An efficient asymmetric synthesis of tarchonanthuslactone

Full text of DOI:10.1021/jo005763j

2512
J . Org. Chem. 2001, 66, 2512-2514
Sch em e 1
An Efficien t Asym m etr ic Syn th esis of
Ta r ch on a n th u sla cton e1
M. Venkat Ram Reddy, Ahmet J . Yucel, and
P. Veeraraghavan Ramachandran*
Herbert C. Brown Center for Borane Research,
Department of Chemistry, Purdue University,
West Lafayette, Indiana 47907-1393
chandran@purdue.edu
Received December 8, 2000
of 1 via a multistep synthesis, starting with optically
active 1,3-butanediol.9 Although this molecule has not
been tested, several lactones from Compositae family
have been shown to have significant medicinal proper-
ties.10 Consequently, there have been several other
approaches to synthesize (-)-1 as well. For example, Mori
and co-workers synthesized this from a chiral dithiane
using a 16-step sequence.11 Solladie and co-workers
utilized a chiral sulfoxide to induce the chirality during
their 12-step synthesis of 1.12 All of the above procedures
for 1 involved an asymmetric substrate-controlled syn-
thetic methodology.
Asymmetric allylboration with B-allyldiisopinocam-
pheylborane13 has been utilized in crucial steps in a large
number of syntheses.14 Also, ring-closing metathesis has
been recently applied for the synthesis of lactones of
different ring sizes contained in several target mol-
ecules.15 However, there have been very few attempts to
combine these two protocols for the convenient syntheses
of unsaturated and saturated lactones.16 Following is the
discussion of a seven-step, reagent-controlled synthesis
of 1.
In tr od u ction
R-Pyrones (5,6-dihydro-2H-pyran-2-ones) are found in
several natural products and have a wide variety of
applications. They act as plant growth inhibitors, feeding
deterrents, antibacterial, and antitumor agents.2 These
pyrones can be readily transformed to other functional
groups, providing new target molecules.3 Accordingly,
several multistep syntheses of such molecules have been
reported.4
To demonstrate the utility of pinane-based versatile
organoboranes5 for the syntheses of natural products and
medicinally active molecules, we undertook the synthesis
of pyrone-containing molecules.6 The title compound,
tarchonanthuslactone (1) is a dihydrocaffeic acid ester
that has been isolated from a compositae, Tarchonanthus
trilobus.7 Caffeic acid has been established as active
principle to lower plasma glucose in diabetic rats.8
Nakata and co-workers determined the stereostructure
(1) Publication No. 11 from Herbert C. Brown Center for Borane
Research.
(2) Davies-Coleman, M. T.; Rivett, D. E. A. Fort. Chem. Org. Natur.
1989, 55, 1.
Resu lts a n d Discu ssion
(3) Reddy, M. V. R.; Brown, H. C.; Ramachandran, P. V. J .
Organomet. Chem. 2001, in press.
Our retrosynthetic analysis is outlined in Scheme 1.
We envisaged the synthesis of 1 via a double asymmetric
allylboration and ring-closing metathesis reactions as key
steps.
Asymmetric allylboration of acetaldehyde with (-)-B-
allyldiisopinocampheylborane (2) in Et2O-pentane (1:1)
at -100 °C yielded the previously reported13 (R)-(+)-4-
penten-2-ol (3) in 71% yield. The enantiomeric excess (ee)
was determined as 94% by comparing the optical rotation
(4) (a) Gopalan, A. S.; J acobs, H. K. Tetrahedron Lett. 1990, 31, 5575.
(b) Sato, M.; Sakaki, J . I.; Sugita, Y.; Nakano, T.; Kaneko, C.
Tetrahedron Lett. 1990, 31, 7463. (c) Pirkle, W. H.; Adams, P. E. J .
Org. Chem. 1980, 45, 4117. (d) Sato, T. Heterocycles 1986, 24, 2173.
(e) Dupont, J .; Donato, A. J . Tetrahedron Asymmetry 1998, 9, 949. (f)
Haase, B.; Schneider, M. P. Tetrahedron Asymmetry 1993, 4, 1017.
(g) Takano, S.; Setoh, M.; Ogasawara, K. Tetrahedron Asymmetry 1992,
3, 533. (h) Bonini, C.; Pucci, P.; Racioppi, R.; Viggiani, L. Tetrahedron
Asymmetry 1992, 3, 29. (i) Midland, M. M.; Tramontano, A.; Kazubski,
A.; Graham, R. S.; Tsai, D. J . S.; Cardin, D. B. Tetrahedron 1984, 40,
1370. (j) Asaoka, M.; Hayashibe, S.; Sonoda, S.; Takei, H. Tetrahedron
Lett. 1990, 31, 4761. (k) Yoshida, T.; Saito, S. Chem. Lett. 1982, 1587.
