Betti's base for crystallization-induced deracemization of substituted aldehydes: synthesis of enantiopure amorolfine and fenpropimorph

Article abstract of DOI:10.1039/c6ob02765b

The acid-promoted crystallization-induced diastereoisomer transformation (CIDT) of naphthoxazines derived from racemic O-protected 2-substituted 4-hydroxybutyraldehydes and enantiopure Betti's base allows the deracemization of the starting aldehydes with ee up to 96%. As an alternative, reduction with lithium aluminum hydride of the diastereoisomerically enriched naphthoxazines leads to enantioenriched primary amines. The utility of the latter strategy was demonstrated by applying it to the synthesis of enantioenriched fenpropimorph and to the first synthesis of enantiopure amorolfine, with ee up to 99.5%.

Full text of DOI:10.1039/c6ob02765b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Carella, G.
Ramos Ferronatto, E. Marotta, A. Mazzanti, P. Righi and C. Paolucci, Org. Biomol. Chem., 2017, DOI:
10.1039/C6OB02765B.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 11
View Article Online
DOI: 10.1039/C6OB02765B
Journal Name
ARTICLE
Betti’s base for crystallization-induced deracemization of
substituted aldehydes: synthesis of enantiopure amorolfine and
fenpropimorph.
Received 00th January 20xx,
Accepted 00th January 20xx
Andrea Carella, Gabriel Ramos Ferronatto, Emanuela Marotta, Andrea Mazzanti, Paolo Righi,
Claudio Paolucci*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The acid-promoted crystallization-induced diastereoisomer transformation (CIDT) of naphthoxazines derived
from racemic O-protected 2-substituted 4-hydroxybutyraldehydes and enantiopure Betti’s base allows the
deracemization of the starting aldehydes with ee up to 96%. As an alternative, reduction with lithium
aluminum hydride of the diastereoisomerically enriched naphthoxazines leads to enantioenriched primary
amines. The utility of the latter strategy was demonstrated by applying it to the synthesis of enantioenriched
fenpropimorph and to the first sysnthesis of enantiopure amorolfine, with ee up to 99.5%.
ethylbutyraldehyde was prepared, using the enantiopure
Enders auxiliary (SAMP), to synthetize plakortone B.12 From the
Introduction
The preparation of enantioenriched chiral molecules still is one
of the most important targets in organic synthesis. In particular,
the obtainment of epimerizable α-substituted aldehydes with
high enantiomeric excess is still an important challenge as they
are useful compounds for the preparation of higher-value
products. O-protected α-substituted 4-hydroxybutyraldehydes
have been obtained with high enantiomeric excess by different
methodologies and used for the synthesis of natural products.
α-Methyl derivatives were prepared from (E)-5-benzyloxypent-
2-en-1-ol by enantioselective Sharpless epoxidation followed by
regio- and stereoselective epoxide ring opening, and oxidative
cleavage of the diol with NaIO4,1-5 as well as by Evans chiral
auxiliaries, and by following the Meyers methodology7 with
(S,S)- and (R,R)-pseudoephedrine as enantiopure auxiliaries.
The above mentioned enantioenriched aldehydes were used to
synthetize biselyngbyolide A1, the C’D’E’F’ ring system of
maitotoxin,2 the synthon of aplyronine A,3 the bis-spiroacetal
core of the spirastrellolide B4 and the A/B-ring fragment of
gamberic acid.5 Moreover, the same aldehydes, obtained by the
Evans method were also used for the total synthesis of
allopumiliotoxin alkaloids 267A and 339B,6. At last, the Meyers
methodology7 was used for the synthesis of A-E subunit of
gamberic acid,8 as well as for the total syntheses of all eight
diastereoisomers of the (11R)-phytophthora hormone α19 and
(–)-callystatin A.10 Another enantiopure chiral auxiliary, a
camphor-derived lactam, was used to obtain the (R)-4-
benzyloxy-2-benzyloxymethylbutyraldehyde and used for the
total synthesis of (–)-rasfonin.11 O-protected (2R)-2-
above Evans methodology, Leahy’s group used (S)-4-
benzyloxazolidin-2-one to obtain an O-protected (S)-2-
allylbutyraldehyde for the total synthesis of rhizoxin.13 In this
context crystallization-induced diastereoisomer transformation
(CIDT)14 is a promising methodology that we had successfully
applied in the past for the deracemization of α-epimerizable
dihydrocinnamic aldehydes15 using enantiopure (S)-Betti’s base
1
as the chiral auxiliary, (Scheme 1).
R
H
Ph
N
Ar
Ph
NH2
OH
R
O
Ar
i
+
O
racemic
Betti's base 1
( )
ii
CIDT
R
H
Ph
N
Ar
*
R
O
Ar
iii
+
1
*
Dowex
supported-
O
ee
to 97%
up
Scheme 1.15 i. MeOH, rt, 2 h ii. CIDT 2-10% AcOH, 60-65% iii. Dowex 50Wx8-100 (2 g
mmol-1), rt, 14-16 h
The main features of this deracemization process are: (a) the
ready availability of both enantiomers16 of Betti’s base, from
relatively inexpensive reagents, which allows to obtain either
stereoisomer of the target aldehyde; b) in all the steps of the
sequence (naphthoxazines fomation; acid-promoted CIDT,
hydrolysis and recovery of the enantioenriched aldehyde and
chiral auxiliary) the products are isolated by simple filtration
a.Dipartimento di Chimica Industriale “Toso Montanari” – Alma Mater Studiorum –
Università di Bologna – Viale del Risorgimento, 4 – I-40136 Bologna (Italy)
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 11
ARTICLE
Journal Name
and c) Dowex® supported Betti’s base can be easily recovered whereas on 5e it does not occur and only the corresponding
View Article Online
DOI: 10.1039/C6OB02765B
PMB-deprotected naphthoxazine is isolated.
and reused with unchanged enantiomeric excess.
