Efficient one-step synthesis of trialkylsubstituted 2(5H)-furanones utilizing direct Ti-crossed aldol condensation and its application to the straightforward synthesis of (R)-mintlactone and (R)-menthofuran

Article abstract of DOI:10.1039/b208077j

TiCl₄-Bu₃N-mediated condensation of ketones with α,α-dimethoxyketones afforded trialkylsubstituted 2(5H)-furanones in a one-pot manner, wherein aldol addition and furanone formation occurred sequentially; its application to straightf

Full text of DOI:10.1039/b208077j

Efficient one-step synthesis of trialkylsubstituted 2(5H)-furanones
utilizing direct Ti-crossed aldol condensation and its application to the
straightforward synthesis of (R)-mintlactone and (R)-menthofuran†
Yoo Tanabe,* Kumi Mitarai, Takahiro Higashi, Tomonori Misaki and Yoshinori Nishii
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen,
Sanda, Hyogo 669-1337, Japan. E-mail: tanabe@kwansei.ac.jp
Received (in Cambridge, UK) 16th August 2002, Accepted 13th September 2002
First published as an Advance Article on the web 1st October 2002
TiCl4–Bu3N-mediated condensation of ketones with a,a-
dimethoxyketones afforded trialkylsubstituted 2(5H)-fur-
anones in a one-pot manner, wherein aldol addition and
furanone formation occurred sequentially; its application to
straightforward synthesis of (R)-mintlactone and (R)-men-
thofuran, two representative natural mint perfumes, is
demonstrated.
(7)5 and (R)-menthofuran (11)6 (Scheme 3). Because of their
interesting structure and usefulness, these compounds have
been challenging synthetic targets. Our present method seems to
be the simplest of the reported methods, because of the one-step
synthesis of 7 and the easy transformation of 7 to 11, using
commercially available substrates and reactants [3-(R)-me-
thylcyclohexanone 6 and 1,1-dimethoxyacetone (3a)]. Thus,
(R)-mintlactone (7) was successfully obtained in 52% yield and
7 was converted into 11 by the reported LAH–i-PrOH-
reduction5a in 80% yield.§
C–C bond formation occurred regioselectively at the 6-posi-
tion of 6 anti to 3-methyl (regioisomers 9 and 10 were not
detected). In addition, furanone formation was stereoselective,
since stereoisomeric (R)-isomintlactone (8) was a very minor
product ( < 10%). Computer-assisted conformation analysis
supports the difference in the energy gap: 7 is 5.46 kcal mol21
2(5H)-Furanones (a,b-butenolides) comprise an important
heterocycle incorporated in natural products and serve as useful
synthetic building blocks for lactones and furans.1 There are
many methods available for their synthesis, however, the
majority of these are limited to the production of mono or
dialkylsubstituted 2(5H)-furanones.1 Previously, one of the
authors (Y. T.) reported the synthesis of trialkylsubstituted
2(5H)-furanones 1 using enol silyl ethers and a,a-dimethox-
yketones, however, three tedious steps were required: (i)
preparation of enol silyl ethers, (ii) isolation of multi-functional
labile aldol adducts, and (iii) use of dry HCl gas for furanone
formation.2 Recently, we developed direct and powerful Ti-
aldol addition reactions using ketones and simple esters,
demonstrating an ability to form C–C bonds which rivals or
surpasses hitherto reported aldol additions.3 We report here the
TiCl4–Bu3N-mediated method for the preparation of trialk-
ylsubstituted 2(5H)-furanones 1 (Scheme 1), and its application
to the one-step total synthesis of (R)-mintlactone (7), and two-
step synthesis of (R)-menthofuran (11), two representative
commercial flavoring materials in natural American peppermint
oil, isolated from Menta piperita.4
Table 1 Preparation of trialkylsubstituted 2-(5H)-furanones 1 from ketones
2 and a,a-dimethoxyketones 3 using the TiCl4–Bu3N system
Yield
Ketone 2
a,a-Dimethoxyketone 3 (%)
77
33
Scheme 1
The present reaction was guided by the reaction of propio-
phenone (2a) with 1,1-dimethoxyacetone (3a) and the desired
trialkylsubstituted compound was obtained in 77% yield under
optimized conditions (Table 1). Several other analogs were
successfully prepared in moderate to good yield.‡
This synthetic method has several advantages over the
previously reported one:2 (i) one-step synthesis; (ii) does not
require the preparation of enol silyl ethers (direct use of starting
ketones) and the isolation of labile aldol intermediates; and (iii)
higher total yields. The proposed mechanism (reaction se-
quence) is illustrated in Scheme 2: Initial Ti-mediated direct
aldol addition gives aldol adduct 4; subsequent formation of
dihydrofuran 5, followed by elimination of Ti(OH)Cl3 gives
1-methoxyfurane 5A, and final isomerization leads to 2(5H)-
furanones 1.
55
64
76
65
55
To demonstrate the present protocol, we performed a simple
and straightforward synthesis of both natural (R)-mintlactone
† Electronic supplementary information (ESI) available: calculated struc-
tures of 7 and 8. See http://www.rsc.org/suppdata/cc/b2/b208077j/
2542
CHEM. COMMUN., 2002, 2542–2543
This journal is © The Royal Society of Chemistry 2002

