Synthesis and SAR exploration of dinapsoline analogues

Bioorganic & Medicinal Chemistry 12 (2004) 715–734

Sing-Yuen Sit,^a,* Kai Xie,^aSwanee Jacutin-Porte,^aKenneth M. Boy,^aJames Seanz,^a

Matthew T. Taber,^bAmit G. Gulwadi,^bCarolyn D. Korpinen,^bKevin D. Burris,^b

Thaddeus F. Molski,^bElaine Ryan,^bCen Xu,^bTodd Verdoorn,^bGraham Johnson,^a

David E. Nichols^cand Richard B. Mailman^d

^aDepartment of Neuroscience Drug Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5Research Parkway,

Wallingford, CT 06492-7660, USA

^bNeuroscience Drug Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, 5Research Parkway,

Wallingford, CT 06492-7660, USA

^cDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-2091, USA

^dDepartments of Psychiatry, Pharmacology, and Medicinal Chemistry, University of North Carolina School of Medicine,

Chapel Hill, NC 2759-7160, USA

Received 24 September 2003; accepted 16 November 2003

Abstract—Dinapsoline is a full D₁dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat

model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was

determined to have the S-(+) conﬁguration, and the opposite enantiomer is essentially devoid of biological activity. Taken toge-

ther, dinapsoline has signiﬁcant metabolic and pharmacological advantages over previous D₁agonists. In an attempt to deﬁne the

structure–activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core

analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed

synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B⁰, C and D ring) of dinap-

soline were synthesized. It was found that aﬃnity for both D₁and D₂receptors was decreased by most substituents on the A, B⁰, and

C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.

1. Introduction^y

dopa or benserazide) remains unsurpassed in clinical

eﬃcacy, and is eventually used by almost all Parkinson’s

patients.⁴It is generally accepted that the therapeutic

beneﬁts of levodopa result from its conversion to dopa-

mine in striatal terminals of residual dopaminergic neu-

rons. Because the disease is progressive, however, and

dopamine-producing cells continue to die, the eﬀective-

ness of such dopamine replacement therapy with levo-

dopa decreases with time. For most patients, dose

escalation, decreased eﬃcacy, and the emergence of

intolerable side eﬀects such as nausea and dyskinesias

are inevitable results. Thus, drugs that directly activate

one or more dopamine receptors have been the target

for rational PD drug design for three decades.

Parkinson’s disease (PD) is a slowly progressive dis-

order of the central nervous system. The disease aﬀects

several million people worldwide, and its prevalence

rises sharply with age, and as many as 15% of PD

patients are 50 years old or younger. Although current

practice is to start most newly diagnosed PD patients on

one of the available D₂dopamine agonists (i.e., ropi-

nirole or pramipexole), the combination of levodopa

and a peripheral decarboxylase inhibitor (e.g., carbi-

Keywords: Dinapsoline; Dopamine agonist; Dopamine D₁receptor;

Parkinson’s disease; SAR; Dihydrexidine.

Due to an oversight, the biologically active enantiomer of dinapso-

line formerly had been labeled as (R)-(+)-dinapsoline. The correct

nomenclature should have been (S)-(+)-dinapsoline.¹This change

does not aﬀect the results of the present work, nor the conclusions in

y

Dopamine receptors are known to fall into two phar-

macological families (D₁and D₂-like) that are coded by

ﬁve genes.⁵It has been a subject of controversy about

which receptor(s) needs to be activated to obtain ther-

apeutic eﬀects in PD that would equal levodopa. All of

the dopamine agonists current available as anti-

prior publications.^2,3

*

Corresponding author. Tel.: +1-203-677-6678; fax: +1-203-677-5775/

7702; e-mail: sits@bms.com

doi:10.1016/j.bmc.2003.11.015

716

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

parkinson drugs have, in fact, targeted one or more

receptors of the D₂-like family. These D₂agonists,

despite having a place in the treatment of PD,⁴have far

lower eﬃcacy than levodopa, and may also produce side

eﬀects such as nausea and psychotic symptoms that are

associated with D₂receptor activation. D₁agonists

received little attention for many years largely because

early selective D₁agonists had no antiparkinson eﬃ-

cacy, something that is now known to be due to the low

intrinsic activity of compounds like SKF38393.^6ꢀ9On

the other hand, when the ﬁrst full D₁agonist was dis-

covered, it was used to demonstrate that it was D₁, not

D₂, agonism that was responsible for dramatic anti-

parkinson eﬀects.¹⁰Since then, the unmatched anti-

parkinson eﬃcacy of full D₁agonists from diﬀerent

chemical families has not only been shown in non-

human primates treated with MPTP,^11,12but also in

humans with PD.¹³Despite the promise of full D₁ago-

nists, a variety of issues has stymied the development of

earlier compounds.¹⁴

2. Results

We previously reported a highly convergent synthesis of

dinapsoline, along with its resolution into a pair of

enantiomers, and the pharmacological proﬁle of S-(+)-

dinapsoline.²The parent compound, dinapsoline, was

synthesized by a newly developed seven-step procedure

(Schemes 1 and 2). The improved synthesis oﬀers better

synthetic convergence and minimizes the use of protect-

ing groups. More importantly, this new method does

not rely on the late-stage, yield-limiting acid catalyzed

ring closure step described in the original 14-step

synthesis.³

Recently, dinapsoline (8,9-dihydroxy-2,3,7,11b-tetra-

hydro-1H-dibenz[de,h]isoquinoline) was discovered as

the ﬁrst member of a new class of full D₁agonists, albeit

one that was shown to also have signiﬁcant D₂aﬃnity.

In addition, dinapsoline was shown to desensitize D₁

receptors less than either dopamine¹⁵or A77636, a pro-

mising antiparkinson drug¹¹that failed clinically

because it produced rapid tolerance.¹⁶The promise of

dinapsoline was further shown in studies where it had

signiﬁcant eﬃcacy in a rat denervation model and

unlike A77636, did not cause tolerance.¹⁷Dinapsoline,³

like dihydrexidine,¹⁸has signiﬁcant aﬃnity for both D₁

and D₂receptors, although the D₂properties are not

those of a typical agonist.^19,20Of direct relevance to this

work are ﬁndings that relatively subtle additions to dihy-

drexidine²¹or dinapsoline¹can markedly alter both D₁

and D₂aﬃnity and functional characteristics in unex-

pected ways. These data suggest that compounds derived

from these parent structures might have extremely inter-

esting pharmacological properties. Thus, the present

study provides new and detailed data on structure–activ-

ity relationships (SARs) of the dinapsoline backbone.

Figure 1.

Using diﬀerent substituted isoquinolines 4, the improved

synthesis served as the starting point for a number of

dinapsoline analogues. Both dinapsoline core analogues

and substitution analogues were prepared either

through the improved synthesis or with appropriate

modiﬁcations along the seven-step sequence (Fig. 1).

2.1. Core analogues of dinapsoline-7-thia analogue

One of the main objectives of this project was to explore

the SAR within the three-dimensional framework as

provided for by the novel molecular structure of dinap-

soline. The improved synthesis of dinapsoline described

previously was designed with ﬂexibility for modifying

the 7-position in mind. The synthesis was readily adap-

ted to the preparation of the 7-thia and the 7-aza ana-

logues of dinapsoline (Schemes 3 and 4).

Scheme 1. Improved synthesis of the dinapsoline parent molecule. Reagents and reaction conditions: (a) LDA, THF at ꢀ78 ^ꢁC; (b) DMF at ꢀ78 ^ꢁC;

(c) bromine, AlCl₃; (d) n-BuLi, THF at ꢀ78 ^ꢁC; (e) the lithiated species 2, THF at ꢀ78 ^ꢁC.

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

717

Scheme 2. Improved synthesis of the dinapsoline parent molecule. Reagents and reaction conditions: (a) Et₃SiH, TFA at reﬂux; (b) Bu₃SnH, AIBN

in degassed benzene at reﬂux; (c) NaCNBH₃, THF, HCl or PtO₂/H₂in acetic acid at 110–120 psi (pound/in²); (d) resolution by (+)-dibenzoyl-d-

tartaric acid; (e) BBr₃in methylene chloride at ꢀ78 ^ꢁC.

Scheme 3. Synthesis of 7-thia core analogue of dinapsoline. Reagents and reaction conditions: (a) tert-BuLi/THF at ꢀ78 ^ꢁC, tetra-

isopropylthiuram disulﬁde; (b) NaOH, EtOH reﬂux, then HCl neutralization and iodine oxidation; (c) 3-lithio-4-bromo-1,2-(methylenedioxy)-

benzene 2 at ꢀ78 ^ꢁC; (d) Bu₃SnH, AIBN, benzene at 80 ^ꢁC; (e) NaBH₃CN, THF, HCl; (f) BBr₃, CH₂Cl₂at ꢀ78 ^ꢁC.

5-Bromoisoquinoline 5 was converted (Scheme 3) into

the disulﬁde of isoquinoline-5-thiol 14 by a three-step

procedure from 13.²²The subsequent alkaline hydro-

lysis and iodine oxidation were carried out in one pot to

give 14. The ortho lithiated 4-bromo-1,2-(methylene-

dioxy)benzene 2 was thioalkylated with the disulﬁde 14

to furnish 15 in 62% yield. Compound 15 was reduc-

tively cyclized (AIBN, n-Bu₃SnH) in degassed benzene

to give 16 as the major product (71%, mp 223–225 ^ꢁC).

A small amount of the uncyclized des-bromo-15 was

also formed, which was easily removed by trituration

with a mixture of ethyl acetate and hexanes. Selective

ring reduction of 16 using sodium cyanoborohydride in

acidic medium gave 17 in 50% yield. The ﬁnal depro-

tection was performed as before with boron tri-

bromide.²The desired product 18 was isolated as its

HBr salt.

DMF to give the ipso product 22 in greater than 60%

yield. In contrast to all of the other dinapsoline analo-

gues, this adduct with a nitro group attached to the 8-

position of the isoquinoline moiety deﬁed all cyclization

attempts using tin hydride/AIBN. Under forcing condi-

tions, the nitro was reduced to the amino group, which

was isolated in moderate yield. All further attempts to

cyclize the 8-amino compound or the corresponding

acetamide were unsuccessful. In view of this failure, an

alternative approach was envisioned that allowed for

the introduction of a ﬂuorine atom into the molecule

prior to the free-radical cyclization, which might alter

the course of reaction. Indeed, a denitroﬂuorination in

DMF using tetramethylammonium ﬂuoride as the ﬂuo-

ride source gave good yields of the desired 8-ﬂuoro

product 23.²⁴The AIBN/tin-hydride free radical cycli-

zation of the ﬂuoro derivative 23 proceeded smoothly to

aﬀord the cyclized compound 24 in good yield. The

usual reduction and deprotection sequence did not,

however, work well with the 7-aza analogue. Instead of

performing the deprotection step at the end, we found

that it was more expedient to deprotect the methylene-

dioxy moiety and the tert-butyl carbamate of 24 all in

one pot with boron tribromide. The ﬁnal ring reduction

to 25 was done without further puriﬁcation other than

the removal of solvents. The combined yield of the last

two steps (deprotection and sodium cyanoborohydride

reduction) was in excess of 58% (Scheme 4).

2.2. Core analogues of dinapsoline-7-aza analogue

The carbanion 2 (Scheme 4) was quenched with carbon

dioxide to give 81% of the expected carboxylic acid 19.

A Curtius rearrangement using diphenylphosphoryl

azide (DPPA) in tert-butanol and triethylamine pro-

vided a 65% yield of the tert-butylcarbamate 20. 5-

Bromo-8-nitroisoquinoline 21, prepared by nitration of

5-bromoisoquinoline,²³was allowed to react with the

carbamate in the presence of potassium carbonate in

718

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

Scheme 4. Synthesis of the 7-aza core analogue of dinapsoline. Reagents and reaction conditions: (a) CO₂, THF; (b) DPPA, Et₃N, tert-BuOH at

reﬂux; (c) K₂CO₃, DMF at 85 ^ꢁC; (d) Me₄NF, DMF at 65 ^ꢁC; (e) Bu₃SnH/AIBN, benzene at 80 ^ꢁC; (f) BBr₃, CH₂Cl₂at ꢀ78 ^ꢁC; (g) NaBH₃CN,

THF/HCl.

2.3. B⁰-Ring substitution analogues of dinapsoline

and 11-chloro derivatives 29 were carried to the end to

aﬀord 11-nitro and 11-chloro dinapsoline 31b and 31a.

The 7-thia and 7-aza analogues of dinapsoline could

aﬀect catechol recognition by altering the overall elec-

tron density of the catechol ring. With regard to steric

eﬀects, substitution analogues at the 7-position on

dinapsoline were prepared to study the steric inﬂuence

at this position. The hydrogens attached to the 7-meth-

ylene, ﬂanked by two adjacent phenyl rings, are suﬃ-

ciently acidic to be deprotonated using strong base.

Indeed, the carbanion of compound 10 was generated

easily using sodium hydride in DMF. Alkylation of the

resulting anion was carried out as usual to aﬀord a wide

range of 7-alkyl substituted derivatives as mixtures of

diastereomers (Scheme 5).

The nitro group in compound 29b was also converted

into the amino derivative 29c. Unfortunately, this com-

pound was not stable enough to be carried through to

the end. The 11-ﬂuoro was analogously prepared by an

electrophilic aromatic substitution with the commercial

ﬂuorinating agent SelectFluoro^TM; however, the synth-

esis of this analogue was abandoned after 11-chlor-

odinapsoline was found to be inactive.

Scheme 5. B⁰ring modiﬁcation. Reagents and reaction conditions:

(a) NaH in DMF at 0 ^ꢁC followed by the addition of alkyl bromide or

iodide.

Scheme 6. A-ring modiﬁcation. Reagents and reaction conditions:

(a) nitration with HNO₃, HOAc; chlorination with SO₂Cl₂, methylene

chloride; (b) SnCl₂, methanol at reﬂux temperature; (c) ﬂuorination with

SelectFluoro^TMin MeCN and HOAc; (d) NaCNBH₃, THF, HCl at rt.

2.4. A-Ring substitution analogues of dinapsoline

Compound 10 is also a good starting point for a num-

ber of A-ring substituted dinapsoline analogues. The

robust methylenedioxy moiety in compound 10 can

withstand a variety of electrophilic aromatic substitu-

tion conditions. Nitration, ﬂuorination, and chlorina-

tion of 10 all proceeded smoothly to give essentially a

single product substituted at the 11-position (Scheme 6).

The regiochemical assignment was performed by NMR

spectroscopy, with results as expected.^25ꢀ27The 11-nitro

2.5. C-Ring substitution analogues of dinapsoline

Because the isoquinoline system allows for speciﬁc

reactions on the nitrogen-bearing side of the hetero-

cycle, access to C-ring derivatives was achieved in a

straightforward manner. First, the C-ring nitrogen was

quaternized using electrophiles such as methyl or ethyl

iodide; the resulting isoquinolinium salt 32 (Scheme 7)

was easily reduced with a hydride nucleophile to give

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

719

the 1,2,3,4-tetrahydroisoquinoline product 34. Nucleo-

philes other than hydride added to the quaternary salt

and led to 33. Subsequent reduction gave substituted

derivatives 34.²⁸The boron tribromide deprotection of

34 uneventfully furnished the ﬁnal targets.

respectively. These D-ring derivatives were therefore

prepared through the appropriate isoquinoline deriva-

tives substituted at the 6-, 7-, and 8-positions while the 5-

position was kept as the connecting handle to form the

bridging B-ring. With this synthetic strategy in mind,

several important dinapsoline analogues were prepared.

In order to carry out the reaction sequence depicted in

Scheme 2, a suitably substituted isoquinoline with a

nucleophilic handle at the 5-position (isoquinoline

numbering) was required. Therefore, bromine was

introduced (Scheme 2) at the 5-position of the iso-

quinoline congeners. Subsequent transmetalation furn-

ished the 5-lithiated intermediate suitable for coupling

with the aldehyde functionality on the catechol ring.

