Synthesis of γ-Oxo-α-amino Acids via Radical Acylation with Carboxylic Acids

Note

Synthesis of γ‑Oxo-α-amino Acids via Radical Acylation with

Carboxylic Acids

Kay Merkens, Francisco Jos é Aguilar Troyano, Khadijah Anwar, and Adri á n G ó mez-Su á rez*

†

Cite This: J. Org. Chem. 2021, 86, 8448 −8456

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sı Supporting Information

ABSTRACT: Herein we present a highly eﬃcient, light-mediated,

deoxygenative protocol to access γ-oxo-α-amino acid derivatives.

This radical methodology employs photoredox catalysis, in

combination with triphenylphosphine, to generate acyl radicals

from readily available (hetero)aromatic and vinylic carboxylic acids.

This approach allows for the straightforward synthesis of γ-oxo-α-

amino acids bearing a wide range of functional groups (e.g., Cl, CN,

furan, thiophene, Bpin) in synthetically useful yields (∼60%

average yield). To further highlight the utility of the methodology,

several deprotection and derivatization reactions were carried out.

γ-Oxo-α-amino acids are highly versatile building blocks in

organic synthesis, as well as key components in biologically

active molecules. They can be used as precursors for

Recently, the development of deoxygenative radical

strategies to access acyl radicals has attracted increased

attention. Seminal independent studies by Rovis and

13e

13d

homophenylalanine derivatives, γ-hydroxy-α-amino acids, γ-

Doyle and Zhu described the use of photoredox catalysis

to generate phosphine radical cations that swiftly react with

carboxylates to generate acyl radicals and phosphine oxide after

valerolactones, or γ-valerolactames, for example. As it is often

the case in synthetic chemistry, one of the main challenges

associated with this interesting class of amino acids is their

stereoselective synthesis. There are four main retrosynthetic

pathways to achieve this goal: (a) via acylation reactions,

β-scission (vide infra). Encouraged by these reports, we

envisioned that it might be possible to develop a diaster-

eoselective synthesis of γ-oxo-α-amino acids using I and readily

available carboxylic acids as acyl radical sources (Figure 1C).

Herein we present a highly eﬃcient, light-mediated

deoxygenative protocol to access products II from readily

and commercially available (hetero)aromatic and vinylic

carboxylic acids. In addition, the utility of this methodology

is further highlighted by several derivatizations and depro-

starting from L- or D-aspartic acid, (b) via asymmetric or

diastereoselective Mannich reactions, (c) via asymmetric

Stetter reactions, or (d) via transition metal-mediated cross-

couplings with iodoalanine or β-metalated alanine derivatives

(

Figure 1A). While powerful, these methodologies often

present limitations regarding the scope of coupling partners, or

require the use of chiral catalysts.

tections of II.

Initial optimization studies were carried out using benzoic

Radical chemistry oﬀers exciting and highly attractive

acid as the acylating reagent. The targeted product (1) could

be isolated in 95% yield and excellent diastereoselectivity (d.r.

> 20:1) using 1.0 equiv of I, 1.5 equiv of benzoic acid, 1.8

approaches to access new chemical space in a rapid fashion.

As such, it has been exploited for the synthesis and

derivatization of amino acids and peptides. We recently

equiv. of PPh , 2.0 equiv. of 2,4,6-collidine, and 1.0 mol%

contributed to this area with the development of a

decarboxylative protocol for the diastereoselective synthesis

of a wide range of unnatural amino acids (UAAs) using the

[

Ir(dFCF ppy) (dtbbpy)][PF ] (Ir−F) in 1,4-dioxane (0.2

M) while irradiating with 32 W blue LEDs (λ = 440 nm) for

max

24 h at room temperature. Control experiments showed that

the reaction needs both light and a photocatalyst to proceed,

Beckwith−Karady alkene I as radical acceptor. Although

this methodology granted access to γ-oxo-α-amino acids

derivatives (II) when using α-keto acids as acylating reagents

and that it does not proceed when using 4CzIPN, an

(

Figure 1B), it aﬀorded diminished yields with electron

deﬁcient or (hetero)aromatic systems. In addition, α-keto

acids are not readily available, and their synthesis often

Received: December 15, 2020

Published: June 1, 2021

requires the use of hazardous reagents, such SeO . Since II is a

highly versatile species, we became interested in developing

alternative methodologies for its synthesis using more readily

available starting materials.

2021 American Chemical Society

The Journal of Organic Chemistry

448

J. Org. Chem. 2021, 86, 8448−8456

Note

desired product in moderate yields (16), no product was

observed with picolinic or pyrazinoic acids (18−19).

Surprisingly, when the reaction was carried out using 4-

chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylic acid,

the main product was the dechlorinated species 17 (39%),

while the expected product 17′ was isolated in 18% yield. The

use of 5-membered heterocycles (20−22), such as unprotected

pyrroles (20), furans (21), and thiophenes (22) aﬀorded the

desired products in variable yields (21−71%). Overall, our new

methodology presents a broad functional group tolerance,

where compounds bearing several vectors for further

functionalization, such as halides, boronic esters, or amines,

can be readily obtained.

To further challenge the limits of our methodology, the use

of aliphatic, cinnamic, and vinylic carboxylic acids as acylating

reagents was evaluated. While hydrocinnamic acid failed to

aﬀord the desired product, cinnamic acid delivered a

complex mixture, from where the targeted product could not

be isolated. However, the use of cyclic, vinylic carboxylic

acids aﬀorded interesting γ-oxo-α-amino acid derivatives

bearing 5- and 6-membered heterocycles, such dihydrofuranes

(

27), tetrahydropyrines (26), and tetrahydropyrans (24). To

the best of our knowledge, this is the ﬁrst time that vinylic

carboxylic acids have been directly used as acyl radical

precursors.

To highlight the utility of our methodology, a series of

derivatization reactions were carried out. Acidic deprotection

of II using concentrated HCl in 1,4-dioxane aﬀorded γ-oxo-α-

amino acid salts 28−30 in quantitative yields (Scheme 2A). To

check the e.r. of the products after the deprotection step,

compound 1 was deprotected and further derivatized to the

corresponding N-Boc protected methyl ester. HPLC analysis of

the latter revealed a 92:8 e.r. Our methodology can also be

applied for the acylation of dehydroalanine derivative IA,

aﬀording the corresponding product 1A in 55% yield (Scheme

Figure 1. Synthetic strategies toward γ-oxo-α-amino acids.

organophotocatalyst possessing similar redox potentials to Ir−

With the optimized conditions in hand, the scope and

limitations, as well as the scalability of the methodology, were

explored (Scheme 1). The standard reaction with benzoic acid

was scaled up to 5.0 mmol (1.4 g of II), aﬀording 1 in 95%

2B), and for the synthesis of C-labeled amino acid derivatives

(Scheme 2C).

Finally, a plausible reaction mechanism for this trans-

formation is shown in Figure 2. First, the excited photocatalyst

III

(

1.9 g) and 73% (1.4 g) yield using 0.5 mol% and 0.25 mol%

(*Ir , *E1/2 = +1.21 V vs SCE) undergoes reductive

of Ir−F, respectively. This highlights the high catalytic

eﬃciency of the methodology, aﬀording TON up to 288.

Regarding the scope, aromatic carboxylic acids were ﬁrst tested

quenching by PPh (E1/2 = +0.98 V vs SCE) to generate

triphenhylphosphine radical cation III and a Ir species. III

reacts with the corresponding carboxylic acid to aﬀord

phosphoranyl radical IV, which readily undergoes β-scission

(2−15). Both electron rich and poor para-substituents on the

aromatic ring were tolerated (2−10), although the latter

aﬀorded diminished yields. However, this represents a

signiﬁcant improvement compared to our previous method-

ology employing α-keto acids as acylating reagents, e.g.,

compound 9 was isolated in 61% yield vs 31% yield using α-

to deliver OPPh and the key acyl radical V. Subsequent radical

addition of the latter to I aﬀords α-amino radical VI, which

after reduction by the reduced Ir (E1/2 = −1.37 V vs SCE)

and protonation delivers the desired product II. This

mechanism is in accordance with previous proposals for

acylation reactions using photoredox catalysis to access

phosphoranyl radicals. Quantum yield determinations

suggest that there is also a signiﬁcant contribution from a

radical-chain pathway (Φ = 13.5). On the basis of further

experiments, 2,4,6-collidine seems to play a crucial role in the

chain process. However, at this point, the nature of the chain

keto acids. Free nucleophilic motifs, such as hydroxy groups,

were not tolerated (2); however, this limitation could be

circumvented by the use of protecting groups (3 and 4).

