Heteroatomic effects on the reducibility of C-2 carbinol centers in 6- ethoxy-3,6-dihydropyrans and -thiopyrans

Full text of DOI:10.1021/jo990011e

J . Org. Chem. 1999, 64, 3783-3786
3783
Sch em e 1
Heter oa tom ic Effects on th e Red u cibility of
C-2 Ca r bin ol Cen ter s in
6-Eth oxy-3,6-d ih yd r op yr a n s a n d
-th iop yr a n s
Fang-Tsao Hong† and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University,
Columbus, Ohio 43210
Received J anuary 4, 1999
Ketones of type 1, which we considered to be accessible
by Diels-Alder cycloaddition of a chiral R-acyloxy acrylo-
nitrile1 to the appropriate 2H-pyran or thiopyran (2),2-5
were desired in conjunction with a current synthetic
undertaking (Scheme 1). The feasibility of advancing to
2 from alkoxy precursors6 exemplified by 3 led to the
search for a mild and generally useful method for their
preparation. This paper records a practical route to the
sulfur analogue and demonstrates an unanticipated
reactivity difference that disallows comparable access in
the oxygen series.
Carboxylic acid 4 was prepared by heating γ-butyro-
lactone with p-methoxyphenol and potassium hydroxide
pellets at 190 °C according to a modification of literature
methods.7,8 Ensuing conversion9 to the Weinreb amide 5
proceeded in 70% yield and set the stage for the nucleo-
philic addition of an equivalent of (Z)-2-ethoxy-1-ethen-
yllithium10 to provide the R,â-unsaturated ketone 6 (65%,
Scheme 2). To secure arrival at the labile diene 7 in an
acceptable yield, it was imperative that olefination be
performed under neutral conditions. It was soon discov-
ered that dimethyltitanocene in THF at 55 °C11 was well-
suited to this task.
A (4 + 2)π intermolecular cycloaddition involving 7 and
thiodiethylpyrocarboxylate (generated in situ), which
would result in assembly of the sulfur-containing six-
membered ring, was considered probable if 7 possessed
intrinsic reactivity approaching that exhibited by the
Danishefsky diene.12 Indeed, slow addition of diethyl
bromomalonate to an acetonitrile solution containing
sulfur, triethylamine, and 7 at room temperature gave
rise to the desired adduct 8 in virtually quantitative yield.
Reduction of the geminal diester groups within 8 with
DIBAL-H furnished the diol, whose unpurified dimesy-
late derivative underwent 2-fold hydride displacement
in the presence of lithium triethylborohydride to generate
the desired 10 without event.
In the hope that 14 could be generated in a comparable
manner, 7 was subjected to hetero Diels-Alder reac-
tion13-15 with ethyl glyoxylate in toluene at room tem-
perature. This simple protocol produced 11 as a diaster-
eomeric mixture in 98% yield (Scheme 3). Interestingly,
doubly activated dienophiles such as diethyl pyrocarbon-
ate did not cycloadd to 7, presumably for steric reasons.
Recourse to high-pressure conditions was to no avail. This
problem was solved by virtue of the ease with which the
enolate anion of 11 could be generated. Exposure of this
reactive intermediate to methyl cyanoformate and to
methyl iodide produced 12 and 15, respectively. The
carboalkoxy substituents projecting from the C2 position
of these esters proved amenable to hydride reduction.
Unfortunately, all efforts to realize the further reduction
of 13 and 16 to 14 were unsuccessful. Quite unlike the
dimesylate of 9 which was transformed cleanly into 10,
the sulfonate esters derived from diol 13 and alcohol 16
afforded very complex product mixtures. Direct reduction
with lithium triethylborohydride and the other hydridic
reagents with a view to minimizing degradation gave no
sign of the desired gem-dimethyl product.
† Present address: Department of Chemistry, University of Cali-
fornia at Irvine, Irvine, CA 92717-2025.
(1) Warm, A.; Vogel, P. J . Org. Chem. 1986, 51, 5348 and relevant
references therein.
(2) (a) General review of pyran chemistry: (a) Kuthan, J .; Sebek,
P.; Boehm, S. Adv. Heterocycl. Chem. 1995, 62, 19. (b) Obrecht, D. Helv.
