Tetrahydrocannabinol revisited: Synthetic approaches utilizing molybdenum catalysts

Article abstract of DOI:10.1135/cccc20011257

Δ⁹-Tetrahydrocannabinol 1 and its isomers were synthesized via domino-type methodology. The first approach, leading to (±)-1, relies on the Mo(IV)-catalyzed, one-pot cascade reaction of citral (4) with olivetol (15), affording (±)-Δ⁹-tetrahydrocannabinol as a 69 : 31 mixture of the trans-(natural) and cis-isomers in 20% yield. The alternative approach, leading to natural (-)-1, commenced with epoxidation of (+)-limonene (R)-(+)-16; opening of the resulting cis-epoxide 17 with PhSeNa, followed by elimination, afforded tertiary alcohol 21, whose acetate 22 was treated with olivetol 15 in the presence of Mo(II) catalyst IV to afford (-)-1 in 52% yield.

Full text of DOI:10.1135/cccc20011257

Tetrahydrocannabinol
1257
TETRAHYDROCANNABINOL REVISITED: SYNTHETIC APPROACHES
UTILIZING MOLYBDENUM CATALYSTS
1,
2,
Andrei V. MALKOV * and Pavel KOČOVSKÝ *
Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, U.K.;
1
2
e-mail: amalkov@chem.gla.ac.uk, p.kocovsky@chem.gla.ac.uk
Received April 23, 2001
Accepted May 17, 2001
Dedicated to the memory of Dr Václav Černý.
∆9-Tetrah ydrocan n abin ol 1 an d its isom ers were syn th esized via dom in o-type m eth odology.
Th e first approach , leadin g to (±)-1, relies on th e Mo(IV)-catalyzed, on e-pot cascade reaction
of citral (4) with olivetol (15), affordin g (±)-∆9-tetrah ydrocan n abin ol as a 69 : 31 m ixture of
th e trans- (n atural) an d cis-isom ers in 20% yield. Th e altern ative approach , leadin g to n atu-
ral (–)-1, com m en ced with epoxidation of (+)-lim on en e (R)-(+)-16; open in g of th e resultin g
cis-epoxide 17 with Ph SeNa, followed by elim in ation , afforded tertiary alcoh ol 21, wh ose ac-
etate 22 was treated with olivetol 15 in th e presen ce of Mo(II) catalyst IV to afford (–)-1 in
52% yield.
Keyw ord s: Terpen oids; Can n abin oids; Total syn th esis; Asym m etric catalysis; Allylic substitu-
tion ; Cascade reaction s; Natural products.
Few n atural products h ave en joyed as m uch con troversy as ∆9-tetrah ydro-
can n abin ol 1 an d its ∆8-isom er 2 (Ch art 1), th e active con stituen ts of m ari-
h uan a1. Wh ile ban n ed in m ost coun tries of th e Western civilization , th is
an cien t plan t h as been legalized in som e, an d its application in specific m e-
dicin al in dication s is bein g debated in oth ers, th ereby creatin g a gray area
on th e borderlin e between legality an d crim in al offen se.
OH
OH
O
O
(−)-1
(−)-2
CHART 1
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi:10.1135/cccc20011257

1258
Malkov, Kočovský:
In view of th e recen tly revitalized debate on legalizin g m arih uan a in th e
U.K. an d oth er coun tries for term in ally ill patien ts to ease th eir sufferin g,
we felt th at a n ew, preferably catalytic approach to 1, 2, an d th eir an a-
logues, would be justified. Furth erm ore, 1 an d its isom ers th us syn th esized
could also be em ployed as stan dards in foren sic scien ce an d related disci-
plin es con cern ed with drug-abuse detection . Herein , we presen t two
straigh tforward syn th eses, on e producin g a racem ate in on e step (an d am e-
n able to asym m etric catalysis) an d th e oth er utilizin g th e ch iral pool.
We h ave recen tly developed a n ew set of Lewis-acidic Mo(II) catalysts,
such as IV an d V (Sch em e 1), wh ich proved to prom ote an in tram olecular
carbon yl-en e cyclization of citron ellal (3), affordin g m ain ly th e cis-product 5
(Sch em e 2)2. By con trast, m ost of th e kn own Lewis acids produce m ain ly th e
trans-isom er 7. Th e m olybden um an om aly was attributed by us to th e steric
bulk of th e catalyst, n am ely to th e protrudin g CO group attach ed to Mo
th at ren ders th e tran sition state leadin g to th e cis-product lower in en ergy2.
Th e sam e Mo(II) com plex proved to catalyze allylic substitution of allylic
acetates with silyl en ol eth ers3 an d electron -rich arom atics an d
h eteroarom atics4. Wh ilst th ese substitution reaction s were successful in th e
case of allylic esters, th e correspon din g alcoh ols proved in ert. However, we
h ave sh own th at allylic alcoh ols would react with Mo(IV) catalysts, such as
II an d III (ref.5), wh ich can be readily gen erated from th e acac com plex I
(wh ich , in turn , is obtain ed from MoCl5 an d acac6) by an an ion exch an ge
with TfOAg (ref.5) or AgSbF6 (I → II or III). Fin ally, we h ave also observed
th e electroph ilic cyclization of olefin ic ph en ols with both Mo(II) an d
Mo(IV) com plexes in selected exam ples4.