In this work, we show that the same strategy can be used for
the obtainment of enantioenriched O-p-methoxybenzyl (PMB)
α-substituted 4-hydroxybutyraldehydes (Scheme 2).
R
.
i 88-93%
H
Ph
N
R
.
ii 75-94%
OPMB
We also show that the diastereomerically enriched
naphthoxazines, obtained from CIDT step, can be selectively
reduced to yield several interesting primary amines in high
+
O
1
S
( )-
PMBO
O
4a-f
racemic
enantiomeric purity
(12a-d, Scheme 6). Finally, several
=
=
=
=
5a dr 35:1; 5b dr 40:1;
5c dr 14:1; 5d dr 50:1;
stereoisomers of fenpropimorph and amorolfine were prepared
>
=
5e dr 50:1; 5f dr 25:1
in high optical purity from two of the amines (12c,d; Table 1)
.
.
iii 85-97%
Results and discussion
Enantioenriched O-PMB-α-substituted 4-hydroxybutyraldehydes
-
1 • Dowex
S
( )
supported
+
The aldehydes 4a-f were prepared as showed in Scheme 2.
R
R
.
iv 81-96%
PMBO
PMB
OEt
OEt
PMBO
ii
i
HO
O
OH
O
86%
37-92%
O
R
O
2
;
;
4a
4c
4f
4b
(+)-
(+)-
;
;
er =
er
er =
er =
97.3:2.7;
(–)-
(+)-
(+)-
6a
6c
6f
96.7:3.3;
92.6:7.4;
96.6:3.4
6b
6d
(+)-
(–)-
(+)-
(–)-
(+)-
R
4d
=
er =
97.2:2.8;
iii
PMB
PMB
OEt
O
O
58-83%
3
O
a:
=
c:
O
4
R
benzyl; b: p-F-benzyl;
d: cinnamyl; f:
thiophen-2-methyl
allyl;
d.
cinnamyl-Br;a
Scheme 3. i. MeOH, rt, 2 h ii. CIDT: 2.5-20% AcOH in MeOH, 60 °C, 16-69 h for 5a,b,d,e;
rt, 70 h for 5c iii. Dowex 50Wx8-100 (1.2 g mmol-1); THF : AcOH : H2SO4 (0.06 M in water)
= 3 : 0.5 : 0.25 mL mmol-1; 3-5 h; iv. NaBH4 , MeOH, 0 °C
=
a.
c.
RX
BnBr;
-F-BnBr;
b. p
allyl-Br;
e.
3-bromomethyl-Py; f. 2-chloromethylthiophene
Scheme 2. i. O-PMB-trichloroacetamide, PTSA cat., c-hexane-DCM ii. a) LDA, -70 °C b) RX,
HMPA, -70 to -40 °C iii. DIBAL, DCM, -70 °C; a(for entry d.: LAH, THF, rt then DCM, PIPO,
KBr, NaClO at pH 9)
After the hydrolysis steps and filtration from the polymer-
supported Betti’s base, the aldehydes were purified by bulb to
bulb distillation under high vacuum. Betti’s base was recovered
enantiomerically pure from the filtered resin by basic washing.15
A sample of aldehydes 4a-d,f were reduced to alcohols 6a-d,f
and the enantiomeric enrichment was determined by HPLC on
chiral stationary phase. Finally, from comparison with literature
From the reaction of aldehydes 4a-f with (S)-Betti base 1, in
MeOH at room temperature, the corresponding
naphthoxazines (S,R,S)- and (S,R,R)-5a-f, in 1:1 ratio, were
isolated by filtration, Scheme 3. Fülöp and co-workers17 showed
by NMR analysis that 1,3-substituents on the naphthoxazinic
ring prefer the trans configuration.18 The diastereoisomeric
naphthoxazines 5a-f underwent an acid-promoted CIDT that
resulted in the enrichment of the less soluble isomer. The
subsequent step, an acid promoted hydrolysis, gave back the
enantioenriched aldehydes and resin-supported enantiopure
data of the optical rotation of diols 7a21 and 8c 22 it was possible
,
to assign a R configuration to the aldehydes 4a and 4c, Scheme
4, while the absolute configurations of aldehydes and 4b, 4d
and 4f were not determined.
Bn
Bn
Betti’s base.
The last step had been previously15 carried out
i
PMB
with non pre-washed Dowex 50Wx8-100 (2 g mmol-1) in a
THF : EtOAc : 2% aq.TsOH mixture (1 : 1 : 0.05; 4 mL mmol-1) at
room temperature in 13-15 hours.19 Later, we observed that by
using pre-washed resin the hydrolysis does not take place.
