F
N. D. Bartolo et al.
Paper
Synthesis
Reduction of Ketone 1; Representative Procedure
To a cooled (–78 °C) solution of LiAlH4 (0.064 g, 1.7 mmol) in Et2O (3
mL) was added a solution of ketone 1 (0.082 g, 0.50 mmol) in Et2O (3
mL) dropwise. After 4 h, MeOH (2 mL) was added. The solution was
warmed to room temperature and brine (10 mL) was added. The mix-
ture was extracted with CH2Cl2 (3 × 10 mL) and the combined organic
layers were dried over Na2SO4. 1H NMR spectroscopic analysis of the
unpurified reaction mixture revealed a 96:4 mixture of diastereomers
(2/3). Purification by flash chromatography (EtOAc–hexanes, 15:85)
afforded a mixture of alcohols 2 and 3 as a colorless oil, with a diaste-
reomeric ratio of 94:6; yield: 0.071 g (85%). The spectroscopic data
are consistent with literature data.28,29
IR (neat): 3458, 2980, 1451, 1026, 824 cm–1
.
1H NMR (400 MHz, CDCl3): = 7.35–7.28 (m, 5 H), 4.91 (m, 1 H), 3.57–
3.51 (m, 1 H), 3.42 (s, 3 H), 2.55 (br s, 1 H), 0.98 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 140.7 (C), 128.4 (CH), 127.5 (CH),
126.5 (CH), 81.0 (CH), 74.7 (CH), 56.9 (CH3), 12.8 (CH3).
HRMS (APCI): m/z [(M + H) – H2O]+ calcd for C10H13O: 149.0961;
found: 149.0957.
Figure 1 Diastereoselectivity in the reductions of chiral -alkoxy ke-
tone 1 is not necessarily correlated with chelation-induced rate acceler-
ation
Competition Experiment between Ketone 4 and Ketone 5; Repre-
sentative Procedure
To a cooled (–78 °C) solution of ketone 4 (0.045 g, 0.30 mmol) and ke-
tone 5 (0.040 mL, 0.30 mmol) in Et2O (3 mL) was added Zn(BH4)2
(0.500 mL, 0.15 M solution in Et2O, 0.075 mmol) dropwise. After stir-
ring for 12 h, MeOH (1 mL) was added, and the reaction mixture was
warmed to room temperature over 15 min. An aliquot of the reaction
mixture (1 mL) was filtered through a plug of silica gel and analyzed
by GC (start temperature = 80 °C, ramp = 10 °C/min, final temperature
= 170 °C) to show a 93:7 mixture of products (6/7), using the reten-
tion times of authentic samples prepared as a reference.
1H NMR spectra were obtained at room temperature using Bruker
AVIII-400 (400 MHz and 100 MHz, respectively), AVIIIHD-400 (400
MHz and 100 MHz, respectively), AV-500 (500 MHz and 125 MHz, re-
spectively), and AV-600 (600 MHz and 150 MHz, respectively) spec-
trometers; spectroscopic data are reported as follows: chemical shifts
in ppm on the scale, referenced to residual solvent (1H NMR: CDCl3
7.26; 13C NMR: CDCl3 77.2), multiplicity (standard abbreviations),
coupling constant(s) (Hz), and integration. Ratios of products were
obtained from one-pulse 1H NMR integrations using diagnostic peaks
in unpurified reaction mixtures. One-pulse 1H spectra were taken
with a relaxation delay of 30 s when determining product ratios. Mul-
tiplicities of carbon peaks were determined using HSQC experiments.
Product distributions of competition experiments were determined
by gas chromatography, using an Agilent 6850 Series gas chromato-
graph with the carrier gas (helium) set to 15 psi and equipped with a
capillary column (14% cyanopropylphenyl, 86% methylpolysiloxane,
30 m × 0.321 mm × 0.25 m). High-resolution mass spectra were ac-
quired on an Agilent 6224 Accurate-Mass time-of-flight spectrometer
with an atmospheric pressure chemical ionization (APCI) source. In-
frared (IR) spectra were recorded using a Thermo Nicolet AVATAR
Fourier Transform IR spectrometer using attenuated total reflectance
(ATR). Liquid chromatography was performed using forced flow (flash
chromatography) of the indicated solvent system on silica gel 60
(230–400 mesh). Tetrahydrofuran, diethyl ether, dichloromethane,
benzene, hexane, acetonitrile, dimethylformamide, and methanol
were dried and degassed using a solvent purification system before
use. All anhydrous reactions were run under a nitrogen atmosphere
in glassware that had been flame-dried under vacuum. Ketone 1,25 ke-
tone 4,8 ketone 8,26 and zinc borohydride27 were prepared by known
methods. Unless otherwise noted, all reagents and substrates were
commercially available. The concentrations of commercially available
reagents were assumed to be near the concentrations reported by the
suppliers.
Competition Experiment between Ketone 8 and Ketone 5; Repre-
sentative Procedure
To a cooled (–78 °C) solution of ketone 8 (0.088 g, 0.30 mmol) and ke-
tone 5 (0.040 mL, 0.30 mmol) in Et2O (3 mL) was added Zn(BH4)2
(0.500 mL, 0.15 M solution in Et2O, 0.075 mmol) dropwise. After stir-
ring for 12 h, MeOH (1 mL) was added, and the reaction mixture was
warmed to room temperature over 15 min. An aliquot of the reaction
mixture (1 mL) was filtered through a plug of silica gel and analyzed
by GC (start temperature = 150 °C, ramp = 50 °C/min, final tempera-
ture = 250 °C) to show a 52:48 mixture of products (9/7), using the
retention times of authentic samples prepared as a reference. This ra-
tio was corrected to 32:68 using a GC to 1H NMR calibration curve
(second-order polynomial regression, y = –0.0067x2 + 1.6296x +
2.7501, R2 = 0.9992) derived from seven mixtures of pure alcohols 9
and 7; the variable y = the percentage of 9 by GC, and x = the percent-
age of 9 by 1H NMR spectroscopy.
Funding Information
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund for support of this research (57206-
ND1). The Shared Instrumentation Facility in the Department of
Chemistry was constructed through the support of the National Cen-
ter for Research Resources, National Institutes of Health, under Re-
search Facilities Improvement Award Number C06 RR-16572-01. The
cryogenic probe for the 600 MHz NMR was acquired through the sup-
port of the National Institute of Health S10 grant under Award Num-
ber OD016343.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G
Bartolo, Nicole D.
