Enantioselective synthesis and photoracemization studies of (±)-2- cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylic acid methyl ester, an advanced intermediate of a dihydrofolate reductase inhibitor

Full text of DOI:10.1021/jo990352s

J . Org. Chem. 1999, 64, 5321-5324
5321
En a n tioselective Syn th esis a n d
P h otor a cem iza tion Stu d ies of
(+)-2-Cyclop r op yl-7,8-d im eth oxy-2H-
ch r om en e-5-ca r boxylic Acid Meth yl Ester ,
a n Ad va n ced In ter m ed ia te of a
Dih yd r ofola te Red u cta se In h ibitor
Peter Wipf* and Warren S. Weiner
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
F igu r e 1.
Sch em e 1
Received February 26, 1999
Several new inhibitors of dihydrofolate reductase
(DHFR) have recently progressed into clinical develop-
ment due to their potent anticancer and antibiotic
properties.1,2 For the treatment of bacterial diseases,
DHFR inhibitors such as trimethoprim are often applied
in combination with a sulfonamide (Bactrim, Septra).
Representative clinical applications include the treat-
ment of urinary tract infections, bronchial infections, and
pneumonia.2 Chromene 1 was recently reported to have
submicromolar activities against pathogenic microorgan-
isms such as Staphylococcus aureus and Pseudomonas
carinii (Figure 1).3 Since only racemic 1 was evaluated
for biological activity and the reported synthetic strategy
was limited to the preparation of racemic products, we
embarked on an enantioselective synthesis of this inter-
esting lead structure.
Sch em e 2
Chromenes have been obtained by the cyclization of
allylic ethers using Grubbs’ ruthenium catalyst.4 An
attractive aspect of this methodology is the use of a chiral
ether of type 3 for the installation of the stereocenter at
C(2) of chromene 2 (Scheme 1).5 Allyl ether 3 could be
obtained from a Mitsunobu displacement with phenol 4,
and the vinyl substituent appeared to be readily derived
by an organometallic coupling of a halogenated derivative
of 5. In this paper, we report the successful realization
of this strategy, albeit with less than the desired high
enantioselectivity due to an unexpectedly facile chromene
photoracemization process.
dimethoxybenzoic acid (6) according to Tanaka’s protocol
(Scheme 2).6 Stille-coupling of 7 with tributylvinyltin
provided styrene 4 in 81% yield. Subsequent Mitsunobu
reaction7 with carbinol (R)-8 in the presence of triethyl-
amine8 provided the allylic ether 9 in 66% yield. The
propargyl alcohol 8 was prepared by Friedel-Crafts
acylation9 of bis(trimethylsilyl)acetylene with cyclopro-
panecarbonyl chloride followed by asymmetric reduction
Resu lts a n d Discu ssion
The polysubstituted o-bromophenol 7 was synthesized
in two steps from commercially available 3-hydroxy-4,5-
(1) Balasubramanian, B. N.; Kadow, J . F.; Kramer, R. A.; Vyas, D.
M. Annu. Rep. Med. Chem. 1998, 33, 151.
(2) McCormack, J . J . In Comprehensive Medicinal Chemistry;
Sammes, P. G., Taylor, J . B., Eds.; Pergamon: Oxford 1990; Vol. 2,
Chapter 7.2, p 271.
(3) Masciadri, R. U.S. Patent 5,773,446; Hoffmann-La Roche, J une
30, 1998.
(4) (a) Harrity, J . P. A.; Visser, M. S.; Gleason, J . D.; Hoveyda, A.
H. J . Am. Chem. Soc. 1997, 119, 1488. (b) Chang, S.; Grubbs, R. H. J .
Org. Chem. 1998, 63, 864. (c) Harrity, J . P. A.; La, D. S.; Cefalo, D. R.;
Visser, M. S.; Hoveyda, A. H. J . Am. Chem. Soc. 1998, 120, 2343. (d)
J ohannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda, A. H. J .
Am. Chem. Soc. 1998, 120, 8340.