This approach was used to prepare 4-hydroxydinapso-

line 55, 4-ﬂuorodinapsoline 57, and 6-ethyldinapsoline

56. The starting substituted isoquinolines were prepared

in accordance with known procedures (Pomeranz-Fritsch

Synthesis, Scheme 8, and subsequently Scheme 10)^29ꢀ32

with minor modiﬁcations (see Experimental).

Scheme 7. C-Ring modiﬁcation. Reagents and reaction conditions:

(a) alkyl iodide, dichloroethane at room temperature; (b) alkyl lithium

[R⁰Li] or alkyl Grignard reagent [R⁰MgBr]; (c) sodium triacetoxy-

borohydride, THF at ꢀ78 ^ꢁC to rt; (d) BBr₃, methylene chloride at

ꢀ78 ^ꢁC.

The 6-ﬂuorodinapsoline 39 was a special case. The 6-

ﬂuoroisoquinoline was suﬃciently reactive to be depro-

tonated directly at the 5-position (ﬂuorine-directed

deprotonation) without the need for a bromine handle

(Scheme 9).³³This ﬂuorine atom-mediated regioselec-

tive deprotonation appeared to be speciﬁc to the iso-

quinoline system because evidence of benzyne

generation through elimination of HF was never

observed. The ﬁnal target compound (ꢂ)-39 was pre-

pared in much the same way as dinapsoline (Schemes 1

and 2). The regiochemical outcome of this ﬂuorine-

directed metalation was later conﬁrmed by comparing

the end product with other dinapsoline derivatives

(Scheme 9). Racemic 39 was further separated into a

pair of enantiomers on a preparative HPLC equipped

with a Chiralcel OD column using conditions as descri-

bed previously (see Experimental).²

2.6. D-Ring substitution analogues of dinapsoline

As we have shown, intermediate 10 is a versatile starting

point for dinapsoline derivatives. This utility is attrib-

uted partly to the robust methylenedioxy catechol pro-

tecting group, and more importantly to the secondary

amine moiety disguised as part of an isoquinoline sys-

tem. Chemical modiﬁcations on the A-, B⁰-, and C-rings

are made possible through these unique qualities. D-

ring analogues of dinapsoline are not readily derived

from compound 10, however, and these compounds

must be prepared by the seven-step procedure developed

for the dinapsoline parent compound. Substituted iso-

quinoline 4, a nucleophilic 6 could be generated

according to Scheme 1 to provide compounds that are

otherwise unavailable by way of compound 10. It is well

known that substituted isoquinolines are diﬃcult to

obtain starting materials but synthetic approaches do

exist to gain access to 6-, 7-, and 8-substituted iso-

quinolines. The 6-, 7-, and 8-positions of isoquinoline

correspond to the 6-, 5-, and 4-positions of dinapsoline,

Once the suitable isoquinoline precursors, and the coupled

products were prepared (Schemes 8, 9 and 10), the sub-

sequent free-radical initiated ring closure, the reduction,

and the BBr₃deprotection were carried out in accordance

with the general procedure described in Scheme 2.

Scheme 8. Synthesis of substituted isoquinolines for D-ring modiﬁcations. Reagents and reaction conditions: (a) reﬂux in benzene, azeotropic

removal of water; (b) ﬁrst step: ethyl chloroformate, trimethyl phosphite in THF, second step: titanium tetrachloride in chloroform; (c) concd H₂SO₄

and solid KNO₃; (d) Fe powder, NH₄Cl in H₂O; (e) NaNO₂, HBF₄and water.

720

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

These changes result in a novel dopamine D₁receptor

agonist that oﬀers fresh opportunities for drug devel-

opment. The introduction of the B⁰-ring and therefore

the C-7 bridging methylene unit (absent in the dihy-

drexidine chemotype), served as a handle for designing

both ‘core’ modiﬁcations and substitution analogues

within the molecular framework of dinapsoline. Closer

examination reveals that the rigidity imposed on the

dinapsoline core structure by the 7-methylene unit also

renders the molecule somewhat more planar relative to

dihydrexidine.

There have been no full D₁agonists synthesized that

have not contained the catechol moiety,³⁷and it was

therefore of interest to explore the regions ﬂanking the

catechol moiety. To achieve this goal, core analogues

were prepared where the C-7 atom in dinapsoline was

modiﬁed by heteroatom replacement.

Scheme 9. Synthesis of 6-ﬂuoro dinapsoline. Reagents and reaction

conditions: (a) LDA in THF at ꢀ78 ^ꢁC; (b) DMF at ꢀ78 ^ꢁC; (c) LDA

at ꢀ78 ^ꢁC; (d) THF at ꢀ78 ^ꢁC.

Changing the 7-carbon to a sulfur appeared to be detri-

mental (Table 1) to D₁receptor aﬃnity. This 7-thia

analogue of dinapsoline (18) was about an order of

magnitude less active at the D₁site, whereas aﬃnity at

the D₂receptor remained roughly the same. The sulfur

replacement had an even greater impact on the intrinisic

activity as determined by cAMP production. Replacing

the 7-carbon with a larger sulfur atom transformed the

7-thia analogue into a partial agonist (70% of dopa-

mine, Table 2). The diminished activity of the sulfur

compound could partly be explained by the larger size

of the sulfur atom, providing steric bulk adjacent to the

catechol moiety that may hinder receptor interaction

with the hydroxy groups. Furthermore, the introduction

of a larger atom such as sulfur may push the accessory

phenyl ring (D-ring) into a region less able to accom-

modate hydrophobic elements. On the other hand, the

eﬀect of substituting a sulfur atom adjacent to the cate-

chol function in the prototypical dopamine D₁agonist

7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza-

zepine (SKF-38393) is more subtle, where a shift from

activity at peripheral receptors to central activity was

reported.³⁸It could be argued, however, that increased

lipophilicity of the sulfur might account for that

diﬀerence.

Scheme 10. Preparation of D-ring analogues.

3. Discussion

Earlier work had demonstrated that despite minor dif-

ferences in structure, dinapsoline retained many of the

pharmacological characteristics of dihydrexidine.^3,18

Structural comparison of dihydrexidine and dinapsoline

reveals (Fig. 2) the molecular features shared by both

chemotypes. Both molecules can be considered as a

‘rigidiﬁed’ form of 4-(3,4-dihydroxyphenyl)-tetrahydro-

isoquinoline³⁴in which conformational constraint is

introduced using either an ethyl tether to create an

additional ‘B-ring’ as in the case of dihydrexidine, or a

methylene tether to create the ‘B⁰-ring’ of dinapsoline.

In the case of the 7-aza analogue (26), D₁receptor aﬃ-

nity was lost, whereas D₂aﬃnity was decreased 3-fold.

For the 7-aza analogue, the possibility of hydrogen

bonding and lone pair delocalization may fundamen-

tally change the nature of the molecule. The existence of

a weakly basic NH may also allow for competition with

respect to the catechol recognition site.³⁹It is doubtful

that steric factors alone could be the cause of the loss of

Such modiﬁcations largely preserve all of the critical

structural elements of a D₁receptor agonist,³⁶including

the relative position and orientation of the basic nitro-

gen, catechol hydroxyls, and the accessory phenyl ring.

Figure 2. Dinapsoline created by Nichol’s rigid b-phenyl dopamine model.^34,35

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

721

Table 1. Results of D₁/D₂binding assays^a

Compd

Dinapsoline ring substitution

D₁Aﬃnity

(rat striatum)

(K_0.5, nM)

D₂Aﬃnity

(rat striatum)

(K_0.5, nM)

D₂Aﬃnity

(hD_2L-HEK)

(K_0.5, nM)

R₂

R₃

R₄

R₆

R_7a,_7b

R₁₁

(ꢂ)-12

S-(ꢀ)-12

R-(+)-12

18

26

28a

28b

28c

28e

31a

31b

35a

35b

35c

35d

35e

35f

35g

H

Me

n-Pr

H

Me

n-Bu

Me

Et

C₄F₉

n-Bu

H

F

H

F

H,H

7-S

7-NH

H,Me^c

Me,Me

H,Et

H

Cl

NO₂

H

67ꢂ9 (35)

5300ꢂ1000 (4)

33ꢂ8 (11)

536ꢂ129 (2)

>10000

139ꢂ31 (3)

870ꢂ120 (3)

430ꢂ64 (3)

2400ꢂ1000 (2)

1500 (1)

56ꢂ10 (17)

1500ꢂ500 (2)

38ꢂ6 (7)

34.5ꢂ1.5 (2)

160 (1)

160ꢂ27 (2)

390ꢂ8 (2)

440ꢂ30 (2)

990 (1)

10.7ꢂ2.7 (3)

N/A^b

11.1ꢂ3.0 (9)

N/A

15 (1)

190 (1)

40 (1)

N/A

H

OH

H

F

H,CH₂COOMe

H,H

16 (1)

>10000 (2)

382ꢂ79 (2)

>2000 (1)

>3000 (1)

>2000 (1)

299ꢂ35 (2)

410ꢂ90 (2)

9500ꢂ500 (2)

340ꢂ70 (2)

>3000 (2)

71ꢂ13 (2)

72ꢂ7 (2)

1100 (1)

70ꢂ5 (2)

N/A

93ꢂ6 (2)

220ꢂ8 (2)

N/A

H,H

H

Me

H

Me

H

N/A

>10000 (1)

N/A

27 (1)

N/A

35h

78ꢂ1 (2)

(ꢀ)-39

(+)-39

55

56

57

170 (1)

7 (1)

H

F

H

Et

H

15 (1)

N/A

28 (1)

14ꢂ4 (2)

H,H

69 (1)

^aSee experimental for details.

^bN/A stands for data not available

^cMixture of diastereomers.

that the ligand binding site of the D₂receptor has less

stringent requirements than does the D₁.

Table 2. Adenylate cyclase (AC) response (in vitro functionality)

Compd

D₁(SK-N-MC)^a

Introduction of substitutions on the 7-carbon also

diminished D₁receptor aﬃnity with the magnitude of

the eﬀect being related to the size of the substituent.

Compound 28a (mixture of two diastereomers) had

about one-half the D₁, and one-third the D₂, receptor

aﬃnity of the unsubstituted parent dinapsoline, yet at

the maximal dose 28a showed full intrinsic activity in

activating adenylate cyclase (AC) (Table 2) and robust

rotational activity (Table 3) comparable to that of

dinapsoline. The halved D₁receptor aﬃnity of 28a

might further suggest that only one of the two diaster-

eomers is active. Conceivably the active isomer has the

7-methyl positioned so that it does not interfere with

catechol recognition. Taken together, these results

demonstrate that the region surrounding the 7-atom is

sensitive to substitution, and has low tolerance for

bulky substituents. Smaller alkyl groups such as methyl

may be tolerated, however, if they do not interfere with

catechol recognition. This result strongly suggests that

molecular recognition of the catechol moiety may

require an open access space that cannot be occluded by

substituents at the 7-position. One of the initial objectives

I.A.ꢂSE^b

EC₅₀ꢂSE(n), nM^c

(ꢂ)-12

(ꢀ)-12

(+)-12

18

28a

28b

(ꢂ)-39

(ꢀ)-39

(+)-39

55

56

57

1.2ꢂ0.06

190ꢂ60 (3)

>10,000 (3)

220ꢂ40 (5)

5600ꢂ2,200 (3)

110 (1)

>10,000 (1)

300ꢂ80 (3)

>10,000

200ꢂ90 (2)

670ꢂ200 (3)

350ꢂ90 (3)

240ꢂ100 (2)

0^d

1.0ꢂ0.04

0.69ꢂ0.17

1.26

0

1.29ꢂ0.06

0

0.97ꢂ0.01

0.98ꢂ0.2

1.40ꢂ0.06

1.30ꢂ0.00

^aNeuroblastoma cell preparation.

^bIntrinsic activityꢂStandard error.

^cSE (number of repeat).

^dNo detectable cylase activity at the maximum concentration.

D₁/D₂aﬃnity. Although D₁aﬃnity and intrinsic activ-

ity were dramtically attenuated by replacing the 7-car-

bon with a sulfur or nitrogen, D₂activity was aﬀected to

a lesser extent. This ﬁnding is consistent with the idea

722

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

Table 3. In vivo pharmacology⁴

polarity because the perﬂuorinated n-butyl chain gave

results comparable to that of the n-butyl group. Mot-

tola et al.³⁶suggested previously that the piperidine (C-

ring, 5-position) in dihydrexidine was a potentially fer-

tile site for generation of active analogues. From these

results with substituted dinapsoline, however, it seems

less likely that any substantial gain in activity can be

achieved by modiﬁcation at the corresponding C-5

region in dihydrexidine, which corresponds to the 3-

position of dinapsoline.

Comp

Dose (mg/kg s.c.)

Rotations/10 h (meanꢂSEM)

n

(ꢂ)-12

(+)-12

(ꢀ)-12

0.2

2

0.2

2

0.2

2

0.2

2

1900ꢂ200

4800ꢂ500

4100ꢂ400

7000ꢂ1000

8ꢂ2

10

5

8

7

5

(ꢀ)-12

7ꢂ2

A-86929

(ꢂ)-28a

(ꢂ)-39

1100ꢂ200

4200ꢂ1000

180ꢂ100

3700ꢂ800

1100ꢂ200

0.2

2

0.2

6

8

Finally, substitutions on the D-ring were investigated.

Based on studies of dihydroxybenzopyrans, dihydrex-

idine, and ABT-431, it was expected that D₁receptor

aﬃnity could be at least maintained or even improved

by attaching hydrophobic groups to the D-ring (4-, 5-,

and 6-positions).⁴⁶Our early hypothesis about a D₁

pharmacophore³⁴included the existence of an accessory

hydrophobic binding pocket, as deﬁned by the region

surrounding the D-ring in both dihydrexidine and

dinapsoline.^3,47,48Both the orientation of the basic

nitrogen and the co-planarity of the accessory ring with

respect to the catechol moiety are essential to achieving

high levels of in vitro and functional D₁receptor activity.³⁶

of our eﬀorts was to develop compounds with enhanced

metabolic stability. Catechol compounds, in general, are

metabolized rapidly through sulfation and glucuronida-

tion, processes that are aﬀected by the lipophilicity of

the substance and the steric environment proximal to

the hydroxy groups.^40ꢀ44Introduction of steric bulk

near the catechol moiety could conceivably slow down

this degradation. Unfortunately, steric elements that

may retard metabolism also appear to prevent eﬃcient

recognition of the catechol by the receptor.

All D-ring analogues of dinapsoline synthesized showed

D₁/D₂receptor activity in the same range as the parent

compounds, consistent with a recent report.¹Substitu-

tions at the 6-position were distinguished as the most

potent analogues tested in vitro at D₁/D₂binding while

analogues substituted at the 4-position were equipotent

to dinapsoline. It is also remarkable to see very little

dependence on the nature of the substituent at these

positions with respect to in vitro binding aﬃnity. Within

the series 4-OH, 4-F, 6-F, and 6-Et substituted dinap-

soline, 4-hydroxy and 4-ﬂuoro dinapsoline had almost

identical D₁/D₂aﬃnity despite the vastly diﬀerent nat-

ure of the attached groups. Evidently, the presence of a

hydroxy group at the 4-position did not have any sig-

niﬁcant inﬂuence on in vitro binding, in spite of the

expectation that this general region of the receptor

would be fairly hydrophobic. On the other hand, ﬂuoro

and ethyl substitutions at the 6-position yielded com-

pounds with improved D₁/D₂receptor aﬃnities over

dinapsoline, although the gains were not substantial.

The 6-ﬂuoro dinapsoline had enhanced activity at both

the D₁and D₂receptors whereas an increase in subtype-

selective binding was detected at the D₁site only for the

6-ethyl analogue. It is possible that both steric and

electrostatic recognition elements operate in this region

of the molecule. Further useful improvements in this

series may be achieved by optimizing the nature of sub-

stituents attached to these positions.

Likewise, introducing substitution on the A-ring (cate-

chol ring) oﬀered no advantages in augmenting D₁

receptor aﬃnity. In fact, the negative eﬀects of either a

chlorine or a nitro group substitution were substantial.

