Enantioselective synthesis of 1-methoxy- and 1-deoxy-2′-methyl- Δ8-tetrahydrocannabinols: New selective ligands for the CB 2 receptor

Bioorganic & Medicinal Chemistry 14 (2006) 247–262

Enantioselective synthesis of 1-methoxy- and

1-deoxy-2⁰-methyl-D⁸-tetrahydrocannabinols: New selective

ligands for the CB₂receptor

John W. Huﬀman,^a,*Simon M. Bushell,^aSudhir N. Joshi,^a

Jenny L. Wiley^band Billy R. Martin^b

^aHoward L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA

^bDepartment of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University,

Richmond, VA 23298-0613, USA

Received 22 July 2005; accepted 3 August 2005

Available online 13 September 2005

Abstract—Two new series of cannabinoids were prepared and their aﬃnities for the CB₁and CB₂receptors were determined. These

series are the (2⁰R)- and (2⁰S)-1-methoxy- and 1-deoxy-3-(2⁰-methylalkyl)-D⁸-tetrahydrocannabinols, with alkyl side chains of three

to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol

precursors to the cannabinoid ring system. All of these compounds have greater aﬃnity for the CB₂receptor than the CB₁receptor

and four of them, (2⁰R)-1-methoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-359), (2⁰S)-1-deoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-352),

(2⁰S)-1-deoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-255), and (2⁰R)-1-deoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-255), have good

aﬃnity (K_i= 13–47 nM) for the CB₂receptor and little aﬃnity (K_i= 1493 to >10,000 nM) for the CB₁receptor. In the 1-deoxy-

3-(2⁰-methylalkyl)-D⁸-THC series, the 2⁰S-methyl compounds in general have greater aﬃnity for the CB₂receptor than the corre-

sponding 2⁰R isomers.

1. Introduction

Until recently, the role of the CB₂receptor was not well

deﬁned. It is known that cannabinoids are involved

in immunomodulation and since the CB₂receptor is

expressed primarily in the immune system it has been

suggested that this receptor is responsible for the immu-

nomodulatory eﬀects of cannabinoids,¹⁴a conclusion

that is supported by the fact that these immunomodula-

tory eﬀects are absent in CB₂receptor knockout mice.¹⁵

There is also evidence that the CB₂receptor is involved

in inﬂammatory pain^16–23and it has been implicated

in cardioprotection.²⁴Both CB₁and CB₂receptors

are expressed in various cancer cells, and cannabinoid

receptor agonists have been found to inhibit tumor

growth.^25,26In particular, CB₂receptors are expressed

in C6 glioma cells,²⁷and both CB₁and CB₂receptors

are expressed in nonmelanoma skin cancer cells.²⁸

A highly selective CB₂receptor ligand, 3-(1⁰,1⁰-dim-

ethylbutyl)-D⁸-tetrahydrocannabinol (3-(1⁰,1⁰-dimethylbu-

tyl)-D⁸-THC, JWH-133, 1), causes the regression of both

glioma tumors and nonmelanoma skin tumors.^27,28

The CB₂receptor has recently been found to be associ-

ated with osteoporosis.^29,30Although a number of high-

ly selective CB₂receptor agonists of several structural

Cannabinoids exhibit a complex array of pharmacolog-

ical eﬀects that are generally considered to be mediated

through at least two G-protein coupled receptors. One

of these receptors, designated CB₁, is found principally

in the central nervous system while the other, designated

CB₂, is expressed primarily in the periphery.^1–5Recently,

evidence has been presented that indicates the existence

of an additional cannabinoid receptor or receptors.^6–9It

is generally accepted that the CB₁receptor is responsible

for most of the overt pharmacological eﬀects of cannab-

inoids and there is good correlation between CB₁recep-

tor aﬃnity and the in vivo activity of cannabinoids.^10,11

These eﬀects are blocked by the cannabinoid antagonist

SR141716A and are absent in CB₁receptor knockout

mice.^12,13

Keywords: Cannabinoids; Structure–activity relationships; Cannabi-

noid receptors; Enantioselective synthesis.

*

Corresponding author. Tel.: +1 864 65 63 133; fax: +1 864 65 66

613; e-mail: huﬀman@clemson.edu

doi:10.1016/j.bmc.2005.08.013

248

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

types have been described, the structure–activity rela-

tionships (SAR) at the CB₂receptor are not as well de-

ﬁned as those at the CB₁receptor.^31,32

well known that a geminal dimethyl substituent at

C-1⁰increases CB₁receptor aﬃnity in the D⁸-THC

series as it does at the CB₂receptor in the correspond-

ing 1-methoxy and 1-deoxy analogs.^34,35,38To further

explore the structure–activity relationships at the

cannabinoid CB₂receptor and to develop additional

high aﬃnity ligands for that receptor with little aﬃnity

for the CB₁receptor, the enantioselective synthesis of

the 3-(2⁰-methylalkyl)-1-deoxy- and 1-methoxy-D⁸-

THCs has been carried out, and their CB₁and CB₂

receptor aﬃnities have been determined.

Based upon the observation that 3-(1⁰, 1⁰-dimethylhep-

tyl)-1-deoxy-11-hydroxy-D⁸-THC (2, JWH-051) and

3-(1⁰,1⁰-dimethylheptyl)-1-deoxy-D⁸-THC (3, JWH-057)

show 37-fold and nearly 8-fold selectivity, respectively,

for the CB₂receptor,³³we synthesized a number of 1-de-

oxy- and 1-methoxy-D⁸-THC analogs.^34,35Several of

these compounds show very high selectivity for the CB₂

receptor with little aﬃnity for the CB₁receptor. Among

the most selective compounds are JWH-133 (1) which

has K_i= 677 132 nM at the CB₁receptor with

2. Results

34

K_i= 3.4 1.0 nM at CB₂and JWH-229 (4, 1-meth-

oxy-3-(1⁰, 1⁰-dimethylhexyl)-D⁸-THC) with K_i= 3134

110 nM at CB₁and K_i= 18 2 nM at CB₂.³⁵

In the synthesis of the (2⁰R)- and (2⁰S)-methyl isomers in

the THC and 3-heptyl-THC series, the key intermediate,

3-(3,5-dimethoxyphenyl)-2-methylpropanoic acid (7),

was resolved via tedious chromatographic separation

of the corresponding phenethylamides.³⁶Hydrolysis of

the amides to the individual enantiomers of acid 7,

reduction of these acids to the corresponding alcohols

(8), conversion to the p-toluenesulfonate esters, and

reaction with either ethylmagnesium bromide or n-

butylmagnesium chloride in the presence of Li₂CuCl₄

gave resorcinol ethers 9 and 10.^36,37Cleavage of the

methyl ethers, followed by condensation with mentha-

dienol, provided the THC analogs.

CH OH

2

11 CH

9

3

10

8

7

1

4

2

3

R

H C

3

6

O

C H

9 19

O

5

H C

3

H C

3

1 R = C(CH ) (CH ) CH

2

3 2

2 2

3

3 R = C H

9

19

CH

3

OCH

3

OCH

OH

3

CH

3

H C

3

(CH ) CH

2 n

3

H CO

3

R

O

C H

8

O

17

H C

3

H C

3

CH

3

4

5 n = 3

6 n = 5

7 R = CO H

2

8 R = CH OH

2

From earlier work in these series of 1-deoxy- and 1-

methoxy-D⁸-THC analogs and the corresponding 11-hy-

droxy-D⁸-THCs, it has been possible to develop some

tentative SAR at the CB₂receptor for these traditional

cannabinoids. In general, in both the 1-deoxy- and 1-

methoxy-D⁸-THC series an 11-hydroxyl substituent

enhances aﬃnity for both receptors. 1⁰,1⁰-Dimethyl sub-

stitution on the C-3 alkyl side chain leads to enhanced

aﬃnity for the CB₂receptor, and in the 1⁰,1⁰-dimethyl-

1-deoxy-D⁸-THC series, compounds with a three to sev-

en carbon side chain all have high aﬃnity for the CB₂

receptor (K_i= <20 nM). The length of the side chain

plays a critical role in determining aﬃnity at both recep-

tors, although the eﬀect is signiﬁcantly less upon CB₂

aﬃnity than upon CB₁receptor aﬃnity. For signiﬁcant

CB₁aﬃnity, a chain length of at least ﬁve carbon atoms

is essential.

9 R = C H

7

11

3

10 R = C H

5

25 R = CH

3

For the synthesis of the (2⁰R)-1-deoxy-2⁰-methylalkyl-

(11, n = 1–4) and (2⁰R)-1-methoxy-3-(2⁰-methylalkyl)-

D⁸-THCs (12, n = 1–4), the corresponding (2⁰R)-3-(2⁰-

methylalkyl)-D⁸-THCs (13, n = 1–4) were required. For

the corresponding (2⁰S)-methyl series of analogs (14

and 15, n = 1 to 4), (2⁰S)-3-(2⁰-methylalkyl)-THCs 16

(n = 1 to 4) were needed. Conversion of THCs 13 and

16 to the 1-deoxy (11 and 14) and 1-methoxy (12 and

15) analogs would be carried out by procedures used

previously in our laboratory for the preparation of

1-deoxy- and 1-methoxy-cannabinoids.^34,35

CH

Several years ago, we reported the synthesis and pharma-

cology of all the isomeric 3-methylpentyl-D⁸-THCs (5)³⁶

and 3-methylheptyl-D⁸-THCs (6).³⁷In these two series

of compounds, it was found that a methyl substituent at

the 1⁰-position increased the aﬃnity for the CB₁receptor

from 2- to 40-fold relative to the analogs with an unsub-

stituted side chain. Substitution at the 2⁰-position in-

creased CB₁receptor aﬃnity from 2- to 15-fold. It is

3

R

CH

3

H C

3

CH

3

O

(CH )

O

(CH )

2 n

2

n

H C

3

H C

3

11 R = H

12 R = OCH

13 R = OH

14 R = H

15 R = OCH

16 R = OH

3

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

249

dienol as shown in Scheme 1.^34,41Conversion to 1-deoxy

cannabinoid 11 (n = 0) was eﬀected by conversion to the

phosphate ester followed by dissolving metal reduc-

tion.^34,35The 1-methoxy analog (12, n = 0) was prepared

by reaction with potassium hydroxide and methyl

iodide.³⁵

The immediate precursors to cannabinoids 16 and 13 are

(S) and (R) resorcinol methyl ethers (17 and 18, respec-

tively, n = 1–4), which are available from the (R) (19)

and (S) (20) enantiomers of 2-methyl-3-(3,5-dimethoxy-

phenyl)-1-propanol. Although it would have been possi-

ble to obtain alcohols 19 and 20 by the classical

resolution procedure employed in our earlier work, this

would have required very careful and tedious chroma-

tography on a large scale. A far more eﬃcient approach

is their preparation by asymmetric synthesis. For the

preparation of the (R)-enantiomer of 2-methyl-3-(3,5-

dimethoxyphenyl)-1-propanol (19), alkylation of propi-

onyl imide 21 obtained from EvansÕ ^L-valine derived chi-

ral auxiliary with 3,5-dimethoxybenzyl bromide to give

22 would provide an approach to the (S) series of resor-

cinol methyl ethers.³⁹For the synthesis of the (R)-resor-

cinol methyl ethers, a possible approach would use

imide 23 derived from the reaction of 3-(3,5-dimethoxy-

phenyl)propanoic acid with the EvansÕ chiral auxiliary.

Alkylation with methyl iodide would aﬀord (S)-methyl

imide 24. Although alkylation of imides similar to 21

and 23 proceeds with greater stereoselectivity using larg-

er alkyl halides, based upon literature precedent it was

anticipated that it would be possible to obtain reason-

able yields of pure imide 24.^39bAlternatively, it would

be possible to employ the enantiomer of 21 derived from

the unnatural amino acid, ^D-valine. However D-valine is

relatively costly and a second alternative approach to

(S)-enantiomer 20 that was considered was the use of

a diﬀerent chiral auxiliary.

Alkylation of oxazolidinone 21,³⁹prepared by the meth-

od of Kelly et al.⁴²was eﬀected using LDA in THF at

ꢀ78 °C under carefully controlled conditions. It was

found necessary to treat 21 with LDA for no more than

1 min to prevent decomposition, apparently to the par-

ent oxazolidinone and the ketene derived from propion-

ic acid. Alkylation with 3,5-dimethoxybenzyl bromide

aﬀorded the oxazolidinone of (R)-3,5-dimethoxyphe-

nyl-2-methylpropionic acid (22) in 94% yield as a single

diastereomer. Reduction of 22 with lithium aluminum

hydride gave (R)-3-(3,5-dimethoxyphenyl)-2-methyl-1-

propanol (19) the spectroscopic properties of which were

identical to those reported previously.³⁶The optical

purity of alcohol 19 was conﬁrmed by conversion to

the Mosher ester derived from (R)-(ꢀ)-a-methoxy-a-(tri-

ﬂuoromethyl)phenylacetyl chloride [(R)-(ꢀ)-MTPA-

1

Cl].⁴³The 500 MHz H NMR spectrum of this Mosher

ester was clearly diﬀerent from that derived from (S)-

enantiomer 20. This spectrum was completely devoid

of the signals due to the Mosher ester of 20 and indicat-

ed that alcohol 19 was optically pure within the limita-

tions of the NMR method that was used.

Using a modiﬁcation of the procedure we reported pre-

viously, conversion of alcohol 19 to the methanesulfo-

nate ester, followed by copper catalyzed coupling

reactions using ethyl through butylmagnesium halides,

provided (S)-resorcinol dimethyl ethers 17 (n = 2–

4).^36,37Reaction of the methanesulfonate ester of 19

with methylmagnesium bromide did not proceed in ade-

quate yield; however, reaction of the triﬂuoromethane-

sulfonate ester under the same conditions gave (S)-1-

(3,5-dimethoxyphenyl)-2-methylbutane (17, n = 1) in

acceptable (70%) yield. Conversion of resorcinol methyl

ethers 17 (n = 1–4) to (2⁰S)-3-(2⁰-methyl)-D⁸-THC ana-

logs 16 and then to 1-deoxy and 1-methoxy cannabi-

noids 14 and 15 (n = 1–4) was carried out by the

procedures shown in Scheme 1.

OCH

3

CH

3

H CO

R

H CO

R

3

17 R = (CH ) CH

19 R = CH OH

18 R = (CH ) CH

3

2 n

3

2 n

20 R = CH OH

2

CH

N

CH

N

3

OCH

3

H C

3

CH

3

O

H C

3

H CO

3

O

21

22

Attempts to prepare (S)-alcohol 20 via methylation of chi-

ral oxazolidinone 23 were not encouraging. Methylation

of 23 under conditions similar to those employed for the

alkylation of 21 provided a 3:1 mixture of the desired

(S)-oxazolidinone (24) and the (R)-isomer (22). These

diasteroisomeric oxazolidinones have very similar R_fval-

ues and while it was possible to separate them by very

careful and rather tedious chromatography, this proce-

dure was not practical for the preparation of quantities

of (S)-alcohol 20 and an alternative approach to the

(2R)-methyl series of cannabinoids was investigated.⁴⁴

CH

N

CH

N

OCH

3

OCH

3

H C

CH

3

O

H CO

3

H CO

3

O

23

24

The parent members of the series of 2⁰-methyl-1-deoxy-

and 1-methoxy-D⁸-THCs, the 3-(2-methylpropyl) ana-

logs 11 and 12 (n = 0) require achiral resorcinol dimethyl

ether 25 as a precursor. This compound was prepared by

the copper catalyzed reaction of isopropylmagnesium

chloride with 3,5-dimethoxybenzyl bromide.⁴⁰Reaction

of 25 with boron tribromide gave the corresponding res-

orcinol, which was converted to D⁸-THC analog 13

(n = 0) by acid catalyzed condensation with p-mentha-

Both enantiomers of OppolzerÕs camphor derived auxil-

iary (26), 1R,2S-enantiomer shown, (Scheme 2) are

readily available in a few steps from the inexpensive,

commercially available, enantiomeric camphor-10-sul-

fonic acids.⁴⁵Reaction of 26 with sodium hydride, fol-

250

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

CH₃

OH

H₃C

OH

a

+

HO

R

H₃C

O

CH₃

R

H₃C

CH₂

b

c,d

CH₃

OCH₃

H₃C

O

CH₃

R

O

CH₃

R

Scheme 1. Reagents and conditions: (a) HOTs/C₆H₆, 80 °C; (b) CH₃I/KOH/DMF, 25 °C; (c) NaH/THF, 0 °C then (C₂H₅O)₂P(O)Cl; (d) Li/NH₃,

THF, ꢀ78 °C.

