Synthesis of (+/-)-curcumene ether

Article abstract of DOI:10.1055/s-2003-40343

A 9 step synthesis of (+/-)-curcumene ether is described starting from 5-bromo-2-methyl-2-pentene and 2-amino-5-methylphenol in 7% overall yield using an intramolecular Heck reaction as the key transformation to generate a stereogenic quaternary center.

Full text of DOI:10.1055/s-2003-40343

LETTER
1349
Synthesis of (+/–)-Curcumene Ether
S
ynthesis of (+/
r
–)-Curcu
o
mene
E
thery D. Vickers, Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
Fax +1(403)2841372; E-mail: keay@ucalgary.ca
Received 20 November 2003
The sesquiterpene curcumene ether (1) was isolated from
the plant Thuja orientalis in 1969.4 To date there have
been three syntheses of (+/–)-1 reported in the literature.
The first of these was reported by Vig and coworkers5 in
1973 but their synthesis could not be repeated by Paknikar
and coworkers in 1980.6 Consequently, there are only two
valid syntheses of (+/–)-1. The first by Mashrequi and
Trivedi7 in 1978 and the second by Kametani et al in
1984.8 Only recently has the first stereoselective synthesis
of (R)-(+)-1 been reported by Serra.9 This synthesis in-
volved a resolution of cinenic acid and provided (R)-(+)-
1 in 13 steps with an overall yield of 3%.
Abstract: A 9 step synthesis of (+/–)-curcumene ether is described
starting from 5-bromo-2-methyl-2-pentene and 2-amino-5-meth-
ylphenol in 7% overall yield using an intramolecular Heck reaction
as the key transformation to generate a stereogenic quaternary
center.
Key words: total synthesis, intramolecular Heck reaction, spiro
compounds, lactones, natural products
Our interest in the asymmetric intramolecular Heck reac-
tion as a key step for the synthesis of natural products1 has
resulted in our expanding the application of this reaction
towards the synthesis of pyran containing natural
products2 whereby a stereogenic center is created at the C-
2 position of the pyran ring. To our knowledge, the in-
tramolecular Heck strategy3 has not been used to generate
pyran rings containing an aryl group as one of the substit-
uents on the stereogenic center at C-2. This paper de-
scribes the synthesis of (+/–)-curcumene ether (1) in
which the stereogenic center is created via an intramolec-
ular Heck reaction.
The retrosynthesis towards curcumene ether (1) is illus-
trated in Scheme 1. Retrooxygenation of 1 at the C-2 me-
thyl group and ortho-position of the aromatic ring
provides 2. Retrooxidation of the hydroxymethyl group
and ring closure to a lactone gives 3 that should be formed
via an intramolecular Heck reaction with ester 4. Discon-
nection of ester 4 gives acid 5 and iodophenol 6. Com-
pounds 5 and 6 are easily prepared as outlined in
Scheme 2.
2-Iodo-5-methylphenol (6) was prepared by diazotization
of 2-amino-5-methylphenol (7)10 with isoamyl nitrite and
HBF4 in ether to give the stable diazonium tetrafluorobo-
rate intermediate 8 in 86% yield.11 Treatment of 8 with
NaI in refluxing acetone afforded the 2-iodo-5-meth-
ylphenol (6)12 in 71% yield.
The synthesis of pyran acid 5 started with 5-bromo-2-me-
thyl-2-pentene (9).13 Bromide 9 was converted to iodide
10 using NaI in acetone. Halogen-metal exchange of io-
dide 10 with t-BuLi (ether, –78 °C) provided an alkyllith-
ium species that was added slowly to a –78 °C solution of
10 equiv of diethyl oxalate in ether. Standard workup pro-
vided ketoester 11 in 52% yield from bromide 9. Hydrol-
ysis of ester 11 to an acid followed by purification by
distillation unexpectedly gave pyran acid 5 in 65% yield.
Previous syntheses of 5 from the corresponding acid of
1113 required heating the acid with formic acid for 15 min-
utes. In our hands, the heat applied during the distillation
must resulted in the acid auto catalyzing itself to form py-
ran 5 in the distillation bulb. DCC coupling of acid 5 and
phenol 6 in CH2Cl2 with DMAP gave 4 in 88% yield.
