Stereospecific Hydrogenolysis of Benzylic Alcohols over Pd/C

DOI: 10.1021/acs.joc.0c00827

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Journal of Organic Chemistry (2020)

Update date:2022-09-26

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Authors:

Bochet, Christian G.

Harvey, Freya M.

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Article abstract of DOI:10.1021/acs.joc.0c00827

Hydrogenolysis of tertiary benzylic alcohols on palladium on carbon (Pd/C) generally proceeds with inversion of configuration. However, little is known about the hydrogenolysis mechanism of primary and secondary benzylic alcohols. Literature precedents su

Full text of DOI:10.1021/acs.joc.0c00827

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Stereospeciﬁc Hydrogenolysis of Benzylic Alcohols over Pd/C

Freya M. Harvey and Christian G. Bochet*

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ABSTRACT: Hydrogenolysis of tertiary benzylic alcohols on

palladium on carbon (Pd/C) generally proceeds with inversion of

conﬁguration. However, little is known about the hydrogenolysis

mechanism of primary and secondary benzylic alcohols. Literature

precedents suggest that these substrates may interact diﬀerently

with the catalyst. To study the mechanism, we synthesized a pair of

deuterated diastereoisomers with a chiral center at the benzylic

position. Chemical derivatization of the hydrogenolysis products

showed that the reaction proceeds with inversion of conﬁguration

for these substrates.

enzylic bonds have an unusually low dissociation energy,¹

This explanation has been used to rationalize the opposing

B_{giving the benzylic position its unique reactivity toward}stereochemical outcomes of the reactions.⁴

The stereochemistries of Pd/C and Raney nickel hydro-

homolytic cleavage of carbon−heteroatom (and recently,

carbon−carbon)²bonds under mild conditions. A familiar

example of such reactivity is the benzyl protecting group,

which can be removed from an alcohol by the hydrogenolysis

of the benzylic carbon−oxygen bond with transition metal

catalysts such as Raney nickel or palladium on carbon (Pd/

C).³

It is widely accepted that hydrogenolysis reactions on Raney

nickel and Pd/C are stereospeciﬁc: hydrogenolysis on Raney

nickel proceeds with retention of conﬁguration at the benzylic

center, and hydrogenolysis on Pd/C proceeds with inversion of

conﬁguration. While both metals strongly adsorb the aromatic

ring, their reactivity diﬀers in their aﬃnity for oxygen: Raney

nickel has a high aﬃnity for oxygen (Figure 1a) and interacts

with it preferentially, whereas Pd/C has a low aﬃnity for

oxygen (Figure 1b) and interacts with the other substituents.

genolysis reactions are supported by a wealth of experimental

data. However, for hydrogenolysis reactions on Pd/C, there are

many examples in the literature of reactions that proceed with

retention of conﬁguration rather than inversion, depending on

the size of the benzylic substituents and the identity of the

leaving group.⁵For example, the hydrogenolysis of aryl ether

leaving groups tends to proceed with retention of conﬁguration

(presumably because of adsorption of the aryl on the catalyst),

and bulky substituents at the benzylic position can lead to

nonselective hydrogenolysis or retention of conﬁguration.

Notably, Kieboom⁶observed that benzyl alcohol is more

strongly adsorbed on Pd/C than its toluene product, indicating

that the oxygen atom may contribute to the adsorption on the

catalyst in the case of nontertiary benzylic alcohols. This

suggests that the hydrogenolysis mechanism on Pd/C may be

fundamentally similar to that on Raney nickel but is more

sensitive to the steric crowding of a quaternary benzylic

carbon.

To investigate the reaction mechanism on Pd/C, we looked

at the hydrogenolysis of deuterated secondary alcohols 3 and

4, leading to diastereoisomers 1 and 2 (Scheme 1).

These nontertiary alcohols will allow us to probe the

fundamental hydrogenolysis mechanism on Pd/C without the

added parameter of steric hindrance, while still possessing a

Received: April 2, 2020

Figure 1. Hydrogenolysis mechanisms on Raney nickel and

palladium. Image reproduced from ref 5e.

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Scheme 1. Hydrogenolysis of Diastereoisomers 3 and 4

Table 1. Hydrogenolysis of Benzylic Alcohols, Acetates, and

Triﬂuoroacetates

no.

solvent

cat., additive (equiv) T (min)

EtOH

EtOAc

MeOH

EtOAc

MeOH

EtOAc

EtOH

MeOH

EtPh

Pd/C

Pd(OH)₂

Pd/Al₂O₃

Pd/BaSO₄

Pd/C

Pd/C, AcOH

Pd/C, Na₂CO₃

Pd/C

Pd/C, Na₂CO₃

Pd/C, NaOAc

Pd/C, Na₂CO₃

Pd/C, NaOAc

Pd/C, EtPh (3)

Pd/C, EtPh (10)

Pd/C

OAc

TFAc

chiral center at the benzylic position. Analysis of 1 and 2 will

give information about whether the reaction proceeds with

inversion or retention of conﬁguration.

Deuterated alcohols 3 and 4 were accessible in three steps

from acetophenone (Scheme 2). They are spectroscopically

distinct and chromatographically separable.

f g

40 ^,

Scheme 2. Synthesis of Deuterated Alcohols 3 and 4

TFAc

e f

Reagents and conditions: (a) ethyl glyoxylate, 100 °C, 3 days, 75%;

Reaction conditions: 5 mol % of Pd/C was suspended in the

(b) TBSCl, imidazole, CH₂Cl₂, rt, 98%; (c) NaBD₄, MeOD, 0 °C, 45

min, 92%.

speciﬁed solvent under a H₂atmosphere. The substrate (and additive)

were added. After the speciﬁed time at rt, the reaction was ﬁltered on

Celite. Yield after column chromatography. Isotopic purity (IP) was

To assign their stereochemistry as syn or anti, we decided to

chemically derivatize their nondeuterated counterparts, 7 and 8

(Scheme 3). Hydroxy esters 7 and 8 readily cyclize to lactones

determined by the integration of the benzylic ¹HNMR spectral signal.

No reaction. Preactivation of the catalyst (10−20 min). Lactone

observed. Alcohol observed (saponiﬁed acetate).

Scheme 3. Cyclization to Lactones 9 and 10

In all cases, whether alcohol 3 or 4 was used, the same

corresponding diastereoisomer 1 or 2 was consistently

obtained. The reaction was highly stereospeciﬁc: we did not

observe scrambling of the benzylic center at any point during

the reaction optimization process. Dilution of the isotopic

purity occurred by an overreaction of the product on the

catalyst, after hydrogenolysis of the benzylic C−O bond had

taken place.

Other palladium catalysts either showed the same dilution of

the isotopic purity (entry 2, palladium hydroxide) or were

unreactive under the chosen conditions (entries 3 and 4).

Acetylating the alcohol shortened the reaction time, which

allowed for improved isotopic purity, but was still not optimal

(entry 5). Acidic conditions with acetic acid lowered the yield

and isotopic purity (entry 6). Basic conditions with sodium

carbonate improved the yield and isotopic purity (entry 7). To

reach even higher isotopic purity, we installed a triﬂuoroacetate

leaving group and preactivated the catalyst by stirring under

the H₂atmosphere for a given time before adding the

substrate. This shortened the reaction time and, even without

added sodium carbonate, aﬀorded the deuterated esters in

good yield and isotopic purity in various solvents (entries 8, 9,

and 10). However, in the presence of sodium carbonate, the

yield was lowered (entry 11). This is due to the saponiﬁcation

of the triﬂuoroacetate group to the alcohol in basic medium,

even in a non-nucleophilic solvent (entry 12). With sodium

acetate, the yield and isotopic purity improved (entry 13). To

verify whether the acetate leaving group itself aﬀected the

reaction once saponiﬁed, we tested the hydrogenolysis reaction

9 and 10. These lactones, and their relative conﬁgurations, are

known in the literature and have been veriﬁed by ¹H NMR and

NOE experiments.⁷Lactone 9 (originating from 7) is cis

according to literature precedents, allowing us to assign its

starting ester 7 (and its deuterated counterpart 3) as anti.