Therefore, we concluded that the free strong acid present in the
commercial resin might be responsible for the naphthoxazine
HO
O
73%
OH
OH
7a
R
(+)-( )-
6a
(+)-
i
ii
98%
PMB
HO
HO
O
72%
OH
OH
OH
7c
(–)-
6c
R 8c
(–)-( )-
(+)-
hydrolysis. After several attempts we established
a
reproducible hydrolysis protocol, independent from the free
acidity of a given resin lot. By using pre-washed resin20 (1.2 g
mmol-1) in a mixture of aq. H2SO4 (0.06 M), THF and acetic acid
(0.5 : 3 : 0.25 mL mmol-1), naphthoxazines hydrolysis occurs
faster, within 3-5 hours, and the aldehydes are obtained with
higher enantiomeric enrichment than with the previous
methodology.15 The release of aldehydes 4a-d,f by acidic
hydrolysis of the naphthoxazines 5a-d,f (Scheme 3) works well,
Scheme 4 i. DDQ (1 eq), DCM-H2O 20:1, -5 °C to rt ii. H2 (15 psi), PtO2 (4% w/w), MeOH
Enantiopure primary amines: synthesis of fenpropimorph and
amorolfine
It is known that 1,3-oxazines can undergo
hydrogenolysis to give amines.
a double
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 11
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C6OB02765B
R
R
*
H
H
R
Ph
N
Ar
ii. iii.
Ph
N
Ar
1. enantiopure
Betti base
2. CIDT
Ar
NH2.HCl
i
R
OH
11a-d
O
*
R''
10a-d
H
[
]
Ar
N
80-95%
84-89%
Ar
·
12a-d HCl
CHO
R
R'
racemic
Figure 1. General strategy to enantioenriched amines
enantioenriched
:
:
:
=
=
=
=
=
=
Ar benzo[
d
][1,3]dioxol-5-yl
R
R
12a
12b
12c
R
R
R
R
R
R
R
(
(
(
(
(
)-
)-
(
(
(
(
(
)-Me;
)-
=
i-Pr; Ar
[4-methoxy-3-(3-methoxypropoxy)]phenyl
=
Ar 4-(tert
S
R
S
S
R
S
)-
)-
)-Me;
)-Me;
-butyl)phenyl
-pentyl)phenyl
-pentyl)phenyl
:
:
=
Ar 4-(tert
12d
=
Ar 4-(tert
12d
)-Me;
)-
Envisaging the application of amines as possible useful building
blocks for biologically active compounds,23 and considering the
possibility to control the stereochemistry of the 2-alkyl group, a
synthetic route to enantiomerically enriched amines is
proposed from naphthoxazines 10a
enriched by CIDT as described in a previous paper,15 Figure 2,
and from both diastereoisomers (S,R,S)-and (S,R,R)-10d
Scheme 6. i. LiAlH4 , THF, rt, 2 h ii. MeOH, Pd/C, HCO2 NH4, 6 h iii. Et2 O, HCl 2N, 0 °C
Crystallization of naphthoxazine 10c from cyclohexane led to an
increase of its diastereoisomeric ratio from 85:15 to 94:6. The
product in the cyclohexane mother liquors was recovered and
recycled for another CIDT process. The carbon-oxygen bond
cleavage, on the enriched naphthoxazines 10a-d, yielded aryl
-c, diastereomerically
.
OMe
O
amines 11a-d, Scheme 6, and, for two of them, the
O
O
H
N
H
N
diastereoisomeric ratio was further slightly increased by
crystallization: 11a (from 97.5:2.5 to 98.4:1.6) in i-propanol and
11c (from 94.4:5.6 to 96.3:3.7) in n-hexane. A catalytic transfer
hydrogenation reaction was used to reduce C–N bond, and the
amines 12a-d were then isolated as the corresponding
hydrochloride salts by filtration from an ethereal solution,
Scheme 6. The enantiomeric ratios were determined by HPLC,
Ph
Ph
O
3
O
O
10b
10a
tBu
H
N
H
Ph
on chiral stationary phase, on amine derivatives 14a
and 14d, Scheme 7 and 8.
,
14b, 16c
Ph
N
O
O
,
,
O
R
10d
S
SR
)-
10c
i
(
NHBoc
Ar
NH2.HCl
O
Figure 2
R
er =
14a
(–)-( )-
(90%)
97.4:2.6
·
R
12a HCl
(–)-( )-
The tert-amyl derivatives 10d were prepared, as showed in
Scheme 5, by a Heck24 reaction on the 1-iodo-4-(tert-
pentyl)benzene.25 Contrary to the naphthoxazines 10a
-c,
NH.HCl
O
O
ii.
iii
derivatives 10d do not undergo a significant diastereoisomeric
enrichment by CIDT.26 However, both isomers were isolated by
flash-chromatography on silica gel, after a partial enrichment by
crystallization from isopropanol.
R
15a
(-)-( )-
(79%)
i
NH2.HCl
NHBoc
Ar
O
·
I
12c HCl
S
14c
S
(+)-( )-
ii.
iii
(+)-( )-
(85%)
i
ii iii
,
+
OH
NH.HCl
iv.
v.