MeCN
MoCl5
Mo(CO)6
Br2
(MeCN)3Mo(CO)3
SnCl4
1. CH2(COMe)2
2. AgX
OC
Br
II
Mo
X
IV
Mo
CO
II
CO
CO
CO
II Cl
Mo
OC
OC
Br
O
O
O
O
OC
OC
Mo
SnCl3
Br
OC
X
CO Br
MeCN NCMe
I, X = Cl
IV
V
II, X = OTf
III, X = SbF6
SCHEME 1
We reason ed th at th e th ree reaction s, i.e., en e-cyclization , allylic substitu-
tion , an d electroph ilic cyclization (vide supra), m igh t be tam ed to occur in a
on e-pot cascade, provided th at suitably design ed substrates are em ployed.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Tetrahydrocannabinol
1259
Th us, we h ave en visaged th at cyclization of (Z)-citral (4) would gen erate cy-
clic dien ol 6 (Sch em e 2) th at could react in situ with an electron -rich ph e-
n ol, such as p-cresol (10), to furn ish th e ortho-substituted4 product 12,
wh ose electroph ilic cyclization would lead to th e tricyclic skeleton 14.
Model experim en ts with citral (4), com m ercially available as ca 1 : 1
(E/Z)-m ixture7, ph en ol (9), an d th e Mo(IV) catalyst II or III m et with partial
success. Th us, at room tem perature an d with h exafluoroan tim on ate III as
catalyst, th e expected tricyclic product 13 was form ed in 24% yield8 as a ca
7 : 1 m ixture of cis- an d trans-an n ulated isom ers.9
Sin ce th e relatively low yield in th e case of ph en ol (9) can be partly at-
tributed to th e n on -regioselective electroph ilic arom atic substitution (fur-
n ish in g th e correspon din g para-isom er alon g with 11), we n ext carried out
th e sam e cyclization cascade with p-cresol (10), wh ose para-position is
blocked. In deed, an in creased yield was observed (42%) an d th e tricyclic
product 14 was isolated as a 3 : 1 cis-/trans-m ixture (again with III as cata-
lyst).
Th e en e-cyclization of 4 can be viewed as in itially gen eratin g a m ixture of
epim ers 6 an d 8, in wh ich th e form er m ay prevail in an alogy to th e
cyclization of 3. However, th e in stability of th e allylic alcoh ol precluded a
detailed NMR an alysis of th e pure m aterial.
[Mo]
CH2Cl2
rt
+
O
OH
OH
3, monoene
4, diene
5, monoene
6, diene
7, monoene
8, diene
R
HO
9, R = H
10, R = Me
R
R
O
OH
13, R = H
11, R = H
14, R = Me
12, R = Me
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

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Malkov, Kočovský:
Bein g en couraged by th e successful m odel experim en ts, we th en focused
on th e tetrah ydrocan n abin ol itself. In deed, th e sam e sequen ce, th is tim e
carried out with olivetol (15) as th e electron -rich ph en ol (CH2Cl2, room
tem perature, 4 h ), an d III as th e catalyst [(acac)2MoCl2 (3 m ole %), AgSbF6
(6 m ole %), CH2Cl2, room tem perature, 4 h ], produced8 (±)-1 (20%), iso-
lated by flash ch rom atograph y as a 3 : 7 cis-/trans-m ixture (Sch em e 3). It is
n oteworth y th at th e stereoch em istry of an n ulation h as n ow been altered in
favour of th e n atural trans-isom er. Th is effect can be attributed eith er to th e
in fluen ce of th e addition al ph en olic h ydroxyl in th e allylic substitution
step, or to th e in terven tion of an altern ative m ech an ism th at would first in -
volve th e Lewis-acid catalyzed electroph ilic attack by th e carbon yl group of
citral (4) at olivetol (15) followed by cyclization 9b,10 (Sch em e 4). Sin ce a
gradual sh ift from cis- to trans-epim er correlates with th e in creasin g elec-
tron den sity of th e arom atic rin g (ph en ol-cresol-olivetol), th is altern ative
seem s m ore likely.