Likewise, lactone 10 is trans according to the literature,

meaning that its starting ester 8 (and its deuterated

counterpart 4) is syn.

Our ﬁrst attempt at the hydrogenolysis of 3−1 on Pd/C did

prove to be stereospeciﬁc (Table 1, entry 1) but suﬀered from

dilution of the isotopic purity (IP): the Pd/C catalyst also

hydrogenolyses the deuterium atom oﬀ the benzylic center.

This (over-) reactivity is known and has been exploited to fully

deuterate the benzylic position.⁸To minimize the hydro-

genolysis of the deuterium atom, we screened various

additives, solvents, and benzylic leaving groups (alcohols 3

and 4, acetates 11 and 12, and triﬂuoroacetates (TFAc) 13 and

14).

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with sodium acetate and sodium carbonate on the free alcohol

(entries 15 and 16). There was no reaction after the allotted

reaction time. We also tested ethylbenzene (EtPh) as an

additive (entries 17 and 18). This aﬀorded the highest yields

and almost no dilution of the isotopic purity. We proposed that

an excess of EtPh as an additive occupied the free active sites

on the catalyst and protected the product from overreaction,

acting as a mild catalyst poison. Conducting the reaction in

EtPh as the solvent completely inhibited the hydrogenolysis

reaction (entry 19).

Next, we sought to prove the stereochemistry of the

reaction. X-ray crystallography techniques cannot reliably

distinguish between hydrogen and deuterium atoms, and

linear esters 1 and 2 were not amenable to NMR techniques

like NOESY, which require rigidity of the structure. Thus, we

decided to chemically derivatize the linear esters to chromanes

15 and 16, whose cyclic structures could be analyzed by NMR

techniques (Scheme 4).

C does fundamentally proceed with inversion of conﬁguration,

and the oxygen atom in the leaving group does not interact

with the catalyst.

Given the unique reactivity of the benzylic position and, in

drug substances, its ready oxidation by P450 enzymes,¹⁰

labeling this position stereospeciﬁcally could be of great

interest for the elucidation of reaction mechanisms and drug

metabolism pathways. To our knowledge, methods to

stereospeciﬁcally deuterate the benzylic position are currently

limited to S_N2 reactions, where a deuteride displaces a leaving

group at the benzylic position.¹¹These harsh conditions can

often cause the elimination of the leaving group to give a

styrene derivative instead of the desired S_N2 product. Thus, we

decided to widen the scope of our reaction and optimize the

conditions for substrates with electron-withdrawing and

electron-donating substituents on the aromatic ring (Table

2). The starting triﬂuoroacetates were synthesized using the

same reaction sequence as for the previous triﬂuoroacetates

(Scheme 5).

Scheme 4. Synthesis of Chromane Derivatives

Table 2. Hydrogenolysis of Benzylic Triﬂuoroacetates with

a Varying Electron Density

Reagents and conditions: (a) Pd/C, H₂, ethylbenzene, MeOH, rt,

no. solvent

cat.

Pd/C

Pd/C, EtPh

Pd/C

Pd/C, EtPh

Pd/C

t (min) yield (%)

IP (%)

95%; (b) LiAlH₄, THF, 0 °C, 92−93%; (c) Oxone, KCl, TFA (cat.),

MeCN/H₂O 10:1, 39−55%; (d) Pd(OAc)₂, Trixiephos, Cs₂CO₃,

toluene, 80 °C, 16%.

EtOH

EtOAc

EtOH

EtOAc

CF₃

OMe

92−95

e f

The reaction conditions were carefully chosen to avoid

scrambling of the chiral centers; no epimerization was

observed at any stage of the synthesis. First, esters 1 and 2

could be reduced to diols with concomitant removal of the

TBS group by LiAlH₄. The diols could then undergo

chlorination on the aromatic ring to aﬀord an inseparable

mixture of ortho- and para-chlorinated products, 19 and 20.

These were subjected to Buchwald cyclization conditions⁹to

give the desired chromane products 15 and 16.

41−67

Reaction conditions: 5 mol % of Pd/C was suspended in the

speciﬁed solvent under an H₂atmosphere and stirred for 20 min. The

substrate and additive were added. After the speciﬁed time at rt, the

reaction was ﬁltered on Celite. Yield after column chromatography.

Isotopic purity was determined by the integration of the benzylic

¹HNMR spectral signal. Incomplete reaction. Lactone observed.

Alcohol observed (saponiﬁed triﬂuoroacetate).

Analysis of the methylene coupling constants (Ha, Hb, and

Hc) by ¹H NMR spectroscopy allowed us to assign chromane

15 as cis, meaning that the conﬁguration of ester 1 is anti

(Figure 2; see Supporting Information for details). Chromane

16 was assigned as having a trans conﬁguration, starting from

syn ester 2. ROESY experiments showed an interaction

between protons Hd and Hc for cis chromane 15, which was

not observed in trans chromane 16. As a result, we can

conclude that the hydrogenolysis reaction mechanism on Pd/

Scheme 5. Synthesis of the Triﬂuoroacetates

Figure 2. Coupling constants for chromanes 15 and 16. Note that a

chair representation was used for clarity, but the molecule is likely not

in a perfect chair conformation.

Reagents and conditions: (a) ethyl glyoxylate, 100 °C; (b) TBSCl,

imidazole, CH₂Cl₂, rt; (c) NaBD₄, (CeCl₃), MeOD, 0 °C; (d) TFAA,

TEA, 0 °C.

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1H), 4.26 (qd, J = 7.2, 0.9 Hz, 2H), 3.39−3.61 (m, 2H), 3.32 (bs,

1H), 1.27 ppm (td, J = 7.1, 1.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 197.5, 173.7, 136.3, 133.5, 128.6 (2 C), 128.1 (2 C), 67.1, 61.8,

42.1, 14.0; FT-IR (ATR, neat, cm⁻¹) 3486; 2982; 2360; 1732; 1682;

1597; 1682; 1449; 1367; 1268; 1206; 1097; 1040; 758; 691; 624;

HR-MS (ESI+) m/z calcd for C₁₂H₁₄O₄Na [M + Na]⁺245.0784,

found 245.0784.

Even when ﬁltered before reaction completion and with a

large excess of EtPh, the isotopic purity of 33 or 34 after

hydrogenolysis of 27 or 28 in ethanol did not exceed 94%

(entries 1 and 2). However, hydrogenolysis in ethyl acetate

allowed for excellent isotopic purity even at long reaction

times, and no additives were needed (entry 3).

For electron-rich 35 or 36, ethyl acetate was again required

due to the instability of the triﬂuoroacetate group to

nucleophilic solvents (entry 4). Adding EtPh as a mild catalyst

poison caused the triﬂuoroacetate group to saponify, giving

only the free alcohol and lactone (entry 5). The hydrogenolysis

of electron-rich substrates 31 and 32 is almost instantaneous,

allowing us to reach satisfactory isotopic purities and yields by

ﬁltering the reaction after only 3 min (entry 6).

