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Synthesis of (±)-camphor
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1973 2109
Synthesis of (*)-Camphor
By John C. Fairlie, Gordon L. Hodgson, and Thomas Money,' Department of Chemistry, University of
British Columbia, Vancouver 8, British Columbia, Canada
An alternative proposal for the biosynthesis of the bornane series of bicyclic monoterpenes forms the basis of a new
synthesis of camphor from p-menth-8-en-2-one (dihydrocarvone).
mediate (2; 2 = biological leaving group) which can insight into the biosynthesis of bicyclic monoterpenes no
subsequently cyclise to produce the bornane, pinane, conclusive evidence has been presented which demon-
335
carane , and thujane series of bicyclic mon0terpenes.t strates the exact nature of the monocyclic intermediate
( 3 ) a; R'=OH, 'R = H
4 (51
b: R ' = H R'=OH
(10)
In the bornane group bornan-2a-01 (borneol) (3a) is con- involved in the cyclisation process. I n addition, various
sidered to be the initial product of cyclisation and the laboratory efforts to form bicyclo[2.2.l]heptane deriva-
subsequent derivation of camphor (4),camphene (6), t ives by solvolysis of appropriate cyclohex-3-enylmethyl
and tricyclene ( 5 ) would involve oxidation or dehydra- systems (2; 2 = C1, OH, fi-02N*C,H4C0,, phosphate, or
tion processes for which there is ample laboratory pyrophosphate) have failed.6 Efforts in our laboratory
3 D. V. Banthorpe, B. V. Charlwood, and M. J. 0. Francis,
Alternative explanations for the biosynthesis of bicyclic Chem. Rev., 1972, 72, 115; A. G. Battersby, D. G. Laing, and
monoterpenes are available. For example, pin-2-ene and R. Ramage, J.C.S. Perkin I , 1972, 2743.
pin-2( 10)-ene could be formed directly by concerted cyclisation E. von Rudolff, Phytoclzemz'stvy, 1966, 5, 331; E. Zavarin,
of neryl pyrophosphate and there is ample chemical analogy for ibid., 1970, 9, 1049.
the postulate that pinene or derivatives could act as precursors 5 D. V. Banthorpe and A. Wirz-Justice, J . Chem. SOC.( C ) ,
of the bornane series. A monocyclic intermediate seems 1969, 541.
necessary, however, t o explain the formation of the carane and 6 C. F. Wilcox, M. F. Wilcox, and S. S. Chibber, J . Org.
thujane groups. Chem., 1962, 27, 2286; W. Rittersdorf, Angew. Chem. Internat.
1 Preliminary communication, J. C. Fairlie, G. L. Hodgson, Edn., 1965, 4, 444; F. Cramer and W. Rittersdorf, Tetrahedron,
and T. Money, Chem. Comm., 1969, 1196. 1967, 23, 3015; C. F. Wilcox and S. S. Chibber, J . Org. Chenz.,
2 L. Ruzicka, Experientia, 1953, 9, 357; Proc. Chem. Soc., 1962, 27, 2332; cf. T. Money, Progr. Org. Chem., 1972, 8, 29.
1959, 341. 7 H. Felkin and C. Lion, Chem. Comnt., 1968, 60.
View Article Online
OAc
(181
( 2 1I
(22) (23)
bornane series. Thus an appropriate monocyclic enol (+)-$-Menth-%en-2-one (dihydrocarvone) (14) j- was
ester, enol ether, or enamine (8) was considered- as an obtained in 87% yield by reduction of (-)-$-mentha-
intermediate potentially capable of cyclisation to 6,8-dien-2-one (carvone) (13) with zinc and ethanolic
camphor (4). The subsequent derivation of structurally potassium h y d r o ~ i d e . ~Subsequent
.~~ treatment of (14)
related monoterpenes would then involve reduction, with isopropenyl acetate in the presence of toluene-$-
dehydration, and rearrangement processes which are well sulphonic acid l1 resulted in a mixture (ca. 4 : 1) of (+)-2-
documented. In terms of absolute configuration the acetoxy-$-mentha-l,8-diene (15) and Z-acetoxy-9-
hypothesis would predict a biosynthetic relationship mentha-2,s-diene (16) ( +906"), which were sepa-
between (+)-camphor (4), (+)-bornan-Za-ol (3a), (-)- rated by preparative g.1.c. Treatment of a 0.1% solu-
bornan-2$-01(3b),(+)-camphene (6),and the appropriate tion of (15) in wet methylene chloride with boron tri-
monocyclic intermediate (8).* While the biosynthetic fluoride gas at room temperature for 10 min provided
validity of these proposals has yet to be tested, the
8 E. J. Corey, N. N. Girotra, and C. T. Mathew, J . Amer.
* Several possible precursors of (8) can be considered, e.g. Chem. SOC.,1969, 91, 1557.
