Enantiopure 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Received: 3 May 2019

Revised: 13 June 2019

Accepted: 14 June 2019

DOI: 10.1002/chir.23109

R E G U L A R A R T I C L E

Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐

oxazolidinones as chiral building blocks in a divergent

asymmetric synthesis of heterocycles

Blanca M. Santoyo¹| Carlos González‐Romero^1,2| Daniel Zárate‐Zárate¹|

R. Israel Hernández‐Benitez¹| Vanessa Pelayo¹| Edson Barrera¹| Carlos H. Escalante¹|

Aydeé Fuentes‐Benites^1,2| Guadalupe Martínez‐Morales¹| Julio López³| Miguel A. Vázquez³|

Francisco Delgado¹| Hugo A. Jiménez‐Vázquez¹| Joaquín Tamariz¹

¹Departamento de Química Orgánica,

Abstract

Escuela Nacional de Ciencias Biológicas,

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evalu-

Instituto Politécnico Nacional, Mexico

City, Mexico

²Departamento de Química Orgánica,

ated as chiral building blocks for the divergent construction of heterocycles

with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group

Facultad de Química, Universidad

of these compounds proved to be an efficient chiral auxiliary for the asymmet-

Autónoma del Estado de México, Toluca,

State of Mexico, Mexico

³Departamento de Química, Universidad

ric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through

thermal and MW‐promoted nucleophilic conjugated addition to Michael accep-

de Guanajuato, Guanajuato, Guanajuato,

tors and alkyl halides. The resulting adducts were transformed via a cascade

Mexico

process into fused six‐membered carbo‐ and heterocycles. The structure of

Correspondence

Joaquín Tamariz, Departamento de

the reaction products depended on the electrophiles and reaction conditions

used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral pre-

Química Orgánica, Escuela Nacional de

Ciencias Biológicas, Instituto Politécnico

Nacional, Prol Carpio y Plan de Ayala

S/N, Mexico City 11340, Mexico.

Email: jtamarizm@gmail.com;

cursors for a versatile and divergent approach to highly substituted cyclic car-

bamates. DFT quantum calculations showed that the formation of bicyclic

pyranyl compounds was generated by a diastereoselective concerted hetero‐

Diels‐Alder cycloaddition.

jtamariz@woodward.encb.ipn.mx

Funding information

KEYWORDS

National Laboratory of the Universidad de

Guanajuato, Grant/Award Number:

260373; SIP‐IPN, Grant/Award Numbers:

20181307, 20171928, 20160567, 20195287,

20181332, 20170902, 20160791, 20195228

and 20180198; CONACYT, Grant/Award

Numbers: 282033, A1‐S‐17131, 178319 and

83446

(R)‐ and (S)‐1‐phenylethylamine, 4‐methylene‐2‐oxazolidinones, 4‐oxazolin‐2‐ones, hetero‐Diels‐

Alder reaction, microwave irradiation

1 | INTRODUCTION

based on the approach of the transformation of chiral

1,3‐oxazolidin‐2‐ones,^10-13which in turn can be obtained

Chiral 1,3‐oxazolidin‐2‐ones have been widely used as

efficient auxiliaries for the asymmetric synthesis of a

large variety of enantiopure and highly functionalized

carbonylic compounds.^1-9Likewise, the preparation of

α‐amino alcohols and α‐amino acids has been designed

from optically pure α‐amino alcohols¹⁰and α‐amino

acids, among other substrates.^1-9The synthetic applica-

bility of these heterocycles has increased with the devel-

opment of new methods for their construction.^14-21

Functionalized 4‐methylene‐1,3‐oxazolidin‐2‐ones have

Chirality. 2019;1–31.

wileyonlinelibrary.com/journal/chir

1

2

SANTOYO ET AL.

also proven to be versatile synthons in the formation of

diverse molecular systems.^22,23

by the enamide moiety, leading to the addition product

at C‐5 of compound 9 (R²= Me). The use of acrolein

(8a) as the electrophile did not afford the expected con-

jugated addition product 9 (R²= H), but instead, the

bicyclic pyranyl compound 10 or to the cyclohexadiene

product 11, depending on the reaction conditions.^45,46

More severe thermal conditions for the reaction

between substrates 1 and 8b, or thermal treatment of

the 1,4‐addition product 9 yielded the fused bicyclic

compounds 10 or 11 (R²= Me), respectively.

These favorable properties make 4‐oxazolin‐2‐ones

very adaptable tools for asymmetric synthesis. Because

of the importance of chiral oxazolidinones in the develop-

ment of optically pure β‐amino alcohols or β‐hydroxy

amides, we herein describe an extensive evaluation of

the chiral heterocycles 1 and 2 as useful and versatile chi-

ral building blocks in the construction of a variety of

substituted bicyclic structures bearing quaternary

stereocenters. A computational study was conducted to

rationalize the diastereoselectivity and reaction mecha-

nisms present in such processes.

Preformed or in situ‐generated chiral enamines and

enamides proved to be highly diastereoselective species

in diversity‐oriented asymmetric synthesis.^24-30It is possi-

ble to carry out this synthetic approach via aldol,

Mannich, Michael condensations, addition to metal π‐

double and π‐triple activated C–C bonds, and Heck

arylation,^31-33as well as in cascade vicinal

difunctionalization or pericyclic reactions, leading to the

formation of complex molecules with the generation of

a number of stereogenic centers, including the total syn-

thesis of natural products.^34,35Among the chiral auxil-

iaries used in asymmetric synthesis, those based on the

1‐phenylethylamino group‐containing scaffolds proved

to be very efficient in many diastereoselective pro-

cesses.^36-43

On the basis of the previously developed regioselec-

tive synthesis of N‐substituted 4‐oxazolin‐2‐ones 1 and

4‐methylene‐2‐oxazolidinones 2, resulting from the con-

densation of α‐ketol 3a and isocyanates

4

(Scheme 1),^44,45in a preliminary report, we presented

the one‐pot synthesis of the optically pure version of

heterocycles 1‐2 by introducing the N‐(S)‐methylbenzyl

moiety as the chiral auxiliary.⁴⁶Although this method-

ology was also efficient for the preparation of the corre-

sponding 3‐substituted 4‐oxazolin‐2‐thiones 6 and 4‐

methylene‐1,3‐oxazolidin‐2‐thiones 7,⁴⁷these heterocy-

cles were not able to undergo further reactions when

utilizing the thioenamide functionality as a nucleo-

phile.^44-46In contrast, compounds 1 behave as an

enolate equivalent in the presence of a Michael accep-

tor, in which the regioselectivity was totally controlled

2 | MATERIALS AND METHODS

2.1 | General

Melting points were determined with an Electrothermal

capillary melting point apparatus. IR spectra were

recorded on a FT‐IR Perkin Elmer 2000 spectrophotom-

1

eter. H (300 or 500 MHz) and ¹³C (75.4 or 125 MHz)

NMR spectra were recorded on Varian Mercury‐300 or

Varian VNMR System instruments, with TMS as

SCHEME 1 Synthesis of 4‐oxazolin‐ and oxazolidin‐2‐ones as well as 4‐oxazolin‐ and oxazolidin‐2‐thiones, and evaluation of their

reactivity with Michael acceptors

SANTOYO ET AL.

3

internal standard. Mass spectra (MS) were taken in the

electron impact (EI) mode on Hewlett‐Packard 5971A

and Thermo‐Finnigan Polaris Q spectrometers. High‐

resolution mass spectra (HRMS) were obtained in elec-

tron impact and FAB⁺modes on Jeol JSM‐GCMateII

and Jeol JMS‐SX 102 spectrometers, respectively. Optical

rotations were determined on a Jasco P‐200 polarimeter.

X‐ray crystallographic structures were accomplished on

Siemens P4 (Cu Kα radiation) and Oxford XcaliburS

(Mo Kα radiation) diffractometers. Microwave (MW)

irradiation was carried out on a CEM MW reactor and

SEV/MIC‐1 (Mexico) MW reactor.⁴⁸All air moisture

sensitive reactions were carried out under nitrogen

atmosphere with oven‐dried glassware. Prior to use,

THF, toluene, and xylene were freshly distilled from

sodium, and ethyl acetate, methylene chloride, and

MeCN from calcium hydride. DMF was distilled from

4 Å molecular sieves, and Et₃N from NaOH. Li₂CO₃

was dried overnight at 120°C before use. All other

reagents and solvents were employed without further

purification.

9:1) to afford a mixture of 1a (0.135 g, 55%)

as an amber oil and 2a (65:35) (0.072 g,

29%) as a white solid. Data for 1a: Rf 0.35

26

(hexane/EtOAc, 8:2). [α]_D= +27.0 (c

0.200, CHCl₃). IR (film): ν = 1750, 1701,

1

1451, 1355, 1246, 1025, 758, 700 cm⁻¹. H

NMR (300 MHz, CDCl₃): δ = 1.67 (q,

J

=

0.9 Hz, 3H, CH₃C‐4), 1.81 (d,

7.2 Hz, 3H, CH₃C‐1′), 1.98 (q,

0.9 Hz, 3H, CH₃C‐5), 5.33 (q,

J = 7.2 Hz, 1H, H‐1′), 7.24‐7.39 (m, 5H, Ph‐

H) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 8.8 (CH₃C‐4), 9.7 (CH₃C‐5), 18.3

(CH₃C‐1′), 51.7 (C‐1′), 117.1 (C‐4), 126.4 (2

C, arom. CH), 127.6 (arom. CH), 128.6 (2

C, arom. CH), 131.7 (C‐5), 140.1 (arom. C),

155.6 (C‐2) ppm. EM (70 eV): m/z

(%) = 218 (17) [M + 1]⁺, 114 (60), 106

(100), 104 (34), 80 (38), 77 (21). HRMS

(EI): m/z = 217.1103 [M]⁺, calcd for

C₁₃H₁₅NO₂217.1103. Data for 2a (65:35): R_f

0.60 (hexane/EtOAc, 7:3); m.p. 72‐75°C; [α]

23

D

= +56.5 (c 0.20, CHCl₃). IR (film):

ν = 2922, 1745, 1698, 1449, 1351, 1243,

2.2 | Synthesis

1021, 756, and 697 cm⁻¹

.

¹H NMR

(300 MHz, CDCl₃): δ = 1.46 (d, J = 6.3 Hz,

3H, CH₃C‐5), 1.79 (br d, J = 7.2 Hz, 3H,

CH₃C‐1′), 3.89‐3.95 (m, 2H, C), 4.94‐5.05

(m, 1H, H‐5), 5.32 (q, J = 7.2 Hz, 1H, H‐

1′), 7.25‐7.40 (m, 5H, Ph‐H). Signals attrib-

uted to the minor isomer: 1.47 (d,

J = 6.3 Hz, CH₃C‐5), 1.77 (d, J = 7.5 Hz,

CH₃C‐1′) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 15.6 (CH₃C‐5), 21.3 (CH₃C‐1′),

51.3 (C‐1′), 74.3 (C‐5), 82.7 (C), 126.5 (2 C,

arom. CH), 127.5 (arom. CH), 128.5 (2 C,

arom. CH), 138.7 (arom. C), 144.5 (C‐4),

156.5 (C‐2). Signals attributed to the minor

isomer: 21.2 (CH₃C‐1′), 51.4 (C‐1′), 144.6

(C‐4) ppm. EM (70 eV): m/z (%) = 218 (16)

[M + 1]⁺, 114 (22), 106 (100), 105 (38), 80

(32), 78 (18). HRMS (EI): m/z = 217.1105

[M]⁺, calcd for C₁₃H₁₅NO₂217.1103.

2.2.1 | General procedures for the prepa-

ration of 4,5‐dimethyl‐3‐((R)‐1‐phenylethyl)

oxazol‐2(3H)‐ones (1a) and

5‐methyl‐4‐methylene‐3‐((R)‐1‐

phenylethyl)oxazolidin‐2‐one (2a)

Method A. A mixture of 3‐hydroxy‐2‐butanone (3a)

(0.030 g, 0.34 mmol), 4a (0.050 g,

0.34 mmol), and Et₃N (0.069 g, 0.68 mmol)

was placed in a threaded ACE glass pres-

sure tube with a sealed Teflon screw cap

under N₂atmosphere. It was stirred and

heated at 120°C for 24 hours. The reaction

crude was filtered over celite and purified

by column chromatography over silica gel

(30 g/1 g of crude, hexane/EtOAc, 9:1) to

give 1a (0.055 g, 75%) as an amber oil.

Method B. A mixture of 3a (0.100 g, 1.14 mmol) and 4a

(0.200 g, 1.36 mmol) was put into a threaded

ACE glass pressure tube with a sealed Tef-

lon screw cap under N₂atmosphere. It was

stirred and irradiated with MW (200 W) at

170°C for 8.0 minutes. The mixture was

diluted with CH₂Cl₂(10 mL), stirred for

30 minutes and filtered. The solvent was

removed under vacuum. The residue was

purified by column chromatography over

silica gel (30 g/g of crude, hexane/EtOAc,

2.2.2 | 4,5‐Dimethyl‐3‐((S)‐1‐phenylethyl)

oxazol‐2(3H)‐one (1b) and

5‐methyl‐4‐methylene‐3‐((S)‐1‐phenylethyl)

oxazolidin‐2‐one (2b)

Method A. Following method A for the preparation of

1a/2a, the mixture of 3a (0.144 g,

4

SANTOYO ET AL.

1.64 mmol), 4b (0.200 g, 1.36 mmol), and

Et₃N (0.275 g, 2.72 mmol) provided 1b

(0.221 g, 75%) as an amber oil.

2.2.3 | (4R,5R)‐4‐Hydroxy‐4,5‐dimethyl‐3‐

((S)‐1‐phenylethyl)oxazolidin‐2‐one (12)

and (4R,5S)‐4‐hydroxy‐4,5‐dimethyl‐3‐((S)‐1‐

phenylethyl)oxazolidinone (13)

Method B. According to method B for the preparation

of 1a/2a, the mixture of 3a (0.072 g,

0.818 mmol), 4b (0.100 g, 0.68 mmol), and

Et₃N (0.069 g, 0.68 mmol) was irradiated

with MW (200 W) at 140°C for 8 minutes

to furnished a mixture of 1b (0.023 g, 16%)

as an amber oil and 2b (54:46) (0.058 g,

39%) as a pale yellow powder. Data for

A mixture of 3a (0.880 g, 0.01 mol) and 4b (1.470 g,

0.01 mol) was placed in a threaded ACE glass pressure

tube with a sealed Teflon screw cap under N₂atmo-

sphere. It was stirred and irradiated with MW (200 W)

at 120°C for 90 minutes. The mixture was diluted in

CH₂Cl₂(40 mL), poured into H₂O (100 mL), and stirred

for 30 minutes. The precipitate was filtered, and the

aqueous layer was washed with CH₂Cl₂(2 × 40 mL).

The combined organic layers were dried (Na₂SO₄), and

the solvent was removed under vacuum. The residue

was purified by column chromatography over silica gel

(30 g/g of crude, hexane/EtOAc, 9:1) to give 1b

(1.10 g, 51%) and a mixture of 12/13 (61:39) (0.82 g,

35%), which after recrystallization (hexane/CH₂Cl₂, 6:1)

resulted in 12 as a white solid. Data for 12: R_f0.15 (hex-

1b:^46,49R_f0.35 (hexane/EtOAc, 8:2). [α]

26

D

= −33.8 (c 0.500, CHCl₃). IR (film):

ν = 1743, 1700, 1495, 1448, 1351, 1244,

1122, 1024, 979, 757, and 698 cm⁻^{1 1}H

.

NMR (300 MHz, CDCl₃): δ = 1.67 (q,

J = 0.9 Hz, 3H, CH₃C‐4), 1.81 (d, J = 7.2 Hz,

3H, CH₃C‐1′), 1.98 (q, J = 0.9 Hz, 3H,

CH₃C‐5), 5.33 (q, J = 7.2 Hz, 1H, H‐1′),

7.22‐7.40 (m, 5H, Ph‐H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 8.7 (CH₃C‐4), 9.6

(CH₃C‐5), 18.2 (CH₃C‐1′), 51.7 (C‐1′), 117.1

(C‐4), 126.3 (2 C, arom. CH), 127.5 (arom.

CH), 128.5 (2 C, arom. CH), 131.6 (C‐5),

140.1 (arom. C), 155.5 (C‐2) ppm. EM

(70 eV): m/z (%) = 217 (5) [M]⁺, 146 (15),

120 (35), 113 (30), 105 (100), 103 (34), 91

(15), 79 (36), 77 (44). HRMS (EI): m/

z = 217.1101 [M]⁺, calcd for C₁₃H₁₅NO₂

217.1103. Data for 2b (54:46): R_f0.66 (hex-

26

ane/EtOAc, 7:3); m.p. 87°C to 88°C. [α]_D= −51.0 (c

0.100, CHCl₃). IR (film): ν = 3325, 2982, 1720, 1655,

1551, 1418, 1379, 1311, 1213, 1176, 1081, 913, 766,

700 cm⁻^{1 1}H NMR (300 MHz, CDCl₃): δ = 1.37 (d,

.

J = 6.6 Hz, 3 H, CH₃C‐1′), 1.40 (s, 3 H, CH₃C‐4), 1.83

(d, J = 7.1 Hz, 3 H, CH₃C‐1′), 3.96 (br s, 1 H, OH),

4.27 (q, J = 6.6 Hz, 1 H, H‐5), 4.66 (q, J = 7.1 Hz, 1

H, H‐1′), 7.20‐7.37 (m, 3 H, Ph‐H), 7.40‐7.51 (m, 2 H,

Ph‐H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 13.0

(CH₃C‐5), 20.1 (CH₃C‐4), 23.9 (CH₃C‐1′), 51.6 (C‐1′),

79.4 (C‐5), 89.0 (C‐4), 127.2 (2 C, arom. CH), 127.4

(arom. CH), 128.5 (2 C, arom. CH), 142.3 (arom. C),

156.6 (C‐2) ppm. C₁₃H₁₇NO₃(235.28): calcd. C, 66.36;

H, 7.28; N, 5.95; found C, 66.50; H, 7.35; N, 6.17. Signals

ane/EtOAc, 7:3); m.p. 71‐73°C. [α]

23

D

= −55.5 (c 0.200, CHCl₃). IR (film):

ν = 1757, 1672, 1449, 1377, 1320, 1221,

1

1201, 1072, 1024, 756, 696 cm⁻¹. H NMR

1

(300 MHz, CDCl₃): δ = 1.46 (d, J = 6.3 Hz,

3H, CH₃C‐5), 1.78 (d, J = 7.4 Hz, 3H,

CH₃C‐1′), 3.88‐3.95 (m, 2H, C), 4.94‐5.04

(m, 1H, H‐5), 5.32 (q, J = 7.4 Hz, 1H, H‐

1′), 7.16‐7.45 (m, 5H, Ph‐H). Signals attrib-

uted to the minor isomer: 1.47 (d,

J = 6.3 Hz, CH₃C‐5), 1.79 (d, J = 6.9 Hz,

CH₃C‐1′) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 15.6 (CH₃C‐5), 21.2 (CH₃C‐1′),

51.5 (C‐1′), 74.3 (C‐5), 82.7 (CH₂=), 126.5

(2 C, arom. CH), 127.5 (arom. CH), 128.5

(2 C, arom. CH), 138.7 (arom. C), 144.5 (C‐

4), 156.4 (C‐2). Signals attributed to the

minor isomer: 21.3 (CH₃C‐1′), 51.3 (C‐1′),

126.6 (arom. CH), 144.7 (C‐4) ppm. EM

(70 eV): m/z (%) = 218 (39) [M + 1]⁺, 174

(14), 159 (11), 114 (22), 106 (100), 80 (30),

77 (18). HRMS (EI): m/z = 217.1106 [M]⁺,

calcd for C₁₃H₁₅NO₂217.1103.

attributed to the minor isomer 13: H NMR (300 MHz,

CDCl₃): δ = 1.26 (s, CH₃C‐4), 1.31 (d, J = 6.6 Hz,

CH₃C‐5), 3.72 (br s, OH), 4.19 (q, J = 6.6 Hz, H‐5),

5.00 (q, J = 7.1 Hz, H‐1′) ppm. ¹³C NMR (75.4 MHz,

CDCl₃):

δ = 12.8 (CH₃C‐5), 17.8 (CH₃C‐4), 23.4

(CH₃C‐1′), 51.0 (C‐1′), 79.8 (C‐5), 88.8 (C‐4), 127.4

(arom. CH), 128.6 (arom. CH), 141.6 (arom. C), 157.0

(C‐2) ppm.