OH
OH
a
+
O
HO
C5H11
O
C5H11
4
15
(±)-1 (trans/cis = 69 : 31)
a, (acac)2Mo(OTf)2, CH2Cl2, rt, 4 h
SCHEME 3
Th e on e-pot procedure h igh ligh ted in Sch em e 3 sh ould be am en able to
asym m etric catalysis, wh ere a ch iral catalyst would con trol th e absolute
stereoch em istry of th e in itial en e-cyclization 11. However, our experim en ts
with various ch iral ligan ds, in cludin g our recen tly developed ch iral
bipyridin es12, were un successful to date. Th erefore, in order to syn th esize
n atural (–)-1, we turn ed to th e ch iral pool an d em ployed a m odified strat-
[Mo]
4
+
15
1
O[Mo]
Ar
SCHEME 4
egy. Th e crude cis-/trans-m ixture (ca 1 : 1) of epoxides 17 an d 18, obtain ed
by epoxidation of (R)-(+)-lim on en e (R)-(+)-16 (88% ee) with MCPBA
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Tetrahydrocannabinol
1261
(Sch em e 5)13, was treated with Ph SeNa (Ph SeSePh , NaBH4, EtOH, reflux,
2 h ) to afford a m ixture of isom eric ph en ylselen en yl derivatives 19 an d 20
(refs13,14) wh ich , with out purification , was subjected to oxidation (30%
aqueous H2O2, THF, room tem perature, 5 h ). Wh ile th e selen eoxide arisin g
from 20 spon tan eously elim in ated at room tem perature to produce 23, th at
derived from 19 proved stable, wh ich allowed a sim ple separation of th e
liquid olefin 23 from th e solid selen eoxide by extractin g th e form er with
petroleum eth er. Heatin g of th e selen eoxide th us obtain ed from 19 in pure
state at reflux in CHCl3 for 30 m in afforded pure13–15 21 (30% overall from
lim on en e)16. Th e latter allylic alcoh ol 21 was th en acetylated (Ac2O, DMAP,
Et3N, Et2O, room tem perature, 4 h ) to produce tertiary acetate 22 (85%).
SePh
OH
OH
O
SePh
PhSeNa
+
20
17 (cis)
19
18 (trans)
1. H2O2, heating
2. Ac2O, Et3N
H2O2
heating
MCPBA
OR
OH
(R)-(+)-16
21, R = H
22, R = Ac
23
SCHEME 5
Th e catalytic reaction of both alcoh ol 21 an d its acetate 22 with olivetol
(15) was in vestigated with several m olybden um catalysts (Sch em e 6 an d
Table I). Th us, th e reaction of alcoh ol 21, catalyzed by th e Mo(IV) triflate
com plex II in CH2Cl2 at room tem perature, gave a m ixture of two tricyclic
products, n am ely ∆8-tetrah ydrocan n abin ol (–)-2 an d its isom er17 25, in
wh ich th e form er prevailed (Table I, en try 1). Wh ile th e form ation (–)-2 re-
sults from th e isom erization of th e in itially gen erated ∆9-THC (–)-1 to its
th erm odyn am ically m ore stable isom er, 25 arises from
a “wron g”
cyclization of th e sam e in term ediate in th e fin al step. Lowerin g th e reac-
tion tem perature to –20 °C led to a lon ger reaction tim e an d form ation of
bicyclic products 26 an d 27 (en try 2). Apparen tly, th e fin al cyclization was
disabled in th is in stan ce by th e low tem perature. Acetate 22 gave sim ilar re-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

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Malkov, Kočovský:
OH
b
a
+
OR
HO
C5H11
15
21, R = H
22, R = Ac
O
C5H11
OH
OH
+
+
OH
24
O
O
C5H11
O
C5H11
(−)-1
(−)-2
C5H11
+
OH
C5H11
+
C5H11
OH
OH
25
OH
26
OH
27
SCHEME 6
TABLE I
Molybden um -catalyzed reaction of allylic substrates 20 an d 21a with olivetol 15 in CH2Cl2
at room tem perature
Yield, %
Allyl
com p.
Tem p.
°C
Total yield
%
En try
Catalyst
Tim e
1
2
24 25 26 27
1
2
3
4
5
6
7
21
21
22
22
22
22
22
II
II
20
–20
20
15 m in
3 h
56
14
70
72
52
65
74
72
65
20 52
b
b
II
15 m in
30 m in
15 m in
4 h
52
13
74
II
–10
20
22 30
b
b
III
IV
V
20
51
39
23
12
20
4 h
14
a
Th e en an tiopurity of th e startin g alcoh ol 21 an d acetate 22 an d of th e product sh ould re-
b
flect th at of (+)-lim on en e 16 (88% ee; vide supra). Th e com poun d h as n ot been isolated.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Tetrahydrocannabinol
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sults with th e sam e catalyst (en tries 3 an d 4). Th e Mo(IV) h exafluoro-
an tim on ate catalyst III gave a m uch clean er reaction , with (–)-2 bein g th e
on ly isolable product in 74% yield (en try 5).
Wh ile th e Mo(IV) catalysts in duced th e double bon d isom erization to
produce th e ∆8-isom er (–)-2 (Table I, en tries 1–5), switch in g to Mo(II)
proved to elim in ate th is problem an d, alth ough th eir application lead to
th e deceleration of th e cascade, th e desired ∆9-isom er (–)-1 becam e th e
m ain product. Th us, with brom ide IV, n atural ∆9-THC (–)-1 was obtain ed in
51% yield (en try 6) alon g with th e product of “wron g” cyclization 24
(23%). With th e bim etallic catalyst V, th e fin al cyclization was in com plete,
affordin g ∆9-THC (–)-1 (39%) an d its bicyclic precursor 26 (14%), again
alon g with a sm all am oun t of th e “wron g” tricyclic product 24 (en try 7). In
view of th e sligh tly lower overall yield of th e latter reaction , it appears th at
th e dibrom ide com plex IV can be regarded as th e m ost suitable catalyst,
with practically n o isom erization of ∆9- to ∆8-THC.