(+)-limonene 1,2-epoxide, a-terpineol epoxide, or (+)-dihydro- 0. Wallach, Annalen, 1894, 275, 377; cf. T. G. Halsall,
carvone. D. W. Theobald, and K. B. Walshaw, J . Chem. SOC.,1964, 1029.
t The n.m.r. spectrum of this compound indicated that it lo hl. Yoshida, Chem. and Pharm. B u l l ( J a p a n ) , 1955, 3, 215.
was a mixture of C-1 epimers (trans : cis 3 : 1). l1 H. 0. House and H. W. Thompson, J . Org. Chem., 1961, 26,
$ Similar treatment of (16) yielded carvenone (17) as major 3729 and references therein; R. B. Moffet and D. I. Weisblat,
product. J . A m e r . Chem. SOC.,1952, 74, 2183.
View Article Online
1973 2111
(&)-camphor [(4) + (4a)l in 90% yield (estimated by the latter instrunient. Microanalyses were performed by
g.1.c.). Higher concentrations of enol acetate (15) re- Mr. P. Borda.
sulted in a lower yield of camphor and a corresponding (+)-p-17Menth-8-en-2-one (14) lo-A .g3 mixture of zinc
powder (250 g), potassium hydroxide (100 g, 1.78 mol),
increase in the yield of P-menth-3-en-2-one (carvenone) 95% ethanol (1000 ml), and water (400 ml) was heated to
(17) and other unidentified products. For example a reflux with vigorous stirring and (-)-p-mentha-6,8-dien-2-
0.7% solution of (15) gave a mixture of at least ten com- one (13) (203 g), [aID3O-58.6" (c 4.78 in CHCl,), dissolved in
pounds including camphor (loyo), carvenone (35%), 95% ethanol (400 ml), was added dropwise during 6 h.
and an unknown compound (39%). Structure (18) was Refluxing was continued (1 h) until the disappearance of
assigned to the last compound on the basis of its spectral U.V. absorption at 234 nm. The cooled mixture was
characteristics. When the reaction was run in dry filtered and evaporated under reduced pressure. The
rnethylene chloride or when other acid catalysts (q. residue was extracted with petroleum (3 x 250 ml) and
HCl, HF, AlCl,, or BF,-Et,O) were used, negligible the combined extracts were washed until neutral and dried
Published on 01 January 1973. Downloaded by 203561 on 08/01/2016 18:28:25.
yields of camphor were obtained." (Na,SO,). Removal of the solvent and distillation of the
residual oil afforded (+)-fi-menth-8-en-2-one (14) (178 g )
The racemic nature of synthetic camphor obtained by as a mixture of C-1 epimers [cis-1,4 : trans-1,4 ; 1 : 3 by
cyclisation of (+)-2-acetoxy-&mentha-l ,S-diene (15) n.m.r.1, b.p. 80" at 6 mmHg (1it.,lo 100-104" at 17 mmHg),
was unexpected; we are investigating this aspect of the homogeneous by g.1.c. (column A; 150"); +18.3"
cyclisation reaction. (+)-Camphor (4) does not racemise (c 10.4, CHCl,); t , ,A 284 nm (E 30); vmK (neat) 3100,
under these conditions and it is likely that disruption of 1710, 1650, and 892 cm-l; z (CC1,) 9.04 and 8.99 (3H, two
the chiral centre in (15) is occurring through double- doublets, relative area 76 : 24, J 6-0and 6-5Hz, respectively,
bond migration or 1,Zhydride shift. In any event the epimeric CHMe), and 8-27 (3H, m, C%H).
result is probably quite general since we have found that ( +)-2-A cetoxy-p-mentha-1,8-diene (15 ) and (+) -2-Acetoxy-
cyclisation of optically active enol acetates [(21), l 2 (22),13 p-mentha-2,8-diene (16).+-Menth-8-en-2-one (14) (6.00 g,
and (23) l*] provides racemic bicyclic products. 0.039 mol) was heated with isopropenyl acetate (15 ml) and
toluene-9-sulphonic acid monohydrate (100 mg) for 30 h
The extension of our biosynthetic ideas and synthetic with slow removal of the generated acetone by distillation.