2.2.4 | 5,5‐Dimethyl‐4‐methylene‐3‐((R)‐1‐

phenylethyl)oxazolidin‐2‐one (14a)

A mixture of 3b (0.200 g, 1.96 mol) and 4a (0.346 g,

2.35 mmol) was placed in a threaded ACE glass pressure

tube with a sealed Teflon screw cap under N₂atmo-

sphere. It was stirred and irradiated with MW (60 W) at

200°C for 20 minutes. The mixture was diluted with

CH₂Cl₂(10 mL) and stirred for 30 minutes and filtered.

SANTOYO ET AL.

5

The solvent was removed under vacuum. The residue was

purified by column chromatography over silica gel (30 g/g

of crude, hexane/EtOAc, 9:1) to give 14a (0.30 g, 66%) as a

CDCl₃): δ = 1.47 (s, 3 H, CH₃C‐5), 1.48 (s,

3 H, CH₃C‐5), 1.78 (d, J = 7.4 Hz, 3H,

CH₃C‐1′), 3.85‐3.89 (m, 2 H, C), 5.33 (q,

J = 7.4 Hz, 1H, H‐1′), 7.20‐7.41 (m, 5 H,

Ph‐H) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 15.5 (CH₃C‐1′), 27.8 (CH₃C‐5), 27.9

(CH₃C‐5), 51.2 (C‐1′), 81.4 (C‐5), 81.9 (C),

126.4 (2 C, arom. CH), 127.4 (arom. CH),

128.4 (2 C, arom. CH), 138.8 (arom. C),

148.6 (C‐4), 155.6 (C‐2) ppm. MS (70 eV):

m/z (%) = 232 (100) [M + 1]⁺, 231 (25) [M]

⁺, 187 (10), 132 (10), 120 (94), 105 (96), 91

(14), 79 (25), 77 (16). HRMS (EI):

m/z = 231.1258 [M]⁺, calcd for C₁₄H₁₇NO₂

231.1259.

pale yellow oil. R_f= 0.69 (hexane/EtOAc, 7:3). [α]

23

= +53.0 (c 0.200, CHCl₃). IR (film): ν = 1760, 1678,

D

1455, 1393, 1296, 1200, 1098, 1076, 1039, 817, 760,

1

698 cm⁻¹. H NMR (300 MHz, CDCl₃): δ = 1.47 (s, 3 H,

CH₃C‐5), 1.48 (s, 3 H, CH₃C‐5), 1.78 (d, J = 7.1 Hz, 3H,

CH₃C‐1′), 3.85‐3.90 (m, 2 H, C), 5.33 (q, J = 7.1 Hz, 1H,

H‐1′), 7.22‐7.40 (m, 5 H, Ph‐H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 15.5 (CH₃C‐1′), 27.8 (CH₃C‐5),

27.9 (CH₃C‐5), 51.2 (C‐1′), 81.5 (C‐5), 81.9 (C), 126.4

(2 C, arom. CH), 127.4 (arom. CH), 128.5 (2 C, arom.

CH), 138.8 (arom. C), 148.7 (C‐4), 155.6 (C‐2) ppm. MS

(70 eV): m/z (%) = 233 (54) [M + 2]⁺, 188 (20), 173

(11), 128 (22), 106 (100), 105 (24), 80 (29). HRMS (EI):

m/z = 231.1260 [M]⁺, calcd for C₁₄H₁₇NO₂231.1259.

2.2.5 | General procedures for the prepa-

ration of 5,5‐dimethyl‐4‐methylene‐3‐((S)‐1‐

phenylethyl)oxazolidin‐2‐one (14b)⁴⁶

2.2.6 | (4S,5R)‐4,5‐Dimethyl‐4‐methylene‐

3‐((S)‐1‐phenylethyl)oxazolidin‐2‐one (15)

and (4R,5S)‐4,5‐dimethyl‐4‐methylene‐3‐

((S)‐1‐phenylethyl)oxazolidin‐2‐one (16)⁴⁶

Method A. A mixture of 3b (0.200 g, 1.96 mol) and 4b

(0.346 g, 2.35 mmol) was placed in a

threaded ACE glass pressure tube with a

sealed Teflon screw cap under N₂atmo-

sphere. The mixture was stirred and heated

at 130°C for 24 hours. The mixture was

diluted with CH₂Cl₂(15 mL), stirred for

30 minutes, and then filtered. The solvent

was removed under vacuum. The residue

was purified by column chromatography

over silica gel (30 g/g of crude,

hexane/EtOAc, 9:1) to give 14b (0.354 g,

78%) as a pale yellow oil.

A mixture of 1b (0.326 g, 1.50 mmol), Pd/C (10%) (0.06 g,

0.3 mmol), and AcOH (0.2 mL) in EtOAc (40 mL) was

placed in a high pressure hydrogenation Parr vessel

(750 psi) under H₂atmosphere. It was stirred and heated

at 60°C for 24 hours. The mixture was filtered over celite,

and the solvent was removed under vacuum. The residue

was purified by column chromatography over silica gel

(30 g/g of crude, hexane/EtOAc, 9:1) to give a mixture

of 15/16 (84:16) (0.24 g, 73%) as a colorless oil. R_f= 0.45

23

(hexane/EtOAc, 7:3). [α]_D= −40.1 (c 0.177, CHCl₃).

IR (film): ν = 2981, 2937, 1740, 1678, 1451, 1410, 1382,

1236, 1190, 1078, 1024, 765, and 701 cm⁻^{1 1}H NMR

.

Method B. A mixture of 3b (0.200 g, 1.96 mmol) and 4b

(0.346 g, 2.35 mmol) was put into in a

threaded ACE glass pressure tube with a

sealed Teflon screw cap under N₂atmo-

sphere. It was stirred and irradiated with

MW (300 W) at 140°C for 3 hours. The mix-

ture was diluted with CH₂Cl₂(10 mL),

stirred for 30 minutes, and filtered. The sol-

vent was removed under vacuum. The

residue was purified by column chromatog-

raphy over silica gel (30 g/g of crude,

hexane/EtOAc, 9:1) to give 14b (0.38 g,

84%) as a pale yellow oil. R_f= 0.67 (hex-

(300 MHz, CDCl₃): δ = 0.75 (d, J = 6.5 Hz, 3 H, CH₃C‐

4), 1.26 (d, J = 6.5 Hz, 3 H, CH₃C‐5), 1.70 (d,

J = 7.3 Hz, 3H, CH₃C‐1′), 3.86 (dq, J = 7.5, 6.5 Hz, 1 H,

H‐4), 4.58 (dq, J = 7.5, 6.5 Hz, 1 H, H‐5), 5.03 (q,

J = 7.3 Hz, 1H, H‐1′), 7.22‐7.42 (m, 5 H, Ph‐H) ppm. Sig-

nals attributed to the minor isomer 16: 1.09 (d, J = 6.5 Hz,

CH₃C‐4), 1.66 (d, J = 7.3 Hz, CH₃C‐1′), 3.45 (dq, J = 7.5,

6.5 Hz, H‐4), 4.48 (dq, J = 7.5, 6.5 Hz, H‐5), 5.16 (q,

J = 7.3 Hz, 1 H, H‐1′) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 14.1 (CH₃C‐4), 14.8 (CH₃C‐5), 17.0 (CH₃C‐1′), 51.4

(C‐1′), 53.0 (C‐4), 73.7 (C‐5), 126.9 (2 C, arom. CH),

127.5 (arom. CH), 128.4 (2 C, arom. CH), 141.6 (arom.

C), 157.8 (C‐2) ppm. Signals attributed to the minor iso-

mer 16: 14.6 (CH₃C‐4), 15.4 (CH₃C‐5), 18.5 (CH₃C‐1′),

52.2 (C‐1′), 73.9 (C‐5), 127.2 (arom. CH), 127.7 (arom.

CH), 128.6 (arom. CH), 139.4 (arom. C) ppm. HRMS

(EI): m/z = 219.1260 [M]⁺, calcd for C₁₃H₁₇NO₂219.1259.

23

ane/EtOAc, 7:3). [α]_D= −54.3 (c 0.233,

CHCl₃). IR (film): ν = 1763, 1678, 1452,

1393, 1373, 1296, 1201, 1098, 1039, 966,

816, 760, 699 cm⁻^{1 1}H NMR (300 MHz,

.

6

SANTOYO ET AL.

2.12 (m, 1H, CH₂C‐5), 2.12 (s, 3 H, CH₃CO), 2.24‐2.38

(m, 1H, CH₂CO), 2.43‐2.59 (m, 1H, CH₂CO), 3.86 (d,

J = 3.3 Hz, 1 H, C), 3.98 (d, J = 3.3 Hz, 1 H, C), 5.38 (q,

J = 7.4 Hz, 1 H, H‐1′), 7.26‐7.39 (m, 5 H, Ph‐H) ppm. Sig-

nals attributed to the minor isomer 20a: 2.09 (s, CH₃CO),

5.28 (q, J = 6.9 Hz, H‐1′) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 15.2 (CH₃C‐1′), 27.0 (CH₃C‐5), 29.9 (CH₂C‐

5), 33.9 (CH₃CO), 37.3 (CH₂CO), 51.3 (C‐1′), 82.6 (C),

82.8 (C‐5), 126.6 (2 C, arom. CH), 127.6 (arom. CH),

128.4 (2 C, arom. CH), 138.5 (arom. C), 146.5 (C‐4),

155.6 (C‐2), 207.1 (CO) ppm. Signals attributed to the

minor isomer 20a: 15.8 (CH₃C‐1′), 27.0 (CH₃C‐5), 34.0

(CH₃CO), 37.2 (CH₂CO), 51.6 (C‐1′), 82.7 (C‐5), 126.4 (2

C, arom. CH), 127.5 (arom. CH), 128.5 (2 C, arom. CH),

146.7 (C‐4) ppm. MS (70 eV): m/z (%) = 230 (26)

[M − 57]⁺, 187 (13), 114 (51), 106 (100), 80 (20), 78 (17).

HRMS (EI): m/z = 287.1516 [M]⁺, calcd for C₁₇H₂₁NO₃

287.1521.

2.2.7 | (4S)‐4,5,5‐Trimethyl‐3‐((S)‐1‐

phenylethyl)oxazolidin‐2‐one (17) and (4R)‐

4,5,5‐trimethyl‐3‐((S)‐1‐phenylethyl)

oxazolidin‐2‐one (18)⁴⁶

A mixture of 14b (0.231 g, 1.00 mmol) and Pd (OH)₂

(20%) (0.028 g, 0.2 mmol) in MeOH (10 mL) was placed

in a round‐bottomed flask with a septum provided with

an H₂balloon. It was stirred at room temperature for

24 hours and then filtered over celite. The solvent was

removed under vacuum. The residue was purified by col-

umn chromatography over silica gel (30 g/g of crude,

hexane/EtOAc, 97:3) to give a mixture of 17/18 (96:4)

(0.23 g, 99%) as a pale yellow oil. R_f= 0.40 (hexane/

22

EtOAc, 7:3). [α]_D= −129.6 (c 0.100, MeOH). IR (film):

ν¯ = 2979, 2936, 1740, 1452, 1408, 1374, 1302, 1282, 1234,

1192, 1083, 1024, 962, 897, 767, 701 cm⁻^{1 1}H NMR

.

(500 MHz, CDCl₃): δ = 0.76 (d, J = 6.5 Hz, 3 H, CH₃C‐

4), 1.26 (s, 3 H, CH₃C‐5), 1.37 (s, 3 H, CH₃C‐5), 1.70 (d,

J = 7.3 Hz, 3H, CH₃C‐1′), 3.51 (q, J = 6.5 Hz, 1 H, H‐4),

5.05 (q, J = 7.3 Hz, 1 H, H‐1′), 7.23‐7.44 (m, 5 H, Ph‐H)

ppm. Signals attributed to the minor isomer 18: 1.09 (d,

J = 6.5 Hz, CH₃C‐4), 1.23 (s, CH₃C‐5), 1.66 (d,

J = 7.3 Hz, CH₃C‐1′), 3.09 (q, J = 6.5 Hz, H‐4) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 14.8 (CH₃C‐4), 16.4

(CH₃C‐1′), 21.5 (CH₃C‐5), 26.9 (CH₃C‐5), 51.1 (C‐1′),

58.9 (C‐4), 80.2 (C‐5), 126.9 (2 C, arom. CH), 127.4 (arom.

CH), 128.3 (2 C, arom. CH), 141.6 (arom. C), 157.4 (C‐2)

ppm. Signals attributed to the minor isomer 18: 16.2

(CH₃C‐4), 127.3 (arom. CH), 127.7 (arom. CH), 128.6

(arom. C) ppm. HRMS (EI): m/z = 233.1411 [M]⁺, calcd

for C₁₄H₁₉NO₂233.1416.

2.2.9 | (5S)‐5‐Methyl‐4‐methylene‐5‐(3‐

oxobutyl)‐3‐((S)‐1‐phenylethyl)oxazolidin‐

2‐one (19b) and (5R)‐5‐methyl‐4‐methylene‐

5‐(3‐oxobutyl)‐3‐((S)‐1‐phenylethyl)

oxazolidin‐2‐one (20b)^46,49

A mixture of 1b (0.200 g, 0.922 mmol) and 8b (0.258 g,

3.69 mmol) in anhydrous xylene (2 mL) was placed in a

threaded ACE glass pressure tube with a sealed Teflon

screw cap under N₂atmosphere. It was stirred and heated

at 100°C for 72 hours. The solvent was removed under

vacuum, and the crude was purified by column chroma-

tography over silica gel (30 g/g of crude, hexane/EtOAc,

91:9) to give a mixture of 19b/20b (91:9) (0.11 g, 42%) as

a colorless oil. R_f= 0.42 (hexane/EtOAc, 8:2). [α]

2.2.8 | (5R)‐5‐Methyl‐4‐methylene‐5‐(3‐

oxobutyl)‐3‐((R)‐1‐phenylethyl)oxazolidin‐

2‐one (19a) and (5S)‐5‐methyl‐4‐methylene‐

5‐(3‐oxobutyl)‐3‐((R)‐1‐phenylethyl)

oxazolidin‐2‐one (20a)

23

= −74.1 (c 0.338, MeOH). IR (film): ν = 2924, 1751,

D

1702, 1448, 1355, 1243, 1024, 758, 700 cm⁻¹. H NMR

1

(300 MHz, CDCl₃): δ = 1.46 (s, 3 H, CH₃C‐5), 1.78 (d,

J = 7.5 Hz, 3 H, CH₃C‐1′), 1.80‐1.93 (m, 1 H, CH₂C‐5),

2.00‐2.12 (m, 1 H, CH₂C‐5), 2.11 (s, 3 H, CH₃CO), 2.23‐

2.38 (m, 1 H, CH₂CO), 2.45‐2.58 (m, 1 H, CH₂CO), 3.85

(d, J = 3.0 Hz, 1 H, C), 3.98 (d, J = 3.0 Hz, 1 H, C), 5.38

(q, J = 7.5 Hz, 1 H, H‐1′), 7.25‐7.41 (m, 5 H, Ph‐H)

ppm. Signals attributed to the minor isomer 20b: 1.51 (s,

CH₃C‐5), 3.88 (d, J = 3.3 Hz, C), 5.28 (q, J = 6.9 Hz, H‐

1′) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 15.2 (CH₃C‐

1′), 27.1 (CH₃C‐5), 30.0 (CH₂C‐5), 34.0 (CH₃CO), 37.4

(CH₂CO), 51.4 (C‐1′), 82.6 (C), 82.9 (C‐5), 126.7 (2 C,

arom. CH), 127.7 (arom. CH), 128.5 (2 C, arom. CH),

138.6 (arom. C), 146.6 (C‐4), 155.6 (C‐2), 207.1 (CO)

ppm. Signals attributed to the minor isomer 20b: 15.9

(CH₃C‐1′), 27.0 (CH₃C‐5), 34.1 (CH₃CO), 37.2 (CH₂CO),

51.7 (C‐1′), 82.8 (C‐5), 126.5 (2 C, arom. CH), 127.6 (arom.

A mixture of 1a (0.210 g, 0.968 mmol) and 8b (0.203 g,

2.90 mmol) in anhydrous xylene (3 mL) was placed in a

threaded ACE glass pressure tube with a sealed Teflon

screw cap under N₂atmosphere. It was stirred and heated

at 160°C for 96 hours. The solvent was removed under

vacuum, and the crude was purified by column chroma-

tography over silica gel (30 g/g of crude, hexane/EtOAc,

9:1) to give a mixture of 19a/20a (72:28) (0.161 g, 58%)

as a pale yellow oil. R_f= 0.36 (hexane/EtOAc, 7:3). [α]

23

= +15.3 (c 0.700, CHCl₃). IR (film): ν = 2928, 1760,

D

1716, 1676, 1373, 1199, 1025, 759, 699 cm⁻¹. H NMR

1

(300 MHz, CDCl₃): δ = 1.47 (s, 3 H, CH₃C‐5), 1.70‐1.96

(m, 1H, CH₂C‐5), 1.78 (d, J = 7.4 Hz, CH₃C‐1′), 2.00‐

SANTOYO ET AL.

7

CH), 128.6 (2 C, arom. CH), 138.9 (arom. C), 147.0 (C‐4),

155.5 (C‐2) ppm. HRMS (EI): m/z = 287.1529 [M]⁺, calcd

for C₁₇H₂₁NO₃287.1521.

(81:19) (0.215 g, 55%) as a pale yellow oil. R_f= 0.25

(hexane/EtOAc, 8:2). [α]_D= −45.1 (c 0.218, MeOH).

23

IR (film): ν = 2979, 2936, 1753, 1714, 1684, 1449, 1406,

1

1372, 1324, 1199, 1166, 1045, 1027, 759, 699 cm⁻¹. H

NMR (300 MHz, CDCl₃): δ = 1.56 (s, 3 H, CH₃C‐5),

1.57 (s, 3 H, CH₃C‐5), 1.74 (d, J = 7.3 Hz, 3 H, CH₃C‐

1′), 2.00 (s, 3 H, CH₃CO), 2.12‐2.23 (m, 2 H, CH₂CH=),

2.25‐2.32 (m, 2 H, CH₂CO), 4.15 (dd, J = 8.0, 7.5 Hz, 1

H, CH=), 5.32 (q, J = 7.3 Hz, 1 H, H‐1′), 7.20‐7.40 (m,

5 H, Ph‐H) ppm. Signals attributed to the minor isomer

22b: 1.50 (s, CH₃C‐5), 1.51 (s, CH₃C‐5), 1.88 (d,

J = 7.3 Hz, CH₃C‐1′) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 15.7 (CH₃C‐1′), 20.6 (CH₂CH=), 26.5 (CH₃C‐5), 26.6

(CH₃C‐5), 30.1 (CH₃CO), 43.9 (CH₂CO), 50.9 (C‐1′), 80.9

(C‐5), 98.8 (CH=), 126.2 (2 C, arom. CH), 127.2 (arom.

CH), 128.4 (2 C, arom. CH), 139.0 (arom. C), 140.3 (C‐

4), 155.4 (C‐2), 207.5 (CO) ppm. Signals attributed to

the minor isomer 22b: 43.5, 84.9, 126.8 ppm. HRMS

(EI): m/z = 301.1672 [M]⁺, calcd for C₁₈H₂₃NO₃

301.1678.

