Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors

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DOI: 10.1002/cmdc.201300261

Tetrahydroisoquinolinone-Based Steroidomimetic and

Chimeric Microtubule Disruptors

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

Eric Ferrandis,^[c]Ann Fiore,^[d]Philip G. Kasprzyk,^[d]and Barry V. L. Potter*^[a]

A structure–activity relationship (SAR) translation strategy was

used for the discovery of tetrahydroisoquinoline (THIQ)-based

steroidomimetic and chimeric microtubule disruptors based

upon a steroidal starting point. A steroid A,B-ring-mimicking

THIQ core was connected to methoxyaryl D-ring ring mimics

through methylene, carbonyl and sulfonyl linkers to afford

steroid derivatives that inspired its design. Linkage of the

THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent

in colchicine site binding microtubule disruptors delivered

a series of chimeric molecules whose activity (GI₅₀=40 nm) sur-

passes that of the parent steroid derivatives. Validation of this

strategy was obtained from the excellent oral activity of 7-me-

thoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (20z) relative to a benchmark steroidal bis-

sulfamate in an in vivo model of multiple myeloma.

a

number of steroidomimetic hits (e.g., 7-methoxy-2-(3-

methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline

(20c) GI₅₀=2.1 mm). Optimisation and control experiments

demonstrate the complementary SAR of this series and the

Introduction

Colchicine site binding microtubule disruptors seemingly pos-

sess great potential as therapies for cancer yet attempts to

translate their preclinical promise into the clinical domain have

proven elusive. The vinca alkaloids, taxanes and other taxane-

site binders, in contrast, have found wide therapeutic applica-

tion and together they constitute arguably the most successful

class of anticancer agents.^[1]Problems associated with existing

microtubule disruptor drugs remain with, for example, limited

therapeutic windows, acquired resistance, lack of oral bioavail-

ability and problematic formulation typifying this class. Consid-

erable potential for new microtubule disruptors with enhanced

profiles and tissue-specificity is thus clearly evident. Colchicine

site binders, such as, the combretastatins, 2-methoxyestradiol

(2-MeOE2), and molecules inspired by, or derived from, these

and related compounds, are in clinical development and pur-

portedly address some of the drawbacks associated with the

existing clinical agents.^[2]Our own involvement in this field

arose from the discovery that a non-estrogenic steroid sulfa-

tase inhibitor, 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE),

displays antiproliferative activity against both estrogen recep-

tor positive and negative cancer cells, and, surprisingly, this ac-

tivity surpasses that of 2-MeOE2.^[3]Further studies demonstrat-

ed that 2-MeOEMATE, and a range of related 2-substituted es-

tratriene-3-O-sulfamates, possess a dual antiproliferative and

anti-angiogenic mechanism of action that was ascribed to

their ability to disrupt normal microtubule assembly.^[4]The es-

tratriene sulfamate derivatives, like 2-MeOE2, bind to tubulin in

a competitive manner to colchicine,^[5]and their activity is inde-

pendent of estrogen receptor status.^[3a]Furthermore, these

new steroidal sulfamates proved effective in cell lines express-

ing drug resistance through P-glycoprotein^[6]and BCRP^[7]and

classIII b-tubulin^[8]expression and are thus able to inhibit the

growth of tumours resistant to taxanes and vinca alkaloids. In

contrast to 2-MeOE2, sulfamate derivatives such as 2-methox-

yestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE; 1a) also

display high oral bioavailability (>85% in rodents).^[9]This ap-

pears to derive from the ability of the sulfamate groups to

block both inactivating metabolism and deactivating conjuga-

tion, while also allowing the molecule to interact reversibly

with carbonic anhydrase.^[9,10]Through this latter interaction,

which has been characterised by protein crystallography,^[12d]

first-pass liver metabolism may be circumvented through se-

questration of the sulfamate drugs in red blood cells.^[9,11]The

promising combination of activity, and drug profile, encour-

aged extensive structure–activity relationship (SAR) studies to

enumerate key elements of the pharmacophore for antiproli-

ferative activity.^[3b,5,12]These studies revealed that a 2-methoxy,

2-ethyl or 2-methylsulfanyl group, a 3-O-sulfamate, and a hy-

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

Prof. B. V. L. Potter

Department of Pharmacy and Pharmacology

University of Bath

Claverton Down, Bath BA2 7AY (UK)

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

[b] Dr. E. Hamel

Sceening Technologies Branch

National Cancer Institute (NCI)

Frederick, MD 21702 (USA)

[c] Dr. E. Ferrandis

Institut de Recherche Henri Beaufour

91966 Les Ulis Cedex (France)

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

IPSEN

27 Maple St, Milford, MA (USA)

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drogen bond acceptor projecting from the steroidal D-ring, as

typified in 1, are the key elements of the pharmacophore.

We investigated whether the SAR acquired in our steroidal

series could be employed to design nonsteroidal microtubule

disruptors anticipating that, by decorating a suitable nonsteroi-

dal core structure with motifs key for activity in the steroidal

series, new microtubule disruptors might be generated. Tetra-

hydroisoquinolines (THIQs) are common motifs in natural and

synthetic compounds with interesting biological activity.^[13]Re-

ports on the use of THIQs for the generation of selective estro-

gen receptor modulators (SERMs)^[14]encouraged our selection

of this heterocycle as a prototypical mimic of the estrane A,B-

ring system. We envisaged that the C-2 and C-3 pharmaco-

phore elements of the steroidal A-ring could be introduced at

C-7 and C-6, respectively, of the THIQ core. Groups projecting

a hydrogen-bond acceptor into the region of space around the

D-ring in the steroidal series could then be introduced at N-2

to deliver candidate steroidomimetic microtubule disruptors.

The N-2 site offers an achiral, tractable point for elaboration

and could also conceivably allow the products to be salified to

promote formulation of any active compounds discovered. We

have reported preliminary data from this approach^[15]and now

disclose full details of, in particular, our exploration of

Figure 1. Design of steroidomimetic 2 and chimeric tetrahydroisoquinoline 4

based microtubule disruptors.

the optimal linkage between the THIQ core and the

aryl group and the nature of the decorating hydro-

gen-bond acceptor. In addition, derivatives with a pol-

ymethoxylated aryl group are described, and their

differential SARs indicate a chimeric nature.

Results and Discussion

Chemistry

The pharmacophore of the steroidal microtubule dis-

ruptors 1 is composed of a relatively rigid, lipophilic

hydrocarbon core decorated with two substituents in

the aromatic A-ring, namely a 2-substituent (optimal-

Scheme 1. Pictet–Spengler- and Pomeranz–Fritsch-based approaches to functionalised

1,2,3,4-tetrahydroisoquinolines. Reagents and conditions: a) MeNO₂, NH₄OAc, HOAc,

1408C; b) NaBH₄, dioxane/DMF, 08C; c) Raney nickel, hydrazine hydrate, MeOH, 408C;

d) Ac₂O, Et₃N, CH₂Cl₂, 0!258C; e) (CH₂O)n, p-TsOH, toluene, 1208C f) NaOH, EtOH/H₂O,

1208C; g) Pd/C (10%), full hydrogen, H-cube, MeOH, 258C; h) TIPSCl, imidazole, CH₂Cl₂,

258C; i) H₂NCH₂CH(OEt)₂, 608C then NaBH₄, EtOH, 1208C; j) 6m HCl, dioxane, 458C;

k) NaBH₄, TFA, CH₂Cl₂, 0!258C.

ly MeO, Et or MeS) and an adjacent, unsubstituted, 3-

O-sulfamate group, in combination with a hydrogen-

bond acceptor group projecting from C-17 of the

steroidal D-ring (Figure 1). In order to translate these

features into a nonsteroidal system, we retained in its

entirety the steroidal A-ring and chose to mimic the

B-ring with an appropriately fused heterocycle. To ex-

pedite the synthesis of compound screening sets, it was envis-

aged that a nitrogen atom in the B-ring mimic would offer

a simple extension point into steroidal D-ring space. The tetra-

hydroisoquinoline (THIQ) ring was thus selected as a core het-

erocyclic mimic of the steroidal A,B-ring system for preliminary

investigation. For reasons of synthetic ease, we chose to

extend into the D-ring region of space with benzyl, benzoyl or

benzenesulfonyl groups attached at N-2, and envisaged that,

by making respective 2’-, 3’- and 4’-methoxy derivatives,

a meaningful prototypical screening set would be generated

for both the 6-hydroxy and 6-O-sulfamoylated classes.

based approach^[16]was first explored (see Scheme 1). Benzyl

isovanillin 5 was subjected to a Henry aldol reaction with nitro-

methane, and the resultant nitro alkene 6 was reduced in two

steps. Sodium borohydride reduction of the alkene^[17]followed

by Raney nickel reduction of the nitro group proved superior

in our hands to other approaches and delivered the desired

phenethylamine in reasonable yield. In order to achieve good

yields from the key Pictet–Spengler cyclisation it proved expe-

ditious to first acylate the phenethylamine to give 7, since pu-

rification of the cyclised product was greatly simplified and

higher isolated yields possible. An alternate Pomeranz–Fritsch-

based approach to 8 was also explored and proved superior

for large-scale synthesis. This route involves an initial reductive

A practical approach to protected 6-hydroxy-7-methoxy-

1,2,3,4-tetrahydroisoquinolines 8 and 10 via a Pictet–Spengler-

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amination of benzyl vanillin 11 with 2,2-diethoxyethylamine to

deliver the acetal precursor 12 to Pomeranz–Fritsch cyclisation.

Ring closure was then executed with 6m HCl.^[18]4-Hydroxy-

tetrahydroisoquinoline 13 was then reduced with sodium bor-

ohydride/trifluoroacetic acid (TFA) to deliver 8. In order to

access a number of compounds with functions unstable under

the hydrogenolytic deprotection conditions required to

remove the benzyl protecting group, a batch of 8 was convert-

ed to the 6-O-triisopropylsilyl (TIPS) derivative 10. Hydrogena-

tion of 8 followed by TIPS protection afforded THIQ 10.

With the protected THIQ core system in hand, we then ela-

borated the prototypical screening set 17–22a–d by reacting

8 or 10 with the respective 2’-, 3’- and 4’-methoxybenzyl, -ben-

zoyl and -benzenesulfonyl halides under the appropriate con-

ditions (Scheme 2). Simple and broadly applicable reactions

and commercially available starting materials were used. N-

Benzyl THIQ derivatives 14 were typically generated by heating

the appropriately protected THIQ and benzyl halide with two

equivalents of triethylamine in ethanol at reflux, or more con-

veniently by heating at 1308C for 0.5 h under microwave irradi-

ation. A few benzyl halides were synthesised by chlorinating

the corresponding benzyl alcohol with thionyl chloride, or by

brominating the appropriate tolyl derivative at the benzylic po-

sition with N-bromosuccinimide (NBS) in tetrachloromethane.

In some cases, N-benzyl derivatives were approached from

benzoic acid starting materials, with initial 1-ethyl-3-(3-dime-

thylaminopropyl)carbodiimide (EDCI) coupling reactions used

to form amides that were then reduced to N-benzyl derivatives

14 with LiAlH₄in tetrahydrofuran (THF). N-Benzoyl THIQ deriva-

tives 15 were typically synthesised by reaction of the appropri-

ately protected THIQ with a slight excess of benzoyl halide and

two equivalents of triethylamine in chloroform at room tem-

perature. N-Benzenesulfonyl THIQ derivatives 16 were synthes-

ised in a similar manner to the benzoyl derivatives, albeit in

dichloromethane and with shorter reaction times required.

After any requisite functional group interconversion, the 6-hy-

droxy group of the THIQ derivatives could be unmasked by hy-

drogenation or fluoride-mediated desilylation to give desired

phenols 17–19 that in turn were sulfamoylated with sulfamoyl

chloride in dimethylacetamide^[19]or, alternatively, with 2,6-di-

tert-butyl-4-methylpyridine and sulfamoyl chloride in dichloro-

methane^[20]to give the target sulfamates 20–22. Functional

group interconversions were carried out by standard literature

methods with, for example, ethers being formed from the cor-

responding phenols by generating the phenolate with sodium

hydride and then quenching with the appropriate alkyl halide.

A number of control compounds was also synthesised to

test the nascent SAR (Scheme 3). Thus, THIQs in which each of

Scheme 3. Synthesis of control compounds. Reagents and conditions: a) HBr

(48%), 1208C; b) ArCH₂Br, DIPEA, DMF, 808C; c) H₂NSO₂Cl, DMA, 258C.

the three key pharmacophore elements were individually de-

leted were synthesised. The phenols 17–19 that lack the sulfa-

mate group are intermediates in the synthesis of 20–22 (keys

enumerating the substituents are provided in the tables

below) and were thus available for biological evaluation. Deriv-

ative 20a, bereft of the hydrogen-bond acceptor re-

quired in the steroidal D-ring region of space, was

also easily accessible through reaction of benzyl bro-

mide with the protected THIQ and conversion of the

product to the sulfamate as outlined in Scheme 2. In

order to determine whether, as we predicted, a 7-me-

thoxy group would prove necessary for activity, 6-

benzyloxy-1,2,3,4-tetrahydroisoquinoline 24 was syn-

thesised from commercially available 3-methoxyphe-

nethylamine by a Pictet–Spengler approach analo-

gous to that found in the literature.^[21,22]Compound

24 was then transformed to the target control com-

pounds 25 and 26 by the routes outlined in

Scheme 2.

Biology

The THIQ derivatives were initially assayed for their

ability to inhibit the proliferation of DU-145 human

Scheme 2. Synthesis of N-2 substituted tetrahydroisoquinoline derivatives. Reagents and

conditions: a) for X=CH₂: ArCH₂Cl or ArCH₂Br, EtOH, Et₃N, MW 1308C or b) ArCO₂H, EDCI,

THF, 258C then c) LiAlH₄, THF, 258C; for X=CO: ArCOCl, CHCl₃, RT; for X=SO₂: ArSO₂Cl,

CH₂Cl₂, 258C; d) for P=Bn: H₂, Pd/C, 258C, 1 atm; for P=TIPS: TBAF, THF, 258C;

e) H₂NSO₂Cl, DMA, 258C or H₂NSO₂Cl, 2,6-di-tert-butyl-4-methyl pyridine, CH₂Cl₂, 258C.

prostate cancer cells in vitro. Where available, activity

against the proliferation of MDA MB-231 human

breast cancer cells is also presented. The magnitude

and trends in activity obtained proved consistent

across these two cell lines and thus, to simplify the

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discussion, only the data for DU-145 are discussed herein. The

results obtained for the initial screening set, composed of the

2’-, 3’- and 4’-methoxybenzyl, -benzoyl and -benzenesulfonyl

THIQ derivatives, are presented in Table 1. The corresponding

core and the aryl group has a significant effect on biological

activity, and we thus chose to focus our studies on explora-

tions in the N-benzyl THIQ series 20, reasoning that the meth-

ylene linker, the smallest of the three groups surveyed in the

prototype libraries, should allow for the THIQ derivatives to

access all possible conformations and minimise any potential

off-target interactions. The fact that the best activity in the

simple methoxy substituted series is obtained with the methyl-

ene linker also supports this approach.

Table 1. Antiproliferative activity of monomethoxy-substituted N-benzyl,

N-benzoyl and N-benzenesulfonyl THIQs against DU-145 prostate cancer

cells in vitro.

For clarity, the series of control compounds that lacks one or

more elements of the pharmacophore from the initial design

(compound 20c) is presented alongside their activity data in

Figure 2. As can be seen, all of the control compounds prove

Compd

R¹

X

R²

R³

R⁴

GI₅₀[mm]^[a]

DU-145

17a

17b

17c

17d

18a

18b

18c

19a

19b

19c

20a

20b

20c

20d

21a

21b

22a

22b

22c

H

CH₂

CO

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

H

OMe

>100

60.2

CO

31.3

>100

80.5

SO₂

CH₂

CO

H

SO₂NH₂

7.8

2.1

57.2

45.2

Figure 2. Activities of control compounds lacking one or more elements of

the target pharmacophore against the proliferation of DU-145 cells in vitro.

CO

4.4

>100

56.7

SO₂

inactive. These results provide support for our hypothesis that

compounds acting in an analogous manner to the steroids

could be generated as the combination of all three pharmaco-

phore elements is required for good activity in the steroidal

series prove to be essential for activity in this prototype THIQ-

based series. To consolidate these preliminary results, we first

aimed to establish a preliminary SAR for the 3’-substituent in

the N-benzyl series, and results obtained for a series of ether

and ester derivatives are presented in Table 2. As observed in

the methoxy series, phenol derivatives 17e–i show only

modest activity and are not indicative of activity of the corre-

sponding sulfamates. Of the sulfamate derivatives, 3’-hydroxy

compound 20e is inactive, whereas trifluoromethoxy com-

pound 20 f is essentially equipotent to methoxy compound

20c. 3’-Ethoxy derivative 20g (GI₅₀=1.15 mm) is the most

active, with activity against DU-145 cells approximately twofold

better than 20c and against MDA MB-231 cells in the sub-

micromolar range. The larger isopropyl 20h and phenyl 20i

ethers display reduced activity which correlates to their in-

creasing steric size. The 3’-O-acetate 20k and 3’-O-sulfamate

20j derivatives exhibit only modest activity. From these results

it appears that the pocket available around the 3’-position is

relatively small.

OMe

H

>100

[a] Values are the mean of three determinations.

compounds with a 6-O-benzyl group were also screened but

proved less active (half-maximal growth inhibitory concentra-

tion (GI₅₀)>100 mm) and thus these data are omitted in the in-

terests of clarity. As can be seen, phenol derivatives in the

benzyl 17, benzoyl 18 and benzenesulfonyl 19 series show

little or no antiproliferative activity as was expected, since

these compounds lack the sulfamate group key to activity in

the steroidomimetic series. For the same reason, the finding

that N-benzyl derivative 20a lacking methoxy substitution is

inactive was unsurprising. The N-benzyl THIQ sulfamate deriva-

tives that possess all pharmacophore elements of the design

do however show promising activity, with the 2’- and 3’-me-

thoxy 20b and 20c derivatives causing 50% growth inhibition

at concentrations in the single-figure micromolar range. The

activity of 3’-methoxy derivative 20c (GI₅₀=2.1 mm) is approxi-

mately fourfold better than the 2’-methoxy compound 20b. In

the case of the sulfamoylated N-benzoyl THIQs, the 3’- and 4’-

methoxy compounds 21b and 21c display promising activity,

with the 3’-methoxy derivative 21b most active. In this case,

however, the difference in activity between 21b and 21c is

not great. The sulfamoylated N-benzenesulfonyl compounds

22a–c show little activity, with very modest growth inhibition

only observed for 3’-methoxy derivative 22b. It was clear from

these results that the nature of the linker between the THIQ

We thus explored the introduction of alternate motifs at the

3’-position to determine whether a hydrogen-bond acceptor

group is really requisite for activity. The antiproliferative activi-

ties of the series of 3’-substituted compounds 20l–t synthes-

ised are presented in Table 3. The series of 3’-substituted phe-

nols 17l–t (Table 3), as with the foregoing phenol derivatives,

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philic interactions make some contribution to activity, an ob-

servation in concord with the relative activities of the 3’-hy-

droxy 20e, 3’-methoxy 20c and 3’-ethoxy 20g compounds dis-

cussed above. It is clear, however, that a hydrogen-bond

acceptor (available lone electron pair) is highly favoured, al-

though its projection from the aromatic ring is not simply lim-

ited to a single bond length, since the acetate 20q, nitro 20r

and cyano 20p derivatives exhibit reasonable activity.

Table 2. Antiproliferative activity of 3’-hydroxy-, 3’-ether- and 3’-ester-

substituted N-Benzyl THIQs against DU-145 human prostate cancer cells

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

Compd

R¹

R³

GI₅₀[mm]^[a]

MDA MB-231

DU-145

3’-Chloro derivative 20m, which is capable of participating

in both lipophilic and electrostatic interactions, also displays

low-micromolar activity. While we had obtained good prelimi-

nary activity from this THIQ design approach, it became evi-

dent that the degree of rotational freedom of the N-benzyl

group is likely a limitation to activity and that biasing of the

conformational population such that the N-benzyl group proj-

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

might be desirable. Preliminary results obtained with such con-

formationally restrained THIQ-based systems have been report-

ed elsewhere.^[15]

17e

17c

17 f

17g

17h

17i

20e

20c

20 f

20g

20h

20i

H

OH

>100

55

>100

37.6

95.8

2.1

>100

ND^[b]

>100

86

ND^[b]

41

ND^[b]

2.29

0.65

4.65

ND^[b]

34.9

37

OMe

OCF₃

OEt

O-iPr

OPh

OH

OMe

OCF₃

OEt

O-iPr

OPh

OSO₂NH₂

OAc

SO₂NH₂

2.39

1.15

6.7

35.7

18.5

78.9

20j

20k

In the N-benzyl series, we also explored whether polysubsti-

tuted N-benzyl groups could deliver enhanced activity. For rea-

sons of simplicity and availability of starting materials, a series

of dimethoxy (20u–x) and trimethoxy (20y–ab) derivatives

was synthesised, and their activities are reported in Table 4. It

is useful here to consider what effect on activity can be attrib-

uted to the additional substituent by comparing the lead 3’-

methoxy compound 20c and its various dimethoxy analogues.

As can be seen for sulfamoylated 2’,3’-dimethoxy derivative

20u, introduction of an additional substituent at the 2’-posi-

tion can provide a modest enhancement in activity, as 20u is

[a] Values are the mean of three determinations. [b] ND: Not determined.

shows no significant activity. The sulfamate derivatives, in con-

trast, once more display interesting activities that provide fur-

ther insights on the SAR at this position. Fluoro-substituted

compound 20l, like methyl 20n and ethyl 20o derivatives, is

much less active than those compounds in which substituents

offer the potential for hydrogen bonding or alternate electro-

static interactions. It appears, given the activity of ethyl deriva-

tive 20o against MDA MB-231 proliferation, that positive lipo-

Table 4. Antiproliferative activity of polymethoxylated THIQs against DU-

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

cells in vitro.

Table 3. Antiproliferative activities of 3’-substituted N-benzyl THIQs

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

breast cancer cells in vitro.

Compd

R¹

R³

GI₅₀[mm]^[a]

MDA MB-231

Compd R¹

R²

H

R³

R⁴

R⁵

R⁶

GI₅₀[mm]^[a]

DU-145 MDA MB-231

DU-145

17l

H

F

Cl

Me

Et

>100

84

ND^[b]

>100

ND^[b]

>100

ND^[b]

20b

17u

20u

17v

20v

17w

20w

17x

SO₂NH₂

OMe

H

OMe

H

2.1

>100

1.2

>100

8.54

52.7

2.5

95

2.61

>100

17

0.65

ND^[b]

>100

0.888

ND^[b]

3.15

ND^[b]

37

1.85

>100

11.9

0.62

17m

17n

17o

17p

17r

17s

17t

20l

20m

20n

20o

20p

20q

20r

20s

20t

H

OMe OMe

SO₂NH₂OMe OMe

>100

51.8

H

OMe OMe

OMe

CN

SO₂NH₂

H

SO₂NH₂

H

NO₂

NHAc

NHSO₂Me

F

Cl

Me

Et

CN

Ac

H

OMe

H

SO₂NH₂

20x

SO₂NH₂

H

SO₂NH₂OMe OMe OMe

6.2

41.7

35

8.1

ND^[b]

ND^[a]

8

17y

20y

17z

OMe OMe OMe

H

OMe

OMe OMe OMe

H

4.7

20z

SO₂NH₂

H

0.297

7.8

0.66

0.329

4.1

0.491

1.85

3.03

>100

0.983

1.91

>100

17aa

20aa

17ab

20ab

OMe OMe

OMe

NO₂

NHAc

NHSO₂Me

SO₂NH₂OMe

OMe

SO₂NH₂OMe

H

OMe >100

>100

[a] Values are the mean of three determinations. [b] ND: Not determined.

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approximately twofold more active than 20c. In contrast, 3’,4’-

dimethoxy compound 20v is fourfold less active than 20c.

This pattern reflects the SAR observed in the monomethoxy-

benzyl series where 3’>2’@4’. It thus appears reasonable that

a 4’-methoxy group might preclude binding of the THIQ deriv-

atives in a manner analogous to the steroidal microtubule dis-

ruptors that they are designed to mimic. In contrast, the 2’-

substituent appears able to provide extra beneficial interac-

tion(s) at the site of action. Combination of the 3’-methoxy

with a methoxy group at either the 5’- or 6’-position has little

effect on activity and shows that, while there is space for these

groups to be tolerated, they apparently contribute no further

positive interaction. Furthermore, it appears that increasing the

electron density of the aryl ring provides no apparent en-

hancement in activity, suggesting that any putative p-facial in-

teractions are not improved.

3’,4’,5’-trimethoxy series, whereas in monosubstituted N-benzyl

systems their effects are profound.^[15]The 2’,4’,6’-trimethoxy

compounds 17ab and 20ab are inactive, which is unsurpris-

ing, and they appear to conform to the general steroidomi-

metic SAR where 4’-substitution is detrimental for activity.

With excellent activity established for the 3’,4’,5’-trimethoxy

compound 20z we modified the THIQ at C-7 and the linker

while retaining this motif and synthesised the C-7-ethyl deriva-

tives 17ac and 20ac. Replacing the C-7-methoxy group with

an ethyl group leads to a near 10-fold reduction in activity for

phenol 17ac relative to 17z and an approximately eightfold

gain in activity for the sulfamate 20ac relative to 20z (see

Table 5). Interestingly, this effect on activity reflects the trends

Table 5. Antiproliferative activity of polymethoxylated THIQs against DU-

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

cells in vitro.

The activities of sulfamoylated trimethoxy derivatives 20y–

ab are extremely interesting, and in this case it is illustrative to

compare them with the corresponding sulfamoylated disubsti-

tuted compounds. 2’,3’,4’-Trimethoxy derivative 20y displays

only modest activity with a GI₅₀value of 17 mm; this is approxi-

mately 10-fold worse than the value for 2’,3’-dimethoxy com-

pounds 20u and twofold worse than the value for 3’,4’-dime-

thoxy derivative 20v. As before, substitution at C-4 appears to

be detrimental to activity. 3’,4’,5’-Trimethoxy compound 20z,

with its GI₅₀value of 297 nm, is extremely active; it is 10-fold

more active than the 3’,5’-dimethoxy analogue 20w and ap-

proximately 30-fold better than 3’,4’-dimethoxy compound

20v. This contrasts strongly with results discussed above,

where 4’-methoxy substitution is universally detrimental to ac-

tivity. The activity of the corresponding phenol 17z (GI₅₀=

650 nm) is also notable with, for the first time, the activities of

phenol 17z and sulfamate 20z derivatives proving to be of

a similar magnitude. It is thus apparent that the activities of

3’,4’,5’-trimethoxy derivatives 17z and 20z do not follow the

SAR established above for the foregoing mono- and disubsti-

tuted N-benzyl THIQs, where all three pharmacophore ele-

ments from the steroidal series are requisite for activity and 4’-

substitution is detrimental to activity. The 3’,4’,6’-trimethoxy

derivatives also show good activity for both the phenol 17aa

(GI₅₀=7.8 mm) and sulfamate 20aa (GI₅₀=660 nm), with the

latter proving 10-fold and fourfold better than the 3’,4’-me-

thoxy 20v and 3’,6’-dimethoxy 20x derivatives, respectively.

