Highly efficient and diastereoselective synthesis of (+)-lineatin

Article abstract of DOI:10.1021/ol0497032

A linear sequence was used to synthesize (+)-lineatin in 14 steps and 14% overall yield from a homochiral 2(5H)-furanone. Key steps of this synthetic approach feature the diastereoselective construction of a cyclobutene through a photochemical [2 + 2] cyc

Full text of DOI:10.1021/ol0497032

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1449-1452
Highly Efficient and Diastereoselective
Synthesis of (+)-Lineatin
Ramon Alibe´s,* Pedro de March, Marta Figueredo, Josep Font,*
Marta Racamonde, and Teodor Parella†
Departament de Qu´ımica and SerVei de Ressona`ncia Magne`tica Nuclear,
UniVersitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
josep.font@uab.es
Received February 19, 2004
ABSTRACT
A linear sequence was used to synthesize (+)-lineatin in 14 steps and 14% overall yield from a homochiral 2(5H)-furanone. Key steps of this
synthetic approach feature the diastereoselective construction of a cyclobutene through a photochemical [2 + 2] cycloaddition and a
regiocontrolled oxymercuration reaction.
(+)-Lineatin, 1, is the most important constituent of the
aggregation pheromone isolated from the frass of the female
ambrosia beetle Trypodendron lineatum Olivier, which is a
deleterious pest to coniferous forests in Europe and North
America (Figure 1).1
Its intriguing structural features, its significant biological
activity, and our previous experience in developing syntheses
of other naturally occurring cyclobutane pheromones4
prompted us to select (+)-lineatin as a synthetic target. In
this letter we present a highly stereoselective synthesis of
this molecule that is superior to previous approaches and
proceeds from a readily available chiral 2(5H)-furanone as
starting material.
Our synthetic strategy takes advantage of the easy and
diastereoselective preparation of cyclobutenes through a
novel methodology recently developed in our laboratories.
(2) Racemic lineatin: (a) Mori, K.; Sasaki, M. Tetrahedron Lett. 1979,
1329-1332. (b) McKay, W. R.; Ounsworth, J.; Sum, P.-E.; Weiler, L. Can.
J. Chem. 1982, 60, 872-880. (c) White, J. D.; Avery, M. A.; Carter, J. P.
J. Am. Chem. Soc. 1982, 104, 5486-5489. (d) Skattebøl, L.; Strestrøm, Y.
Tetrahedron Lett. 1983, 24, 3021-3024. (e) Johnston, B. D.; Slessor, K.
N.; Oehlschlager, A. C. J. Org. Chem. 1985, 50, 114-117. (f) Skattebøl,
L.; Stenstrøm, Y. Acta Chem. Scand., Ser. B 1985, 39, 291-304. (g)
Aljancic-Solaja, I.; Rey, M.; Dreiding, A. S. HelV. Chim. Acta 1987, 70,
1302-1307. (h) Kametani, T.; Toya, T.; Ueda, K.; Tsubuki, M.; Honda, T.
J. Chem. Soc., Perkin Trans. 1 1988, 2433-2438. (i) Baeckstro¨m, P.; Li,
L.; Polec, I.; Unelius, C. R.; Wimalasiri, W. R. J. Org. Chem. 1991, 56,
3358-3362. (j) Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P.; Rosini,
G.; Serra, R.; Venturelli, F. Tetrahedron 1994, 50, 3235-3250.
(3) (+)-Lineatin: (a) Mori, K.; Sasaki, M. Tetrahedron 1980, 36, 2197-
2208. (b) Slessor, K. N.; Oehlschlager, A. C.; Johnston, B. D.; Pierce, H.
D.; Grewal, S. K.; Wickremesinghe, L. K. G. J. Org. Chem. 1980, 45,
2290-2297. (c) Mori, K.; Uematsu, T.; Minobe, M.; Yanagi, K. Tetrahedron
1983, 39, 1735-1743. (d) Kandil, A. A.; Slessor, K. N. J. Org. Chem.
1985, 50, 5649-5655. (e) Mori, K.; Nagano, E. Liebigs Ann. Chem. 1991,
341-344.
Figure 1.
In the past two decades, this cyclobutane monoterpene has
attracted the attention of many synthetic chemists.2,3 Among
the large number of syntheses of lineatin published to date,
only a few were devised to provide the pure (+)-enantiomer3
and, with a unique exception,3d they all required resolution
steps. Furthermore, the yields achieved in these syntheses
were very low (0.2-4%).
† Servei de Ressona`ncia Magne`tica Nuclear.
(1) MacConnell, J. G.; Borden, J. H.; Silverstein, R. M.; Stokkink, E. J.
Chem. Ecol. 1977, 3, 549-561.
10.1021/ol0497032 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004