(6) Tanaka, M.; Ikeya, Y.; Mitsuhashi, H.; Maruno, M.; Wakamatsu,
T. Tetrahedron 1995, 51, 11703.
(7) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127.
(8) Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994, 35, 4705.
(9) (a) Walton, D. R. M.; Waugh, F. J . Organomet. Chem. 1972, 37,
45. (b) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96,
3280.
(10) (a) Parker, K. A.; Ledeboer, M. W. J . Org. Chem. 1996, 61, 3214.
(b) Helal, C. J .; Magriotis, P. A.; Corey, E. J . J . Am. Chem. Soc. 1996,
118, 10938.
(5) For the use of kinetic resolution or chromatographic separation
of chiral chromenes, see: (a) Vander Velde, S. L.; J acobsen, E. N. J .
Org. Chem. 1995, 60, 5380. (b) Loncartomaskovic, L.; Mintas, M.;
Trotsch, T.; Mannschreck, A. Enantiomer 1997, 2, 459. Chiral chromene
was also obtained from dehydrogenation of chromane and cyclization
of an R,â-unsaturated sulfoxide: (c) Stocker, A.; Netscher, T.; Ru¨tti-
mann, A.; Mu¨ller, R. K.; Schneider, H.; Todaro, L. J .; Derungs, G.;
Woggon, W.-D. Helv. Chim. Acta 1994, 77, 1721. (d) Solladie, G.; Moine,
G. J . Am. Chem. Soc. 1984, 106, 6097.
(11) The enantiomeric excess was determined by integration of the
500 MHz 1H NMR spectrum of the (R)-acetylmandelic acid ester
derivative of 8. A plot of the optical rotation of carbinol 8 (c ≈ 1, CDCl3)
vs the %de of the (R)-AMA ester yielded the following relationship: %
ee ) -1.9129[R]D - 3.1769 (R ) 0.99). (R)-AMA-Cl was prepared in
two steps from mandelic acid by treatment with acetyl chloride (neat)
then acid chloride formation using oxalyl chloride in CH2Cl2 in the
presence of catalytic DMF: Thayer, F. K. Organic Syntheses; Gilman,
H., Ed.; Wiley: New York, 1932; Coll. Vol. 1, p 12.
10.1021/jo990352s CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/19/1999

5322 J . Org. Chem., Vol. 64, No. 14, 1999
Notes
Sch em e 3
using Corey’s (R)-oxazaborolidine catalyst.10 In the pres-
ence of 50 mol % of the chiral catalyst and 2.5 equiv of
BH3‚THF complex, 8 was obtained in 68% ee.11 The
enantiomeric excess was strongly dependent on catalyst
loadings. It could be increased to a maximum of 87% ee
when one full equivalent of (R)-oxazaborolidine was used.
The absolute stereochemistry of propargyl alcohol 8 was
determined by degradation via ozonolysis to known
2-cyclopropyl-2-hydroxyacetic acid.12,13
F igu r e 2. Plot of the logarithm of the % ee of a solution of 2
in hexanes as a function of time and light source (0 dim hood
light; ] standard lab room light; 4 bright desk light) at room-
temperature behind Pyrex.
purity of our substrate in the conversion of 8 to 2.
Moreover, exposure of chromene 2 to ambient light on a
benchtop led to a rapid decrease in the optical activity.
Half-lives for racemization of 2 ranged from 513 h (hood
light) to 57.2 h (standard room light) to 16.5 h (desk light,
Figure 2). In contrast, a sample of 2 kept in the dark did
not show any detectable racemization over a period of
27 days.