Chim. Acta 1991, 74, 27. (c) Hamming, K.; Taylor, R. J . K. J . Chem.
Soc., Chem. Commun. 1993, 1409. (d) For molybdenum π-complexes
of 2H-pyran, see Hansson, S.; Miller, J . F.; Liebeskind, L. S. J . Am.
Chem. Soc. 1990, 112, 9660.
(3) For references pertinent to the stabilizing effect of substitution
on the kinetic stability of 2H-pyrans, consult (a) Sarel, S.; Rivilin, J .
Tetrahedron Lett. 1965, 821. (b) Royer, J .; Dreux, J . Tetrahedron Lett.
1968, 5589. (c) Marvell, E. N.; Chadwick, T.; Caple, G.; Gosink, T.;
Zimmer, G. J . Org. Chem. 1972, 37, 2992. (d) Marvell, E. N.; Gosink,
T. J . Org. Chem. 1972, 37, 3036. (e) Safieddine, A.; Royer, J .; Dreux,
J . Bull. Soc. Chim. Fr. 1972, 703, 1646. (f) Royer, J .; Dreux, J . Bull.
Soc. Chim. Fr. 1972, 707. (g) Roedig, A.; Neukam, T. Chem. Ber. 1974,
107, 3463. (h) Roedig, A.; Neukam, T. Liebigs Ann. Chem. 1975, 240.
(i) Moorhoff, C. M. Synthesis 1997, 685.
(4) (a) Fleming, R. H.; Murray, B. M. J . Org. Chem. 1979, 44, 2280.
(b) Gra¨fing, R.; Brandsma, L. Recueil 1978, 97, 208. (c) Ward, D. E.;
Gai, Y. Can. J . Chem. 1992, 70, 2627. (d) Ward, D. E.; Nixey, T. E.;
Gai, Y.; Hrapchak, M. J .; Abaee, M. S. Can. J . Chem. 1996, 74, 1418.
(e) Ward, D. E.; Gai, Y. Can. J . Chem. 1997, 75, 681.
(5) For an evaluation of the 6π-electrocyclization of 1,2-dihydro-
pyridines, see Maynard, D. F.; Okamura, W. H. J . Org. Chem. 1995,
60, 1763.
(6) (a) Kang, K. T.; Park, C.-K.; Yoon, U. C. Bull. Korean Chem.
Soc. 1994, 13 41. (b) See also Li, W.-T.; Lai, F.-C.; Lee, G.-H.; Peng,
S.-M.; Liu, R.-S. J . Am. Chem. Soc. 1998, 120, 4520.
(7) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
A possible explanation for this dichotomy in chemical
behavior is the availability of an activation process in
the sulfur series not shared comparably by the oxa
(11) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392.
(12) Grisoni, S.; Huon, C.; Peyronel, J .-F. Biorg. Med. Chem. Lett.
1995, 5, 1591.
(13) For a recent review, see Waldmann, H. Synthesis 1994, 5352.
(14) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. Synlett 1992,
255.
(8) Tandon, V. K.; Chandra, A.; Dua, P. R.; Srimal, R. C. Arch.
Pharm. 1993, 326, 221.
(9) Einhorn, J .; Einhorn, C.; Luche, J .-L. Synth. Commun. 1990, 20,
1105.
(10) Wollenberg, R. H.; Albizati, K. F.; Peries, R. J . Am. Chem. Soc.
1977, 99, 7365.
(15) Mikami, K.; Motoyama, Y.; Terada, M. J . Am. Chem. Soc. 1994,
116, 2812.
10.1021/jo990011e CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/20/1999

3784 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
Sch em e 2
Sch em e 3
Sch em e 4
on Merck Kieselgel 60 F254 aluminum-backed plates. Flash
column chromatography was accomplished in glass columns with
Woelm silica gel (230-400 mesh). NMR spectra were acquired
at 300 MHz for 1H and 75 MHz for 13C. Melting points are
uncorrected. Solvents were reagent grade and in most cases
dried prior to use. The high-resolution mass spectra were
obtained at The Ohio State University Campus Chemical
Instrumentation Center. Elemental analyses were performed by
Atlantic Microlab, Inc., Norcross, GA.