Once more, there are two points of divergence from the SAR

established for the mono- and disubstituted N-benzyl THIQ

series. This led us to postulate that trimethoxy-substituted

compounds, rather than mimicking steroidal colchicine-site-

binding microtubule disruptors, might better be considered

chimeric systems composed of the steroidal A,B-ring mimick-

ing motif and the trimethoxyaryl group prevalent in colchicine-

site-binding natural products. The binding of the trimethoxyar-

yl group in this case is likely the predominant interaction, and

the THIQ component can still potentially access the binding

site occupied by the steroidal A-ring.

Compd

R¹

X

Y

GI₅₀[mm]^[a]

MDA MB-231

DU-145

17ac^[b]

20ac^[b]

18d

H

CH₂

O

CH₂

CO

3.85

5.41

SO₂NH₂

H

SO₂NH₂

0.041

0.921

1.81

0.052

0.733

1.72

21d

O

CO

[a] Values are the mean of three determinations.

in activity change in the steroidal series wherein the 2-ethyl

derivatives are less and more active than the 2-methoxy-3-hy-

droxy and 2-methoxy-3-O-sulfamoyl derivatives, respective-

ly.^[3b,12d]The N-3’,4’,5’-trimethoxybenzoyl THIQ derivatives 18d

and 21d are less active than the corresponding 3’,4’,5’-trime-

thoxybenzyl compounds 17z and 20z (see Table 5), albeit 18b

and 21b display enhanced activity relative to the other N-ben-

zoyl derivatives described above. The improvement in activity

for phenol 18d relative to 18b is more than 30-fold, whereas

3’,4’,5’-trimethoxybenzoyl sulfamate 21d is more modest and

only twofold more active than 21b. It is striking in this case

that the phenol is more active that the sulfamate. Although it

is not possible to provide a definite explanation, it is plausible

to suggest that these compounds are chimeras and that the

bulkier carbonyl linker precludes optimal binding of the sulfa-

mate of 21d and thus the phenol 18d is the more active. The

activities of 18d and 17z are comparable, indicating that the

carbonyl linker does not significantly inhibit binding in the

phenol series.

Several of the more active chimeras were evaluated for their

ability to inhibit both tubulin assembly and the binding of tu-

bulin to colchicine alongside combretastatin A-4 (CA-4;

Table 6). IC₅₀values for both 17z and 20z are >20 mm, with no

observable effect observed at this concentration for 17z. Com-

pound 20z, however, shows some activity at 20 mm and is also

better at inhibiting colchicine binding. A better indication of

on-target activity was however available for 20ac, the 7-ethyl

Although not discussed in this paper, it is notable that

groups at C-1 and C-3 of the THIQ core that can effect a confor-

mational biasing have no significant effect on activity in the

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arrest and subsequent apoptosis.^[23b]Additionally, it is a potent

anti-angiogenic agent both in vitro and in vivo with additional

vascular targeting potential. In a hormone-independent breast

cancer xenograft model, 20z suppressed tumour growth by

84% after 35 days of daily dosing, with no signs of toxicity. In

contrast to paclitaxel (Taxolꢁ), the efficacy of 20z was also un-

changed in two clinically relevant models of drug resistan-

ce.^[23b]

Table 6. Activities of selected chimeras as inhibitors of tubulin assembly

and [³H]colchicine binding to tubulin.

Inhibition of

tubulin assembly

IC₅₀[mm]^[a]

Inhibition [%] of

colchicine binding

at 5 mm inhibitor^[b]

Compd

CA-4

17z

20z

1.2ꢁ0.1

98ꢁ0.7

4.1ꢁ2.0

10ꢁ0.9

49ꢁ0.5

>20 (no activity)^[c]

>20 (partial activity)^[c]

2.5ꢁ0.03

20ac

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

are the mean ꢁSD of at least two determinations. [c] Compound 20z in-

hibited tubulin assembly at 20 mm whereas 17z was inactive at this con-

centration.

Conclusions

We have demonstrated that the tetrahydroisoquinoline core is

a useful mimic of the steroidal A,B-ring system which, by use

of the SAR translation strategy outlined above, may find broad-

er application for the elaboration of steroidomimetic systems.

analogue of 20z which, with an IC₅₀value of 2.5 mm

against tubulin assembly, is similar in activity to CA-4.

Likewise, in terms of inhibition of colchicine binding,

ethyl compound 20ac proved superior to both 17z

and 20z. It should be noted that, as with all microtu-

bule disruptors, the concentrations required for cata-

strophic loss of structure are much higher than those

required to trigger cell death, reflecting the fact that

simply perturbing normal assembly is sufficient to

arrest normal cell division.

The acid test for any promising candidate is

whether in vitro activity can be translated into the in

vivo context, and preliminary data for 20ac proved

promising.^[23a]Compound 20z, although clearly less

active in vitro, was selected for evaluation in vivo, as

we had observed a superior drug metabolism and

pharmacokinetics (DMPK) profile for methoxy deriva-

tives over their ethyl analogues in the steroidal

series. Assessment of 20z in the RPMI-8226 xenograft

model of multiple myeloma and relative to the steroi-

dal parent 1a was performed. We determined that

this compound could be formulated as a solution in

2% aqueous citric acid; and 20z was dosed orally in

this form on a daily basis for 28 days at 40 mgkg^ꢀ1

.

The results are presented in Figure 3, wherein strong

inhibition of tumour growth can be seen (64% for

both the 20z and 1a treated cohorts after 28 days).

Furthermore, a prolonged inhibition of tumour

growth is observed in both treated cohorts (66% and

64% growth inhibition 18 days after cessation of

dosing for the 20z and 1a treated cohorts, respec-

tively). This experiment thus both confirms the

strong potential and the favourable formulation char-

acteristics of this class of THIQ-based chimeric micro-

tubule disruptors. The apparent equivalence of 20ac

and 20z in this model (20ac showed 48% growth in-

hibition after 28 days at 40 mgkg^ꢀ1) also confirms

that DMPK factors can override apparently superior Figure 3. a) The activity of 20z (40 mgkg^ꢀ1d^ꢀ1, 28 d, p.o. in 2% aq citric acid) against the

growth of RPMI-8226 (multiple myeloma) xenografts in athymic nude mice was assessed

preliminary in vitro activity in vivo. In further preclini-

alongside the benchmark steroid derivative, 2-MeOE2bisMATE (1a; 20 mgkg^ꢀ1d^ꢀ1, 28 d,

cal evaluations, compound 20z was also shown to

be a tubulin disruptor which induces p53 expression,

p.o.). After 28 day dosing significant inhibition of tumour growth is observed for both co-

horts of treated animals. b) No significant weight loss is observed in either cohort indi-

Bcl2 phosphorylation, caspase 3 cleavage, cell cycle cating that 20z is well tolerated.

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

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

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

accordance with institutional guidelines. Tumour cells (6ꢂ10⁶cells/

animal) were implanted subcutaneously into the left flank of mice.

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

desired size, approximately 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 was calculated using this formula: tumour weight [mg]=

(w²ꢂl)/2 where w=width and l=length in mm of the multiple

myeloma tumour.

In addition, combining pharmacophore elements from differ-

ent series that address the same target protein, yields mole-

cules with a distinct SAR from steroidomimetic tetrahydroiso-

quinolines (THIQs) that are best considered small-molecule chi-

meras. It is notable that chimera construction was achieved re-

maining within the parameters associated with an orally bio-

available drug and, in confirmation, oral dosing of 20z in

a xenograft model of multiple myeloma reveals excellent inhib-

ition of tumour growth, confirming the promise of this series.

We have thus generated a novel series of microtubule disrup-

tors with excellent in vitro and in vivo activity that may fit the

profile of moderate half-life microtubule disruptors explaining

the very desirable drug-like profile (good oral efficacy and

good tolerability). The compounds are easily synthesised, ame-

nable to formulation using benign excipients and also inhibit

the proliferation of taxane-resistant cell lines.^[23]Further optimi-

sation of these series of anticancer agents is in progress.

Chemistry

All chemicals were either purchased from Sigma–Aldrich (Gilling-

ham, UK) or Alfa Aesar (Heysham, UK). Organic solvents of analyti-

cal reagent grade were supplied by Fisher Scientific (Loughbor-

ough, UK) and used as supplied. N,N-dimethylacetamide (DMA)

was purchased from Aldrich and stored under a positive pressure

of N₂after use. Tetrahydrofuran (THF) was distilled from sodium

with benzophenone indicator. Sulfamoyl chloride was prepared by

an adaptation of the method of Appel and Berger^[28]and was

stored in the refrigerator under positive pressure of N₂as a solution

in toluene as described by Woo et al.^[29]An appropriate volume of

this solution was freshly concentrated in vacuo immediately before

use. Reactions were carried out at RT unless stated otherwise. Thin-

layer chromatography (TLC) was performed on precoated alumini-

um plates (Merck, silica gel 60 F₂₅₄). Product spots were visualised

either by UV irradiation at 254 nm or by staining with either alka-

line KMnO₄solution or 5% w/v dodecamolybdophosphoric acid in

EtOH, followed by heating. Flash column chromatography was per-

formed using gradient elution (solvents indicated in text) on either

prepacked columns (Isolute) on a Flashmaster II system (Biotage,

Uppsala, Sweden) or on a CombiFlash Rf Automated Flash Chroma-

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

disposable flash columns. ¹H NMR and ¹³C NMR spectra were re-

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

270 and 67.5 MHz, respectively, or a Mercury VX 400 NMR spec-

trometer (Varian, Paolo Alto, CA, USA) at 400 and 100 MHz, respec-

tively. Chemical shifts are reported in parts per million (ppm) rela-

tive to tetramethylsilane (TMS) as internal standard. Coupling con-

stants J are recorded to the nearest 0.1 Hz. The precursors of com-

pounds 8, 14o and 14ab and compounds 13, 15a,b, 15d, 18a,b,

18d and 21a–c appear each as a set of two conformers in the

¹H NMR spectra. Mass spectra were recorded at the Mass Spec-

trometry Service Center, University of Bath, UK. FAB-MS was carried

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

analyses were performed by the Microanalysis Service, University

of Bath. Melting points were determined using a Stuart SMP3 or an

Optimelt MPA100 melting point apparatus (Stanford Research Sys-

tems, Sunnyvale, CA, USA) and are uncorrected. All compounds

were ꢂ98% pure by reverse-phase HPLC run with CH₃CN/H₂O or

MeOH/H₂O (Sunfire C18 reverse-phase column, 4.6ꢂ150 mm,

3.5 mm pore size).

Experimental Section

Biology

Cell lines: DU-145 (brain metastasis carcinoma of the prostate) and

MDA-MB-231 (metastatic pleural effusion of breast adenocarcino-

ma) 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, supplemented with

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

(0.1 mgmL^ꢀ1).

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

seeded into 96-well microtitre plates (5000 cells/well) and treated

with 10^ꢀ9–10^ꢀ4m of compound 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 concen-

tration of 50% growth inhibition (GI₅₀). All experiments were per-

formed in triplicate.

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

ously,^[24]was used in studies presented here. Assembly IC₅₀values

were determined as described in detail elsewhere.^[25]Briefly,

1.0 mgmL^ꢀ1(10 mm) tubulin was preincubated without GTP with

varying compound concentrations for 15 min at 308C. Reaction

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

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 reduce the turbidity increase by 50% were determined.

The method for measuring inhibition of the binding of

[³H]colchicine to tubulin was described in detail previously.^[26]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 to CA-4, a particularly potent inhibitor of the binding of

colchicine to tubulin.^[27]Reaction mixtures were incubated 10 min

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

reaction mixtures is generally 40–60% complete. A minimum of

two experiments were performed with each compound.

(E)-2-Benzyloxy-1-methoxy-4-(2-nitrovinyl)benzene (6): Com-

pound 5 (75.0 g, 0.31 mol) was treated with MeNO₂(32.2 mL,

0.6 mol) and NH₄OAc (34.7 g, 0.45 mol) in HOAc (500 mL) at 1408C

for 2 h. The solution was cooled to RT. H₂O (800 mL) was added,

and the resulting solid was filtered, washed with H₂O and dried.

The solid was stirred in hot EtOH (800 mL), cooled to RT, filtered

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

from Harlan Labs), were fed ad libitum H₂O and an autoclaved

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and dried to afford compound 6 as a yellow powder (69.0 g, 70%):

mp: 124–1278C; ¹H NMR (270 MHz, CDCl₃): d=3.95 (3H, s), 5.18

(2H, s), 6.94 (1H, d, J=8.4 Hz), 7.04 (1H, d, J=2.4 Hz), 7.18 (1H, dd,

J=8.4, 2.0 Hz), 7.31–7.48 (6H, m), 7.92 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃): d=56.2 (CH₃), 71.2 (CH₂), 111.7 (CH), 113.1 (CH),

122.7 (C_q), 124.9 (CH), 127.3 (CH), 128.3 (CH), 128.8 (C_q), 135.2 (CH),

136.3 (C_q), 139.3 (CH), 148.7 (C_q), 153.5 ppm (C_q); LC-MS (APCI+):

m/z: 286.46 [M+H]⁺.

was stirred in H₂O (50 mL) and extracted with CHCl₃(2ꢂ100 mL).

The combined organic phases were washed with brine, dried

(MgSO₄), filtered and concentrated in vacuo to give a yellow oil

that slowly solidified to afford compound 8 as a yellow solid

(3.45 g, 94%): mp: 74–758C; ¹H NMR (270 MHz, CDCl₃): d=1.76

(1H, s, br), 2.63 (2H, t, J=5.7 Hz), 3.07 (2H, t, J=5.7 Hz), 3.81 (3H,

s), 3.92 (2H, s), 5.10 (2H, s), 6.52 (1H, s), 6.60 (1H, s), 7.27–

7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.3 (CH₂), 43.6

(CH₂), 47.6 (CH₂), 55.5 (CH₃), 70.8 (CH₂), 109.3 (CH), 114.6 (CH), 126.2

(2ꢂC_q), 126.9 (2ꢂCH), 127.4 (CH), 128.3 (2ꢂCH), 137.0 (C_q), 146.2

(C_q), 147.7 ppm (C_q): LC/MS (APCI+): m/z: 270.40 [M+H]⁺.

N-(3-Benzyloxy-4-methoxyphenethyl)acetamide

(7):

NaBH₄

(12.0 g, 317 mmol) was covered with dioxane (250 mL) and N,N-di-

methylformamide (DMF; 70 mL). Compound 6 (20.0 g, 70.2 mmol)

was added dropwise at 08C within 5 h as solution in dioxane

(200 mL) and DMF (50 mL). The reaction mixture was stirred at RT

for 1 h, cooled to 08C and carefully quenched with HCl (2m). The

reaction mixture was extracted with EtOAc (500 mL), washed with

H₂O and brine, then dried (MgSO₄), filtered and concentrated in

vacuo. Flash column chromatography (hexane/EtOAc 4:1 v/v) af-

6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (8): Com-

pound 13 (1.95 g, 6.8 mmol) was covered with CH₂Cl₂(14 mL) and

trifluoroacetic acid (TFA; 5.1 mL, 68.6 mmol) was added dropwise

at 08C. NaBH₄(515 mg, 13.6 mmol) was added portionwise at 08C,

and the reaction mixture was stirred warming to RT for 18 h, then

diluted with CH₂Cl₂(100 mL), washed with NaHCO₃(2m, 100 mL)

and H₂O (100 mL), then dried (NaCl), filtered and concentrated in

vacuo. The residue was stirred in Et₂O, filtered, washed with Et₂O

and dried to afford compound 8 as a white powder (1.762 g, 96%).

Data as described above.

forded 2-(3-benzyloxy-4-methoxyphenyl)nitroethane as

a light

yellow powder (10.0 g, 50%): mp: 88–898C; ¹H NMR (270 MHz,

CDCl₃): d=3.21 (2H, t, J=7.4 Hz), 3.87 (3H, s), 4.52 (2H, t, J=

7.4 Hz), 5.14 (2H, s), 6.73 (1H, d, J=1.9 Hz), 6.75 (1H, dd, J=8.0,

1.9 Hz), 6.85 (1H, d, J=8.0 Hz), 7.29–7.46 ppm (5H, m); LC-MS

(APCIꢀ): m/z: 286.33 [MꢀH]^ꢀ. Raney nickel (50% slurry in H₂O,

7.5 g) was washed in presence of a magnetic stirring bar with

MeOH (3ꢂ5 mL). The nitroalkane (9.0 g, 31.3 mmol) was then

added as a solution in MeOH (50 mL), the reaction cooled to 08C,

and hydrazine hydrate (6.0 mL, 123 mmol) was added dropwise.

The reaction mixture was stirred at 408C for 1 h, cooled to RT, fil-

tered through celite and washed with MeOH (40 mL). The filtrate

was concentrated in vacuo and the residue was stirred in EtOAc

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

filtered and concentrated in vacuo to afford 3-benzyloxy-4-meth-

6-Hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (9): Com-

pound 8 (4.30 g, 16.0 mmol) was dissolved in MeOH (320 mL) and

filtered. The solution was sucked at 1.0 mLmin^ꢀ1into the H-cube

and treated with full hydrogen over Pd/C (10%, 140 mg cartridge)

at RT. The resulting solution was concentrated in vacuo to give

a white solid that was stirred in EtOAc, filtered and dried to afford

compound 9 as a white solid (2.853 g, 99%): mp: 195–1978C;

¹H NMR (270 MHz, CD₃OD): d=3.01 (2H, t, J=6.2 Hz), 3.47 (2H, t,

J=6.2 Hz), 3.87 (3H, s), 4.28 (2H, s), 6.68 (1H, s), 6.78 ppm (1H, s);

¹³C NMR (67.5 MHz, CD₃OD): d=25.7 (CH₂), 43.3 (CH₂), 45.9 (CH₂),

56.9 (CH₃), 110.9 (CH), 116.4 (CH), 120.0 (C_q), 125.2 (C_q), 147.9 (C_q),

148.8 ppm (C_q); LC-MS (APCI+): m/z: 180.05 [M+H]⁺.

oxyphenethylamine as

a

colourless oil (7.2 g, 88%): ¹H NMR

(270 MHz, CDCl₃): d=1.27 (2H, s, br), 2.62 (2H, t, J=6.7 Hz), 2.86

(2H, t, J=6.7 Hz), 3.85 (3H, s), 5.14 (2H, s), 6.72 (1H, s), 6.75 (1H, d,

J=1.7 Hz), 6.82 (1H, dd, J=7.2, 1.5 Hz), 7.26–7.46 ppm (5H, m).

The amine (7.2 g, 28.0 mmol) was dissolved in CH₂Cl₂(50 mL) and

Et₃N (5.0 mL, 36.0 mmol) and cooled to 08C. Ac₂O (3.7 mL,

39.2 mmol) was added dropwise, and the solution was stirred at

08C for 2 h then at RT for 2 h. The reaction mixture was diluted

with CH₂Cl₂(50 mL) and washed with H₂O and brine, then dried

(MgSO₄), filtered and concentrated in vacuo. Flash column chroma-

tography (hexane/EtOAc 2:1!1:4 v/v) afforded compound 7 as

a white solid (4.50 g, 54%): mp: 126–1278C; ¹H NMR (270 MHz,

CDCl₃): d=1.86 (3H, s), 2.68 (2H, t, J=6.9 Hz), 3.40 (2H, q, J=

6.9 Hz), 3.86 (3H, s), 5.13 (2H, s), 5.34 (1H, s, br), 6.70 (1H, s), 6.72

(1H, d, J=8.4 Hz), 6.83 (1H, d, J=8.4 Hz), 7.26–7.45 ppm (5H, m).

7-Methoxy-6-triisopropylsiloxy-1,2,3,4-tetrahydroisoquinoline

(10): Compound 9 (3.136 g, 17.5 mmol) was treated with chlorotrii-

sopropylsilane (4.07 g, 21.1 mmol) and imidazole (3.577 g,

52.5 mmol) in CH₂Cl₂(90 mL) at RT for 48 h. The reaction mixture

was washed with H₂O (200 mL) containing NH₄Cl (saturated,

20 mL). The aqueous layer was extracted with CH₂Cl₂/EtOAc (4:1

v/v, 2ꢂ100 mL). The combined organics were dried (NaCl), filtered

and concentrated in vacuo. Flash column chromatography (SiO₂:

120 g, EtOAc/MeOH 4:1!1:1!1:1 v/v and 2% Et₃N) afforded com-

1

pound 10 as a light yellow solid (4.95 g, 84%): H NMR (270 MHz,

CDCl₃): d=1.05 (18H, d, J=6.9 Hz), 1.12–1.30 (3H, m), 2.81 (2H, t,

J=6.1 Hz), 3.21 (2H, t, J=6.0 Hz), 3.72 (3H, s), 4.04 (2H, s), 6.46

(1H, s), 6.58 (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=12.8 (CH), 17.9

(CH₃), 28.3 (CH₂), 43.9 (CH₂), 48.0 (CH₂), 55.5 (CH₃), 109.7 (CH), 120.7

(CH), 126.4 (C_q), 128.2 (C_q), 143.6 (C_q), 148.9 ppm (C_q).

6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (8): Com-

pound 7 (4.20 g, 14.0 mmol) was treated with paraformaldehyde

(1.00 g, 33.3 mmol) and p-toluenesulfonic acid (p-TsOH; 30 mg,

0.16 mmol) in toluene (80 mL) at 1208C for 4 h. After cooling to RT

the reaction mixture was concentrated in vacuo and EtOAc was

added. The mixture was washed with H₂O and brine, then dried

(MgSO₄), filtered and concentrated in vacuo to afford the N-acetyl-

N-(4-Benzyloxy-3-methoxybenzyl)-N-(2,2-diethoxyethyl)amine

(12): Compound 11 (25.0 g, 103 mmol) was treated with aminoace-

taldehyde diethyl acetal (11.7 mL, 108 mmol) at 608C for 8 h. The

mixture was dissolved in EtOH (150 mL), and NaBH₄(4.20 g,

110 mmol) was added portionwise. The mixture was stirred at

1208C for 4 h, then poured into ice–H₂O, stirred for 0.5 h and ex-

tracted with EtOAc. The organic layer was washed with H₂O and

brine, then dried, filtered and concentrated in vacuo to afford com-

pound 12 as a light yellow oil (35.90 g, 97%): ¹H NMR (270 MHz,

CDCl₃): d=1.19 (6H, t, J=7.2 Hz), 1.51 (1H, s, br), 2.72 (2H, d, J=

5.5 Hz), 3.51 (2H, dq, J=7.2, 1.9 Hz), 3.67 (2H, dq, J=7.2, 1.9 Hz),

3.72 (2H, s), 3.88 (3H, s), 4.60 (1H, t, J=5.5 Hz), 5.13 (2H, s), 6.75

(1H, dd, J=8.3, 1.4 Hz), 6.81 (1H, d, J=8.3 Hz), 6.89 (1H, d, J=

1

THIQ as a light yellow solid (4.25 g, 98%): mp: 121–1228C; H NMR

(270 MHz, CDCl₃): d=2.14 and 2.16 (3H, 2 s), 2.69 and 2.74 (2H, 2t,

J=5.9 and 5.7 Hz), 3.62 and 3.77 (2H, 2t, J=5.9 and 5.7 Hz), 3.84

and 3.85 (3H, 2s), 4.53 and 4.61 (2H, 2s), 5.11 (2H, 2s), 6.59 and

6.65 (1H, 2s), 6.64 (1H, s), 7.26–7.45 ppm (5H, m); LC-MS (APCI+):

m/z: 312.34 [M+H]⁺. The N-acetyl-THIQ (4.25 g, 13.7 mmol) was

treated with aq NaOH (10%, 30 mL) in EtOH (120 mL) at 1208C for

16 h. The reaction mixture was concentrated in vacuo. The residue

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1.4 Hz), 7.27–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.5

(2ꢂCH₃), 51.6 (CH₂), 53.8 (CH₂), 56.1 (CH₃), 62.4 (2ꢂCH₂), 71.2 (CH₂),

102.3 (CH), 111.9 (CH), 114.0 (CH), 120.3 (CH), 127.3 (2ꢂCH), 127.8

(CH), 128.6 (2ꢂCH), 133.6 (C_q), 137.4 (C_q), 147.2 (C_q), 149.7 ppm

(C_q); HRMS (ES+): m/z [M+H]⁺calcd for C₂₁H₃₀NO₄⁺: 360.2169,

found: 360.2161.

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

isoquinoline (14c): Prepared as described for 14a using com-

pound 8 (404 mg, 1.5 mmol), 3-methoxybenzyl bromide (0.29 mL,

2.1 mmol) and Et₃N (0.84 mL, 6.0 mmol) in EtOH (20 mL) at 1208C

for 72 h. Flash column chromatography (hexane/EtOAc 10:1!3:1

v/v) afforded compound 14c as a white solid (0.39 g, 67%): mp:

71–728C; ¹H NMR (270 MHz, CDCl₃): d=2.64–2.76 (4H, m), 3.54

(2H, s), 3.64 (2H, s), 3.80 (3H, s), 3.81 (3H, s), 5.10 (2H, s), 6.51 (1H,

s), 6.63 (1H, s), 6.83 (1H, ddd, J=8.2, 2.8, 0.9 Hz), 6.97 (3H, m),

7.25–7.45 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.7 (CH₂),

50.8 (CH₂), 55.3 (CH₃), 55.9 (CH₂), 56.1 (CH₃), 62.8 (CH₂), 71.2 (CH₂),

110.1 (CH), 112.8 (CH), 114.3 (CH), 114.4 (CH), 121.5 (CH), 126.3 (C_q),

127.3 (2ꢂCH), 127.5 (C_q), 127.8 (CH), 128.5 (2ꢂCH), 129.3 (CH),

137.3 (C_q), 140.2 (C_q), 146.7 (C_q), 148.0 (C_q), 159.8 ppm (C_q); LC-MS

(APCI+): m/z 390.55 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for

C₂₅H₂₈NO₃⁺: 390.2064, found: 390.2063.

6-Benzyloxy-4-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquino-

line (13): A suspension of compound 12 (20 g, 55.6 mmol) in diox-

ane (20 mL) and HCl (6m, 250 mL) was stirred at 458C for 1.5 h.

After cooling to 08C, the white solid was filtered, washed succes-

sively with cold H₂O and Et₂O, and then poured into H₂O (200 mL).

The suspension was stirred at 08C and made alkaline with NaOH.