strategy to an appropriate group of sesquiterpenes is The mixture was cooled and diluted with petroleum, and
described in the following paper. the organic layer was washed with aqueous sodium hydrogen
carbonate and dried. Solvent removal under reduced
EXPERIMENTAL pressure followed by distillation (b.p. 41-44" at 0.02
mmHg) yielded a mixture of (+)-2-acetoxy-9-mentha-1 ,8-
M.p.s were determined on a KoAer liot-stage apparatus. diene (15) and (+)-2-acetoxy-p-mentha-2,8-diene (16).
G.1.c. was carried out on either a 1-arian Aerograph 90-P G.1.c. analysis (column A; 140") indicated that (15) and
or an Aerograph Autoprep 700 instrument, and the follow- (16) were present in a ratio of ca. 4 : 1 (relative retention
ing columns were employed : times, 3.7 and 3.0 min, respectively). Pure samples were
Stationary obtained by preparative g.1.c. (column C; 175") followed by
Column Dimensions phase Support Mesh distillation.
A 1 0 ft x 1/4 in 3% SE 30 Varoport 30 100-120 2-Acetoxy-$-mentha-l,8-diene(15) showed nD35 1.4757;
B 1 0 ft x 3/8 in 30% F F A P Chromosorb W 60-80 [aID2*+81.1" (c 2.46 in CHCl,) (another preparation gave a
C 20 f t X 3/8 in 30% SE 30 Chromosorb W 45-60 +77" rotation); v,,, (neat) 3090, 1745, 1705, 1645, 1210,
and 888 cm-l; z (CCl,) 8.51br (3H, s), 8-26 (3H, m), 7-95
Carrier gas (helium) flow-rate for 1/4 in columns was 60 (3H, s), and 5-26 (2H, m ) ; in/e 194 (5-1%, M+), 152 (67.0),
ml min-l and for 3/8 in columns was 170 ml min-1. Optical 109 (loo), 84 (37.3), 43 (72-9),and 41 (51.7).
rotations were measured with either a Perkin-Elmer 141 2-Aceto~y-p-mentha-2~8-diene +
(16) showed [aIDz8 90.5"
polarimeter or a Rudolph polarimeter. C.d. spectra were (c 2.56 in CHCl,); ,,v, (neat) 3090, 1745, 1680, 1645, 1210,
recorded on a JASCO J-20 spectropolarimeter. U.V. and 890 cm-l; T (CCl,), 9.04 (3H, J 6.5 Hz, CHMe), 8.26
spectra were recorded for solutions in methanol on a Unicam (3H, m, C=CMe), 7.93 (3H, s, OAc), 5-23 (2H, m, =CH,), and
SP 800 spectrophotometer. Routine i.r. spectra were 4.86 ( l H , m, C=CH); in/e 194 (5.574, M + ) , 152 (90.4), 137
recorded on a Perkin-Elmer Infracord 137 spectrophoto- ) ~ (35.2), 95 (35.8), 43 (loo), and 41 (51.5).
( 7 9 ~ 4 109
meter and comparison spectra on a Perkin-Elmer 21 or Cyclisation of ( +)-2-Acetoxy-p-rnentha-l,S-diene(15).-A
457 spectrophotometer. The 60 MHz n.m.r. spectra were vigorously stirred solution of (+)-2-acetoxy-p-mentha-l,8-
recorded on a Varian A-60 or T-60 instrument and 100 diene (15) (203 mg, 1-04 mmol), [aIDz3+77", in methylene
MHz spectra on a Varian HA-100 or XL-100 instrument chloride (Baker reagent grade; 0.012% water) (200 ml)
(tetramethylsilane as internal reference) Mass spectra was treated with boron trifluoride gas for 10 min. The re-
were recorded on a n Atlas CH-4 or a n A.E.I. MS-9 spectro- action was quenched by shaking with saturated aqueous
meter. High resolution mass spectra were determined on sodium hydrogen carbonate (50 ml) and the organic phase
* In our description we have assumed that prior formation was washed twice with water and dried (Na,SO,). Solvent
of enol acetate functionality was essential for successful cyclis- removal afforded a faintly yellow residue which became
ation. To provide support for this assumption dihydrocarvone
(14) was treated with boron trifluoride under conditions identical
with those described. Three main reaction products were l2 G. L. Hodgson, J. C . Fairlie, and T. Money, unpublished
isolated by preparative g.1.c. and on the basis of their spectral observations.
characteristics were assigned structures (17), (1 9). and (20). 13 G. L. Hodgson, D. F. MacSweeney, and T. Money, Chem.
t In another preparation using the original procedure9 the Comm., 1971, 766.
product exhibited a rotation of + 12", indicating a different 14 G. L. Hodgson, D. F. MacSweeney, and T. Money, following
ratio of C-1 epimers. paper.