Both 11-chlorodinapsoline (31a) and 11-nitrodinapso-

line (31b) were more than 100-fold less active than the

parent dinapsoline at the D₁site, whereas 11-chlor-

odinapsoline unexpectedly showed enhanced D₂recep-

tor aﬃnity (3-fold greater). The prototypical dopamine

partial D₁receptor agonist SKF-38393, on the other

hand, tolerates some substitutions on its catechol ring

while preserving substantial D₁receptor aﬃnity and in

vivo activity.⁴⁵

We next turned our attention to the C-ring, where the

basic nitrogen is positioned. This region had not been

previously investigated in dinapsoline due mainly to the

diﬃculty in synthesizing these analogues. N-Substituted

dihydrexidine analogues are known, but substitutions

on either side of the basic nitrogen are not. Using the

versatile chemical synthesis reported here, series of 2-

substituted, 3-substituted, and 2,3-disubstituted dinap-

soline derivatives were prepared. Generally speaking,

D₁receptor aﬃnity was negatively aﬀected when either

the 2- or 3-position was substituted, and similar results

were observed if both the 2- and 3-positions were

simultaneously substituted. Surprisingly, substitutions

appeared to aﬀect binding aﬃnity equally among the

smaller alkyl groups such as methyl and ethyl groups.

These smaller groups attached to either, or both of the

2- and 3-positions, produced compounds with an order

of magnitude lower aﬃnity at the D₁receptor than the

dinapsoline parent. This result strongly indicates that a

free secondary basic amine moiety is a prerequisite for

D₁activity, a conclusion consistent with earlier ﬁnd-

ings.^1,21,34The lack of activity of long alkyls at the 3-

position also appeared to be independent of chain

In the unilateral 6-OHDA rat rotation model the activ-

ity of most compounds correlated well with their in

vitro D₁receptor binding aﬃnities and intrinsic activ-

ities. When tested at a single dose (1 mg/kg) adminis-

tered subcutaneously (sc), all but one compound that

had a D₁receptor aﬃnity of 50 nM or better produced

rotational activity (Table 3). The single exception to this

trend was 6-ethyl dinapsoline that was only marginally

active in vivo despite its high in vitro aﬃnity and full

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

723

intrinsic activity (Table 2) at the D₁receptor. This

observation may indicate that the 6-ethyl substitution

aﬀects the pharmacokinetic proﬁle of the dinapsoline

chemotype, modulates brain absorption, or possibly

suggests that the compound may be functionally selec-

tive at the D₁receptor.⁴⁹

min at 37 ^ꢁC in buﬀer (100 mL) consisting of 50 mM Tris

(pH 7.5 at 37 ^ꢁC), 10 mM MgSO₄, 2 mM EDTA, 154

mM NaCl, 20 mg/mL BSA and 1% DMSO. Assays were

stopped by addition of ice-cold wash buﬀer (20 mM

Tris containing 0.9% NaCl). Filtration over glass ﬁber

ﬁlters (Whatman GF/B) was performed using a Brandel

cell harvester. Non-speciﬁc binding was deﬁned with 2

mM (+)-butaclamol. Binding of [¹²⁵I]-7-OH-PIPAT to

D₂receptors was performed using crude membrane

homogenates from rat striatal tissue. Homogenates (10

mg protein/well) from rat striatum were incubated with

4. Conclusions

Systematic SAR studies were performed on the core

structure of dinapsoline. With the exception of the 7-

position, which tolerated limited modiﬁcations, sub-

stitutions on the A-, B⁰-, and C-rings generally produced

compounds with decreased dopamine D₁receptor

activity relative to the parent unsubstituted dinapsoline.

Although aﬃnity at the D₂receptor subtype is not

aﬀected to the same extent as observed at the D₁recep-

tor, it is generally decreased. Substitutions on the D-

ring retained much of the in vitro D₁/D₂activity of the

parent. Relative intrinsic activity, as measured by accu-

mulation of cAMP, remained about comparable to

dopamine or slightly better among the D-ring con-

geners. The active D-ring analogue, 6-ﬂuorodinapsoline

(39) was prepared in enantiomeric pure form by resolu-

tion of a precursor. The (+)-enantiomer was deter-

mined to be the biologically active compound, a result

that was consistent with the activity of (+)-dinapsoline.

Although the absolute conﬁguration of (+)-39 was not

independently determined, it is predicted to have the

11b(S) conﬁguration as required by the dinapsoline core

structure and its shared pharmacological similarity to

other potent and selective D₁agonists such as dihy-

drexidine and A-86929.^2,36,50,51

[

¹²⁵I]-7-OH-PIPAT (200 pM) for 60 min at 37 ^ꢁC in

buﬀer (100 mL) consisting of 50 mM Tris (pH 7.7 at

25 ^ꢁC), 2 mM MgCl₂, 0.1% BSA, 0.025 mN HCl and

1% DMSO. Assays were stopped by addition of ice-

cold wash buﬀer (20 mM Tris). Filtration over glass

ﬁber ﬁlters (Whatman GF/B) was performed using a

Brandel cell harvester. Non-speciﬁc binding was deﬁned

with 2 mM (+)-butaclamol. Binding of [¹²⁵I]-7-OH-

PIPAT to D₂receptors was also performed using HEK-

293 cells that stably express recombinant human dopa-

mine D_2Lreceptors. HEK-D_2Lcells were grown at 37 ^ꢁC

in 5% CO₂as a monolayer in medium consisting of

MEM supplemented with 10% fetal bovine serum and

G418 sulfate (500 mg/mL). To prepare membranes for

radioligand binding experiments, cells were rinsed twice

with phosphate-buﬀered saline (9 g/L NaCl, 0.795 g/L

.

Na₂HPO₄7H₂O, 0.144 g/L KH₂PO₄, pH 7.4), and

incubated for 5–10 min at 4 ^ꢁC in hypotonic lysis buﬀer

consisting of 10 mM Tris (pH 7.4) and 5 mM EDTA.

Cells were transferred from plates to polypropylene

tubes (16ꢃ100 mm), homogenized and centrifuged at

32,000g for 20 min. Following centrifugation, pellets

were resuspended by homogenization in buﬀer consist-

ing of 50 mM Tris (pH 7.7 at 25 ^ꢁC) and 1 mM EDTA.

Homogenates were stored at ꢀ80 ^ꢁC until needed. On

the day of the experiment frozen homogenates were

thawed, homogenized then centrifuged at 32,000g for 20

min. Following centrifugation, supernatants were dis-

carded and remaining pellets were re-suspended in buf-

fer consisting of 50 mM Tris (pH 7.7 at 25 ^ꢁC) and 2

mM MgCl₂. Homogenates (10 mg protein/well) were

assayed for [¹²⁵I]-7-OH-PIPAT binding as described

above for rat striatal homogenate.⁵²

5. Experimental

5.1. In vitro and in vivo assays: materials

[

¹²⁵I]-7-OH-PIPAT (2200 Ci/mmol) and [¹²⁵I]-(+)-

SCH-23982 (2200 Ci/mmol) were purchased from NEN

Life Sciences Products (Boston, MA, USA). Rat striata

were purchased from ABS Inc. (Wilmington, DE,

USA). Frozen striata were thawed rapidly in homo-

genization buﬀer (20 mM HEPES, 154 mM NaCl, 5

mM EDTA, pH 7.5 at 4 ^ꢁC), homogenized and cen-

trifuged at 20,000g for 10 min. Pellets were re-suspended

in homogenization buﬀer, incubated for 30 min at 37 ^ꢁC

and centrifuged again. The ﬁnal pellets were re-sus-

pended in buﬀer consisting of either 50 mM Tris (pH

7.5 at 37 ^ꢁC), 10 mM MgSO₄, 2 mM EDTA, 154 mM

NaCl and 20 mg/mL BSA for use in [¹²⁵I]-(+)-SCH-

23982 binding assays or in buﬀer consisting of 50 mM

Tris (pH 7.7 at 25 ^ꢁC) and 2 mM MgCl₂for use in [¹²⁵I]-

7-OH-PIPAT binding assays.

5.3. cAMP accumulation

cAMP production in SK-N-MC cells endogenously

expressing D₁receptor was measured by using cAMP

radioimmunoassay system from Amersham (code RPA

509). Brieﬂy, cells were seeded at a concentration of 10⁵

cells/mL on 48-well plates and were incubated at 37 ^ꢁC,

5% CO₂1 day before the assay. Assays were initiated by

the addition of 700 mL assay buﬀer containing 1 mM 3-

isobutyl-1-methyl-xanthine in the presence of varying

concentration of compounds. After incubation for 10

min at 37 ^ꢁC, he supernatant was removed, and 1 mL

0.1 N HCl was added to terminate the reaction. The

cAMP production was quantiﬁed using the Amersham

protocol. Non-linear regression curve-ﬁtting (Prism 3.0,

GraphPad Inc., San Diego, CA, USA) was used to ﬁt

dose-response curves. The reported intrinsic activity is

based on the response (E_max) relative to dopamine.

5.2. Radioligand binding assays

Binding of [¹²⁵I]-(+)-SCH-23982 to D₁receptors was

performed using crude membrane homogenates from

rat striatal tissue. Homogenates (6 mg protein/well) were

incubated with [¹²⁵I]-(+)-SCH-23982 (500 pM) for 30

724

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

5.4. In vivo pharmacology

THF was added tert-butyl lithium (1.7 M in pentane, 45

mL, 77 mmol) over a period of 15 min. Metalation was

allowed to proceed at ꢀ78 ^ꢁC for 30 min before it was

treated with a solution of tetraisopropylthiuram dis-

ulﬁde (13.6 g, 39 mmol) in 55 mL THF. TLC showed

complete reaction after 45 min. The reaction mixture

was quenched with 30 mL of a saturated solution of

NH₄Cl and the organic residues were extracted with

ethyl ace_ꢁtate to give the crude product (7.5 g, 63%), mp

Rotation experiments were performed in Sprague–

Dawley rats with unilateral 6-OHDA lesions of the

medial forebrain bundle as described previously.¹⁷Only

animals that met pre-screening criteria for rotational

response to amphetamine (5 mg/kg giving 800 ipsilateral

rotations/3 h) and apomorphine (0.2 mg/kg: 100 con-

tralateral rotations/1 h) were used in these studies.

Four groups of rats were used, and each rat received

four treatments, once per week, in a counterbalanced

order.

1

143–145 C: H NMR (CDCl₃) d 9.29 (d, 1H, J=0.7),

8.59 (d, 1H, J=6.0), 8.11 (d, 1H, J=8.2), 7.95 (t, 2H,

J=7.5), 7.67 (t, 1H, J=7.7), 3.6–3.5 (br, 12H); LC/

MS m/z 305.18 (MH⁺). Anal. calcd for

.

C₁₆H₂₀N₂S₂0.2H₂O: C, 62.38; H, 6.68; N, 9.09. Found:

C, 62.13; H, 6.44; N, 8.89.

5.5. General chemical procedures

Melting points were recorded on a Thomas-Hoover

capillary apparatus and are uncorrected. IR spectra

were recorded on a Perkin–Elmer System 2000 FT-IR

spectrometer, or performed by Robertson Microlit Lab.

Optical rotations were measured on a Perkin–Elmer 241

polarimeter with a 10-cm standard cell; results are

reported as [a]_D. Proton NMR (¹H NMR) and carbon

NMR (¹³C NMR) spectra were obtained on a Bruker

ACP 300 spectrometer and are reported relative to a

tetramethylsilane (TMS) reference. NMR coupling

constants (J) are reported in hertz (Hz). Analytical and

preparative HPLC were performed on YMC columns

(A-302, S-5, 120A ODS, 4.6ꢃ150 mm; S5 ODS, 30ꢃ100

mm) with methanol:water gradients containing 0.1%

triﬂuoroacetic acid. LC–MS were obtained with a Shi-

madzu-MicromassLC unit using the same mobile phase.

TLC and medium pressure chromatography were

performed under ﬂash conditions using EM silica

type-H. THF was used as supplied by Aldrich.

Solutions were dried with magnesium sulfate unless

otherwise noted.

5.7.2. 5,5⁰-Dithiobisisoquinoline (14). The crude N,N-

diisopropyl dithiocarbamate (13, 7.5 g, 24.7 mmol) was

taken up into 300 mL of 95% EtOH containing 10 mL

of 10 M aqueous NaOH solution. The hydrolysis was

conducted at reﬂux temperature for 36 h. The ﬁnal dis-

ulﬁde formation was accomplished by the addition of

iodine solution in EtOH and the progress was mon-

itored by LC/MS. The desired product was isolated by

crystallization to give 1.8 g (21%), mp 143–146 ^ꢁC: H

1

NMR (CDCl₃) d 9.25 (d, 2H, J=0.8), 8.54 (d, 2H,

J=5.0), 7.9 (m, 4H), 7.74 (d, 2H, J=7.0), 7.43 (t, 2H,

J=7.5); LC/MS m/z 321.12 (MH⁺). Anal. calcd for

.

C₁₈H₁₂N₂S₂0.2H₂O: C, 66.72; H, 3.86; N, 8.65. Found:

C, 66.54; H, 4.17; N, 8.35.

5.7.3. 5-[(5-Bromo-1,3-benzodioxol-4-yl)thio]isoquinoline

(15). To a solution of 4-bromo-1,2-(methylenedioxy)-

benzene (1, 1.2 g, 6.0 mmol) in 38 mL THF at ꢀ78 ^ꢁC

was added lithium diisopropyl amide (LDA) solution in

THF (Aldrich, 1.5 M, 4.7 mL, 7.1 mmol) over a period

of 10 min. Deprotonation was allowed to proceed at

ꢀ78 ^ꢁC for 30 min before adding a solution of disulﬁde

14 (1.8 g, 5.6 mmol) in 9.2 mL THF. The mixture was

stirred at ꢀ78 ^ꢁC for 45 min, and at room temperature

for a further 30 min and was then quenched with a

saturated solution of NH₄Cl. The crude product was

extracted with ethyl acetate. The ﬁnal pure material was

obtained by ﬂash chromatography on silica gel type-H

(Merck) eluted with mixtures of ethyl acetate and hex-

anes. The yield of the desired product was 1.3 g (62%),

mp 140–141 ^ꢁC : ¹H NMR (CDCl₃) d 9.24 (d, 1H,

J=0.9), 8.59 (d, 1H, J=6.0), 8.17 (d, 1H, J=6.5), 7.82

(dd, 1H, J=6.5, 2.0), 7.45–7.41 (m, 2H), 7.20 (d, 1H,

5.6. Compounds 3, 5, and 7–12

The synthetic procedure for compounds 3, 5, and 7–12

has been described recently.²It should be noted that the

numbering system on polycyclic condensed system often

changes with additional rings attached. Here we include

the CAS nomenclature and numbering for the following

systems. For clarity in discussing SAR, dinapsoline core

numbering was used throughout.

J=8.3), 6.73 (d, 1H, J=8.3), 5.91 (s, 2H); LC/MS m/z

+

.

362.03 (MH ). Anal. calcd for C₁₆H₁₀BrNO₂S 0.2H₂O:

C, 52.82; H, 2.88; N, 3.85. Found: C, 52.60; H, 2.96; N,

3.81.

5.7.4. 8,9-(1,3-Dioxolyl)[1]benzothiopyrano[4,3,2-de]iso-

quinoline (16). To a solution of bromide 15 (1.0 g, 2.6

mmol) in benzene (107 mL), acetic acid (0.9 mL) and

2,2⁰-azobisisobutyronitrile (AIBN, 0.45 g) were added.

