺[M+H]⁺requires 440.2980.

1

a colourless oil (151 mg, 40%); H NMR (270 MHz, CDCl₃): d=1.11

(3H, d, J=6.4 Hz), 2.46 (1H, dd, J=16.1, 5.7 Hz), 2.87 (1H, dd, J=

16.1, 4.8 Hz), 3.04–3.11 (1H, m), 3.46–3.75 (4H, m), 3.80 (3H, s), 3.84

(3H, s), 3.84 (6H, s), 5.10 (2H, s), 6.50 (1H, s), 6.60 (2H, s), 6.61 (1H,

s), 7.26–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.1,

34.8, 51.4, 52.0, 56.1, 56.2, 57.4, 61.0, 71.2, 105.4, 109.9, 114.4,

125.8, 126.8, 127.4, 127.8, 128.6, 135.4, 136.7, 146.7, 146.8, 147.9,

153.2 ppm; LC–MS (ES+): m/z 464.22 [M+H]⁺; HRMS (ES+): m/z

(ꢀ)-2-(2-Chlorobenzyl)-7-methoxy-3-methyl-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17d): Method as for 16b

using compound 15 (315 mg, 0.9 mmol), 2-chlorobenzyl bromide

(278 mg, 1.35 mmol) and DIPEA (234 mg, 1.8 mmol) in DMF

(2.5 mL) at 808C for 18 h. Flash column chromatography (hexane/

EtOAc 9:1 to 9:1 and 2% Et₃N) afforded 17d as a yellow wax

(328 mg, 76%); ¹H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=

6.6 Hz), 1.14 (3H, d, J=6.6 Hz), 1.16–1.32 (3H, m), 2.47 (1H, dd, J=

16.0, 5.8 Hz), 2.88 (1H, dd, J=16.1, 4.8 Hz), 3.12 (1H, sext, J=

6.1 Hz), 3.51–3.87 (4H, m), 3.70 (3H, s), 6.41 (1H, s), 6.57 (1H, s),

7.16 (1H, dt, J=7.4, 1.9 Hz), 7.22 (1H, dt, J=7.4, 1.8 Hz), 7.33 (1H,

dd, J=7.4, 1.9 Hz), 7.54 ppm (1H, dd, J=7.4, 1.9 Hz); ¹³C NMR

(67.5 MHz, CDCl₃): d=12.9, 15.3, 17.9, 34.7, 51.4, 52.8, 53.7, 55.5,

110.0, 120.4, 125.7, 126.6, 126.6, 128.5, 127.8, 129.3, 134.1, 137.1,

143.8, 148.9 ppm; HRMS (ES+): m/z found 474.2575,

C₂₇H₄₁ClNO₂Si⁺[M+H]⁺requires 474.2590.

found 464.2436, C₂₈H₃₄NO₅[M+H]⁺requires 464.2431.

+

(ꢀ)-6-Benzyloxy-3-ethyl-7-methoxy-2-(3,4,5-trimethoxybenzyl)-

tetrahydroisoquinoline (16i): Method as for 16b using compound

13b (297 mg, 1.0 mmol), 3,4,5-trimethoxybenzyl chloride (238 mg,

1.1 mmol) and DIPEA (264 mg, 2.0 mmol) in DMF (3.0 mL) at 808C

for 18 h. Flash column chromatography (hexane to hexane/EtOAc

1:1) afforded 16i as a pale-yellow oil (350 mg, 73%); ¹H NMR

(270 MHz, CDCl₃): d=0.97 (3H, t, J=7.0 Hz), 1.43 (1H, sept, J=

7.0 Hz), 1.67 (1H, sept, J=7.0 Hz), 2.42–2.58 (1H, m), 2.72–2.95 (2H,

m), 3.51–3.74 (4H, m), 3.80 (3H, s), 3.83 (6H, s), 3.88 (3H, s), 5.10

(2H, s), 6.45–6.56 (1H, m), 6.56–6.70 (3H, m), 7.24–7.52 ppm (5H,

(ꢀ)-7-Methoxy-3-methyl-2-(2-methylbenzyl)-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17e): Method as for 16b

using compound 15 (315 mg, 0.9 mmol), 2-methylbenzyl bromide

(251 mg, 1.35 mmol) and DIPEA (236 mg, 2.0 mmol) in DMF

(2.5 mL) at 808C for 18 h. Flash column chromatography (hexane/

EtOAc 9:1 to 9:1 and 2% Et₃N) afforded 17e as a yellow wax

(286 mg, 70%); ¹H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=

6.6 Hz), 1.13 (3H, d, J=6.3 Hz), 1.16–1.32 (3H, m), 2.35 (3H, s), 2.45

(1H, dd, J=16.0, 5.8 Hz), 2.86 (1H, dd, J=16.0, 4.7 Hz), 3.07 (1H,

sext, J=6.0 Hz), 3.42–3.65 (3H, m), 3.69 (3H, s), 3.75 (1H, d, J=

13.2 Hz), 6.39 (1H, s), 6.56 (1H, s), 7.09–7.21 (3H, m), 7.28–

7.36 ppm (1H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=12.9, 14.8, 17.9,

19.3, 34.8, 51.1, 52.6, 55.0, 55.5, 110.0, 120.4, 125.5, 125.8, 126.8,

129.7, 130.2, 137.3, 137.5, 143.6, 148.9 ppm; HRMS (ES+): m/z

found 454.3128, C₂₈H₄₄NO₂Si⁺[M+H]⁺requires 454.3136.

m); HRMS (ES+): m/z found 478.2593, C₂₉H₃₆NO₅[M+H]⁺re-

+

quires 478.2588.

(ꢀ)-7-Methoxy-2-(2-methoxybenzyl)-3-methyl-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17a): Method as for 16b

using compound 15 (524 mg, 1.5 mmol), 2-methoxybenzyl chloride

(282 mg, 1.8 mmol) and DIPEA (389 mg, 3.0 mmol) in DMF (4.5 mL)

at 808C for 18 h. Flash column chromatography (hexane/EtOAc 4:1

to 1:1) afforded 17a as a yellow wax (572 mg, 81%); ¹H NMR

(270 MHz, CDCl₃): d=1.07 (18H, d, J=6.9 Hz), 1.15 (3H, d, J=

6.6 Hz), 1.14–1.32 (3H, m), 2.48 (1H, dd, J=16.0, 6.3 Hz), 2.84 (1H,

dd, J=16.6, 4.3 Hz), 3.10 (1H, sext, J=6.2 Hz), 3.53–3.88 (4H, m),

3.70 (3H, s), 3.81 (3H, s), 6.41 (1H, s), 6.56 (1H, s), 6.85 (1H, d, J=

8.0 Hz), 6.92 (1H, t, J=7.4 Hz), 7.20 (1H, dd, J=7.7, 1.6 Hz),

7.42 ppm (1H, dd, J=7.4, 1.4 Hz); HRMS (ES+): m/z found

470.3076, C₂₈H₄₄NO₃Si⁺[M+H]⁺requires 470.3085.

(ꢀ)-7-Methoxy-3-methyl-2-(3-nitrobenzyl)-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17 f): Method as for 16b

using compound 15 (418 mg, 1.2 mmol), 3-nitrobenzyl chloride

(248 mg, 1.45 mmol) and DIPEA (310 mg, 2.4 mmol) in DMF

(3.6 mL) at 808C for 18 h. Flash column chromatography (hexane/

(ꢀ)-7-Methoxy-2-(4-methoxybenzyl)-3-methyl-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17b): Method as for 16b

using compound 15 (524 mg, 1.5 mmol), 4-methoxybenzyl bro-

mide (423 mg, 2.1 mmol) and DIPEA (391 mg, 3.0 mmol) in DMF

(4.5 mL) at 808C for 20 h. Flash column chromatography (hexane/

EtOAc 4:1 to 1:1) afforded compound 17b as a yellow wax

(587 mg, 83%); ¹H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=

6.6 Hz), 1.11 (3H, d, J=6.6 Hz), 1.13–1.31 (3H, m), 2.45 (1H, dd, J=

16.0, 6.1 Hz), 2.84 (1H, dd, J=16.0, 5.0 Hz), 3.03 (1H, sext, J=

5.9 Hz), 3.41–3.64 (3H, m), 3.69 (3H, s), 3.74 (1H, d, J=12.7 Hz),

3.79 (3H, s), 6.39 (1H, s), 6.55 (1H, s), 6.85 (2H, d, J=8.5 Hz),

7.27 ppm (2H, d, J=8.5 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=12.8,

15.2, 17.9, 34.4, 51.1, 52.1, 55.2, 55.5, 56.2, 110.0, 113.7, 114.8, 120.3,

130.3, 130.8, 149.0, 158.7 ppm; HRMS (ES+): m/z found 470.3084,

C₂₈H₄₄NO₃Si⁺[M+H]⁺requires 470.3085.

1

EtOAc 9:1) afforded 17 f as a yellow wax (409 mg, 70%); H NMR

(270 MHz, CDCl₃): d=1.07 (18H, d, J=6.9 Hz), 1.12 (3H, d, J=

6.6 Hz), 1.14–1.32 (3H, m), 2.47 (1H, dd, J=16.0, 6.1 Hz), 2.87 (1H,

dd, J=16.1, 4.8 Hz), 3.07 (1H, sext, J=6.1 Hz), 3.41–3.59 (2H, m),

3.65 (1H, d, J=14.0 Hz), 3.69 (3H, s), 3.84 (1H, d, J=13.8 Hz), 6.37

(1H, s), 6.57 (1H, s), 7.46 (1H, t, J=8.0 Hz), 7.72 (1H, d, J=7.7 Hz),

8.09 (1H, dd, J=8.2, 1.7 Hz), 8.23 ppm (1H, s); ¹³C NMR (67.5 MHz,

CDCl₃): d=12.9, 15.4, 17.9, 34.6, 51.5, 52.6, 55.5, 56.4, 109.9, 120.4,

122.0, 123.6, 125.5, 126.0, 129.1, 134.9, 142.2, 143.9, 148.4,

149.1 ppm; HRMS (ES+): m/z found 485.2813, C₂₇H₄₁N₂O₄Si⁺[M+

H]⁺requires 485.2830.

(ꢀ)-2-(3-Chlorobenzyl)-7-methoxy-3-methyl-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17g): Method as for 16b

using compound 15 (418 mg, 1.2 mmol), 3-chlorobenzyl bromide

(298 mg, 1.45 mmol) and DIPEA (311 mg, 2.4 mmol) in DMF

(3.6 mL) at 808C for 18 h. Flash column chromatography (hexane/

EtOAc 19:1 to 9:1) afforded 17g as a yellow wax (338 mg, 59%);

¹H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=6.6 Hz), 1.11 (3H, d,

(ꢀ)-2-Benzyl-7-methoxy-3-methyl-6-(triisopropylsilyloxy)-1,2,3,4-

tetrahydroisoquinoline (17c): Method as for 16b using com-

pound 15 (419 mg, 1.2 mmol), benzyl bromide (249 mg,

1.46 mmol) and DIPEA (391 mg, 3.0 mmol) in DMF (4.5 mL) at 808C

for 18 h. Flash column chromatography (hexane/EtOAc 9:1) afford-

1

ed 17c as an orange oil (361 mg, 68%); H NMR (270 MHz, CDCl₃):

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J=6.6 Hz), 1.14–1.32 (3H, m), 2.46 (1H, dd, J=16.0, 6.1 Hz), 2.85

(1H, dd, J=16.0, 5.0 Hz), 3.04 (1H, sext, J=6.1 Hz), 3.42–3.64 (3H,

m), 3.70 (3H, s), 3.75 (1H, d, J=13.2 Hz), 6.39 (1H, s), 6.56 (1H, s),

7.17–7.26 (3H, m), 7.37 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃):

d=12.9, 15.3, 17.9, 34.7, 51.6, 52.4, 55.5, 56.6, 110.0, 120.4, 125.6,

126.3, 127.0, 127.1, 128.9, 129.5, 134.2, 141.8, 143.9, 149.0 ppm;

HRMS (ES+): m/z found 474.2580, C₂₇H₄₁ClNO₂Si⁺[M+H]⁺requires

474.2590.

chromatography (hexane/EtOAc 19:1 to 9:1) afforded 17k as

a yellow wax (438 mg, 72%); ¹H NMR (270 MHz, CDCl₃): d=1.07

(18H, d, J=6.6 Hz), 1.11 (3H, d, J=6.3 Hz), 1.14–1.32 (3H, m), 2.46

(1H, dd, J=16.0, 5.8 Hz), 2.88 (1H, dd, J=16.0, 4.6 Hz), 3.11 (1H,

sext, J=6.1 Hz), 3.43–3.84 (4H, m), 3.71 (3H, s), 3.76 (3H, s), 6.41

(1H, s), 6.57 (1H, s), 6.71 (1H, dd, J=8.8, 3.0 Hz), 7.13 (1H, d, J=

3.0 Hz), 7.22 ppm (1H, d, J=8.5 Hz); ¹³C NMR (67.5 MHz, CDCl₃):

d=12.9, 15.2, 17.9, 34.6, 51.5, 52.6, 53.8, 55.5, 55.5, 110.1, 113.5,

115.8, 120.5, 125.3, 125.7, 126.6, 129.9, 138.3, 143.8, 149.0,

158.4 ppm; HRMS (ES+): m/z found 504.2683, C₂₈H₄₃ClNO₃Si⁺[M+

H]⁺requires 504.2695.

(ꢀ)-2-(3-Acetylbenzyl)-7-methoxy-3-methyl-6-(triisopropylsily-

loxy)-1,2,3,4-tetrahydroisoquinoline (17h): Method as for 16b

using compound 15 (349 mg, 1.0 mmol), 3-acetylbenzyl bromide

(445 mg, 72 wt%, 1.5 mmol) and DIPEA (260 mg, 2.0 mmol) in DMF

(2.0 mL) at 808C for 18 h. Flash column chromatography (hexane/

EtOAc 9:1 to 9:1 and 2% Et₃N) afforded 17h as a yellow glass

(272 mg, 56%); ¹H NMR (270 MHz, CDCl₃): d=1.06 (18H, d, J=

6.9 Hz), 1.12 (3H, d, J=6.6 Hz), 1.15–1.32 (3H, m), 2.46 (1H, dd, J=

16.0, 6.1 Hz), 2.59 (3H, s), 2.86 (1H, dd, J=15.8, 4.8 Hz), 3.06 (1H,

sext, J=6.1 Hz), 3.41–3.65 (3H, m), 3.69 (3H, s), 3.83 (1H, d, J=

13.2 Hz), 6.37 (1H, s), 6.56 (1H, s), 7.40 (1H, t, J=7.6 Hz), 7.60 (1H,

d, J=7.5 Hz), 7.83 (1H, d, J=7.7 Hz), 7.92 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=12.9, 15.2, 17.9, 26.8, 34.7, 51.5, 52.3, 55.5,

56.9, 110.0, 120.4, 125.6, 126.3, 127.0, 128.5, 128.7, 133.8, 137.2,

140.2, 143.8, 149.0, 198.4 ppm; HRMS (ES+): m/z found 482.3089,

C₂₉H₄₄NO₃Si⁺[M+H]⁺requires 482.3085.