NTs
62%
9
S
16c
(72%)
95.8:4.2
(+)-( )-
S
15c
(80%)
(+)-( )-
er =
H
H
N
Ph
N
Ph
Scheme 7 i. a) NaOH aq., t-BuOH b) Boc2O; ii. THF, NaH, MeI; iii. a) CF3CO2H; b) HCl 2N
in Et2 O; iv. Na2CO3 10% in H2O; v. TsCl, Py, DCM
+
O
O
,
,
, ,
S R R 10d
)-
S R S 10d
(+)-( )-
(–)-(
The absolute configuration of (+)-14d, Scheme 8, was
Scheme 5 i. MeCN, Pd(OAc)2, Et3 N, 100 °C, 3 h ii. (S)-Betti, MeOH, rt, 2 h, 97 % iii. flash
chromatography on silica-gel, 78-98 %
determined as S by X-ray diffraction analysis on single crystal
(Figure 3).29 The unit cell contains two independent molecules
with the same absolute configuration, related by a pseudo-
symmetry center.
Amines 12a-d were obtained as the corresponding
hydrochlorides from oxazines 10a-d by two consecutive
hydrogenolysis: the C–O bond was first cleaved by hydrides,
then benzylic C–N bond was cleaved by the action of
hydrogen,27 as showed in Scheme 6.28
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 11
ARTICLE
Journal Name
View Article Online
i
ii
(86%)
(86%)
DOI: 10.1039/C6OB02765B
HO
OH
HO
OBn
OTs
O
O
(
(S)
(S)
,
,
18
S S
(
)-
17
S S
)-
iii
(85%)
TsO
I
I
O
O
,
,
19
)-
S S
20
S S
(
(
)-
I
i
ii
iii
(92%), (88%), (85%)
I
HO
OBn
17
O
O
(R)
(S)
-
Figure 3. Structure of compound (+)-(S)-14d obtained by single crystal X-ray diffraction
analysis.29 The terminal methyl of the t-amyl group was disordered over three positions
and could not be modelled. Only one of the two independent molecules is shown.
,
meso
20
R
S
(
)-
Scheme 9 i. H2 , Pd/C, MeOH; ii. Py, TsCl, 0-4 °C; iii. acetone, NaI, reflux
We envisaged that the preparation of fenpropimorph and amorolfine
stereoisomers might be obtained via a double alkylation of amines
12c and 12d with diiodo compound (S,S)- and meso-20 (Scheme 9).
Diiodo derivatives 20 were easily obtained from known
monoprotected diols 17,32 via standard chemistry, as shown in
Scheme 9. We were then pleased to find that reaction of amines (S)-
12c, (S)- and (R)-12d with meso- and (S,S)-20 in refluxing acetonitrile
gave the fenpropimorph and amorolfine isomers in good yields, as
shown in Table 1.
O
O
3
i
NHTs
·
12b HCl
S
(+)-( )-
85%
O
R 14b
(+)-( )-
er =
:
99.8 0.2
NHTs
i
·
R 12d HCl
(–)-( )-
97%
R 14d
(–)-( )-
er =
:
99.4 0.6
Table 1. Synthesis of fenpropimorph and amorolfine stereosiomers
NHTs
i
2'
2
K
MeCN
2CO3,
·
12d HCl
S
(+)-( )-
N
70 °C, 20 h
91%
14d
S
(+)-( )-
er =
+
12c,d
20
6
:
O
99.7 0.3
R
or
21 22
Scheme 8 i. a) aq. Na2CO3, CH2Cl2 b) i-Pr2 NEt, TsCl, DCM, 0 °C to rt, 24 h
Fenpropimorph30 and amorolfine31 are two fungicides which
are obtained as isomeric mixtures of 3-aryl-2-methylpropane
amines with a cis-substituted morpholine moiety. The first one
is employed to control disease in cereal crops, whereas
amorolfine, is used as a hydrochloride salt in fungal nail and skin
infections, Figure 4.
Entry Amine 12
Diiodo 20
meso-20
R
product
Yield (%)
(–)-(S)-12c
er 97 : 3
1
2
3
4
5
6
t-butyl
(2R,6S,2’S)-21 82
(2S,6S,2’S)-21 90
(2R,6S,2’S)-22 86
(2S,6S,2’S)-22 86
(–)-(S)-12c
er 97 : 3
(S,S)-20
meso-20
(S,S)-20
meso-20
(S,S)-20
t-butyl
(–)-(S)-12d
er 99.8 : 0.2
(–)-(S)-12d
er 99.8 : 0.2
(+)-(R)-12d
er 99.4 : 0.6
(+)-(R)-12d
er 99.4 : 0.6
t-pentyl
t-pentyl
t-pentyl
t-pentyl
N
N
O
O
(2R,6S,2’R)-22 83
(2S,6S,2’R)-22 83
Amorolfine
Fenpropimorph
Figure 4
To our knowledge, in literature it is reported the synthesis of
only one of the enantiopure stereoisomers of fenpropimorph,
(S)-(–)-3-(4-tert-butyl)phenyl-1-N-(cis-2,6-dimethyl)-
morpholinyl-2-methylpropane, cis (S)-(–)-2130b or (2S,6S,2’S)-21
(Table 1).
The following is a short synthesis, in high enantiomeric excess,
of two stereoisomers of fenpropimorph and of four
stereoisomers of amorolfine, with ee’s up to 99%.