The reaction mixture was cooled to ꢀ78 ^ꢁC and

degassed (four times) followed by purging with argon

gas. After warming to room temperature, the solution

was slowly warmed to 80 ^ꢁC and tributyltin hydride

(2.8 mL) in degassed benzene (29 mL) was added

5.7. Synthesis of 1,2,3,11b-tetrahydro[1]benzothio-

pyrano[4,3,2-de]isoquinolin-8,9-diol (18)

5.7.1. [Bis(1-methylethyl)amino]carbodithioic acid, 5-iso-

quinolinyl ester (13). To a chilled (ꢀ78 ^ꢁC) solution of

5-bromoisoquinoline (1, 8.0 g, 39 mmol) in 250 mL

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

725

dropwise through a dropping funnel over a period of

3.5 h. Starting material was consumed after stirring

overnight at 80 ^ꢁC. Triethylamine (0.22 mL) was

added to the solution and the mixture was stirred for

5 min. The solvent was removed and puriﬁcation was

performed by precipitation of the product with

EtOAc/CH₂Cl₂/hexanes to obtain compound 16 (0.56 g,

71%), mp 223–225 ^ꢁC: ¹H NMR (CDCl₃) d 8.91 (s, 1H),

8.83 (s, 1H), 7.57–7.52 (m, 2H), 7.40–7.35 (m, 2H),

ture (2:1 v/v) of EtOAc and hexanes. The aqueous layer

was acidiﬁed to pH 1–2 with 6 N HCl. The precipitates

were collected, washed with water, and dried under

vacuum to furnish the desired product as a white solid

(3.14 g, 12.8 mmol, 81%): mp 166–168 ^ꢁC; MS m/z 243

1

(MꢀH); H NMR (DMSO-d₆) d 13.75 (br s, 1H), 7.12

(d, 1H, J=8.4), 6.95 (d, 1H, J=8.4), and 6.13 (s, 2H);

¹³C NMR (DMSO-d₆) d 164.7, 147.4, 146.3, 125.6,

117.9, 110.7, 119.3, and 102.6. Anal. calcd for

C₈H₅BrO₄: C, 39.21; H, 2.06; N, 0.00. Found: C, 39.34;

H, 2.11; N, 0.00.

7.10 (d, 1H, J=8.29), 6.07 (s, 2H); MS (ESI) m/z

+

.

280.07 (MH ). Anal. calcd for C₁₆H₉NO₂S 0.5H₂O:

C, 66.65; H, 3.50; N, 4.86. Found: C, 66.82; H, 3.65;

N, 4.85.

5.7.8.N-(5-Bromo-1,3-benzodioxol-4-yl)carbamic

acid,

1,1-dimethylethyl ester (20). To a solution of acid 19

(0.50 g, 2.0 mmol) in tert-BuOH (15 mL) was added

Et₃N (0.45 g, 4.5 mmol) followed by diphenylpho-

sphoryl azide (DPPA, 0.62 g, 2.2 mmol). The resulting

mixture was stirred at room temperature for 15 min.

The stirring continued while the temperature was raised

to reﬂux for 1 h. All the volatile solvents were removed

by evaporation in vacuo. The residue was puriﬁed by

ﬂash chromatography on silica gel (Type-H, Merck),

eluted with 1:1 v/v mixture of EtOAc in hexanes, ﬁnal

recrystalization from hexanes furnished the desired

product as white ﬂakes (4.2 g, 1.3 mmol, 65%): mp 87–

88 ^ꢁC; MS m/z 314 (MꢀH); ¹H NMR (DMSO-d₆) d

8.68 (s, 1H), 7.09 (d, 1H, J=8.4), 6.80 (d, 1H, J=8.4),

6.07 (s, 2H), and 1.42 (s, 9H); ¹³C NMR (DMSO-d₆) d

153.0, 147.6, 144.9, 124.3, 119.9, 114.1, 107.8, 102.1,

79.0, and 28.0. Anal. calcd for C₁₂H₁₄BrNO₄: C, 45.59;

H, 4.46; N, 4.43. Found: C, 45.43; H, 4.51; N, 4.44.

5.7.5. 1,2,3,11b-Tetrahydro-8,9-(1,3-dioxolyl)[1]benzo-

thiopyrano[4,3,2-de]isoquinoline, (17). The cyclized com-

pound 16 (0.06 g) was dissolved in warm THF (15 mL)

followed by hydrochloric acid (2 N, 1.1 mL). Sodium

cyanoborohydride (0.19 g) was added after the tem-

perature returned to ambient (25 ^ꢁC). Stirring proceeded

for an h and then saturated sodium bicarbonate was

added to neutralize the mixture. The organic layer was

separated and concentrated. Puriﬁcation was performed

by column ﬁltration to obtain 17 as a gum in 50% yield:

¹H NMR (CDCl₃) d 7.36 (d, 1H, J=7.56), 7.13 (t, 1H,

J=7.62), 6.98 (d, 1H, J=7.44), 6.73 (q, 2H, J=8.13 and

13.62), 6.03 (dd, 2H, J=1.05 and 9.87), 4.16–4.03 (m,

2H), 3.98–3.88 (m, 1H), 3.59–3.50 (m, 2H); LC/MS m/z

284.00 (MH⁺).

5.7.6.

1,2,3,11b-Tetrahydro.[1]benzothiopyrano[4,3,2-

de]isoquinolin-8,9-diol (18) To a solution of the tetra-

hydroisoquinoline 17 (0.03 g, 0.11 mmol) in dichloro-

methane (2 mL) cooled to ꢀ78 ^ꢁC was added boron

tribromide (1 M solution in dichloromethane, 0.5 mL).

The reaction solution was stirred at ꢀ78 ^ꢁC for 2 h and

was then warmed to room temperature and stirring

continued overnight. The solution was cooled to ꢀ78 ^ꢁC

and dry methanol was added to quench the reaction.

After stirring for 10 min, the solution was gradually

warmed to reﬂux at 70 ^ꢁC for 30 min. The solvents were

evaporated and puriﬁcation was performed by pre-

cipitation with CH₂Cl₂to obtain solid product 18 (0.031

5.7.9. 5-Bromo-8-nitroisoquinoline (21). This prepara-

tion followed literature procedures, with minor modiﬁ-

cations described herein: to a mixture of KNO₃(5.1 g,

50.5 mmol) and concentrated H₂SO₄(42 mL) was

slowly added 5-bromoisoquinoline (5). Once the addi-

tion was complete, the reaction mixture was stirred at

0 ^ꢁC for an h and was then poured into 400 g of crushed

ice. The solution phase was neutralized to pH 8–9 using

concentrated aqueous NH₃solution. The precipitates

were ﬁltered oﬀ and puriﬁed by recrystallization

(MeOH) to provide product as a grayish solid (4.1 g,

1

g, 84%): H NMR (CD₃OD) d 7.50 (d, 1H, J=7.77),

16.2 mmol, 84.4%): H NMR (CDCl₃) d 10.06 (s, 1H),

8.86 (d, 1H, J=5.7), 8.23 (d, 1H, J=8.1), 8.20 (d, 1H,

J=5.7), 8.14 (d, 1H, J=8.1).

7.28 (t, 1H, J=7.71), 7.18 (d, 1H, J=7.65), 6.79 (d, 1H,

J=8.28), 6.66 (d, 1H, J=8.52), 4.52–4.40 (m, 2H), 4.34–

4.27 (m, 1H), 3.93 (t, 1H, J=11.13), 3.83–3.77 (m, 1H);

LC/MS m/z 272.12 (MH⁺). Anal. calcd for

C₁₅H₁₃NO₂S: C, 47.04; H, 3.78; N, 3.66. Found: C,

47.07; H, 4.07; N, 3.53.

5.7.10. N-(5-Bromo-1,3-benzodioxol-4-yl)-N-(8-nitroiso-

quinolin-5-yl)carbamic acid, 1,1-dimethylethyl ester (22).

To a solution of 5-bromo-8-nitro-isoquinoline (0.67 g,

2.6 mmol) in dimethylformamide (DMF) was added 20

(0.83 g, 2.6 mmol) followed by KNO₃(1.0 g, 9.9 mmol).

The resultant mixture was stirred at 85 ^ꢁC under N₂for

11 h and then poured into H₂O. The product was

extracted with EtOAc and dried over Na₂SO₄.

Chromatography (silica gel, 25% v/v ethyl acetate in

hexanes) provided product as a dry foam (0.78 g, 1.6

mmol, 61.5%): MS m/z 488 (MH⁺). Anal. calcd for

5.7.7. 5-Bromo-1,3-benzodioxole-4-carboxylic acid (19).

To a cooled (ꢀ78 ^ꢁC) solution of 4-bromo-1,2-(methy-

lenedioxy)benzene (1, 3.2 g, 15.9 mmol) in THF (100

mL) was added dropwise LDA (Aldrich, 11.2 mL of

1.5 M solution in cyclohexane, 16.8 mmol). The result-

ing mixture was stirred at ꢀ78 ^ꢁC under nitrogen for an

hour. Dry CO₂was introduced by bubbling through a

needle over a period of an hour. The reaction mixture

was then allowed to warm to room temperature and

H₂O was added. The mixture was neutralized to pH 10–

11 by dropwise addition of 10 N aqueous NaOH. The

remaining organic residues were extracted with a mix-

.

C₂₁H₁₈BrN₃O₆0.27C₆H₁₄0.37H₂O: C, 52.44; H, 4.38;

N, 8.11. Found: C, 52.45; H, 4.06; N, 8.29.

5.7.11. N-(5-Bromo-1,3-benzodioxol-4-yl)-N-(8-ﬂuoroiso-

quinolin-5-yl)carbamic acid, 1,1-dimethylethyl ester (23).

726

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

Me₄NF (0.80 g, 7.9 mmol) was added to a solution of 22

(0.94 g, 1.9 mmol) in DMF (120 mL). The reaction

mixture was stirred at 65 ^ꢁC under N₂for 25 min and

then poured into H₂O. The product was extracted with

EtOAc and dried over Na₂SO₄. Chromatography (silica

gel, 25% v/v EtOAc in hexanes) gave product as a yel-

extracted with ethyl acetate and the combined organic

layers were washed with water, brine, and dried over

MgSO₄. After ﬁltration and concentration in vacuo, the

residue was puriﬁed by ﬂash chromatography (SiO₂,

type-H eluted with mixtures of EtOAc/hexanes).

low foam (0.40 g, 0.9 mmol, 47.3%): MS m/z 461

+

5.8.2. 12-Methyl-12H-benzo[de]-1,3-benzodioxol[4,5-h]-

isoquinoline (27a). This compound was obtained as a

yellowish dry foam (yield 57%): MS m/z 276.1 (MH⁺).

¹H NMR (DMSO-d₆) d 1.43 (d, J=7.14, 3H), 4.6 (q,

1H), 6.1 (s, 1H), 6.2 (s, 1H), 7.05 (d, J=9.03, 1H), 7.7 (t,

1H), 7.8 (m, 1H), 7.9 (d, J=8.34, 1H), 9.16 (d, J=11.4,

1H). ¹³C NMR (DMSO-d₆) d 27.34, 32.16, 101.57,

107.62, 117.50, 122.15, 122.86, 122.93, 125.25, 127.62,

127.75, 127.94, 129.06, 135.92, 136.95, 145.07, 147.17,

150.65. Anal. calcd for C₁₈H₁₃NO₂: C, 78.53; H, 4.76;

N, 5.09. Found: C, 78.38; H, 4.94; N, 5.05.

.

(MH ). Anal. calcd for C₂₁H₁₈BrFN₂O₄0.2H₂O: C,

54.26; H, 3.99; N, 6.03. Found: C, 54.49; H, 4.20; N,

5.95.

5.7.12. 8,9-(1,3-Dioxolyl)-4-ﬂuoro-7H-pyrido[3,4,5-k]ac-

ridine-7-carboxylic acid, 1,1-dimethylethyl ester (24). To

a solution of 23 (0.38 g, 1.0 mmol) in benzene (40 mL)

was added glacial acetic acid (0.34 g, 5.6 mmol) followed

by AIBN (0.18 g, 1.1 mmol). The resultant mixture was

cooled to ꢀ78 ^ꢁC, degassed, purged with N₂, and heated

to 80 ^ꢁC. A solution of tributyltin hydride (1.0 g, 3.4

mmol) in benzene (10 mL) was added dropwise in the

course of 80 min. The stirring continued at 80 ^ꢁC under

N₂for 16 h. The mixture was neutralized by adding Et3N

(0.80 mL) and the solvent was removed. Chromato-

graphy (silica gel, 25% v/v EtOAc in hexanes) gave the

desired product as a yellow solid (0.20 g, 0.7 mmol,

5.8.3. 12,12⁰-Dimethyl-12H-benzo[de]-1,3-benzodioxol[4,5-

h]isoquinoline (27b). This compound was obtained as a

dry yellow foam (65% yield): MS m/z 290.1 (MH⁺). ¹H

NMR (DMSO-d₆) d 1.75 (s, 6H), 6.15 (s, 2H), 7.04 (d,

J=8.4, 1H), 7.76 (t, 1H), 8.02 (m, 1H), 9.17 (d, J=1.62,

2H). ¹³C NMR (DMSO-d₆) d 8.48, 32.67, 37.74, 101.49,

107.58, 117.36, 120.41, 123.39, 124.30, 125.28, 127.28,

127.56, 129.05, 129.37, 134.81, 135.91, 144.97, 147.10,

150.61. Anal. calcd for C₁₉H₁₅NO₂: C, 78.87; H, 5.23;

N, 4.84. Found: C, 78.55; H, 5.47; N, 4.72.

67%): mp 171–173 ^ꢁC; MS m/z 381 (MH⁺); H NMR

1

(CDCl₃) d 9.13 (s, 1H), 8.82 (s, 1H), 7.87 (dd, 1H, J=8.7

and 4.5), 7.31 (d, 2H, J=8.4), 7.11 (dd, 1H, J=9.9 and

9.0), 6.74 (d, 2H, J=8.1), 5.99 (s, 2H), and 1.38 (s, 9H).

5.7.13. 4-Fluoro-7H-pyrido[3,4,5-k]acridin-8,9-diol (25)

and 4-ﬂuoro-2,3,7,11b-tetrahydro-1H-pyrido[3,4,5-k]acri-

din-8,9-diol (26). BBr₃(2.6 mL of 1.0 M in CH₂Cl₂2.6

mmol) was added to a chilled solution (ꢀ78 ^ꢁC ) of 24

(0.13 g, 0.5 mmol) in CH₂Cl₂(26 mL). The resulting

mixture was stirred at room temperature for 3 h and

then was cooled to ꢀ78 ^ꢁC. Methanol (10 mL) was

added dropwise at ꢀ78 ^ꢁC while stirring. Stirring was

continued at room temperature for 16 h. The dry resi-

due (25) remaining after solvent removal was dissolved

in THF (50 mL) and cooled to 0 ^ꢁC. HCl (2.6 mL of

2.0 N in H₂O) was added followed by NaCNBH₃(0.52

g, 8.3 mmol). The reaction mixture was stirred at room

temperature for 3 h. The precipitates were ﬁltered oﬀ.

Chromatography (silica gel type-H, 10% MeOH in

CH₂Cl₂) of the ﬁltrate provided product 26 as a pink

solid (0.070 g, 0.29 mmol, 58%): mp>280 ^ꢁC; MS m/z

273 (MH⁺); ¹H NMR (DMSO-d₆) d 7.01 (dd, 1H,

J=9.0 and 5.7), 6.93 (d, 1H, J=9.3), 6.69 (d, 1H,

J=11.7), 6.53 (br. s, 2H), 6.31 (br. s, 2H), 6.10 (dd, 1H,

J=36.9 and 8.1), and 4.23–3.90 (m, 5H).

5.8.4. 12-Ethyl-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (27c). This compound was obtained as a pale-

yellow dry foam (57% yield): MS m/z 290.1 (MH⁺). ¹H

NMR (DMSO-d₆) d 0.395 (t, 3H), 1.75 (m, 1H), 1.96

(m, 1H), 4.6 (t, 1H), 6.1 (s, 1H), 6.20 (s, 1H), 7.01 (d,

J=8.34, 1H), 7.77 (m, 3H), 7.85 (d, J=8.4, 1H), 9.15 (d,

J=13.4, 2H). ¹³C NMR (DMSO-d₆) d 31.34, 36.66,

100.99, 107.95, 117.30, 122.14, 122.54, 125.27, 126.62,

126.83, 127.27, 127.50, 127.88, 136.00, 142.07, 145.15,

147.89, 150.55. Anal. calcd for C₁₉H₁₅NO₂: C, 78.87; H,

5.23; N, 4.84, Found: C, 78.67; H, 5.29; N, 4.80.