After an additional 0.5 h stirring, the white solid was filtered off,

washed with H₂O then Et₂O and dried in vacuo to afford com-

pound 13 as a white powder (12.80 g, 81%): mp: 148–1498C;

¹H NMR (270 MHz, CDCl₃): d=2.33 (2H, s, br), 2.94 (1H, dd, J=13.0,

2.8 Hz), 3.15 (1H, dd, J=12.9, 3.0 Hz), 3.69 and 3.79 (2H, 2d, J=0.5

and 2.2 Hz), 3.84 (3H, s), 4.39 (1H, t, J=2.8 Hz), 5.12 (2H, s), 6.49

(1H, s), 6.89 (1H, s), 7.27–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=47.8 (CH₂), 51.3 (CH₂), 56.1 (CH₃), 65.4 (CH), 71.1 (CH₂),

109.1 (CH), 114.7 (CH), 127.5 (2ꢂCH), 127.9 (CH), 128.6 (2ꢂCH),

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

isoquinoline (14d): Prepared as described for 14a using com-

pound 8 (404 mg, 1.5 mmol), 4-methoxybenzyl bromide (0.23 mL,

1.6 mmol) and Et₃N (0.42 mL, 3.0 mmol) in EtOH (30 mL) at 1208C

for 48 h. Flash column chromatography (hexane/EtOAc 10:1!3:1

v/v) afforded compound 14d as a white solid (0.33 g, 57%): mp:

96–978C; ¹H NMR (270 MHz, CDCl₃): d=2.65–2.79 (4H, m), 3.53

(2H, s), 3.61 (2H, s), 3.81 (3H, s), 3.81 (3H, s), 5.11 (2H, s), 6.51 (1H,

s), 6.63 (1H, s), 6.88 (2H, dd, J=7.4, 2.0 Hz), 7.26–7.45 ppm (7H,

m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.7 (CH₂), 50.8 (CH₂), 55.3 (CH₂),

55.7 (CH₃), 56.1 (CH₃), 62.3 (CH₂), 71.2 (CH₂), 110.1 (CH), 113.7 (2ꢂ

CH), 114.3 (CH), 126.3 (C_q), 127.3 (2ꢂCH), 127.5 (C_q), 127.8 (CH),

128.6 (2ꢂCH), 130.5 (2ꢂCH), 137.1 (C_q), 146.6 (C_q), 147.8 (C_q),

158.8 ppm (C_q); LC-MS (APCI+): m/z 390.49 [M+H]⁺; HRMS (ES+):

m/z [M+H]⁺calcd for C₂₅H₂₈NO₃⁺: 390.2064, found: 390.2065.

128.8 (C_q), 128.9 (C_q), 137.1 (C_q), 147.0 (C_q), 149.5 ppm (C_q); HRMS

(ES+): m/z [M+H]⁺calcd for C₁₇H₂₀NO₃

: 286.1438, found:

+

286.1425.

2-Benzyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(14a): Compound 8 (404 mg, 1.5 mmol) was treated with benzyl

bromide (0.19 mL, 1.6 mmol) and Et₃N (0.42 mL, 3.0 mmol) in EtOH

(30 mL) at 1208C for 18 h. The reaction mixture was concentrated

in vacuo. The residue was dissolved in EtOAc (80 mL), washed with

H₂O and brine, then dried (MgSO₄), filtered and concentrated in

vacuo. Flash column chromatography (hexane/EtOAc 10:1!4:1

v/v) afforded compound 14a as a white solid (0.32 g, 59%): mp:

97–988C; ¹H NMR (270 MHz, CDCl₃): d=2.66–2.78 (4H, m), 3.53

(2H, s), 3.66 (2H, s), 3.80 (3H, s), 5.10 (2H, s), 6.50 (1H, s), 6.61 (1H,

s), 7.25–7.45 ppm (10H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.7

(CH₂), 50.9 (CH₂), 55.9 (CH₂), 56.1 (CH₃), 62.9 (CH₂), 71.1 (CH₂), 110.1

(CH), 114.3 (CH), 126.3 (C_q), 127.2 (CH), 127.4 (2ꢂCH), 127.5 (C_q),

127.8 (CH), 128.4 (2ꢂCH), 128.6 (2ꢂCH), 129.2 (2ꢂCH), 137.4 (C_q),

6-Benzyloxy-(2-(3-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydro-

isoquinoline (14e): Prepared as described for 14b using com-

pound 8 (2.15 g, 8.0 mmol), 3-triisopropylsilyloxybenzyl chloride^[30]

(3.59 g, 12.0 mmol) and Et₃N (2.5 mL, 18.0 mmol) in EtOH (10 mL)

at 1208C for 1.5 h in the microwave oven. Flash column chroma-

tography (hexane/EtOAc 6:1 v/v) afforded the benzyl-silyl-bispro-

1

tected phenol as a white solid (3.50 g, 82%); mp 78–798C; H NMR

138.5 (C_q), 146.7 (C_q), 147.9 ppm (C_q); LC-MS (APCI+): m/z: 360.52

(270 MHz, CDCl₃): d=1.08 (18H, d, J=6.7 Hz), 1.15–1.30 (3H, m),

2.64–2.75 (4H, m), 3.52 (2H, s), 3.60 (2H, s), 3.81 (3H, s), 5.10 (2H,

s), 6.49 (1H, s), 6.61 (1H, s), 6.75–6.80 (1H, m), 6.91–6.96 (2H, m),

7.16 (1H, t, J=7.7 Hz), 7.27–7.44 ppm (5H, m); LC-MS (APCI+): m/z

532.71 [M+H]⁺. The silyl-protected phenol (2.70 g, 5.1 mmol) was

treated with tetra-n-butylammonium fluoride (TBAF; 1m in THF,

5.5 mL, 5.5 mmol) in THF (50 mL) at 08C for 1.5 h. EtOAc (80 mL)

was added, and the mixture was washed with H₂O and brine, then

dried (MgSO₄), filtered and concentrated in vacuo. The resulting

solid was washed with hexane, filtered and dried to afford com-

[M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₂₄H₂₆NO₂

:

+

360.1958, found: 360.1955.

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

isoquinoline (14b): Compound 8 (404 mg, 1.5 mmol) was treated

with 2-methoxybenzyl chloride (0.25 mL, 1.8 mmol) and Et₃N

(0.42 mL, 3.0 mmol) in EtOH (4.0 mL) at 1208C for 1 h in the micro-

wave oven. The mixture was poured into H₂O (20 mL) and extract-

ed with EtOAc (2ꢂ50 mL). The combined organics were washed

with H₂O and brine, then dried (MgSO₄), filtered and concentrated

in vacuo. Flash column chromatography (hexane/EtOAc 8:1!2:1

v/v) afforded compound 14b as a white solid (0.37 g, 63%): mp:

85–868C; ¹H NMR (270 MHz, CDCl₃): d=2.75 (4H, s), 3.59 (2H, s),

3.70 (2H, s), 3.81 (3H, s), 3.83 (3H, s), 5.10 (2H, s), 6.51 (1H, s), 6.63

(1H, s), 6.87 (1H, dd, J=8.4, 1.0 Hz), 6.94 (1H, dt, J=7.4, 1.0 Hz),

7.21–7.45 ppm (7H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.8 (CH₂),

50.9 (CH₂), 55.5 (CH₃), 55.8 (CH₂), 56.1 (CH₃), 60.5 (CH₂), 71.1 (CH₂),

110.2 (CH), 110.4 (CH), 114.3 (CH), 120.4 (CH), 126.4 (C_q), 126.5 (C_q),

127.4 (2ꢂCH), 127.8 (CH), 127.8 (C_q), 128.1 (CH), 128.5 (2ꢂCH),

130.5 (CH), 137.4 (C_q), 146.6 (C_q), 147.9 (C_q), 157.9 ppm (C_q); LC-MS

(APCI+): m/z 390.49 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for

C₂₅H₂₈NO₃⁺: 390.2064, found: 390.2064.

1

pound 14e as a white solid (1.70 g, 90%): mp: 141–1428C; H NMR

(270 MHz, CDCl₃): d=2.63–2.78 (4H, m), 3.52 (2H, s), 3.58 (2H, s),

3.79 (3H, s), 5.08 (2H, s), 6.48 (1H, s), 6.60 (1H, s), 6.68 (1H, dd, J=

8.2, 2.5 Hz), 6.82 (1H, d, J=2.5 Hz), 6.88 (1H, d, J=7.7 Hz), 7.15

(1H, dd, J=8.2, 7.7 Hz), 7.26–7.47 ppm (5H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.3 (CH₂), 50.8 (CH₂), 55.4 (CH₂), 56.0 (CH₃),

62.4 (CH₂), 71.0 (CH₂), 110.0 (CH), 114.1 (CH), 114.4 (CH), 116.3 (CH),

121.4 (CH), 126.0 (C_q), 127.0 (C_q), 127.2 (2ꢂCH), 127.7 (CH), 128.5

(2ꢂCH), 129.4 (CH), 137.2 (C_q), 139.7 (C_q), 146.6 (C_q), 147.8 (C_q),

155.9 ppm (C_q); LC-MS (APCI+): m/z 376.59 [M+H]⁺.

7-Methoxy-2-(3-trifluoromethoxybenzyl)-6-(triisopropylsiloxy)-

1,2,3,4-tetrahydroisoquinoline (14 f): Prepared as described for

14b using compound 10 (300 mg, 0.9 mmol), 3-trifluoromethoxy-

benzyl bromide (0.16 mL, 0.99 mmol) and Et₃N (0.17 mL, 1.8 mmol)

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in EtOH (3.0 mL) at 1308C for 1 h in the microwave oven. Flash

column chromatography (hexane/EtOAc gradient) afforded com-

pound 14 f as a pale blue oil (238 mg, 52%): ¹H NMR (270 MHz,

CDCl₃): d=1.07 (18H, d, J=6.7 Hz), 1.14–1.28 (3H, m), 2.65–2.74

(4H, m), 3.53 (2H, s), 3.66 (2H, s), 3.71 (3H, s), 6.43 (1H, s), 6.58

(1H, s), 7.09–7.12 (1H, m), 7.20–7.38 ppm (3H, m); LC-MS (ES+):

m/z 510.49 [M+H]⁺.

2-(3-Acetoxybenzyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydro-

isoquinoline (14k): Compound 14e (450 mg, 1.2 mmol) was treat-

ed with Ac₂O (0.13 mL, 1.4 mmol) and Et₃N (0.20 mL, 1.4 mmol) in

CHCl₃(10 mL) at RT for 18 h. The reaction mixture was diluted with

CHCl₃(50 mL), washed with H₂O and brine, then dried (MgSO₄), fil-

tered and concentrated in vacuo. Flash column chromatography

(hexane/EtOAc 4:1!3:1 v/v) afforded compound 14k as a white

powder (450 mg, 90%): mp: 94–958C; ¹H NMR (270 MHz, CDCl₃):

d=2.28 (3H, s), 2.65–2.77 (4H, m), 3.52 (2H, s), 3.65 (2H, s), 3.80

(3H, s), 5.10 (2H, s), 6.50 (1H, s), 6.61 (1H, s), 6.98 (1H, ddd, J=7.9,

2.2, 1.2 Hz), 7.13–7.19 (1H, m), 7.21–7.44 ppm (7H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=21.3 (CH₃), 28.7 (CH₂), 50.9 (CH₂), 55.8 (CH₂),

56.1 (CH₃), 62.4 (CH₂), 71.2 (CH₂), 110.1 (CH), 114.3 (CH), 120.4 (CH),

122.0 (CH), 126.2 (C_q), 126.5 (CH), 127.3 (2ꢂCH), 127.4 (C_q), 127.8

(CH), 128.6 (2ꢂCH), 129.3 (CH), 137.4 (C_q), 140.6 (C_q), 146.7 (C_q),

147.9 (C_q), 150.8 (C_q), 169.7 ppm (C_q); LC-MS (ES+): m/z 418.48

[M+H]⁺.

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

isoquinoline (14g): Compound 14e (450 mg, 1.2 mmol) was treat-

ed with iodoethane (0.19 mL, 2.4 mmol) and K₂CO₃(207 mg,

1.5 mmol) in EtOH (10 mL) at RT for 18 h. EtOAc was added and

the mixture was washed with H₂O and brine, then dried (MgSO₄),

filtered and concentrated in vacuo. Flash column chromatography

(hexane/EtOAc 4:1 v/v) afforded compound 14g as a yellow oil

(200 mg, 41%): ¹H NMR (270 MHz, CDCl₃): d=1.39 (3H, t, J=

6.9 Hz), 2.65–2.79 (4H, m), 3.54 (2H, s), 3.63 (2H, s), 3.80 (3H, s),

4.01 (2H, q, J=6.9 Hz), 5.09 (2H, s), 6.50 (1H, s), 6.61 (1H, s), 6.79

(1H, ddd, J=7.9, 2.2, 1.0 Hz), 6.93–6.96 (2H, m), 7.20 (1H, t, J=

7.9 Hz), 7.26–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=15.0

(CH₃), 28.7 (CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.1 (CH₃), 62.8 (CH₂), 63.4

(CH₂), 71.2 (CH₂), 110.1 (CH), 113.3 (CH), 114.3 (CH), 115.1 (CH),

121.4 (CH), 126.3 (C_q), 127.3 (2ꢂCH), 127.5 (C_q), 127.8 (CH), 128.6

(2ꢂCH), 129.3 (CH), 137.4 (C_q), 140.1 (C_q), 146.6 (C_q), 147.9 (C_q),

159.1 ppm (C_q); LC-MS (APCI+): m/z 404.59 [M+H]⁺.

6-Benzyloxy-2-(3-fluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (14l): Prepared as described for 14b using compound 8

(300 mg, 1.1 mmol), 3-fluorobenzyl bromide (0.15 mL, 1.2 mmol)

and Et₃N (0.31 mL, 2.2 mmol) in EtOH (3.0 mL) at 1308C for 1 h in

the microwave oven. Flash column chromatography (hexane!

hexane/EtOAc 1:1 v/v) afforded compound 14l as a colourless

1

solid (336 mg, 80%): mp: 78–808C; H NMR (270 MHz, CDCl₃): d=

2.67–2.75 (4H, m), 3.53 (2H, s), 3.64 (2H, s), 3.81 (3H, s), 5.10 (2H,

s), 6.50 (1H, s), 6.61 (1H, s), 6.91–6.98 (1H, m), 7.10–7.15 (2H, m),

7.23–7.44 ppm (6H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.7 (CH₂),

50.9 (CH₂), 55.8 (CH₂), 56.2 (CH₃), 62.3 (CH₂), 71.2 (CH₂), 110.1 (CH),

114.1 (d, J=21.2 Hz, CH), 114.3 (CH), 115.8 (d, J=21.2 Hz, CH),

124.6 (d, J=2.5 Hz, CH), 126.2 (C_q), 127.3 (C_q), 127.4 (2ꢂCH), 127.8

(CH), 128.6 (2ꢂCH), 129.8 (d, J=8.1 Hz, CH), 137.4 (C_q), 141.4 (d,

J=7.5 Hz, C_q), 146.8 (C_q), 148.0 (C_q), 163.1 ppm (d, J=245.6 Hz, CF);

LC-MS (APCI+): m/z 378.52 [M+H]⁺.

6-Benzyloxy-2-(3-isopropoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (14h): Compound 14e (300 mg, 0.8 mmol) was

treated with NaH (48 mg, 1.2 mmol) in THF (10 mL) at RT for

20 min. 2-Iodopropane (0.12 mL, 1.2 mmol) was added, and the re-

action mixture was stirred at 408C for 22 h. A further aliquot of 2-

iodopropane (0.12 mL, 1.2 mmol) was added, and the reaction was

heated to 508C for 22 h before a final aliquot of 2-iodopropane

(0.12 mL, 1.2 mmol) was introduced and the reaction was heated

at 608C for 3 h. The reaction was cooled to RT and concentrated in

vacuo. H₂O was added, and the mixture was extracted with EtOAc,

washed with brine, then dried, filtered and evaporated. Flash

column chromatography (hexane/EtOAc gradient) afforded com-

pound 14h as a colourless oil (259 mg, 77%): ¹H NMR (270 MHz,

CDCl₃): d=1.31 (6H, d, J=6.2 Hz), 2.66–2.75 (4H, m), 3.54 (2H, s),

3.62 (2H, s), 3.80 (3H, s), 4.54 (1H, sept, J=6.2 Hz), 5.09 (2H, s),

6.50 (1H, s), 6.61 (1H, s), 6.77–6.81 (1H, m), 6.91–6.94 (2H, m),

7.16–7.47 ppm (6H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=22.2 (2ꢂ

CH₃), 28.8 (CH₂), 50.8 (CH₂), 55.9 (CH₂), 56.2 (CH₃), 62.9 (CH₂), 69.8

(CH), 71.2 (CH₂), 110.1 (CH), 114.3 (CH), 114.6 (CH), 116.5 (CH), 121.3

(CH), 126.3 (C_q), 127.4 (2ꢂCH), 127.6 (C_q), 127.8 (CH), 128.6 (2ꢂCH),

129.3 (CH), 137.4 (C_q), 140.2 (C_q), 146.7 (C_q), 147.9 (C_q), 158.0 ppm

(C_q); LC-MS (APCIꢀ): m/z 416.35 [MꢀH]^ꢀ.

2-(3-Chlorobenzyl)-7-methoxy-6-(triisopropylsiloxy)-1,2,3,4-tetra-

hydroisoquinoline (14m): Prepared as described for 14b using

compound 10 (300 mg, 0.9 mmol), 3-chlorobenzyl bromide

(221 mg, 1.07 mmol) and Et₃N (0.25 mL, 1.8 mmol) in EtOH (3.0 mL)

at 1308C for 0.75 h in the microwave oven. Flash column chroma-

tography (hexane!hexane/EtOAc 1:1 v/v) afforded compound

1

14m as a yellow oil (322 mg, 78%): H NMR (270 MHz, CDCl₃): d=

1.08 (18H, d, J=6.7 Hz), 1.13–1.29 (3H, m), 2.66–2.75 (4H, m), 3.52

(2H, s), 3.62 (2H, s), 3.72 (3H, s), 6.43 (1H, s), 6.59 (1H, s), 7.23–7.28

(3H, m), 7.40 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=13.0 (3ꢂ

CH), 18.1 (6ꢂCH₃), 28.5 (CH₂), 50.9 (CH₂), 55.7 (CH₃), 55.9 (CH₂), 62.4

(CH₂), 110.3 (CH), 120.2 (CH), 126.2 (C_q), 127.1 (C_q), 127.3 (CH), 127.4

(CH), 129.2 (CH), 129.7 (CH), 134.3 (C_q), 140.8 (C_q), 144.0 (C_q),

149.1 ppm (C_q); LC-MS (APCI+): m/z 460.43 [M+H]⁺.

6-Benzyloxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-

isoquinoline (14i): Prepared as described for 14b using compound

8 (404 mg, 1.5 mmol), 3-methylbenzyl bromide (0.24 mL, 1.8 mmol)

and Et₃N (0.42 mL, 3.0 mmol) in EtOH (2.5 mL) at 1208C for 1 h in

the microwave oven. Flash column chromatography (hexane/

EtOAc 8:1!3:1 v/v) afforded compound 14i as a white solid

6-Benzyloxy-2-(3-methylbenzyl)-7-methoxy-1,2,3,4-tetrahydro-

isoquinoline (14n): Prepared as described for 14b using com-

pound 8 (404 mg, 1.5 mmol), 3-methylbenzyl bromide (0.24 mL,

1.8 mmol) and Et₃N (0.42 mL, 3.0 mmol) in EtOH (2.5 mL) at 1208C

for 1 h in the microwave oven. Flash column chromatography

(hexane/EtOAc 8:1! 3:1 v/v) afforded compound 14n as a white

solid (0.46 g, 82%): mp: 81–828C; ¹H NMR (270 MHz, CDCl₃): d=

2.35 (3H, s), 2.69–2.76 (4H, m), 3.52 (2H, s), 3.63 (2H, s), 3.81 (3H,

s), 5.10 (2H, s), 6.51 (1H, s), 6.62 (1H, s), 7.07–7.44 ppm (9H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=21.5 (CH₃), 28.8 (CH₂), 50.9 (CH₂),

55.8 (CH₂), 56.2 (CH₃), 62.9 (CH₂), 71.1 (CH₂), 110.1 (CH), 114.3 (CH),

126.3 (C_q), 126.4 (CH), 127.3 (2ꢂCH), 127.5 (C_q), 127.8 (CH), 128.0

(CH), 128.2 (CH), 128.6 (2ꢂCH), 130.0 (CH), 137.4 (C_q), 138.0 (C_q),

138.4 (C_q), 146.7 (C_q), 147.9 ppm (C_q); LC-MS (APCI+): m/z 374.62

[M+H]⁺.

1

(0.53 g, 78%): mp: 111–1128C; H NMR (270 MHz, CDCl₃): d=2.65–

2.75 (4H, m), 3.54 (2H, s), 3.64 (2H, s), 3.82 (3H, s), 5.10 (2H, s),

6.51 (1H, s), 6.62 (1H, s), 6.91 (1H, ddd, J=8.2, 2.5, 1.0 Hz), 6.98–

7.15 (5H, m), 7.25–7.45 ppm (8H, m); ¹³C NMR (67.5 MHz, CDCl₃):

d=28.7 (CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.2 (CH₃), 62.5 (CH₂), 71.1

(CH₂), 110.1 (CH), 114.3 (CH), 117.7 (CH), 118.3 (2ꢂCH), 119.7 (CH),

123.2 (CH), 124.0 (CH), 126.3 (C_q), 127.3 (2ꢂCH), 127.4 (C_q), 127.8

(CH), 128.6 (2ꢂCH), 129.6 (CH), 129.8 (2ꢂCH), 137.4 (C_q), 140.7 (C_q),

146.7 (C_q), 147.9 (C_q), 157.3 (C_q), 157.4 ppm (C_q); LC-MS (APCI+):

m/z 452.56 [M+H]⁺.

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

quinoline (14o): Compound 8 (592 mg, 2.2 mmol) and 3-ethylben-

zoic acid^[30](495 mg, 3.3 mmol) were dissolved in CH₂Cl₂(4.5 mL)

and THF (1.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

(EDCI; 842 mg, 4.4 mmol) was added, and the reaction mixture was

stirred at RT for 18 h. The reaction mixture was diluted with CH₂Cl₂

(200 mL), washed with HCl (1m, 100 mL) and brine (20 mL), dried

(MgSO₄), filtered and concentrated in vacuo. Flash column chroma-

tography (hexane!hexane/EtOAc 7:3 v/v) afforded the amide as

at 1308C for 0.75 h in the microwave oven. Flash column chroma-

tography (hexane!hexane/EtOAc 1:1 v/v) afforded compound 14r

1

as a yellow solid (452 mg, 83%): H NMR (270 MHz, CDCl₃): d=1.07

(18H, d, J=6.7 Hz), 1.13–1.28 (3H, m), 2.69–2.76 (4H, m), 3.54 (2H,

s), 3.71 (3H, s), 3.74 (2H, s), 6.42 (1H, s), 6.59 (1H, s), 7.49 (1H, t,

J=7.9 Hz), 7.75 (1H, d, J=7.7 Hz), 8.12 (1H, ddd, J=8.2, 2.5,

1.1 Hz), 8.25 ppm (1H, t, J=1.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=

13.0 (3ꢂCH), 18.1 (6ꢂCH₃), 28.5 (CH₂), 51.0 (CH₂), 55.7 (CH₃), 55.9

(CH₂), 62.0 (CH₂), 110.2 (CH), 120.2 (CH), 122.4 (CH), 123.9 (CH),

126.0 (C_q), 126.7 (C_q), 129.3 (CH), 135.2 (CH), 141.0 (C_q), 144.1 (C_q),

148.4 (C_q), 149.1 ppm (C_q); LC-MS (APCI+): m/z 471.58 [M+H]⁺.

1

colourless glass (805 mg, 91%): H NMR (270 MHz, CDCl₃): d=1.24

(3H, t, J=7.6 Hz), 2.67 (2H, q, J=7.6 Hz), 2.71 and 2.83 (2H, 2 s,

br), 3.59 and 3.95 (2H, 2 s, br), 3.77 and 3.87 (3H, 2 s, br), 4.50 and

4.82 (2H, 2 s, br), 5.11 (2H, s), 6.41 and 6.70 (1H, 2s, br), 6.65 (1H,

s, br), 7.18–7.47 ppm (9H, m); HRMS (ES+): m/z [M+H]⁺calcd for

C₂₆H₂₈NO₃⁺: 402.2064, found: 402.2053. LiAlH₄(229 mg, 6.0 mmol)

was covered with THF (4.0 mL). The amide (802 mg, 2.0 mmol) was

added dropwise as solution in THF (8.0 mL) via a syringe, and the

reaction mixture was stirred at RT for 2 h. The mixture was carefully

diluted with EtOAc (100 mL) and left standing without stirring for

0.5 h. After the salts settled, the mixture was filtered through

celite, washed with EtOAc (4ꢂ10 mL) and concentrated in vacuo.

Flash column chromatography (hexane/EtOAc 9:1 v/v and 1%

Et₃N) afforded compound 14o as a pale yellow oil (543 mg, 70%):

¹H NMR (270 MHz, CDCl₃): d=1.24 (3H, t, J=7.7 Hz), 2.63–2.79 (4H,

m), 2.65 (2H, q, J=7.7 Hz), 3.54 (2H, s), 3.64 (2H, s), 3.81 (3H, s),

5.10 (2H, s), 6.51 (1H, s), 6.62 (1H, s), 7.08–7.46 ppm (9H, m);

HRMS (ES+): m/z [M+H]⁺calcd for C₂₆H₃₀NO₂⁺: 388.2271, found:

388.2258.

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

droisoquinoline (14s): Prepared as described for 14b using com-

pound

8 (1.62 g, 6.0 mmol), 3-nitrobenzyl chloride (1.24 g,

7.2 mmol) and Et₃N (2.5 mL, 18.0 mmol) in EtOH (10 mL) at 1208C

for 1.5 h in the microwave oven. Flash column chromatography

(hexane/EtOAc 3:1!2:1) afforded the nitro compound as a light

beige powder (2.00 g, 83%): mp: 109–1108C; ¹H NMR (270 MHz,

CDCl₃): d=2.70–2.74 (2H, m), 2.76–2.78 (2H, m), 3.55 (2H, s), 3.75

(2H, s), 3.81 (3H, s), 5.09 (2H, s), 6.50 (1H, s), 6.63 (1H, s), 7.24–7.44

(5H, m), 7.49 (1H, t, J=7.8 Hz), 7.74 (1H, d, J=7.8 Hz), 8.12 (1H, d,

J=7.8 Hz), 8.25 ppm (1H, s); LC-MS (APCI+): m/z 405.60 [M+H]⁺.

The nitro compound (1.61 g, 4.0 mmol) was added to a suspension

of Raney nickel (50% slurry in H₂O, 1.5 g, washed with 3ꢂ5 mL of

MeOH) in MeOH (50 mL). Hydrazine hydrate (1.0 mL, 20.6 mmol)

was added dropwise, and the mixture was stirred at 808C for 0.5 h.