(ꢀ)-6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5a): Compound 17a (564 mg, 1.2 mmol)

was treated with TBAF (1m in THF, 1.44 mL, 1.44 mmol) in THF

(3.0 mL) at 08C for 0.5 h. MeOH (10 mL) was then added, and the

reaction mixture was evaporated. CH₂Cl₂(30 mL) was added, and

the reaction mixture was once more evaporated. Flash column

chromatography (hexane/EtOAc 4:1 to 1:1) afforded 5a as a pale-

yellow glass (362 mg, 96%); ¹H NMR (270 MHz, CDCl₃): d=1.17

(3H, d, J=6.6 Hz), 2.51 (1H, dd, J=16.2, 6.3 Hz), 2.88 (1H, dd, J=

16.0, 5.0 Hz), 3.14 (1H, sext, J=6.2 Hz), 3.51–3.87 (4H, m), 3.80 (3H,

s), 3.82 (3H, s), 5.12 (1H, s, br), 6.45 (1H, s), 6.63 (1H, s), 6.86 (1H,

d, J=8.3 Hz), 6.93 (1H, dt, J=7.4, 0.8 Hz), 7.23 (1H, dt, J=7.8,

1.6 Hz), 7.44 ppm (1H, d, J=7.4 Hz); ¹³C NMR (67.5 MHz, CDCl₃):

d=15.7, 34.2, 49.7, 51.4, 52.6, 55.3, 55.9, 108.7, 110.3, 114.5, 120.3,

125.5, 126.6, 127.3, 127.8, 130.2, 143.9, 144.8, 157.7v; LC–MS (ES+):

(ꢀ)-2-(2,3-Dimethoxybenzyl)-7-methoxy-3-methyl-6-(triisopro-

pylsilyloxy)-1,2,3,4-tetrahydroisoquinoline (17i): Method as for

16b using compound 15 (419 mg, 1.2 mmol), 2,3-dimethoxybenzyl

chloride (562 mg, 1.5 mmol) and DIPEA (317 mg, 2.45 mmol) in

DMF (3.6 mL) at 808C for 18 h. Flash column chromatography

(hexane/EtOAc 19:1 to 9:1) afforded 17i as a yellow wax (445 mg,

m/z 314.1 [M+H]⁺; HRMS (ES+): m/z found 314.1751, C₁₉H₂₄NO₃

[M+H]⁺requires 314.1751.

+

(ꢀ)-6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5b): Pd/C (10%, 33 mg) was covered with

EtOH (6 mL) and compound 16a (330 mg, 0.82 mmol) was added

as solution in THF (6 mL). The reaction mixture was degassed then

placed under H₂at room temperature for 0.75 h before filtering

through Celite. The filtrate was evaporated and purified by flash

column chromatography (hexane/EtOAc 2:1) to give an oil which

crystallised from hexane to afford 5b as a pale-yellow solid

1

74%); H NMR (270 MHz, CDCl₃): d=1.06 (18H, d, J=6.9 Hz), 1.12

(3H, d, J=6.6 Hz), 1.12–1.30 (3H, m), 2.45 (1H, dd, J=15.8, 6.2 Hz),

2.85 (1H, dd, J=15.7, 4.1 Hz), 2.98–3.14 (1H, m), 3.47–3.91 (4H, m),

3.67–3.71 (3H, m), 3.77–3.81 (3H, m), 3.84–3.88 (3H, m), 6.39 (1H,

d, J=6.0 Hz), 6.54 (1H, d, J=6.3 Hz), 6.81 (1H, dd, J=7.4, 1.9 Hz),

7.00 (1H, dd, J=7.7, 2.5 Hz), 7.03–7.10 ppm (1H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=12.9, 15.1, 17.9, 34.9, 50.7, 51.5, 52.5, 55.5,

55.7, 60.9, 110.1, 110.8, 120.4, 122.4, 123.7, 125.8, 126.9, 133.5,

143.6, 148.9, 152.7 ppm; HRMS (ES+): m/z found 500.3175,

C₂₉H₄₆NO₄Si⁺[M+H]⁺requires 500.3191.

1

(118 mg, 46%); mp: 100–1058C; H NMR (270 MHz, CDCl₃): d=1.12

(3H, d, J=6.7 Hz), 2.49 (1H, dd, J=16.1, 5.8 Hz), 2.89 (1H, dd, J=

16.1, 4.8 Hz), 3.01–3.12 (1H, m), 3.48–3.74 (4H, m), 3.78 (3H, s),

3.79 (3H, s), 5.42 (1H, s), 6.42 (1H, s), 6.63 (1H, s), 6.77–6.81 (1H,

m), 6.93–6.96 (2H, m), 7.21 ppm (1H, d, J=8.2 Hz); ¹³C NMR

(67.5 MHz, CDCl₃): d=15.4, 34.7, 51.4, 52.3, 55.3, 56.0, 57.1, 108.7,

112.5, 114.4, 114.5, 121.4, 125.5, 126.6, 129.3, 141.2, 144.0, 144.9,

159.8 ppm; LC–MS (ES+): m/z 314.18 [M+H]⁺; HRMS (ES+): m/z

(ꢀ)-2-(3,4-Dimethoxybenzyl)-7-methoxy-3-methyl-6-(triisopro-

pylsilyloxy)-1,2,3,4-tetrahydroisoquinoline (17j): Method as for

16b using compound 15 (419 mg, 1.2 mmol), 3,4-dimethoxybenzyl

bromide (336 mg, 1.45 mmol) and DIPEA (312 mg, 2.4 mmol) in

DMF (3.6 mL) at 808C for 18 h. Flash column chromatography

(hexane/EtOAc 9:1 to 9:1 and 2% Et₃N) afforded 17j as a yellow

found 314.1748, C₁₉H₂₄NO₃[M+H]⁺requires 314.1751.

+

(ꢀ)-3-Ethyl-6-hydroxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (5c): Method as for 5b using compound

16b (292 mg, 0.7 mmol) and Pd/C (10%, 30 mg) in THF (6.0 mL)

and EtOH (2.0 mL) at room temperature for 2 h. Flash column chro-

matography (hexane to hexane/EtOAc 3:2) afforded 5c as a yellow

oil (211 mg, 92%); ¹H NMR (270 MHz, CDCl₃): d=0.98 (3H, t, J=

7.2 Hz), 1.42 (1H, sept, J=7.1 Hz), 1.69 (1H, sept, J=6.8 Hz), 2.52

(1H, dd, J=16.4, 6.3 Hz), 2.80 (1H, dd, J=16.4, 5.1 Hz), 2.86–2.90

(1H, m), 3.58–3.73 (4H, m), 3.80 (6H, s), 6.42 (1H, s), 6.64 (1H, s),

6.79 (1H, dd, J=8.0, 2.2 Hz), 6.92–6.98 (2H, m), 7.22 ppm (1H, t,

J=7.8 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=11.1, 23.0, 29.5, 50.9,

55.0, 55.1, 55.9, 58.5, 108.8, 112.3, 114.1, 114.6, 121.1, 125.3, 126.7,

129.1, 141.5, 143.9, 144.9, 159.6 ppm; LC–MS (ES+): m/z 328.1 [M+

H]⁺.

1

wax (411 mg, 68%); H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=

6.0 Hz), 1.10 (3H, d, J=6.3 Hz), 1.14–1.32 (3H, m), 2.45 (1H, dd, J=

15.8, 5.6 Hz), 2.85 (1H, dd, J=16.0, 4.4 Hz), 2.95–3.11 (1H, m), 3.39–

3.79 (4H, m), 3.67–3.71 (3H, m), 3.81–3.88 (6H, m), 6.39 (1H, d, J=

5.2 Hz), 6.56 (1H, d, J=5.5 Hz), 6.74–6.89 (2H, m), 6.92 ppm (1H,

dd, J=5.2, 1.6 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=12.8, 14.8, 17.9,

34.7, 51.4, 51.8, 55.4, 55.8, 55.8, 56.8, 110.0, 110.7, 112.0, 120.3,

121.0, 125.7, 126.6, 131.9, 143.7, 147.9, 148.9, 148.9 ppm; HRMS

(ES+): m/z found 500.3149, C₂₉H₄₆NO₄Si⁺[M+H]⁺requires

500.3191.

(ꢀ)-2-(2-Chloro-5-methoxybenzyl)-7-methoxy-3-methyl-6-(triiso-

propylsilyloxy)-1,2,3,4-tetrahydroisoquinoline (17k): Method as

for 16b using compound 15 (418 mg, 1.2 mmol), 2-chloro-5-me-

thoxybenzyl bromide (471 mg, 76 wt%, 1.5 mmol) and DIPEA

(311 mg, 2.4 mmol) in DMF (3.6 mL) at 808C for 18 h. Flash column

(ꢀ)-6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5d): Method as for 5a using compound

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17b (519 mg, 1.1 mmol) and TBAF (1m in THF, 1.35 mL, 1.35 mmol)

in THF (5.0 mL) at 08C for 0.5 h. Flash column chromatography

(hexane/EtOAc 4:1 to 1:1) afforded 5d as a pale-yellow solid

J=7.6 Hz), 2.51 (1H, dd, J=16.1, 6.2 Hz), 2.64 (2H, q, J=7.5 Hz),

2.90 (1H, dd, J=16.2, 5.0 Hz), 3.09 (1H, sext, J=6.1 Hz), 3.49–3.67

(3H, m), 3.75–3.83 (1H, m), 3.79 (3H, s), 6.43 (1H, s), 6.63 (1H, s,

br), 7.07–7.14 (1H, m), 7.15–7.29 ppm (3H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=15.3, 15.6, 28.8, 34.5, 51.3, 52.2, 55.9, 56.9, 108.6, 114.4,

125.3, 126.3, 126.4, 128.2, 128.5, 139.1, 143.9, 144.3, 144.8 ppm;

LC–MS (ES+): m/z 312.4 [M+H]⁺.

1

(305 mg, 88%); mp: 136–1398C; H NMR (270 MHz, CDCl₃): d=1.13

(3H, d, J 6.6 Hz), 2.48 (1H, dd, J=16.2, 6.1 Hz), 2.87 (1H, dd, J=

16.1, 5.1 Hz), 3.05 (1H, sext, J=6.1 Hz), 3.41–3.80 (4H, m), 3.78 (3H,

s), 3.79 (3H, s), 5.37 (1H, s, br), 6.41 (1H, s), 6.61 (1H, s), 6.84 (2H,

d, J=8.5 Hz), 7.26 ppm (2H, d, J=8.8 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=15.3, 34.6, 51.2, 52.1, 55.2, 55.9, 56.3, 108.6, 113.6, 114.4,

125.3, 126.5, 130.1, 131.2, 143.9, 144.8, 158.6 ppm; LC–MS (ES+):

(ꢀ)-2-(3-Ethoxybenzyl)-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5i): Method as for 5b using compound

16d (314 mg, 0.75 mmol) and Pd/C (10%, 28 mg) in THF (24 mL)

and EtOH (8 mL) at room temperature for 2 h. Flash column chro-

matography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5i

as a pale-yellow solid (142 mg, 57%); mp: 98–1038C; ¹H NMR

(270 MHz, CDCl₃): d=1.15 (3H, d, J=6.6 Hz), 1.40 (3H, t, J=6.9 Hz),

2.49 (1H, dd, J=16.1, 5.9 Hz), 2.89 (1H, dd, J=16.1, 4.8 Hz), 3.08

(1H, sext, J=6.1 Hz), 3.43–3.69 (3H, m), 3.78 (3H, s), 3.79 (1H, d,

J=13.2 Hz), 4.02 (2H, q, J=7.0 Hz), 5.33 (1H, s, br), 6.43 (1H, s),

6.62 (1H, s), 6.80 (1H, dd, J=8.3, 2.5 Hz), 6.95 (1H, d, J=7.7 Hz),

6.97 (1H, s), 7.22 ppm (1H, t, J=7.7 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=14.8, 15.3, 34.5, 51.3, 52.2, 55.8, 56.9, 63.3, 108.6, 113.0,

114.5, 114.9, 121.1, 125.1, 126.3, 129.1, 140.8, 144.0, 144.9,

159.0 ppm; LC–MS (ES+): m/z 328.2 [M+H]⁺; HRMS (ES+): m/z

m/z 314.1 [M+H]⁺; HRMS (ES+): m/z found 314.1753, C₁₉H₂₄NO₃

[M+H]⁺requires 314.1751.

+

(ꢀ)-2-Benzyl-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-tetrahydroi-

soquinoline (5e): Method as for 5a using compound 17c

(310 mg, 0.7 mmol) and TBAF (1m in THF, 0.84 mL, 0.84 mmol) in

THF (3.5 mL) at 08C for 0.5 h. Flash column chromatography

(CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5e as a pale-

yellow solid (161 mg, 81%); mp: 131–1348C; ¹H NMR (270 MHz,

CDCl₃): d=1.15 (3H, d, J=6.3 Hz), 2.50 (1H, dd, J=16.2, 6.0 Hz),

2.89 (1H, dd, J=16.2, 5.0 Hz), 3.08 (1H, sext, J=6.1 Hz), 3.44–3.93

(4H, m), 3.78 (3H, s), 5.27 (1H, s, br), 6.42 (1H, s), 6.63 (1H, s), 7.19–

7.41 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.4, 34.6, 51.3,

52.3, 55.9, 57.0, 108.6, 114.4, 125.4, 126.5, 126.9, 128.2, 128.9, 139.4,

143.9, 144.8 ppm; LC–MS (ES+): m/z 284.1 [M+H]⁺; HRMS (ES+):

found 328.1892, C₂₀H₂₆NO₃[M+H]⁺requires 328.1907.