4-(p-Meth oxyp h en oxy)bu tyr ic Acid (4).5 To a mechani-
cally stirred suspension of 4-methoxyphenol (62.1 g, 0.50 mol)
in water (20 mL) was added KOH pellets (34.6 g, 0.52 mol)
followed by careful addition of butyrolactone (77 mL, 1 mol). The
flask was equipped with a Dean-Stark trap and thermometer,
and the mixture was heated at 150 °C under N2 for 3 h and at
195 °C until no more water was removed (ca. 5 h overall). After
cooling to room temperature, 150 mL of water was introduced,
and the mixture was heated to 60 °C until all of the solid had
dissolved. The resulting hot brown solution was poured into 5%
HCl, and the heterogeneous mixture was cooled at 0 °C for 3 h.
The crystals were collected by filtration and rinsed with cold
water until colorless. The crude product was dried under vacuum
to afford acid 4 (132.43 g, 93%) as a white crystalline solid; IR
(film, cm-1) 3387, 1704; 1H NMR (300 MHz, CDCl3) δ 10.30 (br
s, 1 H), 6.83 (s, 4 H), 3.97 (t, J ) 6.1 Hz, 2 H), 3.77 (s, 3 H), 2.58
(t, J ) 7.2 Hz, 2 H), 2.09 (tt, J ) 7.2, 6.1 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 179.4, 153.9, 152.9, 115.5, 114.7, 67.2, 55.7, 30.6,
24.5; MS m/z (M+) calcd 210.0892, obsd 210.0893.
N -Me t h o x y -4-(p -m e t h o x y p h e n o x y )-N -m e t h y lb u t y r -
a m id e (5). To a mixture of 4 (2.10 g, 10.0 mmol), N-methoxy-
N-methylamine hydrochloride (1.075 g, 11.0 mmol), pyridine (0.9
mL, 11.0 mmol), and carbon tetrabromide (3.65 g, 11.0 mmol)
in CH2Cl2 (25 mL) was added triphenylphosphine (2.88 g, 11.0
mmol) in portions during 5 min at room temperature. After 2 h
of stirring, the solvent was evaporated, 20 mL of 1:1 hexanes-
ethyl acetate was poured onto the residue, the solid waste was
filtered off, and the solution was concentrated to furnish a
residue that was purified by flash chromatography on silica gel
analogues. Thus, the substantial nucleophilicity of di-
valent sulfur could prove conducive to transient sulfo-
nium ion formation as in 17 and 18,16 thereby providing
for an enhanced rate of hydride attack at the neopentyl
centers (Scheme 4). In the absence of this neighboring
group participation, ill-defined reaction pathways less
affected by steric retardation appear to gain a kinetic
advantage.
Exp er im en ta l Section
Gen er a l Meth od s. Yields were calculated for material judged
to be homogeneous by TLC and NMR. Magnetic stirring was
used for all reactions. Thin-layer chromatography was performed
(16) Capon, B.; McManus, S. P. Neighboring Group Participation;
Plenum Press: New York, 1976; Volume 1.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3785
(elution with ethyl acetate/hexanes 1:1) to yield 5 as a colorless
oil (1.83 g, 77%); IR (film, cm-1) 1661; 1H NMR (300 MHz, CDCl3)
δ 6.84 (s, 4 H), 3.98 (t, J ) 6.1 Hz, 2 H), 3.76 (s, 3 H), 3.68 (s, 3
H), 3.18 (s, 3 H), 2.63 (t, J ) 7.2 Hz, 2 H), 2.10 (tt, J ) 7.2, 6.1
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 173.7, 153.6, 152.9, 115.3,
114.5, 67.5, 61.0, 55.5, 32.1, 28.1, 24.2; MS m/z (M+) calcd
253.1314, obsd 253.1321. Anal. Calcd for C13H19NO4: C, 61.63;
H, 7.57. Found: C, 61.79; H, 7.64.