In n on e of th ese tran sform ation we could detect m ore th an trace
am oun ts of th e cis-an n ulated diastereoisom er (–)-1 or (–)-2 (th at would be
an alogous to 13/14). Th is effect can be un derstood in view of th e sin gle
diastereoisom er of 21/22 bein g em ployed as an in term ediate in th is route,
as opposed to th e diastereoisom eric m ixture of alcoh ols 6 an d 8, gen erated
in situ in th e on e-pot approach .
In sum m ary, we h ave syn th esized racem ic ∆9-tetrah ydrocan n abin ol 1
from th e two com m ercially available precursors 4 an d 15 in a cascade,
on e-pot reaction , catalyzed by th e Lewis-acidic Mo(IV) com plex III
(Sch em e 3). An altern ative route, startin g with scalem ic lim on en e (R)-(+)-16
an d em ployin g th e Mo(II) com plex IV as th e optim al catalyst, afforded
(–)-1 (Sch em es 5 an d 6). Th is m eth odology h as th e advan tage of givin g
clean er products, com pared to th e con ven tion al Lewis acids1,10,11
.
EXPERIMENTAL
Gen eral Meth ods
Optical rotation s were m easured on a Perkin –Elm er 341 polarim eter; [α]D values are given in
10–1 deg cm 2 g–1. Th e NMR spectra were recorded in CDCl3, 1H at 250 an d 400 MHz an d 13C
at 62.9 an d 100.6 MHz with ch loroform -d1 (δ 7.26, 1H; δ 77.0, 13C) as in tern al stan dard;
2D-tech n iques were used to establish th e structures an d to assign th e sign als. Ch em ical
sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Th e m ass spectra (EI an d/or
CI) were m easured on a dual sector m ass spectrom eter usin g direct in let an d th e lowest tem -
perature en ablin g evaporation . Th e GC MS an alysis was perform ed with RSL-150 colum n
(25 m × 0.25 m m ). All reaction s were perform ed un der an atm osph ere of dry, oxygen -free
n itrogen . Solven ts an d solution s were tran sferred by a syrin ge-septum tech n ique. All re-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1264
Malkov, Kočovský:
agen ts were purch ased at h igh est com m ercial quality an d used with out furth er purification ,
un less oth erwise stated. Yields are given for isolated product sh owin g on e spot on a TLC
plate. Th e iden tity of th e products prepared by differen t m eth ods was ch ecked by com pari-
son of th eir NMR, IR, an d MS data an d by th e TLC beh avior. Most of th e products are
kn own com poun ds. Com plexes I, IV, an d V were prepared followin g literature procedures.
Gen eral Procedure A: Reaction of Citral (4) with Ph en ols 9, 10, an d 15
Catalyzed by Mo(IV) Com plex III
(acac)2MoCl2 com plex5,6 (10 m g, 0.029 m m ol, ca 3 m ole %) was added to a stirred solution
of citral 4 (2.0 m m ol) an d an arom atic com poun d (1.0 m m ol) in CH2Cl2 (5 m l) at room
tem perature, followed by addition of solid silver h exafluoroan tim on ate or triflate (ca
0.060 m m ol). Th e m ixture was stirred un der n itrogen for 4 h , th en diluted with eth er
(20 m l), an d th e eth ereal solution was wash ed successively with 5% aqueous NaHCO3 an d
water an d dried with MgSO4. Th e solven t was evaporated un der reduced pressure to give a
crude product, wh ich was purified by flash ch rom atograph y on a n eutral silica gel colum n
with a 9 : 1 m ixture of h exan e–eth yl acetate.
Gen eral Procedure B: Reaction of Olivetol (15) with Allylic Substrates 21 an d 22
Catalyzed by Mo(IV) Com plex III
(acac)2MoCl2 com plex5,6 (5 m g, 0.014 m m ol, ca 3 m ole %) was added to a stirred solution of
th e allylic substrate 21 or 22 (ca 0.5 m m ol) an d olivetol 15 (0.6 m m ol) in CH2Cl2 (5 m l) at
room tem perature, followed by addition of solid silver h exafluoroan tim on ate or triflate (ca
0.060 m m ol). Th e m ixture was stirred un der n itrogen at th e tem perature specified. After th e
reaction was com plete (con trol by TLC, silica gel, h exan e–eth yl acetate 9 : 1), work-up pro-
cedure was perform ed as described in th e previous experim en t. For yields an d oth er reaction
con dition s see Table I.
Gen eral Procedure C: Reaction of Olivetol (15) with Allylic Acetate 22
Catalyzed by Mo(II) Com plexes IV an d V
Com plex IV or V (refs3,4) (ca 3–5 m ole %) was added to a stirred solution of th e allylic ace-
tate 22 (ca 0.5 m m ol) an d olivetol 15 (0.6 m m ol) in CH2Cl2 (5 m l) at room tem perature.
Th e m ixture was stirred un der n itrogen at th e tem perature specified (Table I). Work-up pro-
cedure was perform ed as described in Gen eral Procedure A. For yields an d oth er reaction
con dition s see Table I.