(l) Romeyke, Y.; Keller, M.; Kluge, H.; Grabley, S.; Hammann, P.
Tetrahedron 1991, 47, 3335. (m) Bennet, F.; Knight, D. W.; Fenton,
G. J . Chem. Soc., Perkin Trans. 1 1991, 1543. (n) Rahman, S. S.;
Wakefield, B. J .; Roberts, S. M.; Dowle, M. D. J . Chem. Soc. Chem.
Commun. 1989, 303. (o) Fuganti, C.; Fantoni, G. P.; Sarra, A.; Servi,
S. Tetrahedron Asymmetry 1994, 5, 1135. (p) Sam, T. W.; Yeu, C. S.;
Matsjeh, S.; Gan, E. K.; Razak, D.; Mohamed, A. L. Tetrahedron Lett.
1987, 28, 2541. (q) O’Connor, B.; J ust, G. Tetrahedron Lett. 1986, 27,
5201. (r) Bennet, F.; Knight, D. W. Tetrahedron Lett. 1988, 29, 4625.
(s) Tsubuki, M.; Kanai, K.; Honda, T. Heterocycles 1993, 35, 281. (t)
Bennet, F.; Knight, D. W.; Fenton, G. J . Chem. Soc., Perkin Trans. 1
1991, 519. (u) Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki, Y.;
Tsubuki, M. J . Chem. Soc., Perkin Trans. 1 1990, 1733. (v) Keck, G.
E.; Li, X. Y.; Knutson, C. E. Org. Lett. 1999, 1, 411.
(8) Hsu, F. L.; Chen, Y. C.; Cheng, J . T. Planta Medica 2000, 66,
228.
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28, 5661.
(10) J odynis-Liebert, J .; Murias, M.; Bloszyk, E. Planta Medica
2000, 66, 199.
(11) (a) Mori, Y.; Suzuki, M. J . Chem. Soc., Perkin Trans. 1 1990,
1809. (b) Mori, Y.; Kageyama, H.; Suzuki, M. Chem. Pharm. Bull. 1990,
38, 2574.
(12) Solladie, G.; Gressot-Kempf, L. Tetrahedron: Asymmetry 1996,
7, 2371.
(13) Brown, H. C.; J adhav, P. K. J . Am. Chem. Soc. 1983, 105, 2092.
(14) Representative examples: (a) Smith, A. B.; Cgen, S. S. Y.;
Nelson, F. C.; Reichert, J . M.; Salvatore, B. A. J . Am. Chem. Soc. 1997,
119, 10935. (b) Smith, A. B.; Ott, G. R. J . Am. Chem. Soc. 1996, 118,
13095. (c) Rychnovsky, S. D.; Hoye, R. C. J . Am. Chem. Soc. 1994,
116, 1753.
(5) Brown, H. C.; Ramachandran, P. V. in Advances in Asymmetric
Synthesis; Hassner, A., Ed. J AI Press: Greenwich, CT, 1995; Vol. 1,
Chapter 5.
(6) (a) Reddy, M. V. R.; Rearick, J . P.; Hoch, N.; Ramachandran, P.
V. Org. Lett. 2001, 3, 19. (b) Ramachandran, P. V.; Reddy, M. V. R.;
Brown, H. C. Tetrahedron Lett. 2000, 41, 583. (c) Ramachandran, P.
V.; Reddy, M. V. R.; Brown, H. C. J . Ind. Chem. Soc. 1999, 76, 939.
(7) Bohlmann, F.; Suwita, A. Phytochemistry 1979, 18, 677.
(15) For a recent review see: Furstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012.
(16) Nicolaou, K. C.; Vourloumis, D.; Vallberg, H.; Roschangar, F.;
Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J . I. J . Am. Chem. Soc.
1997, 119, 7960.
10.1021/jo005763j CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/07/2001

Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2513
Sch em e 2
chonanthuslactone, in 7.7% overall yield. The salient
features include asymmetric allylboration using B-allyl-
diisopinocampheylborane and ring-closing metathesis
using Grubbs’s ruthenium catalyst. We believe that this
reaction sequence is considerably shorter than several
procedures currently reported in the literature for the
synthesis of 1.
Exp er im en ta l Section
Gen er a l Meth od s. All operations were carried out under an
inert atmosphere. Techniques for handling air- and moisture-
sensitive materials have been previously described.18 The 1H,
11B, and 13C NMR spectra were plotted on a Varian Gemini-300
spectrometer with a Nalorac-Quad probe. Mass spectra were
recorded using with a Hewlett-Packard 5989B mass spectrometer/
5890 series II gas chromatograph or a Finnigan mass spectrom-
eter model 4000. CI gas used was isobutane. The optical
rotations were measured using a Rudolph Autopol III polarim-
eter.