CH

3

H C

3

H C

3

O

H CO

3

H

N

a, b, c

S

O

OCH

3

26

27

CH

3

H C

3

O

3

H CO

3

d, e

N

S

CH

O

OCH

3

28

Scheme 2. Reagents and conditions: (a) NaH, toluene, 0 °C; (b) 3,5-dimethoxycinnamoyl chloride, 25 °C; (c) H₂, Pd/C, EtOAc; (d) NaN(SiMe₃)₂,

THF, ꢀ78 °C; (e) MeI, HMPA, ꢀ78 to 25 °C.

lowed by treatment with 3,5-dimethoxycinnamoyl chlo-

CH

N

CH

N

3

OCH

3

ride and hydrogenation, gave imide 27 in 80% yield.

Base catalyzed alkylation of 27 with methyl iodide pro-

vided a 92:8 mixture of the desired (2S)-isomer (28) and

the (2R)-epimer. Although this reaction proceeded in

good (78%) yield to give the mixture of stereoisomers,

they could not be separated by chromatography.

Repeated recrystallization gave pure 28, but in only

30% yield. Attempts to improve the yield were unsuc-

cessful and this approach was not pursued further.⁴⁶

H C

3

H C

3

CH

3

O

H C

3

H CO

3

O

29

30

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

251

Since alternative approaches to (S)-alcohol 20, the pre-

cursor to the (2⁰R)-methyl series of cannabinoids, were

not satisfactory, these compounds were prepared from

the ^D-valine derived enantiomer of 21 (29) by the proce-

dure that was employed successfully for the synthesis of

the (2⁰S) series of 1-deoxy-(14) and 1-methoxy-D⁸-THC

(15) analogs. As expected, alkylation of 29 with 3,5-

dimethoxybenzyl bromide proceeded smoothly to pro-

vide 30, which was identical to 22, except for the sign

of rotation. Lithium aluminum hydride reduction of

30 provided (S)-2-methyl-3-(3,5-dimethyoxyphenyl)-1-

propanol (20). Alcohol 20 was identical to that prepared

rized in Table 1. Also included in Table 1 are the recep-

tor aﬃnities for JWH-133 (1), 1-deoxy-D⁸-THC-DMH

(3), D⁸-THC-DMH, and D⁸- and D⁹-THC.

None of the 1-methoxy-D⁸-THC analogs (12 and 15,

n = 0–4) have appreciable aﬃnity for the CB₁receptor,

with K_i= 427 31 nM (JWH-247) to >10,000 nM

(JWH-339 and JWH-351). In contrast to their lack of

aﬃnity for the CB₁receptor, several of these compounds

have appreciable aﬃnities for the CB₂receptor. In par-

ticular, JWH-359 (12, n = 1) has very high aﬃnity for

the CB₂receptor (K_i= 13 0.2 nM). This high aﬃnity

for the CB₂receptor combined with very little aﬃnity

for the CB₁receptor (K_i= 2918 450 nM) indicates that

JWH-359 is more than 200-fold selective for the CB₂

receptor. JWH-358 (12, n = 4) also has relatively high

aﬃnity for the CB₂receptor with K_i= 52 3 nM.

JWH-256 (15, n = 3, K_i= 97 18 nM) and JWH-247

(15, n = 4, CB₂, K_i= 99 4 nM) both have appreciable

aﬃnity for the CB₂receptor. Although these three com-

pounds show selectivity for the CB₂receptor, the most

selective, JWH-256, is signiﬁcantly less selective than

JWH-359.

1

previously.³⁶The 500 MHz H NMR spectrum of the

Mosher ester derived from 20 with (R)-(ꢀ)-MTPA-Cl

is clearly diﬀerent from that of its enantiomer (19) and

showed that 20 is optically pure within the limits of

the experimental method. The balance of the synthesis

of the (2⁰R)-1-deoxy-(11) and (2⁰R)-1-methoxy-2⁰-meth-

yl-D⁸-THC (12) analogs was carried out as described

above for the (2⁰S)-methyl series.

The aﬃnities of the 1-methoxy- and 1-deoxy-D⁸-THC

analogs for the CB₁receptor were determined by mea-

suring their ability to displace the potent cannabinoid

[³H] CP-55,940 from its binding site in a membrane

preparation from rat brain as described by Compton

et al.¹¹Aﬃnities for the CB₂receptor were determined

by measuring the ability of the compounds to displace

[³H]CP-55,940 from a cloned human receptor prepara-

tion using the procedure described by Showalter

et al.⁴⁷The results of these determinations are summa-

In the 1-deoxy series (11 and 14, n = 0–4) one com-

pound, JWH-257 (14, n = 3) has high aﬃnity for the

CB₁receptor with K_i= 25 2 nM. All of the other 1-de-

oxy-2⁰-methyl-D⁸-THC analogs have very little aﬃnity

for the CB₁receptor with K_i= 332 to >10,000 nM.

These 1-deoxy-D⁸-THC analogs all have from good to

modest aﬃnities for the CB₂receptor with K_i= 1–

Table 1. Receptor aﬃnities (means SEM) of 1-methoxy-2⁰-methylcannabinoids, 1-Deoxy-2⁰-methylcannabinoids and related compounds

Compound

K_i(nM)

CB₁

CB

CB₁/CB₂

D⁹-THC

41 2^a

36 10^b

1.1

1.0

7.9

199

16

D⁸-THC

44 12^c

44 17^c

2.9 1.6^d

3.4 1.0^c

57 12^c

1-Deoxy-D⁸-THC-DMH (3)

22.8 7.3^d

677 132^c

924 104^c

3-(1⁰,1⁰-Dimethylbutyl)-1-deoxy-D⁸-THC (JWH-133, 1)

1-Methoxy-D⁸-THC-DMH

1-Methoxy-3-(2⁰-methylpropyl)-D⁸-THC (JWH-339, 12, n = 0)

(2⁰S)-1-Methoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-351, 15, n = 1)

(2⁰R)-1-Methoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-359, 12, n = 1)

(2⁰S)-1-Methoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-254, 15, n = 2)

(2⁰R)-1-Methoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-354, 12, n = 2)

(2⁰S)-1-Methoxy-3-(2⁰-methylhexyl)-D⁸-THC (JWH-256, 15, n = 3)

(2⁰R)-1-Methoxy-3-(2⁰-methylhexyl)-D⁸-THC (JWH-356, 12, n = 3)

(2⁰S)-1-Methoxy-3-(2⁰-methylheptyl)-D⁸-THC (JWH-247, 15, n = 4)

(2⁰R)-1-Methoxy-3-(2⁰-methylheptyl)-D⁸-THC (JWH-358, 12, n = 4)

1-Deoxy-3-(2⁰-methylpropyl)-D⁸-THC (JWH-338, 11, n = 0)

(2⁰S)-1-Deoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-352, 14, n = 1)

(2⁰R)-1-Deoxy-3-(2⁰-methylbutyl)-D⁸-THC (JWH-360, 11, n = 1)

(2⁰S)-1-Deoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-255, 14, n = 2)

(2⁰R)-1-Deoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-353, 11, n = 2)

(2⁰S)-1-Deoxy-3-(2⁰-methylhexyl)-D⁸-THC (JWH-257, 14, n = 3)

(2⁰R)-1-Deoxy-3-(2⁰-methylhexyl)-D⁸-THC (JWH-355, 11, n = 3)

(2⁰S)-1-Deoxy-3-(2⁰-methylheptyl)-D⁸-THC (JWH-264, 14, n = 4)

(2⁰R)-1-Deoxy-3-(2⁰-methylheptyl)-D⁸-THC (JWH-357, 11, n = 4)

>10,000

2918 450

2317 93

3

>4.3

>34

224

15

295

13 0.2

319 16

241 14

97 18

4724 509

1961 21

4300 888

5837 701

427 31

8.1

44

108 17

54

99

52

4

3

4.3

24

1243 266

>10,000

2449 606

111 16

90

47

160

24

2

8

9

1

212

15

4307 649

1493 10

179

48

31

25

2

1.0 0.3

108 17

146 28

25

20

2162 220

332 43

647 78

2.3

3.5

185

4

^aRef. 8.

^bRef. 47.

^cRef. 33.

^dRef. 34.

252

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

185 nM and all are selective for the CB₂receptor. Two

compounds in this series, JWH-352 (14, n = 1) and

JWH-255 (14, n = 2), show >212- and 179-fold selectiv-

ity, respectively, for the CB₂receptor. The more selec-

tive of this pair of compounds, JWH-352, has

moderately high aﬃnity for the CB₂receptor

(K_i= 47 2 nM) with K_i> 10,000 nM at CB₁. JWH-

255 has slightly greater aﬃnity for the CB₂receptor

(K_i= 24 9 nM), but also has somewhat greater aﬃnity

for the CB₁receptor with K_i= 4307 649 nM. A third

moderately selective ligand for the CB₂receptor,

JWH-353 (11, n = 2), has high aﬃnity (K_i= 31 1 nM)

for the CB₂receptor and K_i= 1493 10 nM at the CB₁

receptor. JWH-257 (14, n = 3) the 1-deoxy-D⁸-THC ana-

log with the highest aﬃnity at the CB₂receptor

(K_i= 1.0 0.3 nM) also has high aﬃnity for the CB₁

receptor with K_i= 25 2 nM. Although all of the other

1-deoxy-D⁸-THC analogs show from 2.3- to 90-fold

selectivity for the CB₂receptor, none has K_i< 108 nM

at the CB₂receptor.

logs has K_i< 647 nM. The (2⁰R)-epimer of JWH-257

(2⁰R)-1-deoxy-3-(2⁰-methylhexyl)-D⁸-THC (JWH-355,

11, n = 3) has nearly 100-fold less aﬃnity than JWH-

257 for the CB₁receptor with K_i= 2162 220 nM. This

large diﬀerence in CB₁receptor aﬃnity as a function of

stereochemistry at the 2⁰-position of the THC side chain

is in contrast to the relative CB₁receptor aﬃnities of the

2⁰-methyl isomers in the D⁸-THCs and 3-heptyl-D⁸-

THCs in which there is little diﬀerence in the aﬃnities

as a function of stereochemistry at C-2⁰.^36,37At the pres-

ent time, there is no obvious explanation for the large

diﬀerence in the CB₁receptor aﬃnities of JWH-257

and JWH-355.

The 1-deoxy-3-(2⁰-methylalkyl)-D⁸-THCs have aﬃnities

for the CB₂receptor that range from 1.0 to 185 nM

and all are selective for the CB₂receptor. Three of these

compounds have the desirable property of good to

excellent aﬃnity for the CB₂receptor and little aﬃnity

for the CB₁receptor. The most selective (>212-fold) of

these 3-(2⁰-methyl)-1-deoxy-D⁸-THCs is (2⁰S)-1-deoxy-

3-(2⁰-methylbutyl)-D⁸-THC (JWH-352, 14, n = 1) with

K_i= 47 2 nM at CB₂and K_i= >10,000 nM at the

CB₁receptor. (2⁰S)-1-Deoxy-3-(2⁰-methylpentyl)-D⁸-

THC (JWH-255, 14, n = 2) shows 179-fold selectivity

for the CB₂receptor with K_i= 24 9 nM at CB₂and

K_i= 4307 649 nM at CB₁. The least selective (48-fold)

of these three compounds is (2⁰R)-1-deoxy-3-(2⁰-methyl-

3. Discussion

In the 2⁰-methyl series, none of the 1-methoxy-D⁸-THC

analogs have signiﬁcant aﬃnity for the CB₁receptor

with K_i= 427 to >10,000 nM. This parallels the results

in the 1-methoxy-3-(1⁰,1⁰-dimethylalkyl)-D⁸-THC series

in which the CB₁receptor aﬃnities ranged from 677 to

>10,000 nM.³⁵The CB₂receptor aﬃnities of 1-meth-

oxy-D⁸-THC analogs 12 and 15 are considerably higher

than their aﬃnities for the CB₁receptor (K_i= 13–

2317 nM). The compound with the least aﬃnity for

the CB₂receptor is 1-methoxy-3-(2⁰-methylpropyl)-D⁸-

THC (JWH-339, 12, n = 0) and the compound with

the greatest aﬃnity (K_i= 13 0.2 nM) is the next high-

est homologs, (2⁰R)-2⁰-methylbutyl analog (JWH-359,

12, n = 1). JWH-339 is a very highly selective (224-fold)

ligand for the CB₂receptor with little aﬃnity for the

CB₁receptor. Interestingly, the epimeric (2⁰S)-2⁰-meth-

ylbutyl analog (JWH-351, 15, n = 1) has little aﬃnity

for the CB₂receptor with K_i= 295 3 nM. The other

1-methoxy-3-(2⁰-methyl)-D⁸-THC analog with better

than modest aﬃnity for the CB₂receptor is the (2⁰R)-

2⁰-methylheptyl analog (JWH-358, 12, n = 4) with

K_i= 52 3 nM. This compound has little aﬃnity

(K_i= 1243 266 nM) at CB₁and is 24-fold selective

for the CB₂receptor. Although all of these 1-methoxy-

3-(2⁰-methylalkyl)-D⁸-THC analogs are selective for the

CB₂receptor, only JWH-359 (12, n = 1) and JWH-358

(12, n = 4) have the combination of signiﬁcant aﬃnity

for the CB₂receptor combined with little aﬃnity for

the CB₁receptor. In this series of 1-methoxy-D⁸-THC

analogs in general the (2⁰R)-methyl compounds have

greater aﬃnity for the CB₂receptor than the (2⁰S)-

isomers.

pentyl)-D⁸-THC

(JWH-353,

11,

n = 2)

with

K_i= 31 1 nM at CB₂and K_i= 1493 10 nM at the

CB₁receptor. In contrast to the 1-methoxy series, the

(2⁰S)-methyl deoxy cannabinoids have either similar or

greater aﬃnity than the (2⁰R)-epimers at the CB₂recep-

tor. In the (2⁰S)-methyl series, the butyl (JWH-352),

pentyl (JWH-255), and hexyl (JWH-257) compounds

(14, n = 1–3) all have good aﬃnity for the CB₂receptor

with K_i= 1.0–47 nM. The only (2⁰R) compound with

signiﬁcant CB₂receptor aﬃnity (K_i= 31 1 nM) is

(2⁰R)-1-deoxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-353,

11, n = 2).