2.2.10 | (E)‐5,5‐Dimethyl‐4‐(4‐

oxopentylidene)‐3‐((R)‐1‐phenylethyl)

oxazolidin‐2‐one (21a) and (Z)‐5,5‐dimethyl‐

4‐(4‐oxopentylidene)‐3‐((R)‐1‐phenylethyl)

oxazolidin‐2‐one (22a)

To a solution of 8b (0.109 g, 1.56 mmol) in anhydrous

CH₂Cl₂(2.0 mL) at 0°C and under N₂atmosphere, iodine

(0.0066 g, 0.026 mmol) was added and the mixture stirred

at the same temperature for 30 minutes (the solution

turned dark red). Subsequently, 14a (0.120 g, 0.519 mmol)

in anhydrous CH₂Cl₂(2.0 mL) was added, and the mix-

ture stirred at 0°C for 4 hours. The mixture was then

diluted with CH₂Cl₂(20 mL) and poured into a 10% aque-

ous solution of sodium thiosulfate (10 mL). The aqueous

layer was washed with CH₂Cl₂(2 × 20 mL), the organic

layer was dried (Na₂SO₄), and the solvent was removed

under vacuum. The crude was purified by column chro-

matography over silica gel (30 g/g of crude,

hexane/EtOAc, 9:1) to give 21a (0.08 g, 51%) as a pale yel-

2.2.12 | (4S)‐5,5‐Dimethyl‐4‐(4‐oxopentyl)‐

3‐((S)‐1‐phenylethyl)oxazolidin‐2‐one (23a)

and (4R)‐5,5‐dimethyl‐4‐(4‐oxopentyl)‐3‐

((S)‐1‐phenylethyl)oxazolidin‐2‐one (24a)

23

low oil. R_f= 0.32 (hexane/EtOAc, 7:3). [α]_D= +17.3 (c

0.400, CHCl₃). IR (film): ν = 2921, 1753, 1714, 1681, 1449,

1405, 1370, 1318, 1197, 1026, 757, 697 cm⁻¹. H NMR

1

A mixture of 21b/22b (81:19) (0.075 g, 0.25 mmol) and

Pd (OH)₂(20%) (0.035 g, 0.05 mmol) in MeOH

(3.0 mL) was placed in a round‐bottom flask (25 mL)

provided with an H₂balloon and stirred at room tem-

perature for 24 hours. The reaction mixture was filtered

over celite and washed with CH₂Cl₂(10 mL). The sol-

vent was removed under vacuum, and the crude was

purified by column chromatography over silica gel

(30 g/g of crude, hexane/EtOAc, 95:5) to give a mixture

of 23a/24a (98:2) (0.031 g, 41%) as a colorless oil.

(300 MHz, CDCl₃): δ = 1.57 (s, 6 H, 2CH₃C‐5), 1.74 (d,

J = 7.3 Hz, 3 H, CH₃C‐1′), 2.00 (s, 3 H, CH₃CO), 2.10‐

2.23 (m, 2 H, CH₂CH=), 2.24‐2.33 (m, 2 H, CH₂CO),

4.16 (t, J = 7.8 Hz, 1 H, CH=), 5.32 (q, J = 7.3 Hz, 1 H,

H‐1′), 7.20‐7.39 (m, 5 H, Ph‐H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 15.7 (CH₃C‐1′), 20.5 (CH₂CH=),

26.5 (CH₃C‐5), 26.6 (CH₃C‐5), 30.1 (CH₃CO), 43.9

(CH₂CO), 50.9 (C‐1′), 80.9 (C‐5), 98.8 (CH=), 126.2 (2 C,

arom. CH), 127.2 (arom. CH), 128.4 (2 C, arom. CH),

139.0 (arom. C), 140.3 (C‐4), 155.4 (C‐2), 207.4 (CO)

ppm. MS(70 eV): m/z (%) = 259 (3) [M − 42]⁺, 198 (17),

180 (25), 136 (55), 111 (42), 106 (100), 80 (55), 78 (28).

HRMS (EI): m/z = 301.1672 [M]⁺, calcd for C₁₈H₂₃NO₃

301.1678.

22

R_f= 0.30 (hexane/EtOAc, 7:3). [α]_D= −23.4 (c 0.261,

MeOH). IR (film): ν = 2976, 1738, 1452, 1412, 1374,

1

1302, 1221, 1192, 1171, 1025, 765, 702 cm⁻¹. H NMR

(300 MHz, CDCl₃): δ = 1.02‐1.13 (m, 1 H, CH₂C‐4),

1.15‐1.29 (m, 2 H, CH₂C‐4, CH₂CH₂C‐4), 1.30‐1.39 (m,

1 H, CH₂CH₂C‐4), 1.35 (s, 3 H, CH₃C‐5), 1.39 (s, 3 H,

CH₃C‐5), 1.70 (d, J = 7.2 Hz, 3 H, CH₃C‐1′), 2.04 (s, 3

H, CH₃CO), 2.18 (td, J = 6.6, 2.4 Hz, 2 H, CH₂CO),

3.38 (dd, J = 9.0, 3.0 Hz, 1 H, H‐4), 5.06 (q,

J = 7.2 Hz, 1 H, H‐1′), 7.24‐7.37 (m, 3 H, Ph‐H), 7.37‐

7.44 (m, 2 H, Ph‐H) ppm. Signals attributed to the minor

isomer 24a: 2.09 (s, CH₃CO), 5.14 (q, J = 7.2 Hz, CH₃C‐

1′) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 16.6 (CH₃C‐

1′), 19.5 (CH₂CH₂C‐4), 21.4 (CH₃C‐5), 28.4 (CH₃C‐5),

28.5 (CH₂C‐4), 30.0 (CH₃CO), 43.0 (CH₂CO), 51.5 (C‐

1′), 63.2 (C‐4), 80.4 (C‐5), 126.9 (2 C, arom. CH), 127.5

2.2.11 | (E)‐5,5‐Dimethyl‐4‐(4‐

oxopentylidene)‐3‐((S)‐1‐phenylethyl)

oxazolidin‐2‐one (21b) and (Z)‐5,5‐dimethyl‐

4‐(4‐oxopentylidene)‐3‐((S)‐1‐phenylethyl)

oxazolidin‐2‐one (22b)

Following the method for the preparation of 21a/22a, a

mixture of 14b (0.300 g, 1.30 mmol), 8b (0.182 g,

2.60 mmol), and iodine (0.017 g, 0.067 mmol) was

stirred at 0°C for 6 hours, to give a mixture of 21b/22b

8

SANTOYO ET AL.

(arom. CH), 128.4 (2 C, arom. CH), 141.5 (arom. C),

157.4 (C‐2), 207.9 (CO) ppm. Signals attributed to

the minor isomer 24a: 43.3 ppm. HRMS (EI):

m/z = 303.1864 [M]⁺, calcd for C₁₈H₂₅NO₃303.1834.

(500 MHz, CDCl₃): δ = 1.78 (s, 3 H, CH₃C‐5), 1.79 (s, 3

H, CH₃C‐5), 1.83 (d, J = 7.3 Hz, 3 H, CH₃C‐1′), 5.21 (d,

J = 7.5 Hz, 1 H, CH=), 5.47 (q, J = 7.3 Hz, 1 H, H‐1′),

7.26‐7.34 (m, 3 H, Ph‐H), 7.35‐7.40 (m, 2 H, Ph‐H), 9.62

(d, J = 7.5 Hz, 1 H, CHO) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 15.6 (CH₃C‐1′), 27.9 (CH₃C‐5), 28.0 (CH₃C‐

5), 52.4 (C‐1′), 83.1 (C‐5), 101.8 (CH=), 126.2 (2 C, arom.

CH), 128.1 (arom. CH), 129.0 (2 C, arom. CH), 137.2

(arom. C), 154.2 (C‐2), 161.5 (C‐4), 186.4 (CHO) ppm.

MS (70 eV): m/z (%) = 215 (66) [M − 44]⁺, 200 (100),

186 (20), 172 (24), 110 (80), 105 (88), 91 (25), 79 (39), 77

(50). HRMS (FAB) (mNBA): m/z = 260.1290 [M + 1]⁺,

calcd for C₁₅H₁₈NO₃260.1287.

2.2.13 | (E)‐2‐(5,5‐Dimethyl‐2‐oxo‐3‐((R)‐1‐

phenylethyl)oxazolidin‐4‐ylidene)acetalde-

hyde (25a)

A mixture of POCl₃(0.058 g, 0.378 mmol) and anhy-

drous DMF (0.028 g, 0.384 mmol) in anhydrous CH₂Cl₂

(0.5 mL) was stirred at 0°C for 30 minutes. Subse-

quently, a solution of 14a (0.080 g, 0.346 mmol) in anhy-

drous CH₂Cl₂(0.5 mL) was added, and the mixture was

stirred to the same temperature for 3 hours. The reaction

mixture was diluted with CH₂Cl₂(20 mL) and washed

with a 10% aqueous solution of NaOH (2 × 20 mL)

and with water until neutral. The organic layer was

dried (Na₂SO₄), the solvent removed under vacuum,

and the crude purified by column chromatography over

silica gel (30 g/g of crude, hexane/EtOAc, 95:5) to give

25a (0.069 g, 77%) as a pale yellow solid. R_f= 0.58 (hex-

2.2.15 | (E)‐4‐(Bromomethylene)‐5,5‐

dimethyl‐3‐((S)‐1‐phenylethyl)oxazolidin‐2‐

one (26)

A mixture of 14b (0.100 g, 0.433 mmol), NBS (0.077 g,

0.433 mmol), and p‐TsOH (0.124 g, 0.653 mmol) in MeCN

(5.0 mL) was stirred at 60°C for 1 hour. The solvent was

removed under vacuum, and the crude was purified by

column chromatography over silica gel (30 g/g of crude,

hexane/EtOAc, 95:5) to give 26 (0.076 g, 57%) as a pale

yellow solid. R_f= 0.75 (hexane/EtOAc, 7:3); m.p. 54‐

23

ane/EtOAc, 7:3); m.p. 102‐104°C. [α]_D= +40.0 (c

0.100, CHCl₃). IR (film): ν = 1779, 1657, 1619, 1578,

1454, 1404, 1374, 1296, 1262, 1168, 1136, 1029, 758,

1

23

699 cm⁻¹. H NMR (500 MHz, CDCl₃): δ = 1.78 (s, 3

55°C. [α]_D= −18.0 (c 0.200, CHCl₃). IR (film):

H, CH₃C‐5), 1.79 (s, 3 H, CH₃C‐5), 1.83 (d, J = 7.3 Hz,

3 H, CH₃C‐1′), 5.21 (d, J = 7.5 Hz, 1 H, CH=), 5.47 (q,

J = 7.3 Hz, 1 H, H‐1′), 7.26‐7.34 (m, 3 H, Ph‐H), 7.36‐

7.40 (m, 2 H, Ph‐H), 9.62 (d, J = 7.5 Hz, 1 H, CHO)

ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 15.6 (CH₃C‐1′),

27.9 (CH₃C‐5), 28.0 (CH₃C‐5), 52.4 (C‐1′), 83.1 (C‐5),

101.9 (CH=), 126.3 (2 C, arom. CH), 128.2 (arom. CH),

129.0 (2 C, arom. CH), 137.2 (arom. C), 154.2 (C‐2),

161.5 (C‐4), 186.4 (CHO) ppm. MS (70 eV): m/z

(%) = 215 (75) [M − 44]⁺, 200 (100), 186 (21), 172

(27), 157 (13), 110 (78), 105 (84), 77 (56), 70 (23). HRMS

(FAB) (mNBA): m/z = 260.1278 [M + 1]⁺, calcd for

C₁₅H₁₈NO₃260.1287.

ν = 1764, 1644, 1450, 1389, 1369, 1298, 1230, 1199, 1079,

1030, 759, 698 cm⁻^{1 1}H NMR (300 MHz, CDCl₃):

.

δ = 1.71 (s, 3 H, CH₃C‐5), 1.72 (s, 3 H, CH₃C‐5), 1.75 (d,

J = 7.2 Hz, 3 H, CH₃C‐1′), 4.90 (s, 1 H, CH=), 5.40 (q,

J = 7.2 Hz, 1 H, H‐1′), 7.23‐7.44 (m, 5 H, Ph‐H) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 15.4 (CH₃C‐1′), 24.4

(CH₃C‐5), 24.5 (CH₃C‐5), 51.4 (C‐1′), 76.1 (CH=), 82.8

(C‐5), 126.2 (2 C, arom. CH), 127.8 (arom. CH), 128.8 (2

C, arom. CH), 137.9 (arom. C), 143.0 (C‐4), 154.7 (C‐2)

ppm. MS (70 eV): m/z (%) = 312 (16) [M + 2]⁺, 310 (15)

[M]⁺, 230 (17), 207 (30), 205 (31), 126 (21), 105 (100), 77

(28). HRMS (FAB) (mNBA): m/z = 310.0439 [M + 1]⁺,

calcd for C₁₄H₁₇NO₂Br 310.0443.

2.2.14 | (E)‐2‐(5,5‐Dimethyl‐2‐oxo‐3‐((S)‐1‐

phenylethyl)oxazolidin‐4‐ylidene)acetalde-

hyde (25b)

2.2.16 | 5‐Methyl‐3‐((R)‐1‐phenylethyl)oxa-

zolidine‐2,4‐dione (27)

To a mixture of 2a (52:48) (0.100 g, 0.461 mmol) in

anhydrous CH₂Cl₂(2 mL), MCPBA (77%) (0.310 g,

1.38 mmol) was added at room temperature and under

N₂atmosphere. The mixture was stirred for 72 hours,

diluted with CH₂Cl₂(30 mL) and washed with a

saturated aqueous solution of NaHCO₃(2 × 15 mL)

and with cold water until neutral. The organic

layer was dried (Na₂SO₄), and the solvent was removed

under vacuum. The crude was purified by column

According to the method of preparation of 25a, POCl₃

(0.124 g, 0.808 mmol), DMF (0.059 g, 0.808 mmol) and

14b (0.170 g, 0.736 mmol) were mixed in anhydrous

CH₂Cl₂(1.5 mL) and stirred at 0°C for 6 hours to give

25b (0.165 g, 87%) as a pale yellow solid. R_f= 0.54 (hex-

23

ane/EtOAc, 7:3); m.p. 102‐103°C. [α]_D= −47.5 (c

0.200, CHCl₃). IR (film): ν = 1778, 1656, 1618, 1404,

1375, 1296, 1168, 1137, 969, 759, 699 cm⁻^{1 1}H NMR

.

SANTOYO ET AL.

9

chromatography over silica gel (30 g/g of crude,

hexane/EtOAc, 95:5) to give a mixture of 27 (56:44)

(0.078 g, 77%) as a pale yellow oil. R_f= 0.55 (hexane/

2.2.18 | (3aR,7aS)‐3a,7a‐Dimethyl‐3‐((R)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (29a) and

(3aS,7aR)‐3a,7a‐dimethyl‐3‐((R)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (30a)

23

EtOAc, 7:3). [α]_D= +60.0 (c 0.400, CHCl₃). IR (film):

ν = 1810, 1734, 1447, 1404, 1369, 1312, 1218, 1182,

.

1074, 764, 698 cm⁻^{1 1}H NMR (500 MHz, CDCl₃):

δ = 1.54 (d, J = 7.0 Hz, 3 H, CH₃C‐5), 1.86 (d,

J = 7.5 Hz, 3 H, CH₃C‐1′), 4.74 (q, J = 7.0 Hz, 1 H,

H‐5), 5.31 (q, J = 7.5 Hz, 1 H, H‐1′), 7.28‐7.37 (m, 3

H, Ph‐H), 7.44‐7.48 (m, 2 H, Ph‐H) ppm. Signals attrib-

uted to the minor isomer: 1.55 (d, J = 7.0 Hz, CH₃C‐

5), 1.87 (d, J = 7.5 Hz, CH₃C‐1′), 4.75 (q, J = 7.0 Hz,

H‐5), 5.30 (q, J = 7.5 Hz, H‐1′) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 16.59 (CH₃C‐5), 16.63 (CH₃C‐

1′), 51.78 (C‐1′), 75.2 (C‐5), 127.4 (2 C, arom. CH),

128.3 (arom. CH), 128.6 (2 C, arom. CH), 138.7 (arom.

C), 154.6 (C‐2), 173.4 (C‐4) ppm. Signals attributed to

the minor isomer: 16.57, 16.8, 51.81 (C‐1′), 127.3, 138.8

(arom. C), 173.3 (C‐4) ppm. MS (70 eV): m/z

(%) = 220 (58) [M + 1]⁺, 219 (15) [M]⁺, 192 (9), 174

(12), 160 (24),146 (92), 132 (39), 120 (19), 105 (92), 104

(100), 77 (23). HRMS (EI): m/z = 219.0900 [M]⁺, calcd

for C₁₂H₁₃NO₃219.0895.

A mixture of 1a (0.150 g, 0.691 mmol) and 8a (0.155 g,

2.77 mmol) in anhydrous xylene (3 mL) was placed in a

threaded ACE glass pressure tube with a sealed Teflon

screw cap under N₂atmosphere. It was kept in the dark,

stirred, and heated at 60°C for 5 days. The content of

the tube was extracted with EtOAc (3 × 15 mL) and

CH₂Cl₂(3 × 15 mL). The combined organic layers were

filtered, the solvent was removed under vacuum, and

the crude was purified by column chromatography over

silica gel (30 g/g of crude, hexane/EtOAc, 9:1) to give

29a/30a (<1:99) (0.173 g, 92%) as colorless crystals.

R_f

[α]_D= +111.5 (c 0.200, CHCl₃). IR (film): ν = 1739,

1413, 1353, 1227, 1051, 1025, 975, 733, 697 cm⁻^{1 1}H

= 0.54 (hexane/EtOAc, 7:3); m.p. 153‐154°C.

23

.

NMR (300 MHz, CDCl₃): δ = 1.46 (s, 3 H, CH₃C‐3a),

1.51 (s, 3 H, CH₃C‐7a), 1.82 (d, J = 7.2 Hz, 3 H, CH₃C‐

1′), 2.19 (dt, J = 16.5, 2.7 Hz, 1 H, H‐7), 2.42 (dd,

J = 16.5, 6.9 Hz, 1 H, H‐7), 4.58 (q, J = 7.2 Hz, 1 H, H‐

1′), 5.14‐5.26 (m, 1 H, H‐6), 6.40 (dd, J = 5.7, 2.7 Hz, 1

H, H‐5), 7.20‐7.52 (m, 5 H, Ph‐H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 19.4 (CH₃C‐1′), 21.2 (CH₃C‐7a),

24.3 (CH₃C‐3a), 29.6 (C‐7), 51.5 (C‐1′), 83.6 (C‐7a), 94.8

(C‐3a), 105.5 (C‐6), 126.2 (2 C, arom. CH), 127.1 (arom.

CH), 128.5 (2 C, arom. CH), 142.2 (arom. C), 143.3

(C‐5), 155.4 (C‐2) ppm. HRMS (EI): m/z = 273.1372

[M]⁺, calcd for C₁₆H₁₉NO₃273.1365.

2.2.17 | 5‐Methyl‐3‐((S)‐1‐phenylethyl)oxa-

zolidine‐2,4‐dione (28)

Following the method of preparation of 27, a mixture of

2b (54:46) (0.060 g, 0.276 mmol) and MCPBA (77%)

(0.123 g, 0.553 mmol) in anhydrous CH₂Cl₂(2 mL) was

stirred at 0°C for 8 hours to give a mixture of 28 (56:46)

(0.057 g, 94%) as a pale yellow oil. R_f= 0.52 (hexane/

23

EtOAc, 7:3). [α]_D= −68.0 (c 0.200, CHCl₃). IR (film):

ν = 1811, 1735, 1451, 1406, 1376, 1314, 1219, 1183, 1075,

1

764, 699 cm⁻¹. H NMR (500 MHz, CDCl₃): δ = 1.54 (d,

2.2.19 | (3aR,7aS)‐3a,7a‐Dimethyl‐3‐((S)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (29b) and

(3aS,7aR)‐3a,7a‐dimethyl‐3‐((S)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (30b)⁴⁶

J = 7.0 Hz, 3 H, CH₃C‐5), 1.87 (d, J = 7.0 Hz, 3 H,

CH₃C‐1′), 4.74 (q, J = 7.0 Hz, 1 H, H‐5), 5.31 (q,

J = 7.0 Hz, 1 H, H‐1′), 7.29‐7.38 (m, 3 H, Ph‐H), 7.44‐

7.49 (m, 2 H, Ph‐H) ppm. Signals attributed to the minor

isomer: 1.53 (d, J = 7.0 Hz, CH₃C‐5), 1.86 (d, J = 7.0 Hz,

CH₃C‐1′), 4.76 (q, J = 7.0 Hz, H‐5), 5.30 (q, J = 7.0 Hz, H‐

1′) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 16.7 (CH₃C‐5),

16.8 (CH₃C‐1′), 51.8 (C‐1′), 75.2 (C‐5), 127.4 (2 C, arom.