-15 °C. The separated aqueous layer was extracted with CH2-
Cl2 and ethyl acetate, the combined organic layers were dried
and evaporated, and the resulting diol (85 mg, 96%) was used
directly; IR (film, cm-1) 3418, 1504; 1H NMR (300 MHz, C6D6) δ
6.80 (m, 4 H), 5.42 (d, J ) 1.1 Hz, 1 H), 4.15 (m, 1 H), 4.16-3.78
(series of m, 4 H), 3.57 (t, J ) 6.1 Hz, 2 H), 3.34 (s, 3 H), 3.36-
3.27 (m, 1 H), 3.14-3.04 (m, 1 H), 2.72 (d, J ) 17.0 Hz, 1 H),
2.53 (d, J ) 17.0 Hz, 1 H), 1.89 (t, J ) 7.5 Hz, 2 H), 1.54 (m, 2
H), 0.88 (t, J ) 7.0 Hz, 3 H), 0.48 (br s, 2 H); 13C NMR (75 MHz,
C6D6) δ 153.5, 152.7, 135.6, 122.8, 114.7, 114.0, 76.4, 66.5, 64.6,
64.2, 63.1, 54.2, 51.0, 32.8, 26.6, 24.8, 14.4; MS m/z (M+) calcd
368.1657, obsd 368.1663.
(Z)-1-Eth oxy-6-(p-m eth oxyp h en oxy)-1-h exen -3-on e (6). A
flame-dried, two-necked, round-bottomed flask was charged with
(2(Z)-ethoxyethenyl)-1-tributylstannane (0.248 g, 0.688 mmol)
and THF (2.5 mL) into which n-butyllithium (1.3 M in hexanes,
0.58 mL) was dropped at -78 °C, and the solution was stirred
at this temperature for 1 h. A solution of 5 (0.158 g, 0.625 mmol)
in THF (2.5 mL) was added during 2 min at the same temper-
ature. The resulting mixture was stirred for another 1 h, allowed
to warm to room temperature during 0.5 h, poured into ice-cooled
5% HCl, and diluted with ether and brine. The separated
aqueous phase was extracted with ether. The combined organic
layers were washed with saturated NaHCO3 solution and brine
and then dried. Filtration and concentration in vacuo provided
a pale yellow product which was purified by flash chromatog-
raphy on silica gel (elution with ethyl acetate/hexanes 1:1) to
6-Eth oxy-3,6-d ih yd r o-4-[3-(p-m eth oxyp h en oxy)p r op yl]-
2H-d im eth yl-2H-th iop yr a n (10). A solution of 9 (90 mg, 0.20
mmol) and triethylamine (0.11 mL, 0.80 mmol) in CH2Cl2 (3 mL)
was treated dropwise at 0 °C with methanesulfonyl chloride (80
mg, 0.70 mmol). The reaction mixture was stirred at room
temperature for 2.5 h prior to dilution with CH2Cl2, and the
combined organic phases were dried and concentrated to give
the dimesylate. The yellow oil was dissolved in dry THF (1 mL)
and treated dropwise with lithium triethylborohydride (0.6 mL
of 1.0 M in THF) at 0 °C. After 5 min, the reaction mixture was
allowed to warm to room temperature for 1 h, quenched with
ether and water, and extracted with ether. The combined organic
phases were washed with brine, dried, and concentrated to leave
a residue that was purified by chromatography on silica gel.
Elution with hexanes/ethyl acetate (1:10) gave 10 (39 mg, 48%
overall) as a colorless syrup; IR (film, cm-1) 1509, 1232; 1H NMR
(300 MHz, CDCl3) δ 6.83 (s, 4 H), 5.48 (br s, 1 H), 3.91 (t, J )
6.3 Hz, 2 H), 3.78 (br s, 1 H), 3.77 (s, 3 H), 3.76-3.65 (m, 1 H),
3.53-3.47 (m, 1 H), 3.25 (m, 1 H), 2.84 (m, 1 H), 2.19 (m, 2 H),
1.91 (m, 2 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.20 (t, J ) 7.0 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 153.8, 152.4, 138.3, 122.0, 115.4,
114.6, 73.0, 67.5, 65.4, 55.7, 51.7, 46.3, 33.9, 27.3, 26.8, 15.5 (1
C overlapping); MS m/z (M+) calcd 336.1754, obsd 336.1761.