Challenging substrates bearing sensitive functional groups,

such as nitriles (8) or aldehydes (10), aﬀorded the desired

products in moderate to poor yields, while compound 15,

bearing a meta-boronic ester substituent, was obtained in 76%

yield. Gratifyingly, ortho-substituents were well tolerated (12

and 13), and salicylic acid derived 13 was obtained in an

excellent 92% yield. More complex aromatic carboxylic acids

bearing multiple functional groups (14) aﬀorded the targeted

γ-oxo-α-amino acid derivative in excellent yield.

3,14

carrier remains elusive.

In conclusion, we have developed a highly eﬃcient, light-

mediated, deoxygenative strategy for the synthesis of γ-oxo-α-

amino acid derivatives. This radical methodology exploits the

addition of acyl radicals, generated from readily available

carboxylic acids, to Beckwith−Karady alkene I, allowing for the

straightforward synthesis of a wide range of γ-oxo-α-amino acid

derivatives in excellent diastereoselectivities and synthetically

The use of heteroaromatic carboxylic acids was also

investigated (16−22). While nicotinic acid aﬀorded the

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J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Note

Scheme 1. Scope and Limitations of the Methodology

.0 mmol scale, Ir−F 0.5 mol%. 5.0 mmol scale, Ir−F 0.25 mol%, 72 h. 48 h. DMF (0.2 M). Reaction conditions: Acid (0.75 mmol, 1.5

equiv.), I (0.50 mmol, 1.0 equiv.), Ir−F (1.0 mol%), PPh (0.9 mmol, 1.8 equiv.), 2,4,6-collidine (1.0 mmol, 2.0 equiv.), 1,4-dioxane (0.2 M), RT,

4 h; product d.r. > 20:1.

useful yields (∼60% average yield). Furthermore, the synthetic

utility of this protocol was highlighted by a series of

derivatization reactions, granting access to in good yields and

diastereoselectivities.

and subsequent heating. Flash column chromatography was

performed on silica gel (40−60 μm), and the eluent used is reported

in the respective experiments.

H NMR spectra were recorded with 400 or 600 MHz instruments,

C{ H} NMR spectra at 101 or 151 MHz. Chemical shifts are

reported in ppm relative to the solvent signal, coupling constants J in

Hz. Multiplicities were deﬁned by standard abbreviations. Low-

resolution mass spectra (LRMS) were recorded using a LC/MS-

combination (ESI). High-resolution mass spectra (HRMS) were

obtained using ESI ionization (positive) on a Bruker micrOTOF.

All carboxylic acids were commercially available, while [Ir-

EXPERIMENTAL SECTION

General Information. Commercial reagents and solvents were

used as purchased. Unless otherwise noted, all reactions were carried

■

out under an atmosphere of N in ﬂame-dried glassware. The solvents

used were puriﬁed by distillation over standard drying agents and

were stored over molecular sieves or transferred under N . Blue LEDs

Kessil PR-160, 32 W, λ_m_a_x= 440 nm or EvoluChem CREE XPE, 30

W, λ_m_a_x= 450 nm) were used for irradiation, in combination with an

EvoluChem PhotoRedOx Box. The reaction temperature was kept at

7 °C thanks to the fans incorporated in the reactor.

TLC were conducted with precoated glass-backed plates (silica gel

0 F254) and visualized by exposure to UV light (254 nm) or stained

with ceric ammonium molybdate (CAM), basic potassium

(dFCF ppy) (dtbbpy)][PF ] (Ir−F), I and IA were synthesized

10c

(

according to literature procedures.

Synthesis and Characterization of Products. General

Procedure A (GP-A). An 8 mL Biotage microwave vial was charged

with the corresponding carboxylic acid (0.75 mmol, 1.5 equiv.), I

(145 mg, 0.50 mmol, 1.0 equiv.), PPh (235 mg, 0.9 mmol, 1.8

equiv.), Ir−F (5.5 mg, 5 μmol, 1 mol%), and sealed with a septum

cap. The vial was put under a vacuum for 1 min and reﬁlled with N

permanganate (KMnO ), Ninhydrin or p-anisaldehyde solutions,

(× 3). Afterward, 2,4,6-collidine (132 μL, 1.0 mmol, 2.0 equiv.) and

450

J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Note

Synthesized following GP-A using benzoic acid (90 mg, 0.75 mmol

.5 equiv.). The crude product was puriﬁed by ﬂash column

Scheme 2. Deprotection and Derivatization Reactions

chromatography (cyclohexane/EtOAc, 4:1) to provide 1 as a yellow

oil in 95% yield (190 mg, 0.48 mmol). The spectroscopic data are

consistent with those previously reported.

H NMR (400 MHz,

CDCl ) δ 7.94−7.88 (m, 2H), 7.62−7.55 (m, 1H), 7.49−7.42 (m,

H), 7.32−7.27 (m, 3H), 7.24−7.20 (m, 2H), 5.61 (s, 1H), 5.24 (dd,

J = 6.9, 5.0 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.00 (d, J = 12.1 Hz,

H), 3.56 (dd, J = 16.4, 6.9 Hz, 1H), 3.38 (dd, J = 16.4, 5.0 Hz, 1H),

.02 (s, 9H).

In 5.0 mmol scale: Synthesized following GP-A using benzoic acid

(

916 mg, 7.5 mmol 1.5 equiv.) and Ir−F (28 mg, 25 μmol, 0.5 mol%).

The crude product was puriﬁed by ﬂash column chromatography

(

cyclohexane/EtOAc, 4:1) to provide 1 as a yellow oil in 97% yield

1.9 g, 4.8 mmol).

In 5.0 mmol scale: Synthesized following GP-A using benzoic acid

916 mg, 7.5 mmol 1.5 equiv.) and Ir−F (14 mg, 12.5 μmol, 0.25 mol

(

) for 72 h. The crude product was puriﬁed by ﬂash column

chromatography (cyclohexane/EtOAc, 4:1) to provide 1 as a yellow

oil in 73% yield (1.4 g, 3.6 mmol).

Benzyl (2R,4R)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-phenylethyl-

- C)oxazolidine-3-carboxylate (1- C). Synthesized following GP-

A using benzoic acid-α- C (92.3 mg, 0.75 mmol, 1.5 equiv.). The

crude product was puriﬁed by column chromatography (cyclohexane/

EtOAc, 4:1) to provide 1- C as a yellow oil in 85% yield (110 mg,

.27 mmol). H NMR (400 MHz, CDCl ) δ 7.91 (ddd, J = 8.5, 3.8,

.3 Hz, 2H), 7.58 (tt, J = 6.9, 1.4 Hz, 1H), 7.46 (tt, J = 7.1, 0.7 Hz,

H), 7.31−7.27 (m, 3H), 7.25−7.19 (m, 2H), 5.61 (s, 1H), 5.24

ddd, J = 6.9, 5.0, 3.6 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.00 (d, J =

(

2.0 Hz, 1H), 3.56 (ddd, J = 16.3, 6.9, 5.5 Hz, 1H), 3.38 (ddd, J =

16.3, 6.0, 5.0 Hz, 1H), 1.02 (s, 9H). C{ H} NMR (151 MHz,

CDCl ) δ 194.8, 172.2, 172.1, 155.7, 136.7, 136.2, 135.3, 133.6, 128.9,

28.7, 128.5, 128.4, 96.4, 68.4, 53.8, 42.3, 41.8, 37.6, 24.9. HRMS

(FI) [m/z] calculated for C₂₂CH NNaO ([M + Na] ) 419.1664,

25 5

found 419.1666.

Methyl 2-(bis(tert-butoxycarbonyl)amino)-4-oxo-4-phenylbuta-

noate (1A). Synthesized following GP-B using benzoic acid (91.5 mg,

.75 mmol, 1.5 equiv.) and IA (190.1 mg, 0.50 mmol, 1.0 equiv.). The

crude product was puriﬁed by column chromatography (cyclohexane/

EtOAc, 4:1) to provide 1A as a yellow oil in 54% yield (110 mg, 0.27

mmol). H NMR (400 MHz, CDCl ) δ 8.00−7.95 (m, 2H), 7.57 (s,

H), 7.48 (dd, J = 7.3, 0.9 Hz, 2H), 5.73 (dd, J = 6.8, 5.7 Hz, 1H),

.04 (dd, J = 17.5, 6.8 Hz, 1H), 3.72 (s, 3H), 3.28 (dd, J = 17.5, 5.7

Hz, 1H), 1.51 (s, 18H). C{ H} NMR (151 MHz, CDCl ) δ 196.7,

70.9, 152.1, 136.8, 133.3, 128.8, 128.3, 83.5, 54.8, 52.6, 40.0, 28.2.

