Stereoselective synthesis of 3-hydroxy-2-aryltetrahydrofurans from β- (triethylsilyl)oxyaldehydes and aryldiazomethanes

Full text of DOI:10.1021/jo991362w

8754
J . Org. Chem. 1999, 64, 8754-8757
Sch em e 1
Ster eoselective Syn th esis of
3-Hyd r oxy-2-a r yltetr a h yd r ofu r a n s fr om
â-(Tr ieth ylsilyl)oxya ld eh yd es a n d
Ar yld ia zom eth a n es
Steven R. Angle* and Martin L. Neitzel
Department of Chemistry, University of
CaliforniasRiverside, Riverside, California 92521-0403
Ta ble 1. Syn th esis of 2-P h en yltetr a h yd r ofu r a n s
Received August 26, 1999
The biological importance of C-aryl glycosides has led
to the development of a large number of synthetic
methods for their construction.1,2 We have recently
reported a new stereoselective synthesis of 2-furanoic
acids from â-(triethylsilyl)oxyaldehydes and R-diazo-
ester,3 and hoped to apply this same strategy to the
synthesis of deoxy C-aryl glycosides. Our progress toward
this goal is presented here with the report of a new
method for the synthesis of 2-aryltetrahydrofurans.
The addition of aryldiazo compounds to aldehydes in
the presence of Lewis acids and lithium salts is a well-
known process that normally affords benzyl ketones.4
This reaction is thought to proceed by addition of the
diazo compound to the aldehyde carbonyl followed by
pinacol- type migration of hydride and loss of nitrogen
to afford ketone 4 (Scheme 1, path b).4a The synthesis of
tetrahydrofurans might by possible via a related pathway
involving activation of a â-(triethylsilyl)oxyaldehyde with
a Lewis acid followed by addition of an aryldiazomethane
to initially give 2, which could then react with the ether
oxygen to afford THF 3 (Scheme 1, pathway a).
In an attempt to test the viability of the THF synthesis,
several Lewis acids (BF3‚OEt2, TiCl4, ZrCl4, SnCl4, SnCl2)
were screened for effectiveness in the reaction of aldehyde
1c (Table 1) and phenyldiazomethane.5 The best results
were obtained with BF3‚OEt2 and TiCl4. Despite the fact
the yields were virtually identical, the TiCl4-mediated
reaction was difficult to purify due to the presence of
myriad byproducts derived from phenyldiazomethane.
Thus, BF3‚OEt2 was the Lewis acid of choice. A brief
survey of the reaction conditions showed 0.4 equiv of
a
The benzyl ketone was not isolated or detected (1H NMR) in
b
this case. Desilylation was necessary for isolation of the ketone.
c Major diastereomer shown. Inseparable mixture of diastereo-
d
mers, see text.
(1) (a) Townsend, L. B. Chemistry of Nucleosides and Nucleotides;
Plenum Press: New York, 1988. (b) Hacksell, U.; Daves, G. D. The
Chemistry and Biochemistry of C-Nucleosides and C-Arylglycosides;
Ellis, G. P., West, G. B., Ed.; Elsevier Science Publishers: London,
1985; Vol. 22, pp 1-65. (c) J aramillo, C.; Knapp, S. Synthesis 1994,
1-20.
(2) For leading references to the synthesis of C-Glycosides see: (a)
Du, Y. G.; Linhardt, R. J .; Vlahov, I. R. Tetrahedron 1998, 54, 9913-
9959. (b) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, 1995. (c) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599.
(d) Calter, M. A.; Zhu, C. J . Org. Chem. 1999, 64, 1415-1419. (e)
Urban, D.; Skrydstrup, T.; Beau, J . M. Chem. Commun. 1998, 955-
956. (f) Kim, G.; Kang, S.; Kim, S. N. Tetrahedron Lett. 1993, 34, 7627-
7628. (g) Maeba, I.; Ito, Y.; Wakimura, M.; Ito, C. Heterocycles 1993,
36, 1617-1623
BF3‚OEt2 at -78 °C with 2.2 equiv of phenyldiaz-
omethane to afford optimal yields of THF 3c.
Table 1 summarizes the results of our study with
phenyldiazomethane and a series of readily available
aldehydes using the optimized reaction conditions. Steric
bulk R to the aldehyde maximized formation of THF
products 3 over benzyl ketones 4. Reaction of 1a with
phenyldiazomethane5 in the presence of BF3‚OEt2 af-
forded THF 3a in 81% yield. Benzyl ketone 4a was not
isolated. R,R-Diethylaldehyde 1b with phenyldiazomethane
afforded THF 3b and benzyl ketone 4b in 73% and 8%
yields, respectively. THF's 3a and 3b were obtained as
single diastereomers (1H NMR and GC-MS analysis).
The less sterically bulky R,R-dimethyl aldehyde 1c af-
forded THF 3c in 62% yield as a 4:1 mixture of diaster-
eomers and benzyl ketone 4c in 15% yield. The major
diastereomer of 3c possessed the trans-orientation be-
tween the hydroxy and phenyl groups, and the minor
diastereomer had these two groups in a cis orientation.
(3) (a) Angle, S. R.; Bernier, D. S.; Chann, K.; J ones, D. E.; Kim, M.
S.; Neitzel, M. L.; White, S. L. Tetrahedron Lett. 1998, 39, 8195-8198.