With ester 4 in hand, the intramolecular Heck cyclization
was attempted. Treatment of a mixture of pentamethyl-
piperidine and 4 in N,N-dimethylacetamide (DMA) with
a mixture of Pd2(dba)3 and (+/–)-BINAP (in DMA) fol-
lowed by refluxing the solution for 4 d provided a 1:1
mixture of double bond isomers 12 and 13.14–16 Changing
the source of Pd, base and/or solvent resulted in complex
Scheme 1
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1349,1351,ftx,en;S04602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1350
T. D. Vickers, B. A. Keay
LETTER
Acknowledgment
We thank the Natural Science and Engineering Research Council of
Canada and the University of Calgary for financial support.
References
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1998, 231. (d) Shibasaki, M.; Boden, C. D. J.; Kojima, A.
Tetrahedron 1997, 53, 7371. (e) Gibson, S. E.; Middleton,
R. J. Contemp. Org. Synth. 1996, 3, 447.
(4) (a) Tomida, B.; Hirose, Y.; Nakatsuka, T. Mokuzai
Gakkaishi 1969, 15, 47. (b) Tomida, B.; Hirose, Y. Mokuzai
Gakkaishi 1969, 15, 337.
(5) Vig, O. P.; Kumar, H.; Salota, J. P.; Sharma, S. D. Indian J.
Chem. 1973, 11, 86.
(6) Paknikar, S. K.; Dinge, A. S. Indian J. Chem. 1980, 19, 80.
(7) Mashrequi, S. H.; Trivedi, G. K. Indian J. Chem. 1978, 16,
849.
(8) Kametani, T.; Kawamura, K.; Tsubuki, M.; Honda, T. J.
Chem. Soc., Perkin Trans. 1 1984, 1305.
(9) Serra, S. Synlett 2000, 890.
Scheme 2 Reagents and conditions: a) HBF4, Et2O, isoamyl nitrite,
EtOH, 0 °C, 30 min (86%); b) NaI, acetone, reflux, 3 d (71%); c) NaI,
acetone, r.t., 20 h (92%); d) 2 equiv. t-BuLi, Et2O, –78 °C, 1 h; then
10 equiv diethyl oxalate, Et2O, –78 °C, 4 h (52% 2 steps); e) KOH,
H2O, EtOH, reflux, 20 h; 1% HCl, purification at 100 °C, 0.4 mmHg
(64%); f) 6, DCC, DMAP, CH2Cl2, r.t., 20 h (88%); g) Pd2(dba)3,
(+/–)-BINAP, N,N-dimethylacetamide, N2, r.t., 45 min; then add to 4,
pentamethylpiperidine, N,N-dimethylacetamide, argon, 100 °C, 4 d
(90%); h) LiAlH4, Et2O, r.t., 20 h; i) 1 atm H2, 5% Pd/C, EtOH, r.t.,
20 h (86%, 2 steps); j) 2.2 equiv NaH, THF, then add diethylchloro-
phosphate, r.t., 2 h; k) Li(s), NH3(l), Et2O, –78 °C, 30 min (57%, 2
steps).
(10) Purchased from the Aldrich Chemical Company.
(11) (a) Sawaguchi, M.; Fukuhara, T.; Yoneda, N. J. Fluor.
Chem. 1999, 97, 127. (b) Yoneda, N.; Fukuhara, T.;
Mizokami, T.; Suzuki, A. Chem. Lett. 1991, 459.
(12) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.;
Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161.
(13) Hiranuma, S.; Shibata, M.; Hudlicky, T. J. Org. Chem. 1983,
48, 5321.