Conclusions
In summary, we demonstrated that the (S)-Betti’s base is an
efficient chiral auxiliary for deracemization of α-epimerizable 4-
hydroxybutyraldeydes such as 4a-d,f. The availability of both
enantiomers of Betti’s base from relatively inexpensive
materials and the ease of reactions and isolation of the products
makes this methodology a very straightforward source of
enantioenriched α-epimerizables aldehydes. Moreover, Betti’s
base, through a double hydrogenolysis on naphthoxazines 10a-
d, can be also a source of nitrogen for the preparation of amines
with high optical purity, such as 12a-d, which can be interesting
synthons to more complex molecules. As examples, we propose
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 11
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
(d, J = 4.8 Hz, 1H), 3.33 (m, 2H); 13C NMR (100 MHz, VCiDewCAl3rt)ic:leδO7n2lin.4e
(S,R,R), 72.3 (S,R,S), 68.1 (S,R,R), 67.8 (S,R,S),D3O9.I2: 1(0S.,1R0,3R9)/,C368O.9B(0S2,7R6,S5)B,
34.6 (S,R,R), 33.8 (S,R,S), 29.0 (S,R,S), 29.9 (S,R,R).
the synthesis of two stereoisomers of fenpropimorph, 21, with
er = 97:3, and four stereoisomers of amorolfine, 22, with er >
99.4:0.6.
(1S,3R,SR)-3-((E)-1-((4-Methoxybenzyl)oxy)-6-phenylhex-5-en-3-
yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine,
Experimental part
General information
19
(1S,3R,SR)-5d. It was isolated with 92% yield, as a white solid; [α]D
1
–30.0 (c 0.93, CH2ClCH2Cl); diagnostic signals: H NMR (600 MHz,
CDCl3): first isomer: δ 6.78 (m, 2H), 5.49 (s, 1H), 4.61 (d, J = 5.4 Hz,
1H), 4.29 (s, 2H), 3.39 (m, 2H); second isomer δ 6.73 (m, 2H), 5.46 (s,
1H), 4.68 (d, J = 3.8 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.21 (d, J = 11.4
Hz, 1H), 3.39 (m, 2H); 13C NMR (150 MHz, CDCl3): Irst-isomer δ 83.8,
67.9, 39.5, 33.9; second isomer: δ 83.7, 68.2, 39.9, 32.9.
Unless otherwise noted, materials and reagents were obtained
from commercial suppliers and were used without further
purification. THF was dried on Na-benzophenone and distilled
before use. Dichloromethane, diisopropylamine, diisopropyl-
ethylamine, hexamethylphosphoramide were freshly distilled
from CaH2 and pyridine from KOH. Air and moisture-sensitive (1S,3R,SR)-3-(4-((4-methoxybenzyl)oxy)-1-(pyridin-3-yl)butan-2-
yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine,
reaction were performed under a nitrogen atmosphere.
Purification of reaction products was carried out by flash
chromatography on silica gel (230−400 mesh). Yields are for
isolated compounds. Melting point were obtained with a Büchi
23
(1S,3R,SR)-5e. It was isolated with 86% yield, as a white solid; [α]D
1
–29.0 (c 1.21, CH2ClCH2Cl); diagnostic signals: H NMR (600 MHz,
CDCl3): first isomer δ 8.40-8.38 (m, 2H), 5.49 (s, 1H), 4.60 (d, J = 4.8
Hz, 1H), 4.19 (s, 2H), 3.28 (m, 2H); second isomer δ 8.28 (m, 1H), 8.16
(m, 1H), 5.46 (s, 1H), 4.49 (d, J = 3.2 Hz, 1H), 4.37 (d, J = 11.2 Hz, 1H),
4.29 (d, J = 11.2 Hz, 1H), 3.58 (m, 2H).
1
apparatus and are uncorrected. H and 13C NMR spectra were
recorded on Varian spectrometer and chemical shifts are in ppm
down-field of TMS. Optical rotations were measured on a Perkin
Elmer 341 polarimeter. Bulb to bulb distillations were done on
a Büchi GRK-50 Kugelrohr. Mass spectra were recorded on
(1S,3R)-3-(4-((4-methoxybenzyl)oxy)-1-(thiophen-2-yl)butan-2-yl)-
1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine, (1S,3R,SR)-
Waters micromass ZQ400. HR-MS (ESI) were recorded on 5f. It was isolated with 93% yield, as a white solid, [α]D24 –16.2 (c 1.0,
CH2ClCH2Cl); diagnostic signals: 1H NMR (600 MHz, CDCl3): first
Waters XEVO Q-TOF instrument. X-ray data were acquired on a
isomer δ 5.48 (s, 1H), 4.59 (d, J = 3.3 Hz 1H), 4.36 and 4.30 (ab-system,
J = 11.2 Hz, 2H), 3.71 (s, 3H), 3.56 (m, 2H), 1.66 (m, 1H); second
isomer δ 5.47 (s, 1H), 4.64 (d, J = 4.9 Hz, 1H), 4.24 and 4.22 (ab-system
J = 11.8 Hz, 2H), 3.73 (s, 3H), 3.34 (m, 2H); 13C NMR (150 MHz, CDCl3):
first isomer δ 83.3, 72.5, 68.2, 53.8, 42.3, 30.7, 28.8; second isomer
δ 83.4, 72.3, 67.9, 53.9, 41.7, 29.9, 28.7.