CH), 128.3 (arom. CH), 128.7 (2 C, arom. CH), 138.8

(arom. C), 154.6 (C‐2), 173.4 (C‐4) ppm. Signals attributed

to the minor isomer: 16.6 (CH₃C‐5), 16.7 (CH₃C‐1′), 51.9

(C‐1′), 127.3 (2 C, arom. CH), 138.7 (arom. C), 173.3 (C‐

4) ppm. MS(70 eV): m/z (%) = 219 (16) [M]⁺, 176 (9),

160 (22), 146 (100), 132 (42), 120 (19), 105 (77), 104 (91),

77 (46). HRMS (EI): m/z = 219.0894 [M]⁺, calcd for

C₁₂H₁₃NO₃219.0895.

Method A. According to the method of preparation of

29a/30a, the reaction of 1b (0.217 g,

1.00 mmol) and 8a (0.56 g, 1.0 mmol)

resulted in a mixture of 29b/30b (93:7)

(0.202 g, 74%) as a white solid.

Method B. A mixture of 1b (0.100 g, 0.46 mmol) and

8a (0.103 g, 1.84 mmol) was stirred under

MW irradiation (100 W) at 110°C for

5 hours. The reaction crude was purified

by column chromatography over silica gel

10

SANTOYO ET AL.

(30 g/g of crude, hexane/EtOAc, 95:5) to

give a mixture of 29b/30b (92:8) (0.06 g,

48%) as white crystals. R_f= 0.40 (hexane/

EtOAc, 8:2); m.p. 156‐157°C (hexane/

H, H‐7), 4.57 (q, J = 7.5 Hz, 1 H, H‐1′), 4.87 (dq,

J = 7.0, 1.0 Hz, 1 H, H‐6), 7.22‐7.27 (m, 1 H, Ph‐H),

7.30‐7.35 (m, 2 H, Ph‐H), 7.41‐7.45 (m, 2 H, Ph‐H)

ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 19.7 (CH₃C‐5),

20.6 (CH₃C‐1′), 21.4 (CH₃C‐7a), 24.2 (CH₃C‐3a), 30.5

(C‐7), 51.7 (C‐1′), 83.3 (C‐7a), 94.8 (C‐3a), 99.1 (C‐6),

126.5 (2 C, arom. CH), 127.1 (arom. CH), 128.6 (2 C,

arom. CH), 143.0 (arom. C), 150.9 (C‐5), 155.7 (C‐2)

ppm. MS (70 eV): m/z (%) = 243 (1) [M − 44]⁺, 228

(32), 200 (5), 186 (12), 113 (51), 105 (100), 103 (26), 79

(31), 77 (30). HRMS (EI): m/z = 287.1519 [M]⁺, calcd

for C₁₇H₂₁NO₃287.1521.

23

EtOAc, 9:1). [α]_D= −114.9 (c 0.123,

23

MeOH); [α]_D= −101.0 (c 2.20, CHCl₃).

IR (film): ν = 1733, 1650, 1412, 1352,

1228, 1075, 1052, 1027, 976, 735, 699 cm

1

⁻¹. H NMR (300 MHz, CDCl₃): δ = 1.47

(s, 3 H, CH₃C‐3a), 1.51 (s, 3 H, CH₃C‐7a),

1.82 (d, J = 7.3 Hz, 3 H, CH₃C‐1′), 2.20

(dt, J = 16.1, 2.8 Hz, 1 H, H‐7), 2.43 (dd,

J = 16.1, 6.8 Hz, 1 H, H‐7), 4.58 (q,

J = 7.3 Hz, 1 H, H‐1′), 5.19 (ddd, J = 6.8,

5.2, 2.8 Hz, 1 H, H‐6), 6.40 (dd, J = 5.2,

2.9 Hz, 1 H, H‐5), 7.22‐7.36 (m, 3 H, Ph‐

H), 7.40‐7.45 (m, 2 H, Ph‐H) ppm. Signals

attributed to the minor isomer 30b: 2.37

(dd, J = 16.3, 6.5 Hz, H‐7), 4.91 (q,

J = 7.2 Hz, H‐1′), 5.01 (ddd, J = 6.5, 5.4,

2.6 Hz, H‐6) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 19.4 (CH₃C‐1′), 21.2 (CH₃C‐

7a), 24.3 (CH₃C‐3a), 29.6 (C‐7), 51.5 (C‐1′),

83.6 (C‐7a), 94.8 (C‐3a), 105.5 (C‐6), 126.6

(2 C, arom. CH), 127.2 (arom. CH), 128.5

(2 C, arom. CH), 142.3 (arom. C), 143.3

(C‐5), 155.4 (C‐2) ppm. MS(70 eV): m/z

(%) = 274 (45) [M + 1]⁺, 255 (15), 218

(32), 212 (45), 211 (40), 170 (24), 152 (15),

113 (50), 105 (100), 79 (83), 77 (68), 51

(24). HRMS (EI): m/z = 273.1344 [M]⁺,

calcd for C₁₆H₁₉NO₃273.1365.

2.2.21 | (3aR,7aS)‐3a,5,7a‐Trimethyl‐3‐((S)‐

1‐phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (29d) and

(3aS,7aR)‐3a,5,7a‐trimethyl‐3‐((S)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (30d)

Method A. According to method A for the preparation

of 29b/30b, a mixture of 1b (0.200 g,

0.922 mmol) and 8b (0.258 g, 3.69 mmol)

in anhydrous xylene (3 mL) was stirred at

60°C for 7 days to give 29d/30d (>99:1)

(0.037 g, 14%) as a pale yellow solid.

Method B. According to method B for the preparation

of 29b/30b, a mixture of 1b (0.100 g,

0.46 mmol) and 8b (0.129 g, 1.84 mmol) pro-

vided 29d/30d (98:2) (0.055 g, 42%) as white

crystals.

Data for the mixture of 29d/30d (>99:1): R_f= 0.55 (hex-

23

ane/EtOAc, 7:3); m.p. 152‐154°C. [α]_D= −50.5 (c

2.2.20 | (3aR,7aS)‐3a,5,7a‐Trimethyl‐3‐((R)‐

1‐phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (29c) and

(3aS,7aR)‐3a,5,7a‐trimethyl‐3‐((R)‐1‐

phenylethyl)‐3,3a,7,7a‐tetrahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (30c)

0.200, CHCl₃). IR (film): ν = 1734, 1686, 1417, 1357,

1227, 1135, 1090, 1049, 745, 698 cm⁻¹

.

¹H NMR

(300 MHz, CDCl₃): δ = 1.42 (s, 3 H, CH₃C‐3a), 1.43 (s,

3 H, CH₃C‐7a), 1.81 (br s, 3H, CH₃C‐5), 1.84 (d,

J = 7.2 Hz, 3 H, CH₃C‐1′), 2.16 (dm, J = 16.2 Hz, 1 H,

H‐7), 2.35 (dd, J = 16.2, 6.8 Hz, 1 H, H‐7), 4.57 (q,

J = 7.2 Hz, 1 H, H‐1′), 4.86 (dm, J = 6.8 Hz, 1 H, H‐

6), 7.20‐7.36 (m, 3 H, Ph‐H), 7.39‐7.46 (m, 2 H, Ph‐H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 19.6 (CH₃C‐5),

20.5 (CH₃C‐1′), 21.4 (CH₃C‐7a), 24.1 (CH₃C‐3a), 30.4

(C‐7), 51.6 (C‐1′), 83.3 (C‐7a), 94.7 (C‐3a), 99.1 (C‐6),

126.4 (2 C, arom. CH), 127.1 (arom. CH), 128.5 (2 C,

arom. CH), 143.0 (arom. C), 150.8 (C‐5), 155.6 (C‐2)

ppm. MS (70 eV): m/z (%) = 288 (1) [M + 1]⁺, 228

(32), 186 (11), 113 (47), 105 (100), 103 (23), 77 (27).

HRMS (EI): m/z = 287.1521 [M]⁺, calcd for C₁₇H₂₁NO₃

287.1521.

Following the method of preparation of 29a/30a, a mix-

ture of 1a (0.060 g, 0.28 mmol) and 8b (0.097 g,

1.39 mmol) in anhydrous xylene (5 mL) was stirred at

60°C for 5 days to give 29c/30c (<1:99) (0.036 g, 45%)

as a pale yellow solid. R_f= 0.57 (hexane/EtOAc, 7:3);

23

m.p. 141‐143°C. [α]_D= +43.0 (c 0.100, CHCl₃). IR

(film): ν = 2924, 1758, 1714, 1675, 1371, 759, 699 cm⁻¹

.

¹H NMR (500 MHz, CDCl₃): δ = 1.427 (s, 3 H, CH₃C‐

3a), 1.431 (s, 3 H, CH₃C‐7a), 1.81 (br s, 3H, CH₃C‐5),

1.84 (d, J = 7.5 Hz, 3 H, CH₃C‐1′), 2.17 (dm,

J = 16.0 Hz, 1 H, H‐7), 2.35 (dd, J = 16.0, 7.0 Hz, 1

SANTOYO ET AL.

11

1 H, H‐6), 1.60‐1.69 (m, 1 H, H‐7), 1.84 (d, J = 7.0 Hz, 3

H, CH₃C‐1′), 2.13 (dt, J = 15.0, 3.1 Hz, 1 H, H‐7), 3.43‐

3.50 (m, 1 H, H‐5), 4.55 (q, J = 7.0 Hz, 1 H, H‐1′), 7.21‐

7.25 (m, 1 H, Ph‐H), 7.30‐7.34 (m, 2 H, Ph‐H), 7.40‐7.44

(m, 2 H, Ph‐H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 16.9 (CH₃C‐3a), 19.4 (CH₃C‐1′), 21.8 (CH₃C‐5), 24.6

(CH₃C‐7a), 27.9 (C‐6), 30.6 (C‐7), 51.5 (C‐1′), 67.8 (C‐5),

78.8 (C‐7a), 92.6 (C‐3a), 126.7 (2 C, arom. CH), 126.9

(arom. CH), 128.4 (2 C, arom. CH), 142.8 (arom. C),

157.0 (C‐2) ppm. HRMS (EI): m/z = 289.1678 [M]⁺, calcd

for C₁₇H₂₃NO₃289.1678.

2.2.22 | (3aR,7aS)‐3a,7a‐Dimethyl‐3‐((S)‐1‐

phenylethyl)hexahydro‐2H‐pyrano[2,3‐d]

oxazol‐2‐one (31a) and (3aS,7aR)‐3a,7a‐

dimethyl‐3‐((S)‐1‐phenylethyl)hexahydro‐

2H‐pyrano[2,3‐d]oxazol‐2‐one (32a)

A mixture of 29b/30b (93:7) (0.100 g, 0.36 mmol) and Pd

(OH)₂(20%) (0.0024 g, 0.017 mmol) in MeOH (5 mL)

was stirred under H₂(1 atm) atmosphere at room tem-

perature for 12 hours. The content of the flask was fil-

tered, the solvent was removed under vacuum, and the

crude was purified by column chromatography over sil-

ica gel (30 g/g of crude, hexane/EtOAc, 9:1) to give a

mixture of 31a/32a (92:8) (0.10 g, 99%) as colorless crys-

tals. R_f= 0.29 (hexane/EtOAc, 7:3); m.p. 101‐102°C. [α]

2.2.24 | (7aS)‐7a‐Methyl‐3‐((R)‐1‐

phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (33a) and (7aR)‐7a‐Methyl‐3‐((R)‐

1‐phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (34a)

25

= −1.87 (c 0.400, CHCl₃). IR (film): ν = 2951, 2890,

D

1746, 1406, 1344, 1284, 1233, 1140, 1108, 1028, 970, 773,

1

750, 700 cm⁻¹. H NMR (500 MHz, CDCl₃): δ = 1.30 (s,

3 H, CH₃C‐7a), 1.31 (s, 3 H, CH₃C‐3a), 1.66‐1.74 (m, 1

H, H‐7), 1.76‐1.81 (m, 2 H, H‐6), 1.83 (d, J = 7.5 Hz, 3

H, CH₃C‐1′), 1.96 (dt, J = 13.7, 4.0 Hz, 1 H, H‐7),

3.61‐3.71 (m, 2 H, H‐5), 4.45 (q, J = 7.5 Hz, 1 H, H‐

1′), 7.21‐7.25 (m, 1 H, Ph‐H), 7.29‐7.34 (m, 2 H, Ph‐H),

7.41‐7.45 (m, 2 H, Ph‐H) ppm. Signals attributed to the

minor isomer 32a: 1.26 (s, CH₃C‐3a), 1.28 (s, CH₃C‐7a),

7.79‐7.51 (m, Ph‐H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 18.1 (C‐6), 19.5 (CH₃C‐1′), 20.0 (CH₃C‐3a), 24.0

(CH₃C‐7a), 27.3 (C‐7), 51.3 (C‐1′), 57.9 (C‐5), 80.3 (C‐

7a), 92.3 (C‐3a), 126.4 (2 C, arom. CH), 127.0 (arom.

CH), 128.4 (2 C, arom. CH), 142.8 (arom. C), 156.3 (C‐

2) ppm. Signals attributed to the minor isomer 32a:

17.8, 18.3, 19.9, 23.5, 27.5, 50.9, 57.9, 127.2, 127.6,

128.0 ppm. HRMS (EI): m/z = 275.1529 [M]⁺, calcd for

C₁₆H₂₁NO₃275.1521.

A mixture of 1a (0.100 g, 0.46 mmol), 8a (0.155 g,

2.77 mmol), and MeI (0.131 g, 0.923 mmol) in anhydrous

xylene (1 mL) was placed in a threaded ACE glass pres-

sure tube with a sealed Teflon screw cap under N₂atmo-

sphere. It was kept in the dark, stirred, and heated at

140°C for 24 hours. During this period, 8a (0.155 g,

2.77 mmol) was added every 6 hours (four times). The

content of the tube was extracted with CH₂Cl₂

(3 × 20 mL), and the combined organic layers were fil-

tered. The solvent was removed under vacuum, and the

crude purified by column chromatography over silica

gel (30 g/g of crude, hexane/EtOAc, 9:1) to give 33a/34a

(20:80) (0.071 g, 60%) as an amber liquid. R_f= 0.71 (hex-

23

ane/EtOAc, 7:3). [α]_D= +45.2 (c 0.730, CHCl₃). IR

(film): ν = 2926, 1761, 1668, 1584, 1450, 1403, 1371,

1311, 1224, 1197, 1025, 755, 697 cm⁻¹

.

¹H NMR

(300 MHz, CDCl₃): δ = 1.34 (d, J = 0.6 Hz, 3 H, CH₃C‐

7a), 1.75 (d, J = 7.2 Hz, 3 H, CH₃C‐1′), 2.39 (ddd,

J = 16.5, 6.0, 0.6 Hz, 1 H, H‐7), 2.54 (dm, J = 16.5 Hz, 1

H, H‐7), 4.76 (d, J = 5.7 Hz, 1 H, H‐4), 5.38 (q,

J = 7.2 Hz, 1 H, H‐1′), 5.51‐5.58 (m, 1 H, H‐6), 5.79‐5.86

(m, 1 H, H‐5), 7.24‐7.38 (m, 5 H, Ph‐H) ppm. Signals

attributed to the minor isomer 33a: 1.32 (d, J = 0.6 Hz,

CH₃C‐7a), 1.77 (d, J = 7.5 Hz, CH₃C‐1′), 2.38 (br dd,

J = 16.2, 5.4 Hz, H‐7), 4.69 (d, J = 5.1 Hz, H‐4) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 15.9 (CH₃C‐1′), 21.7

(CH₃C‐7a), 33.7 (C‐7), 51.3 (C‐1′), 80.4 (C‐7a), 94.1 (C‐

4), 118.4 (C‐6), 124.4 (C‐5), 126.6 (2 C, arom. CH), 127.6

(arom. CH), 128.5 (2 C, arom. CH), 138.9 (arom. C),

139.7 (C‐3a), 156.5 (C‐2) ppm. Signals attributed to the

minor isomer 33a: 15.8 (CH₃C‐1′), 33.8 (C‐7), 51.8 (C‐

1′), 80.1 (C‐7a), 118.1 (C‐6) ppm. HRMS (EI): m/

z = 255.1265 [M]⁺, calcd for C₁₆H₁₇NO₂255.1259.

2.2.23 | (3aR,5R,7aS)‐3a,5,7a‐Trimethyl‐3‐

((S)‐1‐phenylethyl)hexahydro‐2H‐

pyrano[2,3‐d]oxazol‐2‐one (31b) and

(3aS,5S,7aR)‐3a,5,7a‐trimethyl‐3‐((S)‐1‐

phenylethyl)hexahydro‐2H‐pyrano[2,3‐d]

oxazol‐2‐one (32b)

Following the method of preparation of 31a/32a, the

reaction of 29d/30d (>99:1) (0.100 g, 0.35 mmol) and Pd

(OH)₂(20%) (0.0024 g, 0.017 mmol) resulted in a mixture

of 31b/32b (>99:1) (0.10 g, 99%) as white crystals. R_f= 0.26

25

(hexane/EtOAc, 7:3); m.p. 145‐147°C. [α]_D= +10.3 (c

0.160, MeOH). IR (film): ν = 2988, 2928, 1751, 1497,

1447, 1401, 1387, 1344, 1227, 1100, 1065, 1027, 977, 779,

1

746, 699 cm⁻¹. H NMR (500 MHz, CDCl₃): δ = 1.16 (d,

J = 6.5 Hz, 3 H, CH₃C‐5), 1.24 (s, 3 H, CH₃C‐7a), 1.43‐

1.48 (m, 1 H, H‐5), 1.45 (s, 3 H, CH₃C‐3a), 1.50‐1.60 (m,

12

SANTOYO ET AL.

(75.4 MHz, CDCl₃): δ = 15.9 (CH₃C‐1′),

21.7 (CH₃C‐7a), 33.7 (C‐7), 51.3 (C‐1′),

80.4 (C‐7a), 94.1 (C‐4), 118.5 (C‐6), 124.4

(C‐5), 126.6 (2 C, arom. CH), 127.6 (arom.

CH), 128.5 (2 C, arom. CH), 138.8 (arom.

C), 139.7 (C‐3a), 156.6 (C‐2) ppm. Signals

attributed to the minor isomer 34b: 15.8

(CH₃C‐1′), 33.9 (C‐7), 51.9 (C‐1′), 80.2 (C‐

7a), 118.2 (C‐6), 127.7 (arom. CH), 138.6

(arom. C), 140.1 (C‐3a), 158.5 (C‐2) ppm.

HRMS (EI): m/z = 255.1257 [M]⁺, calcd

for C₁₆H₁₇NO₂255.1259.

2.2.25 | (7aS)‐7a‐Methyl‐3‐((S)‐1‐

phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (33b), (7aR)‐7a‐methyl‐3‐((S)‐1‐

phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (34b), 3‐((7aS)‐7a‐methyl‐2‐oxo‐3‐

((S)‐1‐phenylethyl)‐2,3,7,7a‐

tetrahydrobenzo[d]oxazol‐6‐yl)propanal

(33e), and 3‐((7aR)‐7a‐methyl‐2‐oxo‐3‐((S)‐1‐

phenylethyl)‐2,3,7,7a‐tetrahydrobenzo[d]

oxazol‐6‐yl)propanal (34e)⁴⁶

Method A. Following the method of preparation of 33a/

34a, the reaction of 1b (0.291 g, 1.34 mmol),

8a (0.375 g, 6.70 mmol), and MeI (0.381 g,

2.68 mmol) provided a mixture of 33b/34b

(83:17) (0.207 g, 61%) as a colorless oil, as

Data for 33e/34e (85:15): R_f= 0.35 (hexane/EtOAc, 7:3).

[α]_D= −15.7 (c 0.220, MeOH). IR (film): ν= 1762,

22

1724, 1674, 1608, 1450, 1398, 1316, 1224, 1198, 1072,

1

well as

a

mixture of 33e/34e (86:14)

1025, 972, 760, 701 cm⁻¹. H NMR (300 MHz, CDCl₃):

(0.098 g, 32%) as a colorless oil.

