S.E. Kephart et al. / Tetrahedron xxx (2016) 1e6
5
2H), 7.23e7.30 (m, 1H), 6.70 (d, J¼16.3 Hz, 1H), 6.58 (d, J¼16.3 Hz,
1H), 4.92 (d, J¼7.8 Hz, 2H), 4.82 (d, J¼7.8 Hz, 2H), 2.15 (s, 3H). 13C
added, followed by NaOH (760 mg, 19 mmol). The solution was
heated at 70 ꢀC for 60 min and a 0.25 mL aliquot was removed and
concentrated to dryness. Complete hydrolysis was observed by
checking the 1H NMR of this water soluble intermediate. 1H NMR
NMR (101 MHz, CDCl3)
d 169.3, 135.7, 130.9, 128.5, 128.1, 126.8,
126.6, 81.0, 78.8, 21.0.
(400 MHz, CDCl3)
d 7.23e7.40 (m, 5H), 4.62e4.73 (m, 2H), 4.33 (d,
4.2.3. (E)-3-Styryloxetane (7a). A 1 L round bottom flask was
charged with 6 (15 g, 69 mmol, 70:1 mixture of trans to cis) and dry
1,4-dioxane (300 mL). N2 was bubbled through the solution for
10 min to deoxygenate the solvent. Pd(OAc)2 (154 mg, 0.690 mmol)
and BF4HP(nBu)3 (798 mg, 2.75 mmol) were added followed by
Et3N (31 mL, 240 mmol). After stirring at room temperature for
5 min, the flask was fitted with a reflux condenser and formic acid
(9.1 mL, 240 mmol) was added. The reaction was heated to reflux
with the oil bath temperature set at 110 ꢀC. After 35 min, the re-
action was checked by TLC (5% EtOAc in heptane) which showed the
reaction to be complete. [NOTE: A short reaction time of 35e50 min
is important to avoid over reduction.] The product spot elutes
slightly higher than the starting material on TLC using 5% EtOAc in
heptane. The reaction mixture was cooled to room temperature and
poured into satd aqueous NaCl (80 mL) plus water (80 mL) and the
organics extracted with EtOAc (ꢂ3). The combined organic layer
was washed with satd aqueous NaCl (ꢂ2), dried over MgSO4 and
concentrated to a yellow oil. The oil was purified via flash chro-
matography eluting with a gradient of 1e20% EtOAc in heptane.
Fractions containing 7a and 7b were collected and concentrated to
afford 10 g (91%) as a 3: 1 mixture of isomers. 7a 1H NMR (400 MHz,
J¼6.97 Hz, 1H), 4.26 (dd, J¼6.4, 8.1 Hz, 1H), 3.98 (q, J¼8.0 Hz, 2H),
2.98e3.12 (m, 1H).
4.2.6. 3-((2RS,3RS)-3-Phenyloxiran-2-yl)oxetane (10). 7a (6.5 g,
40 mmol) was dissolved in EtOAc (130 mL) and the mixture was
cooled to 0 ꢀC. mCPBA (21 g of 80%, 97 mmol) was added and the
reaction was allowed to warm to room temperature and stir for
16 h. The reaction was judged complete by TLC (20% EtOAc in
heptane) based on consumption of the starting material and for-
mation of a new, weakly UV active spot formed at lower Rf (0.4 in
20% EtOAc in heptane), staining pink with PAA. The reaction was
diluted with EtOAc and the organic layer was washed with satu-
rated aqueous Na2SO3 (ꢂ2), satd aqueous NaHCO3 (ꢂ3) and satd aq
NaCl (ꢂ1). After drying over MgSO4, the solvent was removed and
the product purified via flash chromatography eluting with a gra-
dient of 5e40% EtOAc in heptane. Fractions containing the product
were pooled and concentrated to afford 7.0 g (96%) of 10 as a col-
orless oil. 1H NMR (400 MHz, CDCl3)
d 7.26e7.41 (m, 5H), 4.84 (dt,
J¼6.3, 7.9 Hz, 2H), 4.59e4.69 (m, 2H), 3.68 (d, J¼2.0 Hz, 1H),
3.30e3.35 (m, 1H), 3.21e3.30 (m, 1H). 13C NMR (101 MHz, CDCl3)
d
136.6, 128.4, 128.2, 125.5, 73.0, 72.8, 62.3, 56.8, 36.3, 62.3, 56.8,
CDCl3)
1H), 4.92 (dd, J¼6.0, 8.1 Hz, 2H), 4.66 (t, J¼6.4 Hz, 2H), 3.80e3.96
(m, 1H). 13C NMR (101 MHz, CDCl3)
136.8, 131.2, 129.6, 128.6,
d
7.16e7.46 (m, 5H), 6.48e6.58 (m, 1H), 6.43 (d, J¼15.9 Hz,
36.3; HRMS (ESI) calcd for [MþH, C11H12O2]þ: 176.0837; found:
176.0839.
d
128.5, 127.5, 126.2, 77.2, 38.7. Anal. Calcd for C, 82.46; H, 7.55.
Found: C, 82.61; H 7.68.