(±)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [other name
(±)-∆9-tetrahydrocannabinol] (±)-(1)9b. Obtain ed from 4 an d 15 as a 69 : 31 m ixture of
trans-/cis-isom ers as a viscous pale yellow oil (20%). EI MS, m/z (%): 314 (86, M• +), 299 (88),
271 (53), 258 (35), 231 (100), 193 (19), 119 (10), 91 (10). Cis-isom er: 1H NMR (taken in a
m ixture with (±)-∆9-trans-THC): 0.90 (t, 3 H, J = 6.6, MeC4H8); 1.27 an d 1.39 (2 × s, 2 × 3 H,
6-Me2); 1.69 (br s, 3 H, 9-Me); 3.55 (br s, 1 H, 10a-H); 5.00 (br s, 1 H, OH); 6.13 an d 6.24
(2 × s, 2 × 1 H, 2,4-H); 6.27 (br s, 1 H, 10-H).
(–)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [other
name (–)-trans-∆9-tetrahydrocannabinol] (–)-(1)9b 1H NMR (taken in a m ixture with 24): 0.87
.
(t, 3 H, J = 6.6, MeC4H8); 1.08 an d 1.40 (2 × s, 2 × 3 H, 6-Me2); 1.67 (br s, 3 H, 9-Me); 3.20
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Tetrahydrocannabinol
1265
(br d, 1 H, J = 10.7, 10a-H); 5.18 (br s, 1 H, OH); 6.12 an d 6.26 (2 × d, 2 × 1 H, J = 1.3,
2,4-H); 6.32 (br s, 1 H, 10-H).
(–)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol [other
name (–)-trans-∆8-tetrahydrocannabinol] (–)-(2)9b. Viscous pale yellow oil, [α ]2D1 –225.0 (c 1.35,
EtOH) (ref.17 gives [α]D –246 (c 0.11, EtOH) for en an tiopure 2). 1H NMR: 0.88 (t, 3 H, J =
6.6, MeC4H8); 1.08 an d 1.40 (2 × s, 2 × 3 H, 6-Me2); 1.29 (m , 4 H); 1.55 (m , 2 H); 1.67 (br s,
3 H, 9-Me); 1.80 (m , 3 H); 2.12 (m , 1 H); 2.43 (m , 2 H); 2.69 (m , 1 H); 3.20 (dd, 1 H, J =
16.3 an d 4.1, 10a-H); 4.90 (br s, 1 H, OH); 5.42 (d, 1 H, J = 4.4, 7-H); 6.09 an d 6.27 (2 × d,
2 × 1 H, J = 1.3, 2,4-H). 13C NMR: 14.4 (Me), 18.9 (Me), 22.9 (CH2), 23.9 (Me), 27.9 (Me),
28.3 (CH2), 31.0 (CH2), 31.9 (CH2), 32.0 (6a-CH), 35.8 (CH2), 36.4 (CH2), 45.3 (10a-CH),
77.1 (6-C), 108.1 an d 110.4 (2,4-CH), 111.0 (C), 119.7 (8-CH), 135.2 (C), 143.1 (C), 155.1
(C), 155.2 (C).
(±)-cis-6,6,9-Trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (±)-(13). Obtain ed from
4 an d 9 as a viscous pale yellow oil (24%). 1H NMR: 1.29 an d 1.43 (2 × s, 2 × 3 H, 6-Me2);
1.59–2.08 (m , 5 H); 1.70 (br s, 3 H, 9-Me); 3.55 (br s, 1 H, 10a-H); 5.94 (d, 1 H, J = 4.1,
10-H); 6.74 (d, 1 H, J = 7.8, 4-H); 6.85 (t, 1 H, J = 7.5, 2-H); 7.05 (t, 1 H, J = 7.5, 2-H); 7.25
(d, 1 H, J = 7.5, 1-H). EI MS, m/z (%): 228 (100, M• +), 213 (60), 186 (11), 185 (67), 171 (13),
160 (21), 159 (12), 157 (12), 146 (10), 145 (73), 135 (16), 131 (12), 128 (11), 115 (15), 107
(16), 91 (17), 77 (12). EI HRMS, m/z: 228.15142 (calculated for C16H20O: 228.15142; M•+).
(±)–2,6,6,9-Tetramethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (±)-(14). Obtain ed
from 4 an d 10 as a 3 : 1 m ixture of cis-/trans-isom ers as a viscous pale yellow oil (42%).