HRMS (FI) [m/z] calculated for C H NNaO ([M + Na] )

−

(

30.1840, found 430.1836. IR v

m), 1967 (m), 1478 (m), 1451 (m), 1367 (s), 1238 (s), 1094 (m),

045 (s), 850 (s), 766 (s), 691 (s), 634 (s), 606 (m), 440 (m). R_f

̃ [cm ] = 2980 (s), 2935 (s), 1797

Figure 2. Plausible reaction mechanism.

(

cyclohexane/EtOAc, 4:1) = 0.62 [p-Anisaldehyde].

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(4-methoxyphenyl)-2-oxoeth-

degassed 1,4-dioxane (2.5 mL, 0.2 M) were added. The reaction

mixture was then sparged with N for 2−5 min and irradiated with

yl)-5-oxooxazolidine-3-carboxylate (3). Synthesized following GP-

A using 4-methoxybenzoic acid (114 mg, 0.75 mmol, 1.5 equiv.). The

crude product was puriﬁed by ﬂash column chromatography

blue LEDs (λ = 440 or 450 nm) in an EvoluChem PhotoRedOx

max

Box for 24 h. Finally, the solvent was evaporated and the crude

reaction mixture was puriﬁed by column chromatography over silica

gel to aﬀord the desired product.

General Procedure B (GP-B). An 8 mL Biotage microwave vial was

charged with the corresponding carboxylic acid (0.75 mmol, 1.5

(

cyclohexane/EtOAc, 4:1) to provide 3 as a yellow oil in 92% yield

195 mg, 0.46 mmol). H NMR (600 MHz, CDCl ) δ 7.92−7.85 (m,

H), 7.38−7.35 (m, 1H), 7.30−7.28 (m, 2H), 7.24−7.21 (m, 2H),

.96−6.87 (m, 2H), 5.61 (s, 1H), 5.23 (dd, J = 7.0, 5.0 Hz, 1H),

.13−5.09 (m, 1H), 5.00 (d, J = 12.1 Hz, 1H), 3.87 (s, 3H), 3.50 (dd,

equiv.), I (145 mg, 0.50 mmol, 1.0 equiv.), PPh (235 mg, 0.9 mmol,

.8 equiv.), Ir−F (5.5 mg, 5 μmol, 1 mol%), and sealed with a septum

J = 16.1, 7.0 Hz, 1H), 3.33 (dd, J = 16.1, 5.0 Hz, 1H), 1.01 (s, 9H).

cap. The vial was put under a vacuum for 1 min and reﬁlled with N

C{ H} NMR (151 MHz, CDCl ) δ 193.3, 172.3, 163.9, 155.7,

(

× 3). Afterward, 2,4,6-collidine (132 μL, 1.0 mmol, 2.0 equiv.) and

35.3, 130.6, 129.5, 128.7, 128.7, 128.6, 128.5, 114.1, 96.4, 68.3, 55.7,

degassed DMF (2.5 mL, 0.2 M) were added. The reaction mixture

3.9, 41.7, 37.6, 24.9. HRMS (FI) [m/z] calculated for C H NNaO

was then sparged with N for 2−5 min and irradiated with blue LEDs

24 27

−1

(

[M + Na] ) 448.1731, found 448.1734. IR v

914 (w), 2874 (w), 2842 (w), 1792 (s), 1718 (s), 1677 (m), 1599

s), 1575 (m), 1511 (m), 1481 (w), 1457 (m), 1393 (m), 1345 (s),

̃ [cm ] = 2964 (w),

(λ

= 440 or 450 nm) in an EvoluChem PhotoRedOx Box for 24 h.

max

Finally, the solvent was evaporated and the crude reaction mixture

was puriﬁed by column chromatography over silica gel to aﬀord the

desired product.

Characterization Data. (2S,4S)-2-(tert-Butyl)-5-oxo-4-(2-oxo-2-

phenylethyl)oxazolidine-3-carboxylate (1). In 0.5 mmol scale:

1291 (s), 1258 (s), 1238 (s), 1217 (s), 1200 (m), 1168 (s), 1118

(m), 1067 (m), 1040 (s), 1027 (s), 989 (s), 889 (m), 840 (m), 824

(m), 783 (m), 738 (m), 697 (s), 633 (m), 596 (m), 563 (m), 531

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J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Note

(

m), 505 (m), 454 (m). R (cyclohexane/EtOAc, 5:1) = 0.31 [p-

5.21 (dd, J = 7.0, 5.0 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.03 (d, J =

12.1 Hz, 1H), 3.51 (dd, J = 16.3, 7.0 Hz, 1H), 3.34 (dd, J = 16.2, 5.0

Anisaldehyde]. [α]_D= +41.1 (ρ = 0.99, CH Cl ).

Benzyl (2S,4S)-4-(2-(4-((tert-butoxycarbonyl)amino)phenyl)-2-

oxoethyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate (4). Syn-

thesized following GP-A using 4-((tert-butoxycarbonyl)amino)-

benzoic acid (178 mg, 0.75 mmol, 1.5 equiv.). The crude product

was puriﬁed by ﬂash column chromatography (cyclohexane/EtOAc,

Hz, 1H), 1.01 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 193.3,

172.1, 166.1 (d, J

= 255.5 Hz), 155.7, 135.2, 132.8 (d, J

= 9.3 Hz), 128.8, 128.7, 128.5, 116.1 (d, J

22.0 Hz), 96.4, 68.5, 53.8, 41.9, 37.6, 24.9. F{ H} NMR (376 MHz,

= 3.1

C−F

Hz), 131.0 (d, J

C−F

CDCl ) δ −104.4. HRMS (FI) [m/z] calculated for C H FNNaO

23 24

−1

:1) to provide 4 as a ﬁne yellowish powder in 80% yield (203 mg,

([M + Na] ) 436.1531, found 436.1535. IR ṽ [cm ] = 3067 (w),

.40 mmol). H NMR (600 MHz, CDCl ) δ 7.92−7.85 (m, 2H),

3035 (w), 2969 (w), 2913 (w), 2875 (w), 1791 (s), 1719 (s), 1687

(s), 1596 (s), 1507 (w), 1481 (w), 1456 (w), 1392 (m), 1345 (s),

1289 (s), 1230 (s), 1199 (s), 1178 (s), 1156 (s), 1122 (m), 1069

(m), 1042 (s), 1018 (m), 993 (m), 911 (w), 891 (w), 842 (m), 822

(m), 786 (w), 732 (m), 697 (m), 637 (w), 593 (m), 561 (w), 531

.38−7.35 (m, 1H), 7.30−7.28 (m, 2H), 7.26−7.20 (m, 2H), 6.96−

.87 (m, 2H), 5.61 (s, 1H), 5.23 (dd, J = 7.0, 5.0 Hz, 1H), 5.12−5.10

(m, 1H), 5.00 (d, J = 12.1 Hz, 1H), 3.87 (s, 3H), 3.50 (dd, J = 16.1,

.0 Hz, 1H), 3.33 (dd, J = 16.1, 5.0 Hz, 1H), 1.01 (s, 9H). C{ H}

NMR (151 MHz, CDCl ) δ 193.4, 172.2, 155.7, 152.2, 143.4, 135.3,

(w), 510 (w), 456 (w), 419 (w). R (cyclohexane/EtOAc, 4:1) = 0.43

31.0, 129.8, 128.7, 128.6, 128.5, 117.7, 96.4, 81.5, 68.3, 53.9, 41.7,

[KMnO ]. [α] = +29.5 (ρ = 1.02, CH Cl ).

4 D 2 2

7.6, 28.4, 24.9. HRMS (FI) [m/z] calculated for C H N NaO

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(4-cyanophenyl)-2-oxoethyl)-5-

oxooxazolidine-3-carboxylate (8). Synthesized following GP-A using

4-cyanobenzoic acid (111 mg, 0.75 mmol, 1.5 equiv.) and irradiating

for 48 h. The crude product was puriﬁed by ﬂash column

chromatography (cyclohexane/EtOAc, 4:1) to provide 8 as an oﬀ-

−1

(

[M + Na] ) 533.2258, found 533.2265. IR v

972 (w), 2930 (w), 2875 (w), 2852 (w), 1792 (m), 1718 (m), 1679

m), 1588 (m), 1525 (m), 1502 (m), 1481 (w), 1454 (w), 1393 (m),

366 (m), 1344 (m), 1312 (m), 1290 (m), 1229 (s), 1149 (s), 1122

̃ [cm ] = 3338 (w),

(

m), 1045 (m), 990 (m), 900 (w), 838 (m), 822 (m), 769 (m), 747

m), 696 (m), 626 (m), 593 (w), 576 (w), 540 (m), 510 (m), 458

m). R (cyclohexane/EtOAc, 4:1) = 0.29 [p-Anisaldehyde]. [α]

white solid in 35% yield (73 mg, 0.17 mmol). H NMR (600 MHz,

CDCl ) δ 7.93 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.35−

7.29 (m, 3H), 7.23 (dd, J = 7.2, 2.0 Hz, 2H), 5.62 (s, 1H), 5.19−5.14

(m, 1H), 5.10 (d, J = 11.9 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 3.52

(dd, J = 16.4, 7.0 Hz, 1H), 3.37 (dd, J = 16.3, 5.0 Hz, 1H), 1.01 (s,

35.6 (ρ = 1.02, CH Cl ).