To conclude, we have proven that, for hydrogenolysis

reactions on Pd/C of secondary benzylic alcohols, the reaction

mechanism fundamentally proceeds with inversion of conﬁg-

uration. Hydrogenolysis on Pd/C is highly stereospeciﬁc and

takes place rapidly and in high yield in many diﬀerent solvents

at room temperature. The deuterium atom at the benzylic

position was prone to hydrogenolysis by the catalyst, lowering

the isotopic purity of the product. We were able to modulate

the catalyst reactivity with common additives such as sodium

carbonate, sodium acetate, or ethylbenzene. Ethylbenzene was

especially useful for preventing overreaction on the catalyst and

allowed for excellent isotopic purity of the product. Stereo-

speciﬁc benzylic deuteration could also be a useful tool for the

elucidation of reaction mechanisms and drug metabolism

pathways. Thus, we widened the scope of the hydrogenolysis

reaction by optimizing the conditions for substrates bearing

electron-rich or electron-poor aromatic rings.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-oxo-4-phenylbuta-

noate (6). Compound 5 (3.55 g, 16.0 mmol, 1 equiv) and imidazole

(5.44 g, 79.9 mmol, 5 equiv) were dissolved in dry CH₂Cl₂(50 mL)

under argon, and TBS-Cl (6 g, 40 mmol, 2.5 equiv) was added. The

reaction was stirred overnight at rt. NaHCO₃sat. solution (50 mL)

was added, and the aqueous phase was extracted with CH₂Cl₂(3 × 40

mL). The organic phases were gathered, dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo to give a pale yellow oil. It was puriﬁed by

column chromatography (eluting with pentane/Et₂O 9:1) to give S2

(5.29 g, 15.7 mmol, 98%) as a transparent oil: H NMR (400 MHz,

CDCl₃) δ 8.04−7.91 (m, 2H), 7.62−7.53 (m, 1H), 7.50−7.43 (m,

2H), 4.87 (dd, J = 4.8, 7.6 Hz, 1H), 4.21 (qd, J = 1.5, 7.2 Hz, 2H),

3.47−3.30 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.84 (s, 9H), 0.12 (s,

3H), 0.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 197.2, 173.0, 137.0,

133.2, 128.6 (2C), 128.3 (2C), 69.1, 61.1, 43.5, 25.6, 18.1, 14.1, −5.0,

−5.4; FT-IR (ATR, neat, cm⁻¹) 2955; 2930; 2896; 2857; 1752; 1686;

1598; 1581; 1472; 1449; 1363; 1275; 1252; 1179; 1131; 1058; 1029;

952; 831; 778; 689; HR-MS (ESI+) m/z calcd for C₁₈H₂₈O₄SiNa [M

+ Na]⁺359.1649, found 359.1641.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenyl-

butanoate (7 and 8). Compound 6 (0.098 g, 0.291 mmol, 1

equiv) was dissolved in 5 mL of MeOH and cooled to 0 °C (ice

bath). Then NaBH₄(0.033 g, 0.873 mmol, 3 equiv) was added. After

45 min at 0 °C, NH₄Cl sat. solution (10 mL) was added and stirred at

rt for 20 min to neutralize all remaining hydride. MeOH was removed

by rotatory evaporation, and the aqueous phase was extracted with

Et₂O (2 × 10 mL). The organic phases were gathered, dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo to give a transparent oil.

The oil was puriﬁed by column chromatography (eluting with

pentane/EtOAc 92:8) to give the isomer anti 7 (0.028 g, 0.082 mmol,

28%) and the isomer syn 8 (0.033 g, 0.098 mmol, 34%) as transparent

oils, as well as a mixture of both diastereoisomers (0.018 g, 0.053

mmol, 18%). Total yield: 0.079 g, 0.233 mmol, 80%.

Ethyl anti-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenyl-

butanoate (7): ¹H NMR (400 MHz, CDCl₃) δ 7.41−7.21 (m,

5H), 4.93 (td, J = 2.8, 9.6 Hz, 1H), 4.57 (dd, J = 4.0, 6.8 Hz, 1H),

4.21 (m, 2H), 2.90 (d, J = 2.7 Hz, 1H), 2.23−2.02 (m, 2H), 1.30 (t, J

= 7.2 Hz, 3H), 0.97 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 173.3, 144.2, 128.4 (2 C), 127.4, 125.6 (2 C),

70.9, 70.6, 61.0, 43.7, 25.7 (3 C), 18.3, 14.2, −4.9, −5.5; FT-IR (ATR,

neat, cm⁻¹) 3512; 2954; 2929; 2894; 2857; 1750; 1733; 1471; 1371;

1251; 1184; 1126; 1062; 1028; 979; 090; 835; 778; 700; 666; 624;

HR-MS (ESI+) m/z calcd for C₁₈H₃₀O₄SiNa [M + Na]⁺361.1806,

found 361.1800.

Ethyl syn-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenylbu-

tanoate (8): ¹H NMR (400 MHz, CDCl₃) δ 7.45−7.22 (m, 5H), 5.00

(td, J = 3.1, 8.8 Hz, 1H), 4.46 (dd, J = 5.3, 6.8 Hz, 1H), 4.18 (d, J =

7.1 Hz, 1H), 3.13 (d, J = 2.7 Hz, 1H), 2.26−2.09 (m, 2H), 1.29 (t, J =

7.2 Hz, 3H), 0.96 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H); ¹³C NMR (101

MHz, CDCl₃) δ 173.4, 143.8, 128.4 (2 C), 127.5, 125.8 (2 C), 71.9,

71.5, 61.1, 43.7, 25.7 (3 C), 18.2, 14.1, −4.8, −5.4; FT-IR (ATR, neat,

cm⁻¹) 3492; 2954; 2929; 2887; 2857; 1472; 1373; 1252; 1188; 1126;

1053; 1029; 834; 779; 701; 630; HR-MS (ESI+) m/z calcd for

C₁₈H₃₀O₄SiNa [M + Na]⁺361.1806, found 361.1800.

EXPERIMENTAL PART

■

Unless otherwise indicated, all reagents were obtained from

commercial suppliers (Fluka, Aldrich, Acros, TCI, Fluorochem,

Strem) and were used without further puriﬁcation. Dry solvents

(toluene, CH₂Cl₂, THF, and Et₂O) were obtained from the building’s

solvent puriﬁcation system (alumina-packed columns). Deuterated

solvents were obtained from Cambridge Isotope Laboratory.

Analytical thin-layer chromatography was performed on Kieselgel F-

254 precoated aluminum sheet TLC plates from Merck. Visualization

was performed with a 254 nm UV lamp and/or a KMnO₄solution.

Flash column chromatography was carried out using Brunschwig silica

gel (SiO₂, 60 Å, 32−63 mesh). ¹H NMR and ¹³C NMR spectra were

recorded on Bruker-DRX-300 spectrometers. All NMR spectra were

recorded in CDCl₃, CD₃CN, and CD₃OD. Data were treated with

ACD laboratories software, and all chemical shifts are expressed in

parts per million (δ) using residual solvent signals as internal

standards. The coupling constants (J) are reported in hertz (Hz).

Splitting patterns are designated as s (singlet), d (doublet), dd

(double doublet), t (triplet), dt (double triplet), q (quartet), bs

(broad singlet), and m (multiplet). IR spectra were recorded with a

Fourier transform IR Bruker Tensor 27 spectrometer, neat;

absorption bands are in cm⁻¹. ESI mass spectra were carried out

with an LTQ Orbitrap XL with a nano ESI spectrometer. Melting

point measurements were performed using a Buchi Melting Point B-

540 device. Microwave heating was performed on a Biotage Initiator

Microwave using Biotage microwave vials.

General Procedure for Cyclization to Lactones 9 and 10. Esters 7

or 8 (1 equiv) were dissolved in a 2:1 v/v mixture of EtOH and TFA

(0.1 M reaction). After 18 h, the solvents were evaporated, and the

resulting oil was puriﬁed by column chromatography (eluting with

pentane/ethyl acetate 2:3) to give the title lactones. NMR shifts

correspond to those in the literature.⁷

Ethyl 2-Hydroxy-4-oxo-4-phenylbutanoate (5). Acetophe-

none (2.9 mL, 25 mmol, 1 equiv) and ethyl 2-oxoacetate 50 wt %

in toluene (4.9 mL, 25 mmol, 1 equiv) were heated to 100 °C in an

oil bath. After 90 h at this temperature, toluene was removed in vacuo,

and the resulting yellow oil was puriﬁed by column chromatography

(eluting with pentane/EtOAc 3:2) to give the title compound (3.55 g,

16.0 mmol, 75%) as a transparent oil: ¹H NMR (300 MHz, CDCl₃) δ

7.85−8.09 (m, 2H), 7.38−7.67 (m, 3H), 4.66 (dd, J = 5.9, 4.0 Hz,

cis-3-Hydroxy-5-phenyldihydrofuran-2(3H)-one (9): 82%

yield, white solid; H NMR (300 MHz, CDCl₃) δ 7.49−7.32 (m,

5H), 5.38 (dd, J = 5.2, 11.0 Hz, 1H), 4.72 (dd, J = 8.1, 11.3 Hz, 1H),

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3.04 (dd, J = 4.9, 7.8 Hz, 1H), 2.99 (dd, J = 4.9, 7.8 Hz, 1H), 2.27 (td,

J = 11.2, 12.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.0, 137.7,

129.0, 128.9 (2 C), 125.9 (2 C), 77.7, 69.0, 39.5.

