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A Biogenetic-Type Synthesisof Cannabifuran andDehydrocannabifuranVaman S. Jorapur a , Richard P. Duffley a & Raj K. Razdan aa The SISA Institute for Research, Inc., 763D ConcordAvenue, Cambridge, MA, 02138Version of record first published: 05 Dec 2006.

To cite this article: Vaman S. Jorapur , Richard P. Duffley & Raj K. Razdan (1984):A Biogenetic-Type Synthesis of Cannabifuran and Dehydrocannabifuran, SyntheticCommunications: An International Journal for Rapid Communication of Synthetic OrganicChemistry, 14:3, 203-207

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SYNTHETIC COMMUNICATIONS, 14(3) , 203-207 (1984)

A BIOGENETIC-TYPE SYNTHESIS OF CANNABIFURAN AND DEHYDROCANNABIFUMN’

* Vaman S. Jorapur , Richard P. Duff ley and Raj K. Razdan

763D Concord Avenue, Cambridge, MA 02138 The SISA I n s t i t u t e f o r Research, Inc .

ABSTRACT: The t i t l e compounds were syn thes i zed from cannab id io l i n y i e l d s of 21% and 29% r e s p e c t i v e l y .

We wish t o r e p o r t a f a c i l e s y n t h e s i s o f two n a t u r a l l y occur r ing

d ibenzofurans , cannabi furan (&) and dehydrocannabifuran (k) which

a r e minor c o n s t i t u e n t s of cannabis i s o l a t e d from green Afghan hash i sh

i n 1975.’

have prompted us t o record our f i n d i n g s a t t h i s t ime.

Recent publication^^'^'^ on t h e s y n t h e s i s of t h e s e compounds

I n e a r l y 1982, Sargent and S t r ansky3 r epor t ed a s y n t h e s i s o f canna-

b i f u r a n (&) based on annu la t ion of benzofuran . This yea r two more syn-

t h e s i s have appeared .

t h e s i s o f bo th cannabi furan and dehydrocannabi furan u t i l i z i n g a copper

( I ) a c e t y l i d e t o b u i l d t h e s i d e cha in benzofuran moiety. The remaining

aromat ic r i n g was syn thes i zed v i a cyc loadd i t ion .

used a novel procedure t o b u i l d t h e a r y l - a r y l bond and then c a r r i e d o u t

t h e f u r a n r ing -c losu re t o s y n t h e s i z e f&.

occur ing cannab id io l (la) as t h e s t a r t i n g m a t e r i a l and proceeds

cannab ie l so in (2), ano the r cannabis c o n s t i t u e n t , t h e s y n t h e s i s of which

w e r epor t ed i n 1974.6

r e a d i l y t ransformed i n r o dehydrocannabi furan and cannab i fu ran , t hus ac-

complishing t h e i r syn theses from cannab id io l i n o v e r a l l y i e l d s o f 29%

and 21% r e s p e c t i v e l y .

Scanne l l and Stevenson4 r epor t ed an e l egan t syn-

5 Novak and Sdemink

Our approach uses t h e n a t u r a l l y

Now w e have found t h a t cannab ie l so in can be

* To whom correspondence should be addressed .

203

Copyright 0 1984 by Marcel Dekker, Inc 0039-791 1/84/14030203$3.50/0

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204 JORAPUR, DUFFLEY, AND RAZDAN

The synthesis of the dibenzofurans and & from cannabielsoin (3,

obtained in 57% yield from via and 2 and subsequent alkali treat-

ment)’ resulted from the dehydration of the tertiary hydroxyl group at

C-1, followed by aromatization. Thus, 3 was dehydrated readily with

thionyl chloride-pyridine to afford & in 85% yield.

then dehydrogenated with DDQ to dehydrocannabifuran acetate (2, 73% yield), which on mild alkaline hydrolysis with sodium carbonate in aqueous methanol

formed dehydrocannabifuran (k). followed by hydrolysis gave cannabifuran. However, the hydrogenation of

- 5a as reported’ (using platinum oxide-ethanol), in our hands, resulted in

incomplete reduction, even after prolonged time (24 h).