(14) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6477. (b) Ashimori, A.;
Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
(15) Experimental procedure for the conversion of 4 to 12 and 13:
A mixture of Pd2(dba)3 (13 mg, 0.0141 mmol), (+/–)-BINAP
(17.0 mg, 0.0273 mmol), and dry DMA (2.5 mL) under N2
was added after 45 min. via syringe to a 2 dram screw-top
vial containing ester 4 (52.3 mg, 0.141 mmol). PMP (127
µL, 0.705 mmol)was added and the mixture was heated in
the sealed vial at 100 °C for 4 days. The solution was poured
into ether and washed with saturated NaHCO3 aq (4 × 10
mL) and NaCl aq (4 × 10 mL). The ether extracts were dried
over anhydrous MgSO4, filtered and ether removed under
reduced pressure to give a red/black residue. The oil was
purified by flash chromatography (20:1, hexanes: EtOAc) to
give a mixture1:1 mixture of 12 and 13 (31 mg, 90%). IR
(cm–1) 1814 (ester C=O), 1629 (alkene C=C); 1H NMR δ
1.35 (br s, 3 H, H-1 or H-2), 1.39 (br s, 3 H, H-10 or H-11),
1.43 (br s, 3 H, H-1 or H-2), 1.49 (br s, 3 H, H-10 or H-11),
2.31 (m, 2 H, H-14), 2.38 (br s, 6 H, H-8 and H-17), 2.44 (m,
2 H, H-3), 5.63 (dt, 1 H, J = 10.1 Hz, J = 2.05 Hz, H-12),
5.89–6.08 (m, 2 H, H-4 and H-5), 6.23 (dt, 1 H, J = 10.3 Hz,
J = 4.2 Hz, H-13), 6.87–7.36 (m, 6 H, H-6, H-7, H-9, H-15,
mixtures wherein unreacted SM, 12, 13 and deiodizied 4
were obtained in varying ratios. Changing the time and
temperature of the reaction did not noticeably change the
ratio of 12:13. This was not a worry as the double bond
was not necessary for the synthesis of curcumene ether.
Reduction of the mixture of lactones 12 and 13 with
LiAlH4 followed by a catalytic hydrogenation of a mix-
ture of the isomeric olefins gave saturated diol 14 in 86%
yield. The last step of the synthesis involved removal of
both the hydroxyl and phenol groups simultaneously. This
was accomplished by converting diol 14 into a bis(dieth-
ylphosphonate)17 followed by removal of both phospho-
nates by treatment with lithium metal in liquid ammonia
to give (+/–)-curcumene ether (1) in 57% yield from 14.
In conclusion, we have developed a 9-step synthesis of
(+/–)-curcumene ether (1) from 5-bromo-2-methyl-2-pen-
tene (9) and 2-amino-5-methylphenol (7) in an overall
yield of 7%. We are currently preparing 2-trifluo-
romethanesulfonyloxy-5-methylphenol in order to at-
tempt the intramolecular Heck reaction under asymmetric
conditions.15 Applications of this strategy towards the
synthesis of other 2-arylpyrans are currently underway.
Synlett 2003, No. 9, 1349–1351 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
H-16, and H-18); 13C NMR δ 21.8 (2 × CH3), 28.6 (CH3),
Synthesis of (+/–)-Curcumene Ether
1351
(16) Attempts to perform the intramolecular Heck reaction on
iodide 4 with enantiopure BINAP, BINAPFu,18
TetFuBINAP19 or Pfaltz’s phosphinooxazoline ligand20 gave
racemic mixtures of double bond isomers 12 and 13.
(17) (a) Fuganti, C.; Serra, S. J. Org. Chem. 1999, 64, 8728.
(b) Rossi, R. A.; Bunnett, J. F. J. Org. Chem. 1973, 38, 2314.
(18) Andersen, N. G.; Parvez, M.; Keay, B. A. Org. Lett. 2000, 2,
2817.
(19) Andersen, N. G.; McDonald, R.; Keay, B. A. Tetrahedron:
Asymmetry 2001, 12, 263.
(20) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A.
Synthesis 1997, 1338.
29.0 (CH3) 29.9 (CH3), 30.1 (CH3), 30.8 (CH2), 35.8 (CH2),
72.9 (Cq), 73.7 (Cq), 74.9 (Cq), 76.9 (Cq), 111.6 (CH), 111.7
(CH), 118.3 (CH), 124.0 (CH), 124.4 (CH), 124.7 (CH),
125.0 (CH), 125.3 (CH), 126.6 (Cq), 127.0 (Cq), 127.4 (CH),
135.6 (CH), 141.1 (Cq), 141.2 (Cq) 153.1 (Cq), 153.4 (Cq),
174.8 (Cq), 175.5 (Cq); Mass spectra: (Compound 12) 244 (1,
M+), 216 (26, M+-CO), 202 (14), 201 (100, M+-CO and
-CH3), 187 (4), 135 (29), 134 (11), 67 (12); (Compound 13)
244 (20, M+), 216 (22, M+-CO), 202(13), 201 (100, M+-CO
and -CH3), 161 (50), 135 (40), 115 (14), 77 (14); Mass
calculated for C15H16O3 (M+): 244.10994, found: 244.10954.
Synlett 2003, No. 9, 1349–1351 ISSN 0936-5214 © Thieme Stuttgart · New York