After cooling to RT the mixture was filtered through celite and

concentrated in vacuo. The resulting yellow solid was stirred in

Et₂O, filtered and dried to afford the aniline as a yellow powder

2-(3-Cyanobenzyl)-7-methoxy-6-(triisopropylsiloxy)-1,2,3,4-tetra-

hydroisoquinoline (14p): Prepared as described for 14a using

compound 10 (300 mg, 0.89 mmol), 3-cyanobenzyl bromide

(193 mg, 0.98 mmol) and Et₃N (0.25 mL, 1.8 mmol) in EtOH (20 mL)

at 1208C for 23 h. Flash column chromatography (hexane!

hexane/EtOAc 1:1 v/v) afforded compound 14p as a colourless oil

(329 mg, 82%): ¹H NMR (270 MHz, CDCl₃): d=1.07 (18H, d, J=

6.7 Hz), 1.13–1.28 (3H, m), 2.66–2.75 (4H, m), 3.51 (2H, s), 3.67 (2H,

s), 3.71 (3H, s), 6.42 (1H, s), 6.59 (1H, s), 7.42 (1H, t, J=7.7 Hz), 7.56

(1H, dt, J=7.7, 1.5 Hz), 7.64 (1H, d, J=7.7 Hz), 7.70 ppm (1H, s,

br); ¹³C NMR (67.5 MHz, CDCl₃): d=12.9 (3ꢂCH), 18.0 (6ꢂCH₃), 28.3

(CH₂), 50.8 (CH₂), 55.6 (CH₃), 55.7 (CH₂), 61.8 (CH₂), 110.1 (CH), 112.4

(C_q), 118.9 (C_q), 120.1 (CH), 125.8 (C_q), 126.5 (C_q), 129.1 (CH), 130.9

(CH), 132.5 (CH), 133.5 (CH), 140.1 (C_q), 144.0 (C_q), 149.1 ppm (C_q);

LC-MS (APCI+): m/z 451.43 [M+H]⁺.

1

(1.40 g, 93%): mp: 114–1158C; H NMR (270 MHz, CDCl₃): d=2.68–

2.77 (4H, m), 3.53 (2H, s), 3.58 (2H, s), 3.81 (3H, s), 5.11 (2H, s),

6.52 (1H, s), 6.59 (1H, dd, J=8.2, 1.5 Hz), 6.63 (1H, s), 6.75–6.78

(2H, m), 7.12 (1H, t, J=8.0 Hz), 7.29–7.45 ppm (5H, m); LC-MS

(APCI+): m/z 375.63 [M+H]⁺. Prepared as described for 14k using

the aniline (300 mg, 0.8 mmol), acetic anhydride (0.26 mL,

2.7 mmol) and Et₃N (0.39 mL, 2.7 mmol) in CHCl₃(30 mL) at RT for

3 h. Flash column chromatography (hexane/EtOAc 1:10 v/v) and

(CH₂Cl₂/EtOAc 2:1!1:5 v/v) afforded compound 14s as a white

powder (180 mg, 54%): mp: 63–668C; ¹H NMR (270 MHz, CDCl₃):

d=2.14 (3H, s), 2.68–2.75 (4H, m), 2.84 (1H, s, br), 3.52 (2H, s),

3.64 (2H, s), 3.79 (3H, s), 5.09 (2H, s), 6.48 (1H, s), 6.60 (1H, s), 7.11

(1H, d, J=7.7 Hz), 7.24–7.43 (7H, m), 7.53 ppm (1H, d, J=8.2 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=24.7 (CH₃), 28.6 (CH₂), 50.9 (CH₂),

55.6 (CH₂), 56.1 (CH₃), 62.5 (CH₂), 71.2 (CH₂), 110.1 (CH), 114.2 (CH),

118.9 (CH), 120.3 (CH), 125.1 (CH), 126.1 (C_q), 127.1 (C_q), 127.3 (2ꢂ

CH), 127.8 (CH), 128.6 (2ꢂCH), 129.1 (CH), 137.3 (C_q), 138.0 (C_q),

139.3 (C_q), 146.7 (C_q), 147.9 (C_q), 168.6 ppm (C_q); LC-MS (APCI+):

m/z 417.51 [M+H]⁺.

2-(3-Acetylbenzyl)-7-methoxy-6-(triisopropylsilyloxy)-1,2,3,4-tet-

rahydroisoquinoline (14q): Prepared as described for 14a using

compound 10 (320 mg, 0.95 mmol), 3-acetylbenzyl bromide^[31]

(59 wt%, 0.82 g, 2.25 mmol) and Et₃N (2.0 mL, 14.4 mmol) in EtOH

(30 mL) at 1208C for 30 h. Flash column chromatography (hexane/

EtOAc 8:1!6:1 v/v) afforded compound 14q as a yellow oil

(290 mg, 65%): ¹H NMR (270 MHz, CDCl₃): d=1.05 (18H, d, J=

6.7 Hz), 1.12–1.30 (3H, m), 2.60 (3H, s), 2.65–2.76 (4H, m), 3.54 (2H,

s), 3.70 (5H, s), 6.42 (1H, s), 6.58 (1H, s), 7.42 (1H, t, J=7.7 Hz), 7.62

(1H, dt, J=7.7, 1.5 Hz), 7.86 (1H, dt, J=7.7, 1.5 Hz), 7.95 ppm (1H,

t, J=1.5 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=13.0 (3ꢂCH), 18.0 (6ꢂ

CH₃), 26.9 (CH₃), 28.4 (CH₂), 50.9 (CH₂), 55.7 (CH₃), 55.9 (CH₂), 62.5

(CH₂), 110.2 (CH), 120.2 (CH), 126.2 (C_q), 126.9 (C_q), 127.3 (CH), 128.7

(CH), 129.0 (CH), 134.1 (CH), 137.3 (C_q), 139.1 (C_q), 144.0 (C_q), 149.1

(C_q), 198.5 ppm (C_q); LC-MS (APCI+): m/z 468.57 [M+H]⁺.

6-Benzyloxy-(2-(3-methanesulfonamido)benzyl)-7-methoxy-

1,2,3,4-tetrahydroisoquinoline (14t): Methanesulfonyl chloride

(0.09 mL, 1.2 mmol) was added dropwise to a solution of the ani-

line (374 mg, 1.0 mmol) in pyridine (2.0 mL, 25.9 mmol). The reac-

tion mixture was stirred at RT for 18 h. H₂O was added slowly, and

the mixture was extracted with EtOAc. The organic layer was

washed with H₂O and brine, then dried (MgSO₄), filtered and con-

centrated in vacuo. Flash column chromatography (hexane/EtOAc

1:4 v/v) afforded compound 14t as a white powder (260 mg, 58%):

mp: 132–1338C; ¹H NMR (270 MHz, CDCl₃): d=2.64–2.76 (4H, m),

2.97 (3H, s), 3.52 (2H, s), 3.63 (2H, s), 3.80 (3H, s), 5.09 (2H, s), 6.49

(1H, s), 6.61 (1H, s), 7.12–7.44 ppm (10H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.7 (CH₂), 39.5 (CH₃), 50.9 (CH₂), 55.8 (CH₂), 56.2 (CH₃),

62.3 (CH₂), 71.1 (CH₂), 110.1 (CH), 114.3 (CH), 119.5 (CH), 121.3 (CH),

7-Methoxy-2-(3-nitrobenzyl)-6-(triisopropylsiloxy)-1,2,3,4-tetra-

hydroisoquinoline (14r): Prepared as described for 14b using

compound 10 (387 mg, 1.15 mmol), 3-nitrobenzyl chloride

(218 mg, 1.27 mmol) and Et₃N (0.32 mL, 2.3 mmol) in EtOH (3.0 mL)

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1

126.1 (CH), 126.2 (C_q), 127.2 (C_q), 127.3 (2ꢂCH), 127.8 (CH), 128.6

(2ꢂCH), 129.6 (CH), 136.9 (C_q), 137.3 (C_q), 140.6 (C_q), 146.8 (C_q),

148.0 ppm (C_q); LC-MS (ES+): m/z 453.40 [M]⁺.

powder (440 mg, 70%): mp: 103–1048C; H NMR (270 MHz, CDCl₃):

d=2.73–2.75 (4H, m), 3.61 (2H, s), 3.69 (2H, s), 3.76 (3H, s), 3.79

(3H, s), 3.82 (3H, s), 5.10 (2H, s), 6.53 (1H, s), 6.62 (1H, s), 6.76 (1H,

dd, J=8.6, 2.9 Hz), 6.81 (1H, d, J=8.6), 7.06 (1H, d, J=2.9), 7.28–

7.46 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.8 (CH₂), 50.9

(CH₂), 55.9 (2ꢂCH₂), 56.2 (2ꢂCH₃), 56.3 (CH₃), 71.2 (CH₂), 110.2 (CH),

111.7 (CH), 112.5 (CH), 114.3 (CH), 116.1 (CH), 126.4 (C_q), 127.4 (2ꢂ

CH), 127.8 (CH), 127.9 (C_q), 128.0 (C_q), 128.6 (2ꢂCH), 137.4 (C_q),

146.7 (C_q), 147.9 (C_q), 152.1 (C_q), 153.7 ppm (C_q); LC-MS (ESꢀ): m/z

418.11 [MꢀH]^ꢀ.

6-Benzyloxy-2-(2,3-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (14u): Prepared as described for 14b using com-

pound

8

(404 mg, 1.5 mmol), 2,3-dimethoxybenzyl chloride^[32]

(50 wt% in CH₂Cl₂, 0.67 g, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in

EtOH (2.5 mL) at 1208C for 1.5 h in the microwave oven. Flash

column chromatography (hexane/EtOAc 3:1!2:1 v/v) gave an oil,

which was dissolved in acetonitrile (1.0 mL). After evaporation of

the solvent, the residue was stirred in Et₂O, filtered and dried to

afford compound 14u as a yellow powder (430 mg, 68%): mp:

6-Benzyloxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (14y): Prepared as described for 14b using

compound 8 (404 mg, 1.5 mmol), 2,3,4-trimethoxybenzyl chlo-

ride^[33](390 mg, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH

(2.5 mL) at 1208C for 1.5 h in the microwave oven. Flash column

chromatography (hexane/EtOAc 3:1!1:1 v/v) afforded compound

1

106–1078C; H NMR (270 MHz, CDCl₃): d=2.73 (4H, s), 3.57 (2H, s),

3.71 (2H, s), 3.80 (3H, s), 3.83 (3H, s), 3.87 (3H, s), 5.09 (2H, s), 6.51

(1H, s), 6.61 (1H, s), 6.84 (1H, dd, J=7.2, 1.7 Hz), 7.00–7.08 (2H, m),

7.27–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=29.0 (CH₂),

51.0 (CH₂), 55.7 (CH₂), 55.8 (CH₃), 56.1 (CH₃), 56.2 (CH₂), 61.0 (CH₃),

71.2 (CH₂), 110.1 (CH), 111.1 (CH), 114.3 (CH), 122.6 (CH), 123.9 (CH),

126.4 (C_q), 127.4 (2ꢂCH), 127.8 (CH), 128.6 (2ꢂCH), 132.4 (C_q),

137.4 (C_q), 146.6 (C_q), 147.8 (C_q), 147.9 (C_q), 152.8 ppm (C_q); LC-MS

(APCIꢀ): m/z 418.11 [MꢀH]^ꢀ.

1

14y as a yellow oil (290 mg, 43%): H NMR (270 MHz, CDCl₃): d=

2.66–2.75 (4H, m), 3.56 (2H, s), 3.63 (2H, s), 3.81 (3H, s), 3.85 (3H,

s), 3.88 (6H, s), 5.09 (2H, s), 6.52 (1H, s), 6.62 (1H, s), 6.65 (1H, d,

J=8.6 Hz), 7.08 (1H, d, J=8.6 Hz), 7.27–7.43 ppm (5H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.9 (CH₂), 50.7 (CH₂), 55.7 (CH₂), 56.1 (CH₃),

56.2 (CH₃), 56.4 (CH₂), 60.9 (CH₃), 61.3 (CH₃), 71.2 (CH₂), 107.2 (CH),

110.3 (CH), 114.4 (CH), 124.4 (C_q), 125.0 (CH), 126.5 (C_q), 127.4 (2ꢂ

CH), 127.8 (CH), 128.0 (C_q), 128.5 (2ꢂCH), 137.5 (C_q), 142.4 (C_q),

146.7 (C_q), 148.0 (C_q), 152.7 (C_q), 152.9 ppm (C_q).

6-Benzyloxy-2-(3,4-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (14v): Prepared as described for 14b using com-

pound

8

(404 mg, 1.5 mmol), 3,4-dimethoxybenzyl chloride

(336 mg, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH (2.5 mL) at

1208C for 1.5 h in the microwave oven. Flash column chromatogra-

phy (hexane/EtOAc 3:1!1:1 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 14v as a white

powder (430 mg, 68%): mp: 98–998C; ¹H NMR (270 MHz, CDCl₃):

d=2.99 (2H, s, br), 3.16 (2H, s, br), 3.81 (3H, s), 3.87 (5H, s), 3.94

(3H, s), 4.01 (2H, s), 5.10 (2H, s), 6.47 (1H, s), 6.64 (1H, s), 6.81 (1H,

d, J=8.2 Hz), 6.91 (1H, dd, J=8.2, 1.7 Hz), 7.26–7.50 ppm (6H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=48.8 (CH₂), 55.9 (CH₃), 56.1 (CH₃),

56.4 (CH₃), 71.0 (CH₂), 109.8 (CH), 110.7 (CH), 113.4 (CH), 113.8 (CH),

122.6 (CH), 127.2 (2ꢂCH), 127.9 (CH), 128.6 (2ꢂCH), 136.7 (C_q),

147.9 (C_q), 148.8 (C_q), 149.5 (C_q), 149.6 ppm (C_q); LC-MS (ES+): m/z

420.61 [M+H]⁺.

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (14z): Prepared as described for 14b using

compound 8 (404 mg, 1.5 mmol), 3,4,5-trimethoxybenzyl chloride

(390 mg, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH (2.5 mL) at

1208C for 1.5 h in the microwave oven. Flash column chromatogra-

phy (hexane/EtOAc 3:1!1:1 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 14z as a white

1

powder (520 mg, 77%): mp: 144–1458C; H NMR (270 MHz, CDCl₃):

d=2.65–2.78 (4H, m), 3.55 (2H, s), 3.58 (2H, s), 3.82 (3H, s), 3.84

(3H, s), 3.85 (6H, s), 5.10 (2H, s), 6.53 (1H, s), 6.61 (2H, s), 6.63 (1H,

s), 7.27–7.44 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.8

(CH₂), 50.7 (CH₂), 56.0 (CH₂), 56.2 (3ꢂCH₃), 61.0 (CH₃), 63.1 (CH₂),

71.2 (CH₂), 105.7 (2ꢂCH), 110.2 (CH), 114.3 (CH), 126.3 (C_q), 127.3

(2ꢂCH), 127.5 (C_q), 127.8 (CH), 128.6 (2ꢂCH), 134.5 (C_q), 136.9 (C_q),

137.4 (C_q), 146.8 (C_q), 148.0 (C_q), 153.2 ppm (2ꢂC_q); LC-MS (ES+):

m/z 450.61 [M+H]⁺.

6-Benzyloxy-2-(3,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (14w): Prepared as described for 14b using com-

pound

8 (404 mg, 1.5 mmol), 3,5-dimethoxybenzyl bromide

(480 mg, 2.1 mmol) and Et₃N (0.42 mL, 3.0 mmol) in EtOH (4.0 mL)

at 1208C for 1 h in the microwave oven. Flash column chromatog-

raphy (hexane/EtOAc 8:1!2:1 v/v) afforded compound 14w as

a white solid (0.36 g, 62%): mp: 95–968C; ¹H NMR (270 MHz,

CDCl₃): d=2.65–2.77 (4H, m), 3.54 (2H, s), 3.60 (2H, s), 3.78 (6H, s),

3.81 (3H, s), 5.10 (2H, s), 6.37 (1H, t, J=2.5 Hz), 6.51 (1H, s), 6.56

(2H, d, J=2.5 Hz), 6.62 (1H, s), 7.27–7.44 ppm (5H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.7 (CH₂), 50.7 (CH₂), 55.4 (CH₃), 55.8 (CH₂),

56.1 (CH₃), 63.0 (CH₂), 71.1 (CH₂), 99.2 (CH), 106.8 (2ꢂCH), 110.1

(CH), 114.2 (CH), 126.2 (C_q), 127.4 (2ꢂCH), 127.4 (C_q), 127.8 (CH),

128.6 (2ꢂCH), 137.4 (C_q), 141.0 (C_q), 146.6 (C_q), 147.9 (C_q),

160.8 ppm (2ꢂC_q); LC-MS (APCI+): m/z 420.39 [M+H]⁺; HRMS

(ES+): m/z [M+H]⁺calcd for C₂₆H₃₀NO₄⁺:420.2169, found:

420.2167.

6-Benzyloxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (14aa): Prepared as described for 14b using

compound 8 (404 mg, 1.5 mmol), 2,4,5-trimethoxybenzyl chlo-

ride^[34](390 mg, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH

(2.5 mL) at 1208C for 1.5 h in the microwave oven. Flash column

chromatography (hexane/EtOAc 3:1!2:3 v/v) gave a solid that

was stirred in Et₂O, filtered and dried to afford compound 14aa as

1

a white powder (240 mg, 35%): mp: 110–1118C; H NMR (270 MHz,

CDCl₆): d=2.65–2.76 (4H, m), 3.58 (2H, s), 3.63 (2H, s), 3.80 (3H, s),

3.81 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 5.09 (2H, s), 6.52 (1H, s), 6.53

(1H, s), 6.61 (1H, s), 7.00 (1H, s), 7.27–7.43 ppm (5H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.8 (CH₂), 50.6 (CH₂), 55.3 (CH₂), 55.9 (CH₂),

56.2 (CH₃), 56.3 (CH₃), 56.7 (CH₃), 56.8 (CH₃), 71.2 (CH₂), 97.9 (CH),

110.3 (CH), 114.3 (CH), 114.5 (CH), 118.3 (C_q), 126.5 (C_q), 127.4 (2ꢂ

CH), 127.8 (CH), 127.9 (C_q), 128.5 (2ꢂCH), 137.5 (C_q), 143.2 (C_q),

146.7 (C_q), 148.0 (C_q), 148.6 (C_q), 152.2 ppm (C_q); LC-MS (ES+): m/z

450.61 [M+H]⁺.

6-Benzyloxy-2-(2,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (14x): Prepared as described for 14b using com-

pound 8 (404 mg, 1.5 mmol) and 2,5-dimethoxybenzyl chloride

(336 mg, 1.8 mmol) and Et₃N (0.5 mL, 3.6 mmol) in EtOH (2.5 mL) at

1208C for 1.5 h in the microwave oven. Flash column chromatogra-

phy (hexane/EtOAc 3:1!2:1 v/v) gave an oil that was stirred in

Et₂O, filtered and dried to afford compound 14x as a yellow

6-Benzyloxy-7-Methoxy-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (14ab): Prepared as described for 14o using

compound 8 (539 mg, 2.0 mmol), 2,4,6-trimethoxybenzoic acid

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1

(446 mg, 2.1 mmol) and EDCI (767 mg, 4.0 mmol) in CH₂Cl₂(25 mL)

at RT for 2 h. Flash column chromatography (hexane/EtOAc 5:1!

EtOAc v/v) afforded the amide as white powder (0.74 g, 80%): mp:

126–1278C; H NMR (270 MHz, CDCl₃): d=2.77 (2H, s, br), 3.67 (2H,

s, br), 3.83 (6H, s), 4.73 (2H, br), 5.11 (2H, s), 6.65 (1H, s), 6.92 (2H,

dt, J=8.6, 2.3 Hz), 7.26–7.45 ppm (8H, m); LC-MS (APCI+): m/z

404.53 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₂₅H₂₆NO₄

1

+

70–728C; H NMR (270 MHz, CDCl₃): d=2.62 and 2.78 (2H, 2t, J=

:

5.5 and 5.8 Hz), 3.44 and 3.96 (2H, 2t, J=5.5 and 5.8 Hz), 3.66 and

3.75 (6H, 2s), 3.78, 3.82, 3.82 and 3.86 (6H, 4s), 4.32 and 4.85 (2H,

2s), 5.10 and 5.11 (2H, 2s), 6.10 and 6.11 (2H, 2s), 6.41 and 6.60

(1H, 2s), 6.67 and 6.68 (1H, 2s), 7.28–7.44 ppm (5H, m); LC-MS

(ESꢀ): m/z 404.4 [M+H]⁺and 486.4 [M+Na]⁺; HRMS (ES+): m/z

[M+H]⁺calcd for C₂₇H₃₀NO₆⁺: 464.2068, found: 464.2070. Prepared

as described for 14o using the amide (720 mg, 1.55 mmol) and

lithium aluminium hydride (76 mg, 2.0 mmol) in THF (30 mL) at RT

for 16 h, then at 808C for 2 h. Flash column chromatography

(hexane/EtOAc 10:1!EtOAc v/v) afforded compound 14ab as

404.1856, found: 404.1858; Anal. calcd for C₂₅H₂₅NO₄: C 74.42, H

6.25, N 3.47, found: C 74.1, H 6.45, N 3.53.

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tet-

rahydroisoquinoline (15d): Prepared as described for 15a using

compound 8 (808 mg, 3.0 mmol), 3,4,5-trimethoxybenzoyl chloride

(765 mg, 3.3 mmol) and Et₃N (2.0 mL, 14.4 mmol) in CHCl₃(20 mL)

at RT for 18 h. Flash column chromatography (hexane/EtOAc 3:1!

1:2 v/v) afforded compound 15d as a white powder (1.10 g, 79%):

mp: 63–648C; ¹H NMR (270 MHz, CDCl₃): d=2.78 (2H, s, br), 3.60

and 3.88 (2H, 2s, br), 3.85 (6H, s), 3.86 (6H, s), 4.50 and 4.77 (2H,

2s, br), 5.12 (2H, s), 6.44 and 6.65 (4H, 2s, br), 7.25–7.44 ppm (5H,

a

white powder (500 mg, 72%): mp: 129–1318C; ¹H NMR

(270 MHz, CDCl₃): d=2.67–2.78 (4H, m), 3.59 (2H, s), 3.69 (2H, s),

3.80 (6H, s), 3.81 (6H, s), 5.07 (2H, s), 6.14 (2H, s), 6.50 (1H, s), 6.56

(1H, s), 7.24–7.41 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.6

(CH₂), 48.8 (CH₂), 50.5 (CH₂), 55.2 (CH₂), 55.4 (CH₃), 55.9 (2ꢂCH₃),

56.2 (CH₃), 71.2 (CH₂), 90.6 (2ꢂCH), 107.2 (C_q), 110.4 (CH), 114.4

(CH), 126.6 (C_q), 127.4 (2ꢂCH), 127.7 (CH), 128.5 (2ꢂCH), 137.5 (C_q),

146.5 (C_q), 147.8 (C_q), 160.2 (2ꢂC_q), 160.6 ppm (C_q); LC-MS (ESꢀ):

m/z 450.5 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for

C₂₇H₃₂NO₅⁺: 450.2275, found: 450.2263; Anal. calcd for C₂₇H₃₁NO₅

0.25H₂O: C 71.42, H 6.99, N 3.08, found: C 71.5, H 6.97, N 3.04.

m); LC-MS (ES+): m/z 464.28 [M+H]⁺and 486.26 [M+Na]⁺; HRMS

(ES+): m/z [M+H]⁺calcd for C₂₇H₃₀NO₆

: 464.2068, found:

+

464.2060; Anal. calcd for C₂₇H₂₉NO₆: C 69.96, H 6.31, N 3.02, found:

C 69.5, H 6.31, N 3.02.

7-Methoxy-2-(2-methoxyphenylsulfonyl)-6-(triisopropylsiloxy)-

1,2,3,4-tetrahydroisoquinoline (16a): Compound 10 (300 mg,

0.9 mmol) was treated with 2-methoxybenzenesulfonyl chloride

(204 mg, 0.99 mmol) and Et₃N (0.14 mL, 0.99 mmol) in CH₂Cl₂

(10 mL). The reaction mixture was stirred at RT for 22 h. The reac-

tion mixture was diluted with CH₂Cl₂(30 mL) and washed with

NaHCO₃(saturated). The aqueous layer was extracted with CH₂Cl₂

(2ꢂ30 mL). The combined organic phases were washed with brine

(30 mL), dried (MgSO₄), filtered and concentrated in vacuo. Flash

column chromatography (hexane!hexane/EtOAc 1:1 v/v) afforded

compound 16a as a light beige solid (332 mg, 73%): ¹H NMR

(270 MHz, CDCl₃): d=1.05 (18H, d, J=6.7 Hz), 1.13–1.29 (3H, m),

2.57 (2H, t, J=5.6 Hz), 3.54 (2H, t, J=5.6 Hz), 3.69 (3H, s), 3.72 (3H,

s), 4.41 (2H, s), 6.47 (1H, s), 6.53 (1H, s), 6.88–6.92 (1H, m), 6.99–

7.05 (1H, m), 7.44–7.51 (1H, m), 7.94–7.98 ppm (1H, m); LC-MS

(ES+): m/z 504.68 [MꢀH]⁺.

6-Benzyloxy-2-(2-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (15a): Compound 8 (404 mg, 1.5 mmol) was treat-

ed with 2-methoxybenzoyl chloride (0.22 mL, 1.65 mmol) and Et₃N

(0.42 mL, 3.0 mmol) in CHCl₃(10 mL) at RT for 18 h. H₂O (10 mL)

was added, and the mixture was extracted with EtOAc (80 mL). The

organic layer was washed with H₂O and brine, then dried (MgSO₄),

filtered and concentrated in vacuo. Flash column chromatography

(hexane/EtOAc 10:1!1:1 v/v) afforded compound 15a as a white

1

powder (0.46 g, 79%): mp: 92–938C; H NMR (270 MHz, CDCl₃): d=

2.59–2.68 and 2.77–2.86 (2H, 2 m), 3.39–3.47 and 3.78–3.96 (2H,

2m), 3.72, 3.76, 3.81 and 3.88 (6H, 4s), 4.27, 4.38, 4.80 and 4.88

(2H, 4d, J=16.6, 16.1, 16.6 and 16.1 Hz), 5.11 (2H, s), 6.38 and 6.61

(1H, 2s), 6.67 and 6.69 (1H, 2s), 6.92 (1H, d, J=8.2 Hz), 6.99 (1H, t,

J=7.4 Hz), 7.24 (1H, dt, J=7.4, 2.0 Hz), 7.28–7.46 ppm (6H, m); LC-

6-Benzyloxy-7-methoxy-2-(3-methoxyphenylsulfonyl)-1,2,3,4-tet-

rahydroisoquinoline (16b): Prepared as described for 16a using

compound

8 (300 mg, 1.11 mmol), 3-methoxybenzenesulfonyl

MS (APCI+): m/z 402.51 [MꢀH]⁺and 404.46 [M+H]⁺; HRMS

chloride (0.19 mL, 1.35 mmol) and Et₃N (0.19 mL, 1.35 mmol) in

CH₂Cl₂(10 mL) at RT for 22 h. Flash column chromatography

(hexane/EtOAc gradient) afforded compound 16b as a colourless

solid (270 mg, 55%): mp: 124–1268C; ¹H NMR (270 MHz, CDCl₃):

d=2.76 (2H, t, J=5.8 Hz), 3.32 (2H, t, J=5.8 Hz), 3.81 (3H, s), 3.83

(3H, s), 4.18 (2H, s), 5.07 (2H, s), 6.52 (1H, s), 6.56 (1H, s), 7.09 (1H,

dt, J=6.9, 2.7 Hz), 7.28–7.45 ppm (8H, m); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.4 (CH₂), 43.9 (CH₂), 47.3 (CH₂), 55.8 (CH₃), 56.2 (CH₃),

71.1 (CH₂), 109.5 (CH), 112.7 (CH), 114.2 (CH), 119.0 (CH), 119.9 (CH),

124.0 (C_q), 125.0 (C_q), 127.3 (2ꢂCH), 128.0 (CH), 128.6 (2ꢂCH),

130.2 (CH), 137.0 (C_q), 137.6 (C_q), 147.1 (C_q), 148.5 (C_q), 160.0 ppm

(C_q); LC-MS (APCI+): m/z 440.54 [M+H]⁺.