128.5 (2 C), 128.1, 126.7 (2 C), 71.8 (t, J = 23.5 Hz), 69.0, 60.8, 41.1,

25.7 (3 C), 21.0, 18.2, 14.2, −4.9, −5.3; FT-IR (ATR, neat, cm⁻¹)

2954; 2930; 2887; 2857; 1745; 1472; 1449; 1368; 1248; 1233; 1198;

1139; 1122; 1057; 1019; 936; 894; 836; 779; 701; 668; 631; HR-MS

(ESI+) m/z calcd for C₂₀H₃₁DO₅SiNa [M + Na]⁺404.1979, found

404.1966.

trans-3-Hydroxy-5-phenyldihydrofuran-2(3H)-one (10): 77%

yield, transparent oil; H NMR (300 MHz, CDCl₃) δ 7.51−7.23 (m,

5H), 5.73 (dd, J = 4.4, 7.6 Hz, 1H), 4.58 (t, J = 7.6 Hz, 1H), 2.80−

2.52 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 138.7, 128.9 (2

C), 128.5, 125.0 (2 C), 78.7, 67.2, 38.2.

General Procedure for Triﬂuoroacetylation (13 and 14). Alcohols

3 or 4 (1 equiv) were dissolved in dry CH₂Cl₂(0.08 M reaction)

under argon, and triethylamine (5 equiv) was added. The mixture was

cooled to 0 °C (ice bath). Then triﬂuoroacetic anhydride (2 equiv)

was added. After 1.5 h, cold NH₄Cl sat. solution was added to quench

the reaction, which was then poured into a separatory funnel. The

aqueous phase was extracted three times with CH₂Cl₂. The organic

phases were gathered, dried over Na₂SO₄, ﬁltered, and concentrated

in vacuo to give a transparent oil. The triﬂuoroacetates were puriﬁed

by column chromatography (eluting with pentane/Et₂O 9:1).

anti-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-phenyl-4-

(2,2,2-triﬂuoroacetoxy)butanoate-4-d (13): obtained as a trans-

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenyl-

butanoate-4-d (3 and 4). Compound 6 (5 g, 14.86 mmol, 1

equiv) was dissolved in 75 mL of MeOD under argon and cooled to 0

°C (ice bath). Then NaBD₄(1.244 g, 29.72 mmol, 2 equiv) was

added. After 45 min, NH₄Cl sat. solution (40 mL) was added and

stirred at rt for 20 min to neutralize all remaining deuteride. MeOD

was removed by rotatory evaporation, and the aqueous phase was

extracted with Et₂O (2 × 50 mL). The organic phases were gathered,

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to give a

transparent oil. The oil was puriﬁed by column chromatography

(eluting with pentane/EtOAc 92:8) to give the isomer anti 3 (0.912 g,

2.69 mmol, 18%), the isomer syn 4 (1.906 g, 5.61 mmol, 38%), and a

mixture of both diastereoisomers (1.83 g, 5.4 mmol, 36%) as

transparent oils successively. Total yield: 4.65 g, 13.7 mmol, 92%.

Ethyl anti-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenyl-

parent oil (98%); H NMR (400 MHz, acetonitrile-d₃) δ 7.45−7.32

(m, 5H), 4.34 (dd, J = 3.9, 8.6 Hz, 1H), 4.05 (d, J = 7.2 Hz, 2H), 2.55

(dd, J = 3.9, 14.5 Hz, 1H), 2.14 (dd, J = 8.6, 14.5 Hz, 1H), 1.21 (t, J =

7.2 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); ¹³C NMR (101

MHz, acetonitrile-d₃) δ 173.4, 157.5 (q, J = 41.8 Hz), 138.8, 130.2,

129.9 (2 C), 127.7 (2 C), 115.6 (q, J = 285.4 Hz), 78.5 (t, J = 23.5

Hz), 69.6, 62.0, 41.9, 26.1 (3 C), 18.9, 14.5, −4.5, −5.3; FT-IR (ATR,

neat, cm⁻¹) 2956; 2932; 2898; 2859; 1787; 1755; 1735; 1473; 1369;

1253; 1220; 1152; 975; 838; 778; 699; 630; HR-MS (ESI+) m/z

calcd for C₂₀H₂₈DO₅SiF₃Na [M + Na]⁺458.1691, found 458.1689.

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-phenyl-4-(2,2,2-

triﬂuoroacetoxy)butanoate-4-d (14): obtained as a transparent oil

butanoate-4-d (3): H NMR (300 MHz, CDCl₃) δ 7.45−7.21 (m,

5H), 4.57 (dd, J = 4.1, 6.9 Hz, 1H), 4.21 (ttd, J = 3.8, 7.2, 10.8 Hz,

2H), 2.20−2.01 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.97 (s, 9H), 0.16

(s, 3H), 0.13 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.4, 144.2,

128.4 (2 C), 127.4, 125.6 (2 C), 70.6, 70.5 (t, J = 22.6 Hz), 61.0, 43.6,

25.7 (3 C), 18.3, 14.2, −4.9, −5.5; FT-IR (ATR, neat, cm⁻¹) 3512;

2955; 2930; 2895; 2857; 1735; 1472;1371; 1130; 837; 779; 701; 630;

HR-MS (ESI+) m/z calcd for C₁₈H₂₉DO₄SiNa [M + Na]⁺362.1868,

found 362.1863.

(98%); H NMR (300 MHz, acetonitrile-d₃) δ 7.42 (m, 5H), 4.28

(dd, J = 4.8, 6.2 Hz, 1H), 4.14 (qd, J = 1.6, 7.1 Hz, 2H), 2.57 (dd, J =

4.7, 14.5 Hz, 1H), 2.31 (dd, J = 6.2, 14.5 Hz, 1H), 1.25 (t, J = 7.1 Hz,

3H), 0.93 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (75 MHz,

acetonitrile-d₃) δ 173.5, 157.3 (q, J = 44.8 Hz), 138.6, 130.3, 130.0 (2

C), 127.9 (2 C), 115.6 (q, J = 285.0 Hz), 77.9 (t, J = 23.7 Hz), 69.3,

61.9, 41.0, 26.1 (3 C), 18.9, 14.5, −4.6, −5.1; FT-IR (ATR, neat,

cm⁻¹) 2955; 2932; 2888; 2859; 1786; 1755; 1735; 1473; 1451; 1370;

1253; 1218; 1052; 981; 948; 836; 777; 727; 698; 667; HR-MS (ESI+)

m/z calcd for C₂₀H₂₈DO₅SiF₃Na [M + Na]⁺458.1691, found

458.1691.

General Procedure for Hydrogenolysis (1 and 2). Pd/C 10%

weight (0.05 equiv) was weighed in a two-neck round-bottom ﬂask

containing a stir bar and suspended in MeOH (0.02 M reaction)

under argon. The ﬂask was chosen such that the air volume above the

reaction was larger than the reaction volume (for example, for a 60

mL reaction volume, a 250 mL two-neck ﬂask was used). The argon

balloon was replaced with a hydrogen balloon. The hydrogen balloon

was triple-layered and remade every 2−3 reactions, and it was

completely ﬁlled with hydrogen for each reaction. The stopper from

the second neck was removed brieﬂy to purge the argon out of the

ﬂask. The solution was stirred vigorously for 20 min, and the

atmosphere was purged with H₂once more. Then the triﬂuoroacetate

13 or 14 (1 equiv) in MeOH (5 mL per gram of triﬂuoroacetate) and

ethylbenzene (10 equiv) was injected and vigorous stirring was

maintained throughout the reaction. After 12 min, the reaction was

ﬁltered on Celite and concentrated in vacuo to give a pale yellow oil.