+

(ꢀ)-6-Hydroxy-7-methoxy-3-methyl-2-(3-nitrobenzyl)-1,2,3,4-tet-

rahydroisoquinoline (5j): Method as for 5a using compound 17 f

(388 mg, 0.8 mmol) and TBAF (1m in THF, 0.96 mL, 0.96 mmol) in

THF (4.0 mL) at 08C for 0.5 h. Flash column chromatography

(CHCl₃/acetone 49:1 to 49:1 and 2% MeOH) afforded 5j as a pale-

yellow solid (236 mg, 89%); mp: 134–1378C; ¹H NMR (270 MHz,

CDCl₃): d=1.14 (3H, d, J=6.3 Hz), 2.50 (1H, dd, J=16.0, 6.0 Hz),

2.90 (1H, dd, J=16.2, 5.0 Hz), 3.09 (1H, sext, J=6.1 Hz), 3.47–3.89

(4H, m), 3.78 (3H, s), 6.40 (1H, s), 6.63 (1H, s), 7.46 (1H, t, J=

7.8 Hz), 7.72 (1H, d, J=7.4 Hz), 8.09 (1H, dd, J=8.2, 1.1 Hz),

8.22 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=15.5, 34.4, 51.3,

52.6, 55.9, 56.2, 108.6, 114.5, 122.0, 123.5, 124.8, 126.3, 129.1, 134.9,

142.1, 144.1, 144.9, 148.3 ppm; LC–MS (ES+): m/z 329.2 [M+H]⁺;

m/z found 284.1633, C₁₈H₂₂NO₂[M+H]⁺requires 284.1645.

+

(ꢀ)-2-(2-Chlorobenzyl)-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5 f): Method as for 5a using compound

17d (260 mg, 0.55 mmol) and TBAF (1m in THF, 0.66 mL,

0.66 mmol) in THF (3.0 mL) at 08C for 0.5 h. Flash column chroma-

tography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5 f as

a yellow glass (149 mg, 85%); ¹H NMR (270 MHz, CDCl₃): d=1.16

(3H, d, J=6.3 Hz), 2.51 (1H, dd, J=16.3, 5.8 Hz), 2.92 (1H, dd, J=

16.2, 5.0 Hz), 3.14 (1H, sext, J=6.1 Hz), 3.48–3.92 (4H, m), 3.79 (3H,

s), 6.44 (1H, s), 6.63 (1H, s), 7.16 (1H, dt, J=7.4, 1.9 Hz), 7.22 (1H,

dt, J=7.5, 1.6 Hz), 7.34 (1H, dd, J=7.3, 1.8 Hz), 7.55 ppm (1H, dd,

J=7.4, 1.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=15.3, 34.5, 51.2, 52.7,

53.6, 55.9, 108.6, 114.5, 125.3, 126.4, 126.6, 127.9, 129.3, 130.6,

134.0, 137.0, 143.9, 144.8 ppm; LC–MS (ES+): m/z 318.2 [M+H]⁺;

HRMS (ES+): m/z found 329.1482, C₁₈H₂₁N₂O₄[M+H]⁺requires

+

329.1496.

HRMS (ES+): m/z found 318.1247, C₁₈H₂₁ClNO₂[M+H]⁺requires

+

(ꢀ)-2-(3-Chlorobenzyl)-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5k): Method as for 5a using compound

17g (285 mg, 0.6 mmol) and TBAF (1m in THF, 0.72 mL, 0.72 mmol)

in THF (3.0 mL) at 08C for 0.5 h. Flash column chromatography

(CHCl₃/acetone 49:1 to 49:1 and 2% MeOH) afforded 5k as

a yellow glass (156 mg, 81%); ¹H NMR (270 MHz, CDCl₃): d=1.07

(3H, dd, J=12.1, 6.0 Hz), 2.52 (1H, dd, J=16.0, 5.5 Hz), 2.91 (1H,

dd, J=16.1, 4.8 Hz), 3.09 (1H, sext, J=5.8 Hz), 3.44–3.80 (4H, m),

3.79–3.84 (3H, m), 5.45 (1H, s, br), 6.45 (1H, t, J=5.5 Hz), 6.65 (1H,

t, J=5.4 Hz), 7.16–7.31 (3H, m), 7.40 ppm (1H, d, J=5.5 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=15.4, 34.5, 51.3, 52.4, 55.9, 56.5,

108.6, 114.5, 125.2, 126.4, 126.9, 127.0, 128.8, 129.5, 134.1, 141.8,

144.0, 144.9 ppm; LC–MS (ES+): m/z 318.2 [M+H]⁺; HRMS (ES+):

318.1256.

(ꢀ)-6-Hydroxy-7-methoxy-3-methyl-2-(2-methylbenzyl)-1,2,3,4-

tetrahydroisoquinoline (5g): Method as for 5a using compound

17e (249 mg, 0.55 mmol) and TBAF (1m in THF, 0.66 mL,

0.66 mmol) in THF (4.0 mL) at 08C for 0.5 h. Flash column chroma-

tography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5g as

a yellow glass (138 mg, 84%); ¹H NMR (270 MHz, CDCl₃): d=1.15

(3H, d, J=6.3 Hz), 2.37 (3H, s), 2.50 (1H, dd, J=16.3, 5.8 Hz), 2.90

(1H, dd, J=16.2, 5.0 Hz), 3.09 (1H, sext, J=6.1 Hz), 3.46–3.65 (3H,

m), 3.78 (1H, d, J=12.9 Hz), 3.79 (3H, s), 6.43 (1H, s), 6.64 (1H, s),

7.09–7.22 (3H, m), 7.28–7.35 ppm (1H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=14.8, 19.2, 34.7, 50.9, 52.5, 55.1, 55.9, 108.6, 114.4, 125.4,

125.6, 126.5, 126.8, 129.7, 130.3, 137.2, 137.5, 143.8, 144.7 ppm;

LC–MS (ES+): m/z 298.2 [M+H]⁺; HRMS (ES+): m/z found

m/z found 318.1249, C₁₈H₂₁ClNO₂[M+H]⁺requires 318.1256.

+

(ꢀ)-2-(3-Acetylbenzyl)-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-

tetrahydroisoquinoline (5l): Method as for 5a using compound

17h (264 mg, 0.55 mmol) and TBAF (1m in THF, 0.66 mL,

0.66 mmol) in THF (2.5 mL) at 08C for 0.5 h. Flash column chroma-

tography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5l as

a yellow glass (154 mg, 86%); ¹H NMR (270 MHz, CDCl₃): d=1.14

(3H, d, J=6.6 Hz), 2.48 (1H, dd, J=16.1, 5.9 Hz), 2.58 (3H, s), 2.88

(1H, dd, J=16.2, 5.0 Hz), 3.07 (1H, sext, J=6.1 Hz), 3.45–3.65 (3H,

m), 3.76 (3H, s), 3.83 (1H, d, J=13.2 Hz), 6.39 (1H, s), 6.61 (1H, s),

298.1809, C₁₉H₂₄NO₂[M+H]⁺requires 298.1802.

+

(ꢀ)-2-(3-Ethylbenzyl)-6-hydroxy-7-methoxy-3-methyl-1,2,3,4-tet-

rahydroisoquinoline (5h): Method as for 5b using compound 16c

(240 mg, 0.6 mmol) and Pd/C (10%, 31 mg) in THF (24 mL) and

EtOH (8 mL) at room temperature for 1 h. Flash column chroma-

tography (hexane to hexane/EtOAc 1:1 to 1:1 and 1% MeOH) af-

forded 5h as a pale-yellow solid (112 mg, 60%); mp: 105–1078C;

¹H NMR (270 MHz, CDCl₃): d=1.16 (3H, d, J=6.6 Hz), 1.24 (3H, t,

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7.40 (1H, t, J=7.7 Hz), 7.60 (1H, d, J=7.4 Hz), 7.83 (1H, dt, J=7.7,

1.4 Hz), 7.93 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=15.3, 26.7,

34.5, 51.2, 52.4, 55.8, 56.6, 108.6, 114.5, 125.0, 126.3, 127.0, 128.5,

128.7, 133.7, 137.1, 140.0, 144.0, 144.9, 198.4 ppm; LC–MS (ES+):

(1H, d, J=8.8 Hz), 7.07 ppm (1H, d, J=2.8 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=15.5, 34.3, 50.0, 51.5, 52.5, 55.7, 55.9, 56.0, 108.7, 111.4,

112.0, 114.5, 116.0, 125.6, 126.6, 128.9, 143.8, 144.8, 152.0,

153.6 ppm; LC–MS (ES+): m/z 344.5 [M+H]⁺.

m/z 326.1 [M+H]⁺; HRMS (ES+): m/z found 326.1742, C₂₀H₂₄NO₃

+

(ꢀ)-2-(2-Fluoro-5-methoxybenzyl)-6-hydroxy-7-methoxy-3-

methyl-1,2,3,4-tetrahydroisoquinoline (5q): Method as for 5b

using compound 16g (337 mg, 0.8 mmol) and Pd/C (10%, 30 mg)

in THF (24 mL) and EtOH (8 mL) at room temperature for 2 h. Flash

column chromatography (CHCl₃/acetone 19:1 to 9:1) afforded 5q

as a pale-yellow solid (221 mg, 83%). A small sample (22 mg) was

[M+H]⁺requires 326.1751.

(ꢀ)-2-(2,3-Dimethoxybenzyl)-6-hydroxy-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (5m): Method as for 5a using

compound 17i (400 mg, 0.8 mmol) and TBAF (1m in THF, 0.96 mL,

0.96 mmol) in THF (4.0 mL) at 08C for 0.5 h. Flash column chroma-

tography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5m

1

further purified by preparative HPLC (RP₁₈, MeCN/H₂O 9:1); H NMR

1

as a yellow glass (204 mg, 74%); H NMR (270 MHz, CDCl₃): d=1.14

(270 MHz, CDCl₃): d=1.13 (3H, d, J=6.3 Hz), 2.49 (1H, dd, J=16.1,

5.9 Hz), 2.88 (1H, dd, J=16.1, 4.8 Hz), 3.09 (1H, sext, J=6.1 Hz),

3.52–3.66 (3H, m), 3.67–3.81 (1H, m), 3.75 (3H, s), 3.79 (3H, s), 6.44

(1H, s), 6.62 (1H, s), 6.72 (1H, dt, J=8.8, 3.6 Hz), 6.93 (1H, t, J=

9.1 Hz), 7.01 ppm (1H, dd, J=5.6, 3.3 Hz); LC–MS (ES+): m/z 332.4

[M+H]⁺.

(3H, d, J=6.6 Hz), 2.48 (1H, dd, J=16.1, 5.9 Hz), 2.89 (1H, dd, J=

16.0, 5.0 Hz), 3.09 (1H, sext, J=6.1 Hz), 3.49–3.90 (4H, m), 3.77 (3H,

s), 3.81 (3H, s), 3.85 (3H, s), 4.97 (1H, s, br), 6.43 (1H, s), 6.61 (1H,

s), 6.82 (1H, dd, J=7.7, 1.9 Hz), 7.01 (1H, t, J=7.7 Hz), 7.07 ppm

(1H, dd, J=7.7, 1.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=15.0, 34.9,

50.8, 51.3, 52.4, 55.6, 55.8, 60.4, 108.6, 110.8, 114.4, 122.4, 123.7,

125.7, 126.5, 133.3, 143.8, 144.8, 147.7, 152.7 ppm; LC–MS (ES+):

(ꢀ)-2-(2-Chloro-5-methoxybenzyl)-6-hydroxy-7-methoxy-3-

methyl-1,2,3,4-tetrahydroisoquinoline (5r): Method as for 5a

using compound 17k (404 mg, 0.8 mmol) and TBAF (1m in THF,

0.96 mL, 0.96 mmol) in THF (4.0 mL) at 08C for 0.5 h. Flash column

chromatography (CHCl₃/acetone 49:1 to 49:1 and 2% MeOH) af-

forded 5r as a pale-yellow solid (249 mg, 89%); mp: 95–978C;

¹H NMR (270 MHz, CDCl₃): d=1.14 (3H, d, J=6.6 Hz), 2.49 (1H, dd,

J=16.3, 5.8 Hz), 2.91 (1H, dd, J=16.2, 5.0 Hz), 3.13 (1H, sext, J=

6.1 Hz), 3.48–3.91 (4H, m), 3.76 (3H, s), 3.79 (3H, s), 6.44 (1H, s),

6.63 (1H, s), 6.72 (1H, dd, J=8.8, 3.0 Hz), 7.15 (1H, d, J=3.0 Hz),

7.22 ppm (1H, d, J=8.8 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=15.2,

34.5, 51.3, 52.6, 53.7, 55.4, 55.9, 108.6, 113.5, 114.5, 115.7, 125.3,

125.4, 126.4, 129.8, 138.2, 144.0, 144.9, 158.3 ppm; LC–MS (ES+):

m/z 348.2 [M+H]⁺; HRMS (ES+): m/z found 348.1347,

m/z 344.2 [M+H]⁺; HRMS (ES+): m/z found 344.1851, C₂₀H₂₆NO₄

[M+H]⁺requires 344.1857.

+

(ꢀ)-2-(3,4-Dimethoxybenzyl)-6-hydroxy-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (5n): Method as for 5a using com-

pound 17j (351 mg, 0.7 mmol) and TBAF (1m in THF, 0.84 mL,

0.84 mmol) in THF (3.5 mL) at 08C for 0.5 h. Flash column chroma-

tography (CHCl₃/acetone 9:1 to 9:1 and 2% MeOH) afforded 5n as

a

pale-yellow solid (218 mg, 90%); mp 98–1048C; ¹H NMR

(270 MHz, CDCl₃): d=1.12 (3H, d, J=6.4 Hz), 2.46 (1H, dd, J=16.1,

5.9 Hz), 2.86 (1H, dd, J=16.2, 5.0 Hz), 3.06 (1H, sext, J=6.1 Hz),

3.41–3.75 (4H, m), 3.77 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 5.36 (1H,

s, br), 6.41 (1H, s), 6.58 (1H, s), 6.79 (1H, d, J=8.3 Hz), 6.86 (1H, dd,

J=8.3, 1.6 Hz), 6.95 ppm (1H, d, J=1.7 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=15.1, 34.5, 51.1, 52.0, 55.8, 55.8, 56.7, 108.6, 110.7, 111.9,

114.5, 121.0, 125.3, 126.4, 131.7, 143.9, 144.9, 147.9, 148.9 ppm;

LC–MS (ES+): m/z 344.3 [M+H]⁺; HRMS (ES+): m/z found

C₁₉H₂₃ClNO₃[M+H]⁺requires 348.1361.