Japan. We also thank Mr. Takeshi Yamamoto (Takasago
International Corp.) for helpful discussions.
Notes and references
‡ Typical procedure exemplified by the synthesis of (R)-mintlactone (7):
TiCl4 (1.0 M solution in CH2Cl2; 1.5 cm3, 1.5 mmol) and Bu3N (371 mg,
2.00 mmol) in dry CH2Cl2 (0.5 cm3) were successively added to a stirred
solution of 3-(R)-methylcyclohexanone (112 mg, 1.00 mmol) in dry CH2Cl2
(2.0 cm3) at 278 °C under an argon atmosphere, followed by stirring for 0.5
h. To the reaction mixture, 1,1-dimetoxy-2-propanone (236 mg, 2.00 mmol)
in dry CH2Cl2 (0.5 cm3) was added. Then, the mixture was allowed to warm
to room temp. and was stirred for 14 h. Water was added to the mixture,
which was extracted with diethyl ether (5 cm3 3 3). The combined organic
phase was washed with water, brine, dried (Na2SO4) and concentrated. The
obtained oil was purified by column chromatography on silica gel (hexane–
ether = 5+1) to give the desired product (87 mg, 52%) as colorless oil.
20
20
[a]D 251.4 (c, 0.842, EtOH) [lit.4a [a]D 251.8 (c, 10, EtOH)]. 1H NMR
(400 MHz; CDCl3): d 4.61 (1H, br dd, J 11.3, 6.1 Hz), 2.79 (1H, ddd, J 13.5,
4.5, 2 Hz), 2.41 (1H, dddd, J 12, 6.1, 2.5, 2.5 Hz), 2.20 (1H, br ddd, J 13.5,
13.5, 5.5 Hz), 1.93 (1H, ddddd, J 13, 5.5, 2.5, 2.5, 2 Hz), 1.79 (3H, t, J 1.6
Hz), 1.70 (1H, m), 1.00 (3H, d, J 6.6 Hz), 1.10–0.90 (2H, m). 13C NMR (100
MHz; CDCl3): d 174.86, 162.32, 119.56, 79.92, 41.94, 34.51, 29.75, 25.44,
21.24, 8.20. IR (neat) 2954, 2927, 2862, 1741, 1683, 1445, 1371, 1325,
Scheme 2
1296, 1265, 1243, 1094, 1072, 1030, 997, 857, 765, 735 cm21
.
§ (R)-Menthofuran (11). colorless oil. [a]D20 +95.3 (c, 0.842, EtOH) [lit.4b
25
[a]D +95.6 (c, 10, EtOH)]. Other spectroscopic data matched those
more stable than 8 in the most stable conformation of each
compound, probably because 7 has a chair-form cyclohexane,
whereas 8 has a twisted boat-form cyclohexane [calculation was
performed using SPARTAN ’02 Windows (Wavefunction, Inc.
Irvine, CA), Hartree-Fock, 6-31G*] (see ESI†).
In conclusion, we achieved a general synthetic method for
trialkylsubstituted 2(5H)-furanones 1 utilizing direct Ti-aldol
condensation and applied it to efficient total syntheses of (R)-
mintlactone (7) and (R)-menthofuran (11).
This research was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ and on Basic Areas (C) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan, and by the Cosmetology Foundation in
reported in the literature.4a,6
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Scheme 3
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