5.8.5. 12,12⁰-Diethyl-12H-benzo[de]-1,3-benzodioxol[4,5-

h]isoquinoline (27d). This compound was obtained as a

pale gray dry foam (8% yield): MS m/z 318.13 (MH⁺).

¹H NMR (DMSO-d₆) d 0.25 (t, 6H), 1.98 (m, 2H), 2.7

(m, 2H), 6.11 (s, 2H), 7.11 (d, J=8.34, 1H), 7.8 (t, 1H),

8.05 (m, 3H), 8.95 (d, J=3.06, 2H).

5.8.6. 12-Ethoxycarbonylmethyl-12H-benzo[de]-1,3-ben-

zodioxol[4,5-h]isoquinoline (27e). This compound was

obtained as a brown gum (24% yield): MS m/z 348

1

(MH⁺). H NMR (DMSO-d₆) d 0.82 (t, 3H), 2.7 (q,

5.8. 12-Alkyl-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (27a to 27i)

1H), 2.9 (q, 1H), 3.7 (q, 2H) 6.1 (s, 1H), 6.2 (s, 1H), 7.05

(d, J=9.8, 1H), 7.7 (m, 2H), 7.8 (d, J=9.8, 1H), 7.9 (d,

J=8.3, 1H), 9.16 (d, J=10.3, 2H).

5.8.1. General procedure. To a mixture of starting mate-

rials 12H-benzo[de]-1,3-benzodioxol[4,5-h]-isoquinoline

(10, 0.77 mmol) and sodium hydride (5.0 mmol) was

added 30 mL of DMF. The resulting suspension was

stirred at room temperature under argon for an h before

addition of the alkylating agent. Stirring was continued

for 5 min after addition of the electrophile, and the

reaction mixture was then quenched by the addition of 5

mL of satd aqueous NH₄Cl solution. The product was

5.8.7. 12-Cyanomethyl-12H-benzo[de]-1,3-benzodioxol[4,5-

h]isoquinoline (27f). This compound was obtained as a

yellow solid (19% yield): MS m/z 301.1 (MH⁺). ¹H

NMR (DMSO-d₆) d 3.15 (d, J=5.0, 2H), 4.9 (t, 1H), 6.1

(dd, J=0.87, 1H), 6.22 (dd,=0.87, 1H), 7.09 (d, J=8.4,

1H), 7.8 (t, 1H), 7.95 (m, 2H), 8.1 (d, J=8.4, 1H), 9.17

(d, J=9.9, 2H).

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

727

5.9. (ꢂ)-7-Alkyl-8,9-methylenedioxy-2,3,7,11b-tetrahydro-

1H-dibenz[de,h]isoquinoline and (ꢂ)-7-alkyldinapsoline

(28a–28f)

5.9.4. (ꢂ)-7,7⁰-Diethyl-8,9-methylenedioxy-2,3,7,11b-tet-

rahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7,7⁰-die-

thyldinapsoline hydrobromide (28d). This compound

was obtained as a pale gray dry foam (8% yield): MS m/

1

Products from alkylation were reduced as described

previously using sodium cyanoborohydride in acidiﬁed

THF. Products from the reduction step were depro-

tected using BBr₃in CH₂Cl₂at ꢀ78 ^ꢁC. The desired

products were isolated in accordance with the proce-

dures described previously. Some of the 7-substituted

intermediates (27d, 27f) could not withstand the BBr₃

deprotection conditions; only four compounds from this

series survived to the end.

z 352.11 (MH⁺). H NMR (DMSO-d₆) d 1.14 (t, 3H),

2.6 (m, 2H), 3.08 (t, 1H), 4.11 (m, 6H), 4.58 (t, 1H), 6.01

(s, 1H), 6.08 (s, 1H), 6.77 (d, J=8.0, 1H), 6.85 (d,

J=8.0, 1H), 7.1 (t, 1H), 7.21 (d, J=4.3, 2H). Attempted

BBr₃deprotection led to extensive decomposition of the

starting material.

5.9.5. (ꢂ)-7-Ethoxycarbonylmethyl-8,9-methylenedioxy-

2,3,7,11b-tetrahydro-1H-dibenz[de,h]isoquinoline

and

(ꢂ)-7-methoxycarbonylmethyldinapsoline (28e). The

5.9.1. (ꢂ)-7-Methyl-8,9-methylenedioxy-2,3,7,11b-tetra-

hydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-methyldi-

napsoline hydrobromide (28a). The reduction product

was obtained as a dry yellow foam (57% yield): MS m/z

reduced compound was obtained as a brown gum (24%

1

yield): MS m/z 284.15 (MH⁺). H NMR (DMSO-d₆) d

2.87 (t, 1H), 3.47 (dd, J=17.8, 3.5, 1H), 3.7 (bt, 1H), 3.9

(d, J=11.4, 3H), 4.2 (d, J=17.9, 1H), 6.01 (s, 1H), 6.07

(s, 1H), 6.82 (q, 2H), 7.01 (d, J=7.6, 2H). Evidently the

ethyl ester group was also trans-esteriﬁed into the methyl

ester upon methanol workup. This compound was

obtained as a pale gray dry foam (8% yield): MS m/z

1

280.2 (MH⁺). H NMR (DMSO-d₆) d 1.31 (d, J=7.2,

3H), 3.09 (t, 1H), 4.28 (m, 5H), 6.02 (s, 1H), 6.1 (s, 1H),

6.87 (m, 2H), 7.06 (d, J=6.7, 1H), 7.24 (t, 1H), 7.30 (d,

J=7.4, 1H). The deprotected ﬁnal product was obtained

as a yellow foam (57% yield): MS m/z 268.18 (MH⁺). ¹H

NMR (DMSO-d₆) d 1.24 (d, J=7.1, 3H), 3.33 (m, 5H),

6.56 (d, J=8.3, 1H), 6.70 (d, J=8.2, 1H), 7.12 (d, J=7.1,

1H), 7.33 (m, 2H), 8.5 (s, 1H), 9.31 (s, 1H).

1

326.19 (MH⁺). 324.14 (MꢀH). H NMR (DMSO-d₆) d

2.482 (m, 2H), 2.62 (dd, J=13. 9, 4.7, 1H), 3.53 (s, 3H),

4.31 (m, 2H), 4.37 (s, 2H), 4.83 (q, 1H), 6.57 (d, J=8.2,

1H), 6.73 (d, J=8.2, 1H), 7.15 (t, 1H), 7.27 (m, 2H),

8.67 (s, 1H), 9.42 (s, 1H). ¹³C NMR (DMSO-d₆) d

14.08, 20.70, 31.88, 35.11, 43.73, 44.18, 51.32, 59.75,

113.38, 114.1, 124.69, 125.71, 126.67, 126.73, 127.06,

127.99, 131.95, 138.45, 142.10, 143.88, 171.17. Anal.

5.9.2. (ꢂ)-7,7⁰-Dimethyl-8,9-methylenedioxy-2,3,7,11b-

tetrahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7,7⁰-di-

methyldinapsoline hydrobromide (28b). The reduction

product was obtained as a yellow foam (65% yield): MS

m/z 294.2 (MH⁺). ¹H NMR (DMSO-d₆) d 1.43 (d,

J=18.0, 3H), 1.98 (d, J=21.4, 3H), 2.94 (t, 1H), 4.19

(m, 4H), 6.10 (t, 2H), 6.82 (m, 2H), 7.17 (m, 1H), 7.22

(m, 1H), 7.5 (m, 1H). The deprotected ﬁnal product was

obtained as a yellow foam (65% yield): MS m/z 282.2

.

calcd for C₁₉H₁₉NO₄1.0HBr: C, 54.12; H, 5.60; N,

3.32. Found: C, 54.06; H, 5.51; N, 3.29.

5.9.6. (ꢂ)-7-Cyanomethyl-8,9-methylenedioxy-2,3,7,11b-

tetrahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-cyano-

methyldinapsoline (28f). This compound was obtained

as a yellow solid (19% yield): MS m/z 292.08 (MH⁺).

¹H NMR (DMSO-d₆) d 0.71 (m, 1H), 1.01 (m, 1H), 1.98

(m, 1H), 2.29 (m, 1H), 4.22 (m, 4H), 5.94 (s, 1H), 5.98

(s, 1H), 6.73 (d, J=8.2, 1H), 6.80 (d, J=8.0, 1H), 7.22

(m, 3H). Attempted deprotection with BBr₃in methyl-

ene chloride at ꢀ78 ^ꢁC caused extensive decomposition

of the starting material.

1

(MH⁺). H NMR (DMSO-d₆) d 1.69 (s, 3H), 1.81 (s,

3H), 4.31 (m, 5H), 6.70 (d, J=8.4, 1H), 6.81 (d, J=8.4,

1H), 7.25 (d, J=7.4, 1H), 7.39 (t, 1H), 7.66 (d, J=7.8,

1H), 8.34 (s, 1H), 9.55 (s, 1H). ¹³C NMR (DMSO-d₆) d

29.22, 29.62, 31.81, 37.35, 43.31, 45.82, 113.48,

116.66, 122.30, 124.39, 126.37, 127.02, 128.90, 129.02,

129.66, 143.71, 144.38, 144.72. Anal. calcd for

.

C₁₈H₁₉NO₂1.6HBr 0.6H₂O: C, 51.28; H, 5.21; N, 3.33;

Br, 30.32. Found: C, 50.89; H, 5.11; N, 3.94; Br, 29.44.

5.9.7. 5-Chloro-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (29a). To a solution of starting material 10

(0.36 g, 1.38 mmol) in CH₂Cl₂(15 mL) was slowly

added SO₂Cl₂(0.276 mL) at 0 ^ꢁC. The mixture was stir-

red at 0 ^ꢁC for 3 h, and was then quenched with satu-

rated NaHCO₃solution. The product was extracted

with CH₂Cl₂, dried over Na₂SO₄, and puriﬁed by chro-

matography (silica gel, EtOAc in hexanes). This com-

pound was obtained as a yellow dry foam (57% yield):

¹H NMR (DMSO-d₆) d 4.35 (s, 2H), 6.21 (s, 2H), 7.18

(s, 1H), 7.66 (t, 1H), 7.73 (d, J=7.6, 1H), 7.98 (d,

J=7.8, 1H), 9.19 (s, 1H), 9.72 (s, 1H).

5.9.3. (ꢂ)-7-Ethyl-8,9-methylenedioxy-2,3,7,11b-tetrahy-

dro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-ethyldinapso-

line hydrobromide (28c). The reduction product was

obtained as a dry pale yellow foam (57% yield): MS m/z

294.2 (MH⁺). ¹H NMR (DMSO-d₆) d 0.90 (t, 3H), 1.61

(m, 2H), 2.79 (t, 1H), 3.9 (m, 4H), 5.96 (s, 1H), 6.05 (s,

1H), 6.79 (m, 2H), 6.96 (m, 1H), 7.14 (m, 2H). This ﬁnal

compound was obtained as a pale yellow dry foam

1

(57% yield): MS m/z 282.4 (MH⁺); 280.3 (MꢀH). H

NMR (DMSO-d₆) d 0.868 (t, 3H), 1.17 (m, 2H), 4.37

(m, 5H), 6.55 (d, J=8.2, 1H), 6.7 (d, J=8.2, 1H), 7.17

(t, 1H), 7.27 (t, 2H), 8.45 (s, 1H), 9.3 (s, 1H). ¹³C NMR

(DMSO-d₆) d 12.33, 27.25, 31.97, 40.85, 43.86, 44.21,

112.82, 114.04, 124.09, 126.38, 126.49, 127.56, 127.70,

131.66, 140.15, 142.21, 143.80. Anal. calcd for

5.9.8. 5-Nitro-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (29b). To a solution of starting material 10

(0.10 g, 0.38 mmol) in acetic acid (4 mL) was added

HNO₃(70%, 0.4 mL). The mixture was stirred at 45 ^ꢁC

until starting material disappeared (about 35 min) and

was then poured into ice-water. The resulting mixture

.

C₁₈H₁₉NO₂1.0HBr: C, 53.25; H, 5.67; N, 3.45. Found:

C, 53.26; H, 5.58; N, 3.44.

728

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

was neutralized by adding saturated NaHCO₃solution

and organic materials were extracted into EtOAc. The

desired product was puriﬁed by chromatography (silica

gel, EtOAc in hexanes). This compound 29b was

obtained as a yellow dry foam (65% yield): MS m/z

125.21, 127.04, 128.29, 130.89, 131.06, 132.25, 141.94,

.

144.61. Anal. calcd for C₁₆H₁₄ClNO₂HBr: C, 40.02; H,

4.25; N, 3.72. Found: C, 39.720; H, 4.270; N, 3.870.

5.9.14. (ꢂ)-11-Nitrodinapsoline hydrobromide (31b).

This compound was likewise obtained as a brown gum

(18% yield): MS m/z 299.04 (MH⁺). ¹H NMR (DMSO-

d₆) d 2.61 (t, 1H), 3.63 (m, 1H), 4.10 (bs, 2H), 4.36 (bs,

2H), 5.03 (m, 1H), 7.41 (m, 3H), 7.61 (bs, 1H).

1

306.31 (MH⁺). H NMR (DMSO-d₆) d 4.42 (s, 2H),

6.31 (s, 2H), 7.54 (s, 1H), 7.73 (q, 1H), 7.79 (d, J=8.0,

1H), 8.02 (d, J=8.0, 1H), 8.31 (s, 1H), 9.2 (s, 1H). ¹³C

NMR (DMSO-d₆) d 26.93, 103.65, 104.61, 116.44,

118.12, 119.34, 125.27, 127.57, 127.79, 129.14, 129.27,

130.02, 137.46, 143.30, 146.58, 147.23, 152.15. Anal.

5.9.15. (ꢂ)-2-Methyl-8,9-methylenedioxy-2,3,7,11b-tet-

rahydro-1H-dibenz[de,h]isoquinoline (34a). To a solution

of 12H-benzo[de]-1,3-benzodioxol[4,5-h]-isoquinoline 10

(0.38 mmol) in warm dichloroethane (4 mL), methyl

iodide (12.8 mmol) was added and a yellow suspension

formed after a few minutes. The mixture was warmed to

40 ^ꢁC with stirring for 20 min. After all the starting

material was gone, nitrogen was passed into the reaction

vessel to remove both the solvent and the excess MeI

and the residue was further dried under high vacuum.

The resulting yellow solids were resuspended in dry

THF, followed by the sequential addition of sodium

triacetoxyborohydride (0.4 g) and sodium cyanobor-

ohydride (0.12 g). After a few minutes, the suspension

turned orange and stirring was continued for 20 min.

Saturated NH₄Cl and HCl (2.0 N) were added to the

suspension to form two layers, which were separated.

The organic layer was evaporated and dried under

vacuum. Partial isolation and puriﬁcation of product

was achieved by recrystallization to give the title com-

pound (0.047 g). The mother liquor was further puriﬁed

by ﬁltration over a bed of silica gel type-H to aﬀord a

second portion of the desired product (0.04 g, totaling

82% yield): ¹H NMR (DMSO-d₆) d 7.39 (d, 1H,

J=7.4), 7.28 (t, 1H, J=7.5), 7.13 (d, 1H, J=7.3), 6.86

(d, 1H, J=8.0), 6.72 (d, 1H, J=8.0), 6.09 (s, 1), 6.02 (s,

1H), 4.60–4.25 (m, 3H), 4.20–4.03 (m, 2H), 3.75–3.68

(m, 1H), 3.60–3.40 (m, 1H), 3.02 (s, 3H); LC/MS m/z

280.13 (MH⁺) as a single homogeneous peak.

.

calcd for C₁₇H₁₀N₂O₄0.35H₂0: C, 65.34; H, 3.45; N,

8.97. Found: C, 65.39; H, 3.67; N, 8.60.

5.9.9. 5-Amino-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (29c). To a solution of starting material 29b

(0.26 g, 0.85 mmol) in MeOH (50 mL) was added

.