+

(ꢀ)-6-Hydroxy-7-methoxy-3-methyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (5s): Method as for 5a using com-

pound 16h (151 mg, 0.33 mmol) and Pd/C (10%, 20 mg) in THF

(3 mL) and EtOH (3 mL) at room temperature for 5 h. Flash column

chromatography (hexane/CH₂Cl₂1:1 to CH₂Cl₂to EtOAc to EtOAc/

MeOH 4:1) afforded 5s as a yellow solid (80 mg, 66%); mp: 127–

344.1841, C₂₀H₂₆NO₄[M+H]⁺requires 344.1857.

+

(ꢀ)-2-(3,5-Dimethoxybenzyl)-6-hydroxy-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (5o): Method as for 5b using com-

pound 16e (148 mg, 0.34 mmol) and Pd/C (10%, 30 mg) in THF

(3.0 mL) and EtOH (3.0 mL) at room temperature for 18 h. The re-

sulting solid was crystallised from EtOAc/hexane to afford 5o as

a pale-yellow powder (81 mg, 69%); mp 155–1588C; ¹H NMR

(270 MHz, CDCl₃): d=1.12 (3H, d, J=6.4 Hz), 2.48 (1H, dd, J=16.1,

5.8 Hz), 2.88 (1H, dd, J=16.1, 4.7 Hz), 3.01–3.12 (1H, m), 3.47–3.78

(4H, m), 3.78 (6H, s), 3.79 (3H, s), 5.52 (1H, s, br), 6.35 (1H, t, J=

2.3 Hz), 6.43 (1H, s), 6.55 (2H, d, J=2.3 Hz), 6.62 ppm (1H, s);

¹³C NMR (67.5 MHz, CDCl₃): d=15.2, 34.6, 51.4, 52.1, 55.3, 55.9,

57.2, 98.9, 106.6, 108.6, 114.4, 125.5, 126.5, 142.1, 143.9, 144.8,

160.7 ppm; LC–MS (ES+): m/z 344.16 [M+H]⁺; HRMS (ES+): m/z

1

1328C; H NMR (270 MHz, CDCl₃): d=1.13 (3H, d, J=6.2 Hz), 2.49

(1H, dd, J=16.0, 5.8 Hz), 2.90 (1H, dd, J=16.0, 4.9 Hz), 3.08–3.11

(1H, m), 3.47–3.80 (4H, m), 3.80 (3H, s), 3.83 (3H, s), 3.84 (6H, s),

5.52 (1H, s, br), 6.45 (1H, s), 6.61 (2H, s), 6.64 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=15.2, 34.6, 51.4, 52.1, 56.0, 56.2, 57.3, 60.9,

105.6, 108.8, 114.6, 125.6, 126.6, 135.4, 136.7, 144.1, 145.0,

155.2 ppm; LC–MS (ESꢁ): m/z 372.32 [MꢁH]^ꢁ; HRMS (ES+): m/z

found 374.1964, C₂₁H₂₈NO₅[M+H]⁺requires 374.1962.

+

(ꢀ)-3-Ethyl-6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (5t): Method as for 5b using com-

pound 16i (334 mg, 0.7 mmol) and Pd/C (10%, 31 mg) in THF

(6 mL) and EtOH (2 mL) at room temperature for 18 h. Crystallisa-

tion from Et₂O/CH₂Cl₂afforded 5t as yellow solid (253 mg, 93%);

mp: 142–1458C; ¹H NMR (270 MHz, CDCl₃): d=0.98 (3H, t, J=

7.4 Hz), 1.42 (1H, sept, J=7.0 Hz), 1.68 (1H, s, br), 2.51 (1H, dd, J=

16.4, 5.9 Hz), 2.75–2.84 (2H, m), 3.51–3.75 (4H, m), 3.80 (3H, s),

3.83 (9H, s), 6.44 (1H, s), 6.60 (2H, s), 6.65 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=11.1, 23.0, 29.4, 50.8, 55.2, 55.9, 56.0, 58.3,

60.9, 105.3, 108.8, 114.6, 125.4, 126.7, 135.6, 136.5, 143.9, 144.9,

153.1 ppm; LC–MS (ES+): m/z 388.1 [M+H]⁺.

found 344.1856, C₂₀H₂₆NO₄[M+H]⁺requires 344.1857.

+

(ꢀ)-2-(2,5-Dimethoxybenzyl)-6-hydroxy-7-methoxy-3-methyl-

1,2,3,4-tetrahydroisoquinoline (5p): Method as for 5b using com-

pound 16 f (346 mg, 0.8 mmol) and Pd/C (10%, 31 mg) in THF

(24 mL) and EtOH (8 mL) at room temperature for 2 h. Flash

column chromatography (EtOAc/MeOH 99:1) afforded 5p as

a pale-yellow solid (230 mg, 83%). A small sample (24 mg) was fur-

ther purified by preparative HPLC (RP₁₈, MeCN/H₂O 9:1); ¹H NMR

(270 MHz, CDCl₃): d=1.14 (3H, d, J=6.3 Hz), 2.49 (1H, dd, J=16.1,

6.2 Hz), 2.87 (1H, dd, J=16.1, 4.8 Hz), 3.11 (1H, sext, J=6.2 Hz),

3.56–3.71 (4H, m), 3.74 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 5.56 (1H,

s, br), 6.44 (1H, s), 6.61 (1H, s), 6.73 (1H, dd, J=8.8, 2.7 Hz), 6.79

(ꢀ)-7-Methoxy-2-(2-methoxybenzyl)-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6a): Sulfamoyl chloride (0.5m in

toluene, 4.2 mL, 2.1 mmol) was concentrated in vacuo and cooled

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to 08C until it solidified. DMA (3.0 mL) was added, and the result-

ing solution was added directly to 5a (220 mg, 0.7 mmol) at 08C

under nitrogen. The reaction mixture was stirred at room tempera-

ture for 4 h. NaHCO₃(saturated, 50 mL) was added, and the mix-

ture was extracted with EtOAc (100 mL). The organic layer was

washed repeatedly with H₂O (50 mL, up to ten times), then brine,

then dried (MgSO₄) and evaporated. Crystallisation from Et₂O/

CH₂Cl₂(~9:1) afforded 6a as a yellow solid (192 mg, 69%); mp:

forded 6e as a pale-yellow solid (81 mg, 56%); mp: 155–1578C;

¹H NMR (270 MHz, CDCl₃): d=1.07 (3H, d, J=6.6 Hz), 2.47 (1H, dd,

J=16.3, 5.8 Hz), 2.87 (1H, dd, J=16.1, 4.8 Hz), 3.03 (1H, sext, J=

6.1 Hz), 3.42–3.87 (4H, m), 3.71 (3H, s), 6.19 (2H, s, br), 6.48 (1H, s),

7.00 (1H, s), 7.13–7.36 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=14.9, 34.2, 51.0, 51.9, 55.9, 56.9, 110.5, 123.9, 126.2, 126.9, 128.1,

128.7, 133.3, 137.3, 149.5 ppm; LC–MS (ES+): m/z 363.2 [M+H]⁺;

HRMS (ES+): m/z found 363.1362, C₁₈H₂₃N₂O₄S⁺[M+H]⁺requires

363.1373.

1

124–1298C; H NMR (270 MHz, CDCl₃): d=1.01–1.17 and 1.34–1.58

(3H, 2m), 1.90–2.07 and 2.34–2.52 (1H, 2m), 2.66–3.30 (3H, m),

3.64, 3.66, 3.68 and 3.71 (6H, 4s), 4.07–4.73 (1H, m), 6.44 and 6.48

(1H, 2s), 6.71–6.91 (2H, m), 6.94 and 6.97 (1H, 2s), 7.03–7.21 (1H,

m), 7.22–7.41 ppm (1H, m); LC–MS (ES+): m/z 393.2 [M+H]⁺;

HRMS (ES+): m/z found 393.1498, C₁₉H₂₅N₂O₅S⁺[M+H]⁺requires

393.1479.

(ꢀ)-2-(2-Chlorobenzyl)-7-methoxy-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6 f): Method as for 6a using com-

pound 5 f (127 mg, 0.4 mmol) and sulfamoyl chloride (1.2 mmol) in

DMA (2.0 mL) at room temperature for 6 h. Crystallisation from

CH₂Cl₂afforded 6 f as a pale-yellow solid (58 mg, 36%); mp: 151–

1

1538C; H NMR (270 MHz, CDCl₃): d=1.05 (3H, d, J=6.3 Hz), 2.44

(ꢀ)-7-Methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6b): Method as for 6a using com-

pound 5b (88 mg, 0.28 mmol) and sulfamoyl chloride (1.4 mmol)

in DMA (1.0 mL) at room temperature for 16 h. Flash column chro-

matography (hexane to EtOAc) afforded 6b as a pale-yellow solid

(1H, dd, J=16.1, 5.4 Hz), 2.85 (1H, dd, J=16.2, 4.7 Hz), 3.05 (1H,

sext, J=5.8 Hz), 3.46–3.83 (4H, m), 3.68 (3H, s), 6.45 (2H, s, br),

6.48 (1H, s), 6.97 (1H, s), 7.04–7.18 (2H, m), 7.23 (1H, dd, J=7.7,

1.6 Hz), 7.40 ppm (1H, dd, J=7.2, 1.9 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=14.8, 34.1, 50.9, 52.2, 53.6, 55.8, 110.4, 123.9, 126.1,

126.4, 127.9, 129.1, 130.3, 133.3, 133.8, 136.4, 137.2, 149.5 ppm;

LC–MS (ES+): m/z 397.1 [M+H]⁺; HRMS (ES+): m/z found

397.0974, C₁₈H₂₂ClN₂O₄S⁺[M+H]⁺requires 397.0984.

1

(56 mg, 51%); mp: 154–1568C; H NMR (270 MHz, [D₆]DMSO): d=

1.06 (3H, d, J=6.5 Hz), 2.44–2.51 (1H, m), 2.89 (1H, dd, J=16.0,

4.6 Hz), 3.01–3.07 (1H, m), 3.46–3.60 (4H, m), 3.70 (3H, s), 3.73 (3H,

s), 6.79 (1H, s), 6.82 (1H, dd, J=7.2, 2.0 Hz), 6.89–6.94 (2H, m), 7.02

(1H, s), 7.24 (1H, t, J=8.0 Hz), 7.85 ppm (2H, s, br); ¹³C NMR

(67.5 MHz, [D₆]DMSO): d=15.0, 39.8, 52.1, 55.5, 56.3, 57.3, 111.5,

112.7, 114.4, 121.2, 123.6, 125.9, 129.8, 133.6, 137.6, 141.7, 150.1,

159.9 ppm; LC–MS (ES+): m/z 393.10 [M+H]⁺.

(ꢀ)-7-Methoxy-3-methyl-2-(2-methylbenzyl)-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6g): Method as for 6a using com-

pound 5g (119 mg, 0.4 mmol) and sulfamoyl chloride (1.2 mmol) in

DMA (2.0 mL) at room temperature for 6 h. Crystallisation from

CH₂Cl₂afforded 6g as a pale-yellow solid (34 mg, 22%); mp: 139–

1

(ꢀ)-3-Ethyl-7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6c): Method as for 6a using com-

pound 5c (164 mg, 0.5 mmol) and sulfamoyl chloride (1.5 mmol) in

DMA (2.0 mL) at room temperature for 2 h. Flash column chroma-

tography (hexane to hexane/EtOAc 1:1) gave an oil which was dis-

solved in CH₂Cl₂(5 mL) and Et₂O (25 mL) then rapidly evaporated

to afford 6c as a yellow foam (106 mg, 52%); ¹H NMR (270 MHz,

[D₆]DMSO): d=0.93 (3H, t, J=7.2 Hz), 1.26–1.39 (1H, sept, J=

7.0 Hz), 1.56–1.68 (1H, sept, J=6.8 Hz), 2.47–2.58 (1H, m), 2.74–

2.88 (2H, m), 3.51–3.68 (4H, m), 3.62 (3H, s), 3.70 (3H, s), 3.72 (3H,

s), 6.78 (1H, s), 6.78–6.83 (1H, m), 6.87–6.93 (2H, m), 7.03 (1H, s),

7.23 (1H, t, J=8.0 Hz), 7.85 ppm (2H, s); ¹³C NMR (67.5 MHz,

[D₆]DMSO): d=11.1, 22.3, 29.2, 50.6, 55.1, 55.1, 56.0, 57.9, 111.4,

112.4, 114.0, 120.8, 123.5, 125.7, 129.5, 133.1, 137.2, 141.5, 149.9,

159.5 ppm; LC–MS (ES+): m/z 405.0 [M+H]⁺.

1448C; H NMR (270 MHz, CDCl₃): d=1.14 (3H, d, J=6.6 Hz), 2.49

(1H, dd, J=16.3, 5.8 Hz), 2.91 (1H, dd, J=16.2, 5.0 Hz), 3.13 (1H,

sext, J=6.1 Hz), 3.48–3.91 (4H, m), 3.76 (3H, s), 3.79 (3H, s), 6.40

(1H, s), 6.72 (1H, dd, J=8.8, 3.0 Hz), 6.84 (2H, s, br), 7.04 (1H, s),

7.15 (1H, d, J=3.0 Hz), 7.22 ppm (1H, d, J=8.8 Hz); LC–MS (ES+):

m/z 377.3 [M+H]⁺; HRMS (ES+): m/z found 377.1517,

C₁₉H₂₅N₂O₄S⁺[M+H]⁺requires 377.1530.