The photoracemization of chromene (2H-1-benzopyran)
derivatives is not well-known although the photo-
chromism of structurally closely related compounds has
been used in the design of materials exhibiting variable
optical transmission.16,17 The barrier (∆G‡) for the ther-
mal racemization of benzopyrans with extended chro-
mophores has been determined as 100-130 kJ /mol.17 The
mechanism for racemization can be envisioned as a
Removal of the trimethylsilyl group in 9 with potas-
sium carbonate in methanol followed by catalytic hydro-
genation using Lindlar’s catalyst in the presence of
quinoline led to the diene 3 in 88% yield (Scheme 3). The
ring-closing metathesis reaction of diene 3 proved to be
more problematic than anticipated. In contrast to less-
substituted substrates,4 the more-hindered 3 required
longer reaction times and higher temperatures as well
as higher catalyst loadings. Since we suspected that the
presence of the ester functionality ortho to the vinyl
group on 3 could engage in undesired chelate formation
with a ruthenium metallocycle intermediate, we followed
Fu¨rstner’s protocol and administered Ti(O-i-Pr)4 to com-
pete with chelation.14 The optimized procedure involved
the addition of a CH2Cl2 solution of 10 mol % of the
catalyst to a solution of diene 3 heated at reflux in the
presence of Ti(O-i-Pr)4. Chromene 2 was also quite labile
in the presence of metal impurities, and for workup the
reaction solution was passed through neutral alumina
before removal of the solvent to avoid significant decom-
position. Since racemic 2 has been converted into diami-
nopyrimidine 1,3 this sequence constitutes a formal
asymmetric synthesis of this potent dihydrofolate reduc-
tase inhibitor. The absolute configuration of 2 was
independently confirmed by circular dichroism spectros-
copy.15
(15) (a) Ishibashi, M.; Ohizumi, Y.; Cheng, J .; Nakamura, H.; Hirata,
Y.; Sasaki, T.; Kobayashi, J . J . Org. Chem. 1988, 53, 2855. (b) Kikuchi,
T.; Mori, Y.; Yokoi, T.; Nakazawa, S.; Kuroda, H.; Masada, Y.;
Kitamura, K.; Kuriyama, K. Chem. Pharm. Bull. 1983, 31, 106. The
absolute configuration of 2 was deduced on the basis of Kikuchi’s
method. The CD of 2 exhibited a positive Cotton effect around 254 nm
(MeOH, [Θ]
+8600) due to the styrene chromophore, indicative of
254
a left-handed helix. The cyclopropyl side chain of 2 adopts a pseu-
doequatorial position and thus the absolute configuration of 2 is S.
Chiral HPLC analysis (Chiralcel OD with 7% EtOAc
in hexanes as eluant) of a sample of 2 revealed an
enantiomeric excess of 59%. Indeed, in all preparations
we found a small but relevant decrease in the optical
(12) (a) Silbert, L. S.; Foglia, T. A. Anal. Chem. 1985, 57, 1404. (b)
Cannon, J . G.; Darko, L. L. J . Org. Chem. 1964, 29, 3419. (c) Bur, D.;
Luyten, M. A.; Wynn, H.; Provencher, L. R.; J ones, J . B.; Gold, M.;
Friesen, J . D.; Clarke, A. R.; Holbrook, J . J . Can. J . Chem. 1989, 67,
1065.
(13) The absolute stereochemistry of the product of the CBS reduc-
tion of alkynyl ketones is somewhat controversial. Our assignment
agrees with the results obtained by Parker et al.10a
(14) (a) Fu¨rstner, A.; Langemann, K. J . Am. Chem. Soc. 1997, 119,
9130. (b) Ghosh, A. K.; Cappiello, J .; Shin, D. Tetrahedron Lett. 1998,
39, 4651.
(16) Van Gemert, B. In Organic Photochromic and Thermochromic
Compounds; Crano, J . C., Guglielmetti, R. J ., Eds.; Plenum: New York
1999; Vol. 1, Chapter 3, p 111.
(17) Harie, G.; Samat, A.; Guglielmetti, R.; Van Parys, I.; Saeyens,
W.; De Keukeleire, D.; Lorenz, K.; Mannschreck, A. Helv. Chim. Acta
1997, 80, 1122.
(18) See, for example: Loncar, L.; Otocan, K.; Mintas, M.; Tro¨tsch,
T.; Mannschreck, A. Croat. Chem. Acta 1993, 66, 209.