(b) Angle, S. R.; Wei, G. P.; Ko, Y. K.; Kubo, K. J . Am. Chem. Soc.
1995, 117, 8041-8042. (c) Angle, S. R.; Bernier, D. S.; El-Said, N. A.;
J ones, D. E.; Shaw, S. Z. Tetrahedron Lett. 1998, 39, 3919-3922.
(4) (a) Mahmood, S. J .; Saha, A. K.; Hossain, M. M. Tetrahedron
1998, 54, 349-358. (b) Loechorn, C. A.; Nakajima, M.; McCloskey, P.
J .; Anselme, J . P. J . Org. Chem. 1983, 48, 4407-4410.
(5) (a) Creary, X. J . Am. Chem. Soc. 1980, 102, 1611-1618. (b)
Creary, X. Organic Synthesis 1985, 64, 207-216. (c) Davies, H. W.;
Schwarz, M. J . Org. Chem. 1965, 30, 1242-1244.
10.1021/jo991362w CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/22/1999

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8755
Ta ble 2. Syn th esis of 2-Ar yltetr a h yd r ofu r a n s
F igu r e 1. Key NOEs.
enough to participate in the initial step of reaction, add
to the aldehyde carbonyl, and afford THF 3i in 44% yield.
The stereochemical assignments for THF's 3b-e are
based on H-H NOESY spectra and that for 3i on an
X-ray crystal structure.7 The stereochemical assignments
for the remaining THFs (3a ,g,h ) are based on comparison
of H-H coupling constants to THF's 3b-e and 3i. The
trans orientation of the hydroxyl and phenyl substituents
in 3b and 3c is based on the key NOE enhancements
(from NOESY spectra) depicted in Figure 1. The H(2)-
H(3) coupling constant for 3b and the major diastereomer
of 3c are nearly identical (6.2 and 6.7 Hz) as are the
chemical shifts for the resonances of these two key
hydrogens. The stereochemistry of the trisubstituted
THFs 3d and 3e was based on the NOE enhancements
(from NOESY spectra) shown in Figure 1. In particular,
the NOE between the hydrogens of the phenyl group and
both H(3) and H(4) show these groups to be in a cis
orientation relative to each other. As expected, the two
compounds, 3d and 3e, show nearly identical chemical
shifts and H-H coupling constants for the analogous
hydrogens.
In conclusion, we have developed a novel, one-step
method for the stereoselective synthesis of 4-alkyl-2-aryl-
3-hydroxytetrahydrofurans from R-alkyl-â-(triethylsilyl)-
oxyaldehydes and aryldiazomethanes. With the ready
availability of substituted phenyldiazomethanes, this
method should be adaptable to the synthesis of a wide
variety of deoxy-C-arylglycoside derivatives. Studies to
further examine the origin of the stereoselectivity, scope,
and limitations of the methodology are currently under
investigation.
A study of aldehydes 1d -f (Table 1, entries 4-6)
showed that as the size of the R-substituent decreased,
the yield of THF's 3 decreased as did the diastereoselec-
tivity. For example, the R-tert-butyl aldehyde 1d gave
THF 3d in 59% yield as a single diastereomer (GC-MS),
and the R-isopropyl aldehyde 1e afforded 3e in 38% yield
as a 17:3:1 mixture (GC analysis) of three diastereomers.
In both cases, the major phenyl THF diastereomer
possessed the 2,3-trans-3,4-cis orientation of substituents
about the tetrahydrofuran. The stereochemistry of the
minor diastereomers of 3e was not determined. In
addition to the THF products, the benzyl ketones 4d and
4e were isolated in 30% and 38% yields, respectively.
Treatment of R-methylaldehyde 1f afforded 2-phenyl
THF 3f in 26% yield (11:5:2:1 inseparable mixture of four
diastereomers, GC-MS) and benzyl ketone 4f in 60%
yield. The relative stereochemistry of the four diastereo-
mers was not assigned.
The higher yields of THFs derived from aldehydes
possessing bulky R-substituents, and decreased yield for
those with smaller R-substituents, coupled with the
reverse trend for yield of benzyl ketones 4 is consistent
with the bifurcated reaction pathway shown in Scheme
1, where a Thorpe-Ingold6 effect might divert the reac-
tion manifold toward C-O bond formation (THF products
3) by facilitating cyclization and/or hindering hydrogen
migration. In the absence of bulky substituents (Thorpe-
Ingold effect), the hydride migration is the dominant
reaction pathway (b, Scheme 1) and the benzyl ketones
4 are formed.
The stereoselectivity is consistent with that seen in the
reaction of diazoesters with these same substrates.3
Particularly intriguing is the selectivity for a trans
orientation between the phenyl and alcohol functional-
ities. This relationship appears to be kinetic in origin
since resubmission of each purified diastereomer of THF
3c to the reaction conditions resulted in recovered THF
Exp er im en ta l Section 8
Gen er a l P r oced u r e for P r ep a r a tion of R-Alk yl(tr ieth -
ylsilyl)oxya ld eh yd es (1a -f) fr om t h e Cor r esp on d in g
2-Alk yl-1,3-p r op a n ed iols. To each respective 2-alkyl-1,3-pro-
panediol (1.0 equiv) in CH2Cl2 (0.2 M) were added triethylamine
(1.1 equiv) and triethylsilyl chloride (0.9 equiv). After 1 h at room
temperature, the CH2Cl2 was removed in vaccuo, diethyl ether
(100 mL) was added, and the resulting suspension was filtered
to remove the amine hydrochloride. The ether solution was
washed with water (3 × 50 mL) to remove unreacted diol, dried
(MgSO4), and concentrated to afford the crude monosilylated
2-alkyl-1,3-propanediols. Dess-Martin (1.4 equiv of oxidant)
oxidation of the monosilylated 2-alkyl-1,3-propanediols in CH2-
Cl2 (0.2 M) for 2-3 h, followed by removal of the solvent and
flash chromatography (silica gel, hexanes/ethyl acetate, 3%
triethylamine) afforded aldehydes 1a -f as clear oils in the yields
indicated.