(ꢀ)-2-(3-Ethylbenzyl)-7-methoxy-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6h): Method as for 6a using com-

pound 5h (93 mg, 0.3 mmol) and sulfamoyl chloride (0.9 mmol) in

DMA (2.0 mL) at room temperature for 18 h. Flash column chroma-

tography (hexane to hexane/EtOAc 1:1) followed by crystallisation

from Et₂O afforded 6h as a pale-yellow solid (66 mg, 56%); mp:

145–1478C; ¹H NMR (270 MHz, CDCl₃): d=1.07 (3H, d, J=6.6 Hz),

1.16 (3H, t, J=7.7 Hz), 2.46 (1H, dd, J=16.2, 5.8 Hz), 2.57 (2H, q,

J=7.6 Hz), 2.86 (1H, dd, J=16.2, 5.0 Hz), 3.01 (1H, sext, J=5.9 Hz),

3.41–3.62 (3H, m), 3.66–3.77 (1H, m), 3.71 (3H, s), 6.21 (2H, s, br),

6.49 (1H, s), 7.00 (1H, s, br), 7.00–7.25 ppm (4H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=14.9, 15.5, 27.5, 28.6, 51.1, 51.9, 55.9, 57.0,

110.6, 124.0, 126.0, 126.3, 126.4, 128.1, 128.2, 133.5, 137.3, 144.2,

149.5 ppm; LC–MS (ES+): m/z 391.4 [M+H]⁺.

(ꢀ)-7-Methoxy-2-(4-methoxybenzyl)-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6d): Method as for 6a using com-

pound 5d (220 mg, 0.7 mmol) and sulfamoyl chloride (2.1 mmol)

in DMA (3.0 mL) at room temperature for 2 h. Crystallisation from

Et₂O/CH₂Cl₂(~9:1) afforded 6d as a yellow solid (195 mg, 70%);

mp: 115–1198C; ¹H NMR (270 MHz, CDCl₃): d=1.01 (3H, d, J=

6.3 Hz), 2.40 (1H, dd, J=16.0, 5.2 Hz), 2.80 (1H, dd, J=16.2, 4.4 Hz),

2.83–3.06 (1H, m), 3.24–3.50 (3H, m), 3.50–3.63 (1H, m), 3.65 and

3.67 (3H, 2 s), 6.43 (1H, s, br), 6.72 (2H, d, J 8.5 Hz), 6.94 (1H, s, br),

7.14 ppm (2H, d, J=8.3 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=14.7,

34.2, 50.8, 51.7, 55.0, 55.8, 56.2, 110.4, 113.4, 123.8, 126.0, 129.7,

130.5, 133.3, 137.2, 149.5, 158.4 ppm; LC–MS (ES+): m/z 393.2 [M+

H]⁺; HRMS (ES+): m/z found 393.1503, C₁₉H₂₅N₂O₅S⁺[M+H]⁺re-

quires 393.1479.

(ꢀ)-2-(3-Ethoxybenzyl)-7-methoxy-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6i): Method as for 6a using com-

pound 5i (98 mg, 0.3 mmol) and sulfamoyl chloride (0.9 mmol) in

DMA (3.0 mL) at room temperature for 4 h. Crystallisation from

CH₂Cl₂afforded 6i as a pale-yellow solid (84 mg, 69%); mp: 94–

1

1018C; H NMR (270 MHz, CDCl₃): d=1.02 (3H, dd, J=6.6, 2.1 Hz),

1.29 (3H, dt, J=6.9, 2.3 Hz), 2.43 (1H, dd, J=16.0, 5.2 Hz), 2.75–

2.89 (1H, m), 2.90–3.05 (1H, m), 3.37–3.60 (3H, m), 3.63–3.72 (1H,

m), 3.68 (3H, d, J=2.5 Hz), 3.92 (2H, dq, J=6.9, 2.2 Hz), 6.44 (1H,

s), 6.64–6.72 (1H, m), 6.77–6.88 (2H, m), 6.97 (1H, s), 7.11 ppm (1H,

dt, J=8.0, 2.3 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=14.6, 14.8, 34.4,

51.1, 51.8, 55.8, 57.0, 63.0, 110.4, 112.6, 114.6, 120.7, 123.9, 126.2,

(ꢀ)-2-Benzyl-7-methoxy-3-methyl-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (6e): Method as for 6a using compound 5e

(114 mg, 0.4 mmol) and sulfamoyl chloride (1.2 mmol) in DMA

(3.0 mL) at room temperature for 2 h. Crystallisation from CH₂Cl₂af-

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129.0, 133.5, 137.1, 140.6, 149.4, 158.8 ppm; LC–MS (ES+): m/z

407.3 [M+H]⁺; HRMS (ES+): m/z found 407.1627, C₂₀H₂₇N₂O₅S⁺

[M+H]⁺requires 407.1635.

149.6, 152.8 ppm; LC–MS (ES+): m/z 423.2 [M+H]⁺; HRMS (ES+):

m/z found 423.1573, C₂₀H₂₇N₂O₆S⁺[M+H]⁺requires 423.1584.

(ꢀ)-2-(3,4-Dimethoxybenzyl)-7-methoxy-3-methyl-6-sulfamoy-

loxy-1,2,3,4-tetrahydroisoquinoline (6n): Method as for 6a using

compound 5n (138 mg, 0.4 mmol) and sulfamoyl chloride

(1.2 mmol) in DMA (3.0 mL) at room temperature for 2 h. Crystalli-

sation from CH₂Cl₂afforded 6n as a pale-yellow solid (63 mg,

(ꢀ)-7-Methoxy-3-methyl-2-(3-nitrobenzyl)-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6j): Method as for 6a using com-

pound 5j (165 mg, 0.5 mmol) and sulfamoyl chloride (1.5 mmol) in

DMA (3.0 mL) at room temperature for 2 h. Crystallisation from

CH₂Cl₂afforded 6j as a pale-yellow solid (80 mg, 49%); mp: 166–

1

37%); mp: 168–1708C; H NMR (270 MHz, CDCl₃): d=1.06 (3H, d,

1

1698C; H NMR (270 MHz, CDCl₃): d=1.01 (3H, d, J=6.3 Hz), 2.42

J=6.3 Hz), 2.46 (1H, dd, J=16.2, 5.5 Hz), 2.86 (1H, dd, J=16.4,

4.8 Hz), 3.02 (1H, sext, J=6.1 Hz), 3.39–3.73 (4H, m), 3.72 (3H, s),

3.80 (6H, s), 6.14 (2H, s, br), 6.49 (1H, s), 6.74 (1H, d, J=8.3 Hz),

6.79 (1H, dd, J=8.3, 1.4 Hz), 6.87 (1H, s), 7.00 ppm (1H, s);

¹³C NMR (67.5 MHz, CDCl₃): d=14.8, 34.2, 51.0, 51.7, 55.7, 55.7,

55.9, 56.7, 92.3, 110.6, 110.6, 111.8, 120.8, 124.0, 126.3, 133.3, 137.3,

147.9, 148.8, 149.5 ppm; LC–MS (ES+): m/z 423.3 [M+H]⁺; HRMS

(ES+): m/z found 423.1551, C₂₀H₂₇N₂O₆S⁺[M+H]⁺requires

423.1584.

(1H, dd, J=16.3, 5.5 Hz), 2.84 (1H, dd, J=16.1, 4.8 Hz), 2.99 (1H,

sext, J=6.1 Hz), 3.37–3.70 (3H, m), 3.64 (3H, s), 3.75 (1H, d, J=

14.0 Hz), 6.42 (1H, s), 6.51 (2H, s, br), 6.96 (1H, s), 7.37 (1H, t, J=

8.0 Hz), 7.58 (1H, d, J=7.7 Hz), 7.97 (1H, dd, J=8.1, 1.5 Hz),

8.09 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=14.7, 34.2, 50.9,

52.1, 55.7, 56.2, 110.3, 121.8, 122.9, 123.9, 125.8, 129.0, 132.7, 134.5,

137.3, 141.5, 148.1, 149.6 ppm; LC–MS (ES+): m/z 408.2 [M+H]⁺;

HRMS (ES+): m/z found 408.1219, C₁₈H₂₂N₃O₆S⁺[M+H]⁺requires

408.1224.

(ꢀ)-2-(3,5-Dimethoxybenzyl)-7-methoxy-3-methyl-6-sulfamoy-

loxy-1,2,3,4-tetrahydroisoquinoline (6o): Method as for 6a using

compound 5o (102 mg, 0.3 mmol) and sulfamoyl chloride

(1.5 mmol) in DMA (1.0 mL) at room temperature for 23 h. Flash

column chromatography (hexane to EtOAc) afforded 6o as a pale-

yellow solid (80 mg, 64%); mp: 146–1498C; ¹H NMR (270 MHz,

[D₆]DMSO): d=1.05 (3H, d, J=6.2 Hz), 2.43–2.51 (1H, m), 2.88 (1H,

dd, J=16.0, 4.7 Hz), 2.98–3.07 (1H, m), 3.66–3.99 (4H, m), 3.70 (3H,

s), 3.71 (6H, s), 6.37 (1H, t, J=2.2 Hz), 6.51 (2H, d, J=2.2 Hz), 6.80

(1H, s), 7.02 (1H, s), 7.85 ppm (2H, s, br); ¹³C NMR (67.5 MHz,

CDCl₃): d=([D₆]DMSO) 15.0, 39.4, 51.2, 52.0, 55.6, 56.3, 57.5, 99.1,

106.7, 111.5, 123.6, 125.9, 133.6, 137.6, 142.5, 150.1, 161.0 ppm; LC–

MS (ES+): m/z 423.09 [M+H]⁺; HRMS (ES+): m/z found 423.1580,

C₂₀H₂₇N₂O₆S⁺[M+H]⁺requires 423.1584.

(ꢀ)-2-(3-Chlorobenzyl)-7-methoxy-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6k): Method as for 6a using com-

pound 5k (127 mg, 0.4 mmol) and sulfamoyl chloride (1.2 mmol) in

DMA (3.0 mL) at room temperature for 2 h. Crystallisation from

CH₂Cl₂afforded 6k as a pale-yellow solid (92 mg, 58%); mp: 172–

1

1758C; H NMR (270 MHz, CDCl₃): d=1.06 (3H, d, J=6.3 Hz), 2.47

(1H, dd, J=16.2, 5.8 Hz), 2.87 (1H, dd, J=16.2, 4.7 Hz), 3.03 (1H,

sext, J=6.0 Hz), 3.41–3.62 (3H, m), 3.71 (1H, d, J=13.2 Hz), 3.72

(3H, s), 6.22 (2H, s, br), 6.49 (1H, s), 7.01 (1H, s), 7.11–7.22 (3H, m),

7.30 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=15.0, 34.3, 51.1,

52.1, 55.9, 56.5, 110.6, 124.1, 126.8, 127.1, 128.5, 129.5, 133.1, 134.0,

137.4, 149.6 ppm; LC–MS (ES+): m/z 397.2 [M+H]⁺; HRMS (ES+):

m/z found 397.0982, C₁₈H₂₂ClN₂O₄S⁺[M+H]⁺requires 397.0984.

(ꢀ)-2-(3-Acetylbenzyl)-7-methoxy-3-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6l): Method as for 6a using com-

pound 5l (130 mg, 0.4 mmol) and sulfamoyl chloride (1.2 mmol) in

DMA (3.0 mL) at room temperature for 4 h. Crystallisation from

CH₂Cl₂afforded 6l as a white solid (66 mg, 41%); mp: 172–1758C;

¹H NMR (270 MHz, CDCl₃/[D₆]DMSO): d=1.07 and 1.09 (3H, 2d, J=

7.0 and 7.4 Hz), 2.52 and 2.56 (3H, s and d, J=1.4 Hz), 2.42–2.51

and 2.90–2.99 (1H, 2 m), 2.83–2.91 (1H, m), 3.07 (1H, sext, J=

5.8 Hz), 3.41–3.67 (3H, m), 3.70 and 3.73 (3H, 2 s), 3.76–3.89 (1H,

m), 6.49 and 6.52 (1H, 2 s), 6.91 (2H, s, br), 7.01 and 7.04 (1H, 2 s),

7.36 and 7.42 (1H, t and dt, J=8.3 and 7.6, 1.1 Hz), 7.52 and 7.55

(1H, 2dd, J=7.4, 1.1 and 7.7, 1.1 Hz), 7.77 and 7.80 (1H, 2dd, J=

7.5, 1.1 and 7.7, 1.1 Hz), 7.86 and 7.89 ppm (1H, s and d, J=

1.1 Hz); ¹³C NMR (67.5 MHz, CDCl₃/[D₆]DMSO): d=14.4, 26.2, 34.1,

50.7, 51.6, 55.4, 56.5, 110.1, 123.5, 125.5, 126.6, 127.7, 128.1, 132.7,

133.0, 136.6, 137.0, 139.5, 149.3, 197.7 ppm; LC–MS (ES+): m/z

405.2 [M+H]⁺; HRMS (ES+): m/z found 405.1484, C₂₀H₂₅N₂O₅S⁺

[M+H]⁺requires 405.1479.

(ꢀ)-2-(2,5-Dimethoxybenzyl)-7-methoxy-3-methyl-6-sulfamoy-

loxy-1,2,3,4-tetrahydroisoquinoline (6p): Method as for 6a using

compound 5p (206 mg, 0.6 mmol) and sulfamoyl chloride

(2.5 mmol) in DMA (3.0 mL) at room temperature for 18 h. Flash

column chromatography (hexane to hexane/EtOAc 3:7 and (CHCl₃/

acetone 4:1 to 3:1) gave a solid that was crystallised from (iPr)₂O

and washed with Et₂O (~20ꢁ1 mL) to afford 6p as a white foam

(33 mg, 12%) still containing (iPr)₂O (5.1 wt% by H NMR); H NMR

(270 MHz, CDCl₃): d=1.12 (3H, d, J=6.3 Hz), 2.51 (1H, dd, J=16.0,

6.1 Hz), 2.90 (1H, dd, J=16.2, 4.7 Hz), 3.11 (1H, sext, J=6.0 Hz),

3.54–3.71 (4H, m), 3.73 (3H, s), 3.75 (3H, s), 3.77 (3H, s), 5.82 (2H,

s, br), 6.56 (1H, s), 6.71 (1H, dd, J=8.8, 3.0 Hz), 6.77 (1H, d, J=

8.8 Hz), 7.01 (1H, d, J=2.8 Hz), 7.04 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=15.0, 33.9, 49.8, 51.1, 52.0, 55.3, 55.7, 110.4,

111.2, 111.5, 115.7, 123.8, 126.2, 128.4, 133.6, 137.1, 149.4, 151.6,

153.3 ppm; LC–MS (ES+): m/z 423.3 [M+H]⁺.

