Concise synthesis of cis- and trans-theaspirones via oxonium ion-initiated pinacol ring expansion

Article abstract of DOI:10.1021/jo951890h

The odoriferous principle of black tea has been produced from 2,2-dimethylcyclopentanone. The reaction sequence begins with 1,2-addition of 5-lithio-2-methyl-2,3-dihydrofuran to this ketone and immediate acid-catalyzed ring expansion of the resulting carbinols to a separable pair of spiro ethers. Individual conversion of these diastereomers to α,β-unsaturated ketones is followed by tandem condensation with the methyllithium-lithium bromide complex and oxidation with pyridinium chlorochromate.

Full text of DOI:10.1021/jo951890h

J . Org. Chem. 1996, 61, 1119-1121
1119
Con cise Syn th esis of cis- a n d tr a n s-Th ea sp ir on es via Oxon iu m
Ion -In itia ted P in a col Rin g Exp a n sion
Leo A. Paquette,* J ames C. Lanter,1 and Hui-Ling Wang2
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received October 23, 1995X
The odoriferous principle of black tea has been produced from 2,2-dimethylcyclopentanone. The
reaction sequence begins with 1,2-addition of 5-lithio-2-methyl-2,3-dihydrofuran to this ketone and
immediate acid-catalyzed ring expansion of the resulting carbinols to a separable pair of spiro ethers.
Individual conversion of these diastereomers to R,â-unsaturated ketones is followed by tandem
condensation with the methyllithium-lithium bromide complex and oxidation with pyridinium
chlorochromate.
A thrust to identify the centrally important aroma
constituent of black tea was rewarded in 1968 with the
isolation of theaspirone by Ina and co-workers.3 A year
later, Nakatani and Hamanishi confirmed the general
structural characteristics by synthesis and showed fur-
ther that only the cis isomer 2 and not the trans epimer
stances,16,17 novel spirocyclic glycosides,18 and sesquiter-
penoids such as dactyloxenes-B and -C19 as well as
grindelic acid.20
1 possesses a sweet, tealike odor.4 The absolute config-
uration of (-)-2 was subsequently elucidated.5
Resu lts a n d Discu ssion
The convergent step in the synthesis depended on the
availability of dihydrofuran 7. Although this heterocyclic
building block has been previously reported,21 we began
by improving the efficiency with which it can be prepared.
To this end, γ-valerolactone (5) was reduced to the lactol
with DIBAL-H and esterified with benzoyl chloride to
give 6 in 94% yield (Scheme 1). Simply heating 6 in a
Kugelrohr apparatus at 180 °C under reduced pressure
gave 7 in a high state of purity.
Following these developments, a number of syntheses
of 1 and/or 2 have been reported. Although there are a
few exceptions,6-8 the great majority of these approaches
have utilized R- or â-ionone as starting material.4,9-14 The
present report describes a very different approach to 1
and 2 in racemic form. Featured is an efficient assembly
of the spirotetrahydrofuran ring without the disadvan-
tages associated with the previous efforts which have
been earlier delineated.13
The central reaction involves the actuation of an
oxonium ion-induced pinacol rearrangement as exempli-
fied by the conversion of 3 to 4.15 This acid-catalyzed
isomerization with ring expansion has previously been
utilized in the elaboration of unusual ionophoric sub-
The metalation of 7 with tert-butyllithium and subse-
quent condensation with 2,2-dimethylcyclopentanone22
gave the highly reactive alcohols 8 in equivalent amounts.
(15) (a) Paquette, L. A.; Lawhorn, D. E.; Teleha, C. A. Heterocycles
1990, 30, 765. (b) Paquette, L. A.; Andrews, J . F. P.; Vanucci, C.;
Lawhorn, D. E.; Negri, J . T.; Rogers, R. D. J . Org. Chem. 1992, 57,
3956.
(16) (a) Negri, J . T.; Rogers, R. D.; Paquette, L. A. J . Am. Chem.
Soc. 1991, 113, 5073. (b) Paquette, L. A.; Negri, J . T.; Rogers, R. D. J .
Org. Chem. 1992, 57, 3947.