4.2.7. Methyl oxetane-3-carboxylate (2). Epoxide 10 (1.0 g,
5.67 mmol) was suspended in H2O (20 mL), stirred and heated at
50 ꢀC for 2 h [NOTE: An aliquot was removed, concentrated to
dryness and the diol mixture treated with excess Ac2O and catalytic
DMAP. 1H NMR analysis of the diacetate mixture showed a 1.5: 1
mixture of 9a to 9b.] To the aqueous diol solution, after cooling to
room temperature, was added MeOH (10 mL). After further cooling
to 0 ꢀC a solution of NaIO4 (1.9 g, 9.1 mmol) dissolved in warm water
(20 mL) was added dropwise over 5 min. After 5 min at 0 ꢀC, the ice
bath was removed and the reaction was warmed and stirred at
room temperature for 3 h 1H NMR analysis of a 0.25 mL aliquot of
the reaction mixture (extraction into CDCl3) showed the oxidative
cleavage reaction to be complete forming benzaldehyde and the
oxetane aldehyde as a mixture of hydrate and aldehyde forms.
NaHCO3 (1.8 g, 21 mmol) was added. The reaction was cooled to
0 ꢀC and Br2 (1.4 g, 8.5 mmol) was added dropwise as a solution in
MeOH (10 mL). The reaction was stirred at 0 ꢀC for 1 h and at room
temperature for 2 h. The excess Br2 was quenched by pouring the
reaction into an ice cold solution of Na2SO3 (3.5 g in 50 mL of ice
water). The mixture was transferred to a separatory funnel and
washed with heptane (ꢂ3) to remove methylbenzoate and
remaining benzaldehyde. Then, the aqueous mixture was extracted
with EtOAc (ꢂ4). The combined extract was washed with satd aq
NaCl (ꢂ2) and dried over MgSO4. After careful removal of the EtOAc
at a water bath temperature of 10e15 ꢀC, purification was accom-
plished using a 10 g silica plug (Varianepre-packed) by loading the
oil on the column using DCM, eluting with 3 column volumes of
heptane followed by 4 column volumes of EtOAc. The fractions
containing 2 (TLC 50% EtOAc in heptane/observing 2 using an I2
chamber, 10 min). After removing the solvent, 313 mg (47%) of 2
was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3)
7b 1H NMR (400 MHz, CDCl3)
d 7.28e7.35 (m, 2H), 7.21e7.26 (m,
1H), 7.16e7.21 (m, 2H), 5.35 (quint, J¼2.3, 7.1 Hz, 1H), 5.20e5.25 (m,
2H), 5.17 (dd, J¼1.2, 2.4 Hz, 2H), 3.22 (d, J¼7.1 Hz, 2H).
4.2.4. (1RS,2RS)-1-(Oxetan-3-yl)-2-phenylethane-1,2-diyl diacetate
(9a). 7a (7.08 g, 44.2 mmol) was dissolved in EtOAc (110 mL). N-
methylmorpholine-N-oxide (5.69 g, 48.6 mmol), deionized water
(4.4 mL), and osmium tetroxide (11.0 mL of a 2.5 wt % solution in t-
butanol, 0.88 mmol) were added. The solution was stirred at room
temperature for 3 h as it darkened from yellow to orange. LCMS
analysis showed most of the starting material had been consumed,
and a new peak formed at the solvent front. To the reaction was
added freshly-ground sodium thiosulfate (10.5 g, 66.3 mmol) and
the reaction was stirred at room temperature for 40 min. The re-
action was then cooled to 0 ꢀC and Ac2O (42 mL, 442 mmol) and
DMAP(545 mg, 4.46 mmol) wereadded. The reactionwas allowed to
gradually warm to room temperature as the ice in the cooling bath
melted and was stirredfor19 hat roomtemperature. Water (125 mL)
was added and the aqueous layer was extracted with EtOAc
(3ꢂ150 mL). The combined organic layers were washed with satd aq
NaCl (100 mL), dried over magnesium sulfate, filtered, and concen-
trated to 13 g as a brown oil. Purification of this oil was accomplished
on a 220 g silica column, eluting with 0e50% EtOAc in heptane.
Obtained 9.2 g (75%) of 9a (Rf¼0.33 in 50% EtOAc/hept) as a colorless
liquid which crystallized on standing to a white solid. 1H NMR
(400 MHz, CDCl3)
d
7.28e7.40 (m, 5H), 5.72 (d, J¼6.7 Hz,1H), 5.55 (t,
J¼6.7 Hz,1H), 4.62 (t, J¼6.7 Hz,1H), 4.56 (dd, J¼6.0, 8.2 Hz,1H), 4.34
(dd, J¼6.5, 8.4 Hz, 1H), 4.14 (t, J¼6.8 Hz, 1H), 3.15e3.28 (m, 1H), 2.09
(s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 170.2, 169.5, 135.9,
128.7, 128.6, 126.8, 75.4, 74.2, 72.7, 72.6, 35.8, 20.8, 20.6. Anal. Calcd
for C, 64.74; H, 6.52. Found: C, 64.56; H 6.56.
d
4.78e4.90 (m, 4H), 3.86 (tt, J¼6.9, 8.5 Hz, 1H), 3.76 (s, 3H). 13C
NMR (101 MHz, CDCl3)
d 172.1, 72.5, 51.5, 38.0. Anal. Calcd for C,
51.72; H, 6.94. Found: C, 52.70; H 6.91.
4.2.5. (1RS,2RS)-1-(Oxetan-3-yl)-2-phenylethane-1,2-diol
(8a). Diacetate 9a (2.4 g, 8.6 mmol) was placed in a 250 mL round
bottom flask and was dissolved in EtOH (10 mL). Water (20 mL) was
4.2.8. Oxetane-3-carboxaldehyde (1). Epoxide 10 (4.4 g, 25 mmol)
was added to water (50 mL) in a 100 mL round bottom flask while