EI MS, m/z (%): 242 (100, M•+), 227 (46), 231 (12), 202 (11),199 (62), 197 (10), 185 (14), 174
(20), 171 (11), 165 (10), 159 (99), 145 (18), 135 (21), 128 (15), 121 (23), 115 (15), 107 (12),
105 (12), 91 (20), 84 (45), 77 (16). EI HRMS, m/z: 242.16712 (calculated for C17H22O:
242.16707; M•+). Cis-isom er: 1H NMR (taken in a m ixture with th e trans-isom er): 1.26 an d
1.41 (2 × s, 2 × 3 H, 6-Me2); 1.50–2.12 (m , 5 H); 1.71 (br s, 3 H, 9-Me); 2.26 (s, 3 H, 2-Me);
3.52 (br s, 1 H, 10a-H); 5.93 (d, 1 H, J = 4.4, 10-H); 6.65 (d, 1 H, J = 8.2, 4-H); 6.86 (br d, 1 H,
J = 8.2, 3-H); 7.06 (br s, 1 H, 1-H). 13C NMR (taken in a m ixture with th e trans-isom er): 20.3
(CH2), 21.2 (Me), 24.0 (Me), 25.9 (Me), 27.0 (Me), 30.9 (CH2), 31.3 (6a-CH), 39.9 (10a-CH),
76.0 (6-C), 117.5 (CH), 122.6 (CH), 124.9 (C), 128.1 (CH), 129.2 (CH), 129.6 (C), 135.5 (C),
150.2 (C). Trans-isom er: 1H NMR (taken in a m ixture with th e cis-isom er): 2.29 (s, 3 H,
2-Me); 3.19 (br d, J = 10.5, 10a-H).
(–)-(2R,5R,6R)-5-Isopropenyl-2-methyl-9-pentyl-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxo-
.
can-7-ol [other name (–)-∆8-iso-THC] (–)-(24)9b 1H NMR (taken in a m ixture with (–)-∆9-THC, 1):
3.48 (br s, 1 H, 6-H); 4.92 an d 4.97 (2 × s, 2 × 1 H, 5-CH2=); 5.02 (br s, 1 H, OH); 6.11 an d
6.28 (2 × s, 2 × 1 H, 8-H an d 10-H).
(–)-(2R,6R)-5-Isopropylidene-2-methyl-9-pentyl-3,4,5,6-tetrahydro-2,6-methano-2H-1-benzoxo-
can-7-ol [other name (–)-∆6-iso-THC] (–)-(25)9b. Viscous pale yellow oil, [α ]2D7 –160.0 (c 1.15,
CHCl3). 1H NMR 0.88 (t, 3 H, J = 6.6, MeC4H8); 1.29 (m , 4 H, MeCH2CH2); 1.35 (s, 3 H,
2-Me); 1.59 (m , 4 H); 1.66 an d 1.92 (2 × s, 2 × 3 H, 5-Me2); 1.82 (m , 2 H); 2.04 (m , 1 H);
2.44 (m , 3 H); 4.16 (br s, 1 H, 6-H); 4.50 (br s, 1 H, OH); 6.12 an d 6.29 (2 × d, 2 × 1 H, J =
1.5, 8-H an d 10-H). 13C NMR: 14.4 (Me), 20.4 (Me), 21.0 (Me), 23.0 (CH2), 23.4 (CH2), 29.2
(Me), 30.4 (6-CH), 31.2 (CH2), 32.0 (CH2), 36.1 (CH2), 37.4 (CH2), 40.8 (CH2), 74.7 (2-C),
106.8 an d 108.5 (8,10-CH), 110.5 (C), 122.0 (C), 132.2 (C), 143.1 (C), 153.0 (C), 157.3 (C).
(–)-2-(p-Mentha-2,8-dien-3-yl)pentylbenzene-1,3-diol [other name (–)-cannabidiol] (–)-(26)9b
.
Viscous pale yellow oil, [α ]2D2 –107.1 (c 1.00, EtOH), [α ]2D3 –69.4 (c 1.65, CHCl3) (ref.9b gives
[α]D –126 (EtOH) for en an tiopure 26). 1H NMR: 0.88 (t, 3 H, J = 6.6, MeC4H8); 1.29 (m , 4 H,
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Malkov, Kočovský:
MeCH2CH2); 1.56 (m , 2 H); 1.65 (s, 3 H, 8′-Me); 1.79 (br s, 3 H, 1′-Me); 1.82 (m , 2 H); 2.12
(m , 2 H); 2.43 (m , 3 H); 3.85 (br d, 1 H, J = 8.8, 3′-H); 4.56 an d 4.66 (2 × s, 2 × 1 H, 9′-CH2);
5.57 (s, 1 H, 2′-H); 6.22 (br s, 2 H, 4-H an d 5-H). 13C NMR: 14.6 (Me), 20.8 (Me), 23.1 (CH2),
24.3 (Me), 28.7 (CH2), 30.8 (CH2), 31.2 (CH2), 31.9 (CH2), 35.9 (CH2), 37.4 (4′-CH), 45.6
(3′-CH), 108.2 an d 110.0 (4.6-CH), 111.4 (9′-CH2), 114.0 (C), 124.4 (2′-CH), 140.7 (C), 143.5
(C), 149.8 (C), 154.2 (C), 156.3 (C).