1

(ꢀ)-2-(2-Fluoro-5-methoxybenzyl)-7-methoxy-3-methyl-6-sulfa-

moyloxy-1,2,3,4-tetrahydroisoquinoline (6q): Method as for 6a

using compound 5q (199 mg, 0.6 mmol) and sulfamoyl chloride

(3.0 mmol) in DMA (5.0 mL) at room temperature for 2 h. Flash

column chromatography (hexane to hexane/EtOAc 1:1) and crystal-

lisation from Et₂O afforded 6q as a white solid (43 mg, 17%); mp:

163–1678C; ¹H NMR (270 MHz, CDCl₃): d=1.16 (3H, d, J=6.3 Hz),

2.54 (1H, dd, J=16.1, 5.4 Hz), 2.94 (1H, dd, J=16.2, 4.4 Hz), 3.12

(1H, sext, J=5.9 Hz), 3.56–3.83 (4H, m), 3.77 (3H, s), 3.80 (3H, s),

6.49 (2H, s, br), 6.60 (1H, s), 6.74 (1H, dt, J=8.8, 3.7 Hz), 6.95 (1H,

t, J=9.4 Hz), 6.96–7.04 (1H, m), 7.08 ppm (1H, s); LC–MS (ES+): m/

z 411.4 [M+H]⁺.

(ꢀ)-2-(2,3-Dimethoxybenzyl)-7-methoxy-3-methyl-6-sulfamoy-

loxy-1,2,3,4-tetrahydroisoquinoline (6m): Method as for 6a using

compound 5m (138 mg, 0.4 mmol) and sulfamoyl chloride

(1.2 mmol) in DMA (3.0 mL) at room temperature for 2 h. Crystalli-

sation from CH₂Cl₂afforded 6m as a pale-yellow solid (41 mg,

1

24%); mp: 152–1558C; H NMR (270 MHz, CDCl₃): d=1.07 (3H, d,

J=6.3 Hz), 2.45 (1H, dd, J=16.1, 5.6 Hz), 2.85 (1H, dd, J=16.1,

4.8 Hz), 3.04 (1H, sext, J=5.9 Hz), 3.43–3.84 (4H, m), 3.71 (3H, s),

3.73 (3H, s), 3.79 (3H, s), 6.15 (2H, s, br), 6.50 (1H, s), 6.72–6.80

(1H, m), 6.94 (1H, s), 6.96 (1H, s), 6.98 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=15.0, 34.8, 51.0, 51.3, 52.3, 55.7, 56.2, 61.0,

110.8, 111.0, 122.3, 123.9, 124.2, 126.7, 133.0, 134.0, 137.4, 147.7,

(ꢀ)-2-(2-Chloro-5-methoxybenzyl)-7-methoxy-3-methyl-6-sulfa-

moyloxy-1,2,3,4-tetrahydroisoquinoline (6r): Method as for 6a

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using compound 5r (173 mg, 0.5 mmol) and sulfamoyl chloride

(1.5 mmol) in DMA (3.0 mL) at room temperature for 2 h. Crystalli-

sation from CH₂Cl₂afforded 6r as a white solid (81 mg, 38%); mp:

146–1488C; ¹H NMR (270 MHz, CDCl₃): d=1.08 (3H, d, J=6.6 Hz),

2.48 (1H, dd, J=16.0, 5.5 Hz), 2.90 (1H, dd, J=16.2, 5.0 Hz), 3.09

(1H, sext, J=5.9 Hz), 3.52–3.81 (4H, m), 3.72 (3H, s), 3.74 (3H, s),

6.10 (2H, s, br), 6.53 (1H, s), 6.67 (1H, dd, J=8.7, 3.2 Hz), 7.02 (1H,

s), 7.05 (1H, d, J=3.0 Hz), 7.18 ppm (1H, d, J=8.8 Hz); ¹³C NMR

(67.5 MHz, CDCl₃): d=14.9, 34.3, 51.1, 52.3, 53.9, 55.4, 56.0, 110.7,

113.3, 115.7, 124.2, 125.1, 126.4, 129.8, 133.6, 137.3, 149.5,

158.3 ppm; LC–MS (ES+): m/z 427.2 [M+H]⁺; HRMS (ES+): m/z

found 427.1081, C₁₉H₂₄ClN₂O₅S⁺[M+H]⁺requires 427.1089.

EtOAc (3ꢁ60 mL). The combined organic layers were washed with

brine (30 mL), then dried (MgSO₄) and evaporated to afford 20 as

white solid (1.34 g, 80%); mp: 170–1738C; ¹H NMR (270 MHz,

[D₆]DMSO): d=1.04 (6H, s), 2.42 (2H, s), 3.70 (3H, s), 3.72 (2H, s),

6.43 (1H, s), 6.54 (1H, s), 8.60 ppm (1H, s, br); LC–MS (ES+): m/z

208.23 [M+H]⁺; HRMS (ES+): m/z found 208.1322, C₁₂H₁₈NO₂

+

[M+H]⁺requires 208.1332.

3,3-Dimethyl-7-methoxy-6-(triisopropylsilanyloxy)-1,2,3,4-tetra-

hydroisoquinoline (21): Method as for 15 using compound 20

(1.25 g, 6.0 mmol), chlorotriisopropylsilane (2.71 mL, 12.7 mmol)

and imidazole (1.73 g, 25.4 mmol) in CH₂Cl₂(50 mL) at room tem-

perature for 22 h. Flash column chromatography (EtOAc/MeOH

10:1 and 1% Et₃N) afforded 21 as a colourless oil (1.78 g, 81%);

¹H NMR (270 MHz, CDCl₃): d=1.06 (18H, d, J=6.7 Hz), 1.14 (6H, s),

1.14–1.28 (3H, m), 2.51 (2H, s), 3.74 (3H, s), 3.89 (2H, s), 6.46 (1H,

s), 6.51 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=13.0, 18.0, 27.8,

41.2, 44.0, 48.8, 55.6, 113.0, 117.4, 126.2, 126.9, 143.6, 149.3 ppm;

LC–MS (ES+): m/z 364.36 [M+H]⁺.

(ꢀ)-7-Methoxy-3-methyl-6-sulfamoyloxy-2-(3,4,5-trimethoxyben-

zyl)-1,2,3,4-tetrahydroisoquinoline (6s): Method as for 6a using

compound 5s (65 mg, 0.17 mmol) and sulfamoyl chloride

(0.52 mmol) in DMA (1.0 mL) at room temperature for 22 h. The re-

sulting solid was stirred in hexane, filtered and dried to afford 6s

as yellow powder (55 mg, 70%); mp: 137–1438C; ¹H NMR

(270 MHz, [D₆]DMSO): d=1.06 (3H, d, J=6.4 Hz), 2.44–2.51 (1H,

m), 2.90 (1H, dd, J=16.5, 5.1 Hz), 3.03–3.09 (1H, m), 3.49–3.66 (4H,

m), 3.64 (3H, s), 3.71 (3H, s), 3.75 (6H, s), 6.65 (2H, s), 6.82 (1H, s),

7.03 (1H, s), 7.82 ppm (2H, s); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=

14.8, 39.5, 51.1, 51.9, 56.4, 57.5, 60.5, 105.9, 111.6, 123.6, 125.9,

133.6, 135.6, 136.8, 137.7, 150.2, 153.4 ppm; LC–MS (ES+): m/z

453.38 [M+H]⁺; HRMS (ES+): m/z found 453.1688, C₂₁H₂₉N₂O₇S⁺

[M+H]⁺requires 453.1690.

3,3-Dimethyl-7-methoxy-2-(3-methoxybenzyl)-6-(triisopropylsi-

lan-yloxy)-1,2,3,4-tetrahydroisoquinoline (22a): Method as for

16a using compound 21 (300 mg, 0.83 mmol), 3-methoxybenzyl

chloride (0.13 mL, 0.91 mmol) and Et₃N (0.3 mL, 1.65 mmol) in

EtOH (3.0 mL) in the microwave at 1308C for 1.5 h. Flash column

chromatography (hexane to hexane/EtOAc 1:1 to EtOAc) afforded

22a as a colourless oil (246 mg, 62%); ¹H NMR (270 MHz, CDCl₃):

d=1.04 (18H, d, J=6.7 Hz), 1.12–1.22 (3H, m), 1.17 (6H, s), 2.65

(2H, s), 3.47 (2H, s), 3.64 (2H, s), 3.74 (3H, s), 3.79 (3H, s), 6.41 (1H,

s), 6.48 (1H, s), 6.77 (1H, ddd, J=8.2, 2.2, 1.2 Hz), 6.95–6.98 (2H,

m), 7.22 ppm (1H, t, J=8.2 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=

12.4, 17.5, 23.3, 42.3, 49.6, 52.1, 53.2, 54.7, 55.0, 111.4, 111.7, 113.8,

117.2, 120.6, 125.7, 126.3, 128.7, 142.1, 142.9, 148.7, 159.2 ppm;

LC–MS (ES+): m/z 484.83 [M+H]⁺; HRMS (ES+): m/z found

484.3242, C₂₉H₄₆NO₃Si⁺[M+H]⁺requires 484.3241.

(ꢀ)-3-Ethyl-7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxyben-

zyl)-1,2,3,4-tetrahydroisoquinoline (6t): Method as for 6a using

compound 5t (194 mg, 0.5 mmol) and sulfamoyl chloride

(1.5 mmol) in DMA (3.0 mL) at room temperature for 2 h. Flash

column chromatography (hexane to hexane/EtOAc 1:4) gave an oil

which was dissolved in CH₂Cl₂(30 mL) and rapidly concentrated to

afford 6t as a yellow foam (172 mg, 73%); ¹H NMR (270 MHz,

[D₆]DMSO): d=0.94 (3H, t, J=7.4 Hz), 1.33 (1H, sept, J=7.0 Hz),

1.62 (1H, sept, J=6.8 Hz), 2.46–2.54 (1H, m), 2.76–2.87 (2H, m),

3.51–3.66 (4H, m), 3.63 (3H, s), 3.70 (3H, s), 3.73 (6H, s), 6.64 (2H,

s), 6.81 (1H, s), 7.03 (1H, s), 7.85 ppm (2H, s); ¹³C NMR (67.5 MHz,

[D₆]DMSO): d=11.2, 22.3, 29.0, 50.5, 55.3, 55.9, 56.0, 57.6, 60.2,

105.3, 111.4, 123.3, 125.7, 133.2, 135.5, 136.3, 137.3, 149.9,

153.0 ppm; LC–MS (ES+): m/z 467.1 [M+H]⁺.

3,3-Dimethyl-7-methoxy-6-(triisopropylsilanyloxy)-2-(3,4,5-trime-

thoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (22b): Method as for

16a using compound 21 (300 mg, 0.83 mmol), 3,4,5-trimethoxy-

benzyl chloride (214 mg, 0.99 mmol) and Et₃N (0.23 mL, 1.65 mmol)

in EtOH (3 mL) in the microwave at 1708C for 0.5 h. Flash column

chromatography (hexane to hexane/CH₂Cl₂1:1) and (hexane/EtOAc

4:1) afforded 22b as a colourless oil (127 mg, 28%); ¹H NMR

(270 MHz, CDCl₃): d=1.04 (18H, d, J=6.7 Hz), 1.12–1.27 (3H, m),

1.17 (6H, s), 2.65 (2H, s), 3.49 (2H, s), 3.60 (2H, s), 3.74 (3H, s), 3.83

(3H, s), 3.84 (6H, s), 6.44 (1H, s), 6.50 (1H, s), 6.61 ppm (2H, s); LC–

MS (ES+): m/z 544.46 [M+H]⁺.

3,3-Dimethyl-6-hydroxy-7-methoxy-3,4-dihydroisoquinoline (19):

KCN (1.29 g, 36.7 mmol) was added in small portions into AcOH

(7.2 mL) at 08C. A mixture of AcOH (3.6 mL) and H₂SO₄(7.3 g) was

then added slowly with stirring. Finally, a solution of compound 18

(6.0 g, 30.6 mmol) in AcOH (4 mL) was added dropwise at 08C. The

reaction mixture was stirred at room temperature for 24 h, then

poured into ice-H₂O and neutralised with Na₂CO₃. After saturating

with NaCl the mixture was extracted with Et₂O (2ꢁ150 mL) and

EtOAc (2ꢁ150 mL). Flash column chromatography (CH₂Cl₂/EtOAc

1:1 to EtOAc to EtOAc/MeOH 4:1) afforded 19 as a colourless solid

3,3-Dimethyl-6-hydroxy-2-(3-methoxybenzyl)-7-methoxy-1,2,3,4-

tetrahydroisoquinoline (5u): Method as for 5a using compound

22a (237 mg, 0.45 mmol) and TBAF (1m in THF, 0.53 mL,

0.53 mmol) in THF (10 mL) at room temperature for 18 h. Flash

column chromatography (hexane to EtOAc) afforded 5u as a col-

1

ourless oil (70 mg, 43%); H NMR (270 MHz, CDCl₃): d=1.18 (6H, s),

1

(1.72 g, 30%); mp: 152–1578C; H NMR (270 MHz, CDCl₃): d=1.21

2.66 (2H, s), 3.50 (2H, s), 3.65 (2H, s), 3.79 (3H, s), 3.83 (3H, s), 6.47

(1H, s), 6.52 (1H, s), 6.75–6.79 (1H, m), 6.95–6.97 (2H, m), 7.21 ppm

(1H, t, J=8.0 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=23.7, 45.5, 50.0,

52.5, 53.5, 55.1, 55.9, 110.7, 111.7, 111.9, 114.1, 120.9, 125.6, 126.9,

129.1, 142.4, 143.5, 145.0, 159.6 ppm; LC–MS (ESꢁ): m/z 326.27

(6H, s), 2.62 (2H, s), 3.91 (3H, s), 5.69 (1H, s, br), 6.60 (1H, s), 6.85

(1H, s), 8.07 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=28.1, 38.0,

54.7, 56.0, 110.6, 113.8, 120.9, 128.0, 144.9, 149.5, 157.2 ppm; LC–

MS (ES+): m/z 205.9 [M+H]⁺; HRMS (ES+): m/z found 206.1169,

C₁₂H₁₆NO₂[M+H]⁺requires 206.1176.