Ma ter ia ls. Anhydrous ethyl ether (Et2O) purchased from
Mallinckrodt, Inc. was used as received. CH2Cl2 was distilled
over CaH2. DIP-chloride,19 allylmagnesium bromide, acetalde-
hyde, osmium tetraoxide, sodium metaperiodate, tetrabutylam-
monium fluoride, and acryloyl chloride, etc., were all obtained
from the Aldrich Chemical Co. Grubbs’s catalyst was obtained
from Strem Chemicals.
Sch em e 3
P r ep a r a tion of (R)-4-P en ten -2-ol (3). Allylmagnesium
bromide (72.6 mL, 1.0 M, 72.6 mmol) was added dropwise to a
well-stirred solution of (+)-DIP-chloride (24.45 g, 76.2 mmol) in
Et2O (200 mL) at -78 °C. The mixture was then stirred for 0.5
h at -78 °C, allowed to warm to room temperature, and stirred
for 4 h. The solvent was removed under aspirator vacuum, and
the residue was extracted with pentane (3 × 150 mL), filtered
l
through a Kramer filter,18 and concentrated to afford Ipc2BAll
(3) (11BNMR δ 79 ppm) in essentially quantitative yield. The
reagent was dissolved in pentane to make a 1 M solution. A 55
l
mmol (55 mL) amount of the above Ipc2BAll was dissolved in
Et2O (55 mL) and cooled to -100 °C. A solution of acetaldehyde
(2.2 g, 50 mmol) in anhydrous Et2O (5 mL) was added dropwise,
and the reaction mixture was stirred at -100 °C for 1 h when
the reaction was complete (11B NMR shift from δ 79 to δ 52).
Addition of methanol (1 mL) to this intermediate, followed by
the usual workup with NaOH and H2O2, afforded the crude
product which was extracted with Et2O, washed with brine, and
dried over anhydrous MgSO4. Distillation (bp 115 °C) provided
3.05 g (71%) of (R)-(-)-4-penten-2-ol (3) as a liquid. The rotation
with that reported in the literature.13 Recrystallizing the
3,5-dinitrobenzoate of 3 and recovering the alcohol by
basic hydrolysis increased the enantiomeric purity to
>99%. Treatment of 3 with TBDMS-protected dihydro-
caffeic acid (4)11,12 provided the corresponding ester 5 in
81% yield. Osmylation of this olefin ester, followed by
periodate cleavage, provided the aldehyde ester 6 in 77%
yield. A second allylboration with (-)-2 furnished the
corresponding enantiomerically pure homoallylic alcohol
7, which was esterified with acryloyl chloride to provide
diester 8. The synthesis of TBDMS-protected ester 10
was achieved via a ring-closing metathesis in refluxing
dichloromethane using Grubbs’s bis(tricyclohexylphos-
phine)benzylidene ruthenium(IV) dichloride (9)17 in 46%
overall yield from 6. Deprotection of 10 was carried out
with tetrabutylammonium fluoride in THF at room
temperature to provide 1 in 80% yield. The sign and value
of the optical rotations as well as the spectral character-
istics of 10 and 1 matched very well with those reported
in the literature.9,11,12 In conclusion, we have carried out
a reagent-controlled asymmetric synthesis of a naturally
occurring 6-substituted-5,6-dihydro-2H-pyran-2-one, tar-
[R]24 -9.18 (c 5.6, Et2O) revealed it to be 94% optically pure.
D
En a n tiom er P u r ifica tion of 3. 3,5-Dinitrobenzoyl chloride
(17.25 g, 75 mmol) was added to the above alcohol (4.3 g, 50
mmol) dissolved in CH2Cl2 (100 mL). The flask was cooled to 0
°C, followed by the addition of Et3N (15 g, 150 mmol). The
mixture was stirred at room temperature for 2 h, filtered through
a pad of silica, concentrated, and chromatographed over silica
(hexanes:EtOAc 98:2) to obtain 11.7 g (84%) of the dinitroben-
zoate. This was recrystallized from hexanes, dissolved in 25 mL
of methanol, and stirred at 0 °C for 2 h with 12 mL of 3 N NaOH.
Quenching the reaction with dilute HCl (1%, 50 mL), followed
by extraction with ether (3 × 50 mL) and purification by
distillation (bp 115 °C), provided 2.01 g (56%) of optically pure
(R)-(-)-4-penten-2-ol. [R]24 -9.84 (c 3.1, Et2O).