2 2

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(p-tolyl)ethyl)-

oxazolidine-3-carboxylate (5). Synthesized following GP-A using

-methylbenzoic acid (103 mg, 0.76 mmol, 1.5 equiv.). The crude

9H). C{ H} NMR (151 MHz, CDCl ) δ 193.8, 171.8, 155.6, 139.3,

135.0, 132.7, 128.9, 128.8, 128.7, 128.6, 117.9, 116.9, 96.6, 68.6, 53.8,

product was puriﬁed by ﬂash column chromatography (cyclohexane/

42.2, 37.6, 24.9. HRMS (FI) [m/z] calculated for C H N NaO

([M + Na] ) 443.1577, found 443.1580. IR ṽ [cm ] = 2964 (w),

−1

EtOAc, 5:1) to provide 5 as a yellow oil in 80% yield (165 mg, 0.40

mmol). H NMR (600 MHz, CDCl ) δ 7.84−7.77 (m, 2H), 7.30−

2875 (w), 2230 (w), 1790 (s), 1719 (s), 1695 (s), 1607 (w), 1567

(w), 1498 (w), 1481 (m), 1455 (m), 1394 (s), 1336 (s), 1289 (s),

1269 (s), 1233 (s), 1198 (s), 1174 (s), 1119 (s), 1069 (m), 1041 (s),

1016 (s), 996 (s), 890 (m), 844 (m), 821 (m), 782 (m), 749 (s), 697

.27 (m, 3H), 7.26−7.24 (m, 2H), 7.23−7.20 (m, 2H), 5.61 (s, 1H),

.23 (dd, J = 6.9, 5.0 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 4.99 (d, J =

2.1 Hz, 1H), 3.53 (dd, J = 16.2, 6.9 Hz, 1H), 3.35 (dd, J = 16.2, 5.1

Hz, 1H), 2.42 (s, 3H), 1.01 (s, 9H). C{ H} NMR (151 MHz,

CDCl ) δ 194.4, 172.2, 155.7, 144.5, 135.3, 134.0, 129.6, 128.7, 128.6,

z] calculated for C H NNaO ([M + Na] ) 432.1781, found

(s), 636 (m), 567 (m), 545 (m), 532 (m), 505 (m), 455 (m). R

(cyclohexane/EtOAc, 4:1) = 0.30 [KMnO ]. [α] = +38.7 (ρ = 0.99,

4 D

28.5, 128.5, 96.4, 68.3, 53.9, 41.9, 37.6, 24.9, 21.8. HRMS (FI) [m/

CH Cl ).

2 2

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(4-

(triﬂuoromethyl)phenyl)ethyl)oxazolidine-3-carboxylate (9). Syn-

thesized following GP-A using 4-(triﬂuoromethyl)benzoic acid (142

mg, 0.75 mmol, 1.5 equiv.) and irradiating for 48 h. The crude

product was puriﬁed by ﬂash column chromatography (cyclohexane/

EtOAc, 4:1) to provide 9 as a yellow oil in 61% yield (141 mg, 0.30

mmol). The spectroscopic data are consistent with those previously

−

32.1789. IR v [cm ] = 3063 (w), 3034 (w), 2966 (w), 2875 (w),

792 (s), 1719 (s), 1682 (s), 1606 (m), 1573 (m), 1480 (w), 1453

(

m), 1393 (s), 1344 (s), 1289 (s), 1235 (s), 1174 (s), 1120 (s), 1068

m), 1041 (s), 1018 (s), 984 (s), 890 (m), 840 (m), 807 (m), 745

s), 697 (s), 635 (w), 592 (m), 560 (m), 531 (m), 506 (m), 455 (m).

R_f(cyclohexane/EtOAc, 4:1) = 0.45 [p-Anisaldehyde]. [α] = +43.6

(ρ = 1.03, CH Cl ).

reported. H NMR (400 MHz, CDCl ) δ 7.96 (d, J = 8.1 Hz, 2H),

Benzyl (2S,4S)-4-(2-(4-bromophenyl)-2-oxoethyl)-2-(tert-butyl)-

7.69 (d, J = 8.2 Hz, 2H), 7.29 (dtt, J = 8.3, 5.5, 2.7 Hz, 4H), 7.24−

7.19 (m, 2H), 5.63 (s, 1H), 5.18 (dd, J = 6.9, 5.1 Hz, 1H), 5.10 (d, J =

12.0 Hz, 1H), 5.03 (d, J = 12.0 Hz, 1H), 3.54 (dd, J = 16.2, 6.9 Hz,

-oxooxazolidine-3-carboxylate (6). Synthesized following GP-A

using 4-bromobenzoic acid (151 mg, 0.75 mmol, 1.5 equiv.). The

crude product was puriﬁed by ﬂash column chromatography

1H), 3.39 (dd, J = 16.2, 5.2 Hz, 1H), 1.02 (s, 9H). C{ H} NMR

(

cyclohexane/EtOAc, 10:1) to provide 6 as a yellow oil in 74%

(151 MHz, CDCl ) 194.1, 171.9, 155.6, 139.1, 135.1, 134.9 (q, J

C−F

yield (175 mg, 0.37 mmol). H NMR (600 MHz, CDCl ) δ 7.73 (d, J

= 32.8 Hz), 128.8, 128.8, 128.7, 128.6, 126.0 (q, J

= 3.7 Hz),

C−F

(

8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 1.5 Hz, 3H),

.24−7.17 (m, 2H), 5.61 (s, 1H), 5.18 (dd, J = 6.9, 5.1 Hz, 1H), 5.10

d, J = 12.0 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H), 3.49 (dd, J = 16.2, 6.9

123.6 (q, J

= 272.6 Hz), 96.5, 68.6, 53.9, 42.2, 37.6, 24.9. F{ H}

C−F

NMR (376 MHz, CDCl ) δ −63.2.

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(4-formylphenyl)-2-oxoethyl)-

5-oxooxazolidine-3-carboxylate (10). Synthesized following GP-A

using 4-formylbenzoic acid (113 mg, 0.75 mmol 1.5 equiv.). The

crude product was puriﬁed by ﬂash column chromatography

Hz, 1H), 3.33 (dd, J = 16.2, 5.1 Hz, 1H), 1.01 (s, 9H). C{ H} NMR

151 MHz, CDCl ) δ 193.9, 172.0, 155.6, 135.1, 135.1, 132.2, 129.8,

(

28.8, 128.8, 128.8, 128.6, 110.0, 96.5, 68.5, 53.8, 41.9, 37.6, 24.9. IR

−1

[cm ] = 2963 (w), 2874 (w), 1791 (s), 1719 (m), 1688 (m), 1584

(cyclohexane/EtOAc, 4:1) to provide 10 as a yellow oil in 10%

(

s), 1581 (m), 1457 (m), 1393 (m), 1343 (m), 1286 (m), 1235 (m),

yield (21.2 mg, 0.05 mmol). H NMR (600 MHz, CDCl ) δ 10.10 (s,

173 (m), 1120 (m), 1068 (m), 1042 (m), 989 (w), 823 (m), 733

1H), 8.01 (t, J = 8.1 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.30 (dd, J =

5.1, 2.1 Hz, 3H), 7.25−7.20 (m, 2H), 5.63 (s, 1H), 5.21 (dd, J = 7.0,

5.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.03 (d, J = 12.1 Hz, 1H),

3.57 (dd, J = 16.3, 7.0 Hz, 1H), 3.41 (dd, J = 16.3, 5.0 Hz, 1H), 1.02

(

m), 697 (s), 509 (s), 453 (s). HRMS (ESI) [m/z] calculated for

C H BrNNaO ([M + Na] ) 496.0729, found 496.0730. R

(

cyclohexane/EtOAc, 4:1) = 0.62 [p-Anisaldehyde]. [α] = +40.5

ρ = 0.93, CH Cl ).

(s, 9H). C{ H} NMR (151 MHz, CDCl ) δ 194.4, 191.5, 171.9,

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(4-ﬂuorophenyl)-2-oxoethyl)-5-

oxooxazolidine-3-carboxylate (7). Synthesized following GP-A using

-ﬂuorobenzoic acid (105 mg, 0.75 mmol, 1.5 equiv.). The crude

155.6, 140.5, 139.4, 135.1, 130.0, 128.8, 128.8, 128.6, 96.5, 68.6, 53.8,

42.4, 37.6, 27.1, 24.9. HRMS (ESI) [m/z] calculated for

C H NNaO ([M + Na] ) 446.1574, found 446.1573. R (cyclo-

product was puriﬁed by ﬂash column chromatography (cyclohexane/

hexane/EtOAc, 4:1) = 0.16 [p-Anisaldehyde].