Notes
J . Org. Chem., Vol. 64, No. 14, 1999 5323
(hexanes:EtOAc, 5:2) to yield colorless crystalline 4,5-dimethoxy-
3-hydroxybenzoic acid methyl ester (8.49 g; 92%): mp 73.5-74.5
°C; Rf ) 0.63 (hexanes:EtOAc,1:1); 1H NMR δ 7.31 (d, 1 H, J )
1.7 Hz), 7.20 (d, 1 H, J ) 2.0 Hz), 5.81 (s, 1 H), 3.97 (s, 3 H),
3.91 (s, 3 H), 3.89 (s, 3 H); 13C NMR δ 166.9, 152.2, 149.2, 139.6,
125.8, 110.1, 105.8, 61.2, 56.2, 52.4; MS (EI) m/z 212 (M+, 100),
197 (61), 181 (54); HRMS calcd for C10H12O5: 212.0685, found
212.0675.
F igu r e 3.
2-Br om o-4,5-d im eth oxy-3-h yd r oxyben zoic Acid Meth yl
Ester (7). Bromine (3.3 mL; 64.1 mmol) was added dropwise
over 10 min to a cold (-78 °C) solution of tert-butylamine (13.4
mL; 128 mmol) in freshly distilled toluene (275 mL). After 15
min a solution of 4,5-dimethoxy-3-hydroxybenzoic acid methyl
ester (11.64 g; 54.9 mmol) in freshly distilled CH2Cl2 (50 mL)
was added dropwise over 10 min. The reaction mixture was
allowed to warm to 0 °C over 1 h, stirred at this temperature
for 1.5 h, allowed to warm to room temperature over 1 h, and
kept at this temperature for 6 h. After addition of EtOAc, the
solution was washed with 1 M HCl, water, and satd NaCl and
then dried (MgSO4), filtered, and concentrated. The resulting
crude brown-green oil was purified on SiO2 (hexanes:EtOAc, 2:1)
to yield 7 as an off-white microcrystalline solid (11.75 g; 74%).
This compound could be recrystallized to transparent, large
crystals by slow evaporation of a CH2Cl2 solution: mp 110.4-
112.8 °C; Rf ) 0.38 (hexanes:EtOAc, 2:1); IR (KBr) 3377, 1716
cm-1; 1H NMR δ 7.05 (s, 1 H), 6.23 (s, 1 H), 3.97 (s, 3 H), 3.93 (s,
3 H), 3.90 (s, 3 H); 13C NMR δ 166.5, 151.2, 147.6, 138.9, 127.0,
107.2, 101.5, 61.4, 56.4, 52.7; MS (EI) m/z 292 ([M + 2]+, 97),
290 (M+, 100), 277 (25), 275 (28); HRMS calcd for C10H11BrO5:
289.9790, found 289.9802.
formal retro-Claisen rearrangement (Figure 3).18 2H-1-
Benzopyrans are generally considerably less photochro-
mic than the corresponding naphthopyrans, and their UV
absorptions are at lower wavelengths.16 The surprisingly
facile photoracemization of colorless chromene 2 at room
temperature in Pyrex flasks is likely due to the presence
of both electron-donating and electron-withdrawing sub-
stitutents at the benzene ring and serves as a reminder
that substituent effects have a considerable influence
over the photochromic properties of these heterocycles.16
It is also noteworthy to point out that several chromene-
containing natural products have been isolated as race-
mates or in variable degrees of optical purity, which could
be a consequence of spontaneous photoracemization.19
In conclusion, Stille-coupling followed by Mitsunobu
etherification and ring-closing metathesis provides a
versatile entry to chiral chromenes. In a formal asym-
metric synthesis of the potent dihydrofolate reductase
inhibitor 1, the enantioenriched building block (S)-2 was
thus obtained in seven steps and in 21% overall yield
from benzoate 6. A caveat in the preparation and
pharmaceutical use of chromenes of type 2 is their
surprisingly facile photoracemization at the stereocenter
next to the chromene oxygen. The half-lives for racem-
ization of a solution of 2 in a Pyrex flask can be as short
as 16 h. To the best of our knowledge, this study
represents the first kinetic analysis of chromene photo-
racemization.