Method B. A mixture of 33b/34b (83:17) (0.100 g,

0.39 mmol), 8a (0.056 g, 1.17 mmol), and

MeI (0.111 g, 0.78 mmol) in anhydrous

xylene (1 mL) was placed in a threaded

ACE glass pressure tube with a sealed Tef-

lon screw cap under N₂atmosphere. It was

kept in the dark, stirred, and heated at

160°C for 24 hours. During this period,

8a (0.056 g, 1.17 mmol) was added twice.

The content of the tube was extracted with

CH₂Cl₂(3 × 20 mL), the combined organic

layers were filtered, and the solvent was

removed under vacuum. The reaction

crude was purified by column chromatog-

raphy over silica gel (30 g/g of crude,

hexane/EtOAc, 9:1) to give 33e/33e

(85:15) (0.05 g, 41%) as an amber liquid.

Data for 33b/34b (83:17): R_f= 0.75 (hex-

δ = 1.31 (s, 3 H, CH₃C‐7a), 1.74 (d, J = 7.3 Hz, 3 H,

CH₃C‐1′), 2.20 (d, J = 15.9 Hz, 1 H, H‐7), 2.36‐2.46

(m, 2 H, CH₂C‐6), 2.52‐2.62 (m, 3 H, H‐7, CH₂CHO),

4.71 (d, J = 5.2 Hz, 1 H, H‐4), 5.38 (q, J = 7.3 Hz, 1

H, H‐1′), 5.53‐5.62 (m, 1 H, H‐5), 7.30‐7.40 (m, 5 H,

Ph‐H), 9.75 (t, J = 1.4 Hz, 1 H, CHO) ppm. Signals

attributed to the minor isomer 34e: 1.31 (s, CH₃C‐7a),

1.78 (d, J = 7.2 Hz, CH₃C‐1′), 4.65 (d, J = 5.2 Hz, H‐

4) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 16.2 (CH₃C‐

1′), 22.2 (CH₃C‐7a), 29.2 (CH₂C‐6), 38.1 (C‐7), 41.8

(CH₂CHO), 51.6 (C‐1′), 80.9 (C‐7a), 94.4 (C‐4), 119.6

(C‐5), 126.9 (2 C, arom. CH), 127.9 (arom. CH), 128.8

(2 C, arom. CH), 130.4 (C‐6), 138.5 (arom. C), 139.1

(C‐3a), 157.0 (C‐2), 201.8 (CHO) ppm. Signals attributed

to the minor isomer 34e: 24.8 (CH₃C‐7a), 45.6

(CH₂CHO), 119.7 (C‐5), 127.0 (arom. CH), 128.0 (arom.

CH) ppm. HRMS (EI): m/z = 311.1531 [M]⁺, calcd for

C₁₉H₂₁NO₃311.1521.

23

ane/EtOAc, 7:3). [α]_D= −68.9 (c 0.195,

MeOH). IR (film): ν = 1762, 1670, 1583,

2.2.26 | (7aS)‐5,7a‐Dimethyl‐3‐((R)‐1‐

phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (33c) and (7aR)‐5,7a‐dimethyl‐3‐

((R)‐1‐phenylethyl)‐7,7a‐dihydrobenzo[d]

oxazol‐2(3H)‐one (34c)

1496, 1451, 1403, 1376, 1314, 1221, 1197,

1069, 1026, 757, 703 cm⁻¹

.

¹H NMR

(300 MHz, CDCl₃):

δ

= 1.34 (d,

J = 0.6 Hz, 3 H, CH₃C‐7a), 1.76 (d,

J = 7.3 Hz, 3 H, CH₃C‐1′), 2.40 (ddd,

J = 16.4, 6.2, 0.6 Hz, 1 H, H‐7), 2.50‐2.60

(m, 1 H, H‐7), 4.76 (dt, J = 5.5, 0.6 Hz, 1

H, H‐4), 5.39 (q, J = 7.3 Hz, 1 H, H‐1′),

5.52‐5.60 (m, 1 H, H‐6), 5.80‐5.87 (m, 1

H, H‐5), 7.30‐7.40 (m, 5 H, Ph‐H) ppm.

Signals attributed to the minor isomer

34b: 1.32 (d, J = 0.5 Hz, CH₃C‐7a), 1.77

(d, J = 7.3 Hz, CH₃C‐1′), 2.39 (ddd,

J = 16.6, 6.2, 0.6 Hz, H‐7), 4.69 (dt,

J = 5.5, 0.6 Hz, H‐4) ppm. ¹³C NMR

A mixture of 1a (0.120 g, 0.55 mmol), 8b (0.193 g,

2.75 mmol), and MeI (0.157 g, 1.11 mmol) in anhydrous

xylene (1.5 mL) was placed in a threaded ACE glass

pressure tube with a sealed Teflon screw cap under N₂

atmosphere. While kept in the dark, it was stirred and

heated at 160°C for 48 hours. The content of the tube

was extracted with CH₂Cl₂(3 × 20 mL), the combined

organic layers were filtered, and the solvent was

removed under vacuum. The reaction crude was purified

by column chromatography over silica gel (30 g/g of

SANTOYO ET AL.

13

crude, hexane/EtOAc, 9:1) to give 33c/34c (12:88)

(0.092 g, 62%) as a pale yellow oil. R_f= 0.42 (hexane/

EtOAc, 7:3). [α]_D= +11.8 (c 0.400, CHCl₃). IR (film):

2.2.28 | (3aS,7aR)‐3a,5,7a‐Trimethyl‐3‐((R)‐

1‐phenylethyl)‐3,3a,7,7a‐tetrahydrobenzo[d]

oxazol‐2(6H)‐one (36a) and (3aR,7aS)‐

3a,5,7a‐trimethyl‐3‐((R)‐1‐phenylethyl)‐

3,3a,7,7a‐dihydrobenzo[d]oxazol‐2(6H)‐one

(37a)

23

ν = 2928, 1766, 1676, 1450, 1378, 1318, 1196, 1026,

1

764, 698 cm⁻¹. H NMR (300 MHz, CDCl₃): δ = 1.33

(s, 3 H, CH₃C‐7a), 1.67 (s, 3 H, CH₃C‐5), 1.76 (d,

J = 7.2 Hz, 3 H, CH₃C‐1′), 2.32 (ddm, J = 16.0,

6.4 Hz, 1 H, H‐7), 2.50 (dm, J = 16.0 Hz, 1 H, H‐7),

4.65 (s, 1 H, H‐4), 5.20‐5.28 (m, 1 H, H‐6), 5.37 (q,

J = 7.2 Hz, 1H, H‐1′), 7.24‐7.40 (m, 5 H, Ph‐H) ppm.

Signals attributed to the minor isomer 33c: 1.26 (s,

CH₃C‐7a), 1.79 (d, J = 7.2 Hz, CH₃C‐1′), 4.61 (s, H‐4)

ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 16.0 (CH₃C‐

1′), 21.7 (CH₃), 21.8 (CH₃), 34.0 (C‐7), 51.3 (C‐1′), 80.8

(C‐7a), 97.7 (C‐4), 113.1 (C‐6), 126.6 (2 C, arom. CH),

127.6 (arom. CH), 128.6 (2 C, arom. CH), 132.4 (C‐5),

138.9 (arom. C), 140.0 (C‐3a), 156.9 (C‐2) ppm.

MS(70 eV): m/z (%) = 271 (16) [M + 2]⁺, 116 (100),

122 (71), 107 (76), 80 (40), 78 (23). HRMS (EI): m/

z = 269.1425 [M]⁺, calcd for C₁₇H₁₉NO₂269.1416.

A mixture of 1a (0.120 g, 0.55 mmol) and 35 (0.412 g,

2.77 mmol) in anhydrous xylene (1.2 mL) was placed in

a threaded ACE glass pressure tube with a sealed Teflon

screw cap under N₂atmosphere. While kept in the dark,

it was stirred and heated at 160°C for 48 hours. The con-

tent of the tube was extracted with EtOAc (3 × 15 mL)

and CH₂Cl₂(3 × 15 mL). The combined organic layers

were filtered, the solvent was removed under vacuum,

and the crude was purified by column chromatography

over silica gel (30 g/g of crude, hexane/EtOAc, 95:5) to

give 36a/37a (54:46) (0.087 g, 55%) as a pale yellow solid.

This mixture was separated by column chromatography

over silica gel (30 g/g of crude, hexane/EtOAc, 98:2) to

obtain 36a (0.044 g, 28%) as a pale yellow solid and 37a

(0.036 g, 23%) as a white solid.

Data for 36a: R_f= 0.49 (hexane/EtOAc, 7:3); m.p. 181‐

23

182°C. [α]_D= −47.0 (c 0.100, CHCl₃). IR (film):

ν = 2916, 1725, 1494, 1441, 1412, 1367, 1348, 1320, 1223,

2.2.27 | (7aS)‐5,7a‐Dimethyl‐3‐((S)‐1‐

phenylethyl)‐7,7a‐dihydrobenzo[d]oxazol‐

2(3H)‐one (33d) and (7aR)‐5,7a‐Dimethyl‐3‐

((S)‐1‐phenylethyl)‐7,7a‐dihydrobenzo[d]

oxazol‐2(3H)‐one (34d)⁴⁶

.

1171, 1083, 1026, 970, 759, 701 cm⁻^{1 1}H NMR

(500 MHz, CDCl₃): δ = 1.16 (s, 3 H, CH₃C‐3a), 1.30 (s, 3

H, CH₃C‐7a), 1.65 (ddd, J = 14.0, 9.5, 5.0 Hz, 1 H, H‐7),

1.69 (br s, 3 H, CH₃C‐5), 1.77 (d, J = 7.5 Hz, 3 H,

CH₃C‐1′), 1.82 (br dt, J = 16.5, 5.0 Hz, 1 H, H‐6), 2.02

(dt, J = 14.0, 5.0 Hz, 1 H, H‐7), 2.18‐2.27 (m, 1 H, H‐6),

4.47 (q, J = 7.5 Hz, 1 H, H‐1′), 5.18 (br s, 1 H, H‐4),

7.22‐7.26 (m, 1 H, Ph‐H), 7.29‐7.34 (m, 2 H, Ph‐H) 7.43‐

7.47 (m, 2 H, Ph‐H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 20.1 (CH₃C‐1′), 21.4 (CH₃C‐3a), 22.0 (CH₃C‐7a),

23.5 (CH₃C‐5), 26.3 (C‐6), 30.8 (C‐7), 51.8 (C‐1′), 62.9

(C‐3a), 80.8 (C‐7a), 122.5 (C‐4), 126.9 (2 C, arom. CH),

127.1 (arom. CH), 128.4 (2 C, arom. CH), 136.9 (C‐5),

143.0 (arom. C), 156.5 (C‐2) ppm. HRMS (EI): m/

z = 285.1725 [M]⁺, calcd for C₁₈H₂₃NO₂285.1729.

According to the method for the preparation of 33c/34c, a

mixture of 1b (0.345 g, 1.59 mmol), 8b (0.556 g,

8.00 mmol), and MeI (0.223 g, 3.18 mmol) in anhydrous

xylene (1.5 mL) was stirred and heated at 140°C for

24 hours to give 33d/34d (80:20) (0.092 g, 63%) as a color-

21

less oil. R_f= 0.45 (hexane/EtOAc, 7:3). [α]_D= −79.7 (c

0.152, MeOH). IR (film): ν = 1763, 1677, 1608, 1450, 1401,

.

1382, 1318, 1197, 1026, 764, 699 cm⁻^{1 1}H NMR

(300 MHz, CDCl₃): δ = 1.32 (s, 3 H, CH₃C‐7a), 1.67 (br

s, 3 H, CH₃C‐5), 1.76 (d, J = 7.3 Hz, 3 H, CH₃C‐1′), 2.32

(ddm, J = 16.0, 6.3 Hz, 1 H, H‐7), 2.51 (dm,

J = 16.0 Hz, 1 H, H‐7), 4.65 (s, 1 H, H‐4), 5.20‐5.28 (m,

1 H, H‐6), 5.36 (q, J = 7.3 Hz, 1 H, H‐1′), 7.20‐7.50 (m,

5 H, Ph‐H) ppm. Signals attributed to the minor isomer

34d: 1.31 (s, CH₃C‐7a), 1.64 (br s, CH₃C‐5), 4.61 (s, H‐4)

ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 16.0 (CH₃C‐1′),

21.6 (CH₃), 21.7 (CH₃), 34.0 (C‐7), 51.3 (C‐1′), 80.8 (C‐

7a), 97.7 (C‐4), 113.0 (C‐6), 126.5 (2 C, arom. CH), 127.6

(arom. CH), 128.5 (2 C, arom. CH), 132.4 (C‐5), 138.9

(arom. C), 139.9 (C‐3a), 156.9 (C‐2) ppm. Signals attrib-

uted to the minor isomer 34d: 34.1, 51.9, 80.7, 97.6,

112.8, 126.4, 140.1 ppm. HRMS (EI): m/z = 269.1419

[M]⁺, calcd for C₁₇H₁₉NO₂269.1416.

Data for 37a: R_f= 0.44 (hexane/EtOAc, 7:3); m.p. 119‐

23

121°C. [α]_D= −15.0 (c 0.100, CHCl₃). IR (film):

ν = 2927, 1738, 1447, 1404, 1317, 1169, 1026, 765,

1

700 cm⁻¹. H NMR (500 MHz, CDCl₃): δ = 1.12 (s, 3 H,

CH₃C‐3a), 1.30 (s, 3 H, CH₃C‐7a), 1.60 (br s, 3 H, CH₃C‐

5), 1.66 (ddd, J = 14.0, 7.5, 5.5 Hz, 1 H, H‐7), 1.80 (d,

J = 7.5 Hz, 3 H, CH₃C‐1′), 1.81‐1.87 (m, 1 H, H‐6), 1.93‐

2.00 (m, 1 H, H‐7), 2.10‐2.17 (m, 1 H, H‐6), 4.63 (q,

J = 7.5 Hz, 1 H, H‐1′), 5.09‐5.12 (m, 1 H, H‐4), 7.21‐7.25

(m, 1 H, Ph‐H), 7.28‐7.32 (m, 2 H, Ph‐H) 7.39‐7.43 (m, 2

H, Ph‐H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 19.6

(CH₃C‐1′), 20.9 (CH₃C‐3a), 21.4 (CH₃C‐7a), 23.3 (CH₃C‐

5), 26.7 (C‐6), 31.3 (C‐7), 51.5 (C‐1′), 62.9 (C‐3a), 80.8

14

SANTOYO ET AL.

(C‐7a), 123.4 (C‐4), 127.1 (arom. CH), 127.2 (2 C, arom.

CH), 128.2 (2 C, arom. CH), 136.8 (C‐5), 142.5 (arom.

C), 156.3 (C‐2) ppm. HRMS (EI): m/z = 285.1705 [M]⁺,

calcd for C₁₈H₂₃NO₂285.1729.

(arom. CH), 127.2 (2 C, arom. CH), 128.2 (2 C, arom.

CH), 136.8 (C‐5), 142.5 (arom. C), 156.3 (C‐2) ppm.

HRMS (EI): m/z = 285.1728 [M]⁺, calcd for C₁₈H₂₃NO₂

285.1729.

2.2.29 | (3aR,7aS)‐3a,5,7a‐Trimethyl‐3‐((S)‐

1‐phenylethyl)‐3,3a,7,7a‐tetrahydrobenzo[d]

oxazol‐2(6H)‐one (36b) and (3aS,7aR)‐

3a,5,7a‐trimethyl‐3‐((R)‐1‐phenylethyl)‐

3,3a,7,7a‐dihydrobenzo[d]oxazol‐2(6H)‐one

(37b)

2.2.30 | (R)‐3‐(1‐Phenylethyl)‐4,5,6,7‐

tetrahydrobenzo[d]oxazol‐2(3H)‐one (39a)

A mixture of 38 (0.228 g, 1.00 mmol) and 4a (0.309 g,

2.10 mmol) was placed in a threaded ACE glass pressure

tube with a sealed Teflon screw cap under N₂atmo-

sphere. It was stirred and heated at 140°C for 48 hours.

Subsequently, it was diluted with CH₂Cl₂(20 mL), stirred

for 30 minutes, and filtered over Na₂SO₄. The solvent was

removed under vacuum, and the crude mixture was puri-

fied by column chromatography over silica gel (30 g/g of

crude, hexane/EtOAc, 97:3) to give 39a (0.240, 99%) as

white needles. R_f= 0.73 (hexane/EtOAc, 7:3); m.p. 72‐

Following the method for the preparation of 36a/37a, a

mixture of 1b (0.100 g, 0.46 mmol) and 35 (0.343 g,

2.30 mmol) in anhydrous xylene (1.0 mL) was stirred

and heated at 140°C for 48 hours to give 36b/37b

(63:37) (0.121 g, 92%) as a pale yellow solid. This mixture

was separated by column chromatography over silica gel

(30 g/g of crude, hexane/EtOAc, 98:2) to obtain 36b

(0.057 g, 44%) as a pale yellow solid and 37b (0.052 g,

40%) as a white solid. Data for 36b: R_f= 0.49 (hexane/

26

73°C. [α]_D= +45.0 (c 0.103, MeOH). IR (film):

ν = 2939, 1752, 1703, 1496, 1450, 1409, 1365, 1321, 1227,

1023, 990, 755, 709, 698 cm⁻^{1 1}H NMR (300 MHz,

.

23

EtOAc, 7:3); m.p. 181‐183°C. [α]_D= +62.0 (c 0.05,

CDCl₃): δ = 1.53‐1.91 (m, 4 H, H‐5, H‐6), 1.76 (d,

J = 7.5 Hz, 3H, CH₃C‐1′), 2.12‐2.23 (m, 2 H, H‐4), 2.29‐

2.37 (m, 2 H, H‐7), 5.34 (q, J = 7.5 Hz, 1H, H‐1′), 7.24‐

7.39 (m, 5H, Ph‐H) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 18.2 (CH₃C‐1′), 20.3 (C‐4), 20.7 (C‐7), 21.5 (C‐5),

21.7 (C‐6), 51.5 (C‐1′), 120.0 (C‐3a), 126.3 (2 C, arom.

CH), 127.4 (arom. CH), 128.3 (2 C, arom. CH), 134.4 (C‐

7a), 139.8 (arom. C), 155.5 (C‐2) ppm. HRMS (EI): m/

z = 243.1261 [M]⁺, calcd for C₁₅H₁₇NO₂243.1259.

CHCl₃). IR (film): ν = 2916, 1725, 1413, 1349, 1321,

1

1224, 1171, 1083, 1027, 970 cm⁻¹. H NMR (500 MHz,

CDCl₃): δ = 1.16 (s, 3 H, CH₃C‐3a), 1.30 (s, 3 H, CH₃C‐

7a),1.65 (ddd, J = 14.0, 9.5, 5.5 Hz, 1 H, H‐7), 1.69 (br s,

3 H, CH₃C‐5), 1.77 (d, J = 7.5 Hz, 3 H, CH₃C‐1′), 1.82

(br dt, J = 17.5, 5.5 Hz, 1 H, H‐6), 2.02 (ddd, J = 14.0,

5.0, 4.5 Hz, 1 H, H‐7), 2.18‐2.27 (m, 1 H, H‐6), 4.47 (q,

J = 7.5 Hz, 1 H, H‐1′), 5.18 (br s, 1 H, H‐4), 7.22‐7.26

(m, 1 H, Ph‐H), 7.30‐7.34 (m, 2 H, Ph‐H), 7.43‐7.47 (m,

2 H, Ph‐H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.1

(CH₃C‐1′), 21.4 (CH₃C‐3a), 22.0 (CH₃C‐7a), 23.5 (CH₃C‐

5), 26.3 (C‐6), 30.8 (C‐7), 51.8 (C‐1′), 62.9 (C‐3a), 80.8

(C‐7a), 122.5 (C‐4), 126.9 (2 C, arom. CH), 127.1 (arom.

CH), 128.4 (2 C, arom. CH), 136.9 (C‐5), 143.0 (arom.

C), 156.5 (C‐2) ppm. HRMS (EI): m/z = 285.1727 [M]⁺,

calcd for C₁₈H₂₃NO₂285.1729.

2.2.31 | (S)‐3‐(1‐Phenylethyl)‐4,5,6,7‐

tetrahydrobenzo[d]oxazol‐2(3H)‐one (39b)

According to the method for the preparation of 39a, a

mixture of 38 (0.228 g, 1.00 mmol) and 4b (0.309 g,

2.10 mmol) provided 39b (0.240, 99%) as a white solid.