EtOAc, 4:1) to provide 7 as a yellowish oil in 61% yield (127 mg, 0.31

(2S,4S)-Benzyl 4-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-2-

(tert-butyl)-5-oxooxazolidine-3-carboxylate (11). Synthesized fol-

lowing GP-A using piperonylic acid (124.5 mg, 0.75 mmol, 1.5

mmol). H NMR (400 MHz, CDCl ) δ 7.96−7.86 (m, 2H), 7.35−

.24 (m, 3H), 7.28−7.19 (m, 2H), 7.16−7.05 (m, 2H), 5.62 (s, 1H),

452

J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Note

−1

equiv.). The crude product was puriﬁed by ﬂash column

chromatography (cyclohexane/EtOAc, 4:1) to provide 11 as a

white solid in 95% yield (208 mg, 0.47 mmol). H NMR (600

Na] ) 580.1868, found 580.1854 IR ṽ [cm ] = 2962 (w), 2358 (w),

1791 (s), 1718 (m), 1621 (s), 1459 (m), 1393 (m), 1344 (m), 1289

(m), 1176 (m), 1121 (m), 1041 (m), 753 (s), 695 (m). R

(cyclohexane/EtOAc, 4:1) = 0.25 [p-Anisaldehyde]. [α] = +36.9

MHz, CDCl ) δ 7.48 (dd, J = 8.2, 1.8 Hz, 1H), 7.37 (d, J = 1.8 Hz,

(

H), 7.32−7.28 (m, 3H), 7.23 (dd, J = 6.6, 2.9 Hz, 2H), 6.81 (d, J =

.1 Hz, 1H), 6.04 (q, J = 1.4 Hz, 2H), 5.61 (s, 1H), 5.21 (dd, J = 6.9,

.0 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 5.02 (d, J = 12.1 Hz, 1H),

(ρ = 0.95, CH Cl ).

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(3-(4,4,5,5-tetra-

methyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)oxazolidine-3-car-

boxylate (15). Synthesized following GP-A using 4-carboxylphenyl-

boronic acid pinacol ester (186 mg, 0.75 mmol, 1.5 equiv.). The crude

product was puriﬁed by ﬂash column chromatography (cyclohexane/

.46 (dd, J = 16.1, 7.0 Hz, 1H), 3.29 (dd, J = 16.1, 5.1 Hz, 1H), 1.01

s, 9H). ¹³C{ H} NMR (151 MHz, CDCl ) δ 192.8, 172.2, 155.7,

52.2, 148.5, 135.3, 131.3, 128.7, 128.6, 128.5, 124.6, 108.1, 108.0,

EtOAc, 4:1) to provide 15 as a white solid in 76% yield (198 mg, 0.38

02.1, 96.3, 68.3, 53.9, 41.7, 37.5, 24.9. HRMS (ESI) [m/z] calculated

mmol). H NMR (600 MHz, CDCl ) δ 8.31 (s, 1H), 8.03−7.98 (m,

for C H NNaO ([M + Na] ) 462.1520, found 462.1523. IR v

−

[

(

cm ] = 2963 (w), 1791 (s), 1718 (m), 1676 (m), 1604 (m), 1485

s), 1443 (s), 1393 (s), 1345 (m), 1235 (w), 1176 (m), 1110 (s),

2H), 7.47 (d, J = 7.7 Hz, 1H), 7.29−7.27 (m, 3H), 7.23−7.18 (m,

2H), 5.61 (s, 1H), 5.24 (dd, J = 6.7, 5.2 Hz, 1H), 5.11 (d, J = 12.1 Hz,

1H), 4.96 (d, J = 12.1 Hz, 1H), 3.55 (dd, J = 16.3, 6.8 Hz, 1H), 3.44

034 (s), 930 (m), 808 (w). 733 (s), 697 (s). R (cyclohexane/

EtOAc, 4:1) = 0.32 [p-Anisaldehyde]. [α]_D= +41.5 (ρ = 0.95,

CH Cl ).

(dd, J = 16.3, 5.2 Hz, 1H), 1.36 (s, 12H), 1.03 (s, 9H). C{ H}

NMR (151 MHz, CDCl ) δ 195.1, 172.2, 155.7, 139.9, 136.0, 135.3,

134.6, 131.0, 128.7, 128.6, 128.5, 128.3, 96.4, 84.4, 68.3, 53.9, 41.9,

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(2-chlorophenyl)-2-oxoethyl)-

-oxooxazolidine-3-carboxylate (12). Synthesized following GP-A

37.6, 25.1, 25.0. HRMS (ESI) [m/z] calculated for C H BNNaO

−1

using 2-chlorobenzoic acid (117.4 mg, 0.75 mmol, 1.5 equiv.). The

([M + Na] ) 544.2480, found 544.2477. IR ṽ [cm ] = 2974 (w),

crude product was puriﬁed by ﬂash column chromatography

2931 (w), 2358 (w), 1793 (s), 1720 (s), 1687 (m), 1482 (m), 1390

(

cyclohexane/EtOAc, 10:1) to provide 12 as a yellow oil in 95%

(m), 1348 (m), 1287 (m), 1140 (m), 1041 (m), 697 (s). R

(cyclohexane/EtOAc, 4:1) = 0.5 [p-Anisaldehyde]. [α]_D= +37.1

yield (203 mg, 0.47 mmol). H NMR (600 MHz, CDCl ) δ 7.47 (d, J

7.7 Hz, 1H), 7.41−7.39 (m, 2H), 7.33 (s, 5H), 7.32−7.28 (m, 1H),

(ρ = 1.14, CH Cl ).

.61 (s, 1H), 5.22 (t, J = 6.1 Hz, 1H), 5.20−5.12 (m, 2H), 3.51−3.48

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(pyridin-3-yl)-

ethyl)oxazolidine-3-carboxylate (16). Synthesized following GP-A

using nicotinic acid (92.25 mg, 0.75 mmol, 1.5 equiv.). The crude

product was puriﬁed by ﬂash column chromatography (cyclohexane/

(m, 2H), 0.97 (s, 9H). C{ H} NMR (151 MHz, CDCl ) δ 197.4,

72.1, 155.6, 138.5, 135.3, 132.4, 131.3, 130.7, 130.0, 128.8, 128.7,

128.6, 127.2, 96.4, 68.5, 53.7, 45.8, 37.6, 24.9. HRMS (ESI) [m/z]

calculated for C H ClNNaO ([M + Na] ) 452.1215, found

EtOAc, 4:1) to provide 16 as a yellow oil in 45% yield (110 mg, 0.28

−

52.1235. IR v

[cm ] = 2968 (w), 1791 (s), 1716 (s), 1589 (s),

mmol). H NMR (400 MHz, CDCl

) δ 9.11−9.08 (m, 1H), 8.80 (dd,

392 (m), 1345 (m), 1284 (m), 1176 (m), 1120 (m), 1076 (m),

040 (m), 976 (m), 757 (m), 697 (m), 697 (s), 633 (m). R

J = 5.0, 1.7 Hz, 1H), 8.19 (dt, J = 8.0, 1.9 Hz, 1H), 7.44 (ddd, J = 8.0,

4.9, 0.8 Hz, 1H), 7.32−7.28 (m, 3H), 7.25−7.22 (m, 2H), 5.62 (s,

1H), 5.21 (dd, J = 6.9, 5.0 Hz, 1H), 5.07 (q, J = 12.0 Hz, 2H), 3.54

(dd, J = 16.4, 6.9 Hz, 1H), 3.39 (dd, J = 16.4, 5.0 Hz, 1H), 1.01 (s,

(

cyclohexane/EtOAc, 4:1) = 0.45 [p-Anisaldehyde]. [α] = +47.2

ρ = 1.03, CH Cl ).