With the exception of (2⁰S)-1-deoxy-3-(2⁰-methylhexyl)-

D⁸-THC (JWH-257, 14, n = 3) none of these compounds

in either the 1-methoxy or 1-deoxy series has signiﬁcant

aﬃnity for the CB₁receptor. JWH-257 has

K_i= 25 2 nM at the CB₁receptor and no other com-

pound in either series has K_i= <332 nM. This is in con-

trast to the 1-deoxy-3-(1⁰,1⁰-dimethylalkyl)-D⁸-THC

series in which the dimethylheptyl and dimethyloctyl

compounds both have good aﬃnity for the CB₁receptor

(K_i= 23 7 and 51 11 nM, respectively).³⁴None of

the 1-methoxy-D⁸-THC analogs has signiﬁcant aﬃnity

for the CB₁receptor and this is in agreement with previ-

ous work in which it was found that in the absence of an

11-hydroxyl substituent 1-methoxy-D⁸-THC analogs

have little or no aﬃnity for the CB₁receptor.³⁵

In the 1-deoxy-3-(2⁰-methyl)-D⁸-THC series, with the

exception of (2⁰S)-1-deoxy-3-(2⁰-methylhexyl)-D⁸-THC

(JWH-257, 14, n = 3), none of the compounds have sig-

niﬁcant aﬃnity for the CB₁receptor. JWH-257 has very

high aﬃnity for the CB₁receptor (K_i= 25 2 nM) while

none of the other 1-deoxy-3-(2⁰-methyl)-D⁸-THC ana-

The SAR at the CB₂receptor in the 1-methoxy-3-(2⁰-

methylalky)-D⁸-THC series (12 and 15, n = 0–4) are very

diﬀerent from those for the corresponding 1⁰,1⁰-

dimethylalkyl-D⁸-THCs.³⁵In the 1⁰,1⁰-dimethylalkyl-

D⁸-THC series, the 1⁰,1⁰-dimethylpentyl through the

1⁰,1⁰-dimethylheptyl analogs have K_i= 18–57 nM,

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

253

increasing from pentyl to heptyl. In the 2⁰-methyl series,

5. Experimental

however, only the (2⁰R)-3-(2⁰-methylbutyl), JWH-359

(12, n = 1), and (2⁰R)-3-(2⁰-methylheptyl), JWH-358

(12, n = 4), compounds have high aﬃnity for the CB₂

receptor (K_i= 13 0.2 nM and 52 3 nM, respective-

ly.). The (2⁰S) isomers have equal or less aﬃnity for

the CB₂receptor than the (2⁰R) isomers. In the (2⁰R) ser-

ies, CB₂receptor aﬃnity increases with chain length

from three to four carbons then decreases with a ﬁve

or six carbon alkyl chain. CB₂receptor aﬃnity then

increases at seven carbons. In the (2⁰S) methyl 1-meth-

oxy-D⁸-THC series, none of the compounds have signif-

icant aﬃnity for the CB₂receptor.

5.1. General

¹H and ¹³C NMR spectra were recorded on a Bruker

300AC or a JEOL 500 MHz spectrometer. Mass spectral

analyses were performed on a Hewlett-Packard 5890A

capillary gas chromatograph equipped with a mass sen-

sitive detector. HRMS data were obtained in the Mass

Spectrometry Laboratory, School of Chemical Sciences,

University of Illinois. Ether and THF were distilled

from Na–benzophenone ketyl immediately before use,

and other solvents were puriﬁed using standard proce-

dures. Column chromatography was carried out on Sor-

bent Technologies silica gel (32–63 l) using the indicated

solvents as eluents. All new compounds were homoge-

neous to TLC and ¹³C NMR. All target compounds

were homogeneous to GLC or TLC in two diﬀerent sol-

vent systems. TLC was carried out using 200 lm silica

gel plates using the indicated solvents. GLC analyses

were performed on the Hewlett-Packard 5890A GC/

MS using a 60 m carbowax column and helium gas as

a carrier. An initial column temperature of 60 °C was

employed and the temperature was increased at a rate

of 1.5 °C/min to a maximum temperature of 300 °C with

a total run time of 20 min.

In the 1-deoxy-3-(2⁰-methylalkyl)-D⁸-THCs, the (2⁰S)-

methyl compounds (11, n = 0, 14, n = 1–4) have higher

aﬃnity for the CB₂receptor than the corresponding

(2⁰R) isomers (11, n = 0–4). Aﬃnity increases with

chain length from three to six carbon atoms and is

maximum for the 2⁰S-methylhexyl compound (JWH-

257, 14, n = 3, K_i= 1.0 0.3 nM). CB₂receptor aﬃnity

then decreases for the (2⁰S)-methylheptyl analog

(JWH-357, 14, n = 4) with K_i= 185 4 nM. In the

(2⁰R)-methyl alkyl series (11, n = 0–4), only (2⁰R)-1-de-

oxy-3-(2⁰-methylpentyl)-D⁸-THC (JWH-353, 11, n = 2)

has signiﬁcant aﬃnity for the CB₂receptor with

K_i= 31 1 nM. The trend in CB₂receptor aﬃnities

in the (2⁰S)-methyl series is somewhat similar to that

in the 1-deoxy-3-(1⁰,1⁰-dimethylalky)-D⁸-THCs in which

CB₂receptor aﬃnity increases from K_i= 58 nM for the

dimethylethyl compound to K_i= 76 nM for the dime-

thyloctyl analog.³⁴Those compounds in this series with

three to seven carbon atoms all have K_i< 20 nM.

Although the CB₂receptor aﬃnities of the 1-deoxy-

(2⁰S)-methyl-D⁸-THCs are not as great as those of

the 1-deoxy-dimethylalkyl compounds, the general

trends are similar. It is apparent that a (2⁰R)-methyl

substituent has an adverse eﬀect upon CB₂receptor

aﬃnity.

5.2. 1-(3,5-Dimethoxyphenyl)-2-methylpropane (25)

To a stirred solution of 1.16 g (5.0 mmol) of 3,5-dimeth-

oxybenzyl bromide⁴⁰in 30 mL of dry THF was added

0.050 g (0.50 mmol) of CuCl. The reaction mixture was

cooled to ꢀ78 °C and 10 mL (16 mmol) of 1.6 molar iso-

propylmagnesium chloride in ether was added. The reac-

tion mixture was stirred at ꢀ78 °C for 2 h, allowed to

warm to ambient temperature, and stirred for 18 h.

After cooling to 0 °C, the reaction was quenched by

the cautious addition of 10 mL of 1 M aqueous HCl.

The resulting black slurry was ﬁltered through a pad

of Celite and extracted with three portions of ether.

The combined ethereal extracts were washed with suc-

cessive portions of water and brine. After drying

(MgSO₄), the solvent was removed at reduced pressure

and the residue was puriﬁed by ﬂash chromatography

(petroleum ether/dichloromethane, 20:80) to give 0.470

(56%) of 1-(3,5-dimethoxyphenyl)-2-methylpropane as

4. Conclusions

Four of these 1-methoxy- and 1-deoxy-3-(2⁰-meth-

ylalkyl)-D⁸-THCs, methoxy cannabinoid, JWH-359

(12, n = 1), and 1-deoxy cannabinoids, JWH-352 (14,

n = 1), JWH-255 (14, n = 2), and JWH-353 (11, n = 2)

are highly selective ligands for the cannabinoid CB₂

receptor, with little aﬃnity for the CB₁receptor. All of

these 2⁰-methyl THC analogs were prepared by an enan-

tioselective synthetic route using chiral auxiliaries

derived from ^L- and D-valine. In the 1-methoxy-3-(2⁰-

methylalkyl)-D⁸-THC series, it was not possible to devel-

op any systematic SAR at either the CB₁or CB₂recep-

tor. In the 1-deoxy-3-(2⁰-methylalkyl)-D⁸-THC series,

the (2⁰S)-methyl compounds in general have greater

aﬃnity for the CB₂receptor than the corresponding

(2⁰R) isomers. In these 1-deoxy-2⁰S-methyl cannabi-

noids, an alkyl side chain of four to six carbon atoms

provides maximum CB₂receptor aﬃnity. With one

1

a colorless oil; H NMR (300 MHz, CDCl₃) d 0.93 (d,

J = 6.5 Hz, 6H), 1.85–1.95 (m, 1H), 2.43 (d,

J = 7.2 Hz, 2H), 3.80 (s, 6H), 6.34 (s, 3H); ¹³C NMR

(75.5 MHz, CDCl₃) d 22.6, 30.3, 46.0, 55.4, 97.8,

107.4, 144.3, 160.7; MS (EI) m/z 194 (23), 152 (100).

5.3. 3-(2-Methylpropyl)-D⁸-THC (13, n = 0)

Cannabinoid 13 (n = 0) was prepared from 1-(3,5-

dimethoxyphenyl)-2-methylpropane (25) by the proce-

dure described below for the preparation of 16 (n = 1).

From 0.632 g (3.81 mmol) of 1-(3,5-dimethoxyphenyl)-

2-methylpropane was obtained 0.344 g (30%) of 3-(2-

methylpropyl)-D⁸-THC (13, n = 0) following chroma-

tography (petroleum ether/ethyl acetate, 97.5:2.5); ¹H

NMR (300 MHz, CDCl₃) d 0.89 (d, J = 6.7 Hz, 6H),

1.12 (s, 3H), 1.24–1.30 (m, 1H), 1.40 (s, 3H), 1.71 (s,

exception,

(2⁰S)-1-deoxy-3-(2⁰-methylhexyl)-D⁸-THC

none of these compounds have signiﬁcant aﬃnity for

the CB₁receptor.

254

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

3H), 1.75–1.91 (m, 3H), 2.07–2.14 (m, 1H), 2.29–2.32,

(m, 2H), 2.72 (td, J = 4.6, 10.8 Hz, 1H), 3.21 (dd,

J = 4.1, 16.3 Hz, 1H), 4.91 (s, 1H), 5.44 (br d,

J = 4.0 Hz, 1H), 6.08 (d, J = 1.4 Hz, 1H), 6.25 (d,

J = 1.4 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) d 18.7,

22.7, 23.7, 27.8, 28.1, 30.0, 31.8, 36.3, 45.1, 45.3, 76.6,

of the benzyl bromide takes place as soon as possible

following deprotonation of the acyl oxazolidinone to

avoid decomposition of the anion via a ketene acetal.

The reaction mixture was stirred at ꢀ78 °C for an addi-

tional 4 h and quenched with pH 7 buﬀer. After warm-

ing to ambient temperature, the THF was removed in

vacuo and the residue was taken up in ether. The ethe-

real solution was washed with water and dried (MgSO₄).

The solvent was removed in vacuo to aﬀord 4.72 g (94%)

of 22, mp 93–95 °C, as a single diastereomer. GLC indi-

cated that less than 1% of the other diastereomer was

present. ¹H NMR (300 MHz, CDCl₃) d 0.84 (d,

J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 1.13 (d,

J = 6.6 Hz, 3H), 2.29–2.34 (m, 1H), 2.57 (dd, J = 7.3,

13.4 Hz, 1H), 2.93 (dd, J = 7.7, 13.4 Hz, 1H), 3.77 (s,

6H), 4.08–4.23 (m, 3H), 4.41–4.43 (m, 1H), 6.41 (t,

J = 1.8 Hz, 1H), 6.43 (d, J = 1.8 Hz, 2H); ¹³C NMR

(75.5 MHz, CDCl₃) d 14.7, 17.6, 17.9, 28.4, 39.2, 39.9,

55.2, 58.6, 63.3, 98.5, 106.9, 141.6, 153.6, 160.5, 176.5;

MS (EI) m/z 335 (45), 179 (100). The oxazolidinine

(30), mp 93–95 °C, derived from ^D-valine via 29 has

identical spectroscopic properties.

108.6, 110.0, 111.1, 119.5, 135.0, 141.7, 154.9; MS (EI)

20

D

m/z300(48),257(35),217(100);½aꢁ ꢀ245(c0.5, CH₂Cl₂).

5.4. 1-Methoxy-3-(2-methylpropyl)-D⁸-THC (JWH-339,

12, n = 0)

Methyl ether 12 (n = 0) was prepared from cannabinoid

13 (n = 0) by the procedure employed for the prepara-

tion of 15 (n = 1) described below. From 0.065 g

(0.216 mmol) of 13 (n = 0) was obtained 0.058 g (85%)

of JWH-339 following chromatography (petroleum

1

ether/ethyl acetate, 99:1); H NMR (300 MHz, CDCl₃)

d 0.93 (d, J = 6.6 Hz, 6H), 1.11 (s, 3H), 1.44 (s, 3H),

1.80 (s, 3H), 1.50–1.93 (m, 4H), 2.00–2.30 (m, 1H),

2.40 (d, J = 7.2 Hz, 2H), 2.66–2.71 (m, 1H), 3.17 (dd

3.5, J = 13.6 Hz, 1H), 3.82 (s, 3H), 5.46 (br s, 1H),

6.24 (s, 1H), 6.30 (d, J = 1.1 Hz, 1H); ¹³C NMR

(75.5 MHz, CDCl₃) d 18.6, 22.8, 23.8, 27.8, 28.2, 30.2,

32.1, 36.5, 45.3, 45.8, 55.3, 76.6, 103.9, 111.3, 112.2,

5.7. (R)-2-Methyl-3-(3,5-dimethoxyphenyl)-1-propanol

(19)

119.5, 135.2, 141.4, 154.4, 159.0; MS (EI) m/z 314 (85),

20

D

Calcd for C₂₁H₃₀O₂, 314.2246; found: 314.2248.

271 (33), 231 (100); ½aꢁ ꢀ227 (c 0.5, CH₂Cl₂); HRMS

To a stirred solution of 0.870 g (2.6 mmol) of acyl oxa-

zolidinone 22 in 20 mL of dry THF was added 0.300 g

(7.9 mmol) of lithium aluminum hydride. The reaction

mixture was stirred at ambient temperature for 1 h

and then quenched by the cautious addition of aqueous

HCl (1 M). The THF was removed in vacuo and the

resulting paste was taken up in ether and washed well

with KOH (1 M) and water. After drying (MgSO₄),

the solvent was removed at reduced pressure to give

0.546 g (99%) of alcohol as a colorless oil after chroma-

5.5. 1-Deoxy-3-(2-methylpropyl)-D⁸-THC (JWH-338, 11,

n = 0)

Deoxyannabinoid 11 (n = 0) was prepared from cannab-

inoid 13 (n = 0) by the procedure employed for the prep-

aration of 14 (n = 1). From 0.160 g (0.53 mmol) of 13

(n = 0) was obtained 0.067 g (44% for two steps) of

JWH-338 following chromatography (petroleum ether/

ether, 98:2). ¹H NMR (300 MHz, CDCl₃) d 0.93 (d,

J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.19 (s, 3H),

1.43 (s, 3H), 1.65–2.05 (m, 4H), 1.77 (s, 3H), 2.10–2.25

(m, 1H), 2.37–2.45 (m, 2H), 2.60–2.80 (m, 2H), 5.49

(br s, 1H), 6.63 (d, J = 1.4 Hz, 1H), 6.70 (dd, J = 1.5,

7.8 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H); ¹³C NMR

(75.5 MHz, CDCl₃) d 19.4, 22.7, 22.8, 23.7, 27.7, 27.9,

30.2, 32.4, 36.8, 43.1, 45.3, 76.9, 117.8, 120.2, 121.1,

1

tography (petroleum ether/ethyl acetate, 4:1). H NMR

(300 MHz, CDCl₃) d 0.92 (d, J = 6.7 Hz, 3H), 1.57 (br s,

1H), 1.89–2.00 (m, 1H), 2.35 (dd, J = 8.1, 13.3 Hz, 1H),

2.70 (dd, J = 6.4, 13.3 Hz, 1H), 3.44–3.55 (m, 2H), 3.78

(s, 6H), 6.31 (t, J = 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 2H);

¹³C NMR (75.5 MHz, CDCl₃) d 16.5, 37.6, 40.0, 55.2,

67.6, 97.7, 107.1, 143.1, 160.6; MS (EI) m/z 210 (50),

20

D

152 (100); ½aꢁ +29.3 (c 0.41, CH₂Cl₂). (S)-2-Methyl-3-

(3,5-dimethoxyphenyl)-1-propanol (20) was prepared

from oxazolidinone 30 by the same procedure and had

identical spectroscopic properties. Alcohols 19 and 20

are identical to the alcohols prepared previously through

resolution of 3-(3,5-dimethoxyphenyl)propanoic acid (7).³⁶

123.2, 126.5, 133.7, 141.3, 152.9; MS (EI) m/z; 284

20

D

HRMS Calcd for C₂₀H₂₈O, 284.2140; found: 284.2147.