Bruker APEX-2 diffractometer.
Syntesis of naphthoxazines 5a-f: general procedure. (S)-1-(α-
Aminobenzyl)-2-napfthol 1 was suspended in methanol (5 mL, mmol-
1) in a round-bottomed flask. The racemic aldehyde was added in a
slight excess (1.01 eq) and the mixture was stirred at room
temperature for 2 h. The naphthoxazine was isolated, as 1:1
distereoisomeric mixture, by filtration.
CIDT of (1S,3R,SR)-3-(1-Arylalk-3-yl)-1-phenyl-2,3-dihydro-1H-
naphtho[1,2-e][1,3]oxazine, (1S,3R,SR)-5a-e: general procedure.
The 1:1 diastereoisomeric mixture of (1S,3R,SR)-5a-f was
suspended in methanol and acetic acid and was added as specified in
each case. The heterogeneous mixture was stirred at the
temperature and time reported below in each case. The products
were collected by filtration and diastereoisomeric ratios determined
by 1H NMR.
(1S,3R,SR)-3-(-4-((4-Methoxybenzyl)oxy)-1-phenylbutan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine, (1S,3R,SR)-5a.
It was isolated with 88% yield, as a white solid; [α]D20 –28.5 (c 0.88,
1
CH2ClCH2Cl); diagnostic signals H NMR (400 MHz, CDCl3): (S,R,R)-
isomer δ 5.51 (s, 1H), 4.64 (d, J = 4.7 Hz, 1H), 4.16 (s, 2H), 3.25 (m,
2H); (S,R,S)-isomer δ 5.47 (s, 1H), 4,56 (d, J = 3.3 Hz, 1H), 4.37 (d, J =
11.3 Hz, 1H), 4.29 (d, J = 11.3 Hz, 1H), 3.58 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 83.4 (S,R,R), 83.0 (S,R,S), 72.5 (S,R,S), 72.2 (S,R,R),
68.4 (S,R,S), 67.9 (S,R,R), 42.1 (S,R,R), 41.3 (S,R,S), 36.8 (S,R,R), 35.5
(S,R,S).
CIDT of (1S,3R,SR)-5a. CIDT condition: 5% AcOH in MeOH (10 mL
mmol-1) at 60 °C for 70 hrs. The isomer (1S,3R,R)-5a was isolated with
22
dr ≥ 35:1 and 90% yield; [α]D +25.1 (c 0.97, CH2ClCH2Cl); major
1
isomer (1S,3R,R): H NMR (600 MHz, CDCl3): δ 7.80-7.71 (m, 2H),
7.38-7.06 (m, 16H), 7.76 (m, 2H), 5,52 (s, 1H), 4.65 (d, J = 4.3 Hz 1H),
4,17 (s, 2H), 3.74 (s, 3H), 3.26 (m, 2H), 3.06 (dd, J = 13.4 and 4.6 Hz,
1H), 2.70 (bs 1H), 2.56 (dd, J = 13.4 and 9.1 Hz, 1H), 2,22 (m, 1H), 1,79
(m, 1H) e 1,65 (m, 1H); 13C NMR (150 MHz): δ 159.0, 152.9, 142.9,
140.2, 131.7, 130.5, 129.36, 129.35, 129.2, 129.0, 128.63, 128.4,
128.2, 128.1, 127.1, 126.5, 125.8, 123.0, 122.8, 119.3, 114.5, 113.6,
83.4, 72.4, 67.9, 55.2, 53.9, 41.3, 35.5, 28.8.
(1S,3R,SR)-3-(1-(4-Fluorophenyl)-4-((4-methoxybenzyl)oxy)butan-
2-yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine,
24
(1S,3R,SR)-5b. It was isolated with 91% yield, as a white solid; [α]D
1
–30.9 (c 1.12, CH2ClCH2Cl); diagnostic signals: H NMR (400 MHz,
CDCl3): first isomer δ 5.48 (s, 1H), 4.59 (d, J = 4.7 Hz, 1H), 4.38 (d, J =
12.2 Hz, 1H), 4.30 (d, J = 12.2 Hz, 1H); second isomer: δ 5.45 (s, 1H),
4.51 (d, J = 3.0 Hz, 1H), 4.20 (s, 2H); 13C NMR (100 MHz, CDCl3): first
isomer δ 67.8, 42.1; second isomer: δ 68.3, 41.3.