(–)-4-(p-Mentha-2,8-dien-3-yl)pentylbenzene-1,3-diol [other name (–)-abnormal cannabidiol]
(–)-(27)9b. Viscous pale yellow oil, [α ]D22 –74.3 (c 2.12, CHCl3) (ref.9b gives [α]D –76 (CHCl3)
for en an tiopure 27). 1H NMR: 0.89 (t, 3 H, J = 6.6, MeC4H8); 1.30 (m , 4 H, MeCH2CH2);
1.46 (m , 2 H); 1.53 (s, 3 H, 8′-Me); 1.78 (br s, 3 H, 1′-Me); 1.81 (m , 2 H); 2.22 (m , 3 H); 2.51
(m , 2 H); 3.53 (br d, 1 H, J = 8.8, 3′-H); 4.46 an d 4.64 (2 × s, 2 × 1 H, 9′-CH2); 5.52 (s, 1 H,
2′-H); 6.20 (s, 2 H, 2,6-H). 13C NMR: 14.4 (Me), 21.7 (Me), 22.9 (CH2), 24.0 (Me), 28.5 (CH2),
30.7 (CH2), 31.5 (CH2), 32.3 (CH2), 34.4 (CH2), 40.5 (4′-CH), 45.4 (3′-CH), 102.6 an d 109.1
(2,6-CH), 111.8 (9′-CH2), 120.3 (C), 125.1 (2′-CH), 140.2 (C), 144.4 (C), 148.1 (C), 155.0 (C),
156.8 (C).
(+)-(1S,4R)-p-Men th a-2,8-dien -1-ol (21)
Th is com poun d was prepared from a 1 : 1 m ixture of (1S,2R,4R)- an d (1R,2S,4R)-lim on en e
oxides 17 an d 18 (1.22 g, 8 m m ol) followin g th e literature procedure13. Th e crude product
was purified by colum n ch rom atograph y on silica gel (2 × 20 cm ) with a 4 : 1 m ixture of
h exan e–eth yl acetate as eluen t to afford th e title com poun d as a colorless oil (370 m g, 30%).
21: [α ]2D2 +68.2 (c 1.15, CH2Cl2) (ref.17 gives [α]D +73.6 or +76.0 (n eat), an d +73 (c 1.2,
CHCl3); ref.13a gives [α]D +76.8 n eat for en an tiopure 21). 1H NMR: 1.29 (s, 3 H, 1-Me);
1.57–1.85 (m , 4 H, 5,6-CH2); 1.74 (s, 3 H, 8-Me); 2.66 (m , 1 H, 4-H); 4.75 an d 4.78 (2 × br s,
2 × 1 H, 9-CH2); 5.67 (m , 2 H, 2,3-H).
(+)-(1S,4R)-p-Men th a-2,8-dien -1-yl Acetate (22)13b
Acetic an h ydride (260 m g, 2.5 m m ol) was added dropwise to a stirred solution of alcoh ol 21
(240 m g, 1.58 m m ol), trieth yl am in e (303 m g, 3 m m ol), an d 4-dim eth ylam in opyridin e
(20 m g, 0.16 m m ol) in eth er (25 m l) at room tem perature. Th e m ixture was stirred at room
tem perature for 4 h , th en it was diluted with water (30 m l) an d extracted with eth er (3 ×
20 m l). Th e com bin ed eth er extracts were dried over MgSO4 an d th e eth er was rem oved in a
vacuum . Th e residue was passed th rough a silica gel colum n (2 × 10 cm ) with a 9 : 1 m ix-
ture of h exan e–eth yl acetate as eluen t to afford th e 22 as a colorless oil (260 m g, 85%).
1H NMR: 1.46–1.76 an d 2.13 (m , 4 H, 5,6-CH2); 1.55 (s, 3 H, 1-Me); 1.71 (s, 3 H, 8-Me); 1.96
(s, 3 H, MeCO); 2.70 (m , 1 H, 4-H); 4.76 (br s, 2 H, 9-CH2); 5.70 (dd, 1 H, J = 10.1 an d 1.9,
3-H); 6.17 (dq, 1 H, J = 10.1 an d 1.3, 2-H).
We thank the EPSRC for grant No. GR/L41448. The work was carried out under the Home Office
(U.K.) license No. 98/DM3/1176.
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REFERENCES AND NOTES
1. a) Nakanishi K., Goto T., Ito S., Natori S., Nozoe S.: Natural Products Chemistry, Vol. 2, p.
151. Academic Press, New York 1975; and references therein. For earlier syntheses, see:
b) Crombie L., Crombie W. M. L., Palmer C. J., Jamieson S. V.: Tetrahedron Lett. 1983,
24, 3129; c) Crombie L., Crombie W. M. L., Jamieson S. V., Palmer C. J.: J. Chem. Soc.,
Perkin Trans. 1 1988, 1243; d) Crombie L., Crombie W. M. L., Firth D. F.: J. Chem. Soc.,
Perkin Trans. 1 1988, 1251; e) Crombie L., Crombie W. M. L., Tuchinda P.: J. Chem. Soc.,
Perkin Trans. 1 1988, 1255; f) Crombie L., Crombie W. M. L., Firth D. F.: J. Chem. Soc.,
Perkin Trans. 1 1988, 1263. For recent synthetic studies, see, e.g.: g) Kachensky D. F., Hui
R. A. F.: J. Org. Chem. 1997, 62, 7065; h) Mahadevan A., Siegel C., Martin B. R., Abood
M. E., Beletskaya I., Radan R. K.: J. Med. Chem. 2000, 43, 3778; and references therein.
2. KočovskýP., Ahmed G., Šrogl J., Malkov A. V., Steele J.: J. Org. Chem. 1999, 64, 2765.
3. a) Malkov A. V., Baxendale I. R., Mansfield D. J., KočovskýP.: Tetrahedron Lett. 1997, 38,
4895; b) Malkov A. V., Baxendale I. R., Mansfield D. J., KočovskýP.: J. Org. Chem. 1999,
64, 2737.