The oil was puriﬁed by column chromatography (eluting with

pentane/Et₂O 95:5).

Ethyl syn-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-phenylbu-

tanoate-4-d (4): ¹H NMR (300 MHz, CDCl₃) δ 7.46−7.19 (m, 5H),

4.45 (dd, J = 5.3, 6.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.27−2.07

(m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.14 (s, 3H), 0.11 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.4, 143.9, 128.4, 127.5, 125.8,

71.4 (t, J = 22 Hz), 71.3, 61.0, 43.5, 25.7 (3 C), 18.2, 14.1, −4.9,

−5.4; FT-IR (ATR, neat, cm⁻¹) 3497; 2954; 2930; 2896; 2857; 1736;

1472; 1448; 1374; 1252; 1190; 1131; 835; 779; 701; 630; HR-MS

(ESI+) m/z calcd for C₁₈H₂₉DO₄SiNa [M + Na]⁺362.1868, found

362.1864.

General Procedure for Acetylation (11 and 12). Alcohols 3 or 4

(1 equiv) were dissolved in dry CH₂Cl₂(0.05 M reaction) under

argon. Triethylamine (5 equiv) was added, followed by acetic

anhydride (2 equiv) and DMAP (0.2 equiv). After 4 h, cold NH₄Cl

sat. solution was added to quench the reaction, which was then

poured into a separatory funnel. The aqueous phase was extracted

three times with CH₂Cl₂. The organic phases were gathered, dried

over Na₂SO₄, ﬁltered, and concentrated in vacuo to give a transparent

oil. The acetates were puriﬁed by column chromatography (eluting

with pentane/Et₂O 9:1).

anti-Ethyl 4-Acetoxy-2-((tert-butyldimethylsilyl)oxy)-4-phe-

nylbutanoate-4-d (11): obtained as a transparent oil (79%); H

NMR (400 MHz, CDCl₃) δ 7.38−7.22 (m, 5H), 4.35 (dd, J = 3.3, 9.5

Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.35 (dd, J = 3.3, 14.3 Hz, 1H),

2.07 (s, 3H), 2.02 (dd, J = 9.6, 14.2 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H),

0.95 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 173.3, 169.9, 140.6, 128.5 (2 C), 127.9, 126.2 (2 C), 72.1

(t, J = 22.7 Hz), 69.0, 60.9, 42.0, 25.7 (3 C), 21.2, 18.2, 14.1, −4.9,

−5.5; FT-IR (ATR, neat, cm⁻¹) 2956; 2930; 2896; 2857; 1744; 1472;

1449; 1368; 1232; 1189; 1125; 1085; 1071; 1022; 975; 938; 837;

779; 700; 667; 647; 629; HR-MS (ESI+) m/z calcd for

C₂₀H₃₁DO₅SiNa [M + Na]⁺404.1979, found 404.1963.

Example on gram-scale: 1.143 g (2.62 mmol) 14 gave 0.785 g (2.42

mmol) 2, 92% yield.

anti-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-phenylbuta-

noate-4-d (1): obtained as a transparent oil (58 mg, 0.18 mmol,

98% yield, 99% IP); H NMR (400 MHz, CDCl₃) δ 7.40−7.19 (m,

5H), 4.31 (dd, J = 5.3, 6.5 Hz, 1H), 4.29−4.16 (m, 2H), 2.81 (t, J =

8.1 Hz, 1H), 2.15−2.05 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.01 (s,

9H), 0.17 (s, 3H), 0.14 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

173.6, 141.5, 128.4 (4 C), 125.9, 71.8, 60.7, 36.8, 31.1 (t, J = 19.1

Hz), 25.7 (3 C), 18.3, 14.2, −4.9, −5.3; FT-IR (ATR, neat, cm⁻¹)

2954; 2930; 2895; 2857; 1752; 1732; 1497; 1472; 1370; 1251; 1184;

syn-Ethyl 4-Acetoxy-2-((tert-butyldimethylsilyl)oxy)-4-phe-

nylbutanoate-4-d (12): obtained as a transparent oil (83%); H

NMR (400 MHz, CDCl₃) δ 7.43−7.24 (m, 5H), 4.30−4.11 (m, 3H),

2.43 (dd, J = 5.0, 14.2 Hz, 1H), 2.21 (dd, J = 6.2, 14.2 Hz, 1H), 2.01

(s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 0.99−0.89 (m, 9H), 0.08 (s, 3H),

0.04 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 173.1, 169.7, 140.0,

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1131; 1031; 970; 834; 777; 738; 699; 663; 627; HR-MS (ESI+) m/z

calcd for C₁₈H₂₉DO₃SiNa [M + Na]⁺346.1919, found 346.1924.

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-phenylbuta-

noate-4-d (2): obtained as a transparent oil (43 mg, 0.13 mmol,

817; 750; 675; HR-MS (ESI+) m/z calcd for C₁₀H₁₂DClO₂Na [M +

Na]⁺224.0565, found 224.0558.

General Procedure for Cyclization (15 and 16). A microwave vial

was charged with Pd(OAc)₂(5 mol %), Trixiephos (10 mol %), and

Cs₂CO₃(2.5 equiv). The vial was sealed, evacuated, and backﬁlled

with argon. Aryl chloride 19 or 20 (1 equiv) in dry toluene (0.07 M

reaction) was added via syringe. The reaction was heated to 80 °C

using microwave irradiation. After 24 h, the reaction was diluted with

EtOAc and ﬁltered through a pad of Celite. The organic phase was

then extracted with NH₄Cl sat. solution (1×) and dried over Na₂SO₄,

ﬁltered, and concentrated in vacuo to give a to give a yellow oil. It was

puriﬁed by column chromatography (eluting with pentane/EtOAc

3:2) to give the desired chromanes.

98% yield, 99% IP); H NMR (300 MHz, CDCl₃) δ 7.41−7.20 (m,

5H), 4.35−4.15 (m, 3H), 3.54 (q, J = 7.0 Hz, 1H), 2.78−2.68 (m,

1H), 2.18−2.00 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.00 (s, 9H), 0.16

(s, 3H), 0.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.6, 141.5,

128.4 (4 C), 125.9, 71.8, 60.7, 36.9, 31.1 (t, J = 19.3 Hz), 25.7 (3 C),

18.3, 14.2, −4.9, −5.3; FT-IR (ATR, neat, cm⁻¹) 2954; 2930; 2896;

2857; 1752; 1732; 1472; 1362; 1251; 1181; 1131; 1029; 981; 833;

777; 738; 699; 666; HR-MS (ESI+) m/z calcd for C₁₈H₂₉DO₃SiNa

[M + Na]⁺346.1919, found 346.1917.

General Procedure for Reduction to Diols (17 and 18).

Deuterated ester 1 or 2 (1 equiv) was dissolved in dry THF (0.03

M reaction) under argon and cooled to 0 °C (ice bath). Then LiAlH₄

(3 equiv) was added. After 20 min, the reaction was quenched with

NH₄Cl sat. solution and stirred until bubbling ceased. The ice bath

was removed, and a saturated solution of Rochelle’s salt was added.

THF was removed under reduced pressure, and the remaining

solution was transferred to a separatory funnel. The aqueous phase

was extracted with EtOAc (3×). The organic phases were gathered,

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to give a

transparent oil. It was puriﬁed by column chromatography (eluting

with EtOAc 100%) to give the desired diol.

(cis-Chroman-2-yl-4-d)methanol (15): pale yellow oil (16%);

¹H NMR (400 MHz, methanol-d₄) δ 7.08−6.95 (m, 2H), 6.83−6.51

(m, 2H), 4.17−3.93 (m, 1H), 3.71 (d, J = 5.1 Hz, 2H), 2.84 (m, 1H),

2.01 (ddd, J = 2.3, 6.1, 13.5 Hz, 1H), 1.84−1.67 (m, 1H); ¹³C NMR

(101 MHz, methanol-d₄) δ 156.3, 130.6, 128.3, 123.4, 121.3, 117.8,

78.0, 65.9, 25.3 (t, J = 19.8 Hz) (2 C); FT-IR (ATR, neat, cm⁻¹)

3379; 2925; 2874; 1720; 1609; 1581; 1487; 1455; 1297; 1229; 1088;

1075; 1043; 997; 939; 906; 881; 841; 752; 701; 632; HR-MS (ESI+)

m/z calcd for C₁₀H₁₁DO₂Na [M + Na]⁺188.0792, found 188.0792.