Eth yl 6-Eth oxy-3,6-d ih yd r o-4-[3-(p-m eth oxyp h en oxy)-
p r op yl]-2H-p yr a n -2-ca r boxyla te (11). A solution of 7 (0.240
g, 0.92 mmol) in toluene (10 mL) was suspended with sodium
bicarbonate (200 mg) for couple of minutes, filtered, and
concentrated. Ethyl glyoxylate (0.467 g, 4.6 mmol) dissolved in
dry toluene (1 mL) was introduced, and the reaction mixture
was stirred at room temperature for 1 h under N2. The volatile
material was removed to leave a pale yellow viscous residue,
which was purified by flash chromatography (silica gel elution
with ethyl acetate/hexanes 1:5) to afford 11 as a colorless oily
2:1 mixture of cis and trans isomers (0.314 g, 99%); IR (film,
cm-1) 2936, 1736, 1508, 1231; 1H NMR (300 MHz, CDCl3) δ 6.81
(s, 4 H), 5.53 (d, J ) 0.7 Hz, 1 H, minor isomer), 5.46 (d, J ) 1.5
Hz, 1 H, major isomer), 5.12 (d, J ) 1.7 Hz, 1 H), 4.54 (dd, J )
10.0, 2.3 Hz, 1 H, minor isomer), 4.35 (dd, J ) 7.0, 5.0 Hz, 1 H,
major isomer), 4.30-4.14 (series of m, 2 H), 3.99-3.78 (series
of m, 3 H), 3.76 (s, 3 H), 3.57 (m, 1 H), 2.42-2.22 (series of m,
4 H), 1.97-1.90 (m, 2 H), 1.34-1.22 (series of m, 6 H); 13C NMR
(75 MHz, CDCl3) δ 171.8, 171.2, 153.8, 153.1, 139.1, 120.5, 119.7,
115.5, 114.7, 96.7, 95.1, 69.9, 67.9, 67.8, 66.2, 63.7, 63.6, 61.1,
61.0, 55.7, 33.0, 32.9, 31.0, 29.5, 27.0, 26.7, 15.3, 15.1, 14.2, 14.1;
MS m/z (M+) calcd 364.1886, obsd 364.1880. Anal. Calcd for
yield pure 6 as a colorless oil (0.133 g, 76%). IR (neat, cm-1
)
1683, 1637, 1617; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J ) 12.7
Hz, 1 H), 6.82 (s, 4 H), 5.62 (d, J ) 12.7 Hz, 1 H), 3.94 (m, 4 H),
3.76 (s, 3 H), 2.65 (t, J ) 7.2 Hz, 2 H), 2.06 (tt, J ) 7.2, 6.1 Hz,
2 H), 1.34 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
199.0, 161.9, 153.8, 153.3, 115.4, 114.7, 106.1, 67.6, 67.0, 55.7,
37.3, 24.1, 14.3; MS m/z (M+) calcd 264.1361, obsd 264.1362.
Anal. Calcd for C15H20O4: C, 68.14; H, 7.63. Found: C, 67.74;
H, 7.68.
1-[[(Z)-6-Eth oxy-4-m eth ylen e-5-h exen yl]oxy]-4-m eth oxy-
ben zen e (7). A base-washed, round-bottomed flask was charged
with 6 (0.486 g, 1.84 mmol) and anhydrous THF (2 mL) to which
a solution of dimethyltitanocene (12.4 mL of 0.3 M in THF, 3.69
mmol) was added. The mixture was heated at 55 °C under N2
for 20 h. The resulting dark-red solution was diluted with
hexanes (100 mL containing 1% of triethylamine), and the
precipitate was removed by filtration. Concentration followed
by flash chromatography on silica gel (elution with ethyl acetate/
hexanes 1:30 containing 1% triethylamine) afforded 7 (0.24 g,
50%) as an unstable yellowish oil; IR (film, cm-1) 1509, 1232,
1040; 1H NMR (300 MHz, CDCl3) δ 6.88-6.80 (m, 4 H), 6.67 (d,
J ) 13.0 Hz, 1 H), 5.73 (d, J ) 13.0 Hz, 1 H), 4.95 (s, 1 H), 4.83
(s, 1 H), 3.73 (t, J ) 6.2 Hz, 2 H), 3.44 (q, J ) 4.7 Hz, 2 H), 3.39
(s, 3 H), 2.35 (t, J ) 7.5 Hz, 2 H), 1.93 (tt, J ) 7.4, 4.7 Hz, 2 H),
1.05 (t, J ) 4.7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 154.4,
153.8, 148.1, 143.8, 115.7, 115.0, 110.6, 108.4, 67.8, 65.1, 55.2,
29.6, 28.5, 14.8; MS m/z (M+) calcd 262.1569, obsd 262.1565.