Data for 37b: R_f= 0.44 (hexane/EtOAc, 7:3); m.p. 120‐

23

121°C. [α]_D= +17.0 (c 0.100, CHCl₃). IR (film):

R_f= 0.72 (hexane/EtOAc, 7:3); m.p. 75‐76°C. [α]

24

D

ν = 2931, 1739, 1494, 1447, 1318, 1226, 1170, 1076, 1027,

= −42.6 (c 0.123, MeOH). IR (film): ν = 2939, 1749,

1

967, 920, 766, 701 cm⁻¹. H NMR (500 MHz, CDCl₃):

1703, 1496, 1450, 1409, 1363, 1321, 1227, 1023, 990, 755,

1

δ = 1.12 (s, 3 H, CH₃C‐3a), 1.30 (s, 3 H, CH₃C‐7a), 1.61

(br s, 3 H, CH₃C‐5),1.66 (ddd, J = 14.0, 7.5, 5.5 Hz, 1 H,

H‐7), 1.80 (d, J = 7.5 Hz, 3 H, CH₃C‐1′), 1.81‐1.87 (m, 1

H, H‐6), 1.97 (ddd, J = 14.0, 6.5, 5.5 Hz, 1 H, H‐7), 2.10‐

2.17 (m, 1 H, H‐6), 4.63 (q, J = 7.5 Hz, 1 H, H‐1′), 5.09‐

5.12 (m, 1 H, H‐4), 7.21‐7.25 (m, 1 H, Ph‐H), 7.28‐7.32

(m, 2 H, Ph‐H) 7.39‐7.43 (m, 2 H, Ph‐H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 19.6 (CH₃C‐1′), 20.9 (CH₃C‐3a),

21.4 (CH₃C‐7a), 23.3 (CH₃C‐5), 26.6 (C‐6), 31.2 (C‐7),

51.5 (C‐1′), 62.9 (C‐3a), 80.8 (C‐7a), 123.4 (C‐4), 127.1

709, 698 cm⁻¹. H NMR (300 MHz, CDCl₃): δ = 1.55‐

1.85 (m, 4 H, H‐5, H‐6), 1.77 (d, J = 7.3 Hz, 3H, CH₃C‐

1′), 2.10‐2.23 (m, 2 H, H‐4), 2.31‐2.43 (m, 2 H, H‐7), 5.36

(q, J = 7.3 Hz, 1H, H‐1′), 7.26‐7.40 (m, 5H, Ph‐H) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 18.4 (CH₃C‐1′), 20.6

(C‐4), 20.9 (C‐7), 21.8 (C‐5), 22.0 (C‐6), 51.7 (C‐1′), 120.2

(C‐3a), 126.6 (2 C, arom. CH), 127.7 (arom. CH), 128.6

(2 C, arom. CH), 134.8 (C‐7a), 140.1 (arom. C), 155.6 (C‐

2) ppm. HRMS (EI): m/z = 243.1267 [M]⁺, calcd for

C₁₅H₁₇NO₂243.1259.

SANTOYO ET AL.

15

(0.117 g, 95%) as colorless needles. R_f= 0.24 (hexane/

EtOAc, 8:2); m.p. 139‐141°C. [α]_D= −40.5 (c 0.111,

2.2.32 | (4aR,8aS)‐9‐((R)‐1‐phenylethyl)‐

5,6,7,8‐tetrahydro‐4H‐4a,8a‐

20

MeOH). IR (film): ν = 2960, 1733, 1416, 1353, 1330,

(epoxymethanoimino)chromen‐10‐one

(40a) and (4aS,8aR)‐9‐((R)‐1‐phenylethyl)‐

5,6,7,8‐tetrahydro‐4H‐4a,8a‐

1

1223, 1050, 995, 882, 752, 701 cm⁻¹. H NMR (500 MHz,

CDCl₃): δ = 0.93‐1.03 (m, 1 H, H‐7), 1.28‐1.37 (m, 1 H,

H‐6), 1.43‐1.51 (m, 1 H, H‐7), 1.51‐1.60 (m, 1 H, H‐6),

1.69‐1.75 (m, 1 H, H‐8), 1.75‐1.78 (m, 1 H, H‐5), 1.83 (d,

J = 7.0 Hz, 3H, CH₃C‐1′), 1.88 (dddd, J = 14.0, 6.5, 4.0,

1.0 Hz, 1 H, H‐5), 2.07 (dm, J = 15.0 Hz, 1 H, H‐8), 2.23

(dt, J = 17.5, 2.5 Hz, 1 H, H‐4), 2.37 (ddd, J = 17.5, 5.5,

1.0 Hz, 1 H, H‐4), 4.53 (q, J = 7.0 Hz, 1 H, H‐1′), 4.93

(td, J = 5.5, 2.5 Hz, 1 H, H‐3), 6.35 (ddd, J = 5.5, 2.5,

0.5 Hz, 1 H, H‐2), 7.25 (tt, J = 7.0, 2.0 Hz, 1 H, Ph‐H),

7.30‐7.35 (m, 2 H, Ph‐H), 7.47‐7.51 (m, 2 H, Ph‐H) ppm.

Signals attributed to the minor isomer 41b: 1.82 (d,

J = 7.5 Hz, CH₃C‐1′), 4.81 (td, J = 5.5, 3.0 Hz, H‐3),

4.85 (q, J = 7.5 Hz, H‐1′), 6.03 (ddd, J = 6.0, 2.5, 1.0 Hz,

H‐2) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 19.5 (C‐6),

20.1 (CH₃C‐1′), 20.2 (C‐7), 26.8 (C‐4), 29.2 (C‐8), 35.3

(C‐5), 51.9 (C‐1′), 80.6 (C‐4a), 93.2 (C‐8a), 100.3 (C‐3),

126.9 (2 C, arom. CH), 127.1 (arom. CH), 128.4 (2 C,

arom. CH), 141.9 (C‐2), 142.6 (arom. C), 156.6 (C‐10)

ppm. HRMS (EI): m/z = 299.1520 [M]⁺, calcd for

C₁₈H₂₁NO₃299.1521.

(epoxymethanoimino)chromen‐10‐one

(41a)

A mixture of 39a (0.100 g, 0.41 mmol) and 8a (0.115 g,

2.06 mmol) in anhydrous toluene (5.0 mL) was placed

in a threaded ACE glass pressure tube with a sealed Tef-

lon screw cap under N₂atmosphere. It was stirred and

heated at 80°C for 120 hours. The solvent was removed

under vacuum, and the crude mixture was purified by

column chromatography over silica gel (30 g/g of crude,

hexane/EtOAc, 97:3) to give a mixture of 40a/41a

(84:16) (0.119 g, 97%) as a white solid. R_f= 0.23 (hex-

20

ane/EtOAc, 8:2); m.p. 130‐132°C. [α]_D= +44.6 (c

0.107, MeOH). IR (film): ν = 2960, 1734, 1416, 1353,

1

1224, 1050, 995, 881, 753, 701 cm⁻¹. H NMR (500 MHz,

CDCl₃): δ = 0.86‐0.96 (m, 1 H, H‐7), 1.30‐1.36 (m, 1 H,

H‐6), 1.36‐1.44 (m, 1 H, H‐7), 1.44‐1.54 (m, 1 H, H‐6),

1.63‐1.67 (m, 1 H, H‐8), 1.67‐1.71 (m, 1 H, H‐5), 1.76 (d,

J = 7.5 Hz, 3H, CH₃C‐1′), 1.81 (dddd, J = 14.0, 6.5, 4.0,

1.0 Hz, 1 H, H‐5), 2.00 (dt, J = 15.0, 4.5 Hz, 1 H, H‐8),

2.21 (dt, J = 17.5, 2.5 Hz, 1 H, H‐4), 2.29 (ddd, J = 17.5,

5.5, 0.5 Hz, 1 H, H‐4), 4.46 (q, J = 7.5 Hz, 1 H, H‐1′),

4.86 (td, J = 5.5, 3.0 Hz, 1 H, H‐3), 6.28 (ddd, J = 6.0,

3.0, 0.5 Hz, 1 H, H‐2), 7.16‐7.20 (m, 1 H, Ph‐H), 7.23‐

7.28 (m, 2 H, Ph‐H), 7.40‐7.44 (m, 2 H, Ph‐H) ppm. Sig-

nals attributed to the minor isomer 41a: 1.75 (d,

J = 7.0 Hz, CH₃C‐1′), 2.14 (dt, J = 17.5, 3.0 Hz, 1 H, H‐

4), 4.75 (td, J = 5.5, 3.0 Hz, H‐3), 4.77 (q, J = 7.0 Hz, H‐

1′), 5.96 (ddd, J = 6.0, 3.0, 0.5 Hz, H‐2) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 19.5 (C‐6), 20.1 (CH₃C‐1′), 20.2

(C‐7), 26.9 (C‐4), 29.3 (C‐8), 35.3 (C‐5), 52.0 (C‐1′), 80.7

(C‐4a), 93.2 (C‐8a), 100.4 (C‐3), 126.9 (2 C, arom. CH),

127.2 (arom. CH), 128.5 (2 C, arom. CH), 141.9 (C‐2),

142.7 (arom. C), 156.6 (C‐10) ppm. HRMS (EI): m/

z = 299.1521 [M]⁺, calcd for C₁₈H₂₁NO₃299.1521.

2.3 | Single‐crystal X‐ray crystallography

Colorless single‐crystals of 30a, 29b, and 29d were

obtained by recrystallization from CH₂Cl₂/hexane (7:3),

of 36b from CH₂Cl₂/hexane (1:6), and of 40b from

CHCl₃. The crystals were mounted on glass fibers. For

29b, crystallographic measurements were performed at

room temperature with Cu Kα radiation (graphite mono-

chromator, λ = 1.5418 Å) and a scintillation detector.

Unit cell parameters were calculated from least‐squares

refinement of 41 reflections in the range of

10.7 < 2θ < 28.2°. Three standard reflections were mon-

itored periodically, showing little change during data col-

lection. Empirical (psi‐scan) absorption corrections were

utilized. The crystal structures of 30a, 29d, 36b, and

40b were obtained at room temperature with Mo Kα

radiation (graphite monochromator, λ = 0.7107 Å) with

a CCD detector. Empirical (multi‐scan) absorption cor-

rections were applied. In all cases, intensities were

corrected for Lorentz and polarization effects. Aniso-

tropic temperature factors were introduced for all

nonhydrogen atoms, while hydrogen atoms were placed

in idealized positions and their atomic coordinates

refined, using unit weights in the refinement (Table 1).

Structures were solved with the SHELXS,⁵⁰SHELXT,⁵⁰

or SIR92⁵¹program as implemented in the WinGX

suite,⁵²and refined within WinGX using SHELXL.⁵³In

2.2.33 | (4aS,8aR)‐9‐((S)‐1‐phenylethyl)‐

5,6,7,8‐tetrahydro‐4H‐4a,8a‐

(epoxymethanoimino)chromen‐10‐one

(40b) and (4aR,8aS)‐9‐((S)‐1‐phenylethyl)‐

5,6,7,8‐tetrahydro‐4H‐4a,8a‐

(epoxymethanoimino)chromen‐10‐one

(41b)

Following the method for the preparation of 40a/41a, the

reaction of 39b (0.100 g, 0.41 mmol) and 8a (0.115 g,

2.06 mmol) provided a mixture of 40b/41b (88:12)

16

SANTOYO ET AL.

17

all cases, ORTEP and packing diagrams were made with

ORTEP3⁵⁴or MERCURY.⁵⁵

resulting in good yield (Scheme 2). Under these reaction

conditions, 4‐methylene‐2‐oxazolidinones 2a‐b were

observed in trace amounts. Solvent‐free MW irradiation

was explored to determine whether the proportion of

these compounds could be improved (entries 2, 3, and

5) during the synthesis of the regioisomeric 4‐oxazolin‐

2‐ones 1a‐b. Thus, heterocycles 2a‐b were obtained in

low yields along with the corresponding isomers 1a‐b,

respectively (entries 3 and 5). However, the reaction

was not diastereoselective and provided a low ratio of

the C‐5 epimers. Hence, the reaction process likely

involves the hemiaminal intermediates 12 and 13 with-

out causing any significant change in the configuration

of the C‐3 carbon of 3a. Indeed, a mixture of 12/13

(61:39) was generated by heating the starting mixture

of 3a and 4b under MW irradiation at a lower tempera-

ture (120°C) for 90 minutes. The absolute configurations

of the C‐4 and C‐5 centers could not be unambiguously

established but were assumed to be in accordance with

the previous^44-46and the current studies. Interestingly,

a mixture of only two of the four possible diastereoiso-

mers was obtained, presumably by a chiral auxiliary‐

controlled cyclization at the stage of the I and II carba-

mate species,⁴⁴in which the epimerization of the C‐4

diastereoisomeric center did not take place.

2.4 | Theoretical calculations

All ab initio and DFT calculations were carried out with

the Gaussian 09 program package.⁵⁶Optimizations of

the stationary points were initially made at the HF/6‐

31G(d) level of theory. The optimized geometries served

as starting points for further optimizations at the

ωB97X‐D/6‐31G(d) and ωB97X‐D/6‐31 + G(d,p) levels of

DFT theory. For all optimizations, the OPT = TIGHT

optimization option was employed. For all DFT calcula-

tions, the INT (GRID = ULTRAFINE) option was used.

The TSs were located with the QST2, QST3, or TS optimi-

zation option. All stationary points were characterized by

frequency calculations. All minima (starting materials

and adducts) showed only real vibrational frequencies,

while each TSs displayed a single negative eigenvalue of

the Hessian matrix. Through visual inspection of the nor-

mal mode associated with the imaginary vibrational fre-

quency, it was confirmed that the TSs corresponded to

motion along the expected reaction coordinate.

In the interest of exploring the reactivity and

diastereoselectivity of the exocyclic double bond in 4‐

methylene‐2‐oxazolidinones, as was done with com-

pounds 2 (Scheme 2), derivatives 14a‐b were synthesized

under similar reaction conditions. Thus, under MW irra-

diation (60 W) at 200°C for 20 minutes, the reaction of

α‐ketol 3b and isocyanate 4a led to enantiopure 3‐

substituted 4‐methylene‐1,3‐oxazolidin‐2‐one 14a in 66%

yield (Scheme 3). Enantiomer 14b was prepared by using

isocyanate 4b under thermal (130°C, 24 h) or MW

(300 W, 140°C, 3 h) protocols to give 78% and 84% yields,

respectively.

3 | RESULTS AND DISCUSSION

3.1 | Functionalization of enantiopure

1,3‐oxazolidin‐2‐ones 1a‐b

An efficient methodology was previously developed for

the preparation of enantiopure (S)‐4,5‐dimethyl‐3‐(1‐

phenylethyl)‐4‐oxazolin‐2‐one (1b) through solvent‐free

thermal conditions by mixing 3a and isocyanate 4b

(Table 2, entry 4).⁴⁹The same procedure was carried

out in the current work for the preparation of (R) enan-

tiomer 1a by reacting 3a with isocyanate 4a (entry 1),

Upon Pd‐catalyzed hydrogenation of 1b, the expected

mixture of 2‐oxazolidinones 15/16 was obtained in good

diastereoisomeric ratios (dr) and high yields (Table 3,

entries 1‐3). The use of high pressures decreased the dr

(entry 3). The diastereoselectivity increased with palla-

dium hydroxide as the catalyst, although the products in

the mixture were obtained in low yield (entry 4). In con-

trast, the highest dr with this catalyst was found with 14b

as the substrate (Scheme 3), generating a mixture of 17/18

in high yield (entry 7).

The Michael addition of 1a to 8b at elevated tempera-

tures afforded a moderate yield of adducts 19a/20a

(72:28) (Scheme 4). Whereas the reaction under milder

thermal conditions between 1b and 8b led to improve

diastereoselectivity, yielding a mixture of adducts 19b/

20b (91:9).⁴⁹

TABLE 2 Preparation of compounds 1a‐b and 2a‐b, obtained by

condensation of α‐ketol 3a and isocyanates 4a‐b^a

Entry

4

Base MW, W T, °C

t

1 (%)^b2 (%)^b

1

2

3

4

5

4a Et₃N ___

120

200

170

120

140

24 h

1a (75) 2a (0)

4a ___

70

15 min 1a (85) 2a (0)

8 min 1a (55) 2a (29)^c

200

4b Et₃N ___

4b Et₃N 200

24 h

1b (75) 2b (0)

8 min 1b (16) 2b (39)^d

^aIn the presence of 3a/4 and Et₃N (2.0 mol equiv).

^bAfter recrystallization or column chromatography.

^cAs a mixture of diastereoisomers (65:35).

^dAs a mixture of diastereoisomers (54:46).

18

SANTOYO ET AL.

SCHEME 2 Thermal‐ and MW‐promoted synthesis of oxazolin‐2‐ones 1a‐b and oxazolidin‐2‐ones 2a‐b, and hemiaminals 12 and 13

SCHEME 3 Thermal‐ and MW‐promoted synthesis of 4‐methylene oxazolidin‐2‐ones 14a‐b, and diastereoselective hydrogenation leading

to oxazolidin‐2‐ones 17 and 18

In the case of 4‐methylene 2‐oxazolidinones 14a and

14b, the Michael addition to 8b proceeded better under

iodine catalysis at 0°C to yield mixtures of E/Z diastereo-

isomers 21a/22a and 21b/22b, respectively (Scheme 5).

The presence of a mixture of the latter compounds is

probably due to the longer reaction time (6 h), which

may favor the isomerization of the double bond, as was

observed after monitoring the reaction.

To test the control of the E/Z functionalization of the

exocyclic double bond of enantiomers 14a‐b, the

formylation and bromination reactions were explored

(Scheme 5). Thus, the Vilsmeier‐Haack method of

formylation was applied to both of the enantiopure 2‐

oxazolidinones to give high yields of the respective E dia-

stereoisomers 25a‐b. No signals of the Z isomers were

1

detected by H NMR analysis of the crude mixtures. The

Interestingly, when the 21b/22b (81:19) mixture was

hydrogenated, the ¹H NMR spectrum of the mixture

crude displayed a set of signals corresponding to diaste-

reoisomers 23a/24a (98:2). Hence, not only was the reac-

tion highly diastereoselective but also the E/Z geometry

of the starting material did not influence the

diastereoselection of the hydrogenation.

E geometry was established by NOE experiments, which

showed an enhancement of the singlets attributed to the

methyl groups when the formyl proton was irradiated.

A reciprocal effect was found when the former signals

were irradiated.

A similar diastereoselectivity was

observed after bromination of 14b with NBS to furnish

the single E isomer 26.

SANTOYO ET AL.

19

TABLE 3 Diastereoselective hydrogenation of 4‐oxazolin‐2‐one 1b and 4‐methylene‐2‐oxazolidinone 14b^a

Entry

Substrate

Cat. (%)

P, psi

Solvent

t, h

Products^b[%]^c

1^d

2

1b

Pd/C (10)

750

EtOAc

MeOH

24

48

18

48

24

15/16 (84:16) [73]

15/16 (87:13) [94]

15/16 (69:31) [92]

15/16 (89:11) [34]

17/18 (69:31) [88]

17/18 (72:28) [90]

17/18 (96:4) [99]

1b

Pd/C (10)

1000

1300

(e)

3

1b

Pd/C (10)

4

1b

Pd (OH)₂(20)

Pd/C (5)

5

14b

1250

1500

(e)

6

Pd/C (10)

7

Pd (OH)₂(20)

^aThe reactions were heated at rt.

^bRatio calculated from the ¹H NMR spectra of the crude mixtures.

^cAfter recrystallization or column chromatography.

^dAcOH was added and heated at 60°C.

^eUnder atmospheric pressure with a balloon.

We previously described a new synthetic approach

for the preparation of 1,3‐oxazolidin‐2,4‐diones starting

from 4‐methylene 1,3‐oxazolidin‐2‐ones via an oxidative

cleavage by treatment with MCPBA.⁴⁹To evaluate the

scope of this methodology, epimeric mixtures of deriva-

tives 2a and 2b were treated under optimized conditions

(Scheme 6). The epimeric ratios of the starting materials

were roughly maintained during the process, to yield

similar epimeric ratios of 2,4‐diones 27 and 28, which

suggests that the mechanism of the oxidative cleavage

does not affect the epimeric center vicinal to the exocy-

clic double bond.