1
with no epimerization evident by H NMR or capillary
GC analysis.
Substituted phenyldiazomethanes can also be em-
ployed in the reaction as shown in Table 2. Three
representative aryldiazomethanes (p-CH3, p-Cl, p-NO2)5
were screened with aldehyde 1b. All three substituted
phenyldiazo compounds afforded THF products. The
decreased yield of 3g (p-CH3) relative to the parent (R )
H) may be due to the instability of the tolyldiazomethane
relative to phenyldiazomethane. In the case of the
p-nitrophenyldiazomethane, the corresponding benzyl
ketone was isolated in 7% yield. It is worth noting that
the p-nitrophenyldiazomethane was still nucleophilic
(7) THF 3a showed a cross-peak in the NOESY spectrum for the
resonances corresponding to the hydroxyl hydrogen and the C(2)-
hydrogen, supportive of the assigned cis orientation between the OH
and the C(2)-hydrogen. See the Supporting Information for details.
(8) Gen er a l In for m a tion . Capillary GC was carried out using an
FID detector on a 25 m HP-102 (methyl silicone) column. The following
standard GC parameters were used: flow rate ) 60 mL/min; injector
temperature ) 235 °C; detector temperature ) 275 °C; temperature
program ) 40-280 °C at 5 °C/min, initial time ) 1 min.
(6) (a) Curtin, M. L.; Okamura, W. H. J . Org. Chem. 1990, 55, 5278-
5287. (b) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224-
232. (c) J ung, M. E.; Marquez, R. Tetrahedron Lett. 1997, 38, 6521-
6524.

8756 J . Org. Chem., Vol. 64, No. 23, 1999
Notes
2,2-Dip h en yl-3-[(tr ieth lysilyl)oxy]p r op a n a ld eh yd e (1a ):
clear oil (78%); 1H NMR (300 MHz, benzene-d6)δ 9.84 (s, 1H),
7.21-7.03 (m, 10H), 4.46 (s, 2H), 0.83 (t, J ) 8.0 Hz, 9H), 0.41
(q, J ) 7.9 Hz, 6H); 13C NMR (75 MHz, benzene-d6)δ 198.5,
139.7, 129.8, 128.6, 127.4, 66.1, 65.4, 6.8, 4.5; IR (neat) 2955,
1721, 1111, 1012, 752 cm-1; MS (EI, 50 eV) m/z 340 (7, M+),
311 (81), 281 (35), 180 (73), 167 (100); HRMS calcd for C21H28O2-
Si 340.1859, found 340.1854.
(2S*,3R*)-4,4-Dieth yl-3-h yd r oxy-2-p h en yltetr a h yd r ofu -
r a n (3b): clear oil; 1H NMR (300 MHz, benzene-d6) δ 7.51 (d, J
) 7.7 Hz, 2H), 7.23 (t, J ) 7.4 Hz, 2H) 7.13 (partially obscured
t, J ) 7.2 Hz, 1H), 4.60 (d, J ) 6.2 Hz, 1H), 3.68 (ABq, J ) 9.2
Hz, ∆ν ) 8.9 Hz, 2H), 3.47 (t, J ) 6.2 Hz, 1H), 1.48 (dq, J )
14.9, 7.7 Hz, 1H), 1.39-1.25 (m, 2H), 1.15 (dq, J ) 14.9, 7.7 Hz,
1H), 0.92 (d, J ) 6.2 Hz, 1H), 0.74 (t, J ) 7.4 Hz, 3H), 0.67 (t, J
) 7.4 Hz, 3H); 13C NMR (75 MHz, benzene-d6) δ 142.9, 128.9,
127.9, 126.2, 87.3, 85.7, 77.2, 48.5, 28.0, 22.3, 8.9, 8.8; IR (neat)
3428, 2965, 1455, 1062, 699 cm-1; MS (EI, 20 eV) m/z 220 (3,
M+), 114 (72), 107 (61), 91 (20), 85(100); HRMS calcd for
C14H20O2 220.1463, found 220.1470.
2,2-Diet h yl-3-[(t r iet h lysilyl)oxy]p r op a n a ld eh yd e (1b ):
1
clear oil (86%); H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 3.66
(s, 2H), 1.66-1.48 (m, 4H), 0.94 (t, J ) 8.0 Hz, 9H), 0.81 (t, J )
7.4 Hz, 6H), 0.57 (q, J ) 8.0 Hz, 6H); 13C NMR (75 MHz,
benzene-d6) δ 205.1, 63.2, 54.5, 22.0, 7.8, 7.0, 4.6 cm-1 IR (neat)
2959, 1729, 1459, 1101, 728; MS (CI, NH3) m/z 245 (25, MH+),
227 (52), 215 (100), 117 (57); HRMS calcd for C13H29O2Si (M +
H) 245.1937, found 245.1948.