4,5-Dim eth oxy-3-h yd r oxy-2-vin yl-ben zoic Acid Meth yl
Ester (4). Tetrakis(triphenylphosphine)palladium(0) (1.57 g;
1.36 mmol) was added to a degassed solution of bromide 7 (3.958
g; 13.6 mmol) and tributylvinyltin (4.92 g; 15.1 mmol) in freshly
distilled toluene (70 mL). The mixture was again degassed and
heated at 90 °C (bath temperature) for 14.5 h and at 110 °C for
21.8 h. After removal of the solvent, the residue was chromato-
graphed on SiO2 (hexanes:EtOAc, 5:2) and the resulting 2.8 g
of a light orange viscous liquid was triturated with hexanes and
stored in a freezer overnight to yield 4 as a pale orange solid
(2.643 g; 81%): mp 51.0-52.5 °C; Rf ) 0.40 (hexanes:EtOAc,
1
5:2); IR (KBr) 3422, 1830, 1701 cm-1; H NMR δ 7.00 (dd, 1 H,
J ) 11.7, 17.9 Hz), 6.98 (s, 1 H), 6.26 (s, 1 H), 5.77 (dd, 1 H, J
) 1.9, 17.9 Hz), 5.53 (dd, 1 H, J ) 1.9, 11.7 Hz), 3.96 (s, 3 H),
3.90 (s, 3 H), 3.88 (s, 3 H); 13C NMR δ 168.1, 150.4, 147.8, 138.2,
130.8, 125.6, 119.3, 119.1, 105.6, 61.0, 55.9, 52.3; MS (EI) m/z
238 (M+, 100), 207 (49); HRMS calcd for C12H14O5: 238.0841,
found 238.0832.
Exp er im en ta l Section
Gen er a l Meth od s. All air- or moisture-sensitive reactions
were performed under an atmosphere of N2 and all glassware
was dried in an oven at 170 °C prior to use. THF and Et2O were
dried by distillation over Na/benzophenone and LAH, respec-
tively. Dry CH2Cl2 and toluene were obtained by distillation from
CaH2. Unless otherwise stated, solvents or reagents were used
without further purification. NMR spectra were recorded at
either 300 MHz/75 MHz (1H/13C NMR) in CDCl3 at 21 °C unless
stated otherwise. Chemical shifts (δ) are reported in parts per
million and the residual solvent peak or TMS was used as an
internal standard. 4,5-Dimethoxy-3-hydroxybenzoic acid was
obtained from Lipomed and the (R)-CBS catalyst ((R)-tetrahydro-
1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1
M in toluene)) was obtained from Aldrich; all other chemicals
were readily available from commercial sources. Chiral HPLC
analyses were performed on a Chiralcel OD column from Chiral
Technologies, eluting with 7% ethyl acetate in hexanes at a flow
rate of 1 mL min-1 with detection at 280 nm.
1-Cyclop r op yl-3-(tr im eth ylsilyl)p r op yn -1-on e. A solution
of bis(trimethylsilyl)acetylene (5.1119 g; 30.0 mmol) and cyclo-
propanecarbonyl chloride (3.1332 g; 30.0 mmol) in CH2Cl2 (20
mL) was added dropwise over 20 min to an ice-cold slurry of
AlCl3 (4.00 g; 30.0 mmol) in CH2Cl2 (100 mL). After 2.5 h at 0
°C, the reaction mixture was treated with 1 M HCl (100 mL)
and stirred at 0 °C for 10 min. The aqueous layer was extracted
with CH2Cl2, and the combined organic extracts were washed
with water and saturated NaCl solution, dried (Na2SO4), and
filtered. The solution was concentrated and chromatographed
on SiO2 (pentane:ether, 20:1). Pure 1-cyclopropyl-3-(trimethyl-
silyl)propyn-1-one was obtained after Kugelrohr distillation (29
mmHg/105 ( 5 °C) as a clear, colorless liquid (4.02 g; 81%): Rf
) 0.38 (pentane:ether, 20:1); IR (neat) 2149, 1662 cm-1; 1H NMR
δ 2.11-2.02 (m, 1 H), 1.34-1.15 (m, 2 H), 1.15-0.95 (m, 2 H),
0.24 (s, 9 H); 13C NMR δ 188.2, 100.3, 97.6, 24.4, 11.2, -0.7; MS
(EI) m/z 166 (M+, 40), 151 (100); HRMS calcd for C9H14OSi:
166.0814, found 166.0811.