SnCl₂2H₂O (0.77 g, 3.4 mmol). The mixture was held at

reﬂux for two h, and then quenched with saturated

NaHCO₃solution. The product was extracted into

EtOAc, dried over Na₂SO₄, and puriﬁed by chromato-

graphy (silica gel, EtOAc in hexanes). This compound

was obtained as a pale yellow dry foam (57% yield): MS

1

m/z 277.03 (MH⁺). H NMR (CD₃OD) d 4.26 (s, 2H),

5.94 (s, 2H), 6.42 (s, 1H), 7.61 (d, J=7.08, 2H), 7.86 (d,

J=7.2, 1H), 8.9 (s, 1H), 9.29 (s, 1H).

5.9.10. 5-Fluoro-12H-benzo[de]-1,3-benzodioxol[4,5-h]-

isoquinoline (29d). To a solution of starting material 10

(0.10 g, 0.38 mmol) in a mixture of MeCN (20 mL) and

CH₃COOH (2 mL) was added SelectFluoro^TM(0.35 g,

0.87 mmol). The mixture was stirred at 70 ^ꢁC for 25 min,

and was then quenched with saturated NaHCO₃solution

and extracted into EtOAc. The desired product was pur-

iﬁed by chromatography (silica gel, EtOAc in hexanes).

This compound was obtained as a pale gray dry foam

1

(8% yield): MS m/z 280.01 (MH⁺). H NMR (DMSO-

d₆) d 4.42 (s, 2H), 6.19 (s, 2H), 7.2 (d, J=10.2, 1H), 7.74

(m, 2H), 7.95 (d, J=8.0, 1H), 9.16 (d, J=6.2, 2H).

5.9.11. (ꢂ)-11-Chloro-8,9-methylenedioxy-2,3,7,11b-tet-

rahydro-1H-dibenz[de,h]isoquinoline (30a). Using the

NaCNBH₃procedure as described, this compound was

obtained as a yellow solid (24% yield): MS m/z 299.97

5.9.16. (ꢂ)-2-Methyl-8,9-dihydroxy-2,3,7,11b-tetrahydro-

1H-dibenz[de,h]isoquinoline, (ꢂ)-2-methyldinapsoline hy-

drobromide (35a). To a solution of 34a (0.16 mmol) in

dichloromethane (4 mL) cooled to ꢀ78 ^ꢁC, boron tri-

bromide (1 M in dichloromethane, 0.77 mmol) was

added. The reaction solution was stirred at ꢀ78 ^ꢁC for 2

h and then warmed to room temperature overnight. The

solution was cooled to ꢀl78 ^ꢁC and dry methanol was

added to quench the reaction. After stirring for 10 min,

the solvent was removed and dry methanol was added

again. The process was repeated three times. Puriﬁca-

tion was performed by recrystallization from MeOH/

CH₂Cl₂to obtain the title compound (0.035 g): ¹H

NMR (CD₃OD) d 7.37 (d, 1H, J=7.3), 7.29 (t, 1H,

J=7.4), 7.11 (d, 1H, J=7.3), 6.72 (d, 1H, J=8.2), 6.59

(d, 1H, J=8.5), 4.7–4.39 (m, 3H), 4.20–4.05 (m, 1H)

3.70–3.40 (m, 2H), 3.20 (s, 3H); LC/MS m/z 268.16

(MH⁺) as a single homogeneous peak.

1

(MH⁺). H NMR (DMSO-d₆) d 3.48 (dd, J=17.3, 5.3,

2H), 4.15 (m, 5H), 6.11 (s, 1H), 6.16 (s, 1H), 7.31 (m, 4H).

5.9.12. (ꢂ)-11-Nitro-8,9-methylenedioxy-2,3,7,11b-tetra-

hydro-1H-dibenz[de,h]isoquinoline (30b). Similarly, the

nitro derivative was converted into the desired tetra-

hydroisoquinoline product. This compound was

obtained as a yellow solid (57% yield): MS m/z 311.06

1

(MH⁺). H NMR (DMSO-d₆) d 1.99 (s, 1H), 4.20 (m,

4H), 4.6 (b, 1H), 4.8 (bd, 1H), 6.27 (s, 1H), 6.32 (s, 1H),

7.37 (m, 3H), 7.60 (s, 1H).

5.9.13. (ꢂ)-11-Chlorodinapsoline hydrobromide (31a).

This compound was obtained through BBr3 deprotection

and was isolated as a brown gum (24% yield): MS m/z

1

288.15 (MH⁺). 286.23 (MꢀH). H NMR (DMSO-d₆) d

5.9.17. (ꢂ)-2-Propyl-8,9-methylenedioxy-2,3,7,11b-tet-

rahydro-1H-dibenz[de,h]isoquinoline (34b). Likewise 34b

was prepared from 10 and n-propyl iodide in 40% yield:

¹H NMR (CDCl₃) d 7.18-7.10 (m, 2H), 6.97 (d, 1H,

3.16 (s, 1H), 4.0 (s, 2H), 4.32 (m, 4H), 6.86 (s, 1H), 7.39

(m, 3H), 8.94 (s, 1H), 9.89 (s, 1H). ¹³C NMR (DMSO-d₆)

d 32.43, 42.79, 48.60, 114.84, 119.22, 121.84, 124.06,

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

729

J=6.9), 6.72 (s, 2H), 5.97 (dd, 2H, J=1.4, 25.4), 4.05 (t,

2H, J=17.5), 3.94–3.80 (m, 1H), 3.84–3.77 (m, 1H), 3.62

(dd, 1H, J=3.5, 17.4), 3.43 (d, 1H, J=14.8), 2.67–2.54

(m, 3H), 1.79–1.69 (m, 2H), 1.02 (t, 3H, J=7.4); LC/MS

m/z 308.15 (MH⁺) as a single homogeneous peak.

J=2.9, 17.2), 3.28 (t, 1H, J=11.8), 2.24–2.02 (m, 2H),

1.50–1.37 (m, 4H), 1.02–0.86 (m, 3H); LC/MS calcd for

C₂₁H₂₃NO₂(M⁺): 321.17. Found: (MH⁺) 322.14; and

1

35e in 82% yield: H NMR (CD₃OD) d 7.36–7.25 (m,

3H), 6.72 (d, 1H, J=8.2), 6.60 (d, 1H, J=8.25), 4.68–

4.65 (m, 1H), 4.38–4.30 (m, 2H), 4.10–4.04 (m, 1H),

3.53–3.41 (m, 2H), 2.40–2.22 (m, 1H), 2.08–1.92 (m, 1H),

1.60–1.40 (m, 4H), 1.15–0.90 (m, 3H); LC/MS m/z

310.14 (MH⁺) as a single homogeneous peak.

5.9.18. (ꢂ)-2-Propyl-8,9-dihydroxy-2,3,7,11b-tetrahydro-

1H-dibenz[de,h]isoquinoline, (ꢂ)-2-Propyldinapsoline hy-

drobromide (35b). Simiarly, 35b was prepared from 34b

in 88% yield: ¹H NMR (CD₃OD) d 7.36 (d, 1H,

J=7.1), 7.29 (t, 1H, J=7. 6), 7.13 (d, 1H, J=7.4), 6.72

(d, 1H, J=8.2), 6.62 (d, 1H, J=8.2), 4.69 (d, 1H,

J=14.7), 4.55–4.49 (m, 1H), 4.42 (d, 1H, J=18.0), 4.20–

4.10 (m, 1H), 3.58–3.38 (m, 5H), 1.98 (q, 2H, J=7.53,

15.4), 1.13 (t, 3H, J=7.4); LC/MS m/z 296.15 (MH⁺)

as a single homogeneous peak.

5.9.23. (ꢂ)-2,3-Dimethyl-8,9-methylenedioxy-2,3,7,11b-

tetrahydro-1H-dibenz[de,h]isoquinoline (34g). To a solu-

tion of 10 (0.3 g) in warm dichloroethane (10 mL), was

added CH₃I (2.4 mL). The reaction was warmed to

40 ^ꢁC for 30 min and a yellow-orange suspension was

formed. All the volatile solvents were removed by a

stream of nitrogen and the residue was dried under high

vacuum. The residue was resuspended in THF, cooled

to ꢀ78 ^ꢁC and methyllithium (2.5 mL, 1.4 M in diethyl

ether) was added. The solution was stirred for 20 min at

ꢀ78 ^ꢁC, then slowly warmed to 0 ^ꢁC for an hour. Satu-

rated NH₄Cl (10 mL) and hydrochloric acid (2 N, 10

mL) were added to the solution followed by sodium

cyanoborohydride (0.72 g). The organic layer was sepa-

rated and concentrated, the desired product was

obtained after a ﬂash silica gel (type-H) column eluted

with mixtures of hexanes and ethyl acetate to give 34g in

5.9.19. 8-Methyl-12H-benzo[de]-1,3-benzodioxol[4,5-h]-

isoquinoline (33d). To a solution of 10 (0.15 g) in a 1:1

(v/v) mixture of diethyl ether/THF (7 mL) was added

boron triﬂuoride etherate (0.11 mL). The mixture was

cooled to ꢀ78 ^ꢁC, and methyllithium (0.61 mL, 1.4 M in

ether) was added dropwise. Stirring was continued for

an hour at ꢀ78 ^ꢁC, then saturated NH₄Cl solution was

added to quench the reaction. The mixture was allowed

to warm to room temperature, the aqueous layer was

extracted (2ꢃ10 mL) with ethyl acetate, and the com-

bined organic layers were washed with saturated NaCl

solution, dried over sodium sulfate, ﬁltered, and con-

centrated. Puriﬁcation was performed by silica column

chromatography to obtain the fully aromatized form of

1

71%: H NMR (CDCl₃) d 7.20–7.11 (m, 3H), 6.73 (q,

2H, J=8.2, 13.1), 5.97 (dd, 2H, J=1.2, 23.2), 4.09 (d,

1H, J=17.3), 3.99-3.94 (m, 1H), 3.74 (dd, 1H, J=5.4,

11.2), 3.66 (dd, 1H, J=3.6, 17.3), 3.52–3.47 (m, 1H), 2.73

(t, 1H, J=11.0), 2.64 (s, 3H), 1.56 (d, 3H, J=6.4); LC/

MS m/z 294.15 (MH⁺) as a single homogeneous peak.

1

33d in 37% yield: H NMR (CDCl₃) d 8.83 (s, IH),

7.94–7.91 (m, 1H), 7.61–7.52 (m, 3H), 6.84 (d, 1H,

J=8.4), 6.06 (s, 2H), 4.39 (s, 2H), 2.91 (s, 3H); LC/MS

m/z 276.15 (MH⁺) as a single homogeneous peak.

5.9.24. (ꢂ)-2,3-Dimethyl-8,9-dihydroxy-2,3,7,11b-tetra-

hydro-1H-dibenz[de,h]isoquinoline, (ꢂ)-2,3-dimethyldi-

napsoline hydrobromide (35g). Likewise the desired

product was obtained as described above in 95% yield:

¹H NMR (CD₃OD) d 7.35–7.24 (m, 3H), 6.72 (d, 1H,

J=8.2), 6.63 (d, 1H, J=7. 6), 5.67–5.55 (m, 1H), 4.42

(d, 1H, J=17.6), 4.15–4.05 (m, 1H), 3.65–3.46 (m, 2H),

3.35–3.20 (m, 4H), 1.84 (d, 3H, J=6.4); LC/MS m/z

282.23 (MH⁺) as a single homogeneous peak.

5.9.20. (ꢂ)-3-Methyl-8,9-dihydroxy-2,3,7,11b-tetrahy-

dro-1H-dibenz[de,h]isoquinoline, (ꢂ)-3-methyldinapso-

line hydrobromide (35d). The reduction and the

subsequent deprotection were carried out as previously

1

described to give 35d in 75% yield: H NMR (CD₃OD)

d 7.37–7.24 (m, 3H), 6.71 (d, 1H, J=8.0), 6.58 (d, 1H,

J=8.0), 4.72–4.65 (m, 1H), 4.45–4.34 (m, 2H), 4.12–4.03

(m, 1H), 3.55–3.43 (m, 2H), 1.78 (d, 3H, J=6.7); LC/MS

m/z 268.16 (MH⁺) as a single homogeneous peak.

5.9.25.

8-Perﬂuorobutyl-12H-benzo[de]-1,3-benzo-

dioxol[4,5-h]isoquinoline (33h). To a suspension of 10

(0.2 g) in ether (8 mL) was added boron triﬂuoride ethe-

rate (0.19 mL). The reaction was cooled to ꢀ78 ^ꢁC, then

perﬂuorobutyl iodide (0.26 mL) was added, followed by

methyllithium (1.1 mL, 1.4 M in diethyl ether) dropwise.

Stirring was continued for an hour at ꢀ78 ^ꢁC before

quenching with saturated NH₄Cl solution. Extractive

workup and concentration gave a gummy crude product

that was further puriﬁed by a silica gel (Type-H) column

to give 9% of the desired product, with the remaining

mass being mostly unreacted starting material: ¹H NMR

(CDCl₃) d 9.08 (s, 1H), 6.96 (d, 1H, J=8.2), 7.69–7.64 (m,

3H), 6.89 (d, 1H, J=8.3), 6.11 (s, 2H), 4.56 (s, 2H); LC/

MS m/z 480.07 (MH⁺) as a single homogeneous peak.

5.9.21. 8-Butyl-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-

quinoline (33e). Likewise 10 was treated with n-butyl

lithium to give 33e in 46% yield: H NMR (CDCl₃) d

8.86 (s, 1H), 8.03 (d, 1H, J=6.8), 7.63–7.59 (m, 3H),

6.87 (d, 1H, J=8.3), 6.08 (s, 2H), 4.44 (s, 2H), 3.33 (t,

2H, J=7.6), 1.89–1.82 (m, 2H), 1.58–1.46 (m, 2H), 1.00

(t, 3H, J=7.3); LC/MS m/z 318.15 (MH⁺) as a single

homogeneous peak.

1

5.9.22. (ꢂ)-3-Butyl-8,9-dihydroxy-2,3,7,11b-tetrahydro-

1H-dibenz[de,h]isoquinoline (34e) and (ꢂ)-3-n-butyldi-

napsoline hydrobromide (35e). The reduction and the

subsequent deprotection were performed as previously

1

described to give 34e in 95% yield: H NMR (CDCl₃) d

7.33–7.31 (m, 2H), 7.15–7.13 (m, 1H), 6.74 (d, 1H,

J=8.0), 6.63 (d, 1H, J=8.0), 5.99 (dd, 2H, J=1.1, 20.9),

4.56–4.50 (m, 1H), 4.29–4.10 (m, 3H), 3.68 (dd, 1H,

5.9.26.

2,3,7,11b-tetrahydro-1H-dibenz[de,h]isoquinoline (34h).

Using the catalytic hydrogenation procedure (PtO₂/

(ꢂ)-3-Perﬂuorobutyl-8,9-methylenedioxy-

730

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

HOAc/H₂, Method B) described for compound (ꢂ)-

11,²34h was obtained in 74% yield: ¹H NMR (CDCl₃) d

7.36–7.31 (m, 1H), 7.27–7.17 (m, 2H), 6.71 (q, 2H, J=8.2,

15.3), 5.99 (dd, 2H, J=1.4, 27.3), 4.68 (dd, 1H, J=6.2,

24.5), 4.16 (d, 1H, J=17.2), 3.86–3.44 (m, 4H); LC/MS

m/z 484.05 (MH⁺) as a single homogeneous peak.

layer was dried over Na₂SO₄. Evaporation of solvent

yielded 36 as a pale yellow solid (7.70 g, 52.4 mmol,

34% yield): mp 48–50 ^ꢁC; MS (ESI) m/z 148 (MH⁺); ¹H

NMR (DMSO-d₆) d 9.33 (s, 1H), 8.51 (d, 1H, J=6.0),

8.25 (dd, 1H, J=9.0, 6.0), 7.83 (d, 1H, J=5.7), 7.77 (dd,

1H, J=10.0, 2.4), 7.60 (td, 1H, J=9.0, 2.4). Anal. calcd

for C₉H₆FN: C, 73.46; H, 4.11; N, 9.52. Found: C,

73.19; H, 3.95, N, 9.49.