4. a) Malkov A. V., Davis S. L., Mitchell W. L., KočovskýP.: Tetrahedron Lett. 1997, 38,
4899; b) Malkov A. V., Davis S. L., Baxendale I. R., Mitchell W. L., KočovskýP.: J. Org.
Chem. 1999, 64, 2751.
5. Malkov A. V., Spoor P., Vinader V., KočovskýP.: J. Org. Chem. 1999, 64, 5308.
6. a) Doyle G.: Inorg. Chem. 1971, 10, 2348; b) van den Bergen A., Murray K. S., West B. O.:
Aust. J. Chem. 1972, 25, 705.
7. Note that the (E)-isomer cannot cyclize, would remain in the reaction mixture
unreacted, and could then be separated from the product by chromatography owing to a
sufficiently different polarity. Two equivalents of citral were employed in this and the
subsequent experiments.
8. The yield is calculated with respect of olivetol.
9. Crucial for the configurational assignment is the signal of the benzylic proton in the
1H NMR spectrum, which appears as a broad singlet at 3.55 ppm for the cis-isomer and
as a broad doublet at 3.20 ppm for the trans-isomer. For further discussion of the
1H NMR characteristics, see: a) Taylor E. C., Lenard K., Shvo Y.: J. Am. Chem. Soc. 1966,
88, 367; b) Razdan R. K., Dalzell H. C., Handrick G. R.: J. Am. Chem. Soc. 1974, 96, 5860.
10. This mechanism has been proposed earlier by another group for conventional Lewis
acids: Kane V. V., Razdan R. K.: Tetrahedron Lett. 1969, 591.
11. For the first asymmetric synthesis of (+)-1 based on the construction of the cyclohexene
ring via the Diels–Alder addition catalyzed by (bisoxazoline)Cu(II), see: Evans D. A.,
Shaughnessy E. A., Barness D. M.: Tetrahedron Lett. 1997, 38, 3193.
12. a) Malkov A. V., Bella M., Langer V., KočovskýP.: Org. Lett. 2000, 2, 3047; b) Malkov
A. V., Baxendale I. R., Fawcett J., Russel D. R., Langer V., Mansfield D. J., Valko M.,
KočovskýP.: Organometallics 2001, 20, 673; c) Malkov A. V., Spoor P., Vinader V.,
KočovskýP.: Tetrahedron Lett. 2001, 42, 509.
13. a) Rickards R. W., Watson W. P.: Aust. J. Chem. 1980, 33, 451; b) Rickards R. W.,
Roennenberg H.: J. Org. Chem. 1984, 49, 572.
14. Note that the regiochemistry of the oxirane ring-opening is controlled by the stereoelectronic
effect, so that it occurs in a diaxial fashion.
15. For a similar strategy, see: Stoss P., Merrath P.: Synlett 1991, 553.
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16. Owing to the non-stereoselective epoxidation of limonene, the overall yield of 21
cannot exceed ≈50%.
17. The structure of these and other products (vide infra) was deduced form their 2D NMR
spectra and from the comparison of their GC MS characteristics with the known data.
See refs9,10 and the following: Petrzilka M., Häflinger W., Sikemeier C.: Helv. Chim. Acta
1969, 52, 1102.
Pavel Kočovský was born in 1951 in Czechoslovakia (now Czech
Republic) and raised and educated in Prague. He received his MSc
in 1974 (1st class) from the Technical University, Prague, where
he did his diploma workwith Prof. O. Červinka in the area of
asymmetric reactions. He obtained a PhD in 1977 from the
CzechoslovakAcademy of Sciences, Institute of Organic Chemistry
and Biochemistry, Prague, where he worked on steroid chemistry
under the guidance of Dr. V. Černý. He was then appointed to his
first academic position at the same Institute and stayed for twelve
years. During this period, he also taught various courses at Charles
University (Prague) as an external lecturer. After the long first six
years, he finally obtained permission to temporarily leave the
(then) communist Czechoslovakia and joined Prof. J. E. McMurry
at Cornell University, U.S.A., as a research associate (1983–84).
He returned to his position in Prague in 1984 and later spent a sabbatical year with Prof. J.-E.
Bäckvall at the University of Uppsala, Sweden (1989–1991). In 1991 he emigrated to the U.K. and
started a new academic career, first at the University of Leicester, where he spent almost nine years,
obtained a DSc (1993), and raised in the ranks to full professor. In 1999 he moved to the Univer-
sity of Glasgow as the Sir William Ramsay Professor of Chemistry. His research interests encompass
all areas of organic and organometallic stereochemistry, mainly asymmetric catalysis, reaction
mechanisms, stereochemistry, organic synthesis, natural products, and sensors for chiral molecules.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)