(R)-1-Cyclop r op yl-3-(tr im eth ylsilyl)p r op -2-yn -1-ol (8). A
solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-
[1,2-c][1,3,2]oxazaborole (1 M in toluene; 1.50 mL; 1.50 mmol)
was cooled to -40 °C and BH3‚THF (1 M in THF; 6.2 mL; 6.2
mmol) was added via syringe, with the solution allowed to run
down the side of a flask in order to cool.20 A solution of
1-cyclopropyl-3-(trimethylsilyl)propyn-1-one (0.30 mM in THF;
8.3 mL; 2.5 mmol) that had been dried with activated 4 Å
4,5-Dim eth oxy-3-h yd r oxyben zoic Acid Meth yl Ester .
Hydrogen chloride gas was bubbled for 15 min into an ice-cold
methanolic (90 mL) solution of 4,5-dimethoxy-3-hydroxybenzoic
acid (6, 8.59 g; 43.3 mmol). The reaction flask was allowed to
warm to room temperature. After 13 h most of the solvent was
removed on a rotary evaporator, and toluene was added and
removed to obtain crude product that was purified on SiO2
(19) (a) Venkateswarlu, Y.; Faulkner, D. J .; Steiner, J . L. R.;
Corcoran, E.; Clardy, J . J . Org. Chem. 1991, 56, 6271. (b) J aipetch,
T.; Kanghae, S.; Pancharoen, O.; Patrick, V. A.; Reutrakul, V.;
Tuntiwachwuttikul, P.; White, A. H. Aust. J . Chem. 1982, 35, 351. (c)
Hamann, M. T.; Scheuer, P. J .; Kelly-Borges, M. J . Org. Chem. 1993,
58, 6565.
(20) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1997, 38, 7511.

5324 J . Org. Chem., Vol. 64, No. 14, 1999
Notes
molecular sieves was likewise added down the side of the flask
via syringe pump over 80 min. After 12.3 h, the reaction was
quenched with dry methanol (2 mL) and, when bubbles ceased
to form, most of the solvent was removed on a rotary evaporator.
Ether was added, and the mixture was washed with water. The
aqueous layer was extracted with pentane and the combined
organic layers were washed with saturated NaCl, dried (Na2-
SO4), filtered, and concentrated. The material was chromato-
graphed on SiO2 (pentane:ether, 4:1) to give 8 as a pale yellow
liquid (264.0 mg; 63%) in 68% ee based on (R)-AMA ester
(R)-3-(1-Cyclop r op yla llyloxy)-4,5-d im eth oxy-2-vin ylben -
zoic Acid Meth yl Ester (3). Lindlar’s catalyst (5% Pd on
CaCO3, poisoned with lead; 11.8 mg) was added to a solution of
(S)-3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-2-vinylben-
zoic acid methyl ester (296.3 mg; 937 µmol) and quinoline (968.1
mg; 7.50 mmol) in methanol (45 mL). The reaction was alter-
nately exposed to reduced pressure (water aspirator) and
hydrogen gas for four times and finally left under hydrogen.