(17) (a) Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmondson,
S. D.; Rogers, R. D. J . Am. Chem. Soc. 1994, 116, 506. (b) Branan, B.
M.; Paquette, L. A. J . Am. Chem. Soc. 1994, 116, 7658. (c) Paquette,
L. A.; Branan, B. M. Heterocycles 1995, 40, 101. (d) Paquette, L. A.;
Branan, B. M.; Rogers, R. D. J . Org. Chem. 1995, 60, 1852. (e)
Paquette, L. A.; Branan, B. M.; Rogers, R. D.; Bond, A. H.; Lange, H.;
Gleiter, R. J . Am. Chem. Soc. 1995, 117, 5992.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) GANN Fellow, 1993-1995.
(2) On leave from the Department of Chemistry, National Tsing Hua
University, Hsinchu 30043, Taiwan, Republic of China.
(3) Ina, K.; Sakato, Y.; Fukami, H. Tetrahedron Lett. 1968, 2777.
(4) Nakatani, Y.; Yamanishi, T. Tetrahedron Lett. 1969, 1995.
Rather than coin new nomenclature for 1 and 2, we have simply
adopted the cis/trans notation earlier used to differentiate these
isomers.
(18) Paquette, L. A.; Dullweber, U.; Cowgill, L. D. Tetrahedron Lett.
1993, 34, 8019.
(19) (a) Paquette, L. A.; Lord, M. D.; Negri, J . T. Tetrahedron Lett.
1993, 34, 5693. (b) Lord, M. D.; Negri, J . T.; Paquette, L. A. J . Org.
Chem. 1995, 60, 191.
(5) (a) Ina, K.; Eto, H. Agr. Biol. Chem. 1972, 36, 1659.b) Weiss, G.;
Koreeda, M.; Nakanishi, K. J . Chem. Soc., Chem. Commun. 1973, 565.
(6) Marx, J . N. Tetrahedron 1975, 31, 1251.
(7) (a) Ba¨ckvall, J .-E.; Andersson, P. G. J . Org. Chem. 1991, 56,
2274.b) Andersson, P. G.; Nilsson, Y. I. M.; Ba¨ckvall, J .-E. Tetrahedron
1994, 50, 559.
(8) Weyerstahl, P.; Meisel, T. Liebigs Ann. Chem. 1994, 415.
(9) Heckman, R. A.; Roberts, D. L. Tetrahedron Lett. 1969, 2701.
(10) Ina, K.; Takano, T.; Imai, Y.; Sakato, Y. Agr. Biol. Chem. 1972,
36, 1033.
(11) Kaiser, R.; Kappeier, A.; Lamparsky, D. Helv. Chim. Acta 1978,
61, 387.
(20) Paquette, L. A.; Wang, H.-L. Tetrahedron Lett. 1995, 36, 6005.
(21) For preparation of the lactol, consult: (a) Arth, G. E. J . Am.
Chem. Soc. 1953, 75, 2413. (b) Tomooka, K.; Okinaga, T.; Suzuki, K.;
Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6335. (c) Ishii, Y.; Yoshida,
T.; Yamawaki, K.; Ogawa, M. J . Org. Chem. 1988, 53, 5549. (d)
Schmitt, A.; Reissig, H. U. Synlett 1990, 40. (e) Ragoussis, V.;
Theodorou, V. Synthesis 1993, 84. (f) Masuyama, Y.; Kobayashi, Y.;
Kurusu, Y. J . Chem. Soc., Chem. Commun. 1994, 1123. (g) Botteghi,
C. Gazz. Chim. Ital. 1975, 105, 233. (h) Mori, K. Tetrahedron 1975,
31, 3011. (i) Schuler, H. R.; Slessor, K. N. Can. J . Chem. 1977, 55,
3280. For synthesis of the dihydrofuran, see: (j) Goldsmith, D. J .;
Liotta, D. C.; Volmer, M.; Hoekstra, W.; Waykole, L. Tetrahedron 1985,
41, 4873. (k) Ducoux, J . P.; Le Menez, P.; Kunesch, N.; Wenkert, E. J .