(2S*,3R*)- a n d (2R*,3R*)-4,4-Dim eth yl-3-h yd r oxy-2-p h e-
n yltetr a h yd r ofu r a n (3c). The diastereomers were separated
by flash chromatography (4:1 mixture based on isolated yields).
Major diastereomer (2S*,3R*): clear oil; 1H NMR (300 MHz,
CDCl3)δ 7.29-7.13 (m, 5H), 4.50 (d, J ) 6.7 Hz, 1H), 3.69 (ABq,
J ) 8.7 Hz, ∆ν ) 12.7 Hz, 2H), 3.54 (d, J ) 5.7 Hz, 1H), 1.75
(br. s, 1H), 1.00 (s, 3H), 0.94 (s, 3H); 13C NMR (75 MHz, CDCl3)δ
141.5, 128.4, 127.5, 125.5, 86.0, 85.5, 79.5, 42.0, 24.6, 19.6; IR
(Neat) 3412, 2931, 1452, 1050, 700 cm-1; MS (EI 20 eV) m/z 192
(13, M+), 107 (100); HRMS calcd for C12H16O2 192.1150, found
192.1149. Minor diastereomer (2R*,3R*): white solid; mp 68-
74 °C; 1H NMR (300 MHz, CDCl3) δ 7.31-7.16 (m, 5H), 5.19 (d,
J ) 3.6 Hz, 1H), 3.85 (d, J ) 7.7 Hz, 1H), 3.68 (d, J ) 3.6 Hz,
1H), 3.61 (d, J ) 7.7 Hz, 1H), 1.07 (d, J ) 18.5 Hz, 6H), 1.00 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 137.7, 128.5, 127.7, 126.6, 84.4,
80.5, 78.9, 44.1, 25.7, 19.3; IR (KBr) 3436, 2961, 1055, 737, 699
cm-1; MS (EI) m/z 192 (5, M+), 107 (100), 86 (54), 71 (96); HRMS
calcd for C12H16O2 192.1150, found 192.1151.
2,2-Dim eth yl-3-[(tr ieth lysilyl)oxy]p r op a n a ld eh yd e (1c):
1
clear oil (84%); H NMR (300 MHz, CDCl3) δ 9.57 (s, 1H), 3.60
(s, 2H), 1.04 (s, 6H), 0.93 (t, J ) 8.0 Hz, 9H), 0.57 (q, J ) 7.9
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 206.1, 68.2, 48.1, 18.5,
6.6, 4.3; IR (neat) 2957, 1733, 1460, 1102, 811, 743 cm-1
.
2-(Dim e t h yl)e t h yl-3-[(t r ie t h lysilyl)oxy]p r op a n a ld e -
1
h yd e (1d ): yellow oil (89%); H NMR (300 MHz, benzene-d6) δ
9.71 (d, J ) 3.6 Hz, 1H), 3.99 (dd, J ) 10.0, 9.0 Hz, 1H), 3.71
(dd, J ) 10.3, 4.1 Hz, 1H), 2.19-2.13 (m, 1H), 0.94 (t, J ) 8.0
Hz, 9H), 0.80 (s, 9H), 0.53 (q, J ) 8.0 Hz, 6H); 13C NMR (75
MHz, benzene-d6) δ 203.6, 63.5, 59.8, 32.5, 28.2, 6.9, 4.7 cm-1
;
IR (neat) 2959, 1726, 1093, 744; MS (CI, NH3) m/z 245 (100,
MH+), 159 (11), 132 (30), 120 (21); HRMS calcd for C13H29O2Si
(M + H) 245.1937, found 245.1945.
2-(Meth yl)eth yl-3-[(tr ieth lysilyl)oxy]pr opan aldeh yde (1e):
clear oil (67%); 1H NMR (300 MHz, CDCl3)δ 9.72 (s, 1H), 3.96
(dd, J ) 10.2, 7.3 Hz, 1H), 3.83 (dd, J ) 10.3, 4.8 Hz, 1H), 2.26-
2.18 (m, 1H), 2.16-2.05 (m, 1H), 1.00-0.91 (m, 15H), 0.58 (q, J
) 8.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 205.2, 60.5, 60.4,
25.7, 20.4, 20.1, 6.7, 4.3; IR (neat) 2958, 2877, 1726, 1107, 1016,
745 cm-1; MS (CI, NH3) m/z 248 (80, M + NH4+), 231 (100, MH+),
201 (15), 132 (54), 120 (7); HRMS calcd for C12H27O2Si (M + H)
231.1780, found 231.1781.
(2S*,3R*,4R*)-4-(Dim eth yl)eth yl-3-h yd r oxy-2-p h en yltet-
r a h yd r ofu r a n (3d ): white solid; mp 117-118 °C; 1H NMR (300
MHz, benzene-d6)δ 7.31 (d, J ) 7.2 Hz, 2H), 7.18 (partially
obscured t, J ) 7.2 Hz, 2H), 7.07 (t, J ) 7.2 Hz, 1H), 4.84 (s,
1H), 4.13 (d, J ) 7.7 Hz), 4.05 (dd, J ) 11.0, 7.5 Hz), 3.99 (t, J
) 4.6 Hz, 1H), 1.76 (ddd, J ) 12.1, 8.2, 4.6 Hz, 1H), 1.14 (d J )
5.6 Hz, 1H), 0.88 (s, 9H); 13C NMR (75 MHz, CDCl3)δ 141.3,
128.3, 127.2, 125.0, 89.7, 80.5, 68.2, 51.4, 30.8, 29.5; IR (KBr)
3409, 3287, 2950, 1448, 1364, 1060, 740 cm-1; MS (EI 20 eV)
m/z 220 (2, M+), 163 (42), 107 (100); HRMS calcd for C14H20O2
220.1463, found 220.1468.