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colourless product, estimated to be 90% camphor by g.1.c. of three major components with tR 13, 20, and 25 min.
analysis (column B; 170"). The component with tn 13 min was assigned structure
Higher concentrations of (15) led to reduced yields of (20) on the basis of the following data: U.V. end absorption
camphor. Thus (16) (335 mg) in methylene chloride (50 ml) vmax. (neat) 1710 and 805 cm-l; T (CCl,) 8-96 (9H, d, J 6.5
was treated for 1 h with boron trifluoride gas. After the Hz, 3 x C H M e ) , 7.26br (2H, s, CH,CO), and 4.46br (lH,
usual work-up the product (300 nig) was shown to consist s, C=CH); T (C,H,) 9-18 (6H, d, J 5 Hz) and 9.01 (3H, d,
of at least ten components by g.1.c. analysis. The three J 5 Hz). The component with t R 20 min did not appear
major components were isolated by preparative g.1.c. pure on spectral analysis but was assigned a tentative
(column B; 170") and had retention times ( t R ) of 10, 25, structure (19) based on the following evidence : v,, (neat)
and 29 min. The component (10%) of tR 10 min was 1705 cm-l; T (CCI,) 8.97 (3H, d, J 6 Hz) and 8.32br (6H, s).
identified as camphor [(4) + (4a)l by comparison of its i.r., The component with t R 25 min exhibited spectral properties
n.m.r. , and mass spectra with those of an authentic sample. (u.v., i.r., n.m.r.) in agreement with those for p-menth-3-en-
The component (35%) having tR 25 niin was identified as 2-one (17).
pmenth-3-en-2-one (17) on the basis of the following data: Treatment of 2-Acetoxy-p-wentha-2,8-diene ( 16) with Boron
, , A 234 nm ( E 13,200); vmaL (neat) 1670, 1210, and 880 Trifluoride.-2-Acetoxy-~-mentha-2,8-diene(16) ( 19 mg) in
crn-l; T (CClJ 8.95 (3H, d, J 6.5 Hz), 8.89 (6H, d, J 6-5 Hz), methylene chloride (9 ml) was added a t room temperature
and 4.27 ( l H , s). The component (39%) with t R 29 min to methylene chloride (10 ml) which had been saturated
was assigned structure (18) on the basis of the following with boron trifluoride gas. A slow stream of the gas was
data: U.V. end absorption; vmx. (neat) 1745, 1210, 840, and maintained through the solution for 10 min. The solution
805 cm-l; z (CCI,) 8.97 (6H, d, J 6.5 Hz), 8.50br (3H, s), was washed with saturated aqueous sodium hydrogen
7.92 (3H, s ) , 7.72 ( l H , m), 7-32br (4H, s), and 4-65 (lH, s). carbonate ( 5 ml) and water and dried (Na,SO,). Solvent
Attempted Racemisation of (+)-Camphor.-A solution of removal afforded almost pure material (93% by g.1.c.;
+
(+)-camphor ([a], 46.4" ; commercial grade used without column B; 170"; t R 25 min) exhibiting spectral charac-
further purification) (152 mg) in methylene chloride (150 teristics (u.v., i.r.) in agreement with those for p-menth-3-
ml) was saturated with boron trifluoride gas and kept in a en-2-one (17).
stoppered vessel for 4 h at room temperature. The mixture
was washed with saturated aqueous sodium hydrogen carb- We thank the National Research Council of Canada for
onate and water and dried (Na,SO,). Solvent removal financial support.
[3/154 Received, 2 3 r d January, 19731
followed by two sublimations (50" at 0-15 mmHg) afforded
(+)-camphor, [0ilD25 +43.6" (c 1.52 in 95% EtOH) {lit.,15 l5 ' Handbook of Chemistry and Physics,' 52nd edn., ed.
[aID2" +44*3" (95% EtOH)}. Another sample of (+)- R. C. Weast, The Chemical Rubber Co., Cleveland, Ohio.