Its acetate *was

Reduction of & with Pd/C in ethanol,

8

The co-occurrence of the two dibenzofurans, cannabifuran and dehydro-

cannabifuran with structurally-related cannabielsoin and the presence of

cannabidiol in the plant suggest the possibility that these compounds may

be biogenetically related. The present facile synthetic pathway (canna-

bidiol+z+M-+? and 5) lends support to this suggestion. cally unambiguous synthesis of cannabielsoin from a, via 2 by stereo-

specific intramolecular epoxide cleavage by phenolate anion‘, parallels

the well established biogenetic pathway to the formation of furansl’ and

those proposed for the formation of certain furanoquinolines.”

the conversion of 2 to & and & follows the pathway established for the

biosynthesis of aromatic monoterpenes12 via terpenen-4-01+6-terpenen-tp-

cymene and thymol. It should be pointed out that Mechoulam in 1970 had

proposed the biogenesis of cannabielsoin by photo-oxidation (sunlight/02)

of cannabidiol .I3

Dehydrocannabielsoin(4a). To a cooled (OOC) stirring solution of cannabielsoin

(3) (200mg, 0.6lmol obtained in 57% yield from

2.lmol) dropwise under N2.

was poured onto an ice cold HC1 solution (2N, 25ml). It was extracted (ether)

and concentrated to afford 2 as a pale yellow oil (17Omg, 90%); nmr 6 (CC14)

6.13 (s , 2H, aromatics), 5 . 7 2 (br, 1, C6-H vinylic), 5 . 4 0 (s, 1, OH), 5.03

(br, 2 , C -2H, vinylics), 4.60 (d. 1, J=BHz, CZ-H), 3.17 (dd, J2,3=8Hz,

Our stereochemi-

Similarly

was added S0Cl2 ( 1 5 0 ~ 1 ,

After 2h stirring at OOC, the reaction mixture

9

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CANNABIFURAN AND DEHYDROCANNABIFURAN 205

2 - - la. R = H cannabidiol b. R = Ac

5Hll

- 4a. R = H

b. R = Ac

- 5a. R = H Dehydrocannabifuran

b. R = Ac

- 3 cannabielsoin

5Hll

6a. R = H cannabifuran b. R = Ac

J

ms (70eV) m/e, 312 (M'), 297, 257, 244, 231 and 193.

Dehydrocannabifuran Acetate(*). Acetylation of with Ac C-pyridine readily

furnished the acetate 3 (85% yield); Analysis Calcd. for C H 0 : C, 77.93;

H, 8.53. Found: C, 77.66; H, 8.66. A solution of 3 (100mg; 0.28mmol) in

4Oml of C6H6 was treated with freshty crystallized DDQ (155mg; 0.68mmol) and

refluxed (NZ) for 18h with stirring.

and the filterate concentrated under reduced pressure to afford a red oil,

which was purified by column chromatography using 5% ethyl acetate-hexane.

Dehydrocannabifuran acetate 3 was obtained as a colorless oil (72mg, 73%);

nmr 6 (CDC13) 7.33 (d, 1, J=lHz, C2-H), 7.13 (d, 1, J=7Hz, C8-H), 6.92

(d, 1, J=7.5Hz, C -HI, 6.76 (d, 1, J=lHz, C4-H), 5.16 (m, 1, vinylic),

4.96 (m, 1, vinylic), 2.73 (t, J=7Hz, Ar-CH ), 2.53 ( s , 3, Ar-CH ), 2.33

( s , 3, acetate), 2.2 (brs, 3, C=C-CH3), 1.23-1.80 (m, (CH ) ), 0.86 (t,

3, w-CH3). Analysis: Calc. for C23H2603: C, 78.85; H, 7.42. Found:

=12Hz,C3-H), 1.87 ( s , 3, CH3), 1.80 (5, 3, CH3), 0.88 (t, 3, u-CH3): 394

2

23 30 3

A yellow precipitate was filtered off

7

2 3

2 3

c, 78.76; H, 7.48.

Dehydrocannabifuran(5a). A solution of 5J (30Omg; 0.84mmol) in 5Oml of

CH OH containing a solution of 5Omg of Na2C03 in 5ml of H 0 was stirred

overnight at room temperature under N2. 3 2

After concentration under re-

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206 JORAPUR, DUFFLEY, AND RAZDAN

duced pressure it was treated with lOOml of cold 5% HC1. Extraction

(ether) and concentration afforded 3 as a dark oil (242mg; 92%; purity >90% by nmr and rlc). A portion of this material was further purified

(prep.tlc; 10% EtOAc-hexane) to give dehydrocannabifuran as a colorless

oil identical with an authentic sample4 (tlc, ir, nmr).