Org. Chem. 1993, 58, 1290.
(12) Mayer, H. Pure Appl. Chem. 1979, 51, 535.
(13) Ko¨nst, W. M. B.; Apeldoorn, W.; Boelens, H. Synth. Commun.
1980, 10, 899.
(14) Etoh, H.; Ina, K.; Iguchi, M. Agr. Biol. Chem. 1980, 44, 2871.
(22) Purchased from the Aldrich Chemical Co.
0022-3263/96/1961-1119$12.00/0 © 1996 American Chemical Society

1120 J . Org. Chem., Vol. 61, No. 3, 1996
Paquette et al.
Sch em e 1
Sch em e 2
Their exposure to a catalytic quantity of camphorsulfonic
acid in CH2Cl2 at rt furnished a chromatographically
separable 1:1 mixture of 9 and 10. A likely explanation
for the coproduction of both diastereomeric cyclohex-
anones is that the rates of 1,2-migration of the geminally
substituted carbon in A and B are not influenced by the
orientation of the methyl substituent resident on the
oxonium ring and are therefore closely comparable.
No effort was expended in distinguishing 9 from 10
since their individual structures would be made clear
upon accessing the theaspirones. The more polar
diastereomer, subsequently identified as 10, was trans-
formed efficiently into enone 12 by oxidation of its silyl
enol ether with palladium acetate in acetonitrile.23 The
yields for the conversion of 9 to 11 and of 10 to 12 are
based on recovered starting materials. The final requi-
site carbon was introduced by reaction of 12 with meth-
yllithium in the presence of anhydrous cerium trichlo-
ride.24 Oxidation of the resulting carbinol with pyridinium
chlorochromate proceeded with allylic rearrangement as
expected25 to give the targeted cis-theaspirone (2). Analo-
gous treatment of 9 afforded 1 with closely comparable
efficiency.
In agreement with reported data, 1 is a white solid,
mp 58-59 °C, while 2 is a colorless liquid.4 The spectral
properties proved identical to those earlier reported,
including corroborative NOE determinations which showed
the vinylic methyl to be proximal to the ether proton in
2 but not in 1.26
Thus, a concise synthesis of the two isomers of
theaspirone has been achieved via a rearrangement
scheme employing a small number of laboratory opera-
tions.
2-Meth yl-2,3-dih ydr ofu r an (7).21j,k Freshly distilled γ-vale-
rolactone (9.37 g, 93.5 mmol) was dissolved in CH2Cl2 (200
mL), cooled to -78 °C under N2, and treated dropwise during
1 h with a solution of diisobutylaluminum hydride in hexanes
(125 mL of 1 M, 125 mmol). The reaction mixture was stirred
at -78 °C for 1.5 h, quenched cautiously with a saturated
solution of Rochelle's salt (100 mL), and stirred for 20 h while
slowly being warmed to rt. The separated aqueous layer was
extracted with ether and the combined organic phases were
washed with a small amount of brine, dried, and concentrated
to give the lactol as a colorless oil (8.95 g, 94%) that was used
directly.
The lactol (8.95 g, 87.6 mmol) was dissolved in dry CH2Cl2
(100 mL), cooled to 0 °C under N2, and treated with freshly
distilled triethylamine (42.0 mL, 301 mmol). After 15 min of
stirring, benzoyl chloride (11.60 mL, 117.2 mmol) was slowly
introduced via syringe, and the reaction mixture was allowed
to warm to rt during 15 h. Approximately half of the solvent
was removed in vacuo, and the remaining solution was washed
with 5% HCl and brine prior to drying and concentration in
vacuo. The benzoate was obtained as a yellowish oil (18.01 g)
which was pyrolyzed without further purification.