(100), 241 (35), 201 (100); ½aꢁ ꢀ190 (c 0.5, CH₂Cl₂);

5.6. Oxazolidinone of (R)-2-methyl-3,5-dimethoxyphelyl-

propanoic acid (22)

5.8. Mosher ester of (R)-3-(3,5-dimethoxyphenyl)-2-meth-

yl-1-propanol

To a solution of 1.51 g (15 mmol) of diisopropylamine

in 15 mL of dry THF at 0 °C under argon was added

7.46 mL of 2 M n-butyllithium in hexanes (15 mmol)

and the mixture was stirred at 0 °C for 10 min. After

cooling to ꢀ78 °C, a solution of 2.76 g (15 mmol) of

the ^L-valine derived oxazolidinone of propionic acid

(21)^39,40in 45 mL of dry THF was added and the deep

yellow solution was stirred for no more than 1 min. A

solution of 3.46 g (15 mmol) of 3,5-dimethoxybenzyl

bromide and 2.85 mL (16.4 mmol) HMPA in 20 mL of

dry THF was added. It is important that the addition

To a stirred solution of 0.0088 g (0.042 mmol) of (R)-

3,5-dimethoxyphenyl-2-methyl-1-propanol (19) and

0.0104 g (0.082 mmol) DMAP in 2 mL of dichlorometh-

ane at ambient temperature was added 0.015 g

(0.060 mmol) (R)-(ꢀ)-MTPA-Cl.⁴³The reaction mixture

was stirred for 24 h, quenched with saturated aqueous

NH₄Cl, and the mixture was extracted with three por-

tions of dichloromethane. The combined extracts were

washed successively with 1 M aqueous HCl, water, and

brine. After drying (MgSO₄), the solvent was removed

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

255

in vacuo and the residue was chromatographed (petro-

leum ether/ether, 9:1) to give 0.011 g of the Mosher ester

as a pale yellow gum; H NMR (500 MHz, CDCl₃) d

0.94 (d, J = 6.9 Hz, 3H), 2.39 (dd, J = 7.8, 13, 8 Hz,

1H), 2.60 (dd, J = 6.8, 13.3 Hz, 1H), 3.56 (s, 3H), 3.76

(s, 6H), 4.14 (dd, J = 5.5, 10.6 Hz, 1H), 4.20 (dd,

J = 6.0, 11.0 Hz, 1H), 6.26 (d, J = 2.3 Hz, 2H), 6.31 (t,

J = 2.3 Hz, 1H), 7.39–7.43 (m, 3H), 7.50–7.55 (m, 2H);

¹³C NMR (125 MHz, CDCl₃) d 16.8, 34.5, 39.8, 55.3,

55.5, 70.3, 98.1, 107.2, 127.5, 128.6, 129.8, 132.4,

2 mL Li₂CuCl₄prepared from 0.0142 g (0.34 mmol)

LiCl and 0.023 g (0.17 mmol) CuCl₂. To this solution

was added at ꢀ78° C 4.17 mL of ethereal methylmagne-

sium bromide (3.17 M) over 2 min; the solution was al-

lowed to warm to ambient temperature and stirred for

24 h. The reaction was cooled to 0 °C and quenched

by the cautious addition of water. The resulting slurry

was passed through a short pad of Celite and concen-

trated in vacuo. The concentrated solution was taken

up in ether, washed with successive portions of 1 N

HCl, water, and brine. After drying (MgSO₄), the sol-

vent was removed in vacuo and the residue was chro-

matographed (petroleum ether/ether, 9:1) to give

1

142.0, 160.8, 166.7; MS (EI) m/z 426 (52), 152 (100);

20

D

½aꢁ ꢀ40.8 (c 0.6, CH₂Cl₂).

1

5.9. Mosher ester of (S)-3-(3,5-dimethoxyphenyl)-2-meth-

yl-1-propanol

0.274 g (70%) of 17 (n = 1) as a colorless oil. H NMR

(300 MHz, CDCl₃) d 0.85 (d, J = 6.6 Hz, 3H), 0.90 (t,

J = 7.4 Hz, 3H), 1.09–1.26 (m, 1H), 1.33–1.44 (m, 1H),

1.58–1.67 (m, 1H), 2.29 (dd, J = 8.1, 13.3 Hz, 1H),

2.57 (dd, J = 6.3, 13.3 Hz, 1H), 3.78 (s, 6H), 6.31 (6,

3H); ¹³C NMR (75.5 MHz, CDCl₃) d 11.5, 18.9, 29.2,

The (R)-(ꢀ)-MTPA-Cl derived Mosher ester of (S)-(3,5-

dimethoxyphenyl)-2-methyl-1-propanol was prepared

by the procedure used for the (R)-enantiomer. From

0.0055 g (0.026 mmol) of alcohol was obtained

36.5, 43.7, 55.2, 97.5, 107.2, 144.2, 160.5; MS (EI) m/z

20

D

1

0.0093 g (84%) of the ester as a pale yellow gum. H

208 (50), 152 (100); ½aꢁ ꢀ18.2 (c 0.75, CH₂Cl₂).

NMR (500 MHz, CDCl₃) d 0.93 (d, J = 6.9 Hz, 3H),

2.12–2.22 (m, 1H), 2.41 (dd, J = 7.3, 13.8 Hz, 1H),

2.61 (dd, J = 6.8, 13.3 Hz, 1H), 3.56 (s, 3H), 3.76 (s,

6H), 4.09 (dd, J = 6.0, 10.5 Hz, 1H), 4.27 (dd, J = 5.5,

11.0 Hz, 1H), 6.27 (d, J = 2.3 Hz, 2H), 6.32 (t,

J = 2.3 Hz, 1H), 7.40–7.42 (m, 3H), 7.50–7.60 (m, 2H);

¹³C NMR (125 MHz, CDCl₃) d 16.8, 34.4, 39.8, 55.3,

55.5, 70.3, 98.1, 107.2, 127.5, 128.6, 129.7, 132.0,

5.12. (2⁰S)-3-(2⁰-Methylbutyl)-D⁸-tetrahydrocannabinol

(16, n = 1)

To 0.060 g (0.29 mmol) of dimethyl ether 17 (n = 1) at

0 °C was added 0.6 mL of 1 M boron tribromide in

CH₂Cl₂. The solution was stirred at 0 °C for 1 h,

warmed to ambient temperature, and stirred for 18 h.

After cooling to 0 °C, water was added to quench the

reaction. After dilution with CH₂Cl₂, the aqueous phase

was drawn oﬀ and the CH₂Cl₂was washed with brine

and dried (MgSO₄). The solvent was removed in vacuo

to give 0.051 g (99%) of resorcinol as a brown oil which

was used in the next step without puriﬁcation. ¹H NMR

(300 MHz, CHCl₃) d 0.82 (d, J = 6.6 Hz, 3H), 0.87 (t,

J = 7.3 Hz, 3H), 1.08–1.18 (m, 1H), 1.25–1.40 (m, 1H),

1.54–1.59 (m, 1H), 2.21 (dd, J = 8.1, 13.3 Hz, 1H),

2.49 (dd, J = 6.3, 13.3 Hz, 1H), 4.94 (br s, 2H), 6.32 (s,

3H); ¹³C NMR (75.5 MHz, CDCl₃) d 11.4, 18.9, 29.1,

36.3, 43.2, 100.2, 108.9, 145.0, 156.3.

141.9, 160.8, 167.0; MS (EI) m/z 426 (44), 152 (100);

20

D

½aꢁ ꢀ13.0 (c 0.37, CH₂Cl₂).

5.10. Triﬂuoromethanesulfonate of (R)-2-methyl-3-(3,5-

dimethoxyphenyl)-1-propanol

To a stirred solution of 0.349 g (1.66 mmol) of alcohol

19 and 0.17 mL (1.99 mmol) of dry pyridine in 10 mL

of dichloromethane at ꢀ78 °C was added 0.33 mL of tri-

ﬂuoromethanesulfonic anhydride. The reaction was stir-

red for 3 h at ꢀ78 °C and then quenched with water.

The phases were separated and the aqueous phase was

extracted with three portions of dichloromethane. The

combined organic extracts were washed with successive

portions of water and saturated brine, dried (MgSO₄),

and the solvent was removed in vacuo. The triﬂuoro-

methanesulfonate was obtained as a pale brown liquid

that was used in subsequent reactions without further

puriﬁcation. ¹H NMR (500 MHz, CDCl₃) d 1.04 (d,

J = 6.9 Hz, 3H), 2.20–2.30 (m, 1H), 2.51 (dd, J = 7.4,

13.3 Hz, 1H), 2.67 (dd, J = 6.9 Hz, 1H), 3.77 (s, 6H),

4.35 (dd, J = 5.5, 9.2 Hz, 1H), 4.38 (dd, J = 5.0,

9.2 Hz, 1H), 6.28–6.32 (m, 2H), 6.34 (t, J = 2.3 Hz,

1H); ¹³C NMR (125 MHz, CDCl₃) d 16.2, 35.2, 39.1,

55.3, 81.0, 98.5, 107.1, 140.9, 161.0. The triﬂuorome-

thanesulfonate of (S)-2-methyl-3-(3,5-dimethoxyphe-

nyl)-1-propanol (20) was prepared by the same

procedure and had identical spectroscopic properties.

To a stirred solution of 0.050 g (0.28 mmol) of the resor-

cinol derived from ether 17 (n = 1) and 0.042 g

(0.28 mmol) of p-menthadienol in 3 mL of dry benzene

at room temperature was added 0.005 g p-toluenesulfon-

ic acid and the solution was heated at reﬂux for 2 h.

After cooling to ambient temperature, the brown solu-

tion was poured into water and extracted with two por-

tions of ethyl acetate, dried (MgSO₄), and the solvent

was removed in vacuo. The residue was chromato-

graphed (petroleum ether/dichloromethane, 3:2) to give

0.086 g (91%) of (2⁰S)-3-(2⁰-methylbutyl)-D⁸-tetrahydro-

cannabinol (16, n = 1) as a yellow gum; ¹H NMR

(300 MHz, CHCl₃) d 0.83–0.91 (m, 6H), 1.11–1.47 (m,

2H), 1.12 (s, 3H), 1.38 (s, 3H), 1.55–1.62 (m, 1H), 1.70

(s, 3H), 1.78–1.90 (m, 3H), 2.13–2.23 (m, 2H), 2.45

(dd, J = 6.2, 13.3 Hz, 1H), 2.70 (td, J = 4.0, 10.8 Hz,

1H), 3.20 (dd, J = 4.0, 16.3 Hz, 1H), 4.79 (br s, 1H),

5.42 (br s, 1H), 6.07 (d, J = 1.2 Hz, 1H), 6.24 (d,

J = 1.2 Hz, 1H); ¹³C NMR (75.5 MHz, CHCl₃) d 11.5,

18.5, 19.1, 23.5, 27.5, 29.2, 31.5, 36.0, 36.3, 42.9, 44.9,

76.6, 108.4, 110.5, 110.9, 119.3, 134.7, 141.5, 154.6;

5.11. (S)-1-(3,5-Dimethoxyphenyl)-2-methylbutane (17,

n = 1)

To a stirred solution of 0.568 g (1.66 mmol) of the

triﬂate of alcohol 19 in 12 mL of THF was added

256

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

20

MS (EI) m/z 314 (50), 258 (100); ½aꢁ ꢀ213 (c 0.5,

To approximately 25 mL of liquid NH₃at ꢀ78 °C was

added, with stirring, 0.016 g of Li metal. The deep blue

solution was stirred at ꢀ78 °C for 10 min and a solution

of 0.080 g (0.18 mmol) of phosphate ester in 2 mL of dry

THF was added via cannula. The solution was stirred at

ꢀ78 °C for 2 h and then quenched with solid NH₄Cl.

The resulting suspension was warmed to ambient tem-

perature and following evaporation of the NH₃the res-

idue was taken up in a mixture of ether and water. The

organic phase was separated and the aqueous phase was

extracted with three portions of ether. The combined

organic extracts were washed with water, dried

(MgSO₄), and the solvent was removed at reduced pres-

sure. The residue was chromatographed (petroleum

ether/ethyl acetate, 99.5:0.5) to give 0.043 g (81%) of

D

CH₂Cl₂).

5.13. (2⁰S)-1-Methoxy-3-(2⁰-methylbutyl)-D⁸-tetrahydro-

cannabinol (JWH-351, 15, n = 1)

To a solution of 0.045 g (0.143 mmol) of cannabinoid 16

(n = 1) in 1 mL DMF was added 0.010 g KOH. The

solution was stirred at ambient temperature for 10 min

and 0.050 g (0.348 mmol) of methyl iodide was added.

The reaction mixture was stirred at ambient temperature

for 18 h, poured into water, and extracted with three

portions of ether. The combined extracts were washed

with water, dried (MgSO₄), and the solvent was re-

moved in vacuo to give, after chromatography (petro-

leum ether/ether, 3:2), 0.039 g (83%) of methoxy

cannabinoid 16 (n = 1) as a colorless oil. ¹H NMR

(500 MHz, CHCl₃) d 0.85 (d, J = 6.9 Hz, 3H), 0.90 (t,

J = 7.8 Hz, 3H), 1.08 (s, 3H), 1.10–1.20 (m, 1H), 1.33–

1.45 (m, 1H), 1.40 (s, 3H), 1.56–1.66 (m, 1H), 1.70 (s,

3H), 1.71–1.85 (m, 3H), 2.10–2.18 (m, 1H), 2.26 (dd,

J = 8.3, 13.3 Hz, 1H), 2.52 (dd, J = 6.0, 13.3 Hz, 1H),

2.66 (dt, J = 5.0, 11.0 Hz, 1H), 3.15 (dd, J = 4.6,

16.5 Hz, 1H), 3.79 (s, 3H), 5.41 (br d, J = 4.2 Hz, 1H),

6.21 (d, J = 1.4 Hz, 1H), 6.27 (d, J = 1.4 Hz, 1H); ¹³C

NMR (125 MHz, CHCl₃) d 11.6, 18.5, 19.2, 23.7, 27.7,

28.1, 29.4, 31.9, 36.4, 36.5, 43.6, 45.2, 55.2, 76.9, 103.8,

deoxycannabinoid as

a

colorless oil. ¹H NMR

(500 MHz, CHCl₃) d 0.84 (d, J = 6.5 Hz, 3H), 0.89 (t,

J = 7.4 Hz, 3H), 1.09–1.20 (m, 1H), 1.15 (s, 3H), 1.34–

1.45 (m, 1H), 1.38 (s, 3H), 1.58–1.75 (m, 2H), 1.73, (s,

3H), 1.77–1.87 (m, 1H), 1.91–2.00 (m, 1H), 2.10–2.20

(m, 1H), 2.27 (dd, J = 8.3, 13.8 Hz, 1H), 2.52 (dd,

J = 6.4, 13.3 Hz, 1H), 2.60 (dd, J = 5.5, 16.5 Hz, 1H),

2.64–2.72 (m, 1H), 5.44 (br d, J = 2.8 Hz, 1H), 6.59 (d,

J = 1.8 Hz, 1H), 6.66 (dd, J = 1.4, 7.8 Hz, 1H), 7.09 (d,

J = 7.8 Hz, 1H); ¹³C NMR (125 MHz, CHCl₃) d 11.6,

19.2, 19.3, 23.6, 27.6, 27.8, 29.3, 32.3, 36.6, 36.7, 43.0,

43.1, 76.9, 117.8, 120.1, 121.1, 123.0, 126.4, 133.6,

141.2, 152.8; MS (EI) m/z 298 (100), 215 (72); ½aꢁ

20

D

111.2, 112.0, 119.4, 135.1, 141.3, 154.2, 158.9; MS (EI)

20

D

m/z 328 (98), 272 (95), 245 (100); ½aꢁ ꢀ275 (c 0.48,

ꢀ220 (c 0.5, CH₂Cl₂); Calcd for C₂₁H₃₀O, 298.2297;

CH₂Cl₂); Calcd for C₂₂H₃₂O₂, 328.2402; found:

328.2402.

found: 298.2292.