(ES+): m/z [M+H]⁺calcd for C₂₅H₂₆NO₄

: 404.1856, found:

+

404.1856.

6-Benzyloxy-2-(3-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (15b): Prepared as described for 15a using com-

pound 8 (404 mg, 1.5 mmol), 3-methoxybenzoyl chloride (0.22 mL,

1.65 mmol) and Et₃N (0.42 mL, 3.0 mmol) in CHCl₃(10 mL) at RT for

18 h. Flash column chromatography (hexane/EtOAc 10:1!1:1 v/v)

afforded compound 15b as a thick colourless oil (0.50 g, 83%):

¹H NMR (270 MHz, CDCl₃): d=2.71 and 2.82 (2H, 2s, br), 3.58 and

3.77 (2H, 2s, br), 3.80 (6H, s), 3.86 and 3.93 (1H, 2s, br), 4.49 and

4.79 (1H, 2s, br), 5.11 (2H, s), 6.41 and 6.69 (1H, 2s, br), 6.64 (1H, s,

br), 6.92–7.05 (2H, m), 6.97 (1H, s), 7.26–7.46 ppm (6H, m); LC-MS

(APCI+): m/z 402.45 [MꢀH]⁺and 404.46 [M+H]⁺; HRMS (ES+):

m/z [M+H]⁺calcd for C₂₅H₂₆NO₄⁺: 404.1856, found: 404.1858;

Anal. calcd for C₂₅H₂₅NO₄: C 74.42, H 6.25, N 3.47, found: C 74.1, H

6.36, N 3.46.

7-Methoxy-2-(4-methoxyphenylsulfonyl)-6-(triisopropylsiloxy)-

1,2,3,4-tetrahydroisoquinoline (16c): Prepared as described for

16a using compound 10 (300 mg, 0.9 mmol), 4-methoxybenzene-

sulfonyl chloride (222 mg, 1.07 mmol) and Et₃N (0.15 mL,

1.07 mmol) in CH₂Cl₂(10 mL) at RT for 18 h. Flash column chroma-

tography (hexane!hexane/EtOAc 1:1 v/v) afforded compound

6-Benzyloxy-2-(4-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (15c): Prepared as described for 15a using com-

pound 8 (406 mg, 1.5 mmol), 4-methoxybenzoyl chloride (318 mg,

1.8 mmol) and Et₃N (0.42 mL, 3.0 mmol) in CHCl₃(30 mL) at RT for

18 h. Flash column chromatography (hexane/EtOAc 10:1!1:1 v/v)

afforded compound 15c as a white powder (0.52 g, 85%): mp:

1

16c as a colourless solid (292 mg, 65%): H NMR (270 MHz, CDCl₃):

d=1.04 (18H, d, J=6.8 Hz), 1.12–1.28 (3H, m), 2.76 (2H, t, J=

5.8 Hz), 3.28 (2H, t, J=5.8 Hz), 3.71 (3H, s), 3.84 (3H, s), 4.13 (2H,

s), 6.44 (1H, s), 6.54 (1H, s), 6.93–6.98 (2H, m), 7.73–7.76 ppm (2H,

m); ¹³C NMR (67.5 MHz, CDCl₃): d=12.9 (3ꢂCH), 18.0 (6ꢂCH₃), 28.1

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(CH₂), 44.0 (CH₂), 47.5 (CH₂), 55.6 (CH₃), 55.7 (CH₃), 109.7 (CH), 114.3

(2ꢂCH), 120.3 (CH), 124.1 (C_q), 125.0 (C_q), 128.0 (C_q), 129.9 (2ꢂCH),

144.3 (C_q), 149.6 (C_q), 163.1 ppm (C_q); LC-MS (ES+): m/z 528.67

[M+Na]⁺.

(CH), 124.6 (C_q), 126.2 (C_q), 128.5 (C_q), 130.9 (2ꢂCH), 144.4 (C_q),

145.5 (C_q), 159.1 ppm (C_q); LC-MS (APCI+): m/z 300.50 [M+H]⁺.

6-Hydroxy-2-(3-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17e): Prepared as described for 17a using compound

14e (340 mg, 0.91 mmol) and Pd/C (10%, 40 mg) in THF (20 mL)

and MeOH (10 mL) at RT for 0.5 h. Flash column chromatography

(EtOAc) afforded compound 17e as a yellow powder (200 mg,

78%): mp: 177–1788C; ¹H NMR (270 MHz, CDCl₃/[D₆]acetone 5:1):

d=2.41–2.51 (4H, m), 3.24 (2H, s), 3.34 (2H, s), 3.53 (3H, s), 6.21

(1H, s), 6.35 (1H, s), 6.49 (1H, ddd, J=7.2, 3.0, 1.2 Hz), 6.61 (1H, d,

J=7.2 Hz), 6.64 (1H, d, J=3.0 Hz), 6.88 ppm (1H, t, J=7.2 Hz);

¹³C NMR (67.5 MHz, CDCl₃/[D₆]acetone 5:1): d=28.3 (CH₂), 50.7

(CH₂), 55.4 (CH₂), 55.7 (CH₃), 62.3 (CH₂), 109.0 (CH), 114.0 (CH), 114.3

(CH), 115.8 (CH), 120.2 (CH), 125.6 (C_q), 126.5 (C_q), 129.1 (CH), 144.1

(C_q), 144.3 (C_q), 145.1 (C_q), 156.9 ppm (C_q); LC-MS (APCI+): m/z

286.52 [M+H]⁺.

2-Benzyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(17a): A solution of compound 14a (230 mg, 0.64 mmol) in THF

(10 mL) and MeOH (10 mL) and Pd/C (10%, 50 mg) was degassed

and treated with hydrogen at RT for 2 h. The reaction mixture was

filtered through celite and the filtrate was concentrated in vacuo.

Flash column chromatography (hexane/EtOAc 3:1!1:2 v/v) afford-

ed compound 17a as a light yellow powder (90 mg, 38%): mp:

1

134–1358C; H NMR (270 MHz, CDCl₃): d=2.68–2.80 (4H, m), 3.52

(2H, s), 3.66 (2H, s), 3.79 (3H, s), 5.49 (1H, br), 6.44 (1H, s), 6.64

(1H, s), 7.22–7.40 ppm (5H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.5

(CH₂), 50.9 (CH₂), 55.8 (CH₂), 56.0 (CH₃), 62.8 (CH₂), 108.8 (CH), 114.3

(CH), 126.1 (C_q), 127.0 (C_q), 127.2 (CH), 128.4 (2ꢂCH), 129.3 (2ꢂCH),

138.4 (C_q), 144.0 (C_q), 144.9 ppm (C_q); LC-MS (APCI+): m/z 270.46

6-Hydroxy-7-methoxy-2-(3-trifluoromethoxybenzyl)-1,2,3,4-tetra-

hydroisoquinoline (17 f): Prepared as described for 14e using

compound 14 f (238 mg, 0.47 mmol) and TBAF (1m in THF,

0.47 mL, 0.47 mmol) in THF (8 mL) at 08C for 1 h. Flash column

chromatography (hexane/EtOAc gradient) afforded compound 17 f

[M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₁₇H₂₀NO₂

:

+

270.1489, found: 270.1488.

6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-

isoquinoline (17b): Prepared as described for 17a using com-

pound 14b (300 mg, 0.77 mmol) and Pd/C (10%, 30 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 2 h. Flash column chromatog-

raphy (hexane/EtOAc 3:1!1:2 v/v) afforded compound 17b as

1

as a yellow solid (95 mg, 60%): mp: 122–1248C; H NMR (270 MHz,

CDCl₃): d=2.67–2.72 (2H, m), 2.76–2.81 (2H, m), 3.53 (2H, s), 3.67

(2H, s), 3.81 (3H, s), 5.47 (1H, s), 6.45 (1H, s), 6.65 (1H, s), 7.09–7.12

(1H, m), 7.26–7.37 ppm (3H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=

28.5 (CH₂), 50.9 (CH₂), 55.8 (CH₂), 56.1 (CH₃), 62.1 (CH₂), 108.9 (CH),

114.4 (CH), 119.6 (CH), 120.5 (d, J=256.5 Hz, CF₃), 121.4 (CH), 125.9

(C_q), 127.0 (C_q), 127.3 (CH), 129.6 (CH), 141.2 (C_q), 144.2 (C_q), 145.0

(C_q), 149.5 ppm (C_q); LC-MS (ES+): m/z 354.57 [M+H]⁺.

a

yellow powder (145 mg, 63%): mp: 128–1298C; ¹H NMR

(270 MHz, CDCl₃): d=2.73–2.82 (4H, m), 3.60 (2H, s), 3.71 (2H, s),

3.80 (3H, s), 3.83 (3H, s), 5.47 (1H, s, br), 6.46 (1H, s), 6.63 (1H, s),

6.87 (1H, d, J=7.9 Hz), 6.94 (1H, dt, J=7.4, 1.0 Hz), 7.24 (1H, dt,

J=7.4, 1.7 Hz), 7.43 ppm (1H, dd, J=7.4, 1.7 Hz); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.5 (CH₂), 51.0 (CH₂), 55.6 (CH₃), 55.8 (CH₂),

55.9 (CH₂), 56.1 (CH₃), 108.9 (CH), 110.5 (CH), 114.3 (CH), 114.6 (C_q),

120.4 (CH), 120.5 (C_q), 126.4 (C_q), 127.1 (C_q), 128.1 (CH), 130.4 (CH),

144.0 (C_q), 144.8 (C_q), 157.9 ppm (C_q); LC-MS (APCI+): m/z 300.44

[M+H]⁺.

2-(3-Ethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17g): Prepared as described for 17a using compound

14g (180 mg, 0.45 mmol) and Pd/C (10%, 20 mg) in THF (5 mL)

and MeOH (25 mL) at RT for 0.5 h. Flash column chromatography

(hexane/EtOAc 2:1!1:1 v/v) afforded compound 17g as a yellow

1

6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydro-

isoquinoline (17c): Prepared as described for 17a using com-

pound 14c (300 mg, 0.75 mmol) and Pd/C (10%, 30 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 0.75 h. Flash column chroma-

tography (hexane/EtOAc 3:1!1:2 v/v) afforded compound 17c as

a light yellow solid (170 mg, 76%): mp: 161–1628C; ¹H NMR

(270 MHz, CDCl₃): d=2.67–2.80 (4H, m), 3.53 (2H, s), 3.64 (2H, s),

3.79 (6H, s), 5.55 (1H, s, br), 6.45 (1H, s), 6.64 (1H, s), 6.81 (1H,

ddd, J=8.1, 2.4, 1.0 Hz), 6.96 (2H, m), 7.23 ppm (1H, t, J=8.1 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=28.6 (CH₂), 50.9 (CH₂), 55.3 (CH₃),

55.9 (CH₂), 56.1 (CH₃), 62.9 (CH₂), 108.9 (CH), 112.8 (CH), 114.2 (CH),

114.5 (CH), 121.4 (CH), 126.2 (C_q), 127.0 (C_q), 129.3 (CH), 140.2 (C_q),

powder (70 mg, 50%): mp: 105–1068C; H NMR (270 MHz, CDCl₃):

d=1.39 (3H, t, J=7.2 Hz), 2.66–2.80 (4H, m), 3.53 (2H, s), 3.64 (2H,

s), 3.79 (3H, s), 4.02 (2H, q, J=7.2 Hz), 6.45 (1H, s), 6.63 (1H, s),

6.80 (1H, ddd, J=8.0, 2.2, 1.0 Hz), 6.93–6.96 (2H, m), 7.22 ppm (1H,

t, J=8.0 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=15.0 (CH₃), 28.5 (CH₂),

50.8 (CH₂), 55.8 (CH₂), 56.0 (CH₃), 62.8 (CH₂), 63.4 (CH₂), 108.9 (CH),

113.3 (CH), 114.3 (CH), 115.1 (CH), 121.4 (CH), 126.1 (C_q), 127.0 (C_q),

129.3 (CH), 140.0 (C_q), 144.0 (C_q), 144.9 (C_q), 159.1 ppm (C_q); LC-MS

(APCI+): m/z 314.55 [M+H]⁺.

6-Hydroxy-2-(3-isopropoxybenzyl)-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (17h): Prepared as described for 17a using com-

pound 14h (246 mg, 0.6 mmol) and Pd/C (10%, 50 mg) in THF

(7 mL) and MeOH (7 mL) at RT for 19 h. Flash column chromatogra-

phy (hexane/EtOAc gradient) afforded compound 17h as a pale

yellow solid (134 mg, 70%): mp: 143–1468C; ¹H NMR (270 MHz,

CDCl₃): d=1.31 (6H, d, J=5.9 Hz), 2.68–2.77 (4H, m), 3.52 (2H, s),

3.62 (2H, s), 3.81 (3H, s), 4.55 (1H, sept, J=5.9 Hz), 6.45 (1H, s),

6.63 (1H, s), 6.76–6.80 (1H, m), 6.92–6.94 (2H, m), 7.21 ppm (1H, t,

J=7.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=22.2 (2ꢂCH₃), 28.6 (CH₂),

50.9 (CH₂), 55.9 (CH₂), 56.1 (CH₃), 62.8 (CH₂), 69.8 (CH), 108.9 (CH),

114.3 (CH), 114.6 (CH), 116.5 (CH), 121.3 (CH), 126.2 (C_q), 127.1 (C_q),

129.3 (CH), 140.2 (C_q), 144.0 (C_q), 144.9 (C_q), 158.0 ppm (C_q); LC-MS

(APCIꢀ): m/z 326.09 [MꢀH]^ꢀ; Anal. calcd for C₂₀H₂₅NO₃: C 73.37, H

7.70, N 4.28, found: C 73.5, H 7.90, N 4.13.

144.0 (C_q), 145.0 (C_q), 159.7 ppm (C_q); LC-MS (APCI+): m/z 300.44

[M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₁₈H₂₂NO₃

:

+

300.1594, found: 300.1591.

6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-

isoquinoline (17d): Prepared as described for 17a using com-

pound 14d (220 mg, 0.56 mmol) and Pd/C (10%, 20 mg) in THF

(10 mL) and MeOH (10 mL) at RT for 1 h. Flash column chromatog-

raphy (hexane/EtOAc 3:1!1:2 v/v) afforded compound 17d as

a light yellow solid (100 mg, 60%): mp: 162–1638C; ¹H NMR

(270 MHz, CDCl₃): d=2.69–2.78 (4H, m), 3.49 (2H, s), 3.60 (2H, s),

3.79 (3H, s), 3.80 (3H, s), 5.41 (1H, br), 6.44 (1H, s), 6.62 (1H, s),

6.86 (2H, dt, J=8.6, 2.5 Hz), 7.29 ppm (2H, dt, J=8.8, 2.5 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=27.5 (CH₂), 50.3 (CH₂), 55.1 (CH₂),

55.3 (CH₃), 55.9 (CH₃), 61.6 (CH₂), 109.1 (CH), 113.7 (2ꢂCH), 114.6

6-Hydroxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydro-

isoquinoline (17i): Prepared as described for 17a using compound

14i (300 mg, 0.66 mmol) and Pd/C (10%, 50 mg) in THF (15 mL)

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and MeOH (15 mL) RT for 1 h. Flash column chromatography

(CH₂), 55.9 (CH₂), 56.0 (CH₃), 62.9 (CH₂), 108.9 (CH), 114.2 (CH), 126.2

(C_q), 126.3 (CH), 127.0 (C_q), 127.9 (CH), 128.2 (CH), 130.0 (CH), 138.0

(C_q), 138.3 (C_q), 144.0 (C_q), 144.9 ppm (C_q); LC-MS (APCI+): m/z

284.38 [M+H]⁺.

(hexane/EtOAc 3:1!1:1 v/v) afforded compound 17i as a yellow

1

powder (170 mg, 71%): mp: 139–1408C; H NMR (270 MHz, CDCl₃):

d=2.67–2.76 (4H, m), 3.53 (2H, s), 3.64 (2H, s), 3.80 (3H, s), 6.45

(1H, s), 6.64 (1H, s), 6.90 (1H, ddd, J=8.2, 1.6 Hz), 6.99–7.15 (5H,

m), 7.28–7.35 ppm (3H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.5

(CH₂), 50.8 (CH₂), 55.7 (CH₂), 56.0 (CH₃), 62.5 (CH₂), 108.8 (CH), 114.2

(CH), 117.6 (CH), 118.8 (2ꢂCH), 119.7 (CH), 123.2 (CH), 124.1 (CH),

126.1 (C_q), 127.0 (C_q), 129.6 (CH), 129.8 (2ꢂCH), 140.7 (C₃), 144.0

(C_q), 144.9 (C_q), 157.3 (C_q), 157.4 ppm (C_q); LC-MS (APCI+): m/z

362.47 [M+H]⁺.

2-(3-Ethylbenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoqui-

noline (17o): Prepared as described for 17a using compound 14o

(502 mg, 1.3 mmol) and Pd/C (10%, 29 mg) in THF (8 mL) and

EtOH (8 mL) at RT for 2 h. Flash column chromatography (CHCl₃/

acetone 9:1!9:1 v/v and 2% MeOH) afforded compound 17o as

a pale yellow solid (260 mg, 67%): ¹H NMR (270 MHz, CDCl₃): d=

1.24 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 2.72 (2H, d, J=

5.2 Hz), 2.77 (2H, d, J=5.2 Hz), 3.53 (2H, s), 3.65 (2H, s), 3.80 (3H,

s), 5.51 (1H, s, br), 6.46 (1H, s), 6.64 (1H, s), 7.11 (1H, d, J=7.2 Hz),

2-(3-Acetoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17k): Prepared as described for 17a using compound

14k (320 mg, 0.77 mmol) and Pd/C (10%, 40 mg) in THF (5 mL)

and MeOH (25 mL) at RT for 0.75 h. Flash column chromatography

(hexane/EtOAc 2:1!1:1 v/v) afforded compound 17k as a light

7.15–7.29 (2H, m), 7.22 ppm (1H, t, J=6.1 Hz); LC-MS (ES+): m/z

298.1 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₁₉H₂₄NO₂

:

+

298.1802, found: 298.1813.

1

yellow powder (125 mg, 50%): mp: 120–1228C; H NMR (270 MHz,

2-(3-Cyanobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

CDCl₃): d=2.28 (3H, s), 2.67–2.80 (4H, m), 3.51 (2H, s), 3.66 (2H, s),

3.80 (3H, s), 5.46 (1H, s), 6.45 (1H, s), 6.64 (1H, s), 6.98 (1H, ddd,

J=7.9, 2.2, 1.2 Hz), 7.14 (1H, t, J=1.7 Hz), 7.21–7.26 (1H, m),

7.32 ppm (1H, t, J=7.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=21.3

(CH₃), 28.6 (CH₂), 51.0 (CH₂), 55.8 (CH₂), 56.1 (CH₃), 62.4 (CH₂), 108.9

(CH), 114.3 (CH), 120.4 (CH), 122.0 (CH), 126.1 (C_q), 126.5 (CH), 127.0

(C_q), 129.3 (CH), 140.6 (C_q), 144.0 (C_q), 144.9 (C_q), 150.8 (C_q),

169.7 ppm (C_q); LC-MS (ES+): m/z 328.36 [M+H]⁺.

quinoline (17p): Prepared as described for 14e using compound

14p (330 mg, 0.74 mmol) and TBAF (1m in THF, 0.74 mL,

0.74 mmol) in THF (10 mL) at 08C for 1 h. Flash column chromatog-

raphy (hexane/EtOAc gradient) gave a yellow oil that crystallised

from Et₂O/hexane to afford compound 17p as a light yellow solid

1

(80 mg, 36%): mp: 113–1158C; H NMR (270 MHz, CDCl₃): d=2.71

(2H, t, J=5.6 Hz), 2.79 (2H, t, J=6.0 Hz), 3.51 (2H, s), 3.68 (2H, s),

3.80 (3H, s), 6.45 (1H, s), 6.65 (1H, s), 7.43 (1H, t, J=8.0 Hz), 7.55

(1H, d, J=8.0 Hz), 7.64 (1H, d, J=8.0 Hz), 7.69 ppm (1H, s);

¹³C NMR (67.5 MHz, CDCl₃): d=28.3 (CH₂), 50.9 (CH₂), 55.6 (CH₃),

55.9 (CH₂), 61.8 (CH₂), 108.7 (CH), 112.3 (C_q), 114.2 (CH), 118.9 (C_q),

125.5 (C_q), 126.7 (C_q), 129.1 (CH), 130.9 (CH), 132.4 (CH), 133.4 (CH),

140.2 (C_q), 144.1 (C_q), 144.9 ppm (C_q); LC-MS (APCIꢀ): m/z 293.45

[MꢀH]^ꢀ.

2-(3-Fluorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17l): Prepared as described for 17a using compound

14l (277 mg, 0.93 mmol) and Pd/C (10%, 40 mg) in THF (5 mL) and

EtOH (5 mL) at RT for 0.75 h. Flash column chromatography

(hexane!hexane/EtOAc 1:1 v/v) afforded compound 17l as

1

a yellow solid (150 mg, 57%): mp: 125–1278C; H NMR (270 MHz,

[D₆]DMSO): d=2.60–2.63 (4H, m), 3.40 (2H, s), 3.62 (2H, s), 3.67

(3H, s), 6.49 (1H, s), 6.54 (1H, s), 7.04–7.21 (3H, m), 7.34–7.40 (1H,

m), 8.70 ppm (1H, s, br); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=28.1

(CH₂), 50.6 (CH₂), 55.1 (CH₂), 55.6 (CH₃), 61.3 (CH₂), 110.1 (CH), 113.8

(d, J=21.3 Hz, CH), 115.2 (d, J=19.9 Hz, CH), 115.3 (CH), 124.7 (d,

J=2.4 Hz, C_q), 124.9 (CH), 125.9 (CH), 130.1 (d, J=8.4 Hz, C_q), 141.8

(d, J=6.9 Hz, C_q), 144.7 (C_q), 145.9 (C_q), 161.3 ppm (d, J=241.9 Hz,

CF); LC-MS (APCI+): m/z 288.35 [M+H]⁺.

2-(3-Acetylbenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17q): Prepared as described for 14e using compound

14q (250 mg, 0.53 mmol) and TBAF (1m in THF, 0.59 mL,

0.59 mmol) in THF (20 mL) at RT for 1 h. Flash column chromatog-

raphy (hexane/EtOAc 3:1!1:2 v/v) afforded compound 17q as

1

a yellow solid (135 mg, 71%): mp: 132–1348C; H NMR (270 MHz,

CDCl₃): d=2.60 (s, 3H), 2.67–2.80 (4H, m), 3.52 (2H, s), 3.71 (2H, s),

3.79 (3H, s), 5.55 (1H, s, br), 6.44 (1H, s), 6.64 (1H, s), 7.42 (1H, t,

J=7.7 Hz), 7.62 (1H, dt, J=7.7, 1.6 Hz), 7.85 (1H, dt, J=7.7, 1.2 Hz),

7.95 ppm (1H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=26.9 (CH₃), 28.6

(CH₂), 51.0 (CH₂), 55.8 (CH₂), 56.0 (CH₃), 62.5 (CH₂), 108.8 (CH), 114.3

(CH), 126.0 (C_q), 127.0 (C_q), 127.3 (CH), 128.7 (CH), 129.0 (CH), 134.0

(CH), 137.3 (C_q), 139.3 (C_q), 144.1 (C_q), 144.9 (C_q), 198.5 ppm (C_q);

LC-MS (APCI+): m/z 312.47 [M+H]⁺.

2-(3-Chlorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-

quinoline (17m): Prepared as described for 14e using compound

14m (322 mg, 0.7 mmol) and TBAF (1m in THF, 0.7 mL, 0.7 mmol)

in THF (15 mL) at 08C for 2 h. Flash column chromatography

(hexane!EtOAc gradient) afforded compound 17m as a yellow

solid (195 mg, 92%): mp: 118–1208C; ¹H NMR (270 MHz, CDCl₃):

d=2.68–2.72 (2H, m), 2.76–2.80 (2H, m), 3.51 (2H, s), 3.62 (2H, s),

3.80 (3H, s), 6.45 (1H, s), 6.65 (1H, s), 7.22–7.27 (3H, m), 7.40 ppm

(1H, d, J=1.2 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=28.5 (CH₂), 51.0

(CH₂), 55.8 (CH₃), 56.1 (CH₂), 62.3 (CH₂), 108.9 (CH), 114.3 (CH), 125.9

(C_q), 126.9 (C_q), 127.3 (CH), 127.4 (CH), 129.1 (CH), 129.7 (CH), 134.3

(C_q), 140.8 (C_q), 144.1 (C_q), 145.0 ppm (C_q); LC-MS (APCI+): m/z

304.53 [M+H]⁺.

6-Hydroxy-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoqui-

noline (17r): Prepared as described for 14e using compound 14r

(410 mg, 0.87 mmol) and TBAF (1m in THF, 0.87 mL, 0.87 mmol) in

THF (20 mL) at 08C for 1 h. Flash column chromatography

(hexane/EtOAc gradient) afforded compound 17r as a yellow solid

(213 mg, 78%): mp: 126–1298C; ¹H NMR (270 MHz, CDCl₃): d=

2.71–2.79 (4H, m), 3.54 (2H, s), 3.74 (2H, s), 3.80 (3H, s), 5.51 (1H,

s), 6.44 (1H, s), 6.65 (1H, s), 7.49 (1H, t, J=7.9 Hz), 7.75 (1H, d, J=

7.9 Hz), 8.12 (1H, ddd, J=8.2, 2.5, 1.0 Hz), 8.24 ppm (1H, t, J=

1.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=28.5 (CH₂), 51.0 (CH₂), 55.8

(CH₂), 56.1 (CH₃), 61.9 (CH₂), 108.8 (CH), 114.4 (CH), 122.4 (CH),

123.8 (CH), 125.6 (C_q), 126.8 (C_q), 126.4 (CH), 135.2 (CH), 141.0 (C_q),

144.2 (C_q), 145.0 (C_q), 148.4 ppm (C_q); LC-MS (APCI+): m/z 315.49

[M+H]⁺.