2-Meth yl-3-[(tr ieth lysilyl)oxy]p r op a n a ld eh yd e (1f): clear
oil (62%); 1H NMR (300 MHz, benzene-d6) δ 9.50 (s, 1H), 3.50
(m, 2H), 2.14-2.03 (m, 1H), 0.92 (t, J ) 8.0 Hz, 9H), 0.85 (d, J
) 6.7 Hz, 3H), 0.50 (q, J ) 7.9 Hz, 6H); 13C NMR (75 MHz,
benzene-d6) δ 202.6, 63.2, 48.9, 10.3, 6.9, 4.6; IR (neat) 2956,
(2S*,3R*,4R*)-3-H yd r oxy-4-(m et h yl)et h yl-2-p h en ylt et -
r a h yd r ofu r a n (3e). Obtained as a 17:3:1 mixture of diastereo-
mers. Flash chromatography afforded the major diastereomer
and a mixture of two minor diastereomers in a 1:3 ratio (GC,
tR ) 33.7 and 34.0 min, respectively). Major diastereomer
1736, 1458, 1097, 744 cm-1
.
Gen er a l P r oced u r e for t h e R ea ct ion of Ar yld ia zo-
.
m eth a n e w ith Ald eh yd es 1. Freshly distilled BF3 Et2O (0.80
1
(2S*,3R*,4R*): white solid; mp 87-89 °C; H NMR (300 MHz,
mmol) was added dropwise over 1 h to a -78 °C solution of
aldehyde 1 (2.0 mmol), aryldiazomethane (4.4 mmol; CAU-
TION: diazo compounds are potentially explosive and toxic), and
CH2Cl2 (40 mL). After the solution was stirred for an additional
30-180 min, the disappearance of the red color of the aryldia-
zomethanes signaled completion of the reaction. This was
verified by TLC. The reaction mixture was poured into a stirring
solution of saturated aqueous NaHCO3 (50 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 100 mL), and the combined
organic extracts were dried (MgSO4) and concentrated to afford
crude products. Flash chromatography (silica gel, gradient
40:1, 7:1, 3:1 hexanes/ethyl acetate) afforded furans 3 and benzyl
ketones 4. Chromatography fractions of impure THFs 3 were
treated with pyridine‚HF (1:1 w/v) in CH3CN. Aqueous workup
followed by flash chromatography afforded additional THF
product (3-15%). In the case of ketones 4b and 4e, impurities
were present after the initial chromatography, and the impure
ketone was treated with pyridine‚HF (1:1 w/v) in CH3CN.
Aqueous workup followed by flash chromatography afforded the
ketones in the yields indicated in Table 1.
(2S*,3R*)-4,4-Dip h en yl-3-h yd r oxy-2-p h en yltetr a h yd r o-
fu r a n (3a ): white solid; mp 132-133 °C; 1H NMR (300 MHz,
CDCl3) δ 7.43-7.32 (m, 15H), 5.03 (d, J ) 9.2 Hz, 1H), 4.74 (dd,
J ) 10.8, 8.2 Hz, 1H), 4.56 (d, J ) 8.2 Hz, 1H), 4.44 (d, J ) 9.2
Hz, 1H), 1.56 (d, J ) 10.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 143.8, 140.9, 140.4, 129.2, 128.6, 128.5, 128.5, 127.8, 127.3,
126.9, 125.7, 83.5, 81.8, 77.2, 57.3; IR (KBr) 3515, 3481, 3030,
2938, 2861, 2355, 1494, 1118 cm-1; MS (CI, NH3) m/z 334 (74,
M + NH4+), 299 (24), 180 (100), 105 (37), 91 (33); HRMS calcd
for C22H24O2N (M + NH4) 334.1807, found 334.1804.
benzene-d6) δ 7.44 (d, J ) 7.7 Hz, 2H), 7.33-7.27 (m, 2H), 7.19
(t, J ) 7.2 Hz, 1H), 5.20 (s, 1H), 4.30 (t, J ) 8.0 Hz, 1H), 4.11 (d,
J ) 4.1 Hz, 1H), 3.97 (dd, J ) 10.8, 7.7 Hz, 1H), 2.11 (s, 1H),
1.97-1.85 (m, 1H), 1.83-1.72 (m, 1H), 0.87 (d, J ) 6.7 Hz, 3H),
0.76 (d, J ) 6.7 Hz, 3H); 13C NMR (75 MHz, benzene-d6) δ 142.3,
128.5, 127.3, 125.5, 89.8, 79.2, 71.9, 50.2, 25.6, 21.7, 21.5; IR
(KBr) 3424, 3287, 2963, 1078, 1043, 919, 744 cm-1; MS (EI, 20
eV) m/z 207 (3, MH+), 162 (18), 107 (100), 100 (19), 91 (11);
HRMS calcd for C13H19O2 (M + H) 207.1385, found 207.1387.