Dieth yl 6-Eth oxy-3,6-d ih yd r o-4-[3-(p-m eth oxyp h en oxy)-
p r op yl]-2H-th iop yr a n -2,2-d ica r boxyla te (8). To a stirred
solution of 7 (52 mg, 0.20 mmol), triethylamine (66 mg, 0.5
mmol), and sulfur (23 mg, 0.72 mmol) in acetonitrile (1 mL) was
added dropwise via syringe pump a solution of diethyl bromo-
malonate (96 mg, 0.40 mmol) in acetonitrile (1 mL) at room
temperature during 3 h. The resulting suspension was stirred
for 24 h, filtered through a small pad of Celite, and concentrated.
Chromatography of the residue on silica gel (elution with ethyl
acetate/hexanes 1:5) afforded 95 mg (100%) of 8 as a yellowish
oil; IR (film, cm-1) 1732, 1505; 1H NMR (300 MHz, C6D6) δ 6.89-
6.74 (m, 4 H), 5.78 (dt, J ) 2.4, 0.6 Hz, 1 H), 4.59 (d, J ) 4.5 Hz,
1 H), 4.14-3.87 (series of m, 4 H), 3.67 (t, J ) 2.7 Hz, 2 H),
3.64-3.36 (m, 2 H), 3.35 (s, 3 H), 3.09 (d, J ) 17.3 Hz, 1 H),
2.92 (d, J ) 17.3 Hz, 1 H), 2.00 (t, J ) 7.3 Hz, 2 H), 1.63 (quintet,
J ) 6.8 Hz, 2 H), 1.02 (t, J ) 7.0 Hz, 3 H), 0.98 (t, J ) 7.1 Hz,
3 H), 0.91 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ 167.8,
166.9, 154.4, 153.8, 137.4, 122.5, 115.6, 115.0, 72.2, 67.2, 64.8,
61.9, 61.7, 61.3, 55.2, 34.4, 27.8, 27.3, 15.8, 14.0, 13.9; MS m/z
(M+) calcd 452.1868, obsd 452.1881. Anal. Calcd for C23H32O7S:
C, 61.04; H, 7.13. Found: C, 60.90; H, 7.16.
C
20H28O6: C, 65.90; H, 7.75. Found: C, 65.82; H, 7.74.
E t h yl Met h yl 6-E t h oxy-3,6-d ih yd r o-4-[3-(p -m et h oxy-
p h en oxy)p r op yl]-2H-p yr a n -2,2-d ica r boxyla te (12). To a
solution of 11 (2.0 g, 5.49 mmoL) in anhydrous THF (50 mL)
was added slowly a solution of sodium hexamethyldisilazide in
THF (16.5 mL, 1.0 M in THF) at -78 °C under N2 during 5 min,
and the pale yellow solution was stirred at the same temperature
for 2 h prior to the slow introduction of neat methyl cyanoformate
(1.44 mL, 18.1 mmol). After being stirred at the same temper-
ature for further hour, the reaction mixture was quenched with
an excess of water at -78 °C, allowed to warm to room
temperature, and diluted with ether. The separated aqueous
layer was extracted with ether, and the combined organic phases
were washed with brine, dried, and concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, elution
with ethyl acetate/hexanes 1:5 containing 2% triethylamine) to
provide 12 as a colorless oil (1.22 g, 53%); IR (film, cm-1) 1770,
6-Eth oxy-3,6-d ih yd r o-4-[3-(p-m eth oxyp h en oxy)p r op yl]-
2H-th iop yr a n -2,2-d im eth a n ol (9). A cold (-15 °C), magneti-
cally stirred solution of 8 (110 mg, 0.24 mmol) in CH2Cl2 (5 mL)
was slowly treated with DIBAL-H (1.45 mL of 1.0 M in hexanes),
allowed to warm to room temperature during 15 min, and
quenched with saturated sodium potassium tartrate solution at
1
1748; H NMR (300 MHz, C6D6) δ 6.82-6.74 (m, 4 H), 5.38 (m,
1 H), 5.16 (d, J ) 1.2 Hz, 1 H), 4.19-3.82 (series of m, 3 H),
3.64 (t, J ) 5.4 Hz, 2 H), 3.40-3.29 (m, 1 H), 3.35 (s, 3 H), 3.34

3786 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
(s, 3 H), 2.89 (dd, J ) 16.9, 9.2 Hz, 1 H), 2.26 (ddd, J ) 16.7,
12.7, 1.8 Hz, 1 H), 2.08 (m, 2 H), 1.73 (m, 2 H), 1.02 (q, J ) 7.0
Hz, 3 H), 0.91 (q, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ
169.5, 169.3, 168.8, 168.7, 154.4, 153.7, 137.4, 119.6, 119.5, 115.7,
114.9, 99.9, 95.7, 95.6, 77.8, 77.6, 67.5, 63.9, 61.7, 61.6, 33.1,
33.0, 32.1, 32.0, 26.8, 15.1, 14.0, 13.7; MS m/z (M+) calcd
422.1940, obsd 422.1952.