(trans-Chroman-2-yl-4-d)methanol (16): pale yellow oil

(16%); H NMR (400 MHz, methanol-d₄) δ 7.06−6.98 (m, 2H),

6.82−6.69 (m, 2H), 4.06−3.98 (m, 1H), 3.71 (d, J = 5.1 Hz, 2H),

2.74 (dd, J = 2.3, 5.0 Hz, 1H), 2.09−1.95 (m, 1H), 1.83−1.65 (m,

1H); ¹³C NMR (101 MHz, methanol-d₄) δ 156.3, 130.7, 128.3, 123.3,

121.3, 117.8, 78.0, 65.9, 25.3 (t, J = 19.8 Hz); FT-IR (ATR, neat,

cm⁻¹) 3387; 2924; 2876; 1718; 1609; 1580; 1487; 1454; 1396; 1345;

1297; 1275; 1232; 1180; 1079; 1033; 924; 930; 907; 837; 752; 701;

631; HR-MS (ESI+) m/z calcd for C₁₀H₁₁DO₂Na [M + Na]⁺

188.0792, found 188.0792.

anti-4-Phenylbutane-4-d-1,2-diol (17). transparent oil (93%); H

NMR (400 MHz, methanol-d₄) δ 7.32−7.08 (m, 5H), 3.65−3.54 (m,

1H), 3.53−3.40 (m, 2H), 2.83−2.72 (m, 1H), 1.85−1.59 (m, 2H);

¹³C NMR (101 MHz, methanol-d₄) δ 143.7, 129.6 (2 C), 129.5 (2

C), 126.9, 72.6, 67.5, 36.5, 32.6 (t, J = 19.8 Hz); FT-IR (ATR, neat,

cm⁻¹) 3350; 3025; 2926; 2871; 2486; 1603; 1496; 1450; 1367; 1103;

1049; 1031; 979; 849; 746; 701; 632; HR-MS (ESI+) m/z calcd for

C₁₀H₁₃DO₂Na [M + Na]⁺190.0954, found 190.0946.

Ethyl 2-Hydroxy-4-oxo-4-(4-(triﬂuoromethyl)phenyl)-

butanoate (21). 1-(4-(Triﬂuoromethyl)phenyl)-ethan-1-one (5.0 g,

26.6 mmol, 1 equiv) and ethyl 2-oxoacetate (6.3 mL, 32 mmol, 1.2

equiv) (50% in toluene) were stirred at 100 °C in an oil bath for 5

days. Toluene was removed in vacuo, and the resulting bright yellow

oil was puriﬁed by column chromatography (eluting with pentane/

syn-4-Phenylbutane-4-d-1,2-diol (18): transparent oil (92%); H

NMR (400 MHz, methanol-d₄) δ 7.37−7.07 (m, 5H), 3.66−3.54 (m,

1H), 3.52−3.39 (m, 2H), 2.71−2.55 (m, 1H), 1.86−1.58 (m, 2H);

¹³C NMR (101 MHz, methanol-d₄) δ 143.7, 129.6 (2 C), 129.5 (2

C), 126.9, 72.7, 67.5, 36.5, 32.7 (t, J = 19.1 Hz); FT-IR (ATR, neat,

cm⁻¹) 3349; 3025; 2930; 2872; 2482; 1603; 1496; 1451; 1102; 1046;

1031; 975; 929; 915; 855; 746; 700; 655; 622; HR-MS (ESI+) m/z

calcd for C₁₀H₁₃DO₂Na [M + Na]⁺190.0954, found 190.0944.

General Procedure for Chlorination (19 and 20). Diol 17 or 18

(1 equiv) was dissolved in MeCN (0.3 M reaction). Water (20 equiv)

was added, followed by TFA (0.1 equiv) and KCl (1.3 equiv). Lastly,

Oxone (1 equiv) was added, and the reaction was rapidly wrapped in

foil. After 5 h of stirring in the dark, the reaction was quenched with

Na₂S₂O₃sat. solution and diluted with EtOAc. It was transferred to an

extraction funnel, and the aqueous phase was extracted with EtOAc

(3×). The organic phases were gathered, dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo to give a to give a pale yellow oil. It was

puriﬁed by column chromatography (eluting with EtOAc 100%) to

give the desired chlorinated products as an inseparable mixture of

ortho- and para-chlorinated diols in a 1:1 ratio.

EtOAc 7:3) to give 21 (5.4 g, 18.6 mmol, 70%) as a white solid: H

NMR (300 MHz, CDCl₃) δ 8.07 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.3

Hz, 2H), 4.68 (td, J = 3.9, 5.6 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H),

3.62−3.41 (m, 2H), 3.28 (d, J = 5.4 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 196.4, 173.6, 139.1, 134.9 (q, J = 33.0

Hz), 128.5 (2 C), 125.8 (q, J = 3.7 Hz, 2 C), 123.5 (q, J = 272.2 Hz),

67.0, 62.1, 42.4, 14.1; FT-IR (ATR, neat, cm⁻¹) 3379; 3328; 2996;

2962; 2938; 2914; 1721; 1694; 1514; 1478; 1413; 1389; 1369; 1328;

1278; 1160; 1125; 1068; 1034; 1017; 997; 950; 894; 859; 842; 730;

700; 640; 608; HR-MS (ESI+) m/z calcd for C₁₃H₁₃F₃O₄Na [M +

Na]⁺313.0664, found 313.0660; mp 65−68 °C.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-oxo-4-(4-

(triﬂuoromethyl)phenyl)butanoate (22). Compound 21 (3.0 g,

10.4 mmol 1 equiv) was dissolved in dry CH₂Cl₂(60 mL) under

argon, and then imidazole (1.5 g, 22.8 mmol, 2.2 equiv) and TBS-Cl

(1.7 g, 11.4 mmol, 1.1 equiv) were added. The reaction was stirred

overnight and then quenched with NH₄Cl sat. solution (50 mL). The

reaction was poured into an extraction funnel, and the aqueous phase

was extracted with CH₂Cl₂(3 × 50 mL). The organic phases were

gathered, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to

give a pale yellow oil. It was puriﬁed by column chromatography

(eluting with pentane/EtOAc 9:1) to give 22 (3.81 g, 9.4 mmol, 91%)

anti-4-(x-Chlorophenyl)butane-4-d-1,2-diol (19): transparent oil

(39%); H NMR (400 MHz, methanol-d₄) δ 7.37−7.07 (m, 4 H),

3.69−3.41 (m, 3H), 2.98−2.70 (m, 1H), 1.89−1.57 (m, 2H); ¹³C

NMR (101 MHz, methanol-d₄) δ 142.5, 141.2, 135.0, 132.7, 131.8,

131.2, 130.6, 129.5, 128.7, 128.2, 72.8, 72.5, 67.5, 36.3, 34.6, 31.9 (t, J

= 19.1 Hz) 30.5 (t, J = 19.1 Hz); FT-IR (ATR, neat, cm⁻¹) 3342;

2929; 2874; 2479; 1492; 1473; 1440; 1405; 1092; 1048; 1037; 1015;

986; 9412; 863; 819; 750; 642; 620; HR-MS (ESI+) m/z calcd for

C₁₀H₁₂DClO₂Na [M + Na]⁺224.0565, found 224.0557.

as a transparent oil. H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 8.1

Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 4.86 (dd, J = 4.8, 7.5 Hz, 1H),

4.26−4.18 (m, 2H), 3.48−3.31 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H),

