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

Article abstract of DOI:10.1002/chir.23109

Enantiopure 3-((R)- and 3-((S)-1-phenylethyl)-4-oxazoline-2-ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N-(R)- or N-(S)-1-phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4- and 5-positions of the 4-oxazolin-2-one ring through thermal and MW-promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six-membered carbo- and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4-methylene-2-oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero-Diels-Alder cycloaddition.

Full text of DOI:10.1002/chir.23109

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‐Romero1,2 | Daniel Zárate‐Zárate1 |
R. Israel Hernández‐Benitez1 | Vanessa Pelayo1 | Edson Barrera1 | Carlos H. Escalante1 |
Aydeé Fuentes‐Benites1,2 | Guadalupe Martínez‐Morales1 | Julio López3 | Miguel A. Vázquez3 |
Francisco Delgado1 | Hugo A. Jiménez‐Vázquez1 | Joaquín Tamariz1
1 Departamento 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
2 Departamento 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
3 Departamento 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,10-13 which 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.1-9 Likewise, the preparation of
α‐amino alcohols and α‐amino acids has been designed
from optically pure α‐amino alcohols10 and α‐amino
acids, among other substrates.1-9 The 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
© 2019 Wiley Periodicals, Inc.
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.24-30 It 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,31-33 as 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.34,35 Among 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),44,45 in 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.46 Although 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 7,47 these heterocy-
cles were not able to undergo further reactions when
utilizing the thioenamide functionality as a nucleo-
phile.44-46 In 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.48 All 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
J
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
C13H15NO2 217.1103. Data for 2a (65:35): Rf
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 C13H15NO2 217.1103.
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 N2 atmosphere. 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 N2 atmosphere. 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 N2 atmo-
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: Rf 0.15 (hex-
1b:46,49 Rf 0.35 (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 1H
.
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): Rf 0.66 (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 1H 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 C13H15NO2 217.1103.
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 N2 atmo-
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. Rf = 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 C14H17NO2 231.1259.
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 N2 atmo-
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 H2 atmosphere. 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. Rf = 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 1H 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 N2 atmo-
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. Rf = 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 C13H17NO2 219.1259.
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 1H 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 H2 balloon. 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. Rf = 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 1H 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 C14H19NO2 233.1416.
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 N2 atmosphere. 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. Rf = 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 N2 atmosphere. 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. Rf = 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 C17H21NO3 287.1521.
(81:19) (0.215 g, 55%) as a pale yellow oil. Rf = 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 N2 atmosphere, 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. Rf = 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 H2 balloon 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
Rf = 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 C18H25NO3 303.1834.
(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 C15H18NO3 260.1287.
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. Rf = 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. Rf = 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
C15H18NO3 260.1287.
ν = 1764, 1644, 1450, 1389, 1369, 1298, 1230, 1199, 1079,
1030, 759, 698 cm−1 1H 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
N2 atmosphere. 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. Rf = 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 1H 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. Rf = 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 1H 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 C12H13NO3 219.0895.
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.
Rf
[α]D = +111.5 (c 0.200, CHCl3). IR (film): ν = 1739,
1413, 1353, 1227, 1051, 1025, 975, 733, 697 cm−1 1H
= 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 C16H19NO3 273.1365.
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. Rf = 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
C12H13NO3 219.0895.
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. Rf = 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 C17H21NO3 287.1521.
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 C16H19NO3 273.1365.
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): Rf = 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. Rf = 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 C17H23NO3 289.1678.
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. Rf = 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
C16H21NO3 275.1521.
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 N2 atmo-
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. Rf = 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 C16H17NO2 255.1259.
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. Rf = 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 C16H17NO2 255.1259.
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): Rf = 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 N2 atmosphere. 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): Rf = 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
C19H21NO3 311.1521.
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. Rf = 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 C17H19NO2 269.1416.
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 N2 atmosphere. 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: Rf = 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 1H 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 C18H23NO2 285.1729.
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. Rf = 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 1H 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 C17H19NO2 269.1416.
Data for 37a: Rf = 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 C18H23NO2 285.1729.
(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 N2 atmo-
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. Rf = 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: Rf = 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 1H 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 C15H17NO2 243.1259.
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 C18H23NO2 285.1729.
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: Rf = 0.44 (hexane/EtOAc, 7:3); m.p. 120‐
23
121°C. [α]D = +17.0 (c 0.100, CHCl3). IR (film):
Rf = 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
C15H17NO2 243.1259.

SANTOYO ET AL.
15
(0.117 g, 95%) as colorless needles. Rf = 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
C18H21NO3 299.1521.
(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 N2 atmosphere. 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. Rf = 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 C18H21NO3 299.1521.
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,50 SHELXT,50
or SIR9251 program as implemented in the WinGX
suite,52 and refined within WinGX using SHELXL.53 In
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.

SANTOYO ET AL.
17
all cases, ORTEP and packing diagrams were made with
ORTEP354 or 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 previous44-46 and 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,44 in 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.56 Optimizations 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).49 The 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‐ba
Entry
4
Base MW, W T, °C
t
1 (%)b 2 (%)b
1
2
3
4
5
4a Et3N ___
120
200
170
120
140
24 h
1a (75) 2a (0)
4a ___
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 14ba
Entry
Substrate
Cat. (%)
P, psi
Solvent
t, h
Productsb [%]c
1d
2
1b
Pd/C (10)
750
EtOAc
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
24
24
48
18
48
24
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
14b
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.49 To 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,45 when 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‐da
Entry
Substrate
8
T, °C
t, days
Productsb [%]c
1
1a
1b
1b
1b
1a
1a
1b
1b
8a
8a
8a
8a
8b
8b
8b
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
4d
0.2
5
5
6
60
5
7
60
7
8d
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,45 the 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,57-60 which 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‐ea
Entry
Substrate
8 (mol equiv)
T, °C
t, h
Productsb [%]c
1
2
1a
1b
8a (18.0)
8a (15.0)
140
160
24
24
33a/34a (20:80) [60]
33b/34b (83:17) [61]
33e/34e (86:14) [32]
3
4
5
1a
8b (5.0)
8b (5.0)
8a (3.0)
160
140
160
48
24
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).62,63 The 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‐5.44 Consequently, 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))67 level of DFT theory (Table 6) using
Gaussian 09.55 The 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.68 Hence, 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)
Åb
,
d(C‐‐‐C)
,
Product
Fractionc
TS
E0‡, u.a.
kcal/Mol
Åb
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
0.000
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)
Åb
,
d(C‐‐‐C)
,
Product
Fractionc
TS
E0‡, u.a.
kcal/Mol
Åb
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
0.000
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).70 Assuming
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 synthesis36-43,71 Hence, 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
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