Inseparable mixture of minor diastereomers (3:1): white solid;
mp 49-54 °C. Major component (GC tR ) 34.0 min): 1H NMR
(300 MHz, benzene-d6)δ 7.47 (d, J ) 7.2 Hz, 2H), 7.24-7.12 (m,
overlaps with diastereomer, 3H), 4.52 (d, J ) 7.2 Hz, 1H), 3.98
(t, J ) 8.7 Hz, 1H), 3.69 (dd, J ) 9.2, 7.2 Hz, 1H), 3.51 (dd, J )
13.1, 7.2 Hz, 1H), 1.76-1.66 (m, 1H), 1.46-1.29 (m, overlaps
with diastereomer, 1H), 0.97 (d, J ) 6.2 Hz, 1H), 0.81 (d, J )
6.7 Hz, 3H), 0.67 (d, J ) 6.7 Hz, overlaps with diastereomer,
3H). Minor component (GC tR ) 33.7 min): 1H NMR (300 MHz,
benzene-d6)δ 7.36 (d, J ) 7.7 Hz, 2H), 7.24-7.08 (m, overlaps
with diastereomer, 3H), 4.57 (d, J ) 4.6 Hz, 1H), 4.20 (t, J )
8.2 Hz, 1H), 3.84 (t, J ) 3.1 Hz, 1H), 3.36 (dd, J ) 8.7, 7.7 Hz,
1H), 1.91-1.81 (m, 1H), 1.38-1.24 (m, overlaps with diastereo-
mer, 1H), 0.88 (d, J ) 6.7 Hz, 3H), 0.67 (d, J ) 6.7 Hz, overlaps
with diastereomer, 3H); 13C NMR (75 MHz, benzene-d6, 3:1
mixture of diastereomers)δ 141.8, 137.8, 128.8, 128.6, 128.5,
127.4, 127.1, 126.1, 86.8, 84.8, 82.7, 77.6, 70.9, 70.6, 55.8, 54.1,
30.7, 30.0, 21.3, 20.8, 20.7; IR (KBr) 3418, 2958, 2872, 1453,
1029, 700 cm-1; MS (EI, 20 eV) m/z 206 (4, M+), 162 (17), 107
(100); HRMS calcd for C13H18O2 206.1307, found 206.1313.

Notes
3-Hyd r oxy-4-m eth yl-2-p h en yltetr a h yd r ofu r a n (3g). Mix-
J . Org. Chem., Vol. 64, No. 23, 1999 8757
3,3-Dieth yl-4-h yd r oxy-1-p h en yl-2-bu ta n on e (4b): clear oil;
1H NMR (300 MHz, CDCl3) δ 7.35-7.17 (m, 5H), 3.79 (s, 2H),
3.74 (d, J ) 6.2 Hz, 2H), 1.89 (t, J ) 6.4 Hz, 1H), 1.83-1.64 (m,
4H), 0.86 (t, J ) 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 213.7,
134.2, 129.8, 128.4, 126.8, 63.7, 56.7, 44.3, 25.4, 8.5; IR (neat)
3662, 2963, 1708, 1031, 722 cm-1; MS (CI, NH3) m/z 238 (35, M
+ NH4+), 221 (100, MH+), 91 (42); HRMS calcd for C14H21O2 (M
+ H) 221.1542, found 221.1534.
3,3-Dim et h yl-1-p h en yl-4-(t r iet h lysilyl)oxy-2-b u t a n on e
(4c): clear oil; 1H NMR (300 MHz, CDCl3) δ 7.36-7.17 (m, 5H),
3.89 (s, 2H), 3.69 (s, 2H), 1.19 (s, 6H), 0.99 (t, J ) 8.0 Hz, 9H),
0.64 (q, J ) 8.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 212.0,
134.9, 129.7, 128.2, 126.5, 70.1, 49.8, 44.9, 21.6, 6.8, 4.3; IR (neat)
2957, 1715, 1099, 725; cm-1; MS (EI, 20 eV) m/z 306 (5, M+),
277 (100), 219 (39), 187 (48), 159 (50), 115 (46); HRMS calcd for
C18H30O2Si 306.2015, found 306.2018.