Into a Kugelrohr apparatus fitted with two traps was placed
4.74 g (23.0 mmol) of 6. The first trap was cooled to -78 °C,
the pressure was reduced to ca. 30 Torr, and the oven
temperature was raised to 180 °C. After 1 h, the apparatus
was allowed to cool and N2 was bled in. The material in the
-78 °C trap was redistilled at 30 Torr to give 1.410 g (73%) of
7 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.24 (q, J )
2.5 Hz, 1 H), 4.83 (q, J ) 2.5 Hz, 1 H), 4.66 (m, 1 H), 2.73 (m,
1 H), 2.19 (m, 1 H), 1.32 (d, J ) 6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 144.8, 98.8, 77.6, 36.3, 21.8.
The approach establishes the feasibility of elaborating
the spirotetrahydrofuran subunit without introducing
impurities that might affect the olfactory properties of
the end product.
Exp er im en ta l Section
(2R*,5S*)-2,10,10-Tr im et h yl-1-oxa sp ir o[4.5]d eca n -6-
on e (9) a n d (2R*,5R*)-2,10,10-Tr im eth yl-1-oxa sp ir o[4.5]-
d eca n -6-on e (10). A solution of 7 (801 mg, 9.53 mmol) in dry
THF (45 mL) was cooled to -78 °C under argon and treated
with tert-butyllithium (5.00 mL of 1.7 M in hexanes, 8.50
mmol). After 2 h of stirring, 2,2-dimethylcyclopentanone (1.00
mL, 7.65 mmol) was introduced via syringe, and the reaction
mixture was stirred overnight, warmed to rt, and recooled to
-78 °C prior to quenching with saturated NaHCO3 solution
See reference 15b for a listing of general experimental
details.
(23) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(24) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(25) Dauben, W. G.; Michno, D. M. J . Org. Chem. 1977, 42, 682.
(26) Nakatani, Y.; Yamanishi, T.; Esumi, N.; Suzuki, T. Agr. Biol.
Chem. 1970, 34, 152.

Synthesis of cis- and trans-Theaspirones
J . Org. Chem., Vol. 61, No. 3, 1996 1121
(5 mL). The aqueous phase was extracted with ether, and the
combined organic phases were washed with brine, dried, and
concentrated in vacuo. NMR analysis indicated that 8 con-
sisted of a 1:1 mixture of diastereomers.
The above alcohols were dissolved in CH2Cl2 (40 mL),
treated with camphorsulfonic acid (20 mg), stirred for 12 h,
and concentrated to leave a semisolid. Chromatography of this
material on silica gel (elution with 4:1 petroleum ether-ether)
afforded a 1:1 mixture of 9 and 10 (993 mg, 66% overall). The
isomerically pure ketones were obtained by flash chromatog-
raphy (silica gel, elution with 5:1 petroleum ether-ether) with
9 being less polar than 10.
solution of the methyllithium-lithium bromide complex in
ether (2.80 mL of 1.5 M, 4.20 mmol) was introduced via syringe
during 30 s, and the resulting yellow solution was stirred at 0
°C for 30 min before 11 (89 mg, 0.46 mmol) dissolved in THF
(2 mL) was added. The reaction mixture was allowed to warm
to rt during 12 h, quenched cautiously with brine (3 mL), and
diluted with ether (20 mL). The separated organic phase was
dried and concentrated to leave a residue which was purified
by flash chromatography on silica gel (elution with 4:1
petroleum ether-ether). The diastereomeric alcohol mixture
(70 mg, 73%) was oxidized without further processing.
Pyridinium chlorochromate (160 mg, 0.743 mmol) and
powdered 4 Å molecular sieves (986 mg) were stirred in CH2-
Cl2 (2 mL) while the above alcohol mixture dissolved in CH2-
Cl2 (1 mL) was added. After 4 h of stirring, the reaction
mixture was freed of solvent under reduced pressure, and the
residue was subjected to flash chromatograhy on silica gel
(elution with 22:3 petroleum ether-ether). There was ob-
tained 49 mg (70%) of 1 as well as 7.2 mg (10%) of the less
polar allylic alcohol diastereomer.