CIDT of (1S,3R,SR)-5b. CIDT condition: 5% AcOH in MeOH (10 mL
mmol-1) at 60 °C for 16 hrs. The naphthoxazines 5b were isolated with
(1S,3R,SR)-3-(1-((4-Methoxybenzyl)oxy)hex-5-en-3-yl)-1-phenyl-
2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine, (1S,3R,SR)-5c. It was
24
dr ≥ 40:1 and 94% yield; [α]D –82.2 (c 1.02, CH2ClCH2Cl); major
isomer: 1H NMR (600 MHz, CDCl3): δ 7.80-7.69 (m, 2H), 7.36-7.06 (m,
12H), 6.78-6.61 (m, 5H), 5.49 (s, 1H), 4.54 (d, J=3.3 Hz, 1H), 4.42 (d, J
= 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 3.76 (s, 3H), 3.62 (m, 2H),
2.75 (bs, 1H), 2.64-2.53 (m, 2H), 2.21 (m, 1H), 1.99 (m, 1H), 1.64 (m,
1H); 13C-NMR (100 MHz, CDCl3): δ 162.2, 159.8, 159.1, 153.0 143.0,
24
isolated with 93% yield, as a white solid; [α]D +9.6 (c 1.16,
CH2ClCH2Cl); diagnostic signals: 1H NMR (400 MHz, CDCl3): (S,R,R)-
isomer δ 5.46 (s, 1H), 4.79 (m, 1H), 4.72 (m,1H), 4.61 (d, J = 4.1 Hz,
1H), 3.53 (m, 2H); (S,R,S)-isomer δ 5.48 (s,1H), 5.07-4.90 (m, 2H), 4.58
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 11
ARTICLE
Journal Name
135.7, 135.7, 131.7, 130.4, 130.4, 130.3, 129.6, 129.3, 129.0, 128.6, aqueous H2SO4 (0.5 mL) were added in succession.VTiehweArrtieclseuOltnilninge
128.4, 128.2, 127.1, 126.4, 123.0, 122.9, 119.2, 114.9, 114.7, 114.5, mixture was stirred for 3-5 hrs until the complete consumption of the
DOI: 10.1039/C6OB02765B
113.6, 82.7, 72.5, 68.3, 55.2, 53.9, 42.1, 35.9, 28.7.
starting material (followed by TLC). The resin was filtered and
washed with Et2O (3 x 4 mL g-1 of resin). The organic solution was
CIDT of (1S,3R,SR)-5c. CIDT condition: 20% AcOH in MeOH (10 mL cooled with a water-ice bath and neutralized by addition of saturated
mmol-1) at rt for 70 hrs. The isomer (1S,3R,R)-5c was isolated with dr aqueous solution of Na2CO3. Transferred into a separator funnel,
20
= 14 :1 and 85% yield; [α]D +17.6 (c 1.17, CH2ClCH2Cl); major the organic layer was washed with water, brine and dried over
isomer (1S,3R,R)-5c: 1H NMR (600 MHz, CDCl3): δ 7.76-7.73 (m, 1H), Na2SO4. After solvent distillation, the non-racemic aldehydes 4a-d,f
7.71 (d, J = 8.9 Hz, 1H), 7.35-7.31 (m, 1H), 7.28-7.08 (m, 10H), 6.74 were purified by bulb to bulb distillation:
(m, 2H), 5.62 (m, 1H), 5.46 (s, 1H), 4.79 (m, 1H), 4.72 (m, 1H), 4.61 (d,
J = 4.1 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.31 (d, J = 11.2 Hz, 1H), 3.72 (R)-2-Benzyl-4-((4-methoxybenzyl)oxy)butanal, (R)-4a. After 3 hrs
(s, 3H), 3.53 (t, J = 6.7 Hz, 2H), 2.65 (bs, 1H), 2.20-2.08 (m, 2H), 1.98 and bulb to bulb distillation, (R)-4a was isolated as a colorless oil
21
(m, 1H), 1.87 (m, 1H), 1.62 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ (97% yield); [α]D –11.5 (c 1.12, CHCl3); 1H and 13C NMR are in
159.0, 152.8, 142.8, 136.4, 131.8, 130.5, 129.3, 129.2, 128.9, 128.6, agreement with those previously reported.
128.4, 128.0, 127.0, 126.4, 123.0, 122.9, 119.3, 116.6, 114.7, 113.6,
83.8, 72.4, 68.2, 55.2, 53.7, 39.2, 34.6, 28.92.
(+)-2-(4-Fluorobenzyl)-4-((4-methoxybenzyl)oxy)butanal, (+)-4b.
After 4 h and bulb to bulb distillation, (+)-4b was isolated as a
CIDT of (1S,3R,SR)-5d. CIDT condition: 5% AcOH in MeOH (10 mL colorless oil (93% yield); [α]D23 +13.4 (c. 1.21, CHCl3); 1H and 13C NMR
mmol-1) at 60 °C for 30 hrs. The naphthoxazines 5d were isolated with are in agreement with those previously reported.
20
dr = 50:1 and 89% yield; [α]D +2.4 (c 1.15, CH2ClCH2Cl); major
1
isomer: H NMR (600 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.72 (d, J = (R)-2-(2-((4-Metoxybenzyl)oxy)ethyl)pent-4-enal, (R)-4c. After 5 hrs
8.9 Hz, 1H), 7.37-7.32 (m, 1H), 7.30-714 (m, 16H), 7.11 (d, J = 8.9 Hz, and bulb to bulb distillation, (R)-4c was isolated as a colorless oil (85%
1H), 6.29 (d, J = 15.8 Hz, 1H), 6.05 (dt, J = 15.8 and 7.2 Hz, 1H), 5.53 yield); [α]D21 +5.2 (c 2.70, CHCl3); 1H and 13C NMR are in agreement
(s, 1H), 4,62 (d, J = 5.2 Hz, 1H), 4.29 (s, 2H), 3.75 (s, 3H), 3.39 (m, 2H), with those previously reported.