Cannabifuran(&). Dehydrocannabifuran acetate (2, 22mg; 0.062mol) in

20ml EtOH was shaken in a Parr hydrogenator with PdlC (lo%, 1Omg) at 3Opsj

overnight to furnish cannabifuran acetate (&) as a pale yellow oil (19mg;

86%); nmr 6 (CC1 ) 7.3 (d, 1, J=lHz, C2-H), 7.23 ( s , 2 , C7 & C8-H), 6.9

(d, 1, J=lHz, C -H) , 4.3 (septet, 1, C!<), 2 . 7 6 (t, 2, Ar-CH2), 2.50 ( s ,

3, Ar-CH 1 , 2.4 ( s , 3, acetate), 1.33 (d, 6, J=6.5Hz CH<'!3) 0.86 (t, 3,

wCH ). Without further purification it was hydrolyzed and chromatographed,

as in the preparation of 2, to give cannabifuran (&) as a pale yellow oil

(76%) identical with an authentic sample4 (tlc, ir, nrnr).

from pet.ether gave needles m.p. 76-78" (lit. 78-79"; 80-81')3'5.

furan (&) was also obtained by catalytic hydrogenation of 2 with Pd/C

(10%) catalyst.

- 5a and & (nmr) even after 24h.

4

4

3 CH3

3

Crystallization

Cannabi-

Hydrogenation of & over PtO/C gave a mixture containing

Acknowledgement: This work was supported by Grant No. DA-00574-08 from

the National Institute on Drug Abuse (NIDA).

REFERENCES

1. Paper 31 in the Hashish Series. For paper 30, see V . S . Jorapur, Z.H.

-Khalil, R.P. Duffley, and R.K. Razdan, Chemical Letters, 299 (1982) .

2 . J. Friedrich-Fiechtl and G. Spiteller, Tetrahedron, 3, 479 (1975).

3. M.V. Sargent and P.O. Stransky, J.Chem.Soc.Perkin Trans.1, 1605 (1982).

4. R.T. Scannel and R. Stevenson, J.Chem.Res. ( S ) , 36 (1983). We are grate-

ful to Professor Stevenson for giving us the preprint of their paper and

providing us with their samples of cannabifuran and dehydrocannabifuran

for comparison purposes.

5. J . Novak and C.A. Salemink, Tetrahedron Letters, 3, 101 (1983).

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CANNABIFURAN AND DEHYDROCANNABIWM 207

6. D. Uliss, R.K. Razdan, and H.C. Dalzell, J.Am.Chem.Soc., 96, 7372 (1974) and the references therein.

The yield is calculated on the basis of recovered la. This incomplete reduction may be attributed to the strong bonding of the

aromatic ring with the active sites of platinum so that the reduction pro-

duct cannot be desorbed.' When platinum oxide was replaced by palladium/

carbon, which binds less strongly to the aromatic ring, the hydrogenation

of the double bond was complete within a short time (3h). The difference

in the catalytic activity of palladium and platinum catalysts towards the

hydrogenation of 2 and 2 is reminiscent of the reduction of phenyl-sub- stituted ethylenes. 9b

7.

8.

9(a) M. Freifelder, "Practical Catalytic Hydrogenation: Techniques and Applica-

tions", pp. 127-128, Wiley-Interscience, New York, N.Y. 1971, (b) N.K.

Yurashevskii, J.Gen.Chem. USSR, 8, 438 (1938); Chem. Abstr., 2, 7908

(1938).

10. D.J. Austin and S.A. Brown, Phytochem., 2, 1657 (1973) and the re-

ferences therein.

11. M.F. Grundon and K.J. Jones, Chem. Commun., 1311 (1971); A . C . Colonna

and E.G. Gros, Phytochern., lo, 1515 (1971). 12. A.J. Poulose and R. Croteau, Arch.Biochem.Biophy., 187, 307 (1978). 13. R. Mechoulam, Science, 168, 159 (1970); A. Shani and R. Mechoulam,

Tetrahedron, 30, 2437 (1974).

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