For 9: IR (CHCl3, cm-1) 1711, 1458, 1384, 1212, 1110, 1076;
1H NMR (300 MHz, C6C6) δ 3.75-3.65 (m, 1 H), 2.86-2.76
(m, 1 H), 2.45-2.36 (m, 1 H), 2.15-2.08 (m, 1 H), 1.95-1.84
(m, 1 H), 1.74-1.64 (m, 1 H), 1.53-1.31 (m, 3 H), 1.13-0.92
(m, 2 H), 1.05 (d, J ) 6 Hz, 3 H), 0.90 (s, 3 H), 0.66 (s, 3 H);
13C NMR 210.3, 92.9, 74.9, 40.3, 37.1, 35.8, 33.9, 25.0, 23.6,
22.2 (2 C), 20.7; MS m/ z (M+) calcd 196.1463, obsd 196.1462.
Anal. Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C,
73.63; H, 10.41.
For 1: colorless crystals, mp 58-59 °C; IR (CHCl3 , cm-1
)
For 10: IR (CHCl3, cm-1) 1713, 1459, 1383, 1224, 1110,
1660, 1474, 1374, 1249, 1082; H NMR (300 MHz, CDCl3) δ
5.74 (d, J ) 1 Hz, 1 H), 4.25-4.19 (m, 1 H), 2.44-2.23 (m, 3
H), 2.18-2.08 (m, 1 H), 1.95 (d, J ) 1 Hz,3 H), 1.90-1.81 (m,
1 H), 1.68-1.55 (m, 1 H), 1.28 (d, J ) 6 Hz, 3 H), 1.05 (s, 3 H);
0.99 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 198.7, 125.2,
88.5, 77.9, 49.9, 41.6, 35.0, 32.7, 32.6, 24.4, 23.7, 21.3, 20.4.
(2R*,5R*)-2,10,10-Tr im eth yl-1-oxa sp ir o[4.5]d ec-7-en -6-
on e (12). Analogous processing of 10 (99 mg, 0.50 mmol)
afforded 136 mg (100%) of the silyl enol ether, whose reaction
with palladium acetate (75 mg, 0.33 mmol) in dry acetonitrile
(1 mL) for 3 days gave 27 mg (41%) of recovered 10 and 32 mg
(49% or 83% corrected) of 12 as a white solid: mp 118 °C dec;
IR (neat, cm-1) 1682, 1386, 1094; 1H NMR (300 MHz, CDCl3)
δ 6.70 (dt, J ) 10.1, 4.0 Hz, 1 H), 5.94 (dt, J ) 10.1, 2.0 Hz, 1
H), 4.09 (m, 1 H), 2.40-1.8 4 (m, 5 H), 1.39-1.21 (m, 1 H),
1.20 (d, J ) 6.0 Hz, 3 H), 1.00 (s, 3 H), 0.93 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 147.0, 127.3, 90.1, 76.1, 45.1, 40.0, 38.8,
33.7, 23.1, 22.8, 20.5 (carbonyl carbon not seen); MS m/ z (M+)
calcd 194.1307, obsd 194.1299.
1
1
1077; H NMR (300 MHz, C6D6) δ 3.84-3.77 (m, 1 H), 3.00-
2.89 (m, 1 H), 2.58-2.51 (m, 1 H), 2.17-2.10 (m, 1 H), 2.04-
1.94 (m, 1 H), 1.62-1.21 (m, 4 H), 1.14-0.94 (m, 1 H), 1.03 (d,
J ) 6 Hz, 3 H), 0.90-0.81 (m, 1 H), 0.88 (s, 3 H), 0.62 (s, 3 H);
13C NMR (75 MHz, C6D6) ppm 210.0, 93.0, 77.7, 41.1, 37.2,
36.0, 34.6, 26.0, 23.9, 22.4, 21.6, 21.5; MS m/ z (M+) calcd
196.1433, obsd 196.1433. Anal. Calcd for C12H20O2: C, 73.43;
H, 10.27. Found: C, 73.39; H, 10.29.
(2R*,5S*)-2,10,10-Tr im eth yl-1-oxa sp ir o[4.5]d ec-7-en -6-
on e (11). To a solution of diisopropylamine (0.40 mL, 2.85
mmol) in dry THF (2.5 mL) cooled to -78 °C under argon was
added 1.6 M n-butyllithium in hexanes (1.60 mL, 2.56 mmol).