+

[MꢁH]^ꢁ; HRMS (ES+): m/z found 328.1904, C₂₀H₂₆NO₃[M+H]⁺

+

3,3-Dimethyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquino-

line (20): To a solution of compound 19 (1.67 g, 8.2 mmol) in EtOH

(30 mL) at 08C was added NaBH₄(618 mg, 16.3 mmol). The reac-

tion mixture was stirred at room temperature for 3 h. H₂O (50 mL)

and HCl (2m) were added, and the mixture was extracted with

requires 328.1907.

3,3-Dimethyl-6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (5v): Method as for 5a using com-

pound 22b (187 mg, 0.34 mmol) and TBAF (1m in THF, 0.38 mL,

0.38 mmol) in THF (10 mL) at 08C for 3 h. Flash column chromatog-

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raphy (hexane/EtOAc 2:1 and 1% Et₃N) gave an oil that crystallised

6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1-methyl-1,2,3,4-

tetrahydroisoquinoline (27a): Method as for 16a using com-

pound 26a (286 mg, 1.0 mmol), 3-methoxybenzyl bromide

(0.17 mL, 1.2 mmol) and Et₃N (0.28 mL, 2.0 mmol) in EtOH (3.0 mL)

in the microwave at 1708C for 0.5 h. Flash column chromatography

(hexane/EtOAc gradient) afforded 27a as a colourless oil (254 mg,

on trituration with CH₂Cl₂/hexane/EtOAc to afford 5v as a yellow

1

powder (72 mg, 54%); mp: 143–1478C; H NMR (270 MHz, CDCl₃):

d=1.17 (6H, s), 2.66 (2H, s), 3.52 (2H, s), 3.60 (2H, s), 3.82 (3H, s),

3.83 (6H, s), 3.84 (3H, s), 5.44 (1H, s, br), 6.50 (1H, s), 6.53 (1H, s),

6.60 ppm (2H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=23.8, 42.4, 50.0,

52.5, 53.8, 55.9, 56.1, 60.8, 105.0, 110.7, 111.7, 125.6, 126.9, 136.4,

143.5, 145.0, 153.1 ppm; LC–MS (ESꢁ): m/z 386.26 [MꢁH]^ꢁ; HRMS

1

62%); H NMR (270 MHz, CDCl₃): d=1.18 (3H, d, J=6.8 Hz), 2.49–

2.55 (1H, m), 2.66–2.82 (2H, m), 2.99–3.07 (1H, m), 3.72–3.81 (2H,

m), 3.80 (3H, s), 3.81–3.86 (1H, m), 3.84 (3H, s), 5.11 (2H, s), 6.56

(1H, s), 6.61 (1H, s), 6.80 (1H, dd, J=8.2, 1.8 Hz), 6.95–6.98 (2H, m),

7.23 (1H, t, J=8.0 Hz), 7.25–7.45 ppm (5H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=19.8, 26.6, 43.8, 55.2, 55.8, 56.1, 58.0, 71.0, 111.0, 112.4,

113.9, 113.9, 121.0, 126.1, 127.3, 127.7, 128.5, 129.1, 132.8, 137.3,

141.4, 146.5, 147.8, 159.6 ppm; LC–MS (ES+): m/z 404.06 [M+H]⁺;

(ES+): m/z found 388.2111, C₂₂H₃₀NO₅[M+H]⁺requires 388.2118.

+

3,3-Dimethyl-7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6u): Method as for 6a using com-

pound 5u (78 mg, 0.24 mmol) and sulfamoyl chloride (1.2 mmol)

in DMA (1.0 mL) at room temperature for 20 h. Flash column chro-

matography (hexane to EtOAc) gave an oil that was stirred in Et₂O/

hexane, evaporated then suspended in hexane, filtered and dried

to afford 6u as cream coloured foam (31 mg, 32%); ¹H NMR

(270 MHz, [D₆]DMSO): d=1.14 (6H, s), 2.69 (2H, s), 3.43 (2H, s),

3.62 (2H, s), 3.73 (3H, s), 3.75 (3H, s), 6.80 (1H, dd, J=8.0, 2.0 Hz),

6.83 (1H, s), 6.89–6.94 (3H, m), 7.23 (1H, t, J=8.0 Hz), 7.79 ppm

(2H, s); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=42.8, 49.4, 52.1, 53.0,

54.9, 55.8, 111.8, 113.0, 114.1, 120.3, 120.6, 125.8, 129.3, 133.0,

136.8, 142.2, 149.9, 159.3 ppm; LC–MS (ES+): m/z 407.28 [M+H]⁺;

HRMS (ES+): m/z found 407.1636, C₂₀H₂₇N₂O₅S⁺[M+H]⁺requires

407.1635.

HRMS (ES+): m/z found 404.2224, C₂₆H₃₀NO₃[M+H]⁺requires

+

404.2220.

6-Benzyloxy-7-methoxy-1-methyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (27b): Method as for 16a using

compound 26a (170 mg, 0.6 mmol), 3,4,5-trimethoxybenzyl chlo-

ride (156 mg, 0.72 mmol) and Et₃N (0.17 mL, 1.2 mmol) in EtOH

(3.0 mL) in the microwave at 1708C for 0.5 h. Flash column chro-

matography (hexane to hexane/EtOAc 1:1) afforded 27b as a col-

1

ourless oil (58 mg, 21%); H NMR (270 MHz, CDCl₃): d=1.36 (3H, d,

J=6.7 Hz), 2.47–2.55 (1H, m), 2.67–2.84 (2H, m), 2.98–3.07 (1H, m),

3.59–3.73 (3H, m), 3.83 (9H, s), 3.88 (3H, s), 5.09 (2H, s), 6.56–6.62

(4H, m), 7.27–7.44 ppm (5H, m); LC–MS (ES+): m/z 464.34 [M+

H]⁺.

3,3-Dimethyl-7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxyben-

zyl)-1,2,3,4-tetrahydroisoquinoline (6v): Method as for 6a using

compound 5v (66 mg, 0.17 mmol) and sulfamoyl chloride

(0.51 mmol) in DMA (1.0 mL) at room temperature for 23 h. Flash

column chromatography (hexane to EtOAc to MeOH) gave a solid

that was further purified by preparative HPLC (MeOH/H₂O 4:1) to

afford 6v as a colourless foam (10 mg, 13%); ¹H NMR (270 MHz,

[D₆]DMSO): d=1.14 (6H, s), 2.69 (2H, s), 3.46 (2H, s), 3.58 (2H, s),

3.63 (3H, s), 3.74 (6H, s), 3.75 (3H, s), 6.64 (2H, s), 6.83 (1H, s), 6.92

(1H, s), 7.80 ppm (2H, s); LC–MS (ES+): m/z 467.18 [M+H]⁺; HRMS

(ES+): m/z found 467.1848, C₂₂H₃₁N₂O₇S⁺[M+H]⁺requires

467.1847.

(ꢀ)-6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-1-methyl-1,2,3,4-

tetrahydroisoquinoline (5w): Method as for 5b using compound

27a (276 mg, 0.68 mmol) and Pd/C (10%, 30 mg) in THF (5 mL)

and EtOH (5 mL) at room temperature for 4 h. Flash column chro-

matography (hexane/EtOAc gradient) afforded 5w as a yellow

1

foam (150 mg, 70%); mp: 97–998C; H NMR (270 MHz, CDCl₃): d=

1.36 (3H, d, J=6.6 Hz), 2.49–2.61 (1H, m), 2.66–2.88 (2H, m), 3.00–

3.12 (1H, m), 3.63–3.83 (3H, m), 3.80 (3H, s), 3.83 (3H, s), 6.51 (1H,

s), 6.63 (1H, s), 6.80 (1H, dd, J=8.2, 2.7 Hz), 6.95–6.99 (2H, m),

7.23 ppm (1H, t, J=7.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=20.2,

26.4, 43.8, 55.3, 55.9, 56.1, 58.1, 109.7, 112.6, 114.0, 114.4, 126.9,

129.3, 131.6, 141.4, 143.8, 145.0, 159.8 ppm; LC–MS (ES+): m/z

6-Benzyloxy-7-methoxy-1-methyl-3,4-dihydroisoquinoline (25a):

24a (2.68 g, 8.9 mmol) was treated with phosphorus oxychloride

(8.23 mL, 53.7 mmol) in toluene (50 mL) at 1408C for 3 h. The reac-

tion mixture was then cooled to room temperature and evaporat-

ed. CHCl₃(100 mL) and ice-H₂O (50 mL) were added, the layers

were separated and the aqueous layer was basified to pH 9 and ex-

tracted with CHCl₃(2ꢁ50 mL). The combined organics were

washed with H₂O, dried, filtered and evaporated to afford 25a as

314.18 [M+H]⁺; HRMS (ES+): m/z found 314.1752, C₁₉H₂₄O₃[M+

+

H]⁺requires 314.1751.

(ꢀ)-6-Hydroxy-7-methoxy-1-methyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (5x): Method as for 5b using com-

pound 27b (187 mg, 0.4 mmol) and Pd/C (10%, 20 mg) in THF

(5 mL) and EtOH (5 mL) at room temperature for 18 h. Flash

column chromatography (CH₂Cl₂/EtOAc gradient) afforded com-

1

a yellow oil (949 mg, 38%); H NMR (270 MHz, CDCl₃): d=2.51 (3H,

s), 2.68 (2H, t, J=7.7 Hz), 3.66 (2H, dt, J=7.7, 1.2 Hz), 3.90 (3H, s),

5.19 (2H, s), 6.72 (1H, s), 7.04 (1H, s), 7.28–7.44 ppm (5H, m); LC–

MS (ES+): m/z 282.06 [M+H]⁺.

1

pound 5x as a pale-yellow foam (72 mg, 65%); H NMR (270 MHz,

CDCl₃): d=1.35 (3H, d, J=6.6 Hz), 2.50–2.57 (1H, m), 2.69–2.85

(2H, m), 3.02–3.11 (1H, m), 3.55–3.84 (3H, m), 3.84 (12H, s), 6.51

(1H, s), 6.62 (2H, s), 6.64 ppm (1H, s); LC–MS (ES+): m/z 374.21

6-Benzyloxy-7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

(26a): Compound 25a (949 mg, 3.4 mmol) was dissolved in EtOH

(15 mL) and NaBH₄(256 mg, 6.8 mmol) was added portionwise at

08C. The reaction was stirred at room temperature for 1.5 h. H₂O

(100 mL) was added, the mixture was neutralised, then saturated

(NaCl) and extracted with EtOAc (3ꢁ100 mL). The combined organ-

ics were washed with NaHCO₃(saturated, 100 mL), dried and

[M+H]⁺; HRMS (ES+): m/z found 374.1959, C₂₁H₂₈NO₅[M+H]⁺

+

requires 374.1962.

(ꢀ)-2-(3-Methoxybenzyl)-7-methoxy-1-methyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6w): Method as for 6a using com-

pound 5w (132 mg, 0.42 mmol) and sulfamoyl chloride (2.1 mmol)

in DMA (1.0 mL) at room temperature for 4 days. Flash column

chromatography (hexane/EtOAc gradient) gave an oil which was

dissolved in Et₂O, then rapidly evaporated to afford 6w as a pale-

1

evaporated to afford 26a as a yellow oil (600 mg, 63%); H NMR

(270 MHz, [D₆]DMSO): d=1.58 (3H, d, J=6.4 Hz), 2.50 (2H, s), 2.82–

2.95 (2H, m), 3.76 (3H, s), 4.42 (1H, q, J=6.4 Hz), 5.06 (2H, s), 6.86

(1H, s), 6.88 (1H, s), 7.31–7.44 (5H, m), 9.40 ppm (1H, s, br); LC–MS

(ES+): m/z 284.13 [M+H]⁺.

1

yellow foam (127 mg, 77%); H NMR (270 MHz, [D₆]DMSO): d=1.31

(3H, d, J=6.4 Hz), 2.50–2.54 (1H, m), 2.63–2.66 (1H, m), 2.73–2.81

(1H, m), 2.93–2.98 (1H, m), 3.62–3.73 (2H, m), 3.73 (3H, s), 3.74

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(3H, s), 3.80 (1H, q, J=6.5 Hz), 6.81 (1H, dd, J=7.8, 2.2 Hz), 6.86

(1H, s), 6.92–6.93 (2H, m), 7.01 (1H, s), 7.24 (1H, t, J=8.0 Hz),

7.86 ppm (2H, s); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=19.2, 25.9,

43.0, 55.0, 55.2, 55.9, 57.2, 112.1, 112.3, 113.7, 120.6, 122.9, 125.8,

129.3, 136.9, 139.1, 141.1, 146.7, 159.4 ppm; LC–MS (ES+): m/z

393.17 [M+H]⁺; HRMS (ES+): m/z found 393.1476, C₁₉H₂₅N₂O₅S⁺

[M+H]⁺requires 393.1479.

6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1-phenyl-1,2,3,4-

tetrahydroisoquinoline (27c): Method as for 16a using compound

26b (270 mg, 0.78 mmol), 3-methoxybenzyl bromide (0.11 mL,

0.82 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH (2.5 mL) in the mi-

crowave at 1308C for 1 h. Flash column chromatography (hexane

to hexane/EtOAc 1:1) afforded 27c as a light-yellow powder

(410 mg, 59%); mp: 117–1188C; ¹H NMR (270 MHz, CDCl₃): d=

2.46–2.55 (1H, m), 2.66 (1H, dt, J=16.0, 4.1 Hz), 2.88–2.99 (1H, m),

3.07 (1H, dt, J=11.6, 4.8 Hz), 3.27 (1H, d, J=13.5 Hz), 3.63 (3H, s),

3.77 (1H, d, J=13.5 Hz), 3.80 (3H, s), 4.56 (1H, s), 5.12 (2H, s), 6.25

(1H, s), 6.66 (1H, s), 6.76–6.80 (1H, m), 6.90 (1H, d, J=7.2 Hz), 6.92

(1H, s), 7.18–7.47 ppm (11H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

28.5, 47.3, 55.3, 56.1, 58.8, 68.3, 71.0, 112.3, 112.5, 113.5, 114.2,

121.1, 127.1, 127.3, 127.4, 127.9, 128.4, 128.6, 129.2, 129.6, 130.9,

137.4, 141.5, 144.4, 146.8, 147.7, 159.7 ppm; HRMS (ES+): m/z

(ꢀ)-7-Methoxy-1-methyl-6-sulfamoyloxy-2-(3,4,5-trimethoxyben-

zyl)-1,2,3,4-tetrahydroisoquinoline (6x): Method as for 6a using

compound 5x (65 mg, 0.17 mmol) and sulfamoyl chloride

(0.87 mmol) in DMA (1.0 mL) at room temperature for 4 days. Flash

column chromatography (hexane to hexane/EtOAc 7:3 to EtOAc)

gave an oil which was successively dissolved in Et₂O and then

evaporated several times to afford 6x as yellow foam (75 mg,

95%); ¹H NMR (270 MHz, [D₆]DMSO): d=1.33 (3H, d, J=6.8 Hz),

2.50–2.55 (1H, m), 2.61–2.82 (2H, m), 2.91–3.11 (1H, m), 3.64 (3H,

s), 3.65 (2H, s), 3.74 (9H, s), 3.82 (1H, q, J=6.8 Hz), 6.67 (2H, s),

6.88 (1H, s), 7.02 (1H, s), 7.87 ppm (2H, s); ¹³C NMR (67.5 MHz,

[D₆]DMSO): d=19.4, 25.7, 42.8, 55.2, 55.8, 55.9, 57.4, 60.0, 105.0,

112.2, 122.9, 125.8, 135.2, 136.1, 136.9, 139.0, 149.7, 152.9 ppm;

LC–MS (ES+): m/z 453.15 [M+H]⁺; HRMS (ES+): m/z found

453.1695, C₂₁H₂₉N₂O₇S⁺[M+H]⁺requires 453.1690.

found 466.2394, C₃₁H₃₂NO₃[M+H]⁺requires 466.2377.