5.15. (2⁰R)-3-(2⁰-Methylbutyl)-D⁸-tetrahydrocannabinol

(13, n = 1)

5.14. (2⁰S)-1-Deoxy-3-(2⁰-methylbutyl)-D⁸-tetrahydrocan-

nabinol (JWH-352, 14, n = 1)

Cannabinoid 13 (n = 1) was prepared from 2R-methyl-1-

(3,5-dimethoxyphenyl)butane (18, n = 1) by the proce-

dure used for the synthesis of 16 (n = 1). From 0.165 g

(0.79 mmol) of 2R-methyl-1-(3,5-dimethoxyphenyl)bu-

tane was obtained 0.100 g (40% for two steps) (2⁰R)-3-

(2⁰-methylbutyl)-D⁸-tetrahydrocannabinol (13, n = 1) as

a pale yellow gum following chromatography (petro-

To a stirred solution of 0.090 g (0.29 mmol) of cannab-

inoid 16 (n = 1) in 1 mL of dry THF at ambient temper-

ature was added 0.011 g (0.27 mmol) of sodium hydride

(60% in mineral oil). The resulting slurry was stirred un-

til the evolution of hydrogen ceased, then cooled to 0 °C,

and 0.063 g (0.58 mmol) of diethyl chlorophosphate was

added. The reaction mixture was allowed to warm to

ambient temperature, stirred for 3 h, poured into water,

and extracted with three portions of ether. The com-

bined ethereal extracts were washed with water and

1 M aqueous KOH, dried (MgSO₄), and the solvent

was removed in vacuo. Chromatography (petroleum

ether/ethyl acetate, 4:1) gave 0.090 g (70%) of phosphate

ester as a yellow oil which was used in the next step with-

1

leum ether/ether, 92:8). H NMR (500 MHz, CDCl₃) d

0.82 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H), 1.10

(s, 3H), 1.09–1.19 (m, 1H), 1.31–1.43 (m, 1H), 1.37 (s,

3H), 1.53–1.63 (m, 1H), 1.69 (s, 3H), 1.67–1.73 (m,

1H), 1.73–1.90 (m, 3H), 2.08–2.20 (m, 2H), 2.47 (dd,

J = 6.0, 13.3 Hz, 1H), 2.68 (dt, J = 4.6, 10.6 Hz, 1H),

3.2 (dd, J = 4.6, 16.5 Hz, 1H), 5.41 (br d, J = 4.2 Hz,

1H), 6.07 (d, J = 1.4 Hz, 1H), 6.23 (d, J = 1.4 Hz, 1H);

¹³C NMR (125 MHz, CDCl₃) d 11.5, 18.6, 19.2, 23.6,

27.7, 28.0, 29.3, 31.7, 36.1, 36.4, 43.0, 45.0, 76.9, 108.5,

1

out further puriﬁcation; H NMR (500 MHz, CHCl₃) d

0.84 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.8 Hz, 3H), 1.09 (s,

3H), 1.30 (t, J = 6.8 Hz, 3H), 1.34–1.44 (m, 1H), 1.35 (t,

J = 6.4 Hz, 3H), 1.56–1.67 (m, 1H), 1.69 (s, 3H), 1.74–

1.94 (m, 3H), 2.08–2.20 (m, 1H), 2.25 (dd, J = 8.3,

13.3 Hz, 1H), 2.51 (dd, J = 6.4, 13.3 Hz, 1H), 2.78 (dt,

J = 4.6, 10.5 Hz, 1H), 3.05 (dd, J = 4.1, 17 Hz, 1H),

4.10–4.30 (m, 4H), 5.42 (br d, J = 4.6 Hz, 1H), 6.46 (s,

1H), 6.69 (s, 1H); ¹³C NMR (125 MHz, CHCl₃) d

11.6, 16.2 (m), 18.5, 19.0, 23.5, 27.5, 27.9, 29.3, 31.8,

36.2, 36.4, 43.0, 64.5 (d, J = 5.7 Hz), 76.9, 112.7, 115.1

(d, J = 6.7 Hz), 115.1, 119.5, 134.5, 141.7, 149.8 (d,

110.6, 110.9, 119.4, 134.9, 141.6, 154.7, 154.8; MS (EI)

20

D

m/z 314 (61), 258 (93), 231 (100); ½aꢁ ꢀ215 (c 0.5,

CH₂Cl₂).

5.16. (2⁰R)-1-Methoxy-3-(2⁰-methylbutyl)-D⁸-tetrahydro-

cannabinol (JWH-359, 12, n = 1)

Methoxycannabinoid 12 (n = 1) was prepared as de-

scribed above for the synthesis of 15 (n = 1). From

0.055 g (0.175 mmol) of cannabinoid 13 (n = 1) was ob-

1

J = 6.7 Hz), 154.5; MS (EI) m/z 450 (28), 367 (100),

tained 0.047 g (82%) of JWH-359. H NMR (500 MHz,

CDCl₃) d 0.85 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.3 Hz,

20

D

296 (34); ½aꢁ ꢀ150 (c 0.5, CH₂Cl₂).

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

257

3H), 1.09 (s, 3H), 1.10–1.22 (m, 1H), 1.33–1.45 (m, 1H),

1.37 (s, 3H), 1.58–1.68 (m, 1H), 1.70 (s, 3H), 1.73–1.85

(m, 3H), 2.08–2.20 (m, 1H), 2.23 (dd, J = 8.3, 13.3 Hz,

1H), 2.54 (dd, J = 6.5, 13.3 Hz, 1H), 2.65 (dt, J = 4.6,

11.0 Hz, 1H), 3.15 (dd, J = 5.5, 17.0 Hz, 1H), 3.79 (s,

3H), 5.41 (br d, J = 4.2 Hz, 1H), 6.21 (d, J = 1.4 Hz,

1H), 6.27 (d, J = 1.4 Hz, 1H); ¹³C NMR (125 MHz,

CDCl₃) d 11.6, 18.5, 19.2, 23.7, 27.7, 28.1, 29.4, 31.9,

36.4, 36.5, 43.6, 45.2, 55.2, 76.9, 103.9, 111.2, 112.0,

added sequentially 0.013 g (0.13 mmol) of CuCl and

1.17 mL (3.90 mmol) of 3 M ethylmagnesium bromide

in ether. The yellow-green solution was stirred at

ꢀ78 °C for 6 h, warmed to ambient temperature, and

stirred for 18 h. The black slurry was ﬁltered through

Celite and the residue was washed well with ether. The

ethereal solution was dried (MgSO₄), and the solvent

was removed at reduced pressure. Chromatography

(petroleum ether/ethyl acetate, 95:5) gave 0.199 g

(87%) of S-1-(3,5-dimethoxyphenyl)-2-methylpentane

(17, n = 2) as a colorless oil. ¹H NMR (300 MHz,

CDCl₃) d 0.85–0.91 (m, 6H), 1.10–1.39 (m, 4H), 1.69–

1.73 (m, 1H), 2.28 (dd, J = 8.2, 13.3 Hz, 1H), 2.57 (dd,

J = 6.1, 13.3 Hz, 1H), 3.78 (s, 6H), 6.31 (s, 3H); ¹³C

NMR (75.5 MHz, CDCl₃) d 14.3, 19.4, 20.2, 34.5,

119.4, 135.1, 141.4, 154.3, 158.9; MS (EI) m/z 328 (67),

20

D

Calcd for C₂₂H₃₂O₂, 328.2402; found: 328.2405.

272 (69), 245 (100); ½aꢁ ꢀ269 (c 0.5, CH₂Cl₂); HRMS

5.17. (2⁰R)-1-Deoxy-3-(2⁰-methylbutyl)-D⁸-tetrahydrocan-

nabinol (JWH-360, 11, n = 1)

39.0, 44.1, 55.2, 97.5, 107.2, 144.2, 160.5; MS (EI) m/z

20

D

Deoxycannabinoid 11 (n = 1) was prepared from (2⁰R)-

3-(2⁰-methylbutyl)-D⁸-tetrahydrocannabinol (13, n = 1)

by the procedure used for the preparation of 14

(n = 1). From 0.099 g (0.31 mmol) of (2⁰R)-3-(2⁰-methyl

butyl)-D⁸-tetrahydrocannabinol was obtained 0.060 g

(62% for two steps) of deoxycannabinoid JWH-360 as

a colorless oil after chromatography (petroleum ether/

ether, 98:2). ¹H NMR (500 MHz, CDCl₃) d 0.84 (d,

J = 6.9 Hz, 3H), 0.89 (t, J = 7.8 Hz, 3H), 1.10–1.21 (m,

1H), 1.15 (s, 3H), 1.34–1.44 (m, 1H), 1.38 (s, 3H),

1.57–1.76 (m, 2H), 1.73 (s, 3H), 1.77–1.86 (m, 1H),

1.91–2.00 (m, 1H), 2.11–2.20 (m, 1H), 2.25 (td, J = 8.3,

13.3 Hz, 1H), 2.50–2.72 (m, 3H), 5.45 (br d,

J = 2.8 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.66 (dd,

J = 1.4, 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) d 11.7, 19.2, 19.3, 23.6, 27.6,

27.8, 29.4, 32.3, 36.6, 36.7, 43.0, 43.1, 76.9, 117.8,

222 (50), 152 (100); ½aꢁ ꢀ14.6 (c 0.50, CH₂Cl₂). (R)-1-

(3,5-Dimethoxyphenyl)-2-methylpentane (18, n = 2)

was prepared from alcohol 20 in 76% yield by the same

procedure. The spectroscopic properties are identical to

those of the S-enantiomer and are identical to those

reported previously for these compounds.³⁶

5.20. (2⁰S)-3-(2⁰-Methylpentyl)-D⁸-tetrahydrocannabinol

(16, n = 2)

Cannabinoid 16 (n = 2) was prepared from dimethyl

ether 17 (n = 2) by the procedure employed for the prep-

aration of 16 (n = 1). From 0.250 g (1.13 mmol) of 17

(n = 2) 0.101 g (29% for two steps) of (2⁰S)-3-(2⁰-methyl-

pentyl)-D⁸-tetrahydrocannabinol (16, n = 2) was ob-

tained as a yellow gum following chromatography

(petroleum ether/dichloromethane, 3:2). ¹H NMR

(300 MHz, CDCl₃) d 0.82 (d, J = 6.5 Hz, 3H), 0.86 (t,

J = 6.8 Hz, 3H), 1.05–1.41 (m, 4H), 1.10 (s, 3H), 1.37

(s, 3H), 1.66–1.72 (m, 1H), 1.69 (s, 3H), 1.78–1.89 (m,

3H), 2.12–2.19 (m, 2H), 2.45 (dd, J = 5.9, 13.3 Hz,

1H), 2.69 (td, J = 4.2, 10.8 Hz, 1H), 3.21 (dd, J = 4.2,

16.2 Hz, 1H), 5.05 (br s, 1H), 5.42 (br s, 1H), 6.06 (d,

J = 1.2 Hz, 1H), 6.24 (d, J = 1.2 Hz, 1H); ¹³C NMR

(75.5 MHz, CDCl₃) d 14.2, 18.4, 19.5, 20.2, 23.4, 27.5,

27.8, 31.6, 34.3, 36.0, 39.1, 43.3, 44.9, 76.6, 108.4,

120.1, 121.2, 123.0, 126.4, 133.6, 141.2, 152.8; MS (EI)

20

D

HRMS Calcd for C₂₁H₃₀O, 298.2297; found: 298.2298.

m/z 298 (100), 215 (85); ½aꢁ ꢀ157 (c 1.0, CH₂Cl₂);

5.18. Methanesulfonate of R-2-Methyl-3-(3,5-dimethoxy-

phenyl)-1-propanol

To a stirred solution of 0.750 g (3.57 mmol) of alcohol 19

in 6 mL of dry CHCl₃were added sequentially 0.5 mL

(3.57 mmol) of triethylamine, 0.409 g (3.57 mmol) of

methanesulfonyl chloride, and 0.043 g (0.357 mmol) of

4-DMAP. The reaction mixture was stirred at ambient

temperature for 1 h, poured into water, and washed with

1 M aqueous KOH, and water. After drying (MgSO₄), the

solvent was removed in vacuo and the residue was chro-

matographed (petroleum ether/ethyl acetate, 4:1) to give

0.966 g (94%) of mesylate as a yellow oil that was used

110.6, 110.8, 119.3, 134.7, 141.4, 154.7; MS (EI) m/z

20

D

328 (50), 258 (100); ½aꢁ ꢀ219 (c 0.5, CH₂Cl₂). The spec-

troscopic properties are identical to those reported

previously.³⁶

5.21. (2⁰S)-1-Methoxy-3-(2⁰-methyl pentyl)-D⁸-tetrahy-

drocannabinol (JWH-254, 15, n = 2)

1

in subsequent reactions without further puriﬁcation. H

Methyl ether 15 (n = 2) was prepared from cannabinoid

16 (n = 2) by the procedure employed for the prepara-

tion of 15 (n = 1). From 0.038 g (0.116 mmol) of 16

(n = 2) was obtained 0.039 g (99%) of JWH-254 as a yel-

low oil following chromatography (petroleum ether/di-

chloromethane, 3:2). ¹H NMR (300 MHz, CDCl₃) d

0.83–0.90 (m, 6H), 1.08–1.43 (m, 4H), 1.12 (s, 3H),

1.37 (s, 3H), 1.66–1.72 (m, 1H), 1.70 (s, 3H), 1.77–1.82

(m, 3H), 2.12–2.13 (m, 1H), 2.24 (dd, J = 8.2, 13.3 Hz,

1H), 2.53 (dd, J = 6.0, 13.3 Hz, 1H), 2.65 (td, J = 6.0,

10.8 Hz, 1H), 3.15 (dd, J = 6.0, 17.0 Hz, 1H), 3.79 (s,

3H), 5.42 (d, J = 4.1 Hz, 1H), 6.21 (d, J = 1.2 Hz, 1H),

6.27 (d, J = 1.1 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃)

NMR (300 MHz, CDCl₃) d 1.01 (d, J = 6.7 Hz, 3H),

2.14–2.25 (m, 1H), 2.47 (dd, J = 7.6, 13.5 Hz, 1H), 2.70

(dd, J = 6.9, 13.5 Hz, 1H), 3.00 (s, 3H), 3.78 (s, 6H),

4.01–4.13 (m, 2H), 6.32 (s, 3H); ¹³C NMR (75.5 MHz,

CDCl₃) d 16.5, 34.8, 37.2, 39.4, 55.3, 73.6, 98.2, 107.2,

20

D

141.5, 160.8; MS (EI) m/z 288 (50), 151 (100); ½aꢁ +25.4

(c 0.21, CH₂Cl₂).