6-Hydroxy-7-methoxy-2-(3-methylbenzyl)-1,2,3,4-tetrahydroiso-

quinoline (17n): Prepared as described for 17a using compound

14n (400 mg, 1.07 mmol) and Pd/C (10%, 50 mg) in THF (20 mL)

and MeOH (20 mL) at RT for 1 h. Flash column chromatography

(hexane/EtOAc 2:1!1:2 v/v) afforded compound 17n as a yellow

1

powder (180 mg, 60%): mp: 128–1298C; H NMR (270 MHz, CDCl₃):

d=2.34 (3H, s), 2.68–2.78 (4H, m), 3.52 (2H, s), 3.63 (2H, s), 3.80

(3H, s), 6.45 (1H, s), 6.64 (1H, s), 7.06–7.10 (1H, m), 7.14–7.25 ppm

(3H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=21.5 (CH₃), 28.5 (CH₂), 51.0

2-(3-Acetamidobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydro-

isoquinoline (17s): Prepared as described for 17a using com-

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pound 14s (140 mg, 0.34 mmol) and Pd/C (10%, 20 mg) in THF

(5 mL) and MeOH (30 mL) at RT for 1.5 h. Flash column chromatog-

raphy (hexane/EtOAc 1:4!1:10 v/v) afforded compound 17s as

a yellow solid (65 mg, 59%): mp: 190–1918C; ¹H NMR (270 MHz,

[D₆]acetone): d=2.06 (3H, s), 2.64–2.73 (4H, m), 3.43 (2H, s), 3.59

(2H, s), 3.75 (3H, s), 6.55 (2H, s), 7.03 (1H, d, J=7.4 Hz), 7.23 (1H,

dd, J=8.2, 7.4 Hz), 7.60 (1H, s), 7.63 (1H, d, J=8.2 Hz), 9.13 ppm

(1H, s, br); ¹³C NMR (67.5 MHz, [D₆]acetone): d=23.5 (CH₃), 28.7

(CH₂), 51.1 (CH₂), 55.4 (CH₃), 55.6 (CH₂), 62.6 (CH₂), 109.6 (CH), 114.7

(CH), 117.8 (CH), 119.2 (CH), 123.5 (CH), 125.9 (C_q), 126.6 (C_q), 128.5

(CH), 139.8 (2ꢂC_q), 145.0 (C_q), 145.9 (C_q), 168.1 ppm (C_q); LC-MS

(ESꢀ): m/z 325.33 [MꢀH]^ꢀ.

(270 MHz, CDCl₃): d=2.68–2.78 (4H, m), 3.53 (2H, s), 3.60 (2H, s),

3.78 (6H, s), 3.80 (3H, s), 6.37 (1H, t, J=2.4 Hz), 6.46 (1H, s), 6.57

(2H, d, J=2.4 Hz), 6.64 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=

28.5 (CH₂), 50.9 (CH₂), 55.5 (CH₃), 55.8 (CH₂), 56.1 (CH₃), 62.9 (CH₂),

99.3 (CH), 106.9 (2ꢂCH), 109.0 (CH), 114.3 (CH), 126.0 (C_q), 127.0

(C_q), 144.0 (C_q), 144.8 (C_q), 160.8 ppm (2ꢂC_q); LC-MS (APCI+): m/z

330.42 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for C₁₉H₂₄NO₄

:

+

330.1700, found: 330.1697.

2-(2,5-Dimethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (17x): Prepared as described for 17a using com-

pound 14x (430 mg, 1.03 mmol) and Pd/C (10%, 50 mg) in THF

(20 mL) and MeOH (20 mL) at RT for 1 h. Flash column chromatog-

raphy (CH₂Cl₂/EtOAc 3:2!1:1 v/v) afforded compound 17x as

a yellow powder (260 mg, 77%): ¹H NMR (270 MHz, CDCl₃): d=

2.71–2.80 (4H, m), 3.60 (2H, s), 3.68 (2H, s), 3.75 (3H, s), 3.79 (3H,

s), 3.80 (3H, s), 5.56 (1H, s, br), 6.47 (1H, s), 6.63 (1H, s), 6.75 (1H,

dd, J=8.9, 2.7 Hz), 6.79 (1H, s), 6.81 (1H, d, J=8.9 Hz), 7.06 ppm

(1H, d, J=2.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=28.6 (CH₂), 50.9

(CH₂), 55.7 (CH₂), 55.8 (CH₃), 55.9 (CH₂), 56.1 (CH₃), 56.3 (CH₃), 108.9

(CH), 111.7 (CH), 112.5 (CH), 114.3 (CH), 116.1 (CH), 126.5 (C_q), 127.2

(C_q), 127.9 (C_q), 144.0 (C_q), 144.9 (C_q), 152.1 (C_q), 153.7 ppm (C_q); LC-

MS (APCIꢀ): m/z 328.29 [MꢀH]^ꢀ.

6-Hydroxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetrahy-

droisoquinoline (17y): Prepared as described for 17a using com-

pound 14y (280 mg, 0.62 mmol) and Pd/C (10%, 30 mg) in THF

(10 mL) and MeOH (10 mL) at RT for 2 h. Flash column chromatog-

raphy (CH₂Cl₂/EtOAc 1:1 v/v) afforded compound 17y as a yellow

powder (165 mg, 74%): mp: 65–668C; ¹H NMR (270 MHz, CDCl₃):

d=2.66–2.75 (4H, m), 3.55 (2H, s), 3.63 (2H, s), 3.80 (3H, s), 3.85

(3H, s), 3.88 (6H, s), 5.49 (1H, s, br), 6.46 (1H, s), 6.63 (1H, s), 6.65

(1H, d, J=8.7 Hz), 7.09 ppm (1H, d, J=8.7 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.6 (CH₂), 50.7 (CH₂), 55.6 (CH₂), 56.1 (2ꢂCH₃), 56.2

(CH₂), 60.9 (CH₃), 61.4 (CH₃), 107.1 (CH), 108.9 (CH), 114.2 (CH),

125.2 (CH), 126.1 (C_q), 127.0 (C_q), 142.0 (C_q), 142.8 (C_q), 144.0 (C_q),

144.9 (C_q), 152.7 (C_q), 153.0 ppm (C_q); LC-MS (APCIꢀ): m/z 358.21

[MꢀH]^ꢀ.

6-Hydroxy-2-(3-(methylsulfonamido)benzyl)-7-methoxy-1,2,3,4-

tetrahydroisoquinoline (17t): Prepared as described for 17a using

compound 14t (200 mg, 0.44 mmol) and Pd/C (10%, 40 mg) in

THF (15 mL) and MeOH (15 mL) at RT for 0.5 h. Flash column chro-

matography (hexane/EtOAc 1:10 v/v) afforded compound 17t as

1

a yellow powder (150 mg, 94%): mp: 99–1018C; H NMR (270 MHz,

CDCl₃): d=2.66–2.78 (4H, m), 2.98 (3H, s), 3.51 (2H, s), 3.64 (2H, s),

3.79 (3H, s), 6.44 (1H, s), 6.62 (1H, s), 7.14–7.33 ppm (5H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=28.5 (CH₂), 39.5 (CH₃), 50.9 (CH₂),

55.8 (CH₂), 56.1 (CH₃), 62.3 (CH₂), 108.9 (CH), 114.4 (CH), 119.5 (CH),

121.4 (CH), 125.9 (C_q), 126.1 (CH), 126.9 (C_q), 129.7 (CH), 136.9 (C_q),

140.5 (C_q), 144.1 (C_q), 145.0 ppm (C_q); LC-MS (ESꢀ): m/z 361.54

[MꢀH]^ꢀ.

2-(2,3-Dimethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (17u): Prepared as described for 17a using com-

pound 14u (340 mg, 0.81 mmol) and Pd/C (5%, 60 mg) in THF

(20 mL) and MeOH (20 mL) at RT for 1.5 h. Flash column chroma-

tography (hexane/EtOAc 1:1!1:4 v/v) and (CH₂Cl₂/EtOAc 4:1!2:1

v/v) gave a solid that was stirred in Et₂O, filtered and dried to

afford compound 17u as a yellow powder (130 mg, 49%): mp:

1

101–1028C; H NMR (270 MHz, CDCl₃): d=2.69–2.78 (4H, m), 3.56

(2H, s), 3.72 (2H, s), 3.78 (3H, s), 3.83 (3H, s), 3.86 (3H, s), 5.41 (1H,

br), 6.46 (1H, s), 6.61 (1H, s), 6.84 (1H, dd, J=7.4, 2.2 Hz), 6.99–

7.08 ppm (2H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.8 (CH₂), 51.0

(CH₂), 55.7 (CH₂), 55.8 (CH₃), 56.0 (CH₃), 56.2 (CH₂), 61.0 (CH₃), 108.9

(CH), 111.1 (CH), 114.2 (CH), 122.6 (CH), 123.9 (CH), 126.5 (C_q), 127.1

(C_q), 132.3 (C_q), 143.9 (C_q), 144.8 (C_q), 147.8 (C_q), 152.8 ppm (C_q); LC-

MS (APCIꢀ): m/z 327.98 [MꢀH]^ꢀ.

6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahy-

droisoquinoline (17z): Prepared as described for 17a using com-

pound 14z (335 mg, 0.75 mmol) and Pd/C (10%, 30 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 1 h. Flash column chromatog-

raphy (hexane/EtOAc 1:1!1:4 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 17z as a yellow

2-(3,4-Dimethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (17v): Prepared as described for 17a using com-

pound 14v (250 mg, 0.60 mmol) and Pd/C (5%, 50 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 1 h. Flash column chromatog-

raphy (hexane/EtOAc 1:1!1:4 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 17v as a yellow

1

powder (160 mg, 60%): mp: 170–1718C; H NMR (270 MHz, CDCl₃):

d=2.66–2.81 (4H, m), 3.53 (2H, s), 3.59 (2H, s), 3.81 (3H, s), 3.84

(3H, s), 3.85 (6H, s), 5.49 (1H, s, br), 6.48 (1H, s), 6.62 (2H, s),

6.66 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=28.6 (CH₂), 50.8

(CH₂), 56.0 (CH₂), 56.1 (CH₃), 56.2 (CH₃), 61.0 (CH₃), 63.0 (CH₂), 105.7

(2ꢂCH), 108.9 (CH), 114.3 (CH), 126.1 (C_q), 127.1 (C_q), 134.4 (C_q),

136.9 (C_q), 144.1 (C_q), 145.0 (C_q), 153.2 ppm (2ꢂC_q); LC-MS (APCIꢀ):

m/z 358.15 [MꢀH]^ꢀ.

1

powder (120 mg, 51%): mp: 146–1478C; H NMR (270 MHz, CDCl₃):

d=2.66–2.79 (4H, m), 3.51 (2H, s), 3.59 (2H, s), 3.80 (3H, s), 3.86

(3H, s), 3.87 (3H, s), 5.56 (1H, s, br), 6.45 (1H, s), 6.64 (1H, s), 6.81

(1H, d, J=8.2 Hz), 6.88 (1H, dd, J=8.2, 1.7 Hz), 6.96 ppm (1H, d,

J=1.7 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=28.5 (CH₂), 50.7 (CH₂),

55.9 (CH₂), 56.0 (2ꢂCH₃), 56.1 (CH₃), 62.6 (CH₂), 108.9 (CH), 110.7

(CH), 112.1 (CH), 114.3 (CH), 121.3 (CH), 126.2 (C_q), 127.1 (C_q), 131.1

(C_q), 144.1 (C_q), 144.9 (C_q), 148.2 (C_q), 149.0 ppm (C_q); LC-MS

(APCIꢀ): m/z 327.98 [MꢀH]^ꢀ.

6-Hydroxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetrahy-

droisoquinoline (17aa): Prepared as described for 17a using com-

pound 14aa (210 mg, 0.47 mmol) and Pd/C (10%, 40 mg) in THF

(10 mL) and MeOH (10 mL) at RT for 2 h. Flash column chromatog-

raphy (CH₂Cl₂/EtOAc 2:1!1:1 v/v) afforded compound 17aa as

1

2-(3,5-Dimethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-

droisoquinoline (17w): Prepared as described for 17a using com-

pound 14w (385 mg, 0.92 mmol) and Pd/C (10%, 30 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 0.75 h. Flash column chroma-

tography (hexane/EtOAc 3:1!1:2 v/v) afforded compound 17w as

a yellow powder (80 mg, 48%): mp: 152–1538C; H NMR (270 MHz,

CDCl₃): d=2.67–2.79 (4H, m), 3.57 (2H, s), 3.64 (2H, s), 3.80 (3H, s),

3.81 (3H, s), 3.82 (3H, s), 3.89 (3H, s), 5.61 (1H, s, br), 6.46 (1H, s),

6.53 (1H, s), 6.62 (1H, s), 7.01 ppm (1H, s); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.6 (CH₂), 50.6 (CH₂), 55.3 (CH₂), 55.8 (CH₂), 56.0 (CH₃),

56.2 (CH₃), 56.6 (CH₃), 56.8 (CH₃), 97.6 (CH), 108.9 (CH), 114.2 (CH),

a

yellow powder (260 mg, 86%): mp: 127–1288C; ¹H NMR

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114.3 (CH), 118.0 (C_q), 126.4 (C_q), 127.1 (C_q), 143.1 (C_q), 144.0 (C_q),

144.9 (C_q), 148.5 (C_q), 152.1 ppm (C_q); LC-MS (APCIꢀ): m/z 358.21

[MꢀH]^ꢀ.

THF (20 mL) and MeOH (20 mL) at RT for 24 h. The resulting solid

was stirred in Et₂O, filtered and dried to afford compound 18d as

a white solid (180 mg, 90%): mp: 172–1738C; ¹H NMR (270 MHz,

CDCl₃): d=2.79 (2H, s, br), 3.62 and 3.83 (2H, 2s, br), 3.85 (12H, s),

4.50 and 4.76 (2H, 2s, br), 5.54 (1H, s), 6.41 and 6.70 (1H, 2s, br),

6.66 ppm (3H, s); LC-MS (ESꢀ): m/z 372.07 [MꢀH]^ꢀ; HRMS (ES+):

m/z [M+H]⁺calcd for C₂₀H₂₄NO₆⁺: 374.1598, found: 374.1581;

Anal. calcd for C₂₀H₂₃NO₆: C 64.33, H 6.21, N 3.75, found: C 63.8, H

6.12, N 3.70.

6-Hydroxy-7-methoxy-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-tetrahy-

droisoquinoline (17ab): Prepared as described for 17a using com-

pound 14ab (460 mg, 1.02 mmol) and Pd/C (10%, 50 mg) in THF

(20 mL) and MeOH (20 mL) at RT for 0.5 h. Flash column chroma-

tography (hexane/EtOAc 10:1 v/v!EtOAc!EtOAc/MeOH 19:1 v/v)

afforded compound 17ab as a light yellow powder (260 mg, 71%):

mp: 150–1518C; ¹H NMR (270 MHz, CDCl₃): d=2.70–2.77 (4H, m),

3.58 (2H, s), 3.69 (2H, s), 3.80 (9H, s), 3.81 (3H, s), 5.56 (1H, s, br),

6.13 (2H, s), 6.44 (1H, s), 6.56 ppm (1H, s); ¹³C NMR (67.5 MHz,

CDCl₃): d=27.1 (CH₂), 48.1 (CH₂), 49.7 (CH₂), 55.3 (CH₂), 55.4 (CH₃),

55.8 (2ꢂCH₃), 56.2 (CH₃), 90.5 (2ꢂCH), 103.8 (C_q), 108.9 (CH), 114.2

(CH), 125.9 (C_q), 126.1 (C_q), 144.2 (C_q), 145.1 (C_q), 160.2 (2ꢂC_q),

160.6 ppm (C_q); LC-MS (ES+): m/z 360.5 [M+H]⁺; HRMS (ES+):

m/z [M+H]⁺calcd for C₂₀H₂₆NO₅⁺: 360.1805, found: 360.1790;

Anal. calcd for C₂₀H₂₅NO₅: C 66.83, H 7.01, N 3.90, found: C 66.6, H

7.04, N 3.85.

6-Hydroxy-7-methoxy-2-(2-methoxyphenylsulfonyl)-1,2,3,4-tetra-

hydroisoquinoline (19a): Prepared as described for 14e using

compound 16a (332 mg, 0.66 mmol) and TBAF (1m in THF,

0.66 mL, 0.66 mmol) in THF (10 mL) at 08C for 1 h. Flash column

chromatography (hexane/EtOAc gradient) afforded compound 19a

as a colourless foam (103 mg, 45%): mp: 140–1428C; ¹H NMR

(270 MHz, CDCl₃): d=2.62 (2H, t, J=5.9 Hz), 3.55 (2H, t, J=5.9 Hz),

3.71 (3H, s), 3.82 (3H, s), 4.41 (2H, s), 5.46 (1H, s), 6.49 (1H, s), 6.61

(1H, s), 6.92 (1H, d, J=8.2 Hz), 7.03 (1H, dt, J=7.7, 1.0 Hz), 7.46–

7.51 (1H, m), 7.96 ppm (1H, dd, J=7.7, 1.7 Hz); ¹³C NMR (67.5 MHz,

CDCl₃): d=28.1 (CH₂), 43.8 (CH₂), 46.8 (CH₂), 55.7 (CH₃), 56.0 (CH₃),

108.1 (CH), 111.1 (CH), 114.4 (CH), 120.3 (CH), 124.0 (C_q), 126.4 (C_q),

127.2 (C_q), 131.7 (CH), 134.4 (CH), 144.1 (C_q), 145.3 (C_q), 156.9 ppm

(C_q); LC-MS (ESꢀ): m/z 348.27 [MꢀH]^ꢀ.

6-Hydroxy-7-methoxy-2-(3-methoxyphenylsulfonyl)-1,2,3,4-tetra-

hydroisoquinoline (19b): Prepared as described for 17a using

compound 16b (285 mg, 0.65 mmol) and Pd/C (10%, 30 mg) in

THF (5 mL) and EtOH (5 mL) at RT for 3 h. The resulting beige solid

was triturated with hexane and collected by filtration to afford

compound 19b as a colourless solid (214 mg, 95%): mp: 168–

1708C; ¹H NMR (270 MHz, CDCl₃): d=2.79 (2H, t, J=5.9 Hz), 3.33

(2H, t, J=5.9 Hz), 3.81 (3H, s), 3.83 (3H, s), 4.18 (2H, s), 5.49 (1H, s),

6.47 (1H, s), 6.61 (1H, s), 7.09 (1H, dt, J=6.9, 2.5 Hz), 7.31–

7.42 ppm (3H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.3 (CH₂), 43.9

(CH₂), 47.4 (CH₂), 55.8 (CH₃), 56.1 (CH₃), 108.4 (CH), 112.7 (CH), 114.3

(CH), 119.0 (CH), 119.9 (CH), 122.8 (C_q), 125.8 (C_q), 130.2 (CH), 137.6

(C_q), 144.6 (C_q), 145.4 (C_q), 160.0 ppm (C_q); LC-MS (APCI+): m/z

350.53 [M+H]⁺.

6-Hydroxy-7-methoxy-2-(2-methoxybenzoyl)-1,2,3,4-tetrahydro-

isoquinoline (18a): Prepared as described for 17a using com-

pound 15a (290 mg, 0.72 mmol) and Pd/C (10%, 50 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 4 h. Flash column chromatog-

raphy (hexane/EtOAc 2:1!3:2 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 18a as a white solid

(200 mg, 89%): mp: 176–1778C; ¹H NMR (270 MHz, CDCl₃): d=

2.62–2.72 and 2.80–2.87 (2H, 2 m), 3.40–3.48 and 4.07–4.21 (2H,

m), 3.74, 3.76, 3.81 and 3.87 (6H, 4s), 4.26, 4.37, 4.80 and 4.86 (2H,

4d, J=16.8, 15.8, 16.0 and 16.1 Hz), 5.55 and 5.57 (1H, 2s), 6.34,

6.64, 6.65 and 6.71 (2H, 4s), 6.92 (1H, d, J=8.4 Hz), 6.98 (1H, ddt,

J=7.7, 2.2, 0.8 Hz), 7.22–7.27 (1H, m), 7.31–7.40 ppm (1H, m); LC-

MS (APCI+): m/z 314.42 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd

+

for C₁₈H₂₀NO₄

: 314.1387, found: 314.1385; Anal. calcd for

C₁₈H₁₉NO₄: C 68.99, H 6.11, N 4.47, found: C 68.8, H 6.13, N 4.42.

6-Hydroxy-7-methoxy-2-(3-methoxybenzoyl)-1,2,3,4-tetrahydro-

isoquinoline (18b): Prepared as described for 17a using com-

pound 15b (340 mg, 0.84 mmol) and Pd/C (10%, 50 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 4 h. Flash column chromatog-

raphy (hexane/EtOAc 2:1!3:2 v/v) gave a solid that was stirred in

Et₂O, filtered and dried to afford compound 18b as a white solid

6-Hydroxy-7-methoxy-2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetra-

hydroisoquinoline (19c): Prepared as described for 14e using

compound 16c (272 mg, 0.54 mmol) and TBAF (1m in THF,

0.54 mL, 0.54 mmol) in THF (10 mL) at 08C for 2 h. Flash column

chromatography (hexane/EtOAc gradient) and crystallisation from

hexane/CH₂Cl₂afforded compound 19c as a colourless solid

1

(180 mg, 68%): mp: 141–1428C; H NMR (270 MHz, CDCl₃): d=2.74

and 2.85 (2H, 2s, br), 3.59 and 3.94 (2H, 2 s, br), 3.78 and 3.87 (6H,

2s), 4.48 and 4.79 (2H, 2s, br), 5.57 (1H, s), 6.36 and 6.64 (1H, 2s),

6.69 (1H, s), 6.94–7.01 (2H, m), 6.98 (1H, s), 7.32 ppm (1H, dd, J=

8.8, 7.4 Hz); LC-MS (APCI+): m/z 314.42 [M+H]⁺; HRMS (ES+): m/z

[M+H]⁺calcd for C₁₈H₂₀NO₄⁺: 314.1387, found: 314.1385.

1

(177 mg, 94%): mp: 147–1498C; H NMR (270 MHz, CDCl₃): d=2.79

(2H, t, J=5.9 Hz), 3.29 (2H, t, J=5.9 Hz), 3.82 (3H, s), 3.85 (3H, s),

4.14 (2H, s), 5.46 (1H, s), 6.47 (1H, s), 6.61 (1H, s), 6.95–6.98 (2H,

m), 7.73–7.76 ppm (2H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.3

(CH₂), 43.9 (CH₂), 47.4 (CH₂), 55.7 (CH₃), 56.1 (CH₃), 108.4 (CH), 114.3

(3ꢂCH), 122.9 (C_q), 125.8 (C_q), 128.0 (C_q), 129.9 (2ꢂCH), 144.4 (C_q),

145.4 (C_q), 163.1 ppm (C_q); LC-MS (ESꢀ): m/z 348.48 [MꢀH]^ꢀ.

2-Benzyl-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquino-

line (20a): Sulfamoyl chloride (0.6m in toluene, 1.0 mL, 0.6 mmol)

was concentrated in vacuo and cooled to 08C until the sulfamoyl

chloride solidified. DMA (1.0 mL) was added and the resulting solu-

tion was added directly to compound 17a (55 mg, 0.20 mmol) at

08C under N₂. The reaction mixture was stirred at RT for 18 h.

NaHCO₃(saturated) was added, and the mixture was extracted

with EtOAc. The organic layer was washed with H₂O (up to 10ꢂ)

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

Flash column chromatography (hexane/EtOAc 1:1!1:3 v/v) gave

an oil that was stirred in Et₂O to afford compound 20a as a light

6-Hydroxy-7-methoxy-2-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-

isoquinoline (18c): Prepared as described for 17a using com-

pound 15c (320 mg, 0.79 mmol) and Pd/C (10%, 30 mg) in THF

(15 mL) and MeOH (15 mL) at RT for 1.5 h. The resulting solid was

stirred in hexane/EtOAc (2:5 v/v, 14 mL), filtered and dried to afford

compound 18c as a white solid (220 mg, 89%): mp: 173–1748C;

¹H NMR (270 MHz, CDCl₃): d=2.68 (2H, t, J=6.9 Hz), 3.56 (2H, s,

br), 3.70 (3H, s, br), 3.80 (3H, s), 4.57 (2H, s, br), 6.55 (1H, s), 6.78

(1H, s, br), 7.00 (2H, dt, J=5.9, 1.7 Hz), 7.41 (2H, dt, J=5.9, 1.7 Hz),

8.84 ppm (1H, s); LC-MS (APCI+): m/z 314.42 [M+H]⁺; HRMS

(ES+): m/z [M+H]⁺calcd for C₁₈H₂₀NO₄

: 314.1387, found:

+

314.1384.

6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetra-

hydroisoquinoline (18d): Prepared as described for 17a using

compound 15d (250 mg, 0.54 mmol) and Pd/C (10%, 40 mg) in

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yellow powder (55 mg, 79%): mp: 113–1148C; ¹H NMR (270 MHz,

CDCl₃): d=2.71–2.84 (4H, m), 3.56 (2H, s), 3.68 (2H, s), 3.80 (3H, s),

4.97 (2H, s, br), 6.60 (1H, s), 7.07 (1H, s), 7.26–7.40 ppm (5H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=28.2 (CH₂), 50.5 (CH₂), 55.7 (CH₂),

56.4 (CH₃), 62.6 (CH₂), 111.2 (CH), 124.2 (CH), 127.4 (CH), 127.7 (C_q),

128.5 (2ꢂCH), 129.2 (2ꢂCH), 134.9 (C_q), 137.3 (C_q), 138.0 (C_q),

149.3 ppm (C_q); LC-MS (APCI+): m/z 349.37 [M+H]⁺; HRMS (ES+):

m/z [M+H]⁺calcd for C₁₇H₂₁N₂O₄S⁺: 349.1217, found: 349.1213.

6.44 (1H, s), 6.62 (1H, s), 6.74–6.81 (1H, m), 6.93–6.96 (2H, m),

7.16 ppm (1H, t, J=7.8 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=12.8

(3ꢂCH), 18.0 (6ꢂCH₃), 28.5 (CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.0 (CH₃),

62.7 (CH₂), 108.9 (CH), 114.4 (CH), 118.6 (CH), 120.8 (CH), 122.0 (CH),

126.2 (C_q), 127.1 (C_q), 129.2 (CH), 139.9 (C_q), 144.0 (C_q), 145.0 (C_q),

156.1 ppm (C_q); LC-MS (APCI+): m/z 532.71 [M+H]⁺. The silyl-pro-

tected phenol (200 mg, 0.45 mmol) and 2,6-tert-butyl-4-methylpyri-

dine (205 mg, 1.0 mmol) were dissolved in CH₂Cl₂(5 mL). Sulfamoyl

chloride (1.80 mmol) was concentrated in vacuo and dissolved in

CH₂Cl₂(~1 mL). The solution was added to the reaction mixture

and stirred at RT for 60 h. NaHCO₃(saturated) was added and the

mixture was extracted with EtOAc. The organic layer was washed

with H₂O, brine, dried (MgSO₄), filtered and concentrated in vacuo.