Benzyl (2S,4S)-4-(2-(2-acetoxyphenyl)-2-oxoethyl)-2-(tert-butyl)-

9H). C{ H} NMR (101 MHz, CDCl ) δ 193.6, 171.9, 155.6, 153.3,

-oxooxazolidine-3-carboxylate (13). Synthesized following GP-A

149.1, 136.2, 135.0, 132.0, 128.8, 128.8, 128.6, 124.1, 96.5, 68.6, 53.6,

using 2-acetoxybenzoic acid (135 mg, 0.75 mmol, 1.5 equiv.). The

42.1, 37.6, 24.9. HRMS (ESI) [m/z] calculated for C H N O ([M

−1

crude product was puriﬁed by ﬂash column chromatography

+ Na] ) 397.1757, found 397.1758. IR ṽ [cm ] = 3035 (w), 1790

(

cyclohexane/EtOAc, 10:1) to provide 13 as a yellow oil in 92%

(s), 1719 (m), 1480 (m), 1392 (m), 1343 (m), 1285 (m), 1176 (m),

yield (208 mg, 0.45 mmol). H NMR (600 MHz, CDCl ) δ 7.67 (dd,

1120 (s), 1040 (m), 1020 (m), 779 (m), 698 (m). R (cyclohexane/

EtOAc, 1:1) = 0.4 [p-Anisaldehyde]. [α] = +42.3 (ρ = 1.04,

J = 7.8, 1.7 Hz, 1H), 7.56−7.52 (m, 1H), 7.33−7.27 (m, 5H), 7.15

(

dd, J = 8.1, 1.1 Hz, 1H), 5.60 (s, 1H), 5.19 (dd, J = 7.0, 4.8 Hz, 1H),

.15 (d, J = 12.1 Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H), 3.47 (dd, J =

6.7, 7.0 Hz, 1H), 3.31 (dd, J = 16.7, 4.8 Hz, 1H), 2.31 (s, 3H), 0.98

CH Cl ).

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(1,3-dimethyl-1H-pyrazolo[3,4-

b]pyridin-5-yl)-2-oxoethyl)-5-oxooxazolidine-3-carboxylate (17)

and Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(4-chloro-1,3-dimethyl-1H-

pyrazolo[3,4-b]pyridin-5-yl)-2-oxoethyl)-5-oxooxazolidine-3-car-

boxylate (17′). Synthesized following GP-B using 4-Chloro-1,3-

dimethylpyrazolo[3,4-b]pyridine-5-carboxylic acid (169 mg, 0.75

mmol 1.5 equiv.), and irradiating for 48 h. The crude product was

puriﬁed by ﬂash column chromatography (cyclohexane/EtOAc, 2:1)

to provide 17 a yellow foam in 39% (98 mg, 0.20 mmol) and 17′ as a

s, 9H). ¹³C{ H} NMR (151 MHz, CDCl ) δ 194.6, 172.1, 169.4,

(

55.6, 149.2, 135.4, 133.6, 130.5, 129.9, 128.8, 128.7, 128.5, 126.2,

24.1, 96.3, 68.4, 53.5, 44.9, 37.6, 24.9, 21.2. HRMS (ESI) [m/z]

calculated for C H NNaO ([M + Na] ) 476.1681, found 476.1680.

−

IR v

346 (m), 1286 (m), 1177 (w), 1120 (m), 1041 (m), 909 (s), 7534

m), 697 (s), 503 (s). R (cyclohexane/EtOAc, 4:1) = 0.37 [p-

[cm ] = 2965 (w), 2875 (m), 1791 (m), 1718 (m), 1603 (s),

(

yellow solid in 18% yield (45 mg, 0.10 mmol). Spectroscopic data for

Anisaldehyde]. [α]_D= +41.5 (ρ = 1.01, CH Cl ).

7: H NMR (600 MHz, CDCl ) δ 9.05 (d, J = 2.0 Hz, 1H), 8.49 (d,

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(3-(5-(2-ﬂuorophenyl)-1,2,4-ox-

J = 2.0 Hz, 1H), 7.23 (q, J = 2.9 Hz, 3H), 7.19 (dd, J = 6.8, 3.1 Hz,

2H), 5.64 (s, 1H), 5.26 (dd, J = 6.8, 5.2 Hz, 1H), 5.11−5.01 (m, 2H),

4.11 (s, 3H), 3.59 (dd, J = 16.0, 6.8 Hz, 1H), 3.43 (dd, J = 16.0, 5.2

adiazol-3-yl)phenyl)-2-oxoethyl)-5-oxooxazolidine-3-carboxylate

(

14). Synthesized following GP-A using 3-[5-(2-ﬂuorophenyl)-1,2,4-

oxadiazol-3-yl] benzoic acid (213 mg, 0.75 mmol, 1.5 equiv.). The

crude product was puriﬁed by ﬂash column chromatography

Hz, 1H), 2.59 (s, 3H), 1.04 (s, 9H). C{ H} NMR (151 MHz,

CDCl ) δ 193.2, 172.0, 155.7, 152.2, 149.5, 143.2, 135.0, 130.8, 128.7,

128.6, 128.5, 125.1, 114.8, 96.5, 68.5, 54.0, 42.0, 37.6, 33.9, 24.9, 12.6.

HRMS (ESI) [m/z] calculated for C25 NaO ([M + Na]+)

[cm ] = 2961 (s), 2926 (s), 1790

(cyclohexane/EtOAc, 4:1) to provide 14 as a yellow oil in 87%

yield (243.7 mg, 0.44 mmol). H NMR (400 MHz, CDCl ) δ 8.69 (t,

J = 1.7 Hz, 1H), 8.40 (dt, J = 7.8, 1.4 Hz, 1H), 8.24 (ddd, J = 7.8, 7.0,

−

.8 Hz, 1H), 8.09−8.03 (m, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.26 (t, J =

487.1957, found 487.1952. IR ṽ

.3 Hz, 4H), 5.64 (s, 1H), 5.27 (dd, J = 6.8, 5.1 Hz, 1H), 5.16−4.99

(w), 1719 (w), 1678 (w), 1599 (w), 1564 (m), 1520 (m), 1478 (m),

1392 (w), 1281 (w), 1177 (w), 1121 (m), 1041 (w), 983 (w), 748

(

m, 2H), 3.61 (dd, J = 16.4, 6.8 Hz, 1H), 3.49 (dd, J = 16.4, 5.1 Hz,

H), 1.04 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 194.3, 173.3

(m), 697 (w), 578 (m), 503 (m), 456 (m), 428 (m). R (cyclohexane/

EtOAc, 1:1) = 0.33 [p-Anisaldehyde]. [α]_D= +40.1 (ρ = 0.92,

(d, J

= 4.4 Hz), 172.1, 168.1, 162.3 (d, J

= 260.8 Hz), 155.7,

= 8.6 Hz), 132.3, 131.1, 130.8, 129.6,

C−F

37.1, 135.2, 135.0 (d, J

28.7, 128.7, 128.5, 127.8 (d, J

.8 Hz), 117.5 (d, J

8.5, 53.8, 42.0, 37.6, 24.9. F{ H} NMR (376 MHz, CDCl ) δ

CH Cl ).

C−F

2 2

= 5.0 Hz), 127.4, 124.9 (d, J

Spectroscopic data for 17′: H NMR (400 MHz, CDCl ) δ 8.67 (s,

C−F

= 20.9 Hz), 112.8(d, J

= 11.3 Hz), 96.5,

1H), 7.40−7.29 (m, 1H), 7.27 (tdd, J = 4.6, 3.4, 2.0 Hz, 4H), 5.63 (s,

1H), 5.23 (dd, J = 6.9, 5.4 Hz, 1H), 5.14 (d, J = 1.0 Hz, 2H), 4.07 (s,

3H), 3.60 (dd, J = 16.3, 6.9 Hz, 1H), 3.53 (dd, J = 16.3, 5.5 Hz, 1H),

C−F

−

108.1. HRMS (ESI) [m/z] calculated for C H FN NaO ([M +

31 28 3 6

453

J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Note

.73 (s, 3H), 1.00 (s, 9H). ¹³C{ H} NMR (101 MHz, CDCl ) δ

chromatography (cyclohexane/EtOAc, 20:1−7:1) to provide 23 as

95.0, 171.9, 155.6, 152.3, 151.0, 142.9, 138.0, 135.1, 128.7, 128.7,

28.6, 126.1, 113.2, 96.5, 68.6, 54.2, 45.9, 37.6, 34.0, 24.9, 15.1.

HRMS (ESI) [m/z] calculated for C H ClN NaO ([M + Na] )

a yellow oil in 35% yield (70 mg, 0.18 mmol). H NMR 600 MHz,

CDCl ) δ 7.37−7.33 (m, 3H), 7.32 (d, J = 2.0 Hz, 3H), 6.84−6.81

(m, 1H), 5.58 (s, 1H), 5.16−5.09 (m, 3H), 3.23 (dd, J = 16.1, 7.3 Hz,

−

(

21.1562, found 521.1560. IR v

m), 1717 (w), 1582 (s), 1547 (m), 1515 (w), 1456 (w), 1391 (m),

332 (w), 1285 (w), 1234 (w), 1175 (w), 1117 (m), 1038 (w), 729

w), 697 (w), 582 (m), 503 (m). R (cyclohexane/EtOAc, 1:1) = 0.43

̃ [cm ] = 2962 (s), 2874 (s), 1791

1H), 3.04 (dd, J = 16.1, 4.7 Hz, 1H), 2.25−2.20 (m, 4H), 1.65−1.56

(m, 6H), 0.98 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 128.6,

128.3, 96.1, 68.2, 53.7, 40.3, 37.4, 24.8, 21.5. HRMS (FI) [m/z]

calculated for C H NNaO ([M + Na] ) 422.1941, found 422.1938.