5.9.27.

tetrahydro-1H-dibenz[de,h]isoquinoline, ((ꢂ)-3-perﬂuoro-

(ꢂ)-3-Perﬂuorobutyl-8,9-dihydroxy-2,3,7,11b-

butyldinapsoline hydrobromide, 35h). Likewise 35h was

1

5.9.31. ꢀ-(5-Bromo-1,3-benzodioxol-4-yl)-6-ﬂuoro-5-iso-

quinolinemethanol (38). A solution of lithium diisopro-

pylamide (103.0 mL of 1.5 M in cyclohexane, 155.0

mmol) was added dropwise to a cooled (ꢀ78 ^ꢁC) solu-

tion of 6-ﬂuoroisoquinoline in THF (500 mL). The

resulting mixture was stirred at ꢀ78 ^ꢁC under nitrogen

for 150 min followed by addition of 2-bromo-5,6-

methylenedioxybenzaldehyde 3²(37.75 g, 165.0 mmol).

Stirring was continued at ꢀ78 ^ꢁC for 45 min and then at

room temperature for 75 min. The reaction was quen-

ched by adding saturated aqueous NH₄Cl solution. The

product was extracted with ethyl acetate. The organic

layers were combined and dried over Na₂SO₄. Chroma-

tography (silica gel, 50% EtOAc in hexanes) provided

38 as a pale yellow solid (23.0 g, 61.2 mmol, 98% yield):

obtained in 70% yield: H NMR (CD₃OD) d 7.32–7.28

(m, 1H), 7.19–7.12 (m, 2H), 6.67 (d, 1H, J=8.2), 6.56

(d, 1H, J=8.2), 4.71 (dd, 1H, J=7.5, 25.5), 4.36 (d, 1H,

J=17.8), 3.78–3.71 (m, 1H), 3.58–3.53 (m, 1H), 3.41

(dd, 1H, J=3.6, 17.7), 3.28–3.24 (m, 1H); LC/MS m/z

472.17 (MH⁺) as a single homogeneous peak.

5.9.28.

(ꢂ)-2-Methyl-3-butyl-8,9-methylenedioxy-

2,3,7,11b-tetrahydro-1H-dibenz[de,h]isoquinoline (34i).

The experimental procedure was identical to that for

34g except that n-butyllithium (2.5 M in hexanes) was

used instead of methyllithium. Puriﬁcation was per-

formed by column ﬁltration to obtain 34i in 39% yield:

¹H NMR (CDCl₃) d 7.21–7.11 (m, 3H), 6.73 (q, 2H,

J=8.0, 18.8), 5.97 (dd, 2H, J=1.2, 23.3), 4.08 (d, 1H,

J=17.3), 3.95–3.85 (m, 1H), 3.75–3.69 (m, 2H), 3.59–

3.51 (m, 1H), 2.72–2.60 (m, 1H), 2.57 (s, 3H), 2.05–1.85

(m, 2H), 1.41–1.25 (m, 4H), 0.88 (t, 3H, J=7.1); LC/MS

m/z 336.27 (MH⁺) as a single homogeneous peak.

mp 149–152 ^ꢁC; MS (ESI) m/z 377 (MH⁺); H NMR

1

(DMSO-d₆) d 9.30 (s, 1H), 8.52 (d, 1H, J=6.0), 8.40 (d,

1H, J=6.0), 8.18 (dd, 1H, J=9.0, 5.4), 7.50 (dd, 1H,

J=10.8, 9.0), 7.06 (d, 1H, J=8.3), 6.83 (dd, 1H, J=8.1,

3.0), 6.62 (d, 1H, J=5.1), 6.32 (d, 1H, J=5.1), 5.99 (s,

1H), 5.94 (s, 1H). Anal. calcd for C₁₇H₁₁BrFNO₃: C,

54.28; H, 2.95; N, 3.72. Found: C, 53.90; H, 2.76, N,

3.45.

5.9.29. (ꢂ)-2-Methyl-3-butyl-8,9-dihydroxy-2,3,7,11b-

tetrahydro-1H-dibenz[de,h]isoquinoline (35i). Puriﬁca-

tion was achieved by precipitation of product with

1

EtOH/CH₂Cl₂to obtain 35i in 54% yield: H NMR

5.9.32. 6-Fluorodinapsoline hydrobromide (39). Product

38 from the previous step was reduced using the exact

procedure as described for compound 7 to give 6-ﬂuoro-

5-[(5-bromo-1,3-benzodioxol-4-yl)methyl]isoquinoline as

a white solid (84% yield): mp 139–142 ^ꢁC; MS (ESI) m/z

(CD₃OD) d 7.39–7.30 (m, 2H), 7.22 (d, 1H, J=7.3),

6.70 (q, 2H, J=8.2, 17.6), 4.62–4.69 (m, 1H), 4.43–4.36

(m, 2H), 4.20–4.09 (m, 1H), 3.56 (dd, 2H, J=3.7, 17.9),

3.15 (s, 3H), 2.30–2.15 (m, 2H), 1.50–1.10 (m, 4H),

0.98–0.85 (m, 3H); LC/MS m/z 324.20 (MH⁺) as a

single homogeneous peak.

1

361 (MH⁺); H NMR (DMSO-d₆) d 9.31 (s, 1H), 8.51

(d, 1H, J=6.0), 8.18 (dd, 1H, J=9.0, 5.4), 7.90 (d, 1H,

J=6.0), 7.56 (t, 1H, J=8.4), 7.10 (d, 1H, J=8.1), 6.79

(d, 1H, J=8.4), 5.92 (s, 2H), 4.42 (s, 2H). Anal. calcd

5.9.30. 6-Fluoroisoquinoline (36). Aminoacetaldehyde

diethyl acetal (21.0 g, 158 mmol) was added to a solu-

tion of 4-ﬂuorobenzaldehyde (19.2 g, 155 mmol) in

CHCl₃(400 mL). The solvents in the mixture were

removed by distillation, and azeotropic removal of

water. The residue was dissolved in chlorobenzene (250

mL) and the solution was cooled to ꢀ10 ^ꢁC. After

addition of ethyl chloroformate (15.0 mL, 157 mmol),

stirring was continued at ꢀ10 ^ꢁC under N₂for 10 min.

Trimethyl phosphite (22.0 mL, 186 mmol) was added,

and the resulting mixture was warmed to room tem-

perature and stirred under N₂for 40 h. After the solu-

tion was cooled to 0 ^ꢁC, TiCl₄(100.0 g, 527 mmol) was

added slowly. The reaction mixture was stirred at

100 ^ꢁC under N₂for 24 h (precipitates were formed in

about 7 h). After cooling to room temperature, the

mixture was diluted with ethyl acetate and was basiﬁed

in an ice bath using 5 N NaOH. The product was

extracted with a mixture of ethyl acetate and hexanes

(1:2, v/v). The organic layers were re-extracted with 1 N

HCl. The aqueous layer was basiﬁed to pH>10 by 5 N

NaOH and was extracted with CH₂Cl₂. The CH₂Cl₂

.

for C₁₇H₁₁BrFNO₂1.1CH₂Cl₂: C, 47.93; H, 2.93; N,

3.09. Found: C, 48.12; H, 2.66, N, 2.90. Likewise the

free radical initiated cyclization of 39 was carried out as

described for 6-ﬂuoro-5-[(5-bromo-1,3-benzodioxol-4-

yl)methyl]isoquinoline to give 6-ﬂuoro-12H-benzo[de]-

1,3-benzodioxol[4,5-h]isoquinoline in 51% yield): mp

233–235 ^ꢁC; MS (ESI) m/z 280 (MH⁺); ¹H NMR

(DMSO-d₆) d 9.13 (d, 2H, J=9.6), 8.09 (dd, 1H, J=9.0,

5.4), 7.87 (d, 1H, J=8.7), 7.63 (t, 1H, J=9.0), 7.00 (d,

1H, J=9.0), 6.16 (s, 2H), 4.31 (s, 2H). Anal. calcd for

.

C₁₇H₁₀FNO₂0.073HBr: C, 71.59; H, 3.56; N, 4.91.

Found: C, 71.63; H, 3.95, N, 4.78. The NaCNBH₃

reduction was carried out as described for 11 to give

(ꢂ)-8,9-methylenedioxy-2,3,7,11b-tetrahydro-1H-6-

ﬂuoro-dibenz[de,h]isoquinoline in 72% yield: mp 125–

127 ^ꢁC; MS (ESI) m/z 284 (MH⁺); H NMR (DMSO-

1

d₆) d 6.99 (d, 2H, J=7.5), 6.80 (d, 1H, J=8.1), 6.75 (d,

1H, J=8.1), 6.07 (s, 1H), 6.00 (s, 1H), 4.15 (d, 1H,

J=18), 3.96–3.81 (m, 3H), 3.67 (m, 1H), 3.43 (dd, 1H,

J=18, 3.6), 2.82 (dd, 1H, J=12.0, 10.8). Finally, the

methylenedioxy protecting group was removed by BBr₃

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

731

deprotection to furnish the desired product as a pale

white solid in 84% yield: mp>275 ^ꢁC; MS (ESI) m/z

349 mmol). After addition was complete, the reaction

was brought to reﬂux for 36 h. After cooling to room

temperature, the reaction was poured into 4 equiv of

10 M NaOH, with cooling as necessary. The thick resi-

due was ﬁltered over sand, and washed with methanol

and then CH₂Cl₂. The ﬁltrate was concentrated; the

resulting aqueous suspension was extracted three times

with methylene chloride and the combined organic

extracts were dried over MgSO₄. The extracts were

concentrated in vacuo, and ﬁnally puriﬁed by silica gel

chromatography eluted with mixtures of hexanes/ethyl

1

272 (MH⁺); H NMR (DMSO-d₆) d 9.33 (br. s, 3H),

8.64 (s, 1H), 7.17 (m, 2H), 6.73 (d, 1H, J=8.1), 6.57 (d,

1H, J=8.1), 4.48 (d, 1H, J=19.2), 4.35–4.25 (m, 3H),

4.00 (m, 1H), 3.32–3.17 (m, 2H). Anal. calcd for

.

C₁₆H₁₄FNO₂0.95HBr 0.40H₂O: C, 54.08; H, 4.47; N,

3.94. Found: C, 53.78; H, 4.30, N, 3.68.

5.9.33. Chiral separation of (ꢂ)-8,9-methylenedioxy-

2,3,7,11b-tetrahydro-1H-6-ﬂuoro-dibenz[de,h]isoquino-

line, (ꢂ)-39. The following HPLC chiral separation

procedure is essentially identical to the one described

previously. Preparative HPLC on a Chiralcel OD col-

umn using 5% EtOH/hexanes+0.1% diethylamine at a

ﬂow rate of 65 mL/min was employed with a loading

per run up to 1 g/10 mL EtOH per injection. Baseline

separation was achieved under these conditions. (ꢀ)-8,9-

methylenedioxy - 2,3,7,11b - tetrahydro - 1H - 6 - ﬂuor-

odibenz[de,h]isoquinoline was obtained as a white solid

(89% recovery): mp 163–165 ^ꢁC; [a]_Dꢀ83.5^ꢁ(c 0.010,

MeOH); chiral analytical HPLC was performed on an

analytical Chiralcel OD column at a reduced ﬂow rate;

enantiomeric purity was estimated to be in excess of

99%, with no discernible signal from the other enantio-

mer. Anal. calcd for C₁₇H₁₄FNO₂: C, 72.07; H, 4.98; N,

1

acetate to provide 9.65 g (35%) of pure product. H

(CDCl₃) d 9.64 (s, 1H), 8.65 (d, 1H, J=6.2), 7.97 (d, 1H,

J=6.2), 7.90 (d, 1H, J=8.4), 6.83 (d, 1H, J=8.4), 4.05

(s, 3H).

5.10.2. 8-Methoxyisoquinoline-5-carboxaldehyde. The

formylation was done essentially as described in Scheme

1

2 to give 75% yield of the desired product: H (CDCl₃)

d 10.22 (s, 1H), 9.71 (s, 1H), 9.07 (d, 1H, J=6.0), 8.73

(d, 1H, J=6.0), 8.16 (d, 1H, J=8.2), 7.04 (d, 1H,

J=8.2), 4.16 (s, 3H).

5.10.3. ꢀ-(5-Bromo-1,3-benzodioxol-4-yl)-8-methoxy-5-

isoquinolinemethanol (46). The condensation was per-

formed in accordance with the procedure described in

Scheme 2, and the desired product was isolated in 68%

1

4.94. Found: C, 71.80; H, 5.00, N, 4.71; MS and H

1

NMR (identical to the racemate). Likewise (+)-8,9-

methylenedioxy - 2,3,7,11b - tetrahydro - 1H - 6 - ﬂuor-

odibenz[de,h]isoquinoline was resolved with 90%

recovery: [a]_D+82.8^ꢁ(c 0.010, MeOH); chiral analytical

HPLC (single peak); mp, elemental analysis, MS and ¹H

NMR were identical to that of the (ꢀ)-enantiomer.

yield: H (CDCl₃) d 9.62 (s, 1H), 8.59 (d, 1H, J=6.2),

8.06 (d, 1H, J=6.2), 7.34 (d, 1H, J=8.3), 7.10 (d, 1H,

J=8.3), 6.76 (d, 1H, J=8.2), 6.72 (d, 1H, J=8.3), 6.66

(br s, 1H), 5.98 (d, 1H, J=1.3), 5.94 (d, 1H, J=1.3),

4.00 (s, 3H), 3.5 (br s, 1H).

5.10.4. 5-[(5-Bromo-1,3-benzodioxol-4-yl)methyl]-8-meth-

oxyisoquinoline. The silane reduction was done as

described in Scheme 3; the desired product was obtained

5.9.34. Chiral 6-ﬂuorodinapsoline hydrobromide. The

resolved (ꢀ) and (+)-isomers from above were depro-

tected as usual to give (ꢀ)-6-ﬂuorodinapsoline hydro-

bromide as a pale solid (84% yield): [a]_Dꢀ43.5^ꢁ(c 0.010,

MeOH) and (+)-6-ﬂuorodinapsoline in 68% yield: [a]_D

+42.8^ꢁ(c 0.010, MeOH). NMR, MS and CHN of these

compounds were identical to that of racemate.

1

in 79% yield: H (CDCl₃) d 9.67 (s, 1H), 8.61 (d, 1H,

J=6.1), 7.94 (d, 1H, J=6.1), 7.14 (d, 1H, J=8.1), 7.12

(d, 1H, J=8.3), 6.79 (d, 1H, J=8.1), 6.69 (d, 1H,

J=8.3), 5.94 (s, 2H), 4.37 (s, 2H), 4.00 (s, 3H).

5.10.5. 9-Methoxy-12H-benzo[de]-1,3-benzodioxolo[4,5-h]

isoquinoline (49). The free radical initiated cyclization

was carried out in exactly the same way as described for

compound 10 in Scheme 3; the desired product was

isolated in about 15% yield along with uncyclized start-

ing material and some des-bromo byproduct: ¹H

(CDCl₃) d 9.41 (s, 1H), 8.95 (s, 1H), 7.61 (d, 1H, J=8.4),

7.50 (dt, 1H, J=1.5, 7.9), 6.90 (d, 1H, J=8.0), 6.84 (d,

1H, J=8.3), 6.06 (br s, 2H), 4.33 (s, 2H), 4.02 (s, 3H).

5.10. Preparation of 4-hydroxydinapsoline hydrobromide

(55)

5.10.1. 5-Bromo-8-methoxy isoquinoline (41). A solution

of 3-bromo-6-methoxybenzaldehyde (25.0 g, 116 mmol)

and aminoacetaldehyde diethyl acetal (15.5 g, 117

mmol) in benzene (200 mL) was heated to reﬂux in a

Dean-Stark apparatus. Approximately 1 equivalent of

water was collected after 2 h. The reaction was cooled to

room temperature, and the solvent removed in vacuo.

The resulting material was dissolved in THF (100 mL)

and cooled to ꢀ10 ^ꢁC. Ethyl chloroformate (11.8 mL,

123 mmol) was added over 5 min. After 10 min of

additional stirring, the ice bath was removed. Tri-

methylphosphite (17.5 mL, 148 mmol) was then added,

the reaction was allowed to stir for another 16 h, and

the solvents were removed in vacuo. Toluene was added

and removed in vacuo, and the process was repeated

twice to remove residual trimethylphosphite. The resi-

due was redissolved in chloroform (220 mL) followed by

the SLOW addition of titanium (IV) chloride (38.3 mL,

5.10.6.