After 4.0 h the suspension was filtered, and the solvent was
removed. Pure 3 (267.2 mg; 90%) was obtained as a yellow,
viscous liquid after chromatography on SiO2 (CH2Cl2:i-PrOH,
200:1): [R]18D +15.7 (c 1.17, CH2Cl2); Rf ) 0.36 (hexanes:EtOAc,
4:1); IR (neat) 1724 cm-1; 1H NMR δ 7.06 (s, 1 H), 6.93 (dd, 1 H,
J ) 11.5, 17.7 Hz), 6.0-5.88 (m, 1 H), 5.55 (1 H, dd, J ) 1.9,
17.8 Hz), 5.42 (dd, 1 H, J ) 1.8, 11.5 Hz), 5.14-5.00 (m, 2 H),
4.02 (t, 1 H, J ) 8.0 Hz), 3.88 (s, 6 H), 3.85 (s, 3 H), 1.2-1.1 (m,
1 H), 0.57-0.42 (m, 2 H), 0.32-0.21 (m, 1 H), 0.21-0.11 (m, 1
H); 13C NMR δ 168.7, 151.7, 149.5, 145.4, 136.9, 131.6, 127.8,
125.6, 119.1, 117.1, 108.5, 88.1, 60.8, 56.0, 52.2, 15.3, 4.3, 1.6;
MS (EI) m/z 318 (M+, 9), 286 (6); HRMS calcd for C18H22O5:
318.1467, found 318.1481.
analysis: Rf ) 0.40 (pentane:ether, 4:1); [R]19 -37.2 (c 1.0,
D
CDCl3); IR (neat) 3354, 2174 cm-1; H NMR δ 4.25 (t, 1 H, J )
1
6.3 Hz), 1.87 (d, 1 H, J ) 6.4 Hz), 1.3-1.15 (m, 1 H), 0.62-0.38
(m, 4 H), 0.17 (s, 9 H); 13C NMR δ 104.2, 89.7, 66.0, 16.8, 3.2,
1.5, -0.1; MS (CI, isobutane) m/z 184 ([M + CH4]+, 15), 167 ([M
- H]+, 43), 151 (92).
(S)-3-(1-Cyclop r op yl-3-(tr im eth ylsilyl)p r op -2-yn yloxy)-
4,5-d im eth oxy-2-vin ylben zoic Acid Meth yl Ester (9). A
solution of diisopropyl azodicarboxylate (400 µL; 1.93 mmol) in
THF (9 mL) was added dropwise over 20 min to an ice-cold
solution of phenol 4 (467.5 mg; 1.96 mmol), carbinol 8 (274.2
mg; 1.63 mmol), Et3N (45 µL, 0.32 mmol), and Ph3P (519.1 mg;
1.96 mmol) in THF (31 mL). The ice bath was removed and the
reaction stirred at room temperature for 22 h. The solvent was
removed, and the product was partially purified on basic alumina
(Brockman I, 80 g, CH2Cl2) followed by chromatography on SiO2
(CH2Cl2) to yield 9 as a yellow liquid (420.5 mg; 66%): Rf ) 0.44
(S)-2-Cyclop r op yl-7,8-d im et h oxy-2H -ch r om en e-5-ca r -
boxylic Acid Meth yl Ester (2). A solution of diene 3 (22.2 mg;
69.7 µmol) in freshly distilled CH2Cl2 (10 mL) was added to Ti-
(OiPr)4 (8.4 mg; 29 µmol). This solution was heated at reflux
under nitrogen for 1.3 h followed by addition of a solution of
RuCl2(CHPh)(PCy3)2 (5.7 mg; 6.9 µmol) in freshly distilled CH2-
Cl2 (2 mL). The whole apparatus was wrapped in aluminum foil
to exclude light. After 5 d at reflux, the product was partially
purified by passing the reaction solution through neutral
alumina (8 g, activity I), followed by washing with CH2Cl2 until
a yellow material had passed through then eluting the product
with CH2Cl2:CH3OH (200:1). Pure chromene 2 was obtained in
59% ee (chiral HPLC) as an off-white solid (13.0 mg; 64%) after
chromatography on SiO2 (hexanes:EtOAc, 11:2): mp 55.9-60.7
°C; Rf ) 0.36 (7:2 hexanes:EtOAc); [R]19D + 43.7 (c 1.23, CDCl3);
IR (KBr) 1713 cm-1; 1H NMR δ 7.33 (dd, 1 H, J ) 1.4, 10.2 Hz),
7.09 (s, 1 H), 5.84 (dd, 1 H, J ) 3.8, 10.3 Hz), 4.24 (ddd, 1 H, J
) 1.5, 3.8, 8.3 Hz), 3.96 (s, 3 H), 3.89 (s, 6 H), 1.32-1.22 (m, 1
H), 0.65-0.28 (m, 4 H); 13C NMR δ 167.2, 152.1, 147.4, 141.0,
124.4, 122.4, 120.9, 118.4, 106.5, 78.8, 61.1, 56.1, 52.1, 15.1, 3.0,
1.6; MS (EI) m/z 290 (M+, 100), 275 (91), 249 (96); HRMS calcd
for C16H18O5: 290.1154, found 290.1149.