D
P r ep a r a tion of 5. Alcohol 3 (2.15 g, 25 mmol) and TBDMS-
protected dihydrocaffeic acid11,12 (10.25 g, 25 mmol) were dis-
solved in 50 mL of CH2Cl2 in a 250 mL round-bottomed flask
and cooled to 0 °C. DCC (35 mL, 1.0 M solution in CH2Cl2) and
DMAP (0.3 g, 2.5 mmol) were added dropwise to the above
mixture and stirred at room temperature for 2 h, filtered through
a pad of silica gel, and concentrated under vacuum to obtain
(18) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975.
Reprinted edition, Vol. 1. Aldrich Chemical Co. Inc., Milwaukee, WI,
1997. Chapter 9.
(19) DIP-chloride (B-chlorodiisopinocampheylborane) is a Trade-
mark of Aldrich Chemical Co. Brown, H. C.; Chandrasekharan, J .;
Ramachandran, P. V. J . Am. Chem. Soc. 1988, 110, 1539.
(17) For a review, see: Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413.

2514 J . Org. Chem., Vol. 66, No. 7, 2001
Notes
crude 5. Silica gel column chromatography (hexane:ethyl acetate
99:1) provided 9.7 g (81%) of pure 5. IR: νmax cm-1 (neat): 2932,
2851, 1732, 1575. MS: EI: m/z: 478 (M+), 421, 179, 73 (100%).
CI: m/z: 479 (M + H)+ (100%).
Rin g-Closin g Meta th esis of 8. Grubbs’s catalyst (9) (0.82
g, 1.0 mmol, 10 mol %) was dissolved in 10 mL of CH2Cl2 and
was added dropwise to a refluxing solution of the above acrylic
ester in 800 mL of CH2Cl2. Refluxing was continued for 12 h by
which time all of the starting material was consumed (TLC).
The solvent was removed under aspirator vacuum, and the crude
product was purified by silica gel column chromatography
(hexane:ethyl acetate 80:20) to obtain 2.53 g (46% overall from
6) of 10.
P r epar ation of Tar ch on an th u slacton e. R-Pyrone 10 (0.274
g, 0.5 mmol) and benzoic acid (0.18 g, 1.5 mmol) were dissolved
in THF (5 mL), followed by the dropwise addition of TBAF (1.25
mL, 1.0 M solution in THF). The mixture was stirred at room
temperature for 1 h, concentrated, and extracted with ethyl
acetate (3 × 50 mL). Evaporation of the solvent and purifica-
tion by silica gel column chromatography (hexane:EtOAc 6:4)
afforded 0.13 g (80%) of 1 as a gummy liquid. IR: νmax cm-1
(neat): 3412, 1691, 1611, 1515. MS: EI: m/z: 320 (M+), 123
(100%). CI: m/z: 321 (M + H)+ (100%).
Osm olysis of 5. OsO4 (0.25 g,1 mmol) was added to the
olefinic ester 5 (4.8 g, 10 mmol) dissolved in dioxane:water (3:1,
1.2 L). The reaction mixture was stirred for 0.5 h, followed by
the slow addition of NaIO4 (6.42 g, 30 mmol) over a period of 5
min. The mixture was kept stirring for 2 h at room temperature,
and the product was extracted with Et2O (3 × 100 mL), washed
with water (250 mL), and purified by column chromatography
(silica gel, hexane: EtOAc (9:1)) to obtain 3.7 g (77%) of 6. IR:
ν
max cm-1 (neat): 2931, 2851, 1731, 1505. Ms: EI: m/z: 480 (M+),
353, 221, 179, 73 (100%). CI: m/z: 481 (M + H)+ (100%).
Allylbor a tion of Ald eh yd ic Ester 6. Aldehyde 6 (4.8 g, 10
mmol) was added to a stirred solution of Ipc2BAll (22 mL of 0.5
M solution in Et2O-pentane) at -100 °C and maintained at that
temperature for an additional 1 h. The reaction was followed
by 11B NMR spectroscopy. Upon completion, the mixture was
worked up with NaOH/H2O2 and extracted with Et2O. The crude
product 7 was used as such for the esterification step.
P r ep a r a tion of Acr yloyl Ester of 7. The above mixture of
7 was dissolved in 20 mL of CH2Cl2 and cooled to 0 °C, and 4.05
g (45 mmol) of acryloyl chloride and 9.9 g (90 mmol) of Et3N
were added, warmed to room temperature, and stirred for 4 h.
The resulting mixture was filtered through a short pad of Celite
to remove solid Et3N‚HCl and poured into water, and the product
was extracted with CH2Cl2. The crude product was filtered
through a short pad of silica gel and was used directly for the
ring-closing metathesis.
Ack n ow led gm en t. Financial assistance from the
Herbert C. Brown Center for Borane Research is
acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1, 5, 6, and 10. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O005763J