3.2 | Enantiopure 1,3‐oxazolin‐2‐ones 1a‐b

as synthons in the construction of fused

hetero‐ and carbocyclic scaffolds

Preliminary results have demonstrated the potential of

enantiopure 4‐oxazolin‐2‐one 1b in Michael/cyclization

cascade reactions with acrolein (8a) to yield the fused

bis‐heterocyclic compounds 29b/30b in high dr (91:9)⁴⁶

(Table 4, entry 3) (Scheme 1). The dr was slightly

improved by reducing the reaction temperature to 60°C

for 5 days, maintaining 29b as the major isomer (entry 2).

This procedure was even more efficient for enantiomer

SCHEME 4 Preparation of 4‐methylene oxazolidin‐2‐ones 19a/20a and 19b/20b by thermal Michael addition of 1a or 1b to 8b,

respectively

20

SANTOYO ET AL.

SCHEME 5 Reactivity and stereoselectivity of 4‐methylene oxazolidin‐2‐ones 14a and 14b in diverse reactions

SCHEME 6 Oxidative cleavage of epimeric mixtures of 4‐methylene oxazolidin‐2‐ones 2a‐b

1a, producing the single diastereoisomer 29a (entry 1). To

further explore the possibility of improving the

diastereoselectivity in the reaction of 1b with 8a, micro-

wave (MW) irradiation was applied (entry 4). The dr

was similar to that found under thermal conditions but

the chemical yield significantly decreased (entry 2).

The reactivity with methyl vinyl ketone (8b) was

lower, as were the yields of the bicyclic pyranyl analogs

29c‐d/30c‐d. Nevertheless, the diastereoselectivity

remained high (Table 4, entries 5‐8), improving at a low

temperature or under MW irradiation.

The Pd (OH)₂‐catalyzed hydrogenation of a mixture

of 29b/30b (93:7) under mild conditions (1 atm, rt,

18 h) led to a total conversion into the corresponding

mixture of fused hexahydro‐2H‐pyrano[2,3‐d]oxazol‐2‐

ones 31a/32a (92:8) (Scheme 7). Interestingly, when

the hydrogenation was carried out on a mixture of

29d/30d (>99:1) under the same reaction conditions, a

single isomer was obtained at the C‐5 chiral center of

the resulting mixture of products 31b/32b (>99:1). The

C‐5 configuration was tentatively assigned in accordance

with the crystal structure of 29d (see Figure 1). Since

the front face (si face) of the dihydropyrane moiety is

concave (as depicted in Scheme 7), the re face is avail-

able for the entry of the catalyst and hydrogen atoms,

giving rise to the major diastereoisomer 31b.

As expected,⁴⁵when 4‐oxazolin‐2‐ones 1a‐b were sub-

mitted to more severe conditions in the presence of the

same Michael acceptors 8a‐b, and with methyl iodide as

the promoting agent, mixtures of dihydrobenzo[d]

oxazol‐2(3H)‐ones 33a‐e/34a‐e were generated (Table 5).

The diastereoselectivity was lower than that of the fused

tetrahydro‐2H‐pyrano[2,3‐d]oxazol‐2‐ones 29/30, pre-

sumably because of the higher temperature applied. It is

SANTOYO ET AL.

21

TABLE 4 Diastereoselective construction of bicyclic dihydropyranyl compounds 29a‐d/30a‐d^a

Entry

Substrate

8

T, °C

t, days

Products^b[%]^c

1

1a

1b

1a

1b

8a

8b

60

5

29a/30a (<1:99) [92]

29b/30b (93:7) [74]

29b/30b (91:9) [66]

29b/30b (92:8) [48]

29c/30c (19:81) [14]

29c/30c (<1:99) [45]

29d/30d (>99:1) [14]

29d/30d(98:2) [42]

2

60

5

3

100

110

80

1

4^d

0.2

5

6

60

5

7

60

7

8^d

110

0.2

^aIn the presence of 1a‐b/8a‐b (1:1 to 1:5 mol equiv) in xylene.

^bRatio calculated from the ¹H NMR spectra of the crude mixtures.

^cAfter recrystallization or column chromatography.

^dIrradiated with MW (100 W).

SCHEME 7 Hydrogenation of mixtures of fused tetrahydro‐2H‐pyrano[2,3‐d]oxazol‐2‐ones 29b/30b and 29d/30d

worth noting that the reaction of 1b with an excess of

acrolein (8a) at 160°C yielded the corresponding dienes

33b/34b along with derivatives 33e/34e, which resulted

from the subsequent Michael addition of the dienes to

the excess of 8a (entry 2). However, cascade products

analogous to 33e/34e were not observed upon using 8b

instead of 8a, even after heating for 48 hours (entry 3).

Derivatives 33e/34e could also be prepared by direct addi-

tion of dienes 33b/34b to acrolein (8a), finding similar

diastereoselectivity (entry 5).

observed. As suggested in a previous report,⁴⁵the reac-

tion mechanism probably proceeds via nucleophilic sub-

stitution at the C‐5 center of the heterocycle to give

intermediate I, which undergoes isomerization of the

prenyl double bond and protonation of the enamide

moiety to furnish active species II. Cyclization of the

latter was followed by isomerization of the endocyclic

double bond formed, providing mixtures of diastereoiso-

mers 36b/37b (Scheme 8).

Furthermore, the diastereoselectivity in reactions was

analyzed with alkyl halides as the electrophile. Thus,

the reaction was carried out with prenyl bromide (35),

yielding mixtures of trimethyl tetrahydrobenzo[d]

oxazol‐2(6H)‐ones 36a‐b/37a‐b in low diastereos-

electivity (Scheme 8). By reducing the reaction tempera-

ture (140°C), a slight enhancement of selectivity was

3.3 | Synthesis of enantiopure bicyclic

1,3‐oxazolidin‐2‐ones 39a‐b as synthons in

the construction of propellanes

The aforementioned results reveal the versatility of (R)‐

and (S)‐4,5‐dimethyl‐3‐(1‐phenylethyl)‐4‐oxazolin‐2‐ones

22

SANTOYO ET AL.

FIGURE 1 Structures of (A) 30a, (B) 29b, (C) 29d, (D) 36b, and (E) 40b as determined by single‐crystal X‐ray diffraction (ellipsoids at the

30% probability level)

1a‐b for the diastereoselective functionalization of their

skeleton through the induction of the chiral moiety. The

presence of the C‐4 and C‐5 methyl groups also plays a

key role in improving such versatility and perhaps the

diastereoselectivity as well. For example, the generation

of dienes 33a‐d/34a‐d stems from the direct cooperation

of the C‐4 methyl group. Therefore, it may be attractive

to integrate the tetrasubstituted heterocyclic double bond

Similar to 4‐oxazolin‐2‐ones 1a‐b, the thermal addition

of 39a‐b to 8a efficiently proceeded to provide the

dihydropyran cycloadducts 40a‐b/41a‐b. However, there

was a lower diastereoselectivity in the formation of these

heterocyclic [4.4.3]propellanes than that found with the

dihydropyrans 29/30 (Table 4). The reaction of 39a with

8a was carried out under MW irradiation (100 W,

120°C) to try to improve the dr,^57-60which turned out to

be even lower for 40a/41a (75:25). It appears that the con-

formational motion of the cyclohexenyl moiety of the

bicyclic 4‐oxazolin‐2‐ones 39a‐b sterically counteracts

the effect of the chiral inductor. Hence, the entry of the

Michael acceptor (or heterodiene, see below) occurs with

a lower diastereoselectivity than in the reaction with 1a‐b

(Table 4).

of the 4‐oxazolin‐2‐one heterocycle within

membered ring and explore its reactivity with Michael

acceptors (eg, 8a). Accordingly, enantiopure

a six‐

tetrahydrobenzo[d]oxazol‐2(3H)‐ones 39a‐b were pre-

pared by reacting adipoin (38) with chiral isocyanates

4a‐b under solvent free conditions in quantitative yields

(Scheme 9).

SANTOYO ET AL.

23

TABLE 5 Diastereoselective synthesis of dihydrobenzo[d]oxazol‐2(3H)‐ones 33a‐e/34a‐e^a

Entry

Substrate

8 (mol equiv)

T, °C

t, h

Products^b[%]^c

1

2

1a

1b

8a (18.0)

8a (15.0)

140

160

24

33a/34a (20:80) [60]

33b/34b (83:17) [61]

33e/34e (86:14) [32]

3

4

5

1a

8b (5.0)

8a (3.0)

160

140

160

48

24

33c/34c (12:88) [62]

33d/34d (80:20) [63]

33e/34e (85:15) [41]

1b

33b/34b (83:17)

^aIn the presence of 1a‐b/8a‐b (1:3 to 1:18 mol equiv) and MeI (2.0 mol equiv) in xylene.

^bRatio calculated from the ¹H NMR spectra of the crude mixtures.

^cAfter column chromatography.

SCHEME 8 Formation of trimethyl tetrahydrobenzo[d]oxazol‐2(6H)‐ones 36a‐b/37a‐b

single‐crystal X‐ray diffraction analysis of oxazolidin‐2‐

one‐based bis‐heterocycles 30a, 29b, and 29d, of trimethyl

3.4 | Assignment of the absolute

configuration of the products derived from

4‐oxazolin‐2‐ones 1a‐b and 39b

tetrahydrobenzo[d]oxazol‐2(6H)‐one

36b,

and

of

propellane 40b (Figure 1).⁶¹

The assignment of the absolute stereochemistry of all the

products derived from the simple functionalization of 4‐

oxazolin‐2‐ones 1a‐b was made on the basis of the

In the case of the first three bicycles, the conformation

of the dihydropyran ring is bent towards the oxazolidin‐2‐

one ring, keeping the double bond far away from the

24

SANTOYO ET AL.

SCHEME 9 Synthesis of enantiopure tetrahydrobenzo[d]oxazol‐2(3H)‐ones 39a‐b, and diastereoselective cycloaddition with acrolein (8a)

to give heterocyclic propellanes 40a‐b/41a‐b

methyl groups. This conformational preference may con-

trol the highly diastereoselective hydrogenation of the

double bond of 29d, in which the hydrogen‐activated cat-

alyst (Pd (OH)₂) approaches from the convex and less

hindered face to yield the tetrahydropyran derivative

31b as the major isomer (Scheme 7).

Interestingly, the vicinal quaternary centers C‐3a and

C‐7a maintained the O(4) and C(7) atoms almost copla-

nar in the dihydropyran fused ring, with the C(7)‐C(7a)‐

C(3a)‐O(4) dihedral angle being 0.3(2) for 30a, 0.5(9) for

29b, 2.2(2) for 29d, and 1.0(3)[C(4)‐C(4A)‐C(8A)‐O(1)]

for 40b. Moreover, the O(1) and N(3) atoms in the

oxazolidin‐2‐one ring are also almost coplanar, with the

N(3)‐C(3a)‐C(7a)‐O(1) dihedral angle being −3.00(15)

for 30a, 2.1(6) for 29b, 4.94(18) for 29d, and 3.81(19)

[O(11)‐C(4A)‐C(8A)‐N(9)] for 40b. However, the C(8)

and C(9) methyl groups adopt a noneclipsed conforma-

tion. The C(8)‐C(3a)‐C(7a)‐C(9) dihedral angle is −9.4(2)

FIGURE 2 Rotamers 1b‐a and 1b‐B of the chiral auxiliary of 1b. Representation of the preferential beta 1,4‐addition of 1b‐a to electrophile

8a, or beta‐exo concerted [4 + 2] cycloaddition to heterodiene 8a, to yield major diastereoisomer 29b and minor 30b (upper three arrows).

Portrayal of the preferential alpha 1,4‐addition of 1b‐B to electrophile 8a, or alpha‐exo concerted [4 + 2] cycloaddition to heterodiene 8a, to

yield diastereoisomers 29b and 30b (below). For a clearer view, only the exo approaches are included, although the endo approaches are the

most favored (see Table 7)

SANTOYO ET AL.

25

for 30a, −10.4(9) for 29b, 9.6(2) for 29d, and 9.3(2) [C(5)‐

C(4A)‐C(8A)‐C(8)] for the dihedral angle including the

quaternary carbons and the methylene groups of the

cyclohexane moiety for 40b. In contrast, the torsion

angles are larger for the structure of compound 36b. For

36b, the dihedral angle is 31.66(17) for C(7)‐C(7a)‐C(3a)‐

C(4), 29.81(13) for N(3)‐C(3a)‐C(7a)‐O(1) and 34.82(18)

for C(9)‐C(7a)‐C(3a)‐C(8). This is likely due to the posi-

tion of the double bond in the cyclohexene ring, vicinal

to the C(3a) angular carbon, which causes the fused rings

and the methyl groups to twist.

affords derivatives 30a and 29b, respectively. Likewise,

the addition of 8b to the same compounds yields the cor-

responding major isomers 30c and 29d, respectively

(Table 4).

Two possible mechanisms can be proposed for the

reaction of 1b with 8a to form diastereoisomers 29b and

30b (Figure 2). The first is a two‐step pathway, including

the formation of zwitterionic intermediate I from the 1,4‐

conjugated addition of 1b to 8a (path a).^62,63The second

one may occur through a concerted hetero‐Diels‐Alder

cycloaddition (path b).^64-66

3.5 | Reaction mechanisms and

diastereoselectivity of the processes

between 4‐oxazolin‐2‐ones 1a‐b and

electrophiles 8a‐b

Regio‐ and diastereoselective reaction pathways can be

suggested for the formation of major adducts 30a and

29b from the addition of 4‐oxazolin‐2‐ones 1a and 1b,

respectively, to acrolein (8a). Such pathways may also

be involved in the formation of 30c and 29d from the

addition of 1a and 1b, respectively, to methyl vinyl

ketone (8b) (Table 4). It is possible to rationalize the

regioselectivity as a consequence of the polarization of

the double bond of heterocycles 1a‐b by the lone‐pair of

the nitrogen atom, which would increase the electron

density at C‐5.⁴⁴Consequently, the latter position is more

nucleophilic than C‐4, attacking the electrophilic β‐

carbon center of the conjugate carbonyl compounds 8a‐b.

Diastereoselectivity should of course be explained by

considering the conformational effect of the chiral auxil-

iary group of 4‐oxazolin‐2‐ones 1a and 1b. This group

must certainly control the additions of the electrophilic

substrates. Thus, the addition of 8a to these compounds

TABLE 6 The conformational analysis of 1b provides the abso-

lute (E₀) and relative (ΔE₀) energies of 1b‐A in relation to con-

former 1b‐B, including zero‐point energies (ωB97X‐D/6‐31 + G(d,

p))

Conformer

E₀, a.u.

ΔE₀, kcal/Mol

θ_{(H‐C‐N‐C4)}, °

FIGURE 3 TSs calculated (ωB97X‐D/6‐31 + G(d,p))for the

cycloaddition between 1b and 8a, starting from conformers (A)

1b‐a and (B) 1b‐B

1b‐A

1b‐B

−709.19572

−709.19761

1.2

0.0

30.9

169.7

26

SANTOYO ET AL.

Figure 2 depicts rotamers 1b‐A and 1b‐B of the chiral

Due to the conformation displayed by the chiral frag-

ment in the X‐ray structures (Figure 1), a systematic con-

formational analysis of 1b was conducted at the ωB97X‐

D/6‐31 + G(d,p))⁶⁷level of DFT theory (Table 6) using

Gaussian 09.⁵⁵The analysis involved rotation of the bond

between the chiral auxiliary and the nitrogen. Only two

conformers were found: 1b‐A and 1b‐B. In the former,

the C–H bond of the chiral fragment is syn in regard to

the N(3)‐C(4) bond in the heterocycle. In the latter, the

C–H bond is anti with respect to the N(3)‐C(4) bond (see

Table 6 for dihedral angles). From the 1.2 kcal/mol

energy difference between these conformers, a 12:88 mix-

ture of 1b‐A/1b‐B would be expected at room tempera-

ture. If the conformation of 1b were the only factor

determining the stereoselectivity, the addition of 8a to

1b would take place on the least hindered alpha face of

1b‐B to yield 30b (Figure 2). However, this compound

was the minor isomer in the actual reaction.

auxiliary 1b. The former corresponds to the conformation

observed in the X‐ray structure of 29b, in which the ben-

zylic proton is quasi coplanar in relation to the plane of

the heterocycle, leaving the methyl and phenyl groups

at the beta and alpha positions, respectively. For the case

of path (a), therefore, electrophile 8a prefers to approach

the C‐5 nucleophilic center from the beta side, as the

approach from the alpha side would be destabilized by

repulsive van der Waals interactions created by the bulk-

ier phenyl group. Thus, zwitterionic intermediate I is

selectively formed, followed by cyclization of the nega-

tively charged oxygen to the iminium C‐4 carbon atom

to give major isomer 29b. The same reasoning fits well

for the opposite configuration of the chiral auxiliary of

1a to preferentially carry out the nucleophilic attack on

8a from the alpha side (the side of the methyl group) to

afford 30a as the major isomer (Table 4, entry 1;

Figure 1A).

A similar explanation can be proposed in an alterna-

tive concerted [4 + 2] hetero‐Diels‐Alder cycloaddition,

where 8a is the heterodiene species also preferentially

approaching the beta side (Figure 2 shows only the exo

approach). In principle, this second mechanism can be

discarded, considering that Michael addition products

19a/20a were isolated from the reaction between 1b and

MVK (8b) as presumable reaction intermediates

(Scheme 4). On the other hand, the corresponding

Michael addition epimeric products coming from the

reaction with acrolein (8a) were never isolated or

detected.

As is well known, the stereoselectivity of a reaction

such as the one under consideration does not necessar-

ily depend on conformational preferences.⁶⁸Hence, a

theoretical analysis was conducted for the addition reac-

tion of oxazolidinone 1b to 8a at the ωB97X‐D/6‐

31 + G(d,p) level of DFT theory (see details of quatum

calculations in Supporting Information). Attempts to

optimize

a

zwitterionic intermediate such as

I

(Figure 2) in the gas phase were unsuccessful, leading

to its dissociation into the starting materials. Unexpect-

edly, the transition states (TSs) for concerted hetero‐

Diels‐Alder cycloadditions could be located, allowing

for the calculation of the TSs for all possible

TABLE 7 Absolute (E₀^‡) and relative (ΔE₀^‡) energies (with respect to the 1b‐a/8a‐anti‐endo TS) for the eight TSs of the [4 + 2] cycload-

dition between 1b and 8a, including zero‐point energies (ωB97X‐D/6‐31 + G(d,p))^a

‡

ΔE₀

,

d_{(O‐‐‐C)}

Å^b

,

d_{(C‐‐‐C)}

,

Product

Fraction^c

TS

E₀^‡, u.a.

kcal/Mol

Å^b

dr, %^d

1b‐A/8a‐anti‐endo

1b‐A/8a‐anti‐exo

1b‐B/8a‐syn‐endo

1b‐B/8a‐syn‐exo

1b‐A/8a‐syn‐endo

1b‐A/8a‐syn‐exo

1b‐B/8a‐anti‐endo

1b‐B/8a‐anti‐exo

−900.97344

−900.96679

−900.96600

−900.96254

−900.96888

−900.96418

−900.97043

−900.96664

0.0

4.2

4.7

6.8

2.9

5.8

1.9

4.3

3.038

2.881

2.778

3.599

2.753

2.954

2.848

3.000

1.914

1.933

1.931

1.899

1.936

1.949

1.958

1.930

0.946

0.001

0.000

0.010

0.000

0.042

0.001

94.7

5.3

^aThe first four TSs lead to 29b, the last four to 30b.

^bDistances between the atoms forming the new bonds in the cycloaddition.

^cProduct fraction assuming kinetic control of the cycloaddition and the Boltzmann distribution (ΔE₀^‡, 25°C) of the TSs, based on the activation energies.

^dDiastereoisomeric ratios considering all the contributions to the TSs for each of the two final products.

SANTOYO ET AL.