Flash column chromatography (hexane/EtOAc 4:1!3:2 v/v) afford-

ed the sulfamate as a yellow powder (100 mg, 63%): mp: 110–

7-Methoxy-2-(2-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20b): Prepared as described for 20a using com-

pound 17b (72 mg, 0.24 mmol) and sulfamoyl chloride (0.72 mmol)

in DMA (1.0 mL) at RT for 18 h. Flash column chromatography

(hexane/EtOAc 1:1!1:3 v/v) gave an oil that was stirred in Et₂O to

afford compound 20b as a light yellow powder (50 mg, 55%): mp:

1

126–1278C; H NMR (270 MHz, CDCl₃): d=2.78 (4H, m), 3.48 (2H, s,

1

112 8C; H NMR (270 MHz, CDCl₃): d=1.08 (18H, d, J=6.9 Hz), 1.16–

br), 3.62 (2H, s), 3.73 (2H, s), 3.79 (3H, s), 3.83 (3H, s), 6.61 (1H, s),

6.90 (1H, d, J=7.9 Hz), 6.95 (1H, dt, J=7.4, 1.0 Hz), 7.09 (1H, s),

7.25–7.36 ppm (2H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=27.6 (CH₂),

50.3 (CH₂), 55.6 (CH₂), 55.6 (2ꢂCH₃), 60.7 (CH₂), 110.6 (CH), 111.0

(CH), 120.5 (CH), 123.8 (CH), 124.8 (C_q), 126.8 (C_q), 128.9 (CH), 131.2

(CH), 133.8 (C_q), 137.5 (C_q), 149.7 (C_q), 158.1 ppm (C_q); LC-MS

(APCI+): m/z 379.34 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd for

C₁₈H₂₃N₂O₅S⁺: 379.1322, found: 379.1323.

1.30 (3H, m), 2.66–2.81 (4H, m), 3.54 (2H, s), 3.61 (2H, s), 3.79 (3H,

s), 5.02 (2H, br), 6.58 (1H, s), 6.78 (1H, ddd, J=7.9, 2.2, 1.0 Hz),

6.89–6.94 (2H, m), 6.78 (1H, s), 7.05 (1H, s), 7.16 ppm (1H, t, J=

7.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=12.7 (3ꢂCH), 18.0 (6ꢂCH₃),

28.2 (CH₂), 50.3 (CH₂), 55.7 (CH₂), 56.3 (CH₃), 62.5 (CH₂), 111.1 (CH),

118.8 (CH), 120.8 (CH), 121.9 (CH), 124.0 (CH), 127.7 (C_q), 129.3 (CH),

134.9 (C_q), 137.3 (C_q), 139.5 (C_q), 149.3 (C_q), 156.2 ppm (C_q); LC-MS

(ESꢀ): m/z 519.56 [MꢀH]^ꢀ; HRMS (ES+): m/z [M+H]⁺calcd for

C₂₆H₄₁N₂O₅SSi⁺: 521.2500, found: 521.2504. Prepared as described

for 14e using the sulfamate (85 mg, 0.16 mmol) and TBAF (1m in

THF, 0.18 mL, 0.18 mmol) in THF (10 mL) at 08C for 1 h. Flash

column chromatography (hexane/EtOAc 3:2!1:5 v/v) gave a solid

that was stirred in Et₂O/hexane (1:2), filtered and dried to afford

compound 20e as a yellow powder (38 mg, 66%): mp: 134–

7-Methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20c): Prepared as described for 20a using com-

pound 17c (105 mg, 0.35 mmol) and sulfamoyl chloride

(1.05 mmol) in DMA (1.0 mL) at RT for 18 h. Flash column chroma-

tography (hexane/EtOAc 1:1!1:3 v/v) gave an oil that was stirred

in Et₂O to afford compound 20c as a light yellow powder (105 mg,

79%): mp: 144–1458C; ¹H NMR (270 MHz, CDCl₃): d=2.66–2.77

(4H, m), 3.10 (2H, s, br), 3.51 (2H, s), 3.60 (2H, s), 3.74 (3H, s), 3.75

(3H, s), 6.55 (1H, s), 6.79 (1H, d, J=7.9 Hz), 6.82 (2H, s), 7.04 (1H,

s), 7.21 ppm (1H, t, J=7.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=27.8

(CH₂), 50.4 (CH₂), 55.3 (CH₃), 55.6 (CH₂), 56.2 (CH₃), 62.7 (CH₂), 110.9

(CH), 112.9 (CH), 114.8 (CH), 121.7 (CH), 123.8 (CH), 126.9 (C_q), 129.4

(CH), 133.9 (C_q), 137.7 (C_q), 138.9 (C_q), 149.6 (C_q), 159.7 ppm (C_q);

LC-MS (APCI+): m/z 379.34 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺

C₁₈H₂₃N₂O₅S⁺: 379.1322, found: 379.1320.

1

1358C; H NMR (270 MHz, [D₆]acetone): d=2.67–2.81 (4H, m), 3.51

(2H, s), 3.59 (2H, s), 3.78 (3H, s), 6.73 (1H, dd, J=7.9, 2.5 Hz), 6.77

(1H, s), 6.84 (1H, d, J=7.4 Hz), 6.88–6.93 (2H, m), 7.04 (1H, s),

7.14 ppm (1H, dd, J=7.9, 7.4 Hz); ¹³C NMR (67.5 MHz, [D₆]acetone):

d=28.4 (CH₂), 50.8 (CH₂), 55.4 (CH₃), 55.6 (CH₂), 62.4 (CH₂), 110.9

(CH), 114.0 (CH), 115.6 (CH), 119.9 (CH), 123.7 (CH), 126.5 (C_q), 129.3

(CH), 134.5 (C_q), 137.5 (C_q), 140.5 (C_q), 150.2 (C_q), 157.6 ppm (C_q);

LC-MS (ESꢀ): m/z 363.37 [MꢀH]^ꢀ.

7-Methoxy-6-sulfamoyloxy-2-(3-trifluoromethoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (20 f): Prepared as described for 20a using

compound 17 f (69 mg, 0.20 mmol) and sulfamoyl chloride

(0.60 mmol) in DMA (1.0 mL) at RT for 20 h. Flash column chroma-

tography (hexane/EtOAc gradient) afforded compound 20 f as

7-Methoxy-2-(4-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20d): Prepared as described for 20a using com-

pound 17d (90 mg, 0.30 mmol) and sulfamoyl chloride (0.90 mmol)

in DMA (1.0 mL) at RT for 18 h. Flash column chromatography

(hexane/EtOAc 1:1!1:3 v/v) gave an oil that was stirred in Et₂O to

afford compound 20d as a light yellow powder (95 mg, 84%): mp:

1

a yellow powder (60 mg, 69%): mp: 109–1108C; H NMR (270 MHz,

[D₆]DMSO): d=2.66–2.69 (2H, m), 2.74–2.76 (2H, m), 3.35 (2H, s),

3.53 (2H, s), 3.71 (3H, s), 6.82 (1H, s), 7.04 (1H, s), 7.26–7.28 (1H,

m), 7.34 (1H, s), 7.40 (1H, d, J=7.6 Hz), 7.49 (1H, t, J=8.0 Hz),

7.84 ppm (2H, s, br); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=27.8 (CH₂),

50.2 (CH₂), 55.0 (CH₂), 55.8 (CH₃), 60.8 (CH₂), 111.2 (CH), 119.6 (CH),

120.1 (q, J=254.6 Hz, CF₃), 120.7 (CH), 122.8 (CH), 125.8 (C_q), 127.7

(CH), 130.3 (CH), 133.5 (C_q), 137.1 (C_q), 141.6 (C_q), 148.6 (C_q),

149.7 ppm (C_q); LC-MS (APCIꢀ): m/z 431.02 [MꢀH]^ꢀ.

2-(3-Ethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20g): Prepared as described for 20a using com-

pound 17g (50 mg, 0.16 mmol) and sulfamoyl chloride (0.32 mmol)

in DMA (1.0 mL) at RT for 60 h. Flash column chromatography

(hexane/EtOAc 2:1!1:1 v/v) afforded compound 20g as a white

solid (45 mg, 71%): mp: 64–658C; ¹H NMR (270 MHz, CDCl₃): d=

1.39 (3H, t, J=6.9 Hz), 2.69–2.84 (4H, m), 3.56 (2H, s), 3.64 (2H, s),

3.80 (3H, s), 4.02 (2H, q, J=6.9 Hz), 5.00 (2H, s, br), 6.59 (1H, s),

6.80 (1H, dd, J=7.9, 2.0 Hz), 6.91–6.94 (2H, m), 7.06 (1H, s),

7.22 ppm (1H, t, J=7.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=15.0

1

104–1058C; H NMR (270 MHz, CDCl₃): d=2.69–2.82 (4H, m), 3.54

(2H, s), 3.61 (4H, s, br), 3.78 (3H, s), 3.79 (3H, s), 6.59 (1H, s), 6.88

(2H, d, J=8.6 Hz), 7.07 (1H, s), 7.26 ppm (2H, d, J=8.6 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=28.2 (CH₂), 50.4 (CH₂), 55.4 (CH₃),

55.6 (CH₂), 56.3 (CH₃), 62.1 (CH₂), 111.1 (CH), 113.7 (2ꢂCH), 124.2

(CH), 127.7 (C_q), 129.9 (C_q), 130.4 (2ꢂCH), 134.4 (C_q), 138.2 (C_q),

150.4 (C_q), 159.6 ppm (C_q); LC-MS (APCI+): m/z 379.34 [M+H]⁺;

HRMS (ES+): m/z [M+H]⁺calcd for C₁₈H₂₃N₂O₅S⁺: 379.1322,

found: 379.1322.

2-(3-Hydroxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20e): Prepared as described for 17a using the

benzyl-silyl-bisprotected phenol (see 14e: 425 mg, 0.8 mmol) and

Pd/C (10%, 40 mg) in THF (10 mL) and MeOH (30 mL) at RT for

0.5 h. Flash column chromatography (hexane/EtOAc 5:1!4:1 v/v)

afforded the silyl-protected phenol as a yellow oil (250 mg, 71%):

¹H NMR (270 MHz, CDCl₃): d=1.09 (18H, d, J=6.7 Hz), 1.16–1.31

(3H, m), 2.66–2.77 (4H, m), 3.52 (2H, s), 3.61 (2H, s), 3.79 (3H, s),

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(CH₃), 28.2 (CH₂), 50.5 (CH₂), 55.7 (CH₂), 56.4 (CH₃), 62.6 (CH₂), 63.5

(CH₂), 111.2 (CH), 113.4 (CH), 115.1 (CH), 121.4 (CH), 124.1 (CH),

127.7 (C_q), 129.4 (CH), 134.8 (C_q), 137.3 (C_q), 139.6 (C_q), 149.3 (C_q),

159.2 ppm (C_q); LC-MS (APCI+): m/z 393.43 [M+H]⁺.

(CH), 134.8 (C_q), 137.3 (C_q), 140.2 (C_q), 149.3 (C_q), 150.8 (C_q),

169.8 ppm (C_q); LC-MS (ESꢀ): m/z 405.17 [MꢀH]^ꢀ.

2-(3-Fluorobenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20l): Prepared as described for 20a using com-

pound 17l (94 mg, 0.33 mmol) and sulfamoyl chloride (0.98 mmol)

in DMA (1.0 mL) at RT for 24 h. Flash column chromatography

(hexane/EtOAc gradient) afforded compound 20l as a yellow

powder (103 mg, 78%): mp: 120–1248C; ¹H NMR (270 MHz,

[D₆]DMSO): d=2.69 (2H, d, J=5.0 Hz), 2.74 (2H, d, J=4.7 Hz), 3.50

(2H, s), 3.67 (2H, s), 3.71 (3H, s), 6.82 (1H, s), 7.04 (1H, s), 7.04–7.22

(3H, m), 7.35–7.43 (1H, m), 7.85 ppm (2H, s, br); ¹³C NMR

(67.5 MHz, [D₆]DMSO): d=27.8 (CH₂), 50.3 (CH₂), 55.0 (CH₂), 55.9

(CH₃), 61.0 (CH₂), 111.2 (CH), 114.0 (d, J=20.6 Hz, CH), 115.3 (d, J=

21.4 Hz, CH), 122.8 (CH), 124.8 (CH), 125.8 (C_q), 130.3 (d, J=8.4 Hz,

CH), 133.5 (C_q), 137.2 (C_q), 141.4 (d, J=6.9 Hz, C_q), 149.7 (C_q),

162.4 ppm (d, J=241.6 Hz, CF); LC-MS (APCI+): m/z 367.44 [M+

H]⁺.

2-(3-Isopropoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (20h): Prepared as described for 20a using

compound 17h (88 mg, 0.27 mmol) and sulfamoyl chloride

(0.8 mmol) in DMA (1.0 mL) at RT for 20 h. Flash column chroma-

tography (hexane!EtOAc gradient) afforded compound 20h as

a yellow solid (78 mg, 72%): mp: 808C (dec.); ¹H NMR (270 MHz,

[D₆]DMSO): d=1.25 (6H, d, J=5.9 Hz), 2.66 (2H, d, J=4.9 Hz), 2.73

(2H, d, J=4.9 Hz), 3.49 (2H, s), 3.60 (2H, s), 3.71 (3H, s), 4.58 (1H,

sept, J=5.9 Hz), 6.79–6.81 (2H, m), 6.88–6.89 (2H, m), 7.03 (1H, s),

7.22 (1H, t, J=8.0 Hz), 7.82 ppm (2H, s, br); ¹³C NMR (67.5 MHz,

[D₆]DMSO): d=22.4 (2ꢂCH₃), 28.5 (CH₂), 50.8 (CH₂), 55.7 (CH₂), 56.4

(CH₃), 62.3 (CH₂), 69.4 (CH), 111.6 (CH), 114.6 (CH), 116.2 (CH), 121.2

(CH), 123.3 (CH), 126.5 (C_q), 129.9 (CH), 134.3 (C_q), 137.6 (C_q), 140.6

(C_q), 150.2 (C_q), 158.0 ppm (C_q); LC-MS (APCIꢀ): m/z 405.07

[MꢀH]^ꢀ.

2-(3-Chlorobenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20m): Prepared as described for 20a using com-

pound 17m (153 mg, 0.5 mmol) and sulfamoyl chloride (2.0 mmol)

in DMA (1.0 mL) at RT for 24 h. Flash column chromatography

(hexane/EtOAc gradient) afforded compound 20m as a yellow

powder (95 mg, 45%): mp: 127–1298C; ¹H NMR (270 MHz,

[D₆]DMSO): d=2.69 (2H, d, J=4.6 Hz), 2.74 (2H, d, J=4.6 Hz), 3.49

(2H, s), 3.66 (2H, s), 3.71 (3H, s), 6.82 (1H, s), 7.04 (1H, s), 7.32–7.42

(4H, m), 7.84 ppm (2H, s, br); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=

28.4 (CH₂), 50.9 (CH₂), 55.5 (CH₂), 56.4 (CH₃), 61.5 (CH₂), 111.7 (CH),

123.3 (CH), 126.4 (C_q), 127.6 (CH), 127.9 (CH), 128.9 (CH), 130.8 (CH),

133.6 (C_q), 134.1 (C_q), 137.6 (C_q), 141.8 (C_q), 150.2 ppm (C_q); LC-MS

(APCI+): m/z 382.93 [M+H]⁺.

7-Methoxy-2-(3-phenoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20i): Prepared as described for 20a using com-

pound 17i (70 mg, 0.25 mmol) and sulfamoyl chloride (0.75 mmol)

in DMA (1.0 mL) at RT for 24 h. Flash column chromatography

(hexane/EtOAc 3:2!1:1 v/v) gave a solid that was stirred in Et₂O,

filtered and dried to afford compound 20i as a yellow powder

1

(105 mg, 82%): mp: 68–698C; H NMR (270 MHz, CDCl₃): d=2.68–

2.79 (4H, m), 3.56 (2H, s), 3.64 (2H, s), 3.80 (3H, s), 4.80 (2H, s, br),

6.59 (1H, s), 6.90 (1H, dd, J=7.9, 1.7 Hz), 7.00 (2H, dd, J=7.7,

1.0 Hz), 7.05–7.12 (4H, m), 7.25–7.35 ppm (3H, m); ¹³C NMR

(67.5 MHz, CDCl₃): d=28.2 (CH₂), 50.4 (CH₂), 55.7 (CH₂), 56.4 (CH₃),

62.3 (CH₂), 111.2 (CH), 117.7 (CH), 118.9 (2ꢂCH), 119.6 (CH), 123.3

(CH), 124.0 (CH), 124.1 (CH), 127.6 (C_q), 129.7 (CH), 129.9 (2ꢂCH),

134.7 (C_q), 137.3 (C_q), 140.2 (C_q), 149.3 (C_q), 157.3 (C_q), 157.4 ppm

(C_q); LC-MS (APCIꢀ): m/z 439.66 [MꢀH]^ꢀ.

7-Methoxy-6-sulfamoyloxy-2-(3-(sulfamoyloxy)benzyl)-1,2,3,4-

tetrahydroisoquinoline (20j): Prepared as described for 20a using

compound 17e (114 mg, 0.4 mmol) and sulfamoyl chloride

(1.6 mmol) in DMA (1.5 mL) at RT for 24 h. Flash column chroma-

tography (hexane/EtOAc 1:1!1:4 v/v) gave a pale yellow oil that

slowly crystallised upon addition of Et₂O and evaporation of the

solvent to afford compound 20j as a light yellow solid (135 mg,

76%): mp: 187–1888C; ¹H NMR (270 MHz, CDCl₃/[D₆]acetone 5:1):

d=2.44–2.55 (4H, m), 3.31 (2H, s), 3.43 (2H, s), 3.55 (3H, s), 6.05

(2H, s, br), 6.30 (2H, s, br), 6.36 (1H, s), 6.80 (1H, s), 6.96 (1H, dt,

J=7.7, 1.0 Hz), 7.03–7.11 ppm (3H, m); ¹³C NMR (67.5 MHz, CDCl₃/

[D₆]acetone 5:1): d=28.1 (CH₂), 50.4 (CH₂), 55.5 (CH₂), 55.8 (CH₃),

61.7 (CH₂), 110.7 (CH), 120.8 (CH), 122.4 (CH), 123.7 (CH), 126.6 (C_q),

127.0 (CH), 129.3 (CH), 134.0 (C_q), 137.3 (C_q), 140.5 (C_q), 149.7 (C_q),

150.4 ppm (C_q); LC-MS (APCI+): m/z 444.32 [M+H]⁺.

7-Methoxy-2-(3-methylbenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20n): Prepared as described for 20a using com-

pound 17n (70 mg, 0.25 mmol) and sulfamoyl chloride (0.75 mmol)

in DMA (1.0 mL) at RT for 24 h. Flash column chromatography

(hexane/EtOAc 3:2!1:1 v/v) gave a solid that was stirred in Et₂O,

filtered and dried to afford compound 20n as a yellow powder

1

(60 mg, 67%): mp: 142–1438C; H NMR (270 MHz, CDCl₃): d=2.34

(3H, s), 2.71–2.84 (4H, m), 3.56 (2H, s), 3.64 (2H, s), 3.80 (3H, s),

5.02 (2H, s, br), 6.60 (1H, s), 7.07 (1H, s), 7.10–7.22 ppm (4H, m);

¹³C NMR (67.5 MHz, CDCl₃): d=21.5 (CH₃), 28.2 (CH₂), 50.5 (CH₂),

55.7 (CH₂), 56.4 (CH₃), 62.7 (CH₂), 111.2 (CH), 124.2 (CH), 126.3 (CH),

127.6 (C_q), 128.1 (CH), 128.3 (CH), 130.0 (CH), 134.8 (C_q), 137.3 (C_q),

137.8 (C_q), 138.2 (C_q), 149.3 ppm (C_q); LC-MS (APCIꢀ): m/z 361.40

[MꢀH]^ꢀ.

2-(3-Ethylbenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydro-

isoquinoline (20o): Prepared as described for 20a using com-

pound 17o (149 mg, 0.5 mmol) and sulfamoyl chloride (1.5 mmol)

in DMA (3.6 mL) at RT for 4 h. Crystallisation from Et₂O/CH₂Cl₂

(~4:1) afforded compound 20o as a pale yellow solid (119 mg,

63%): ¹H NMR (270 MHz, CDCl₃): d=1.25 (3H, t, J=7.6 Hz), 2.67

(2H, q, J=7.6 Hz), 2.74 (2H, d, J=5.2 Hz), 2.78 (2H, d, J=5.2 Hz),

3.54 (2H, s), 3.64 (2H, s), 3.75 (3H, s), 6.19 (2H, s, br), 6.49 (1H, s),

7.01 (1H, s), 7.11 (1H, d, J=7.2 Hz), 7.15–7.29 (2H, m), 7.22 ppm

(1H, t, J=6.1 Hz); LC-MS (ES+): m/z 377.3 [M+H]⁺; HRMS (ES+):

m/z [M+H]⁺calcd for C₁₉H₂₅N₂O₄S⁺: 377.1530, found: 377.1532.

2-(3-Acetoxy)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroiso-

quinoline (20k): Prepared as described for 20a using compound

17k (100 mg, 0.30 mmol) and sulfamoyl chloride (0.6 mmol) in

DMA (1.0 mL) at RT for 4 h. Flash column chromatography

(hexane/EtOAc 2:1!2:3 v/v) afforded compound 20k as a yellow

powder (105 mg, 85%): mp: 64–658C; ¹H NMR (270 MHz, CDCl₃):

d=2.28 (3H, s), 2.70–2.86 (4H, m), 3.55 (2H, s), 3.67 (2H, s), 3.81

(3H, s), 4.98 (2H, s), 6.60 (1H, s), 6.99 (1H, ddd, J=7.9, 2.2, 1.2 Hz),

7.07 (1H, s), 7.12 (1H, dd, J=2.2, 1.2 Hz), 7.20–7.26 (1H, m),

7.34 ppm (1H, t, J=7.9 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=21.3

(CH₃), 28.3 (CH₂), 50.7 (CH₂), 55.7 (CH₂), 56.4 (CH₃), 62.2 (CH₂), 111.1

(CH), 120.5 (CH), 122.0 (CH), 124.2 (CH), 126.4 (CH), 127.7 (C_q), 129.4

2-(3-Cyanobenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20p): Prepared as described for 20a using com-

pound 17p (127 mg, 0.43 mmol) and sulfamoyl chloride (1.3 mmol)

in DMA (1.0 mL) at RT for 22 h. Flash column chromatography

(hexane/EtOAc gradient) gave an oil and crystallisation from

EtOAc/hexane afforded compound 20p as

a yellow powder

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1

(68 mg, 42%): mp: 140–1418C; H NMR (270 MHz, [D₆]DMSO): d=

(67.5 MHz, CDCl₃/[D₆]acetone 3:1): d=28.0 (CH₂), 38.5 (CH₃), 50.2

(CH₂), 55.4 (CH₂), 55.4 (CH₃), 61.9 (CH₂), 110.5 (CH), 118.8 (CH), 120.4

(CH), 123.5 (CH), 124.7 (CH), 126.3 (C_q), 129.0 (CH), 133.9 (C_q), 137.1

(C_q), 137.9 (C_q), 139.9 (C_q), 149.6 ppm (C_q); LC-MS (ESꢀ): m/z 440.43

[MꢀH]^ꢀ.

2.69–2.76 (4H, m), 3.50 (2H, s), 3.71 (5H, s), 6.82 (1H, s), 7.04 (1H,

s), 7.57 (1H, t, J=7.7 Hz), 7.71–7.84 ppm (5H, m); ¹³C NMR

(67.5 MHz, [D₆]DMSO): d=28.4 (CH₂), 50.8 (CH₂), 55.5 (CH₂), 56.3

(CH₃), 61.2 (CH₂), 111.7 (CH), 111.8 (C_q), 119.5 (C_q), 123.3 (CH), 126.3

(C_q), 130.2 (CH), 131.5 (CH), 132.6 (CH), 134.0 (C_q), 134.2 (CH), 137.6

(C_q), 140.9 (C_q), 150.2 ppm (C_q); LC-MS (APCIꢀ): m/z 372.54

[MꢀH]^ꢀ.

2-(3-Acetylbenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahy-

droisoquinoline (20q): Prepared as described for 20a using com-

pound 17q (80 mg, 0.26 mmol) and sulfamoyl chloride (0.52 mmol)

in DMA (1.0 mL) at RT for 18 h. Flash column chromatography

(hexane/EtOAc 2:1!1:3 v/v) gave a solid that was stirred in Et₂O,

filtered and dried to afford compound 20q as a yellow powder

(65 mg, 65%): mp: 144–1458C; ¹H NMR (270 MHz, CDCl₃/

[D₆]acetone 4:1): d=2.15 (s, 3H), 2.27–2.38 (4H, m), 3.12 (2H, s),

3.29 (2H, s), 3.33 (3H, s), 6.19 (3H, s, br), 6.60 (1H, s), 7.00 (1H, t,

J=7.7 Hz), 7.17 (1H, dt, J=7.7, 1.0 Hz), 7.44 (1H, dt, J=7.7, 1.2 Hz),

7.53 ppm (1H, m); ¹³C NMR (67.5 MHz, CDCl₃/[D₆]acetone 4:1): d=

26.1 (CH₃), 27.9 (CH₂), 50.3 (CH₂), 55.3 (CH₂), 55.3 (CH₃), 61.8 (CH₂),

110.4 (CH), 123.5 (CH), 126.1 (C_q), 126.9 (CH), 128.2 (CH), 128.3 (CH),

133.2 (CH), 133.7 (C_q), 136.9 (C_q), 137.1 (C_q), 138.9 (C_q), 149.6 (C_q),

197.3 ppm (C_q); LC-MS (ESꢀ): m/z 389.56 [MꢀH]^ꢀ.

2-(2,3-Dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-

rahydroisoquinoline (20u): Prepared as described for 20a using

compound 17u (80 mg, 0.24 mmol) and sulfamoyl chloride

(0.48 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 1:1!1:2 v/v) gave a solid that was stirred

in Et₂O, filtered and dried to afford compound 20u as a yellow

1

powder (65 mg, 66%): mp: 145–1468C; H NMR (270 MHz, CDCl₃):

d=2.79–2.85 (4H, m), 3.66 (2H, s), 3.79 (2H, s), 3.80 (3H, s), 3.83

(3H, s), 3.87 (3H, s), 4.95 (2H, s, br), 6.61 (1H, s), 6.85–6.89 (1H, m),

7.03–7.07 ppm (3H, m); ¹³C NMR (67.5 MHz, CDCl₃): d=28.1 (CH₂),

50.4 (CH₂), 55.2 (CH₂), 55.7 (CH₂), 55.8 (CH₃), 56.4 (CH₃), 61.1 (CH₃),

111.1 (CH), 111.6 (CH), 122.8 (CH), 124.1 (CH), 124.1 (CH), 127.4 (C_q),

132.8 (C_q), 137.4 (C_q), 141.3 (C_q), 147.9 (C_q), 149.3 (C_q), 152.8 ppm

(C_q); LC-MS (APCIꢀ): m/z 407.15 [MꢀH]^ꢀ.