(ꢂ)-4-Methoxy-8,9-methylenedioxy-2,3,7,11b-

tetrahydro-1H-dibenz[de,h]isoquinoline (52). The selec-

tive ring reduction was done in essentially the same way

as described for compound 11 in Scheme 3; the desired

1

product was isolated in 52% yield: H (CDCl₃) d 7.14

(d, 1H, J=8.2), 6.73–6.67 (m, 3H), 6.00 (d, 1H, J=1.4),

5.92 (d, 1H, J=1.4), 4.27–3.05 (m, 7H), 3.80 (s, 3H),

2.24 (br s, 1H).

5.10.7. 4-Hydroxydinapsoline hydrobromide (55). To a

solution of 52 (40.9 mg, 139 mmol) in 2 mL CH₂Cl₂at

ꢀ78 ^ꢁC was added a 1 M solution of boron tribromide

732

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

(665 mL, 665 mmol) dropwise. The solution was stirred

at this temperature for 4 h, and was then allowed to

warm to room temperature. After 16 h, the reaction was

chilled to ꢀ78 ^ꢁC, followed by the slow addition of dry

methanol (2 mL). The solvents were removed in vacuo.

More methanol was added, and the mixture was

brought to reﬂux for an h. The solvents were removed in

vacuo. Chromatography on C₁₈media using water as

eluent provided the desired pure compound, 25.0 mg

(42%): ¹H (CD₃OD) d 7.17 (d, 1H, J=8.2), 6.73 (d, 1H,

J=8.2), 6.72 (d, 1H, J=8.1), 6.60 (d, 1H, J=8.3), 5.1–

4.7 (m, solvent, 4H), 4.51–4.04 (m, 6H), 3.45–3.32 (m,

solvent, 1H); ¹³C (CD₃OD) d 151.97, 143.63, 141.87,

132.47, 127.21, 127.01, 126.90, 124.19, 113.58, 113.35,

112.21, 112.05, 48.35–46.65 (solvent), 44.32, 33.25, 27.29.

1H), 7.81 (d, J=8.4, 1H), 7.91 (d, J=8.4, 1H), 9.03 (d,

J=6.9, 2H). ¹³C NMR (DMSO-d₆) d 13.51, 24.55,

25.61, 101.89, 107.74, 116.42, 117.03, 123.38, 123.73,

125.50, 126.72, 128.56, 129.580, 136.02, 142.88,

145.52,

147.01,

.

150.72.

Anal.

calcd

for

.

C₁₉H₁₅NO₂0.073H₂0 0.049C₆H₁₆NBr: C, 77.355; H,

5.361; N, 4.905. Found: C, 77.41; H, 5.52; N, 5.12.

5.11.5.

6-Ethyldinapsoline

hydrobromide

(56).

NaCNBH₃reduction of 50 was conducted as usual to

give 53. This compound was obtained as yellow crystals

(57% yield): MS m/z 294.17 (MH⁺). ¹H NMR (DMSO-

d₆) d 1.17 (t, 3H), 2.71 (q, 2H), 2.91 (t, 1H), 3.92 (m,

4H), 4.17 (d, J=17.4, 1H), 6.01 (s, 1H), 6.04 (s, 1H),

6.76 (t, 2H), 6.87 (d, J=7.7, 1H), 6.995 (d, J=7.7, 1H).

The 6-ethyldinapsoline was obtained by the standard

BBr₃deprotection procedure. Compound 56 was

obtained as a yellow solid (24% yield): MS m/z 282.16

5.11. Preparation of 6-ethyldinapsoline hydrobromide

(56)

1

(MH⁺). H NMR (DMSO-d₆) d 1.19 (t, 3H), 2.75 (q,

5.11.1. 6-Ethylisoquinoline (42). This compound was

obtained as an orange oil (57% yield): MS (ESI) m/z

158 (MH⁺); ¹H NMR (DMSO-d₆) d 9.22 (d, 1H,

J=4.0), 8.44 (d, 1H, J=6.0), 8.00 (dd, 1H, J=9.0, 6.0),

7.70 (m, 2H), 7.53 (dd, 1H, J=10.0, 2.4), 2.76 (q, 2H,

J=7.5), 1.22 (t, 3H, J=7.5).

2H), 3.47 (t, 1H), 4.11 (m, 1H), 4.39 (m, 3H), 4.68 (d,

J=18.15, 1H), 6.61 (d, J=7.83, 1H), 6.73 (d, J=8.28,

1H), 7.07 (d, J=7.95, 1H), 7.17 (d, J=7.86, 1H), 8.57

(s, 1H), 9.26 (s, 1H). ¹³C NMR (CD₃OD) d 14.62, 15.69,

25.53, 27.46, 35.11, 46.44, 46.69, 114.05, 115.27,

124.99, 125.42, 125.75, 128.51, 128.69, 133.43, 136.26,

142.54, 145.25, 145.27, 145.33. Anal. calcd for

.

5.11.2. 5-Bromo-6-ethylisoquinoline (43). This com-

pound was prepared in accordance with the bromina-

tion procedure as described previously.²The

brominated desired product was obtained as an orange

C₁₈H₁₉NO₂1.1HBr: C, 58.38; H, 5.47; N, 3.78. Found:

C, 58.50; H, 5.63; N, 3.78.

5.12. Preparation of 4-ﬂuorodinapsoline hydrobromide (57)

1

solid (70% yield): H NMR (DMSO-d₆) d 9.26 (s, 1H),

8.57 (d, 1H, J=6.0), 8.06 (d, 1H, J=8.4), 7.90 (d, 1H,

J=6.0), 7.62 (d, 1H, J=8.4), 2.91 (q, 2H, J=7.5), 1.22

(t, 3H, J=7.5).

5.12.1. 8-Amino-5-bromoisoquinoline (44). To a solution

of 21 (29 g, 0.115 mol) in methanol (380 mL) heated to

reﬂux, a solution of NH₄Cl (30 g, 0.578 mol) in H₂O

(130 mL) was added followed by Fe^ꢁ(iron powder, 21.8

g, 0.391 mol). The mixture was allowed to stir for 3 h,

after which the hot reaction mixture was ﬁltered over

Celite. The ﬁltrate was evaporated and the residue was

triturated in methanol to give a brown solid 44 (15.4 g,

5.11.3. ꢀ-(5-Bromo-1,3-benzodioxol-4-yl)-6-ethyl-5-iso-

quinolinemethanol (47). This compound was obtained

as a brown gum (24% yield): MS m/z 386.05 (MH⁺).

¹H NMR (DMSO-d₆) d 1.10 (t, 3H), 2.90 (q, 2H), 5.75

(s, 1H), 5.79 (s, 1H), 6.23 (d, J=5.13, 1H), 6.63 (d,

J=5.13, 1H), 6.82 (d, J=8.25, 1H), 7.13 (d, J=8.28,

1H), 7.49 (d, J=8.43, 1H), 7.97 (d, J=8.34, 1H), 8.33

(d, J=6.21, 1H), 8.39 (d, J=6.18, 1H), 9.18 (s, 1H). ¹³C

NMR (DMSO-d₆) d 15.42, 27.09, 70.24, 101.45, 109.11,

115.13, 119.05, 125.30, 126.04, 127.74, 133.87, 135.14,

142.33, 143.63, 145.24, 146.82, 147.78, 152.77.

1

62%): H NMR: d 9.27 (1H, s), 8.61 (1H, d, J=6.0),

7.92 (1H, d, J=6.0), 7.72 (1H, d, J=8.1), 6.71 (1H, d,

J=8.1); LC/MS m/z 222.92 (MH⁺) as a single homo-

geneous peak.

5.12.2. 5-Bromo-8-ﬂuoroisoquinoline (45). To a solution

of 44 (15.4 g, 69.4 mmol) in HBF₄(74.4 mL) at ꢀ5 ^ꢁC

was added dropwise a solution of NaNO₂in 20 mL

H₂O. The reaction was stirred for 2 h, ﬁltered, and

washed with cold Et₂O, ethanol, and Et₂O. The residue

was dried overnight under vacuum followed by a pyr-

olysis of the neat material under vacuum at about

120 ^ꢁC. The tarry residue was then taken up in 2 N HCl

and extracted with CH₂Cl₂. The aqueous layer was

adjusted to pH 8 followed by extraction with CH₂Cl₂;

the extract was dried over MgSO₄and evaporated. The

residue was puriﬁed by ﬂash chromatography on silica gel

eluted with 10% EtOAc in hexane to give a white solid 45

5.11.4. 11-Ethyl-12H-benzo[de]-1,3-benzodioxolo[4,5-h]-

isoquinoline (50). Silane deoxygenation of 47 (precursor

of 50). This compound was obtained as a yellow solid

(19% yield): MS m/z 372.08 (MH⁺). ¹H NMR (DMSO-

d₆) d 1.12 (t, 3H), 2.88 (q, 2H), 4.46 (s, 2H), 5.65 (s, 2H),

6.76 (d, J=8.3, 1H), 7.15 (d, J=8.3, 1H), 7.54 (d,

J=8.4, 1H), 7.78 (d, J=6, 1H), 7.96 (d, J=8.4, 1H),

8.41 (d, J=6.1, 1H), 9.2 (s, 1H). ¹³C NMR (DMSO-d₆)

d 15.22, 27.02, 29.48, 101.48, 108.43, 115.50, 117.32,

121.92, 125.74, 126.95, 127.51, 129.32, 130.36, 135.40,

143.12, 145.60, 147.09, 147.18, 152.90. Anal. calcd for

C₁₉H₁₆BrNO₂: C, 61.64; H, 4.36; N, 3.78. Found: C,

61.65; H, 4.54; N, 3.65. Compound 50 was obtained as a

1

(500 mg, 3%): H NMR: d 9.54 (1H, s), 8.74 (1H, d,

J=6.0), 8.00–7.89 (2H, m), 7.17 (1H, dd, J=8.5, 9.7);

LC/MS m/z 207.86 (MH⁺) as a single homogeneous peak.

1

brown gum (18% yield): MS m/z 290.13 (MH⁺). H

NMR (DMSO-d₆) d 1.27 (t, 3H), 2.76 (q, 2H), 4.23 (s,

2H), 6.13 (s, 2H), 6.95 (d, J=8.3, 1H), 7.57 (d, J=8.34,

5.12.3. ꢀ-(5-Bromo-1,3-benzodioxol-4-yl)-8-ﬂuoro-5-iso-

quinolinemethanol (48). Step 1: Preparation of 8-Fluoro-

S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734

733

isoquinoline-5-carboxaldehyde. The formylation was

done in essentially the same way as compound 8 in

Scheme 2 to give 57% yield of the desired product: H

References and notes

1

1. Qandil, A. M.; Lewis, M. M.; Jassen, A.; Leonard, S. K.;

Mailman, R. B.; Nichols, D. E. Bioorg. Med. Chem. 2003,

11, 1451.

2. Sit, S. Y.; Xie, K.; Jacutin-Porte, S.; Taber, M. T.; Gul-

wadi, A. G.; Korpinen, C. D.; Burris, K. D.; Molski,

T. F.; Ryan, E.; Xu, C.; Wong, H.; Zhu, J.; Krishna-

nanthan, S.; Gao, Q.; Verdoorn, T.; Johnson, G. J. Med.

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NMR: d 10.32 (1H, s), 9.64 (1H, s), 9.09 (1H, d, J=6.0),

8.82 (1H, d, J=6.0), 8.22 (2H, dd, J=5.4, 8.1), 7.41

(1H, dd, J=8.1, 9.5). (Step 2) The condensation was

performed in accordance with the preparation of com-

pound 7 in Scheme 2, the desired product was isolated

1

in 47% yield: H NMR (CDCl₃) d 9.57 (1H, s), 8.67

(1H, d, J=6.1), 8.09 (1H, d, J=4.4), 7.49–7.44 (1H, m),

7.15–7.12 (2H, m), 6.77–6.70 (2H, m), 6.0 (1H, s), 5.92

(1H, s); LC/MS m/z 375.96 (MH⁺) as a single homo-

geneous peak.

3. Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.;

Nichols, D. E. J. Med. Chem. 1996, 39, 549.

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Humana: Totowa, NJ, 1997.

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Eur. J. Pharmacol. 1978, 50, 419.

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S. B.; Nichols, D. E.; Mailman, R. B. Eur. J. Pharmacol.

1993, 242, 165.

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5.12.4. 9-Fluoro-12H-benzo[de]-1,3-benzodioxolo[4,5-h]-

isoquinoline (51). Step 1: 5-[(5-Bromo-1,3-benzodioxol-

4-yl)methyl]-8-ﬂuoroisoquinoline. The silane reduction

was done in a procedure essentially identical to that

described for compound 9 in Scheme 3; the desired

1

product was obtained in 61% yield: H (CDCl₃) d 9.57

(1H, s), 8.69 (1H, d, J=6.1), 7.97 (1H, d, J=6.1), 7.15–

7.11 (3H, m), 6.71 (1H, d, J=8.3), 5.95 (2H, s), 4.42

(2H, s); LC/MS m/z 360.04 (MH⁺). Step 2: The free

radical-initiated cyclization was carried out in exactly

the same way as described for compound 10 in Scheme

3; the desired product was isolated in about 15% yield

along with uncyclized, des-bromo byproduct: ¹H

(CDCl₃) d 9.33 (1H, s), 9.02 (1H, s), 7.65 (1H, d,

J=8.4), 7.57–7.53 (1H, m), 7.27–7.21 (1H, m), 6.88,

(1H, d, J=8.4), 6.09 (2H, s), 4.40 (2H, s); LC/MS m/z

280.14 (MH⁺) as a single homogeneous peak.

5.12.5. (ꢂ)-4-Fluoro-8,9-methylenedioxy-2,3,7,11b-tetra-

hydro-1H-dibenz[de,h]isoquinoline (54). The selective

ring reduction was done in essentially the same way as

described for compound 11 in Scheme 3; the desired

1

product was isolated in 52% yield: H (CDCl₃) d 7.15–

7.11 (1H, m), 6.86 (1H, dd, J=9.0, 8.1), 6.72 (2H, s),

6.02 (1H, s), 5.94 (1H, s), 4.08–4.00 (3H, m), 3.75–3.71

(1H,m), 3.61–3.55 (1H, m), 3.10 (1H, dd, J=10.7, 12.0),

2.24 (1H, bs); LC/MS m/z 283.99 (MH⁺) as a single

homogeneous peak.

17. Gulwadi, A. G.; Korpinen, C. D.; Mailman, R. B.;

Nichols, D. E.; Sit, S. Y.; Taber, M. T. J. Pharmacol. Exp.

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J. Pharmacol. Exp. Ther. 2002, 301, 1179.

5.12.6. 4-Fluorodinapsoline hydrobromide (57). The BBr₃

deprotection was performed in essentially the same way

as described for compound 55, the desired product was

1

obtained in 45% yield: H (CD₃OD) d 7.37 (1H, dd,

J=5.6, 8.1), 7.06 (1H, dd, J=9.0, 8.2), 6.72 (1H, d,

J=8.2), 6.01 (1H, d, J=8.2), 4.56 (1H, d, J=16), 4.43–

4.35 (3H, m), 4.08–4.05 (1H, m), 3.50–3.42 (2H, m).

.

Anal. calcd for C₁₆H₁₄FNO₂HBr: C, 54.56; H, 4.29; N,

3.98; Br, 22.69. Found: C, 54.32; H, 4.36; N, 3.94; Br,

22.71; IR (KBr, cm^ꢀ1) 3408, 3295; LC/MS m/z 272.12

(MH⁺) as a single homogeneous peak.

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Acknowledgements

Microanalyses, X-ray analyses, IR spectra, and mass

spectra were kindly provided for by the Bristol-Myers

Squibb Department of Analytical Research and Devel-

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NIH grants MH40537, MH42705, and NS39036.

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Article Doi

Synthesis and SAR exploration of dinapsoline analogues

DOI: 10.1016/j.bmc.2003.11.015

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