This involves the photochemical reaction of 2(5H)-furanones
with 1,2-dichloroethylene followed by reductive elimination
of chlorine.5
provided a more effective solution to the problem of
accessing compound 3 (Scheme 2).
Thus, our retrosynthetic analysis of (+)-1 (Scheme 1)
proceeded by initial disconnection of the ketal moiety and
Scheme 2
Scheme 1. Retrosynthetic Analysis
Thus, irradiation of lactone 4 with (Z)-1,2-dichloroethylene
in acetonitrile through a quartz filter with a high-pressure
mercury lamp for 7.5 h furnished a mixture of seven
stereoisomeric cycloadducts 5 in a combined 89% yield.
Reductive dehalogenation of this mixture proceeded readily
under microwave irradiation9 giving better yields in much
shorter times, compared to the classical thermal conditions.5
Hence, when the mixture of dichlorocyclobutane isomers 5
was treated with activated Zn in aqueous EtOH in a sealed
vessel at 105 °C in a focused microwave reactor for 20 min,
a separable mixture of the known cyclobutenes 3 and 6 was
obtained in 79% yield and a ratio 88:12. As a result, the
pivotal cyclobutene 3 was now available in 61% yield from
lactone 4.
unraveling the keto lactone 2, whose conversion into 1 has
been previously reported.2e-g,3e We envisaged that the ketone
functionality present in the cyclobutane ring would be
regioselectively introduced from a double bond. Given our
previous studies on (+)-grandisol,4 which is structurally
related to the present target, we traced the ketone 2 back to
the bicyclic lactone 3, which in turn could be obtained from
the appropriate homochiral 2(5H)-furanone 4 by a [2 + 2]
photocycloaddition to acetylene or some other synthetic
equivalent. Therefore, a key step in our approach was our
diastereoselective construction of the cyclobutene ring.
Another major challenge was the subsequent regioselective
oxidation of the double bond in 3.
2(5H)-Furanone 4 had previously shown good facial
discrimination in its photocycloaddition to tetramethyl-
ethylene, ethylene, and vinylene carbonate.6 Compound 4 is
prepared in three steps and 75% yield from commercially
available (S)-5-hydroxymethyl-2(5H)-furanone according to
our previously reported procedure.7
This outstanding improvement in the preparation of 3 led
us to proceed further with our proposed synthetic sequence
to (+)-lineatin (Scheme 3). Treatment of 3 with an excess
Scheme 3
Our initial effort focused on the preparation of the key
cyclobutene unit 3. This compound was synthesized by
photochemical [2 + 2] cycloaddition of acetylene to 4 in
only 23% yield.8 Fortunately, our novel two-step procedure
of the photochemical reaction of 4 with (Z)-1,2-dichloro-
ethylene, followed by reductive elimination of chlorine,
(4) (a) Alibe´s, R.; Bourdelande, J. L.; Font, J.; Parella, T. Tetrahedron
1996, 52, 1279-1292. (b) de March, P.; Figueredo, M.; Font, J.; Raya, J.;
Alva´rez-Larena, A.; Piniella, J. F. J. Org. Chem. 2003, 68, 2437-2447.
(5) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Racamonde, M.;
Rustullet, A.; Alva´rez-Larena, A.; Piniella, J. F.; Parella, T. Tetrahedron
Lett. 2003, 44, 69-71.
(6) (a) Alibe´s, R.; Bourdelande, J. L.; Font, J. Tetrahedron: Asymmetry
1991, 2, 1391-1402. (b) Gregori, A.; Alibe´s, R.; Bourdelande, J. L.; Font,
J. Tetrahedron Lett. 1998, 39, 6961-6962. (c) Alibe´s, R.; Bourdelande, J.
L.; Gregori, A.; Font, J.; Rustullet, A.; Parella, T. J. Carbohydr. Chem.
2003, 22, 501-511.
(7) Alibe´s, R.; Bourdelande, J. L.; Font, J.; Gregori, A.; Parella, T.
Tetrahedron 1996, 52, 1267-1278.
(8) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.; Fu, X.; Racamonde,
M.; Alva´rez-Larena, A.; Piniella, J. F.; Parella, T. J. Org. Chem. 2003, 68,
1283-1289.
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Org. Lett., Vol. 6, No. 9, 2004