ture of diastereomers (11:5:2:1 ratio). Flash chromatography
afforded a minor component (the 2 in the 11:5:2:1 mixture)
analytically pure and a mixture of three diastereomers in a ratio
of 11:5:1 (GC, tR ) 20.5, 20.0, 19.7 min respectively). Three-
component mixture (11:5:1): clear oil. Major component (GC, tR
) 20.5 min): 1H NMR (300 MHz, benzene-d6, mixture of
diastereomers) δ 7.33 (d, J ) 7.7 Hz, 2H), 7.23-7.07 (m, overlaps
with diastereomer, 3H), 4.83 (d, 1H), 3.56 (dd, J ) 9.8, 8.2 Hz,
1H), 1.99-1.82 (m, overlaps with diastereomer, 1H), 1.03 (d, J
) 4.6 Hz, 1H), 0.73 (d, J ) 7.2 Hz, overlaps with diastereomer,
3H). Second component (GC, tR ) 20.0 min, 5 in the 11:5:1
mixture): 1H NMR (300 MHz, benzene-d6, mixture of diaster-
eomers) δ 7.45 (d, J ) 7.2 Hz, 2H), 7.23-7.07 (m, overlaps with
diastereomer, 3H), 4.59 (d, J ) 6.7 Hz, 1H), 3.98 (t, J ) 8.0 Hz,
overlaps with diastereomer, 1H), 3.47 (apparent t, J ) 8.0 Hz,
1H), 3.30 (q, J ) 6.3 Hz, 1H), 1.99-1.82 (m, overlaps with
diastereomer, 1H), 1.12 (d, J ) 5.1 Hz, 1H), 0.74 (d, J ) 6.7 Hz,
overlaps with diastereomer, 3H); 13C NMR (75 MHz, benzene-
d6, mixture of 3 diastereomers)δ 142.5, 142.2, 128.5, 128.5, 127.3,
126.0, 125.8, 88.1, 86.4, 85.6, 80.7, 73.6, 73.3, 42.4, 36.9, 15.4,
9.8; IR (KBr) 3417, 2932, 1453, 1048, 700 cm-1; MS (CI, NH3)
m/z 196 (100, M + NH4+), 179 (93, MH+), 134 (42), 107 (30), 91
(54). Minor component (the 2 in the 11:5:2:1 mixture): clear oil;
1H NMR (300 MHz, benzene-d6) δ 7.32 (d, J ) 7.2 Hz, 2H), 7.19-
7.05 (m, 3H), 4.78 (d, J ) 4.1 Hz, 1H), 4.24 (dd, J ) 8.2, 6.7 Hz,
1H), 3.62 (apparent dd, J ) 6.2, 3.6 Hz, 1H), 3.33 (dd, J ) 8.2,
4.6 Hz, 1H), 2.20-2.08 (m, 1H), 0.77 (d, J ) 4.1 Hz, 1H), 0.74
(d, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, benzene-d6) δ 138.2,
128.8, 128.5, 127.3, 83.4, 80.1, 73.8, 41.9, 16.6; IR (neat) 3425,
2963, 1453, 1045, 700 cm-1; MS (CI, NH3) m/z 196 (34, M +
NH4+), 179 (100, M + H), 107 (37), 91 (62); HRMS calcd for
C11H15O2 (M + H) 179.1072, found 179.1070.
(2S*,3R*)-4,4-Dieth yl-3-h yd r oxy-2-(4-m eth ylp h en yl)tet-
r a h yd r ofu r a n (3g): white solid; mp 66 °C; 1H NMR (500 MHz,
benzene-d6) δ 7.45 (d, J ) 8.3 Hz, 2H), 7.07 (d, J ) 7.8 Hz, 2H),
4.61 (d, J ) 6.4 Hz, 1H), 3.69 (ABq, J ) 9.1 Hz, ∆ν ) 21.9 Hz,
2H), 3.51 (t, J ) 6.1 Hz, 1H), 2.14 (s, 3H), 1.48 (dq, J ) 14.5, 7.3
Hz, 1H), 1.37-1.29 (m, 2H), 1.17 (dq, J ) 14.4, 7.2 Hz, 1H), 0.96
(d, J ) 5.9 Hz, 1H), 0.73 (t, J ) 7.6 Hz, 3H), 0.68 (t, J ) 7.3 Hz,
3H); 13C NMR (125 MHz, benzene-d6) δ 139.4, 136.8, 129.3,
126.0, 87.0, 85.2, 76.9, 48.1, 27.7, 21.9, 21.1, 8.6, 8.5; IR (KBr)
3404, 2961, 2360, 1456, 1049, 819 cm-1; MS (EI, 20 eV) m/z 234
(4, M+), 121 (100), 119 (14); HRMS calcd for C15H22O2 234.1620,
found 234.1618.
(2S*,3R*)-2-(4-Ch lor op h en yl)-4,4-d iet h yl-3-h yd r oxyt et -
r a h yd r ofu r a n (3h ): white solid; mp 86 °C; 1H NMR (300 MHz,
benzene-d6) δ 7.24-7.16 (m, 4H), 4.43 (d, J ) 6.7 Hz, 1H), 3.60
(s, 2H), 3.31 (t, J ) 6.2 Hz, 1H), 1.43 (dq, J ) 14.6, 7.6 Hz, 1H),
1.33-1.17 (m, 2H), 0.91 (d, J ) 6.2 Hz, 1H), 1.08 (dq, J ) 14.5,
7.3 Hz, 1H), 0.71 (t, J ) 7.4 Hz, 3H), 0.64 (t, J ) 7.4 Hz, 3H);
13C NMR (75 MHz, benzene-d6) δ 140.9, 133.2, 128.7, 127.2, 86.0,
85.1, 76.8, 48.1, 27.6, 21.8, 8.5, 8.4; IR (KBr) 3408, 2965, 2876,
1492, 1098, 826 cm-1; MS (EI) m/z 255 (13, MH+), 141 (20), 114
(37), 85 (100); HRMS calcd for C14H20O2Cl (M + H) 255.1153,
found 255.1152.