23 29

−1

[

p-Anisaldehyde]. [α]_D= +38.1 (ρ = 0.96, CH Cl ).

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(1H-pyrrol-2-yl)-

IR ṽ [cm ] = 2958 (w), 2935 (w), 2872 (w), 1972 (s), 1719 (s),

1668 (s), 1497 (m), 1452 (m), 1391 (m). 1345 (m). 1289 (m). 1173

ethyl)oxazolidine-3-carboxylate (20). Synthesized following GP-A

using 1H-pyrrole-2-carboxylic acid (84 mg, 0.75 mmol, 1.5 equiv.),

and irradiating for 48 h. The crude product was puriﬁed by ﬂash

column chromatography (cyclohexane/EtOAc, 5:1) to provide 20 as

(m), 1235 (m), 1121 (m). 1040 (s), 985 (m), 736 (w), 697 (s). R

(cyclohexane/EtOAc, 4:1) = 0.50 [p-Anisaldehyde]. [α] = +37.7 (ρ

= 1.03, CH Cl ).

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(3,4-dihydro-2H-pyran-5-yl)-2-

oxoethyl)-5-oxooxazolidine-3-carboxylate (24). Synthesized follow-

ing GP-A using 3,4-dihydro-2H-pyran-5-carboxylic acid (96 mg, 0.75

mmol, 1.5 equiv.). The crude product was puriﬁed by ﬂash column

a dark yellow oil in 20% yield (39 mg, 0.10 mmol). H NMR (600

MHz, CDCl ) δ 9.42 (br, 1H), 7.40−7.27 (m, 3H), 7.24 (dq, J = 6.5,

4.2 Hz, 2H), 7.00 (td, J = 2.7, 1.2 Hz, 1H), 6.87 (ddd, J = 3.8, 2.4, 1.3

Hz, 1H), 6.26 (dt, J = 3.9, 2.5 Hz, 1H), 5.61 (s, 1H), 5.13 (t, J = 6.3

Hz, 1H), 5.09 (d, J = 12.1 Hz, 1H), 5.02 (d, J = 12.1 Hz, 1H), 3.33

chromatography (cyclohexane/EtOAc, 4:1) to provide 24 as a yellow

oil in 48% yield (39 mg, 0.24 mmol). H NMR (600 MHz, CDCl ) δ

(

dd, J = 15.3, 6.6 Hz, 1H), 3.20 (dd, J = 15.3, 5.9 Hz, 1H), 1.01 (s,

7.53 (s, 1H), 7.37−7.31 (m, 5H), 5.58 (s, 1H), 5.16 (dd, J = 7.3, 4.8

Hz, 1H), 5.14 (dd, J = 12.2, 9.7 Hz, 2H), 4.05 (t, J = 5.3 Hz, 2H),

3.08 (dd, J = 15.7, 7.4 Hz, 1H), 2.94 (dd, J = 15.7, 4.8 Hz, 1H), 2.34−

H). ¹³C{ H} NMR (151 MHz, CDCl ) δ 184.7, 172.0, 155.7, 135.3,

31.5, 128.7, 128.6, 128.5, 125.5, 116.7, 111.0, 96.5, 68.4, 54.4, 41.3,

7.5, 25.0. HRMS (ESI) [m/z] calculated for C H N NaO ([M +

2.18 (m, 2H), 1.87−1.79 (m, 2H), 0.98 (s, 9H). C{ H} NMR (151

−1

Na] ) 407.1577, found 407.1587. IR v

875 (w), 2254 (w), 1790 (m), 1715 (s), 1640 (m), 1547 (w), 1481

w), 1397 (s), 1345 (m), 1334 (m), 1292 (s), 1231 (m), 1179 (m),

[cm ] = 3290(w), 2968 (w),

MHz, CDCl ) δ 192.8, 172.3, 157.1, 155.8, 135.5, 128.8, 128.6, 128.4,

(

116.9, 96.2, 68.3, 67.3, 53.9, 40.0, 37.5, 24.9, 21.1, 18.5. HRMS (FI)

[m/z] calculated for C H NNaO ([M + Na] ) 424.1731, found

−

109 (s), 1067 (m), 1041 (s), 1017 (m), 979 (m), 909 (m), 727 (s),

424.1739. IR ṽ [cm ] = 3065 (w), 3034 (w), 2961 (w), 2879 (w),

97 (s), 648 (w), 602 (w), 582 (w), 512 (w), 455 (w). R

1791 (s), 1717 (s), 1656 (m), 1617 (s), 1481 (w), 1465 (w), 1450

(w), 1393 (m), 1345 (m), 1329 (s), 1289 (s), 1267 (m), 1230 (s),

1171 (s), 1122 (m), 1086 (m), 1041 (s), 1005 (s), 985 (s), 963 (m),

930 (m), 908 (m), 852 (m), 779 (m), 736 (m), 697 (s), 676 (m), 637

(

cyclohexane/EtOAc, 4:1) = 0.19 [p-Anisaldehyde]. [α] = +32.9

ρ = 1.00, CH Cl ).

Benzyl (2S,4S)-2-(tert-butyl)-4-(2-(furan-2-yl)-2-oxoethyl)-5-ox-

ooxazolidine-3-carboxylate (21). Synthesized following GP-A

using furan-2-carboxylic acid (84 mg, 0.75 mmol, 1.5 equiv.). The

crude product was puriﬁed by ﬂash column chromatography

(w), 581 (w), 557 (w), 531 (w), 508 (m), 449 (m). R (cyclohexane/

EtOAc, 4:1) = 0.26 [p-Anisaldehyde]. [α] = +39.2 (ρ = 1.04,

CH Cl ).

(

cyclohexane/EtOAc, 1:1) to provide 21 as a yellow oil in 58%

Benzyl (2S,4S)-4-(2-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydro-

pyridin-3-yl)-2-oxoethyl)-2-(tert-butyl)-5-oxooxazolidine-3-carbox-

ylate (26). Synthesized following GP-A using 1-(tert-butoxycarbon-

yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid (171 mg, 0.75 mmol,

1.5 equiv. The crude product was puriﬁed by ﬂash column

chromatography (cyclohexane/EtOAc, 4:1) to provide 26 as an oﬀ-

yield (90 mg, 0.23 mmol). H NMR (400 MHz, CDCl ) δ 7.55 (dd, J

1.7, 0.8 Hz, 1H), 7.32 (dd, J = 5.0, 2.0 Hz, 3H), 7.28−7.24 (m, 2H),

.19 (dd, J = 3.6, 0.8 Hz, 1H), 6.53 (dd, J = 3.6, 1.7 Hz, 1H), 5.60 (s,

H), 5.17−5.10 (m, 2H), 5.00 (d, J = 12.1 Hz, 1H), 3.43 (dd, J =

5.7, 6.5 Hz, 1H), 3.24 (dd, J = 15.7, 6.0 Hz, 1H), 1.01 (s, 9H).

C{ H} NMR (101 MHz, CDCl ) δ 184.0, 171.9, 155.6, 152.5,

white solid in 68% yield (170 mg, 0.34 mmol). H NMR (600 MHz,

46.6, 135.3, 128.8, 128.7, 128.5, 117.4, 112.7, 96.5, 68.4, 53.8, 41.8,

CDCl ) δ 7.35−7.29 (m, 5H), 6.89 (s, 1H), 5.57 (s, 1H), 5.18−5.08

7.5, 24.9. HRMS (ESI) [m/z] calculated for C H NNaO ([M +

(m, 3H), 5.09−5.06 (m, 1H), 4.09 (s, 1H), 3.45 (s, 2H), 3.23 (dd, J =

16.0, 7.2 Hz, 1H), 3.07−3.00 (m, 1H), 2.35−2.27 (m, 2H), 1.46 (s,

−1

Na] ) 408.1412, found 408.1418. IR v

[cm ] = 2967 (w), 1790 (s),

719 (s), 1676 (s), 1569 (s), 1467 (s), 1392 (s), 1345 (s), 1296 (s),

178 (s), 1121 (s), 1017 (m), 978 (m), 756 (w), 697 (s), 594 (s),

9H), 0.97 (s, 9H). C{ H} NMR (151 MHz, CDCl ) δ 193.6, 172.1,

155.6, 154.9, 138.8, 137.0, 135.3, 128.8, 128.7, 128.5, 96.3, 80.2, 77.4,

07 (s). R (cyclohexane/EtOAc, 4:1) = 0.3 [p-Anisaldehyde]. [α]

77.2, 76.9, 68.4, 53.7, 42.3, 40.3, 38.6, 37.5, 28.5, 25.9, 24.8. HRMS

41.4 (ρ = 0.95, CH Cl ).