0.83 (s, 9H), 0.12 (s, 3H), 0.04 (s, 3 H) ¹³C NMR (101 MHz,

CDCl₃) δ 196.4, 172.7, 139.7, 134.5 (q, J = 33.0 Hz), 128.6 (2 C),

125.7 (q, J = 4.2 Hz, 2 C), 123.5 (q, J = 272.2 Hz), 69.1, 61.3, 43.7,

25.6 (3 C), 18.1, 14.1, −4.9, −5.5; FT-IR (ATR, neat, cm⁻¹) 2956;

2931; 2899; 2858; 1752; 1693; 1512; 1473; 1410; 1324; 1256; 1170;

1130; 1110; 1066; 1027; 994; 943; 880; 828; 780; 720; 665; 630;

syn-4-(x-Chlorophenyl)butane-4-d-1,2-diol (20): transparent oil

(55%); H NMR (400 MHz, methanol-d₄) δ 7.37−7.07 (m, 4 H),

3.68−3.37 (m, 3H), 2.85−2.54 (m, 1H), 1.90−1.54 (m, 2 H) ¹³C

NMR (101 MHz, methanol-d₄) δ 142.5, 141.2, 135.0, 132.6, 131.8,

131.2, 130.6, 129.5, 128.7, 128.2, 72.8, 72.5, 67.5, 61.7, 36.3, 34.6,

32.0 (t, J = 19.1 Hz) 30.6 (t, J = 19.8 Hz); FT-IR (ATR, neat, cm⁻¹)

3346; 2929; 2872; 2482; 1595; 1492; 1474; 1440; 1092; 1037; 1015;

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Note

HR-MS (ESI+) m/z calcd for C₁₉H₂₇F₃O₄SiNa [M + Na]⁺427.1528,

found 427.1539.

= 22.0 Hz), 61.2, 43.4, 25.7 (3 C), 18.2, 14.1, −4.9, −5.5; FT-IR

(ATR, neat, cm⁻¹) 3496; 2953; 2932; 2886; 2860; 1734; 1619; 1464;

1406; 1406; 1375; 1323; 1253; 1221; 1103; 1088; 1066; 1011; 970;

956; 885; 832; 779; 723; 664; 638; HR-MS (ESI+) m/z calcd for

C₁₉H₂₈DF₃O₄SiNa [M + Na]⁺430.1748, found 430.1735; mp 53−55

°C.

General Procedure for Triﬂuoroacetylation (27 and 28). Alcohols

25 or 26 (1 equiv) were dissolved in dry CH₂Cl₂(0.06 M reaction)

under argon, and triethylamine (5 equiv) was added. The mixture was

cooled to 0 °C with an ice bath. Then triﬂuoroacetic anhydride (2

equiv) was added. After 1.5 h, cold NH₄Cl sat. solution was added to

quench the reaction, which was then poured into a separatory funnel.

The aqueous phase was extracted three times with CH₂Cl₂. The

organic phases were gathered, dried over Na₂SO₄, ﬁltered, and

concentrated in vacuo to give a transparent oil. The triﬂuoroacetates

were puriﬁed by column chromatography (eluting with pentane/Et₂O

9:1). The triﬂuoroacetates degrade rapidly after puriﬁcation (an exact

mass was not obtained). They were used immediately in the next

reaction.

Ethyl 2-Hydroxy-4-(4-methoxyphenyl)-4-oxobutanoate

(23). 1-(4-Methoxyphenyl)ethan-1-one (6 g, 40 mmol, 1 equiv)

and ethyl 2-oxoacetate (8 mL, 40 mmol, 1 equiv) (50% in toluene)

were stirred at 100 °C in an oil bath for 5 days. Toluene was removed

in vacuo, and the resulting yellow oil was puriﬁed by column

chromatography (pentane/EtOAc 2:3) to give 23 (7.96 g, 31.6 mmol,

79%) as a pale yellow crystalline solid. NMR shifts correspond to

those in the literature:¹²¹H NMR (300 MHz, CDCl₃) δ 7.98−7.90

(m, 2H), 6.98−6.90 (m, 2H), 4.69−4.61 (m, 1H), 4.27 (q, J = 7.2 Hz,

2H), 3.88 (s, 3H), 3.54−3.36 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 196.1, 173.8, 163.9, 130.5 (2 C), 129.5,

113.8 (2 C), 67.4, 61.8, 55.5, 41.7, 14.1.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-(4-methoxyphenyl)-

4-oxobutanoate (24). Compound 23 (6.14 g, 24.35 mmol, 1 equiv)

was dissolved in dry CH₂Cl₂(60 mL) under argon, and imidazole

(3.98 g, 58.44 mmol, 2.4 equiv), followed by TBS-Cl (4.40 g, 29.22

mmol, 1.2 equiv), was added. The reaction was stirred overnight. It

was then quenched with NaHCO₃sat. solution (60 mL) and poured

into an extraction funnel. The aqueous layer was extracted with

CH₂Cl₂(3 × 50 mL). The organic phases were gathered, dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo to give a brown oil. It was

puriﬁed by column chromatography (eluting with pentane/EtOAc

anti-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-(2,2,2-triﬂuoroace-

toxy)-4-(4-(triﬂuoromethyl)phenyl)butanoate-4-d (27): transparent

oil (84%); H NMR (300 MHz, CDCl₃) δ 7.65 (d, J = 8.1 Hz, 2H),

7.49 (d, J = 8.1 Hz, 2H), 4.36 (dd, J = 3.4, 9.4 Hz, 1H), 4.12 (q, J =

7.2 Hz, 2H), 2.51 (dd, J = 3.3, 14.5 Hz, 1H), 2.16 (dd, J = 9.5, 14.5

Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 0.95 (s, 9H), 0.11 (s, 3H), 0.05 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.5, 156.5 (q, J = 42.9 Hz),

141.7 (d, J = 1.1 Hz), 131.2 (q, J = 33.0 Hz, 2 C), 126.8 (2 C), 125.9

(q, J = 3.9 Hz, 2 C), 123.7 (q, J = 272.3 Hz), 114.4 (q, J = 286.1 Hz),

75.9 (t, J = 22.6 Hz), 68.3, 61.3, 41.2, 25.6 (3 C), 18.1, 14.0, −4.9,

−5.8; FT-IR (ATR, neat, cm⁻¹) 2956; 2932; 2898; 2861; 1788; 1755;

1735; 1623; 1473; 1412; 1367; 1325; 1254; 1222; 1127; 1069; 1029;

977; 837; 777; 729; 667; 630; 609.

9:1) to give 24 (6.89 g, 18.8 mmol, 77%) as a transparent oil: H

NMR (400 MHz, CDCl₃) δ 8.00−7.91 (m, 2H), 6.99−6.89 (m, 2H),

4.85 (dd, J = 4.7, 7.6 Hz, 1H), 4.21 (dd, J = 1.3, 7.2 Hz, 2H), 3.43−

3.22 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.83 (s, 9H), 0.11 (s, 3H),

0.03 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 195.7, 173.1, 163.6,

130.6 (2 C), 130.3, 113.7 (2 C), 69.3, 61.1, 55.5, 43.2, 25.6 (3 C),

18.2, 14.1, −5.0, −5.4; FT-IR (ATR, neat, cm⁻¹) 2955; 2930; 2902;

2857; 1750; 1676; 1599; 1576; 1511; 1463; 1420; 1363; 1256; 1213;

1168; 1060; 1009; 990:955; 938; 879; 828; 779; 630; HR-MS (ESI+)

m/z calcd for C₁₉H₃₀O₅SiNa [M + Na]⁺389.1755, found 389.1765.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

(triﬂuoromethyl)phenyl)butanoate-4-d (25 and 26). Com-

pound 22 (3.68 g, 9.10 mmol, 1 equiv) was dissolved in MeOD

(65 mL) and cooled to 0 °C (ice bath). Then NaBD₄(762 mg, 18.2

mmol, 2 equiv) was added in portions. After 20 min, the reaction was

quenched with NH₄Cl sat. solution (30 mL) and stirred at rt for 20

min. Then the reaction was concentrated in vacuo to give a paste. The

paste was diluted with EtOAc (50 mL) and NH₄Cl sat. solution (20

mL) and poured into an extraction funnel. The aqueous phase was

extracted with EtOAc (3 × 50 mL). The organic phases were

gathered, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to

give a yellow oil. It was puriﬁed by column chromatography (eluting

with pentane/EtOAc 9:1) to aﬀord successively the anti isomer 25

(0.63 g, 1.55 mmol, 17%) as a transparent oil and the syn isomer 26

(1.45 g, 3.56 mmol, 39%) as a white solid, followed by a mixture of

both diastereoisomers (1.23 g, 3.0 mmol, 33%) as a transparent oil.