1 H), 3.35 (s, 3 H), 2.50 (d, J ) 16.7 Hz, 1 H), 2.02-1.96 (series
of m, 3 H), 1.72-1.63 (m, 2 H), 1.54 (s, 3 H), 1.16 (t, J ) 7.1 Hz,
3 H), 0.92 (t, J ) 7.1 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ 173.8,
154.5, 153.8, 138.2, 121.0, 115.8, 115.0, 96.0, 76.7, 67.7, 63.0,
60.8, 55.2, 36.4, 33.3, 26.9,,25.8, 15.6, 14.1; MS m/z (M+) calcd
378.2042, obsd 378.2049.
For epi-15: 1H NMR (300 MHz, C6D6) δ 6.85-6.74 (m, 4 H),
5.42 (d, J ) 0.4 Hz, 1 H), 5.05 (t, J ) 1.2 Hz, 1 H), 4.10 (m, 2 H),
3.89 (m, 1 H), 3.69 (t, J ) 6.2 Hz, 2 H), 3.35 (s, 3 H), 3.34 (m, 1
H), 2.54 (d, J ) 16.9 Hz, 1 H), 2.19-2.01 (series of m, 2 H), 1.86-
1.77 (series of m, 3 H), 1.45 (s, 3 H), 1.12 (t, J ) 7.0 Hz, 3 H),
1.00 (t, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ 173.9, 154.4,
153.8, 138.5, 119.4, 115.8, 115.0, 95.9, 72.9, 67.8, 63.5, 60.7, 55.2,
35.5, 33.2, 27.0, 26.7, 15.2, 13.9.
6-E t h oxy-3,6-d ih yd r o-4-[3-p -m et h oxyp h en oxy)p r op yl]-
2H-p yr a n -2,2-d im eth a n ol (13). To a solution of 12 (0.721 g,
1.72 mmoL) in anhydrous THF (25 mL) was added lithium
aluminum hydride (1.0 M in THF, 17.2 mL) dropwise at 0 °C.
After completion of the addition, the cooling bath was removed,
and warming to room temperature occurred over 3 h with
continued stirring until no gas was evolved. The reaction mixture
was carefully quenched by the slow addition of saturated Na2-
SO4 solution followed by solid Na2SO4. The white precipitate was
separated by filtration and washed with CH2Cl2. The white filter
cake was ground into a fine powder and extracted with ethyl
acetate overnight. The combined organic layers were concen-
trated under reduced pressure to give 13 as a viscous colorless
syrup (0.418 g, 76%); IR (film, cm-1) 3464, 1508, 1231; 1H NMR
(300 MHz, C6D6) δ 6.78 (m, 4 H), 5.34 (br s, 1 H), 4.86 (br s, 1
H), 3.74-3.15 (series of m, 11 H), 2.86 (br s, 1 H), 2.38-1.84
(m, 4 H), 1.68 (q, J ) 6.0 Hz, 2 H), 1.32 (br s, 1 H), 1.01 (t, J )
6.0 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ 154.5, 153.8, 138.8,
118.7, 115.8, 115.0, 95.2, 75.9, 67.7, 67.3, 66.0, 64.0, 55.2, 33.4,
30.0, 27.1, 15.3; MS m/z (M+) calcd 352.1886, obsd 352.1885.