(FI) [m/z] calculated for C27

NaO

([M + Na] ) 523.2415,

−

Benzyl (2S,4S)-2-(tert-butyl)-5-oxo-4-(2-oxo-2-(thiophen-2-yl)-

found 523.2410. IR ṽ [cm ] = 2972 (w), 2935 (w), 2874 (w), 1792

(m), 1720 (m), 1693 (s), 1673 (s), 1621 (w), 1479 (m), 1455 (m),

1391 (m), 1365 (m), 1342 (m), 1285 (s), 1234 (s), 1159 (s), 1111

(s), 1068 (m), 1040 (s), 985 (m), 890 (w), 865 (m), 826 (w), 766

(m), 743 (m), 697 (m), 637 (w), 593 (w), 582 (w), 508 (m), 455

(m). R (cyclohexane/EtOAc, 4:1) = 0.20 [KMnO ]. [α] = +37.1 (ρ

= 1.00, CH Cl ).

Benzyl 2-(tert-butyl)-4-(2-(4,5-dihydrofuran-3-yl)-2-oxoethyl)-5-

oxooxazolidine-3-carboxylate (27). Synthesized following GP-A

using 4,5-dihydro-furan-3-carboxylic acid (86 mg, 0.75 mmol 1.5

equiv.), and irradiating for 48 h. The crude product was puriﬁed by

ﬂash column chromatography (cyclohexane/EtOAc, 2:1) to provide

27 as a yellow oil in 31% yield (60 mg, 0.15 mmol). H NMR (400

MHz, CDCl ) δ 7.40−7.31 (m, 5H), 7.26−7.25 (m, 1H), 5.59 (s,

1H), 5.15 (s, 2H), 5.08 (dd, J = 7.1, 5.3 Hz, 1H), 4.56−4.46 (m, 2H),

3.08 (dd, J = 15.2, 7.1 Hz, 1H), 2.95 (dd, J = 15.2, 5.3 Hz, 1H), 2.87−

2.70 (m, 2H), 0.98 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ

189.6, 172.1, 158.5, 155.8, 135.5, 128.8, 128.7, 128.5, 120.4, 96.4,

73.8, 68.4, 54.2, 42.4, 37.5, 27.4, 24.9. HRMS (ESI) [m/z] calculated

for C H NNaO ([M + Na] ) 410.1585, found 410.1574. IR v

−

[cm ] = 2968 (s), 1790 (w), 1716 (w), 1648 (m), 1604 (w), 1392

(m), 1334 (m), 1291 (m), 1178 (m), 1129 (w), 1042 (m), 910 (m),

454

J. Org. Chem. 2021, 86, 8448−8456

The Journal of Organic Chemistry

Universität Wuppertal, 42119 Wuppertal, Germany;

Note

28 (w), 697 (w), 456 (m). R (cyclohexane/EtOAc, 1:1) = 0.33 [p-

AUTHOR INFORMATION

Corresponding Author

■

Anisaldehyde]. [α]_D= +35.2 (ρ = 1.05, CH Cl ).

Derivatization Reactions. General Procedure C (GP-C). In a 4

mL vial, the corresponding oxazolidinone was dissolved in a mixture

of 1,4-dioxane (1.0 mL) and conc. HCl (2.0 mL), and stirred at 80 °C

in an oil bath for 2 h, monitoring by TLC. Afterwards, the reaction

was concentrated in vacuo. To the resulting solid, cyclohexane (3 ×

Adrián Gómez-Suárez − Organic Chemistry, Bergische

orcid.org/0000-0001-8622-0386; Email: gomezsuarez@

uni-wuppertal.de

.0 mL) was added and evaporated in vacuo to azeotrope any water

residues, aﬀording the desired α-amino acid salts.

S)-2-Amino-4-(2-hydroxyphenyl)-4-oxobutanoic acid hydro-

chloride salt (28). Synthesized following GP-C using 12 (62.4 mg,

.14 mmol) to aﬀord the desired α-amino acid salt 28 as an oﬀ-yellow

Authors

(

Kay Merkens − Organic Chemistry, Bergische Universität

Wuppertal, 42119 Wuppertal, Germany; orcid.org/0000-

0003-0753-2117

solid in 97% yield (35.5 mg, 0.136 mmol). H NMR (400 MHz,

D O) δ 7.98 (dd, J = 8.1, 1.6 Hz, 1H), 7.70 (ddd, J = 8.4, 7.3, 1.6 Hz,

Francisco José Aguilar Troyano − Organic Chemistry,

Bergische Universität Wuppertal, 42119 Wuppertal,

Germany; orcid.org/0000-0001-5274-7219

Khadijah Anwar − Organic Chemistry, Bergische Universität

Wuppertal, 42119 Wuppertal, Germany; orcid.org/

0000-0002-2799-0679

H), 7.18−7.07 (m, 2H), 4.53 (t, J = 5.3 Hz, 1H), 3.98 (d, J = 5.3 Hz,

_H₎_.1 C{ H} NMR (101 MHz, D O) δ 204.5, 173.9, 162.1, 139.4,

32.5, 122.0, 120.8, 119.6, 50.9, 40.2. HRMS (ESI) [m/z] calculated

−

for C H ClNO ([M] ) 244.0383, found 244.0382. [α] = +26.7

(ρ = 0.30, MeOH).

(S)-2-Amino-4-(2-chlorophenyl)-4-oxobutanoic acid hydrochlor-

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02951

ide salt (29). Synthesized following GP-C using 13 (51.3 mg, 0.11

mmol) to aﬀord the desired α-amino acid salt 29 as an oﬀ-brown solid

in quantitative yield (27.0 mg, 0.11 mmol). H NMR (400 MHz,

D O) δ 7.80 (dt, J = 7.7, 1.1 Hz, 1H), 7.69−7.61 (m, 2H), 7.55 (dt, J

Author Contributions

K.M. and F.J.A.T. contributed equally.

†

7.7, 4.3 Hz, 1H), 4.50 (t, J = 5.3 Hz, 1H), 3.90 (d, J = 5.3 Hz, 2H).

The characterization data matches the reported literature.

Notes

(S)-2-Amino-4-oxo-4-(pyridin-3-yl)butanoic acid hydrochloride

The authors declare no competing ﬁnancial interest.

salt (30). Synthesized following GP-C using 7 (78.0 mg, 0.19 mmol)

to aﬀord the desired α-amino acid salt 30 as an oﬀ-brown solid in 95%

ACKNOWLEDGMENTS

yield (45.0 mg, 0.18 mmol). H NMR (400 MHz, D O) δ 8.15−8.09

■

(

m, 2H), 7.37−7.29 (m, 2H), 4.45 (dd, J = 5.8, 4.7 Hz, 1H), 3.93−

This work was supported by the Fonds der Chemischen

Industrie (Liebig fellowship to A.G.S. and Ph.D. scholarship to

F.J.A.T.), by the Deutsche Forschungsgemeinschaft (DFG,

German Research Foundation) 443074366, and the Bergische

Universität Wuppertal (BUW). We thank Dr. Lisa Candish

and Jun. Prof. Matthew N. Hopkinson for fruitful discussions

and proof reading of the manuscript. Umicore A.G. is

acknowledged for its generous donation of materials. Prof.

Stefan Kirsch (BUW) is greatly acknowledged for his

continuous support.

.83 (m, 2H). The characterization data matches the reported

literature.

Procedure for the Synthesis of Methyl 2-((tert-

Butoxycarbonyl)amino)-4-oxo-4-phenylbutanoate for e.r.

Measurement. In a 4 mL vial, 1 was dissolved in a mixture of

,4-dioxane (1.0 mL) and conc. HCl (2.0 mL) and stirred at 80 °C in

an oil bath for 2 h, monitoring by TLC. Afterward, the reaction was

concentrated in vacuo. To resulting solid, cyclohexane (3 × 2.0 mL)

was added and evaporated in vacuo to azeotrope any water residues,

aﬀording the desired salt as an oﬀ-white solid. This was dissolved in

2,2-DMP (0.1 mL) and conc. HCl (0.3 mL) was added. The resulting

suspension was stirred at room temperature for 18 h. The reaction

was then concentrated in vacuo. The resulting oil was dissolved in

MeOH (2.0 mL) and NaHCO (94.9 mg) and Boc O (97.5 mg) were

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