5.19. (S)-1-(3,5-Dimethoxyphenyl)-2-methylpentane (17, n = 2)

To a stirred solution of 0.373 g (1.30 mmol) of the mes-

ylate of alcohol 19 in 7 mL of dry THF at ꢀ78 °C were

258

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

d 14.3, 18.4, 19.5, 20.2, 23.5, 27.6, 28.0, 31.8, 34.4, 36.3,

39.2, 43.9, 45.1, 55.1, 76.4, 103.7, 111.1, 119.3, 135.0,

(br dd, J = 3.7, 8.7 Hz, 1H), 2.20 (dd, J = 8.3, 13.3 Hz,

1H), 2.55 (dd, J = 6.0, 13.3 Hz, 1H), 2.65 (dt, J = 4.6,

11.0 Hz, 1H), 3.15 (dd, J = 5.0, 17.0 Hz, 1H), 3.79 (s,

3H), 5.41 (d, J = 3.7 Hz, 1H), 6.20 (s, 1H), 6.28 (s,

1H); ¹³C NMR (125 MHz, CDCl₃) d 14.4, 18.5, 19.6,

20.3, 23.7, 27.7, 28.1, 31.9, 34.6, 36.4, 39.3, 44.0, 45.2,

55.2, 76.9, 103.9, 111.2, 112.0, 119.4, 135.2, 141.4,

141.2, 154.1, 158.8; MS (EI) m/z 342 (50), 272 (100);

½aꢁ

20

D

C₂₃H₃₂O₂, 342.2554; found: 342.2558.

ꢀ131 (c 0.3, CH₂Cl₂); HRMS Calcd for

5.22. (2⁰S)-1-Deoxy-3-(2⁰-methyl pentyl)-D⁸-tetrahydro-

cannabinol (JWH-255, 14, n = 2)

154.3, 158.9; MS (EI) m/z 342 (81), 272 (95), 259

20

D

C₂₃H₃₄O₂, 342.2559; found: 342.2554.

(100); ½aꢁ ꢀ244 (c 0.32, CH₂Cl₂); HRMS Calcd for

Deoxyannabinoid 14 (n = 2) was prepared from cannab-

inoid 16 (n = 2) by the procedure employed for the prep-

aration of 14 (n = 1). From 0.060 g (0.183 mmol) of 16

(n = 2) was obtained 0.060 g (70% for two steps) of

JWH-255 as a yellow gum following chromatography

(petroleum ether/ethyl acetate, 4:1). ¹H NMR

(300 MHz, CDCl₃) d 0.82–0.90 (m, 6H), 1.09–1.43 (m,

4H), 1.15 (s, 3H), 1.38 (s, 3H), 1.66–1.73 (m, 2H), 1.70

(s, 3H), 1.81–1.99 (m, 2H), 2.12–2.19 (m, 1H), 2.25

(dd, J = 8.2, 13.3 Hz, 1H), 2.52–2.70 (m, 2H), 2.55 (dd,

J = 5.8, 13.3 Hz, 1H), 5.42 (d, J = 4.0 Hz, 1H), 6.59 (d,

J = 1.5 Hz, 1H), 6.66 (dd, J = 1.5, 7.8 Hz, 1H), 7.10 (d,

J = 7.8 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) d 14.3,

19.2, 19.5, 20.2, 23.5, 27.5, 27.7, 32.2, 34.5, 36.6, 39.1,

42.9, 43.4, 76.8, 117.7, 119.9, 120.9, 122.9, 126.2,

5.25. (2⁰R)-1-Deoxy-3-(2⁰-methylpentyl)-D⁸-tetrahydro-

cannabinol (JWH-353, 11, n = 2)

Deoxycannabinoid 11 (n = 2) was prepared from (2⁰R)-

3-(2⁰-methyl

pentyl)-D⁸-tetrahydrocannabinol

(13,

n = 2) by the procedure used for the preparation of 15

(n = 1). From 0.099 g (0.31 mmol) of 13 (n = 2) was ob-

tained 0.060 g (62% for two steps) of JWH-353 as a col-

orless oil after chromatography (petroleum ether/ether,

98:2). ¹H NMR (500 MHz, CDCl₃)

d 0.75 (d,

J = 6.9 Hz, 3H), 0.80 (t, J = 6.9 Hz, 3H), 1.00–1.11 (m,

1H), 1.07 (s, 3H), 1.17–1.35 (m, 3H), 1.31 (s, 3H),

1.58–1.68 (m, 2H), 1.65 (s, 3H), 1.68–1.78 (m, 1H),

1.83–1.93 (m, 1H), 2.03–2.11 (m, 1H), 2.15 (dd,

J = 8.3, 13.3 Hz, 1H), 2.46–2.57 (m, 2H), 2.60 (dt,

J = 5.5, 11.5 Hz, 1H), 5.37 (br s, 1H), 6.52 (d,

J = 1.4 Hz, 1H), 6.58 (dd, J = 7.8, 1.4 Hz, 1H), 7.01 (d,

J = 8.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) d 14.4,

19.3, 19.6, 20.3, 23.6, 27.6, 27.8, 32.3, 34.7, 36.7, 39.3,

43.0, 43.5, 76.9, 117.7, 120.1, 121.2, 123.0, 126.4,

133.5, 141.1, 152.7; MS (EI) m/z 312 (60), 229 (100);

20

D

312.2457; found: 312.2453.

½aꢁ ꢀ119 (c 0.5, CH₂Cl₂); HRMS Calcd for C₂₂H₃₂O,

5.23. (2⁰R)-3-(2⁰-methylpentyl)-D⁸-tetrahydrocannabinol

(13, n = 2)

Cannabinoid 13 (n = 2) was prepared from (R)-2-meth-

yl-1-(3,5-dimethoxyphenyl)pentane (18, n = 2) by the

procedure used for the synthesis of 16 (n = 1). From

0.389 g (1.14 mmol) of (R)-2-methyl-1-(3,5-dimethoxy

phenyl)pentane was obtained 0.200 g (56% for two

steps) of cannabinoid 13 (n = 2) as a pale yellow gum

following chromatography (petroleum ether/ether, 9:1).

¹H NMR (500 MHz, CDCl₃) d 0.82 (d, J = 6.4 Hz,

3H), 0.86 (t, J = 6.9 Hz, 3H), 1.06–1.18 (m, 1H), 1.12

(s, 3H), 1.20–1.43 (m, 3H), 1.38, (s, 3H), 1.70 (s, 3H),

1.60–1.75 (m, 1H), 1.76–1.93 (m, 3H), 2.09–2.20 (m,

2H), 2.48 (dd, J = 6.0, 13.3 Hz, 1H), 2.69 (dt, J = 4.6,

11.0 Hz, 1H), 3.20 (dd, J = 4.2, 16.0 Hz, 1H), 4.83 (d,

J = 1.8 Hz, 1H), 5.42 (br d, J = 4.6 Hz, 1H), 6.06 (d,

J = 1.4 Hz, 1H), 6.24 (d, J = 1.9 Hz, 1H); ¹³C NMR

(125 MHz, CDCl₃) d 14.4, 18.6, 19.6, 20.3, 23.6, 27.7,

28.0, 31.7, 34.4, 36.1, 39.2, 43.4, 45.0, 76.9, 108.6,

133.6, 141.2, 152.8; MS (EI) m/z 312 (100), 229 (65);

½aꢁ ꢀ157 (c 0.8, CH₂Cl₂); HRMS Calcd for C₂₂H₃₂O,

20

D

312.2453; found: 312.2446.

5.26. (S)-1-(3,5-Dimethoxyphenyl)-2-methylhexane (17

n = 3)

Dimethyl ether 17 (n = 3) was prepared from the mesy-

late of alcohol 19 by the procedure employed for the

preparation of 17 (n = 2), however n-propylmagnesium

bromide was used in place of ethylmagnesium bromide.

From 0.400 g (1.39 mmol) of mesylate was obtained

0.250 g (76%) of 17 (n = 3) as a yellow oil following

chromatography (petroleum ether/ethyl acetate, 95:5).

¹H NMR (300 MHz, CDCl₃) d 0.83–0.91 (m, 6H),

1.09–1.34 (m, 6), 1.57–1.67 (m, 1H), 2.27 (dd, J = 8.3,

13.3 Hz, 1H), 2.57 (dd, J = 6.1, 13.3 Hz, 1H), 3.78 (s,

6H), 6.31 (s, 3H); ¹³C NMR (75.5 MHz, CDCl₃) d

110.7, 111.0, 119.4, 134.9, 141.6, 154.7, 154.8; MS (EI)

20

D

m/z 328 (80), 258 (100), 245 (79); ½aꢁ ꢀ231 (c 0.6,

14.1, 19.5, 22.9, 29.3, 34.8, 36.5, 44.0, 55.2, 97.5, 107.2,

144.2, 160.5; MS (EI) m/z 236 (50), 152 (100); ½aꢁ

20

D

CH₂Cl₂). The spectroscopic properties of this compound

are identical to those reported previously.³⁶

ꢀ9.2 (c 0.75, CH₂Cl₂).

5.24. (2⁰R)-1-Methoxy-3-(2⁰-methylpentyl)-D⁸-tetrahy-

drocannabinol (JWH-354, 12, n = 2)

5.27. (2⁰S)-3-(2⁰-Methylhexyl)-D⁸-tetrahydrocannabinol

(16, n = 3)

Methoxycannabinoid 12 (n = 2) was prepared as de-

scribed above for the synthesis of 15 (n = 1). From

0.060 g (0.182 mmol) of 13 (n = 2) was obtained

0.045 g (72%) of JWH-354. ¹H NMR (500 MHz,

CDCl₃) d 0.84 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz,

3H), 1.06–1.17 (m, 1H), 1.09 (s, 3H), 1.23–1.44 (m,

3H), 1.38 (s, 3H), 1.63–1.86 (m, 4H), 1.70 (s, 3H), 2.12

Cannabinoid 16 (n = 3) was prepared from dimethyl

ether 17 (n = 3) by the procedure employed for the prep-

aration of 16 (n = 1). From 0.250 g (1.06 mmol) of 16

(n = 3) was obtained 0.140 g (39% for two steps) of

(2⁰S)-3-(2⁰-methylhexyl)-D⁸-tetrahydrocannabinol fol-

lowing chromatography (petroleum ether/dichlorometh-

ane, 3:2). ¹H NMR (300 MHz, CDCl₃) d 0.81 (d,

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

259

J = 6.6 Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H), 1.05–1.41 (m,

6H), 1.10 (s, 3H), 1.38 (s, 3H), 1.63–1.74 (m, 1H), 1.69

(s, 3H), 1.78–1.88 (m, 3H), 2.11–2.28 (m, 2H), 2.45

(dd, J = 5.9, 13.3 Hz, 1H), 2.70 (td, J = 4.2, 11.0 Hz,

1H), 3.21 (dd, J = 4.2, 16.2 Hz, 1H), 5.12 (br s, 1H),

5.40 (br s, 1H), 6.05 (d, J = 1.2 Hz, 1H), 6.24 (d,

J = 1.2 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) d 14.1,

18.4, 19.5, 22.9, 23.5, 27.5, 27.9, 29.4, 31.6, 34.5, 36.0,

tained 0.350 g (89%) of 18 (n = 3) as a colorless oil after

chromatography (petroleum ether/ether, 96.5:3.5). The

spectroscopic properties are identical to those of the

20

D

S-enantiomer: ½aꢁ +6.75 (c 1.41, CH₂Cl₂).

5.31. (2⁰R)-3-(2⁰-Methylhexyl)-D⁸-tetrahydrocannabinol

(13, n = 3)

36.5, 43.3, 44.9, 76.6, 108.4, 110.5, 110.8, 119.3, 134.7,

141.5, 154.5; MS (EI) m/z 342 (50), 258 (100); ½aꢁ

Cannabinoid 13 (n = 3) was prepared from (R)-2-meth-

yl-1-(3,5-dimethoxyphenyl)hexane (18, n = 3) by the

procedure used for the synthesis of 16 (n = 1). From

0.527 g (1.54 mmol) of (R)-2-methyl-1-(3,5-dimethoxy-

phenyl)hexane was obtained 0.210 g (45% for two steps)

of cannabinoid 13 (n = 3) as a pale yellow gum following

chromatography (petroleum ether/ether, 91:9). ¹H

NMR (300 MHz, CDCl₃) d 0.82 (d, J = 6.4 Hz, 3H),

0.87 (t, J = 6.4 Hz, 3H), 1.10 (s, 3H), 1.07–1.18 (m,

1H), 1.20–1.36 (m, 5H), 1.37 (s, 3H), 1.59–1.72 (m,

1H), 1.70 (s, 3H), 1.75–1.90 (m, 3H), 2.12 (dd, J = 8.3,

13.3 Hz, 2H), 2.48 (dd, J = 5.5, 13.3 Hz, 1H), 2.68 (dt,

J = 4.6, 6.0 Hz, 1H), 3.19 (dd, J = 4.6, 16.5 Hz, 1H),

4.89 (s, 1H), 5.41 (d, J = 4.1 Hz, 1H), 6.06 (d,

J = 1.4 Hz, 1H), 6.23 (d, J = 1.4 Hz, 1H); ¹³C NMR

(75.5 MHz, CDCl₃) d 14.3, 18.6, 19.6, 23.0, 23.6, 27.7,

28.0, 29.5, 31.7, 34.7, 36.1, 36.7, 43.4, 45.0, 76.9, 108.5,

20

D

ꢀ207 (c 0.45, CH₂Cl₂).

5.28. (2⁰S)-1-Methoxy-3-(2⁰-methylhexyl)-D⁸-tetrahydro-

cannabinol (JWH-256, 15, n = 3)

Methyl ether 15 (n = 3) was prepared from cannabinoid

16 (n = 3) by the procedure employed for the prepara-

tion of 15 (n = 1). From 0.060 g (0.175 mmol) of 16

(n = 3) was obtained 0.052 g (85%) of JWH-256 follow-

ing chromatography (petroleum ether/dichloromethane,

1

3:2). H NMR (300 MHz, CDCl₃) d 0.83–0.90 (m, 6H),

1.08–1.43 (m, 6H), 1.12 (s, 3H), 1.37 (s, 3H), 1.68–1.72

(m, 1H), 1.69 (s, 3H), 1.76–1.82 (m, 3H), 2.12–2.13 (m,

1H), 2.24 (dd, J = 8.3, 13.3 Hz, 1H), 2.53 (dd, J = 5.9,

13.3 Hz, 1H), 2.65 (td, J = 4.7, 10.8 Hz, 1H), 3.15 (dd,

J = 4.7 Hz, 16.5. 1H), 3.79 (s, 3H), 5.42 (d, J = 4.0 Hz,

1H), 6.20 (d, J = 1.2 Hz, 1H), 6.27 (d, J = 1.2 Hz, 1H);

¹³C NMR (75.5 MHz, CDCl₃) d 14.2, 18.4, 19.6, 23.0,

23.5, 27.6, 28.0, 29.4, 31.8, 34.7, 36.3, 36.6, 43.9, 45.1,

110.6, 110.9, 119.4, 134.9, 141.6, 154.7, 154.8; MS (EI)

20

D

m/z 342 (54), 258 (100); ½aꢁ ꢀ211 (c 0.45, CH₂Cl₂).

5.32. (2⁰R)-1-Methoxy-3-(2⁰-methyl hexyl)-D⁸-tetrahy-

drocannabinol (JWH-356, 12, n = 3)

55.1, 76.4, 103.7, 111.1, 119.3, 135.0, 141.2, 154.1,

20

D

158.8; MS (EI) m/z 356 (50), 272 (100); ½aꢁ ꢀ126 (c

0.5, CH₂Cl₂); HRMS Calcd for C₂₄H₃₆O₂, 356.2714;

found: 356.2715.