2-(3,4-Dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-

rahydroisoquinoline (20v): Prepared as described for 20a using

compound 17v (70 mg, 0.21 mmol) and sulfamoyl chloride

(0.42 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 1:1!1:2 v/v) gave a solid that was stirred

in Et₂O, filtered and dried to afford compound 20v as a yellow

7-Methoxy-2-(3-nitrobenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydro-

isoquinoline (20r): Prepared as described for 20a using com-

pound 17r (131 mg, 0.42 mmol) and sulfamoyl chloride

(1.32 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (hexane/EtOAc gradient) afforded compound 20r as

1

powder (60 mg, 70%): mp: 155–1568C; H NMR (270 MHz, CDCl₃):

d=2.65–2.82 (4H, m), 3.52 (2H, s), 3.59 (2H, s), 3.77 (3H, s), 3.78

(3H, s), 3.79 (3H, s), 6.77 (1H, s), 6.89 (2H, s), 6.91–6.93 (2H, m),

7.00 (1H, s), 7.04 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=28.4

(CH₂), 50.6 (CH₂), 55.2 (CH₃), 55.3 (CH₃), 55.4 (CH₃), 55.6 (CH₂), 62.2

(CH₂), 111.0 (CH), 111.6 (CH), 112.5 (CH), 121.0 (CH), 123.7 (CH),

126.6 (C_q), 131.3 (C_q), 134.5 (C_q), 137.5 (C_q), 148.7 (C_q), 149.5 (C_q),

150.2 ppm (C_q); LC-MS (APCIꢀ): m/z 407.21 [MꢀH]^ꢀ.

a

yellow powder (112 mg, 85%): mp: 168–1708C; ¹H NMR

(270 MHz, [D₆]DMSO): d=2.72–2.77 (4H, m), 3.54 (2H, s), 3.71 (3H,

s), 3.84 (2H, s), 6.81 (1H, s), 7.05 (1H, s), 7.66 (1H, t, J=7.9 Hz),

7.82–7.85 (3H, m), 8.13–8.17 (1H, m), 8.22 ppm (1H, s, br); ¹³C NMR

(67.5 MHz, [D₆]DMSO): d=27.8 (CH₂), 50.3 (CH₂), 54.9 (CH₂), 55.8

(CH₃), 60.5 (CH₂), 111.2 (CH), 122.1 (CH), 122.8 (CH), 123.0 (CH),

125.8 (C_q), 129.9 (CH), 133.5 (C_q), 135.4 (CH), 137.1 (C_q), 141.1 (C_q),

147.9 (C_q), 149.7 ppm (C_q); LC-MS (APCI+): m/z 394.45 [M+H]⁺.

2-(3,5-Dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-

rahydroisoquinoline (20w): Prepared as described for 20a using

compound 17w (132 mg, 0.4 mmol) and sulfamoyl chloride

(1.2 mmol) in DMA (1.5 mL) at RT for 18 h. Flash column chroma-

tography (hexane/EtOAc 1:1!1:3 v/v) gave a yellow oil and crystal-

lisation from Et₂O afforded compound 20w as a light yellow

2-(3-Acetamidobenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (20s): Prepared as described for 20a using

compound 17s (48 mg, 0.15 mmol) and sulfamoyl chloride

(0.6 mmol) in DMA (1.0 mL) at RT for 18 h. The resulting solid was

stirred in Et₂O (5 mL), filtered and dried to afford compound 20s

as a light yellow powder (45 mg, 75%): mp: 124–1268C; ¹H NMR

(270 MHz, CDCl₃/[D₆]acetone 5:1): d=2.06 (3H, s), 2.66–2.77 (4H,

m), 3.52 (2H, s), 3.60 (2H, s), 3.73 (3H, s), 5.89 (2H, s, br), 6.53 (1H,

s), 6.97 (1H, d, J=7.7 Hz), 7.03 (1H, s), 7.21 (1H, dd, J=8.2, 7.7 Hz),

7.26–7.30 (1H, m), 7.61 ppm (1H, ddd, J=8.2, 2.0, 1.0 Hz); ¹³C NMR

(67.5 MHz, CDCl₃/[D₆]acetone 5:1): d=23.9 (CH₃), 27.3 (CH₂), 50.3

(CH₂), 55.4 (CH₂), 56.1 (CH₃), 62.3 (CH₂), 110.8 (CH), 119.5 (CH), 120.4

(CH), 123.8 (CH), 125.3 (CH), 126.2 (C_q), 129.0 (CH), 133.0 (C_q), 136.9

(C_q), 137.7 (C_q), 138.7 (C_q), 149.8 (C_q), 169.9 ppm (C_q); LC-MS (ES+):

m/z 406.43 [M+H]⁺.

1

powder (115 mg, 71%): mp: 147–1488C; H NMR (270 MHz, CDCl₃):

d=2.63–2.77 (4H, m), 3.48 (2H, s), 3.54 (2H, s), 3.61 (2H, s, br),

3.71 (6H, s), 3.72 (3H, s), 6.30 (1H, t, J=2.2 Hz), 6.46 (2H, d, J=

2.2 Hz), 6.53 (1H, s), 7.02 ppm (1H, s); ¹³C NMR (67.5 MHz, CDCl₃):

d=27.7 (CH₂), 50.4 (CH₂), 55.3 (CH₃), 55.6 (CH₂), 56.0 (CH₃), 62.7

(CH₂), 99.3 (CH), 106.1 (2ꢂCH), 110.8 (CH), 123.6 (CH), 126.6 (C_q),

133.8 (C_q), 137.4 (C_q), 139.6 (C_q), 149.6 (C_q), 160.7 ppm (2ꢂC_q); LC-

MS (APCI+): m/z 409.25 [M+H]⁺; HRMS (ES+): m/z [M+H]⁺calcd

for C₁₉H₂₅N₂O₆S⁺: 409.1428, found: 409.1428.

2-(2,5-Dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-

rahydroisoquinoline (20x): Prepared as described for 20a using

compound 17x (110 mg, 0.33 mmol) and sulfamoyl chloride

(0.66 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 1:1!2:3 v/v) gave a solid that was stirred

in Et₂O, filtered and dried to afford compound 20x as a yellow

7-Methoxy-2-(3-(methylsulfonamido)benzyl)-6-sulfamoyloxy-

1,2,3,4-tetrahydroisoquinoline (20t): Prepared as described for

20a using compound 17t (105 mg, 0.29 mmol) and sulfamoyl

chloride (0.6 mmol) in DMA (1.0 mL) at RT for 4 h. Flash column

chromatography (hexane/EtOAc 1:9 v/v) gave a solid that was

stirred in Et₂O, filtered and dried to afford compound 20t as

a light yellow powder (80 mg, 63%): mp: 151–1528C; ¹H NMR

(270 MHz, CDCl₃/[D₆]acetone 3:1): d=2.28–2.39 (4H, m), 2.56 (3H,

s), 3.15 (2H, s), 3.26 (2H, s), 3.38 (3H, s), 6.17 (2H, s, br), 6.23 (1H,

s), 6.64 (1H, s), 6.74–6.96 (4H, m), 8.00 ppm (1H, s, br); ¹³C NMR

1

powder (100 mg, 74%): mp: 138–1398C; H NMR (270 MHz, CDCl₃):

d=2.73–2.82 (4H, m), 3.63 (2H, s), 3.68 (2H, s), 3.76 (3H, s), 3.79

(3H, s), 3.81 (H, s), 4.90 (2H, s, br), 6.61 (1H, s), 6.76 (1H, dd, J=8.8,

2.9 Hz), 6.82 (1H, d, J=8.8 Hz), 7.02 (1H, d, J=2.9 Hz), 7.06 ppm

(1H, s); ¹³C NMR (67.5 MHz, CDCl₃): d=28.2 (CH₂), 50.5 (CH₂), 55.7

(CH₂), 55.8 (CH₂), 55.9 (CH₃), 56.3 (CH₃), 56.4 (CH₃), 111.2 (CH), 111.7

(CH), 112.6 (CH), 116.3 (CH), 124.1 (CH), 127.3 (C_q), 127.8 (C_q), 135.1

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(C_q), 137.2 (C_q), 149.2 (C_q), 152.1 (C_q), 153.6 ppm (C_q); LC-MS

7-Methoxy-2-(2-methoxybenzoyl)-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (21a): Prepared as described for 20a using

compound 18a (100 mg, 0.32 mmol) and sulfamoyl chloride

(0.64 mmol) in DMA (1.0 mL) at RT for 18 h. The resulting solid was

stirred in EtOAc/hexane (1:1 v/v, 8 mL), filtered and dried to afford

(APCIꢀ): m/z 407.02 [MꢀH]^ꢀ.

7-Methoxy-6-sulfamoyloxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (20y): Prepared as described for 20a

using compound 17y (115 mg, 0.32 mmol) and sulfamoyl chloride

(0.64 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 1:1!2:3 v/v) gave a solid that was stirred

in Et₂O, filtered and dried to afford compound 20y as a yellow

powder (110 mg, 79%): mp: 79–808C; ¹H NMR (270 MHz, CDCl₃):

d=2.71–2.82 (4H, m), 3.61 (2H, s), 3.65 (2H, s), 3.80 (3H, s), 3.85

(3H, s), 3.88 (6H, s), 6.61 (1H, s), 6.65 (1H, d, J=8.6 Hz), 7.05 (1H,

s), 7.06 ppm (1H, d, J=8.6 Hz); ¹³C NMR (67.5 MHz, CDCl₃): d=28.3

(CH₂), 50.3 (CH₂), 55.6 (CH₂), 56.0 (CH₃), 56.1 (CH₂), 56.4 (CH₃), 60.9

(CH₃), 61.4 (CH₃), 107.2 (CH), 111.2 (CH), 123.5 (C_q), 124.1 (CH), 125.2

(CH), 127.7 (C_q), 134.8 (C_q), 137.3 (C_q), 142.3 (C_q), 149.3 (C_q), 152.7

(C_q), 153.1 ppm (C_q); LC-MS (APCIꢀ): m/z 437.07 [MꢀH]^ꢀ.

1

compound 21a as a white solid (90 mg, 72%). H NMR (270 MHz,

CDCl₃/CD₃OD 5:1) d=2.61–2.73 and 2.80–2.87 (2H, 2 m), 3.36–3.45

and 3.99–4.09 (2H, 2 m), 3.68, 3.71, 3.76 and 3.82 (6H, 4 s), 4.27,

4.38, 4.77 and 4.83 (2H, 4d, J=16.1, 16.2, 16.1 and 16.1 Hz), 6.45

and 6.78 (1H, 2s), 6.87–7.00 (2H, m), 7.06 and 7.11 (1H, 2s), 7.18

(1H, dt, J=7.4, 1.5 Hz), 7.30–7.39 ppm (1H, m); LC-MS (APCIꢀ): m/z

391.49 [MꢀH]^ꢀ; Anal. calcd for C₁₈H₂₀N₂O₆S: C 55.09, H 5.14, N 7.14,

found: C 54.7, H 5.15, N 7.05.

7-Methoxy-2-(3-methoxybenzoyl)-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (21b): Prepared as described for 20a using

compound 18b (115 mg, 0.37 mmol) and sulfamoyl chloride

(0.74 mmol) in DMA (1.0 mL) at RT for 18 h. The resulting solid was

stirred in EtOAc, filtered and dried to afford compound 21b as

a white solid (95 mg, 66%): mp: 164–1668C; ¹H NMR (270 MHz,

CDCl₃/CD₃OD 5:1): d=2.77 and 2.87 (2H, 2s, br), 3.60 and 3.76

(2H, 2s, br), 3.80 and 3.86 (6H, 2s), 4.53 and 4.81 (2H, 2s, br), 6.52

and 6.80 (1H, 2s, br), 6.91–6.99 (3H, m), 7.12 (1H, s, br), 7.32 ppm

(1H, t, J=8.2 Hz); LC-MS (APCIꢀ): m/z 391.49 [MꢀH]^ꢀ; Anal. calcd

for C₁₈H₂₀N₂O₆S: C 55.09, H 5.14, N 7.14, found: C 55.0, H 5.22, N

7.03.

7-Methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (20z): Prepared as described for 20a

using compound 17z (95 mg, 0.26 mmol) and sulfamoyl chloride

(0.52 mmol) in DMA (1.0 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 4:1!1:2 v/v) gave a solid that was stirred

in Et₂O, filtered and dried to afford compound 20z as a yellow

1

powder (65 mg, 57%): mp: 143–1448C; H NMR (270 MHz, CDCl₃):

d=2.70–2.84 (4H, m), 3.58 (2H, s), 3.61 (2H, s), 3.81 (3H, s), 3.83

(3H, s), 3.84 (6H, s), 5.10 (2H, s, br), 6.61 (3H, s), 7.07 ppm (1H, s);

¹³C NMR (67.5 MHz, CDCl₃): d=28.1 (CH₂), 50.4 (CH₂), 55.7 (CH₂),

56.2 (2ꢂCH₃), 56.4 (CH₃), 61.0 (CH₃), 62.8 (CH₂), 105.7 (2ꢂCH), 111.2

(CH), 124.2 (CH), 127.6 (C_q), 133.7 (C_q), 134.6 (C_q), 137.0 (C_q), 137.4

(C_q), 149.4 (C_q), 153.3 ppm (2ꢂC_q); LC-MS (APCIꢀ): m/z 437.19

[MꢀH]^ꢀ.

7-Methoxy-2-(4-methoxybenzoyl)-6-sulfamoyloxy-1,2,3,4-tetra-

hydroisoquinoline (21c): Prepared as described for 20a using

compound 18c (75 mg, 0.24 mmol) and sulfamoyl chloride

(0.48 mmol) in DMA (1.0 mL) at RT for 24 h. The residue was stirred

in Et₂O, filtered and dried to afford compound 21c as a white

1

powder (80 mg, 85%): mp: 171–1728C; H NMR (270 MHz, CDCl₃/

7-Methoxy-6-sulfamoyloxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (20aa): Prepared as described for 20a

using compound 17aa (45 mg, 0.13 mmol) and sulfamoyl chloride

(0.3 mmol) in DMA (0.5 mL) at RT for 24 h. Flash column chroma-

tography (CH₂Cl₂/EtOAc 3:1 v/v!EtOAc) gave a solid that was

stirred in Et₂O, filtered and dried to afford compound 20aa as

CD₃OD 5:1): d=2.70 (2H, 2s, br), 3.54 and 3.70 (2H, 2s, br), 3.96

(6H, s), 4.50 and 4.64 (2H, 2s, br), 6.41 and 6.69 (1H, 2s, br), 6.81

(2H, dt, J=8.6, 2.3 Hz), 7.01 (1H, s), 7.27 ppm (2H, dt, J=8.6,

2.3 Hz); LC-MS (APCI+): m/z 393.38 [M+H]⁺; HRMS (ES+): m/z

[M+H]⁺calcd for C₁₈H₂₁N₂O₆S⁺: 393.1115, found: 393.1112; Anal.

calcd for C₁₈H₂₀N₂O₆S: C 55.09, H 5.14, N 7.14, found: C 54.9, H

5.15, N 6.94.

1

a yellow powder (35 mg, 64%): mp: 166–1678C; H NMR (270 MHz,

CDCl₃/[D₆]acetone 5:1): d=2.63–2.74 (4H, m), 3.54 (2H, s), 3.58

(2H, s), 3.74 (6H, s), 3.75 (3H, s), 3.82 (3H, s), 5.60 (2H, s, br), 6.47

(1H, s), 6.54 (1H, s), 6.91 (1H, s), 6.99 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃/[D₆]acetone 5:1): d=29.8 (CH₂), 49.7 (CH₂), 55.3

(CH₂), 55.8 (CH₂), 56.0 (CH₃), 56.1 (CH₃), 56.5 (CH₃), 56.6 (CH₃), 97.1

(CH), 110.0 (CH), 110.9 (CH), 114.2 (C_q), 123.8 (CH), 126.4 (C_q), 127.1

(C_q), 143.0 (C_q), 145.4 (C_q), 148.6 (C_q), 149.8 (C_q), 152.2 ppm (C_q); LC-

MS (APCIꢀ): m/z 437.20 [MꢀH]^ꢀ.

7-Methoxy-6-sulfamoyloxy-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-

tetrahydroisoquinoline (20ab): Prepared as described for 20a

using compound 17ab (120 mg, 0.33 mmol) and sulfamoyl chlo-

ride (1.7 mmol) in DMA (1.5 mL) at RT for 24 h. Flash column chro-

matography (hexane/EtOAc 10:1 v/v!EtOAc!EtOAc/MeOH 20:1

v/v) afforded compound 20ab as a yellow powder (110 mg, 76%):

mp: 151–1538C; ¹H NMR (270 MHz, CDCl₃/CD₃OD 10:1): d=2.72–

2.76 (4H, m), 3.24 (2H, s, br), 3.58 (2H, s, br), 3.72 (2H, s), 3.75 (9H,

s), 3.76 (3H, s), 6.09 (2H, s), 6.53 (1H, s), 7.00 ppm (1H, s); ¹³C NMR

(67.5 MHz, CDCl₃/CD₃OD 10:1): d=27.3 (CH₂), 48.4 (CH₂), 49.7 (CH₂),

54.6 (CH₂), 55.2 (CH₃), 55.5 (2ꢂCH₃), 56.0 (CH₃), 90.2 (2ꢂCH), 110.8

(CH), 123.4 (CH), 126.5 (C_q), 133.8 (C_q), 137.3 (C_q), 149.4 (C_q), 160.0

(2ꢂC_q), 160.9 ppm (C_q); LC-MS (ES+): m/z 439.3 [M+H]⁺; HRMS

(ES+): m/z [M+H]⁺calcd for C₂₀H₂₇N₂O₇S⁺: 439.1533, found:

439.1521; Anal. calcd for C₂₀H₂₆N₂O₇S: C 54.78, H 5.98, N 6.39,

found: C 54.6, H 6.11, N 6.08.

7-Methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-

tetrahydroisoquinoline (21d): Prepared as described for 20a

using compound 18d (100 mg, 0.27 mmol) and sulfamoyl chloride

(0.6 mmol) in DMA (1.0 mL) at RT for 24 h. The residue was stirred

in Et₂O, filtered and dried to afford compound 21d as a white

solid (90 mg, 74%): mp: 174–1758C; ¹H NMR (270 MHz, CDCl₃/

[D₆]acetone 1:1) d=2.55 (2H, s, br), 3.41 (2H, s, br), 3.54 (6H, s),

3.57 (6H, s), 4.50 (2H, s, br), 6.16 (2H, s, br), 6.40 (2H, s), 6.53 (1H,

s, br), 6.84 ppm (1H, s); LC-MS (ESꢀ): m/z 451.05 [MꢀH]^ꢀ; HRMS

(ES+): m/z [M+H]⁺calcd for C₂₀H₂₅N₂O₈S⁺: 453.1326, found:

453.1305; Anal. calcd for C₂₀H₂₄N₂O₈S: C 53.09, H 5.35, N 6.19,

found: C 53.0, H 5.39, N 6.03.

7-Methoxy-2-(2-methoxyphenylsulfonyl)-6-sulfamoyloxy-1,2,3,4-

tetrahydroisoquinoline (22a): Prepared as described for 20a

using compound 19a (87 mg, 0.25 mmol) and sulfamoyl chloride

(0.75 mmol) in DMA (1.0 mL) at RT for 18 h. Flash column chroma-

tography (hexane/EtOAc gradient) gave an oil and crystallisation

from Et₂O/hexane afforded compound 22a as a colourless powder

1

(74 mg, 69%): mp: 160–1638C; H NMR (270 MHz, [D₆]DMSO): d=

2.62 (2H, t, J=5.9 Hz), 3.47 (2H, t, J=5.9 Hz), 3.72 (3H, s), 3.74 (3H,

s), 4.37 (2H, s), 7.00 (1H, s), 7.04 (1H, s), 7.11 (1H, dt, J=7.7,

1.0 Hz), 7.18 (1H, d, J=7.9 Hz), 7.59–7.66 (1H, m), 7.82 (1H, dd, J=

7.9, 1.7 Hz), 7.85 ppm (2H, s, br); ¹³C NMR (67.5 MHz, [D₆]DMSO):

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d=27.2 (CH₂), 43.0 (CH₂), 46.6 (CH₂), 55.8 (CH₃), 55.9 (CH₃), 109.0

(CH), 112.9 (CH), 120.2 (CH), 123.0 (CH), 125.3 (C_q), 126.4 (C_q), 130.7

(CH), 131.5 (C_q), 135.0 (CH), 137.3 (C_q), 150.0 (C_q), 156.6 ppm (C_q);

LC-MS (ES+): m/z 451.38 [M+Na]⁺; Anal. calcd for C₁₇H₂₀N₂O₇S₂: C

47.65, H 4.70, N 6.54, found: C 47.7, H 4.73, N 6.54.

127.8 (CH), 129.3 (CH), 135.6 (C_q), 139.5 (C_q), 154.2 (C_q), 159.7 ppm

(C_q); LC-MS (APCI+): m/z 270.46 [M+H]⁺.

2-(3-Methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquino-

line (26): Prepared as described for 20a using compound 25

(90 mg, 0.33 mmol) and sulfamoyl chloride (0.67 mmol) in DMA

(1.0 mL) at RT for 18 h. Flash column chromatography (hexane/

EtOAc 2:1!1:1 v/v) afforded compound 26 as a white solid

7-Methoxy-2-(3-methoxyphenylsulfonyl)-6-sulfamoyloxy-1,2,3,4-

tetrahydroisoquinoline (22b): Prepared as described for 20a

using compound 19b (168 mg, 0.48 mmol) and sulfamoyl chloride

(0.96 mmol) in DMA (1.0 mL) at RT for 22 h. Flash column chroma-

tography (hexane/EtOAc gradient) afforded compound 22b as

1

(80 mg, 69%): mp: 139–1408C; H NMR (270 MHz, CDCl₃): d=2.72

(2H, t, J=5.4 Hz), 2.88 (2H, t, J=5.4 Hz), 3.59 (2H, s), 3.65 (2H, s),

3.79 (3H, s), 4.30 (2H, s, br), 6.82 (1H, ddd, J=8.2, 2.5, 1.0 Hz),

6.92–6.96 (2H, m), 6.99–7.03 (3H, m), 7.23 ppm (1H, t, J=8.2 Hz);

¹³C NMR (67.5 MHz, CDCl₃): d=29.1 (CH₂), 50.1 (CH₂), 55.3 (CH₃),

55.5 (CH₂), 62.6 (CH₂), 112.9 (CH), 114.7 (CH), 119.4 (CH), 121.6 (CH),

122.0 (CH), 128.1 (CH), 129.4 (CH), 134.1 (C_q), 136.5 (C_q), 139.5 (C_q),

148.3 (C_q), 159.8 ppm (C_q); LC-MS (APCI+): m/z 349.56 [M+H]⁺.

a

colourless solid (174 mg, 84%): mp: 153–1568C; ¹H NMR

(270 MHz, [D₆]DMSO): d=2.77 (2H, t, J=5.5 Hz), 3.29 (2H, t, J=

5.5 Hz), 3.74 (3H, s), 3.83 (3H, s), 4.19 (2H, s), 7.00 (1H, s), 7.05 (1H,

s), 7.26–7.30 (2H, m), 7.39 (1H, d, J=7.7 Hz), 7.57 (1H, t, J=7.7 Hz),

7.89 ppm (2H, s); ¹³C NMR (67.5 MHz, [D₆]DMSO): d=27.8 (CH₂),

44.1 (CH₂), 47.7 (CH₂), 56.2 (CH₃), 56.4 (CH₃), 111.7 (CH), 112.8 (CH),

119.7 (CH), 120.0 (CH), 123.4 (C_q), 123.4 (CH), 131.0 (C_q), 131.3 (CH),

137.6 (C_q), 138.0 (C_q), 150.5 (C_q), 160.1 ppm (C_q); LC-MS (APCI+):

m/z 429.52 [M+H]⁺; Anal. calcd for C₁₇H₂₀N₂O₇S₂: C 47.65, H 4.70,

N 6.54, found: C 47.0, H 4.65, N 6.48.

Acknowledgements

This work was supported by Sterix Ltd (Slough, UK), a member of

the IPSEN Group. We thank Alison Smith (University of Bath, UK)

for technical support. We thank Dr. G. R. Pettit (Arizona State Uni-

versity, USA) for providing CA-4.

7-Methoxy-2-(4-methoxyphenylsulfonyl)-6-sulfamoyloxy-1,2,3,4-

tetrahydroisoquinoline (22c): Prepared as described for 20a

using compound 19c (167 mg, 0.48 mmol) and sulfamoyl chloride

(0.96 mmol) in DMA (1.0 mL) at RT for 23 h. Flash column chroma-

tography (hexane/EtOAc gradient) afforded compound 22c as

Keywords: colchicine binding

· microtubule disruptors ·

1

a colourless solid (147 mg, 72%): mp: 83–868C; H NMR (270 MHz,

tetrahydroisoquinolines · tubulin assembly

[D₆]DMSO): d=2.78 (2H, t, J=5.8 Hz), 3.23 (2H, t, J=5.8 Hz), 3.74

(3H, s), 3.84 (3H, s), 4.12 (2H, s), 6.98 (1H, s), 7.05 (1H, s), 7.13–7.18

(2H, m), 7.72–7.77 (2H, m), 7.88 ppm (2H, s, br); ¹³C NMR

(67.5 MHz, [D₆]DMSO): d=28.9 (CH₂), 44.0 (CH₂), 47.7 (CH₂), 56.3

(CH₃), 56.4 (CH₃), 111.7 (CH), 115.2 (2ꢂCH), 123.4 (CH), 125.4 (C_q),

127.7 (C_q), 130.3 (2ꢂCH), 131.0 (C_q), 138.0 (C_q), 150.6 (C_q),

163.4 ppm (C_q); LC-MS (ES+): m/z 451.38 [M+Na]⁺; Anal. calcd for

C₁₇H₂₀N₂O₇S₂: C 47.65, H 4.70, N 6.54, found: C 47.7, H 4.78, N 6.31.

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6-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (24):

Compound 23^[21](15.97 g, 80.0 mmol) was treated with HBr (48%,

182 mL, 1.6 mol) at 1208C for 48 h. The mixture was cooled and

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t, J=6.3 Hz), 4.14 (2H, s), 6.60 (1H, d, J=2.5 Hz), 6.69 (1H, dd, J=

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(25): Compound 24^[22](345 mg, 1.5 mmol) was treated with 3-me-

thoxybenzyl bromide (332 mg, 1.65 mmol) and N,N-diisopropyle-

thylamine (DIPEA; 1.165 g, 9.0 mmol) in DMF (4.5 mL) at 808C for

18 h. After cooling to RT, the reaction mixture was concentrated in

vacuo, H₂O (100 mL) and NH₄Cl (saturated, 10 mL) were added and

extracted with EtOAc (2ꢂ100 mL). The combined organic phases

were dried (NaCl), filtered and concentrated in vacuo. Flash

column chromatography (hexane/EtOAc 3:2 v/v) afforded com-

pound 25 as a white powder (328 mg, 81%): mp: 223–2248C;

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Received: June 10, 2013

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Found in translation! Tetrahydroiso-

quinoline (THIQ)-based steroidomimetic

and chimeric microtubule disruptors

(e.g., 20c) have been identified. Control

experiments demonstrate the comple-

mentary SAR of this series and the

steroidal compounds that inspired its

design. A series of chimeric molecules

whose activity (GI₅₀=40 nm) surpasses

that of the parent steroid derivatives

and a compound that shows excellent

oral activity in an in vivo model of mul-

tiple myeloma were also identified.

M. P. Leese, F. L. Jourdan, M. R. Major,

W. Dohle, E. Hamel, E. Ferrandis, A. Fiore,

P. G. Kasprzyk, B. V. L. Potter*

&& – &&

Tetrahydroisoquinolinone-Based

Steroidomimetic and Chimeric

Microtubule Disruptors

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Article Doi

Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors

DOI: 10.1002/cmdc.201300261

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Authors:

Article abstract of DOI:10.1002/cmdc.201300261

Full text of DOI:10.1002/cmdc.201300261

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