(2R*,6R*)-6-E t h oxy-3,6-d ih yd r o-4-[3-(p -m et h oxyp h en -
oxy)p r op yl]-2-m eth yl-2H-p yr a n -2-m eth a n ol (16). A stirred
THF solution of 15 (57.6 mg, 0.1523 mmol) in THF (1 mL) was
treated with a solution of lithium aluminum hydride (1.0 M in
THF, 0.31 mL) at -5 to 0 °C dropwise by syringe during 1 min,
and the resulting mixture was stirred at this temperature for 2
h, allowed to warm to room temperature during 4 h, and
carefully quenched with saturated Na2SO4 solution until a white
precipitate formed. After filtration, the filtrate was concentrated
under reduced pressure to yield a colorless residue which was
subjected to flash chromatographic purification to provide 16
(40 mg, 78%) as a colorless oil; IR (film, cm-1) 3475, 1510, 1232;
1H NMR (300 MHz, C6D6) δ 6.84 (m, 4 H), 5.54 (s, 1 H), 5.05 (s,
1 H), 3.85 (m, 1 H), 3.68 (t, J ) 6.3 Hz, 2 H), 3.54 (d, J ) 11.0
Hz, 1 H), 3.40 (s, 3 H), 3.39-3.32 (m, 1 H), 2.41 (d, J ) 17.9 Hz,
1 H), 2.05 (d, J ) 7.6 Hz, 2 H), 1.89 (m, 1 H), 1.73 (m, 2 H), 1.39
E t h yl
(2R*,6R*)-6-E t h oxy-3,6-d ih yd r o-4-(3-(p -m et h -
oxyph en oxy)pr opyl]-2-m eth yl-2H-pyr an -2-car boxylate (15).
A stirred solution of 11 (0.299 g, 0.821 mmol) in anhydrous THF
(5 mL) was treated with a solution of potassium hexamethyld-
isilazide (0.5 M in toluene, 2.5 mL) at -78 °C and stirred at
this temperature for 1 h. The resulting yellow solution was
treated with an excess of methyl iodide (0.5 mL), stirred at -78
°C for 2 h, allowed to warm to room temperature during 1 h,
and quenched with saturated NH4Cl solution (0 °C) followed by
ether. The aqueous phase was extracted with ether, and the
combined organic layers were washed with brine, dried, and
evaporated under reduced pressure. The crude material was
purified by flash chromatography (silica gel, elution with ethyl
acetate/hexanes 1:6) to give the two separable methylated esters
15 and its epimer (0.28 g, 91%), both as colorless oils. Diaste-
reomer 15 predominated by a factor in excess of 10:1.
(d, J ) 17.9 Hz, 2 H), 1.29 (s, 3 H), 1.18 (t, J ) 7.1 Hz, 3 H); 13
C
NMR (75 MHz, C6D6) δ 154.2, 153.5, 137.4, 119.3, 115.5, 114.8,
95.2, 72.3, 70.2, 67.5, 62.8, 55.0, 33.5, 33.4, 26.9, 22.3, 15.3; MS
m/z (M+) calcd 336.1937, obsd 336.1940.
Ack n ow led gm en t. This research was supported by
the National Cancer Institute (CA 12115) and Eli Lilly
and Company. We thank Dr. Kurt Loening for as-
sistance with nomenclature.
1
Su p p or tin g In for m a tion Ava ila ble: High-field H NMR
spectra of those compounds lacking combustion analysis. This
material is available free of charge via the Internet at
http://pubs.acs.org.
For 15: IR (neat, cm-1) 2962, 1738, 1510, 1047; 1H NMR (300
MHz, C6D6) δ 6.65 (m, 4 H), 5.57 (d, J ) 1.0 Hz, 1 H), 5.46 (d, J
) 1.0 Hz, 1 H), 3.94 (m, 3 H), 3.60 (t, J ) 6.3 Hz, 2 H), 3.55 (m,
J O990011E