The reaction mixture was stirred at -78 °C for 1 h, treated
with chlorotrimethylsilane (1.10 mL, 8.67 mmol) and 30 min
later with 9 (165 mg, 0.84 mmol) dissolved in THF (0.80 mL),
allowed to warm to rt over a period of 15 h, quenched with
triethylamine (1.20 mL), and concentrated. Repeated tritu-
ration of the resulting semisolid with petroleum ether, filtra-
tion of the combined decanted solutions, and solvent evapo-
ration afforded the silyl enol ether that was used without
further purification.
The above material was dissolved in acetonitrile (15 mL)
under argon, palladium acetate (215 mg, 0.96 mmol) was
introduced, and the reaction mixture was stirred at rt until
no starting material remained (72 h, TLC analysis). After
solvent evaporation, the residue was subjected to flash chro-
matography on silica gel (elution with 5:1 petroleum ether-
ether) to return 45 mg (27%) of 9 and furnish 103 mg (63% or
cis-Th ea sp ir on e (2). From dry cerium trichloride (1.9
mmol), methyllithium (1.9 mmol), and 12 (37 mg, 0.19 mmol),
which were reacted as above, the tertiary carbinol was
obtained as a yellow oil. Oxidation of this material with
pyridium chlorochromate (83 mg, 0.38 mmol) in the presence
of 4 Å molecular sieves (40 mg) followed by chromatography
on silica gel (elution with 20:1 hexanes-ethyl acetate) gave 2
(21 mg, 53% overall) as a colorless oil: IR (neat, cm-1) 1668,
1
1624, 1473, 1443, 1385, 1274, 1155, 1084, 972; H NMR (300
MHz, CDCl3) δ 5.71 (quintet, J ) 1.3 Hz, 1 H), 4.12 (septet, J
) 5.6 Hz, 1 H), 2.39 (dd, J ) 17.1, 0.7 Hz, 1 H), 2.35-2.26 (m,
1 H), 2.20 (dd, J ) 17.1, 1.3 Hz, 1 H), 2.06-1.95 (m, 1 H), 1.97
(d, J ) 1.3 Hz, 3 H), 1.84-1.73 (m, 1 H), 1.56-1.42 (m, 1 H),
1.30 (d, J ) 5.9 Hz, 3 H), 1.01 (s, 3 H), 0.97 (s, 3 H); 13C NMR
(75 MHz, CDCl3) ppm 198.3, 168.3, 124.9, 88.5 77.7, 50.2, 40.8,
34.3, 32.7, 24.4, 23.0, 20.4, 18.9; MS m/ z (M+) calcd 208.1463,
obsd 208.1474.
90% corrected) of 11 as a faintly yellow oil: IR (CHCl3 , cm-1
)
1684, 1470, 1386, 1103; 1H NMR (300 MHz, CDCl3) δ 6.73 (dt,
J ) 10, 4 Hz, 1 H), 5.98 (dt, J ) 10, 1.5 Hz, 1 H), 4.18-4.08
(m, 1 H), 2.41 (br d, J ) 8 Hz, 1 H), 2.15 (br d, J ) 8 Hz, 1 H),
2.06-1.91 (m, 3 H), 1.60-1.52 (m, 1 H), 1.26 (d, J ) 6 Hz, 3
H), 1.05 (s, 3 H), 0.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
199.7, 146.9, 127.4, 78.1, 77.2, 39.9, 39.7, 33.9, 33.8, 23.3, 22.9,
21.1; MS m/ z (M+) calcd 194.1307, obsd 194.1307. Anal.
Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.89; H,
9.39.
Ack n ow led gm en t. These studies have been sup-
ported by a grant from the Hoechst Marion Roussel Co.
We are indebted to Professor C. C. Liao (National Tsing
Hua University) for enabling arrangements in connec-
tion with H.-L. Wang’s visit.
tr a n s-Th ea sp ir on e (1). Cerium trichloride heptahydrate
(1.64 g, 4.40 mmol) was dried under high vacuum (<1 Torr)
while being heated at 100 °C for 1 h and at 140 °C for 12 h.
After argon was bled in, dry THF (15 mL) was added, and the
slurry was stirred for 5 h prior to being cooled to 0 °C.
A
J O951890H