27

diastereoisomeric approaches between the two reactants

that give rise to the formation of 29b/30b. After consid-

ering the two conformers of the chiral fragment in 1b

(1b‐A and 1b‐B), the anti and syn approximations with

regard to the phenyl group, and the endo/exo orienta-

tions of the heterodiene that promote the formation of

29b/30b, eight TSs were obtained. The TSs leading to

the other possible regioisomers were not studied. The

geometries of these stationary points are shown in

Figure 3, while the corresponding energies are summa-

rized in Table 7. Notice that out of the eight TSs, four

lead to 29b (the first four TSs in Table 7) and four to

30b.

addition of 1b to MVK (8b). By taking the same factors

into account, a set of eight TSs were located (Figure 4),

similar to those found for acrolein (8a), indicating that

this is also a concerted process.

The relative energies of the TSs (Figure 4 and Table 8)

are very similar to those found for the cycloadditions with

8a (Table 7), suggesting that the introduction of the

methyl group of 8b does not significantly increase the

repulsive interactions for most of the approaches. The

highest energy values are those for the TSs syn to the phe-

nyl group in conformer 1b‐B, in which the methyl group

of 8b is close to the phenyl ring of the auxiliary, either for

the endo or exo approaches (Figure 4).

All the TSs are very asynchronic (Figure 3 and Table 7

), as the distance between the C‐5 carbon atom of 1b and

the C‐3 carbon of 8a is shorter than that between the C‐4

carbon atom of the heterocycle and the oxygen atom of

the heterodiene. This agrees with the expected polariza-

tion of the π systems for both cycloaddends. The confor-

mations of the chiral N‐phenylethyl moiety are very

similar to those of the isolated heterocycle, with slight

changes in the orientation adopted by the benzene ring.

In the exo TSs, significant steric interactions between

the heterodiene and the methyl groups of the dienophile

are readily apparent, leading to higher energies than

those found for the endo TSs (Table 7).

Due to their higher energy, the exo TSs do not contrib-

ute to the formation of the final products 29b and 30b

(Table 7) under conditions of kinetic control. In particu-

lar, 1b‐B‐syn‐exo is the most energetic and asynchronous

TS, probably because of the stronger steric interactions of

the heterodiene not only with the methyl groups at C‐4

and C‐5 but also with the phenyl group of the chiral frag-

ment that is oriented towards it. Out of the four endo TSs,

1b‐A‐anti‐endo and 1b‐B‐anti‐endo are the significant

ones, both involving the approach of the heterodiene to

the dienophile from the same side of the methyl group

in the chiral fragment of the oxazolinone (Table 7).

Among these TSs, the main factor in controlling the

selectivity in this cycloaddition seems to be the steric

effect of the methyl group, which is oriented away from

the reacting centers of the oxazolidinone in the 1b‐A‐-

anti‐endo TS. Contrarily, the methyl group is oriented

towards the heterodiene in the 1b‐B‐anti‐endo TS,

blocking its approach to the dienophile. In conclusion,

the least hindered approach of the heterodiene to the

oxazolinone dienophile appears to take place on the beta

face of the latter. Interestingly, the diastereoisomeric ratio

of 29b/30b (95:5) obtained from the analysis of the ener-

gies of the TSs is in close agreement with that determined

experimentally (93:7).

FIGURE 4 TSs calculated (ωB97X‐D/6‐31 + G(d,p))for the

cycloaddition between 1b and 8b, starting from conformers (A)

1b‐a and (B) 1b‐B

Since the above theoretical evaluation fits well with

the experimental results, calculations were made for the

28

SANTOYO ET AL.

TABLE 8 Absolute (E₀^‡) and relative (ΔE₀^‡) energies (with respect to the 1b‐a/8b‐anti‐endo TS) for the eight TSs of the [4 + 2] cycload-

dition between 1b and 8b, including zero‐point energies (ωB97X‐D/6‐31 + G(d,p))^a

‡

ΔE₀

,

d_{(O‐‐‐C)}

Å^b

,

d_{(C‐‐‐C)}

,

Product

Fraction^c

TS

E₀^‡, u.a.

kcal/Mol

Å^b

dr, %^d

1b‐A/8b‐anti‐endo

1b‐A/8b‐anti‐exo

1b‐B/8b‐syn‐endo

1b‐B/8b‐syn‐exo

1b‐A/8b‐syn‐endo

1b‐A/8b‐syn‐exo

1b‐B/8b‐anti‐endo

1b‐B/8b‐anti‐exo

−940.26130

−940.25444

−940.25241

−940.24980

−940.25670

−940.25174

−940.25815

−940.25408

0.0

4.3

5.6

7.2

2.9

6.0

2.0

4.5

3.004

2.817

2.780

3.498

2.762

2.856

2.844

2.894

1.882

1.920

1.906

1.885

1.890

1.941

1.918

1.927

0.958

0.001

0.000

0.007

0.000

0.034

0.000

95.9

4.1

^aThe first four TSs lead to 29b, the last four to 30b.

^bDistances between the atoms forming the new bonds in the cycloaddition.

^cProduct fraction assuming kinetic control of the cycloaddition and the Boltzmann distribution (ΔE₀^‡, 25°C) of the TSs, based on the activation energies.

^dDiastereoisomeric ratios considering all the contributions to the TSs for each of the two final products.

SCHEME 10 Mechanism of conversion of fused pyranyl compounds 29/30 into dienes 33/34 via the formation and cyclization of

intermediates 19a/20a

The diastereoselectivity theoretically predicted

(Table 8) for the Diels‐Alder cycloaddition of 8b is not

as high as experimentally observed (Table 4). Neverthe-

less, a higher diastereoselectivity should theoretically be

expected from 8b than from 8a (Tables 7 and 8), and this

is in agreement with the trend in the experimental data.

Since the formation of fused‐pyranyl derivatives 29

and 30 is favored by a concerted TS, the Michael conju-

gated addition products 19a/20a (Scheme 4) probably

result from the pyranyl ring opening of derivatives 29/

30, which occurs as a consequence of raising the temper-

ature of the reaction mixture (Scheme 10). Furthermore,

we have established that dienes 33/34 can be formed by

heating the 1,4‐addition products 19a/20a. Hence, these

dienes would also be formed by conversion of derivatives

29/30 through

a

cascade pyranyl ring opening/

intramolecular cyclization process of 19a/20a via inter-

mediates I and II.⁶⁹

Regarding the behavior of chiral bicyclic oxazolidinones

39a‐b, it is possible to use a similar analysis to propose the

structures of the major isomers (Scheme 9).⁷⁰Assuming

that the electronic, steric, and conformational properties

of the structures of oxazolidinones 39a‐b are analogous to

those of oxazolidinones 1a‐b, the generation of

SANTOYO ET AL.

29

heterocyclic [4.4.3]propellanes 40a‐b/41a‐b may also take

place through a concerted hetero‐Diels‐Alder reaction.

Therefore, their diastereoselectivity should be controlled

by a preferential approach of the heterodiene from the face

opposite to the position of the phenyl ring of the chiral aux-

iliary. As a result, the structures of diastereoisomers 40a‐b

are assigned to the major adducts, which are supported by

the X‐ray structure of 40b (Figure 1E).

and A1‐S‐17131) for financial support. F.D. is also thank-

ful to the SEPI‐IPN (grants 20160791, 20170902, 20181332

and 20195287) and CONACYT (grant 282033), while H.A.

J.‐V. is deeply appreciative to the SEPI‐IPN (grants

20160567, 20171928, and 20181307). C.G.‐R. and A.F.‐B.

are thankful to the Universidad Autónoma del Estado

de México for financial support. M.A.V. gratefully recog-

nized the spectroscopy services provided by the National

Laboratory of the Universidad de Guanajuato (UG‐

UAA‐CONACYT grant 260373). B.M.S., D.Z‐Z., R.I.H.‐

B., V.P., E.B., and J.L. are beholden to CONACYT for

graduate fellowships, to the Programa Institucional de

Formación de Investigadores (BEIFI)‐IPN program, and

to the Ludwig K. Hellweg Foundation for scholarships

awarded. H.A.J.‐V., F.D. and J.T. are fellows of the EDI‐

IPN and COFAA‐IPN programs.

4 | CONCLUSION

Enantiopure

3‐((R)‐

and

3‐((S)‐1‐phenylethyl)‐4‐

oxazoline‐2‐ones 1a‐b are useful diastereoselective chiral

synthons for the construction of diverse hetero‐ and

carbocyclic‐fused polycyclic systems constituted by two

quaternary centers, each containing one heteroatom.

For most of the evaluated processes, the N‐((R) or (S)‐1‐

phenylethyl) chiral auxiliary efficiently induced the

highly diastereoselective functionalization of the 4‐

oxazolin‐2‐one scaffold at the C‐4 and C‐5 stereocenters.

Thus, hydrogenation, electrophilic additions, and

hetero‐Diels‐Alder reactions were carried out either

under mild reaction conditions or thermal or microwave

heating, providing the corresponding products in good

yields and high dr. In particular, the reaction between

compounds 1a‐b and conjugated carbonyl compounds

8a‐b generated the diastereoselective formation of 29a‐

d/30a‐d, which according to the DFT calculations are

the result of concerted hetero‐Diels‐Alder cycloadditions.

The relative energies of the possible diastereoisomeric TSs

indicate that the most favorable approach of the

heterodiene to the oxazolinone is controlled by the orien-

tation of the substituents in the stereogenic center of the

chiral auxiliary, leading to the observed configuration of

the quaternary carbon centers of the major products.

The stereoselectivity estimated from the theoretical calcu-

lations matches the experimental dr very closely. It has

been reported that the chiral α‐phenylethyl auxiliary is

readily removed by hydrogenolysis after acting as a valu-

able inductor for asymmetric synthesis^36-43,71Hence, it is

expected that such auxiliary can be removed in a like

manner for most of the products obtained in the current

study without affecting their functionalities. Experimen-

tal studies are being carried out to test this idea, and the

results will be reported in due course.

ORCID

Joaquín Tamariz https://orcid.org/0000-0002-0600-3857

REFERENCES

1. Evans DA, Bartroli J, Shih TL. Enantioselective aldol condensa-

tions. 2. Erythro‐selective chiral aldol condensations via boron

enolates. J Am Chem Soc. 1981;103(8):2127‐2129.

2. Sibi MP. Are two phenyls better than one? Synthesis and appli-

cations of (R)‐4‐diphenylmethyl‐2‐oxazolidinone. Aldrichimica

Acta. 1999;32:93‐103.

3. Brenner M, Seebach D. Enantioselective preparation of γ‐amino

acids and γ‐lactams from nitro olefins and carboxylic acids, with

the valine‐derived 4‐isopropyl‐5,5‐diphenyl‐1,3‐oxazolidin‐2‐one

as an auxiliary. Helv Chim Acta. 1999;82:2365‐2379.

4. Bull SD, Davies SG, Garner AC, et al. SuperQuat 5,5‐dimethyl‐

4‐iso‐propyloxazolidin‐2‐one as

a mimic of Evans 4‐tert‐

butyloxazolidin‐2‐one. Org Biomol Chem. 2006;4:2945‐2964.

5. Nunnery JK, Suyama TL, Linington RG, Gerwick WH. Expedi-

ent synthesis of α,α‐dimethyl‐β‐hydroxy carbonyl scaffolds via

Evans' aldol reaction with tertiary enolate. Tetrahedron Lett.

2011;52:2929‐2932.

6. Heravi MM, Zadsirjan V. Oxazolidinones as chiral auxiliaries in

asymmetric aldol reactions applied to total synthesis. Tetrahe-

dron: Asymmetry. 2013;24:1149‐1188.

7. Butt L, Hiersemann M. Synthesis of a common cyclopentanoid

building block for the total synthesis of jatropha‐5,12‐ and ‐

6(17),11‐dienes by uncatalyzed intramolecular carbonyl ene

(ICE) reaction. Synthesis. 2014;46:3110‐3120.

8. Suzuki T, Fujimura M, Fujita K, Kobayashi S. Total synthesis of

(+)‐methynolide using a Ti‐mediated aldol reaction of a lactyl‐

bearing oxazolidin‐2‐one, and a vinylogous Mukaiyama aldol

reaction. Tetrahedron. 2017;73:3652‐3659.

ACKNOWLEDGMENTS

We are grateful to Norma Velazquez and Clarisa

Marmolejo for their assistance in spectrometric measure-

ments, and Alan Larsen for proofreading. J.T. acknowl-

edges the SIP‐IPN (grants 20160791, 20170902, 20180198

and 20195228) and CONACYT (grants 83446, 178319,

9. Zhi W, Li J, Zou D, Wu Y, Wu Y. Palladium‐catalyzed

diastereoselective synthesis of 2‐arylbutanoic acid derivatives. J

Org Chem. 2017;82:12286‐12293.

30

SANTOYO ET AL.

10. Ager DJ, Prakash I, Schaad DR. 1,2‐Amino alcohols and their

heterocyclic derivatives as chiral auxiliaries in asymmetric syn-

thesis. Chem Rev. 1996;96:835‐875.

25. d'Angelo J, Desmaële D, Dumas F, Guingant A. The asymmetric

Michael addition reactions using chiral imines. Tetrahedron:

Asymmetry. 1992;3:459‐505.

11. Matsunaga H, Ishizuka T, Kunieda T. Synthetic utility of five‐

membered heterocycles–chiral functionalization and applica-

tions. Tetrahedron. 2005;61:8073‐8094.

26. List B. Proline‐catalyzed asymmetric reactions. Tetrahedron.

2002;58:5573‐5590.

27. List B. The ying and yang of asymmetric aminocatalysis. Chem

Commun. 2006;819‐824.

12. Coeffard V, Beaudet I, Quintard J‐P, Le Grognec E. Preparation

of enantiomerically enriched α‐aminoorganostannanes and

their applications in stereoselective synthesis. Chirality.

2010;22:864‐869.

28. Cheong PH‐Y, Zhang H, Thayumanavan R, Tanaka F, Houk

KN, Barbas CF III. Pipecolic acid‐catalyzed direct asymmetric

Mannich reactions. Org Lett. 2006;8:811‐814.

13. Birrell JA, Jacobsen EN. A practical method for the synthesis of

highly enantioenriched trans‐1,2‐amino alcohols. Org Lett.

2013;15:2895‐2897.

29. Carbery DR. Enamides: valuable organic substrates. Org Biomol

Chem. 2008;6:3455‐3460.

30. Lu T, Lu Z, Ma Z‐X, Zhang Y, Hsung RP. Allenamides: a power-

ful and versatile building block in organic synthesis. Chem Rev.

2013;113:4862‐4904.

14. Larksarp C, Alper H. Palladium(0)‐catalyzed asymmetric cyclo-

addition of vinyloxiranes with heterocumulenes using chiral

phosphine ligands: an effective route to highly enantioselective

31. Melchiorre P, Jørgensen KA. Direct enantioselective Michael

addition of aldehydes to vinyl ketones catalyzed by chiral

amines. J Org Chem. 2003;68:4151‐4157.

vinyloxazolidine

derivatives.

J

Am

Chem

Soc.

1997;119:3709‐3715.

15. Lu L‐Q, Chen J‐R, Xiao W‐J. Development of cascade reactions

for the concise construction of diverse heterocyclic architec-

tures. Acc Chem Res. 2012;45(8):1278‐1293.

32. Wang J, Li H, Zu L, Wang W. Highly enantioselective

organocatalytic Michael addition reactions of ketones with

chalcones. Adv Synth Catal. 2006;348:425‐428.

16. Cruz DC, Sánchez‐Murcia PA, Jørgensen KA. Formal asymmet-

ric enone aminohydroxylation: organocatalytic one‐pot

synthesis of 4,5‐disubstituted oxazolidinones. Chem Commun.

2012;48(49):6112‐6114.

33. Deng Y, Kumar S, Wang H. Synergetic‐cooperative combination

of enamine catalysis with transition metal catalysis. Chem

Commun. 2014;50:4272‐4284.

34. Kotha S, Bandarugattu VB, Krishna NG. Diversity‐oriented

approach to usual amino acid derivatives and heterocycles via

methyl 2‐acetamidoacrylate and its congeners. Tetrahedron.

2014;70:5361‐5384.

17. Chaubey NR, Ghosh SK. An enantiodivergent and formal syn-

thesis

of

paroxetine

enantiomers

by

asymmetric

desymmetrization of 3‐(4‐fluorophenyl)glutaric anhydride with

a chiral SuperQuat oxazolidin‐2‐one. Tetrahedron: Asymmetry.

2012;23(15‐16):1206‐1212.

35. Courant T, Dagousset G, Masson G. Enamide derivatives: versa-

tile building blocks for total synthesis. Synthesis.

2015;47:1799‐1826.

18. Veeraswamy S, Reddy KI, Ragavan RV, Yennam S, Jayashree A.

Ethyl imidazole‐1‐carboxylate (EImC) as a carbonylating agent:

efficient synthesis of oxazolidin‐2‐ones from amino alcohols.

Chem Lett. 2013;42(2):109‐111.

36. Bandala Y, Juaristi E. Recent advances in the application of α‐

phenylethylamine (α‐PEA) in the preparation of enantiopure

compounds. Aldrichim Acta. 2010;43:65‐78.

19. Bandala Y, Reyes‐Rangel G, Obregón‐Zúñiga A, Cruz‐

37. Khatik GL, Kumar V, Nair VA. Reversal of selectivity in acetate

aldol reactions of N‐acetyl‐(S)‐4‐isopropyl‐1‐[(R)‐1‐phenylethyl]

imidazolidin‐2‐one. Org Lett. 2012;14:2442‐2445.

Hernández

C,

Corzo

G,

Juaristi

E.

trans‐

Hexahydrobenzoxazolidinones in the enantioselective synthesis

of β²‐amino acids containing proteinogenic side chains. Eur J

Org Chem. 2014;2275‐2283.

38. Khatik GL, Sharma R, Kumar V, Chouhan M, Nair VA.

Stereselective synthesis of (S)‐dapoxetine: a chiral auxiliary

mediated approach. Tetrahedron Lett. 2013;54:5991‐5993.

20. Fang L‐C, Hsung RP. Stereoselective synthesis of

isoquinuclidines through an aza‐[4+2] cycloaddition of chiral

cyclic 2‐amidodienes. Org Lett. 2014;16:1826‐1829.

39. Davies SG, Fletcher AM, Lebeé C, Roberts PM, Thomson JE,

Yin J. Asymmetric synthesis of (−)‐(1R,7aS)‐absouline. Tetrahe-

dron. 2013;69:1369‐1377.

21. Gutiérrez RU, Rebollar A, Bautista R, et al. Functionalized α‐

oximinoketones as building blocks for the construction of

imidazoline‐based potential chiral auxiliaries. Tetrahedron:

Asymmetry. 2015;26(4):230‐246.

40. Brambilla M, Davies SG, Fletcher AM, Roberts PM, Thomson

JE. Asymmetric syntheses of (−)‐isoretronecanol and (−)‐

trachelantamidine. Tetrahedron. 2014;70:204‐211.

22. Newton R, Savage GP. Regioselective 1,3‐dipolar cycloaddition

reactions of 4‐methylene‐2‐oxazolidinones with benzonitrile

oxide. Aust J Chem. 2008;61:432‐437.

41. Gangar M, Kashyap N, Kumar K, Goyal S, Nair VA.

Imidazolidinone based chiral auxiliary mediated acetate aldol

reactions of isatin derivatives and stereoselective synthesis of

23. Harding SL, Savage GP. Facial selectivity induced by N‐aryl

atropisomerism in benzonitrile oxide cycloadditions with 4‐

methylene‐2‐oxazolidinones. Org Biomol Chem. 2012;10:

4759‐4766.

3‐substituted‐3‐hydroxy‐2‐oxindoles.

2015;56:7074‐7081.

Tetrahedron

Lett.

42. Brambilla M, Davies SG, Fletcher AM, Roberts PM, Thomson

JE. Asymmetric syntheses of (−)‐hastanecine, (−)‐

turneforcidine and (−)‐platynecine. Tetrahedron. 2016;72:

4523‐4535.

24. Hickmott PW. Electrophilic and nucleophilic substitution and

addition reactions of enamines. In: Rappoport Z, ed. The chem-

istry of enamines. Vol.1, 14 Chichester: Wiley; 1994:727.

Article Doi

Enantiopure 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

DOI: 10.1002/chir.23109

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Article abstract of DOI:10.1002/chir.23109

Full text of DOI:10.1002/chir.23109

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