Total yield: 3.38 g, 8.297 mmol, 91%.

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-(2,2,2-triﬂuoroace-

toxy)-4-(4-(triﬂuoromethyl)phenyl)butanoate-4-d (28): transparent

oil (90%); H NMR (300 MHz, CDCl₃) δ 7.67 (d, J = 8.2 Hz, 2H),

7.50 (d, J = 8.1 Hz, 2H), 4.34−4.13 (m, 3H), 2.62 (dd, J = 4.3, 14.5

Hz, 1H), 2.28 (dd, J = 6.5, 14.5 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H),

0.93 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 172.4, 156.3 (q, J = 42.4 Hz) 141.6, 131.3 (q, J = 32.5 Hz) 127.0 (2

C), 126.0 (q, J = 3.9 Hz, 2 C), 123.8 (q, J = 272.3 Hz), 114.4 (q, J =

286.1 Hz), 75.4 (t, J = 22.6 Hz), 68.3, 61.2, 40.6, 25.6 (3 C), 18.2,

14.0, −4.9, −5.5; FT-IR (ATR, neat, cm⁻¹) 2955; 2933; 2888; 2860;

1788; 1755; 1473; 1412; 1369; 1326; 1254; 1222; 1132; 1068; 1025;

1013; 941; 838; 778; 728; 669; 630; 609.

Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

methoxyphenyl)butanoate-4-d (29 and 30). CeCl₃·7H₂O (8.1

g, 21.8 mmol, 2 equiv) was placed in a ﬂask and heated to 90 °C

under a vacuum with stirring for 4 h. Then it was heated to 145 °C

under a vacuum with stirring overnight. The dry CeCl₃was placed

under an argon atmosphere, cooled to rt, and then covered with

MeOD (50 mL). Compound 24 (4.0 g, 10.9 mmol, 1 equiv) in

MeOD (5 mL) was injected, and the mixture was cooled to 0 °C (ice

bath). Then NaBD₄(915 mg, 21.8 mmol, 2 equiv) was added in

portions. After 10 min, the reaction was quenched with NH₄Cl sat.

solution (20 mL) and stirred at rt for 20 min. Then the reaction was

concentrated in vacuo to give a paste. The paste was diluted with

EtOAc (50 mL) and NH₄Cl sat. solution (30 mL) and poured into an

extraction funnel. The aqueous phase was extracted with EtOAc (3 ×

50 mL). The organic phases were gathered, dried over Na₂SO₄,

ﬁltered, and concentrated in vacuo to give a yellow oil. It was puriﬁed

by column chromatography (pentane/EtOAc 17:3) to aﬀord

successively the anti isomer 29 (1.12 g, 3.0 mmol, 28%), the syn

isomer 30 (1.46 g, 3.94 mmol, 36%), and a mixture of both isomers

(0.61 g, 1.66 mmol, 15%) as transparent oils. Total yield: 3.19 g, 8.63

mmol, 79%.

anti-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

(triﬂuoromethyl)phenyl)butanoate-4-d (25): H NMR (300 MHz,

CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.56 (t, J

= 5.2 Hz, 1H), 4.22 (dd, J = 4.8, 7.2 Hz, 2H), 3.28 (s, 1H), 2.10 (d, J

= 5.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H), 0.97 (s, 9H), 0.16 (s, 3H),

0.12 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.0, 148.1, 129.6 (q,

J = 32.3 Hz), 125.9 (2 C), 125.4 (q, J = 3.7 Hz, 2 C), 124.1 (q, J =

272.2 Hz) 70.7, 70.2 (t, J = 22.0 Hz), 61.2, 43.3, 25.7 (3 C), 18.2,

14.2, −4.9, −5.6; FT-IR (ATR, neat, cm⁻¹) 3489; 2955; 2931; 2888;

2859; 1734; 1621; 1465; 1410; 1326; 1256; 1164; 1127; 1068; 1032;

839; 726; 668; 631; HR-MS (ESI+) m/z calcd for C₁₉H₂₈DF₃O₄SiNa

[M + Na]⁺430.1748, found 430.1726.

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

(triﬂuoromethyl)phenyl)butanoate-4-d (26): H NMR (300 MHz,

CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.51−

4.44 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 2.22−2.07 (m, 2H), 1.28 (t, J

= 7.2 Hz, 3H), 0.96 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 173.2, 147.9, 129.6 (q, J = 32.3 Hz), 126.0 (2

C), 125.3 (q, J = 3.7 Hz, 2 C), 124.2 (q, J = 271.0 Hz), 71.3, 70.9 (t, J

anti-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

methoxyphenyl)butanoate-4-d (29): H NMR (300 MHz, CDCl₃)

δ 7.28 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.54 (dd, J = 3.8,

7.2 Hz, 1H), 4.26−4.15 (m, 2H), 3.80 (s, 3H), 2.84−2.79 (m, 1H),

2.17−1.99 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.15 (s,

https://dx.doi.org/10.1021/acs.joc.0c00827

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

3H), 0.12 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.3, 158.8,

136.4, 126.7 (2 C), 113.7 (2 C), 70.4, 69.8 (t, J = 21.3 Hz), 60.8, 55.2,

43.5, 25.6 (3 C), 18.1, 14.1, −5.1, −5.6; FT-IR (ATR, neat, cm⁻¹)

3499; 2954; 2930; 2899; 2857; 1749; 1733; 1613; 1513; 1471; 1362;

1301; 1248; 1176; 1131; 1101; 1037; 836; 780; 734; 669; 632; HR-

MS (ESI+) m/z calcd for C₁₉H₃₁O₅SiDNa [M + Na]⁺392.1974,

found 392.1988.

2930; 2896; 2859; 1751; 1731; 1620; 1473; 1464; 1324; 1252; 1185;

1163; 1122; 1067; 1050; 1019; 971; 832; 813; 777; HR-MS (ESI+)

m/z calcd for C₁₉H₂₈DF₃O₃SiNa [M + Na]⁺414.1799, found

414.1814.

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-(4-(triﬂuoromethyl)-

phenyl)butanoate-4-d (34): transparent oil (665 mg, 1.70 mmol,

92% yield, 99% IP); H NMR (300 MHz, CDCl₃) δ 7.54 (d, J = 8.3

syn-Ethyl 2-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-4-(4-

Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.31−4.10 (m, 3H), 2.74 (t, J = 8.1

Hz, 1H), 2.10−2.00 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.94 (s, 9H),

0.11 (s, 3H), 0.08 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.3,

145.7, 128.7 (2 C), 128.4 (q, J = 32.3 Hz), 125.3 (q, J = 3.7 Hz, 2 C),

124.3 (q, J = 271.4 Hz), 71.6, 60.8, 36.5, 30.9 (t, J = 19.8 Hz), 25.7 (3

C), 18.3, 14.2, −4.9, −5.4; FT-IR (ATR, neat, cm⁻¹) 2955; 2931;

2893; 2859; 1752; 1731; 1620; 1473; 1324; 1251; 1163; 1110; 1067;

1019; 834; 778; 662; 630; HR-MS (ESI+) m/z calcd for

C₁₉H₂₈DF₃O₃SiNa [M + Na]⁺414.1799, found 414.1799.

General Procedure for Hydrogenolysis (35 and 36). Pd/C

10% weight (0.05 equiv) was weighed in a two-neck round-bottom

ﬂask containing a stir bar and suspended in EtOAc (0.02 M reaction)