(CH2Cl2), 0.35 (hexanes:EtOAc, 6:1); [R]18 +9.5 (c 1.16, CH2-
D
Cl2); IR (neat) 2176, 1725 cm-1
;
1H NMR δ 7.07 (s, 1 H), 6.98
(dd, 1 H, J ) 11.5, 17.7 Hz), 5.51 (dd, 1 H, J ) 1.6, 17.6 Hz),
5.41 (dd, 1 H, J ) 1.9, 11.5 Hz), 4.77 (d, 1 H, J ) 6.9 Hz), 3.91
(s, 3 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 1.42-1.32 (m, 1 H), 0.64-
0.50 (m, 3 H), 0.5-0.4 (m, 1H), 0.07 (s, 9 H); 13C NMR δ 168.8,
151.7, 149.1, 145.4, 131.6, 128.1, 125.7, 119.1, 109.0, 101.7, 91.7,
76.5, 60.9, 56.1, 52.2, 15.1, 4.0, 2.0, -0.4; MS (EI) m/z 388 (M+,
13), 329 (55); HRMS calcd for C21H28O5Si: 388.1706, found
388.1695.
(S)-3-(1-Cyclop r op ylp r op -2-yn yloxy)-4,5-d im eth oxy-2-vi-
n ylben zoic Acid Meth yl Ester . Potassium carbonate (817.6
mg) was added to a methanolic (25 mL) solution of TMS-alkyne
9 (408.9 mg; 1.05 mmol). After 50 min most of the solvent was
removed and ether was added. The mixture was washed with
water, and the aqueous layers were re-extracted with CH2Cl2.
The combined organic extracts were washed with saturated
NaCl, dried (Na2SO4), filtered, and concentrated. Pure (S)-3-(1-
cyclopropylprop-2-ynyloxy)-4,5-dimethoxy-2-vinylbenzoic acid
methyl ester was obtained after chromatography on SiO2 (CH2-
Cl2) as a yellow liquid (326.1 mg; 98%): Rf ) 0.28 (4:1 hexanes:
EtOAc); [R]19D +19.3 (c 1.14, CH2Cl2); IR (neat) 3287, 2116, 1723
cm-1; 1H NMR δ 7.10 (s, 1 H), 6.98 (dd, 1 H, J ) 11.5, 17.8 Hz),
5.55 (dd, 1 H, J ) 1.8, 17.8 Hz), 5.44 (dd, 1 H, J ) 1.8, 11.5 Hz),
4.75 (dd, 1 H, J ) 2.1, 7.2 Hz), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.85
(s, 3 H), 2.37 (d, 1 H, J ) 2.2 Hz), 1.46-1.33 (m, 1 H), 0.64-
0.40 (m, 4 H); 13C NMR δ 168.5, 151.7, 148.7, 145.3, 131.3, 127.7,
125.6, 119.3, 109.1, 80.2, 75.6, 74.6, 60.9, 55.9, 52.1, 15.2, 4.1,
1.8; MS (EI) m/z 316 (M+, 11), 301 (13), 285 (15), 257 (100);
HRMS calcd for C18H20O5: 316.1311, found 316.1312.
Ack n ow led gm en t. Partial support of this research
from Arpida and the Camille and Henry Dreyfus
Foundation is gratefully acknowledged. We would also
like to thank Dr. Wenjing Xu for the preparation of 7.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all synthetic intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O990352S