+

6-Benzyloxy-7-methoxy-1-phenyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (27d): Method as for 16a using

compound 26b (415 mg, 1.2 mmol), 3,4,5-trimethoxybenzyl chlo-

ride (277 mg, 1.28 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH

(2.5 mL) in the microwave at 1308C for 1.5 h. Flash column chro-

matography (hexane to hexane/EtOAc 1:1) afforded 27d as

1

a yellow solid (220 mg, 35%); mp: 145–1468C; H NMR (270 MHz,

N-(3-Benzyloxy-4-methoxyphenethyl)benzamide (24b): Method

as for 11 a using compound 23 (4.37 g, 17.0 mmol), Et₃N (2.8 mL,

20.0 mmol) and benzoyl chloride (2.1 mL, 18.3 mmol) in CH₂Cl₂

(50 mL) at 08C for 1 h. Work-up using H₂O (30 mL), CH₂Cl₂(50 mL),

H₂O and brine gave a solid which was suspended in Et₂O, filtered

and dried to afford 24b as a white powder (5.5 g, 87%); mp: 140–

1418C; ¹H NMR (270 MHz, [D₆]DMSO): d=2.81 (2H, t, J=6.7 Hz),

3.62 (2H, t, J=6.7 Hz), 3.86 (3H, s), 5.09 (2H, s), 6.09 (1H, s, br),

6.75–6.79 (2H, m), 6.82–6.86 (1H, m), 7.25–7.50 (8H, m), 7.63–

7.68 ppm (2H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=35.2, 41.2, 56.2,

71.1, 112.1, 114.8, 121.5, 126.9, 127.4, 128.0, 128.6, 128.7, 131.4,

131.5, 134.7 137.1, 148.3, 148.5, 167.5 ppm; HRMS (ES+): m/z

CDCl₃): d=2.51–2.58 (1H, m), 2.70 (1H, dt, J=16.0, 4.3 Hz), 2.88–

2.96 (1H, m), 3.08–3.12 (1H, m), 3.27 (1H, d, J=13.7 Hz), 3.63 (3H,

s), 3.71 (1H, d, J=13.7 Hz), 3.84 (9H, s), 4.58 (1H, s), 5.13 (2H, s),

6.25 (1H, s), 6.58 (2H, s), 6.67 (1H, s), 7.24–7.39 (8H, m), 7.43–

7.46 ppm (2H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.2, 46.5, 55.7,

56.1, 58.7, 60.8, 67.7, 69.9, 105.0, 111.1, 113.7, 127.2, 127.5, 127.7,

128.2, 128.4, 129.5, 135.4, 136.7, 137.2, 144.1, 144.3, 144.8,

153.2 ppm; HRMS (ES+): m/z found 526.2584, C₃₃H₃₆NO₅[M+H]⁺

+

requires 526.2588.

(ꢀ)-6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-1-phenyl-1,2,3,4-

tetrahydroisoquinoline (5y): Method as for 5b using compound

27c (270 mg, 0.58 mmol) and Pd/C (10%, 30 mg) in THF (15 mL)

and MeOH (15 mL) at room temperature for 1 h. Flash column

chromatography (hexane to hexane/EtOAc 3:1) afforded 5y as

found 362.1738, C₂₃H₂₄NO₃[M+H]⁺requires 362.1751.

+

6-Benzyloxy-7-methoxy-1-phenyl-3,4-dihydroisoquinoline (25b):

Method as for 25a using compound 24b (5.0 g, 13.8 mmol) and

phosphorous oxychloride (6.6 mL, 69.0 mmol) in toluene (80 mL) at

1408C for 4 h. The resultant solid that was filtered, washed with

H₂O and dried to afford 25b as light-yellow powder (2.85 g, 61%);

mp: 142–1438C; ¹H NMR (270 MHz, CDCl₃): d=2.63–2.69 (2H, m),

3.72 (3H, s), 3.75–3.80 (2H, m), 5.21 (2H, s), 6.79 (1H, s), 6.81 (1H,

s), 7.28–7.48 (8H, m), 7.56–7.61 ppm (2H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=26.0, 47.8, 56.4, 70.9, 112.2, 112.3, 120.0, 127.3, 128.1,

128.3, 128.8, 128.9, 129.4, 132.5, 136.7, 139.3, 147.6, 150.2,

a

yellow powder (125 mg, 57%); mp: 116–1178C; ¹H NMR

(270 MHz, CDCl₃): d=2.45–2.52 (1H, m), 2.67 (1H, dt, J=16.0,

4.3 Hz), 2.88–2.95 (1H, m), 3.04 (1H, dt, J=11.7, 4.9 Hz), 3.26 (1H,

d, J=13.7 Hz), 3.61 (3H, s), 3.74 (1H, d, J=13.7 Hz), 3.78 (3H, s),

4.52 (1H, s), 5.44 (1H, br), 6.17 (1H, s), 6.66 (1H, s), 6.76 (1H, dd,

J=8.2, 2.3 Hz), 6.87–6.91 (2H, m), 7.17–7.23 (2H, m), 7.28–

7.36 ppm (4H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.2, 47.0, 55.1,

55.8, 58.6, 68.1, 110.9, 112.1, 113.7, 114.1, 121.0, 127.1, 127.7, 128.2,

129.0, 129.5, 129.6, 141.4, 143.8, 144.4, 144.7, 159.5 ppm; HRMS

166.8 ppm; HRMS (ES+): m/z found 344.1648, C₂₃H₂₂NO₂[M+H]⁺

+

(ES+): m/z found 376.1903, C₂₄H₂₆NO₃

[M+H]⁺requires

requires 344.1651.

376.1907.

6-Benzyloxy-7-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline

(26b): Method as for 26a using compound 25b (2.5 g, 7.3 mmol)

and NaBH₄(0.4 g, 10.6 mmol) in EtOH (50 mL) at 1008C for 4 h. The

reaction mixture was cooled to room temperature and poured into

HCl (1m, 80 mL). The resulting solid was filtered off, washed with

H₂O, Et₂O and dried to afford 26b as a white powder (2.3 g, 92%);

mp: 116–1178C; ¹H NMR (270 MHz, CDCl₃): d=1.84 (1H, s, br),

2.62–2.72 (1H, m), 2.81–2.92 (1H, m), 2.96–3.05 (1H, m), 3.14–3.22

(1H, m), 3.63 (3H, s), 5.03 (1H, s), 5.12 (2H, s), 6.26 (1H, s), 6.66

(1H, s), 7.20–7.46 ppm (10H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

29.3, 41.9, 56.1, 61.6, 71.0, 111.6, 114.0, 120.0, 127.4, 127.7, 127.9,

128.5, 128.6, 129.0, 130.5, 137.3, 144.9, 146.9, 147.9 ppm; HRMS

(ꢀ)-6-Hydroxy-7-methoxy-1-phenyl-2-(3,4,5-trimethoxybenzyl)-

1,2,3,4-tetrahydroisoquinoline (5z): Method as for 5b using com-

pound 27d (210 mg, 0.4 mmol) and Pd/C (10%, 30 mg) in THF

(10 mL) and MeOH (10 mL) at room temperature for 1 h. Flash

column chromatography (hexane to hexane/EtOAc 1:2) afforded

5z as a yellow powder (150 mg, 82%); mp: 152–1548C; ¹H NMR

(270 MHz, CDCl₃): d=2.51–2.58 (1H, m), 2.72 (1H, dt, J=16.0,

4.7 Hz), 2.88–2.95 (1H, m), 3.08 (1H, dt, J=11.7, 5.1 Hz), 3.28 (1H,

d, J=13.7 Hz), 3.63 (3H, s), 3.69 (1H, d, J=13.7 Hz), 3.82 (3H, s),

3.83 (6H, s), 4.56 (1H, s), 5.47 (1H, s, br), 6.18 (1H, s), 6.57 (2H, s),

6.69 (1H, s), 7.22–7.36 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=28.0, 46.8, 55.8, 56.0, 58.7, 60.8, 67.7, 105.1, 110.9, 113.7, 127.2,

127.7, 128.2, 129.5, 135.4, 136.5, 143.9, 144.3, 144.8, 153.0 ppm;

(ES+): m/z found 346.1811, C₂₃H₂₄NO₂[M+H]⁺requires 346.1802.

+

ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2014, 9, 350 – 370 369

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HRMS (ES+): m/z found 436.2107, C₂₆H₃₀NO₅[M+H]⁺requires

436.2118.

+

Leblond, A. Smith, S. P. Newman, A. Di Fiore, G. De Simone, C. T. Supur-

an, A. Purohit, M. J. Reed, B. V. L. Potter, J. Med. Chem. 2006 , 49 , 768 3 –

7696; e) M. P. Leese, S. P. Newman, A. Purohit, M. J. Reed, B. V. L. Potter,

Bioorg. Med. Chem. Lett. 2004 , 14 , 313 5 –3 138.

(ꢀ)-7-Methoxy-2-(3-methoxybenzyl)-1-phenyl-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (6y): Method as for 6a using com-

pound 5y (80 mg, 0.21 mmol) and sulfamoyl chloride (1.0 mmol) in

DMA (1.0 mL) at room temperature for 24 h. Flash column chroma-

tography (hexane/EtOAc 20:1 to 2:1) afforded 6y as a light-yellow

[3] M. P. Leese, F. Jourdan, M. R. Kimberley, G. E. Cozier, N. Thiyagarajan, C.

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Reed, J. Steroid Biochem. Mol. Biol. 2003 , 84 , 26 9 –2 78; b) S. P. Newman,

P. A. Foster, C. Stengel, J. M. Day, Y. T. Ho, J. G. Judde, M. Lassalle, G. Pre-

vost, M. P. Leese, B. V. L. Potter, M. J. Reed, A. Purohit, Clin. Cancer Res.

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1

powder (55 mg, 58%); mp: 159–1608C; H NMR (270 MHz, CDCl₃):

d=2.44–2.54 (1H, m), 2.66–2.75 (1H, m), 2.91–3.11 (2H, m), 3.25

(1H, d, J=3.5 Hz), 3.61 (3H, s), 3.73 (1H, d, J=3.5 Hz), 3.78 (3H, s),

4.58 (1H, s), 4.97 (2H, br), 6.33 (1H, s), 6.75–6.78 (1H, m), 6.85–6.88

(2H, m), 7.09 (1H, s), 7.16–7.34 ppm (6H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.0, 46.8, 55.0, 55.8, 58.5, 68.1, 112.0, 113.1, 114.0,

120.8, 123.5, 127.4, 127.6, 128.3, 129.0, 129.3, 137.2, 137.6, 140.8,

143.4, 149.3, 159.4 ppm; HRMS (ES+): m/z found 455.1647,

C₂₄H₂₇N₂O₅S⁺[M+H]⁺requires 455.1635.

(ꢀ)-7-Methoxy-1-phenyl-6-sulfamoyloxy-2-(3,4,5-trimethoxyben-

zyl)-1,2,3,4-tetrahydroisoquinoline (6z): Method as for 6a using

compound 5z (120 mg, 0.28 mmol) and sulfamoyl chloride

(1.65 mmol) in DMA (1.0 mL) at room temperature for 24 h. Flash

column chromatography (hexane/EtOAc 20:1 to 2:1) afforded 6z

as

a

white powder (110 mg, 76%); mp: 90–928C; ¹H NMR

(270 MHz, CDCl₃): d=2.48–2.57 (1H, m), 2.75 (1H, dt, J=11.3,

4.4 Hz), 2.91–3.02 (1H, m), 3.09 (1H, dt, J=11.6, 4.7 Hz), 3.25 (1H,

d, J=13.5 Hz), 3.61 (3H, s), 3.67 (1H, d, J=13.5 Hz), 3.81 (3H, s),

3.82 (6H, s), 4.58 (1H, s), 4.95 (2H, s), 6.33 (1H, s), 6.54 (2H, s), 7.11

(1H, s), 7.25–7.33 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

28.0, 46.7, 56.0, 56.2, 58.7, 60.8, 68.0, 105.1, 113.4, 123.9, 127.6,

128.3, 128.4, 129.5, 135.0, 136.7, 137.2, 138.2, 143.4, 149.1,

153.0 ppm; HRMS (ES+): m/z found 515.1852, C₂₆H₃₁N₂O₇S⁺[M+

H]⁺requires 515.1846.

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This work was supported by Sterix Ltd., a member of the IPSEN

Group. We thank Ms. Alison Smith (University of Bath) for techni-

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screening resources.

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Keywords: colchicine

tetrahydroisoquinolines · tubulin

· microtubules · steric repulsion ·

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Received: October 17, 2013

Published online on January 16, 2014

ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ChemMedChem 2014, 9, 350 – 370 370

Article Doi

Synthesis, antitubulin, and antiproliferative sar of c3/c1-substituted tetrahydroisoquinolines

DOI: 10.1002/cmdc.201300412

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