Methoxycannabinoid 12 (n = 3) was prepared as de-

scribed above for the synthesis of 15 (n = 1). From

0.060 g (0.175 mmol) of cannabinoid 13 (n = 3) was ob-

5.29. (2⁰S)-1-Deoxy-3-(2⁰-methyl hexyl)-D⁸-tetrahydro-

cannabinol (JWH-257, 14, n = 3)

tained 0.053 g (85%) of JWH-356. H NMR (300 MHz,

1

CDCl₃) d 0.84 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 6.9 Hz,

3H), 1.08 (s, 3H), 1.10–1.19 (m, 1H), 1.20–1.40 (m,

5H), 1.37 (s, 3H), 1.62–1.87 (m, 4H), 1.70 (s, 3H),

2.08–2.18 (m, 1H), 2.21 (dd, J = 8.3, 13.3 Hz, 1H),

2.55 (dd, J = 6.0, 13.3 Hz, 1H), 2.65 (dt, J = 5.1,

11.0 Hz, 1H), 3.15 (dd, J = 5.1, 17.0 Hz, 1H), 3.79 (s,

3H), 5.41 (d, J = 4.1 Hz, 1H), 6.20 (d, J = 1.4 Hz, 1H),

6.27 (d, J = 1.8 Hz, 1H);¹³C NMR (75.5 MHz, CDCl₃)

d 14.3, 18.5, 19.7, 23.0, 23.7, 27.7, 28.1, 29.5, 31.9,

34.8, 36.4, 36.7, 43.9, 45.2, 55.2, 76.9, 103.9, 111.2,

Deoxyannabinoid 14 (n = 3) was prepared from cannab-

inoid 16 (n = 3) by the procedure employed for the prep-

aration of 14 (n = 1). From 0.080 g (0.225 mmol) of 16

(n = 3) was obtained 0.058 g (76% for two steps) of 14

(n = 3) following chromatography (petroleum ether/eth-

yl acetate, 4:1). ¹H NMR (300 MHz, CDCl₃) d 0.84–0.91

(m, 6H), 1.10–1.40 (m, 8H), 1.16 (s, 3H), 1.39 (s, 3H),

1.66–1.73 (m, 2H), 1.69 (s, 3H), 1.81–1.99 (m, 2H),

2.14–2.18 (m, 1H), 2.25 (dd, J = 8.2, 13.3 Hz, 1H),

2.52–2.70 (m, 2H), 2.55 (dd, J = 5.8, 13.3 Hz, 1H),

5.45 (d, J = 4.1 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H), 6.67

(dd, J = 1.5, 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H); ¹³C

NMR (75.5 MHz, CDCl₃) d 14.1, 19.2, 19.6, 22.7,

23.5, 27.0, 27.5, 27.7, 29.7, 32.2, 34.8, 36.6, 36.8, 42.9,

112.0, 119.4, 135.1, 141.4, 154.3, 158.9; MS (EI) m/z

20

D

HRMS Calcd for C₂₄H₃₆O₂, 356.2715; found: 356.2712.

356 (79), 273 (100), 272 (72); ½aꢁ ꢀ234 (c 0.7, CH₂Cl₂);

5.33. (2⁰R)-1-Deoxy-3-(2⁰-methyl hexyl)-D⁸-tetrahydro-

cannabinol (JWH-355, 11, n = 3)

43.4, 76.7, 117.7, 119.9, 121.0, 122.9, 126.2, 133.5,

141.5, 152.7; MS (EI) m/z 340 (100), 257 (75); ½aꢁ

20

D

Deoxycannabinoid 11 (n = 3) was prepared from 13

(n = 3) by the procedure used for the preparation of 14

(n = 1). From 0.067 g (0.19 mmol) of 13 (n = 3) was ob-

tained 0.054 g (84% for two steps) of JWH-355 as a col-

orless oil after chromatography (petroleum ether/ether,

97.5:2.5): ¹H NMR (300 MHz, CDCl₃) d 0.84 (d,

J = 6.4 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H), 1.10–1.20 (m,

1H), 1.16 (s, 3H), 1.23–1.38 (m, 5H), 1.39 (s, 3H),

1.66–1.75 (m, 2H), 1.74 (s, 3H), 1.77–1.88 (m, 1H),

1.92–2.01 (m, 1H), 2.12–2.20 (m, 1H), 2.23 (dd,

J = 8.7, 13.3 Hz, 1H), 2.55–2.75 (m, 3H), 5.46 (br s,

ꢀ104 (c 0.17, CH₂Cl₂); HRMS Calcd for C₂₃H₃₄O,

326.2605; found: 326.2609.

5.30. (R)-2-Methyl-1-(3,5-dimethoxyphenyl)hexane (18,

n = 3)

This compound was prepared from the triﬂate of alco-

hol 20 (n = 3) by the procedure employed for the synthe-

sis of (S)-2-methyl-1-(3,5-dimethoxyphenyl)butane (17,

n = 1). From 0.567 g (1.66 mmol) of triﬂate was ob-

260

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

1H), 6.60 (d, J = 1.4 Hz, 1H), 6.67 (dd, J = 1.9, 7.8 Hz,

1H), 7.10 (d, J = 8.3 Hz, 1H); ¹³C NMR (75.5 MHz,

CDCl₃) d 14.3, 19.3, 19.6, 23.0, 23.6, 27.6, 27.8, 29.5,

32.3, 34.9, 36.7, 43.0, 43.5, 76.9, 117.7, 120.1, 121.1,

J = 6.0, 13.3 Hz, 1H), 2.66 (td, J = 4.3, 10.8 Hz, 1H),

3.14 (dd, J = 4.3, 16.5 Hz, 1H), 3.80 (s, 3H), 5.41 (d,

J = 4.0 Hz, 1H), 6.20 (d, J = 1.2 Hz, 1H), 6.27 (d,

J = 1.2 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) d 14.2,

18.3, 19.7, 23.1, 23.5, 27.6, 28.0, 29.4, 31.8, 34.7, 36.3,

36.6, 37.2, 43.9, 45.1, 55.2, 76.4, 103.7, 111 (1), 119.2,

123.0, 126.4, 133.6, 141.3, 152.8; MS (EI) m/z 326

20

D

Calcd for C₂₃H₃₄O, 326.2610; found: 326.2604.

(100), 243 (88); ½aꢁ ꢀ160 (c 0.55, CH₂Cl₂); HRMS

135.1, 141.3, 154.1, 158.8; MS (EI) m/z 370 (50), 272

20

D

C₂₅H₃₈O₂, 370.2872; found: 370.2876.

(100); ½aꢁ ꢀ122 (c 0.18, CH₂Cl₂); HRMS Calcd for

5.34. (S)-1-(3,5-Dimethoxyphenyl)-2-methylheptane (17,

n = 4)

5.37. (2⁰S)-1-Deoxy-3-(2⁰-methyl heptyl)-D⁸-tetrahydro-

cannabinol (JWH-264, 14, n = 4)

Dimethyl ether 17 (n = 4) was prepared from the mesy-

late of alcohol 19 by the procedure employed for the

preparation of 17 (n = 2), however, n-butylmagnesium

bromide was used in place of ethylmagnesium bromide.

From 0.400 g (1.39 mmol) of mesylate was obtained

0.309 g (89%) of 17 (n = 4) as a yellow oil following

chromatography (petroleum ether/ethyl acetate, 95:5).

¹H NMR (300 MHz, CDCl₃) d 0.83–0.91 (m, 6H),

1.05–1.43 (m, 8H), 1.60–1.69 (m, 1H), 2.28 (dd,

J = 8.3, 13.3 Hz, 1H), 2.58 (dd, J = 6.0, 13.3 Hz, 1H),

3.78 (s, 6H), 6.30 (s, 3H); ¹³C NMR (75.5 MHz, CDCl₃)

Deoxyannabinoid 14 (n = 4) was prepared from cannab-

inoid 16 (n = 4) by the procedure employed for the prep-

aration of 14 (n = 1). From 0.080 g (0.225 mmol) of 16

(n = 4) was obtained 0.058 g (76% for two steps) of

JWH-264 following chromatography (petroleum ether/

ethyl acetate, 4:1): ¹H NMR (300 MHz, CDCl₃) d

0.84–0.91 (m, 6H), 1.10–1.40 (m, 8H), 1.16 (s, 3H),

1.39 (s, 3H), 1.66–1.73 (m, 2H), 1.69 (s, 3H), 1.81–1.99

(m, 2H), 2.14–2.18 (m, 1H), 2.25 (dd, J = 8.2, 13.3 Hz,

1H), 2.52–2.70 (m, 2H), 2.55 (dd, J = 5.8, 13.3 Hz,

1H), 5.45 (d, J = 4.1 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H),

6.67 (dd, J = 1.5, 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H);

¹³C NMR (75.5 MHz, CDCl₃) d 14.1, 19.2, 19.6, 22.7,

23.5, 27.0, 27.5, 27.7, 29.7, 32.2, 34.8, 36.6, 36.8, 42.9,

d 14.1, 19.5, 22.7, 26.8, 32.1, 34.8, 36.8, 44.1, 55.2, 97.5,

20

D

107.5, 144.2, 160.5; MS (EI) m/z 250 (50), 152 (100); ½aꢁ

ꢀ5.10 (c 0.65, CH₂Cl₂). The spectroscopic properties of

this compound are identical to those reported

previously.³⁷

43.4, 76.7, 117.7, 119.9, 121.0, 122.9, 126.2, 133.5,

141.5, 152.7; MS (EI) m/z 340 (100), 257 (75); ½aꢁ

20

D

5.35. (2⁰S)-3-(2⁰-methylheptyl)-D⁸-tetrahydrocannabinol

(16, n = 4)

ꢀ104 (c 0.17, CH₂Cl₂); HRMS Calcd for C₂₄H₃₆O,

340.2766; found: 340.2774.

Cannabinoid 16 (n = 4) was prepared from dimethyl

ether 17 (n = 4) by the procedure employed for the prep-

aration of 16 (n = 1). From 0.470 g (1.88 mmol) of 17

(n = 4) was obtained 0.320 g (49% for two steps) of 16

(n = 4) following chromatography (petroleum ether/di-

chloromethane, 3:2). ¹H NMR (300 MHz, CDCl₃) d

0.82 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H),

1.08–1.42 (m, 8H), 1.10 (s, 3H), 1.38 (s, 3H), 1.68–1.74

(m, 1H), 1.70 (s, 3H), 1.78–1.90 (m, 3H), 2.12–2.20 (m,

2H), 2.46 (dd, J = 6.0, 13.3 Hz, 1H), 2.70 (td, J = 4.3,

10.8 Hz, 1H), 3.20 (dd, J = 4.3, 16.2 Hz, 1H), 4.76 (br

s, 1H), 5.43 (d, J = 4.0 Hz, 1H), 6.07 (d, J = 1.2 Hz,

1H), 6.24 (d, J = 1.2 Hz, 1H); ¹³C NMR (75.5 MHz,

CDCl₃) d 14.1, 18.5, 19.5, 22.7, 23.5, 26.8, 27.6, 27.9,

31.6, 32.1, 34.6, 36.0, 36.8, 43.4, 44.9, 76.6, 108.4,

5.38. (R)-2-Methyl-1-(3,5-dimethoxyphenyl)heptane (18,

n = 4)

This compound was prepared from the triﬂate of (S)-2-

methyl-3-(3,5-dimethoxyphenyl)-1-propanol by the

procedure employed for the synthesis of (S)-2-methyl-

1-(3,5-dimethoxyphenyl)butane. From 0.567 g (1.66 mmol)

of triﬂate was obtained 0.290 g (70%) of 18 (n = 4) as

a colorless oil after chromatography (petroleum ether/

ether, 94:6). The spectroscopic properties are identical

to those of the S-enantiomer and of material previously

20

D

reported:³⁷½aꢁ +5.44 (c 1.34, CH₂Cl₂).

5.39. (2⁰R)-3-(2⁰-Methylheptyl)-D⁸-tetrahydrocannabinol

(13, n = 4)

110.5, 111.0, 119.3, 134.7, 141.5, 154.6; MS (EI) m/z

20

D

356 (50), 258 (100); ½aꢁ ꢀ185 (c 0.5, CH₂Cl₂). The spec-

troscopic properties of this compound are identical to

those reported previously.³⁷

Cannabinoid 13 (n = 4) was prepared from (R)-2-meth-

yl-1-(3,5-dimethoxyphenyl)heptane by the procedure

used for the synthesis of 16 (n = 1). From 0.256 g

(1.06 mmol) of (R)-2-methyl-1-(3,5-dimethoxyphe-

nyl)heptane was obtained 0.135 g (36% for two steps)

of cannabinoid 13 (n = 4) as a pale yellow gum following

5.36. (2⁰S)-1-Methoxy-3-(2⁰-methyl heptyl)-D⁸-tetrahy-

drocannabinol (JWH-247, 15, n = 4)

1

Methyl ether 15 (n = 4) was prepared from cannabinoid

16 (n = 4) by the procedure employed for the prepara-

tion of 15 (n = 1). From 0.150 g (0.421 mmol) of 16

(n = 4) was obtained 0.152 g (98%) of JWH-247 follow-

ing chromatography (petroleum ether/dichloromethane,

chromatography (petroleum ether/ether, 9:1). H NMR

(300 MHz, CDCl₃) d 0.82 (d, J = 6.5 Hz, 3H), 0.87 (t,

J = 6.9 Hz, 3H), 1.06–1.15 (m, 1H), 1.10 (s, 3H), 1.8–

1.38 (m, 7H), 1.37 (s, 3H), 1.60–1.72 (m, 1H), 1.70 (s,

3H), 1.75–1.91 (m, 3H), 2.13 (dd, J = 8.8, 13.3 Hz,

2H), 2.49 (dd, J = 5.5, 13.3 Hz, 1H), 2.68 (dt, J = 6.4,

11.0 Hz, 1H), 3.19 (dd, J = 4.6, 16.0 Hz, 1H), 4.79 (s,

1H), 5.42 (br d, J = 4.6 Hz, 1H), 6.06 (d, J = 1.4 Hz,

1H), 6.23 (d, J = 1.9 Hz, 1H); ¹³C NMR (75.5 MHz,

1

3:2). H NMR (300 MHz, CDCl₃) d 0.83–0.90 (m, 6H),

1.08–1.37 (m, 8H), 1.08 (s, 3H), 1.37 (s, 3H), 1.70 (s,

3H), 1.70–1.73 (m, 1H), 1.76–1.81 (m, 3H), 2.12–2.20

(m, 1H), 2.25 (dd, J = 8.3, 13.3 Hz, 1H), 2.53 (dd,

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

261

CDCl₃) d 14.2, 18.6, 19.6, 22.8, 23.6, 26.9, 27.7, 28.0,

31.7, 32.2, 34.7, 36.1, 36.9, 43.4, 45.0, 76.7, 108.5,

5.42.2. CB₂assay. Human embryonic kidney 293 cells

were maintained in DulbeccoÕs modiﬁed EagleÕs medium

(DMEM) with 10% fetal clone II (HyClone, Logan UT)

and 5% CO₂at 37 °C in a Forma incubator. Cell lines

were created by transfection of CB2pcDNA3 into 293

cells by the Lipofectamine reagent (Life Technologies,

Gaithersburg, MD). The human CB₂cDNA was pro-

vided by Dr. Sean Munro (MRC, Cambridge, England).

Stable transformants were selected in growth medium

containing geneticin (1 mg/mL reagent, Life Technolo-

gies, Gaithersburg, MD). Colonies of about 500 cells

were picked (about 2 weeks post transfection) and

allowed to expand, and then tested for expression of

receptor mRNA by Northern blot analysis. Cell lines

containing moderate to high levels of receptor mRNA

were tested for receptor binding properties. Transfected

cell lines were maintained in DMEM with 10% fetal

clone II plus 0.3–0.5 mg/mL geneticin and 5% CO₂at

37 °C in a Forma incubator.