of MeLi in THF resulted in addition of two methyl groups
to the lactone carbonyl carbon and simultaneous removal of
the pivaloyl protecting group, providing triol 7 in 86% yield.
Protection of the vicinal diol as the isopropylidene acetal 8
was achieved in 91% yield by reaction of 7 with acetone in
the presence of p-TsOH.
and H-1, demonstrating the exo orientation of the hydroxyl
group.
Next, the secondary alcohol of 9 was selectively benzyl-
ated under standard conditions to afford 10, which after
removal of the acetonide protecting group with TFA in a
mixture of MeOH/H2O led to the triol 11 in 94% yield.
At this juncture, we intended to introduce the O-function-
ality at C-2′ through an oxymercuration-demercuration
process. Our expectation was that either the hydroxyl group
and/or the closer oxygen atom of the dioxolane in 8 would
coordinate to and guide the Hg2+ to the endo face of the
olefin. A subsequent trans addition of water should then
occur at C-2′ due to the steric hindrance exerted by the
methyl group attached to the cyclobutane (Figure 2).10
Our attention was next directed to construction of the pyran
moiety. Thus, triol 11 underwent clean oxycyclization to give
12 in 84% yield upon treatment with TsCl and a catalytic
amount of DMAP in refluxing pyridine (Scheme 4). The
Scheme 4
Figure 2. Mercurinium complex.
Although the configuration of the new stereogenic center
would be opposite to that in the target pheromone, it was
envisaged that an inversion could be performed at a later
stage of the synthesis through an oxidation-reduction
sequence.
To our great satisfaction, when 8 was treated with mercuric
acetate in THF/water at room temperature for 2.5 h and
demercuration was effected with alkaline sodium boro-
hydride, the alcohol 9 was obtained as a single isomer in
92% yield. The structure and relative stereochemistry of 9
were assigned by one- and two-dimensional NMR tech-
niques. Its regiochemistry was unambiguously proven by an
HMBC experiment in which the signal of the angular methyl
attached to C-3 showed long-ranged coupling to H-4′′, H-2,
and one of the protons attached to C-4, while the C-1′ carbon
coupled to H-1; this indicated that the hydroxyl group was
incorporated at position C-2′ of the cyclobutene 8. The
stereochemistry at the C-1 center of 9 was established on
the basis of 1H/1H correlations observed in the phase-sensitive
NOESY spectrum, which showed a correlation between H-4′′
secondary hydroxyl group was then removed by the Barton-
McCombie procedure,11 which involved treating 12 with
TCDI in THF and submitting 13 to radical reduction with
Bu3SnH in the presence of AIBN. The desired deoxygenated
bicyclic ether 14 was obtained in 84% yield for the two steps.
The final stages of our synthetic approach were as follows.
Hydrogenolysis of the benzyl ether from 14 led to the alcohol
15, which after Dess-Martin (periodinane)12 oxidation
afforded the known and highly volatile bicyclic ketone 16.3e
The latter was treated immediately with RuCl3/NaIO4 in the
two-phase system of CCl4/H2O to give the keto lactone 2 as
a crystalline solid. These transformations all proceeded
efficiently, the conversion of 14 into 2 being achieved in
(9) (a) Strauss, C. R. In MicrowaVe in Organic Synthesis; Loupy, A.,
Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2002; Chapter
2, pp 35-60. (b) Gedye, R. N. In MicrowaVe in Organic Synthesis; Loupy,
A., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2002; Chapter
4, pp 115-146.
(10) (a) Henbest, H. B.; Nicholls, B. J. Chem. Soc. 1959, 227-236. (b)
Henbest, H. B.; McElhinney, R. S. J. Chem. Soc. 1959, 1834-1837. (c)
Bratt, K.; Garavelas, A.; Perlmutter, P.; Westman, G. J. Org. Chem. 1996,
61, 2109-2117. (d) Paquette, L. A.; Bolin, D. G.; Stepanian, M.; Branan,
B. M.; Mallavadhani, U. V.; Tae, J.; Eisenberg, S. W. E.; Rogers, R. D. J.
Am. Chem. Soc. 1998, 120, 11603-11615. (e) Bernardelli, P.; Moradei, O.
M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck, B. P.; Doskotch, R. W.; Lange,
T.; Paquette, L. A. J. Am. Chem. Soc. 2001, 123, 9021-9032.
(11) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(12) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
Org. Lett., Vol. 6, No. 9, 2004
1451

79% overall yield. The physical properties and NMR spectra
of 2 matched those previously reported in the literature.3e
Moreover, our product was found to be enantiomerically pure
(>99.5% ee) by chiral GC analysis, [R]D +209.1 (c 0.93,
acetone) [lit.3e [R]D +206 (c 1.12, acetone)]. The bicyclic
keto lactone 2 has previously been transformed into lineatin
by double carbonyl reduction with DIBAL-H followed by
acid-catalyzed acetalization in 70-74% yield.2e-g,3e
In summary, we have reported a new highly stereoselective
formal synthesis of (+)-lineatin in an overall yield of 14%
starting from furanone 4. The synthesis is characterized by
a diastereoselective photochemical step and a regiocontrolled
oxymercuration reaction.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of DGES (Project BQU2001-2600) and
CIRIT (Project 2001SGR00178) and a grant of Generalitat
de Catalunya (to M.R.). We thank Dr. Antonio de la Hoz,
Universidad de Castilla-La Mancha, for facilitating our use
of the microwave oven.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0497032
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Org. Lett., Vol. 6, No. 9, 2004