3-(Dim eth yl)eth yl-4-h yd r oxy-1-p h en yl-2-bu ta n on e (4d ):
white solid; mp 79-81 °C; 1H NMR (300 MHz, benzene-d6) δ
7.19-7.04 (m, 5H), 3.81 (dt, J ) 10.0, 4.4 Hz, 1H), 3.63 (s, 2H),
3.47 (d, J ) 9.75 Hz, 1H), 2.62 (dd, J ) 10.3, 4.1 Hz, 1H), 1.76
(s, 1H), 0.82 (s, 9H); 13C NMR (75 MHz, benzene-d6) δ 211.9,
135.0, 130.8, 128.9, 127.3, 62.7, 62.6, 54.6, 33.2, 28.8; IR (neat)
3416, 2959, 1712, 1367, 1039, 700 cm-1; MS (EI, 20 eV) m/z 221
(7, MH+), 129 (100), 91 (41), 83 (75), 57 (99); HRMS calcd for
C14H20O2 220.1463, found 220.14620.
4-Hydr oxy-3-(m eth yl)eth yl-1-ph en yl-2-bu tan on e (4e): clear
oil; H NMR (300 MHz, CDCl3)δ 7.36-7.18 (m, 5H), 3.90-3.81
1
(m, 1H), 3.79 (s, 2H), 3.74-3.65 (m, 1H), 2.66 (dq, J ) 8.0, 4.0
Hz, 1H), 2.17-2.06 (m, 1H), 1.87 (dd, J ) 6.7, 5.1 Hz, 1H), 0.93
(d, J ) 6.7 Hz, 6H); 13C NMR (75 MHz, benzene-d6)δ 211.1,
134.5, 130.2, 128.7, 127.0, 62.0, 59.7, 51.5, 27.7, 21.2, 19.9; IR
(neat) 3422, 2961, 1708, 1057, 700 cm-1; MS (EI, 20 eV) m/z 206
(8, M+), 115 (90), 91 (31), 85 (35), 69 (100), 57 (36); HRMS calcd
for C13H18O2 206.1307, found 206.1306.
3-Meth yl-1-p h en yl-4-(tr ieth lysilyl)oxy-2-bu ta n on e (4f):
clear oil; H NMR (300 MHz, benzene-d6) δ 7.15-7.03 (m, 5H),
1
3.70 (dd, J ) 9.7, 7.7 Hz, 1H), 3.57 (ABq, J ) 15.4, ∆ν ) 27.3,
2H), 3.47 (dd, J ) 9.8, 5.6 Hz, 1H), 2.76-2.65 (m, 1H), 0.95 (t,
J ) 8.0 Hz, 6H), 0.86 (d, J ) 6.7 Hz, 3H), 0.53 (q, J ) 7.9 Hz,
9H); 13C NMR (75 MHz, benzene-d6) δ 208.9, 134.9, 129.9, 128.7,
126.9, 65.7, 50.2, 47.8, 13.3, 7.0, 4.6; IR (neat) 2955, 2876, 1714,
1097, 730 cm-1; MS (CI, NH3) m/z 293 (100, MH+), 263 (46), 91
(52); HRMS calcd for C17H29O2Si (M + H) 293.1937, found
293.1925.
3,3-Diet h yl-1-(4-n it r op h en yl)-4-(t r iet h ylsilyl)oxy-2-b u -
ta n on e (4i): clear oil; 7% yield; 1H NMR (300 MHz, benzene-
d6) δ 7.87(d, J ) 9.2 Hz, 2H), 6.85 (d, J ) 8.7 Hz, 2H), 3.62 (s,
2H), 3.38 (s, 2H), 1.71-1.58 (m, 2H), 1.49-1.37 (m, 2H), 0.94 (t,
J ) 8.0 Hz, 9H), 0.66 (t, J ) 7.5 Hz, 6H), 0.52 (q, J ) 7.9 Hz,
6H); 13C NMR (75 MHz, benzene-d6) δ 208.9, 147.2, 142.4, 130.8,
123.3, 63.5, 57.1, 44.3, 23.8, 8.2, 7.0, 4.5; IR (neat) 2960, 1521,
1347, 729 cm-1; MS (CI, NH3) m/z 380 (91, MH+), 350 (10), 132
(100); HRMS calcd for C20H34NO4Si (M + H) 380.2257, found
380.2255.
(2S*,3R*)-4,4-Dieth yl-3-h ydr oxy-2-(4-n itr oph en yl)tetr ah y-
1
d r ofu r a n (3i): white solid; mp 85-87 °C; H NMR (300 MHz,
Ack n ow led gm en t. We thank The National Science
Foundation CHE-9528266 for financial support.
benzene-d6) δ 7.91 (d, J ) 8.7 Hz, 2H), 7.19 (partially obscured
d, J ) 9.8 Hz, 2H), 4.39 (d, J ) 6.7 Hz, 1H), 3.56 (s, 2H), 3.21 (t,
J ) 6.4 Hz, 1H), 1.38 (dq, J ) 15.1, 7.7 Hz, 1H), 1.30-1.10 (m,
2H), 1.0 (dq, J ) 14.6, 7.2 Hz, 1H), 0.84 (d, J ) 6.2 Hz, 1H),
0.70 (t, J ) 7.4 Hz, 3H), 0.61 (t, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, benzene-d6) δ 149.4, 147.6, 125.9, 123.6, 85.6, 84.9, 76.8,
48.3, 27.4, 21.8, 8.5, 8.4; IR (KBr) 3566, 2960, 2874, 1508, 1348
cm-1; MS (EI) m/z 266 (24, MH+), 114 (20), 85 (100); HRMS calcd
for C14H20NO4 (M + H) 266.1392, found 266.1398.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for all new compounds, NOESY spectra for 3a -
e, and X-ray data for 3i. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O991362W