110.6, 111.0, 119.4, 134.9, 141.6, 154.7, 154.8; MS (EI)

20

D

m/z 356 (79), 273 (100), 258 (100); ½aꢁ ꢀ216 (c 0.4,

CH₂Cl₂). The spectroscopic properties of this compound

are identical to those reported previously.³⁷

5.40. (2⁰R)-1-Methoxy-3-(2⁰-methyl heptyl)-D⁸-tetrahy-

drocannabinol (JWH-358, 12, n = 4)

Methoxycannabinoid 12 (n = 4) was prepared as de-

scribed above for the synthesis of 15 (n = 1). From

0.045 g (0.126 mmol) of cannabinoid 13 (n = 4) was

obtained 0.043 g (92%) of JWH-358 as a colorless oil

after chromatography (petroleum ether). ¹H NMR

(300 MHz, CDCl₃) d 0.83 (d, J = 6.5 Hz, 3H), 0.87 (t,

J = 6.9 Hz, 3H), 1.05–1.18 (m, 1H), 1.08 (s, 3H), 1.20–

1.42 (m, 7H), 1.37 (s, 3H), 1.62–1.86 (m, 4H), 1.70 (s,

3H), 2.07–2.18 (m, 1H), 2.20 (dd, J = 8.3, 13.3 Hz,

1H), 2.55 (dd, J = 6.0, 13.3 Hz, 1H), 2.66 (dt, J = 5.0,

1.0 Hz, 1H), 3.15 (dd, J = 5.1, 17.0 Hz, 1H), 3.79 (s,

3H), 5.41 (br d, J = 4.1 Hz, 1H), 6.20 (d, J = 1.8 Hz,

1H), 6.27 (d, J = 1.4 Hz, 1H); ¹³C NMR (75.5 MHz,

CDCl₃) d 14.2, 18.5, 19.7, 22.8, 23.7, 26.9, 27.7, 28.1,

31.9, 33.2, 34.8, 36.4, 37.0, 44.0, 45.2, 55.2, 76.9, 103.9,

The current assay is a modiﬁcation of Compton and co-

workers.^11,47Cells were harvested in phosphate-buﬀered

saline containing 1 mM EDTA and centrifuged at 500g.

The cell pellet was homogenized in 10 mL solution A

(50 mM Tris–HCl, 320 mM sucrose, 2 mM EDTA,

and 5 mM MgCl₂, pH 7.4). The homogenate was centri-

fuged at 1600g (10 min), the supernatant saved, and the

pellet was washed three times in solution A with subse-

quent centrifugation. The combined supernatants were

centrifuged at 1,00,000g (60 min). The (P₂membrane)

pellet was resuspended in 3 mL buﬀer B (50 mM Tris–

HCl, 1 mM EDTA, and 3 mM MgCl₂, pH 7.4) to yield

a protein concentration of approximately 1 mg/mL. The

tissue preparation was divided into equal aliquots, fro-

zen on dry ice, and stored at ꢀ70 °C. Binding was initi-

ated by the addition of 40–50 lg membrane protein to

silanized tubes containing [³H]CP-55,940 (102.9 Ci/

mmol) and a suﬃcient volume of buﬀer C (50 mM

Tris–HCl, 1 mM EDTA, 3 mM MgCl₂, and 5 mg/mL

fatty acid free BSA, pH 7.4) to bring the total volume

to 0.5 mL. The addition of 1 lM unlabelled CP-55,940

was used to assess nonspeciﬁc binding. Following incu-

bation (30 °C for 1 h), binding was terminated by the

addition of 2 mL ice-cold buﬀer D (50 mM Tris–HCl,

pH 7.4, plus 1 mg/mL BSA) and rapid vacuum ﬁltration

through Whatman GF/C ﬁlters (pretreated with poly-

ethyleneimine (0.1%) for at least 2 h). Tubes were rinsed

with 2 mL ice-cold buﬀer D, which was also ﬁltered, and

the ﬁlters were subsequently rinsed twice with 4 mL ice-

cold buﬀer D. Before radioactivity was quantitated by

liquid scintillation spectrometry, ﬁlters were shaken for

1 h in 5 mL of scintillation ﬂuid.

111.2, 112.0, 119.4, 135.1, 141.4, 154.3, 158.9; MS (EI)

20

D

m/z 370 (100), 287 (66), 272 (86); ½aꢁ ꢀ221 (c 0.5,

CH₂Cl₂); HRMS Calcd for C₂₅H₃₈O₂, 370.2872; found:

370.2870.

5.41. (2⁰R)-1-Deoxy-3- (2⁰-methylheptyl)-D⁸-tetrahydro-

cannabinol (JWH-357, 11, n = 4)

Deoxycannabinoid 11 (n = 4) was prepared from (2⁰R)-

1-Methoxy-3-(2⁰-methyl heptyl)-D⁸-tetrahydrocannabi-

nol by the procedure used for the preparation of 14

(n = 1). From 0.069 g (0.19 mmol) of 13 (n = 4) was ob-

tained 0.051 g (76% for two steps) of JWH-357 as a col-

orless oil after chromatography (petroleum ether/ether,

97.5:2.5). ¹H NMR (300 MHz, CDCl₃) d 0.83 (d,

J = 6.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H), 1.09–1.43 (m,

8H), 1.15 (s, 3H), 1.39 (s, 3H), 1.63–1.76 (m, 2H), 1.74

(s, 3H), 1.78–1.89 (m, 1H), 1.91–2.02 (m, 1H), 2.11–

2.20 (m, 1H), 2.22 (dd, J = 8.7, 13.3 Hz, 1H), 2.50–

2.73 (m, 3H), 5.46 (br s, 1H), 6.60 (d, J = 1.4 Hz, 1H),

6.66 (dd, J = 1.9, 7.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H);

¹³C NMR (75.5 MHz, CDCl₃) d 14.3, 19.3, 19.6, 22.8,

23.6, 26.9, 27.6, 27.8, 32.2, 32.3, 34.9, 36.7, 37.0, 43.0,

43.5, 76.9, 117.7, 120.1, 121.2, 123.0, 126.4, 133.6,

141.3, 152.8; MS (EI) m/z 340 (100), 257 (55); ½aꢁ

20

D

ꢀ129 (c 0.6, CH₂Cl₂); HRMS Calcd for C₂₄H₃₆O,

340.2766; found: 340.2761.

5.42. Receptor binding assays

CP-55,940 and all cannabinoid analogs were prepared

by suspension in assay buﬀer from a 1 mg/mL ethanolic

stock without evaporation of the ethanol (ﬁnal concen-

tration of no more than 0.4%). Competition assays were

conducted with 1 nM [³H]CP-55,940 and six concentra-

tions (0.1 nM to 10 lM displacing ligands). Displace-

ment IC₅₀values were originally determined by

unweighted least-squares linear regression of log con-

centration-percent displacement data and then convert-

ed to K_ivalues using the method of Cheng and Prusoﬀ.⁴⁹

5.42.1. CB₁assay. [³H]CP-55,940 (K_D= 690 nM) bind-

ing to P₂membranes was conducted as described

elsewhere,⁴⁸except whole brain (rather than cortex

only) was used. Displacement curves were generated

by incubating drugs with 1 nM [³H]CP-55,940. The

assays were performed in triplicate, and the results

represent the combined data from three individual

experiments.

262

J. W. Huﬀman et al. / Bioorg. Med. Chem. 14 (2006) 247–262

22. Kehl, L. J.; Hamamoto, D. T.; Wacnik, P. W.; Croft, D.

Acknowledgments

L.; Norsted, B. D.; Wilcox, G. L.; Simone, D. A. Pain

2003, 103, 175.

23. Clayton, N.; Marshall, F. H.; Bountra, C.; OÕShaugh-

nessy, C. T. Pain 2002, 96, 253.

24. Lepicier, P.; Bouchard, J.-F.; Lagneux, C.; Lamontagne,

D. Br. J. Pharmacol. 2003, 139, 805.

The work at Clemson was supported by Grants

DA03590 and DA15340 to J.W.H., that at Virginia

Commonwealth University by Grant DA03672 to

B.R.M., all from the National Institute on Drug Abuse.

25. Bifulco, M.; DiMarzo, V. Nature Med. 2002, 8, 547.

26. Guzman, M. Nature Rev. 2003, 3, 745.

References and notes

´

27. Sanchez, C.; de Ceballos, M. L.; Gomez del Pulgar, T.;

Rueda, D.; Corbacho, C.; Velasco, G.; Galve-Roperh, I.;

1. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young,

A. C.; Bonner, T. H. Nature 1990, 346, 561.

2. Herkenham, M.; Lynn, A. B.; Little, M. D.; Johnson, M.

R.; Melvin, L. S.; De Costa, D. R.; Rice, K. C. Proc. Natl.

Acad. Sci. U.S.A. 1990, 87, 1932.

3. Pertwee, R. G. Curr. Med. Chem. 1999, 6, 635.

4. Huﬀman, J. W.; Lainton, J. A. H. Curr. Med. Chem. 1996,

3, 101.

5. Munro, S.; Thomas, K. L.; Abu-Shar, M. Nature (Lon-

don) 1993, 365, 61.

6. Breivogel, C. S.; Griﬃn, G.; Di Marzo, V.; Martin, B. R.

Mol. Pharmacol. 2001, 155.

7. Monory, K.; Tzavara, E. T.; Lexime, J.; Ledent, C.;

Parmentier, M.; Borsodi, A.; Hanoune, J. Biochem.

Biophys. Res. Commun. 2002, 292, 231.

8. Di Marzo, V.; Breivogel, C. S.; Tao, Q.; Bridgen, D. T.;

Razdan, R. K.; Zimmer, A. M.; Zimmer, A.; Martin, B. R.

J. Neurochem. 2000, 75, 2434.

9. Fride, E.; Foox, A.; Rosenberg, E.; Faigenboim, M.;

Cohen, V.; Barda, L.; Blau, H.; Mechoulam, R. Eur.

J. Pharmacol. 2003, 463, 27–34.

´ ´

Huﬀman, J. W.; Ramon y Cajal, S.; Guzman, M. Cancer

Res. 2001, 61, 578.

28. Casanova, M. L.; Blazquez, C.; Martinez-Palacio, J.;

Villanueva, C.; Fernandez-Acenero, M. J.; Huﬀman, J.

W.;Jorcano, J. L.; Guzman, M. J. Clin. Invest. 2003, 111, 43.

29. Bab, I.; Ofek, O.; Karsak, M.; Fogel, M.; Wright, K.; Attar-

Namdar, M.; Shohami, E.; Zimmer, A.; Mechoulam, R.

2004 Symposium on the Cannabinoids; International Can-

nabinoid Research Society: Burlington, VT, 2004, p 74.

30. Karsak, M.; Cohen-Solal, M.; Kornak, U.; Kubisch, C.;

de Vernejoul, M.-C.; Bab, I.; Zimmer, A. 2004 Symposium

on the Cannabinoids; International Cannabinoid Research

Society: Burlington, VT, 2004, p 75.

31. Huﬀman, J. W. Curr. Pharm. Design 2000, 6, 1323.

32. Huﬀman, J. W. Mini-Rev. Med. Chem. 2005, 5, 641.

33. Huﬀman, J. W.; Yu, S.; Showalter, V.; Abood, M. E.;

Wiley, J. L.; Compton, D. R.; Martin, B. R.; Bramblett,

R. D.; Reggio, P. H. J. Med. Chem. 1996, 39, 3875.

34. Huﬀman, J. W.; Liddle, J.; Yu, S.; Aung, M. M.; Abood,

M. E.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem.

1999, 7, 2905.

10. Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin,

L. S.; Martin, B. R. J. Pharmacol. Exp. Ther. 1988, 247,

1046.

11. Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R.

K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R.

J. Pharmacol Exp. Ther. 1993, 265, 218.

12. Compton, D. R.; Aceto, M. D.; Lowe, J.; Martin, B. R.

J. Pharmacol Exp. Ther. 1996, 277, 586.

13. Zimmer, A.; Zimmer, A. M.; Hohmann, A. G.; Herken-

ham, M.; Bonner, T. L. Proc. Natl. Acad. Sci. U.S.A.

1999, 96, 5780.

14. Klein, T. W.; Friedman, H.; Specter, S. J. Neuroimmunol.

1998, 83, 102.

15. Buckley, N. E.; McCoy, K. L.; Mezey, E.; Bonner, T.;

Zimmer, A.; Felder, C. C.; Glass, M.; Zimmer, A. Eur.

J. Pharmacol. 2000, 396, 141.

35. Huﬀman, J. W.; Bushell, S. M.; Miller, J. R. A.; Wiley, J.

L.; Martin, B. R. Bioorg. Med. Chem. 2002, 10, 411.

36. Huﬀman, J. W.; Lainton, J. A. H.; Banner, W. K.; Duncan,

S. G.; Jordan, R. D.; Yu, S.; Dai, D.; Martin, B. R.; Wiley, J.

L.; Compton, D. R. Tetrahedron 1997, 53, 1557.

37. Huﬀman, J. W.; Liddle, J.; Duncan, S. G.; Yu, S.; Martin,

B. R.; Wiley, J. L. Bioorg. Med. Chem. 1998, 6, 2383.

38. Huﬀman, J. W.; Miller, J. R. A.; Liddle, J.; Yu, S.;

Thomas, B. F.; Wiley, J. L.; Martin, B. R. Bioorg. Med.

Chem. 2003, 11, 1397–1410.

39. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am.

Chem. Soc. 1982, 104, 1737; (b) Evans, D. A.; Bartroli, J.;

Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.

40. Stewart, G. M.; Fox, M. A. J. Am. Chem. Soc. 1996, 118.

41. Petrzilka, T.; Sikemeier, C. Helv. Chim. Acta 1967, 50,

1416.

16. Hanus, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Golden-

berg, D.; Horowitz, M.; Pertwee, R. G.; Ross, R. A.;

Mechoulam, R.; Fride, E. Proc. Natl. Acad. Sci. U.S.A.

1999, 96, 14228.

17. Conti, S.; Costa, B.; Colleoni, M.; Parolaro, D.; Giagnoni,

G. Br. J. Pharmacol. 2002, 135, 181.

18. Malan, T. P.; Ibrahim, M. M.; Vanderah, T. W.; Mak-

riyannis, A.; Porreca, F. Chem. Phys. Lipids 2002, 121,

191.

42. Kelly, N. M.; Reid, R. G.; Willis, C. L.; Winton, P. L.

Tetrahedron Lett. 1995, 36, 8315.

43. Dale, J. A.; Dulh, D. L.; Mosher, H. S. J. Org. Chem.

1969, 34, 2543.

44. Bushell, S. M., unpublished work.

45. (a) Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.;

Bernardinelli, G. Helv. Chim. Acta 1987, 70, 2201; (b)

Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron 1989,

45, 479.

19. Malan, T. P.; Ibrahim, M. M.; Deng, H.; Liu, Q.; Main,

H. P.; Vanderah, T.; Porreca, F.; Makriyannis, A. Pain

2001, 93, 239.

20. Ibrahim, M. M.; Deng, H.; Zvonok, A.; Cockayne, D. A.;

Kwan, J.; Mata, H. P.; Vanderah, T. W.; Lal, J.; Porreca,

F.; Makriyannis, A. M.; Malan, T. P. Proc. Natl. Acad.

Sci. U.S.A. 2003, 100, 10529.

46. Joshi, S. N., unpublished work.

47. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood,

M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989.

48. Martin, B. R.; Compton, D. R.; Thomas, B. F.; Prescott,

W. R.; Little, P. J.; Razdan, R. K.; Johnson, M. R.;

Melvin, L. S.; Mechoulam, R.; Ward, S. J. Pharmacol.

Biochem. Behav. 1991, 40, 471.

21. Zhang, J.; Hoﬀert, C.; Vu, H. K.; Groblewski, T.; Ahmad,

S.; OÕDonnell, D. Eur. J. Neurosci. 2003, 2750.

49. Cheng, Y. C.; Prusoﬀ, W. H. Biochem. Pharmacol. 1973,

22, 3099.

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Enantioselective synthesis of 1-methoxy- and 1-deoxy-2′-methyl- Δ8-tetrahydrocannabinols: New selective ligands for the CB 2 receptor

DOI: 10.1016/j.bmc.2005.08.013

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