2.61 (bs, 1H) 2,49 (m, 1H) 2.32 (m, 1H), 2.08 (m, 1H), 1.90 (m, 1H),
1.72 (m, 1H); 13CNMR (150 MHz): δ 159.0, 152.8, 142.9, 137.5, 131.8, (+)-(E)-2-(2-((4-Methoxybenzyl)oxy)ethyl)-5-phenylpent-4-enal,
131.7, 130.6, 129.4, 129.2, 129.0, 128.6, 128.4, 128.3, 128.2, 128.1, (+)-4d. After 4 hrs and bulb to bulb distillation, (+)-4d was isolated as
127.1, 126.8, 126.4, 126.0, 123.0, 122.8, 119.3, 114.5, 113.7, 83.9, a colorless oil (95% yield); [α]D22 +3.2 (c 1.79, CHCl3); H and 13C NMR
1
72.3, 67.9, 55.2, 53.8, 39.5, 32.9, 29.1.
are in agreement with those previously above reported.
CIDT of (1S,3R,SR)-5e. CIDT condition: 2.5% AcOH in MeOH (5 mL (+)-4-((4-Methoxybenzyl)oxy)-2-(thiophen-2-ylmethyl)butanal, (+)-
mmol-1) at 60 °C for 48 hrs. The naphthoxazines 5e were isolated with 4f. After 5 hrs and bulb to bulb distillation, (+)-4f was isolated as a
20
dr > 50:1 and 90% yield; [α]D –79.2 (c 1.10, CH2ClCH2Cl); major colorless oil (91% yield); [α]D24 +15.4 (c 2.1, CHCl3); 1H and 13C NMR
isomer: 1H NMR (600 MHz, CDCl3): δ 8.28 (m, 1H), 8.16 (bs, 1H), 7.76- are in agreement with those previously above reported.
7.73 (m, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.33-7.20 (m, 8H), 7.09 (m, 2H),
7.05 (d, J = 9.0 Hz, 1H), 6.85 (m, 2H), 6.73 (m, 2H), 5.48 (bs, 1H), 4.50 Hydrolysis of diastereoisomerically enriched naphthoxazine 5e. The
(d, J = 3.5, Hz 1H), 4.37 (d, J = 11.3 Hz, 1H), 4.30 (d, J = 11.3 Hz, 1H), hydrolysis of diastereoisomerically enriched naphthoxazine 5e was
3.73 (s, 3H), 3.59 (m, 2H), 2.76 (bs, 1H), 2.65 (dd, J = 13.7 and 5.6 Hz, attempted as above described, but the resin-supported deprotected
1H), 2.60 (dd, J = 13.7 and 9.0 Hz, 1H), 2.23 (m, 1H), 1.96 (m, 1H) e naphthoxazine and 4-metoxy-benzyl alcohol (90% yield after flash-
1.63 (m, 1H); 13CNMR (150 MHz): δ 159.0, 152.8, 150.3, 147.1, 142.9, chromatography on silica gel) were the only isolated products.
136.6, 135.5, 131.7, 130.2, 129.4, 129.2, 129.0, 128.6, 128.4, 128.1,
127.2, 126.4, 123.1, 123.0, 122.8, 119.1, 114.4, 113.6, 82.6, 72.5, Reduction of enriched aldehydes 4a-d,f to enriched alcohols 6a-d,f:
68.1, 55.1, 53.8, 41.7, 33.9, 28.7.
general procedure. NaBH4 (2 eq) was added to a water-ice cooled
solution of enriched aldehydes 4a-d,f in MeOH (2 mL mmol-1). The
CIDT of (1S,3R,SR)-5f. CIDT condition: 2.5% AcOH in MeOH (10 mL resulting solution was stirred for 0.5 hours at 0 °C and 0.5 hours at
mmol-1) at 60 °C for 72 hrs. The naphthoxazines 5f were isolated with ambient temperature. After solvent evaporation the residue was
24
dr = 25:1 and 75% yield; [α]D –49.1 (c 1.20, CH2ClCH2Cl); major suspended in CH2Cl2 and the mixture neutralized34 with aqueous 0.1
isomer: 1H NMR (600 MHz, CDCl3): δ 7.25 (m, 1H), 7.71 (d, J = 9.0 Hz, N HCl. The separated organic layer was washed with water, brine and
1H), 7.33 (m,1H), 7.29 - 7.22 (m, 8H), 7.09 (m, 2H), 6.99 (dd, J = 5.0 dried over Na2SO4. After solvent evaporation the residue was
and 1.2 Hz, 1H), 6.72 (m, 2H), 6.66 (dd, J = 5.0 and 3.4 Hz, 1H), 6.19 purified by flash-chromatography on silica gel.35
(d, J = 3.4 Hz, 1H); 5.48 (s, 1H), 4.59 (d, J = 3.3 Hz, 1H), 4.36 and 4.30
(ab-system, J = 11.2 Hz, 2H), 3.71 (s, 3H), 3.56 (m, 2H), 2.91 (dd, J = (R)-2-Benzyl-4-((4-methoxybenzyl)oxy)butan-1-ol, (R)-6a. The
14.7 and 8.2 Hz, 1H), 2.85 (dd, J = 14.7 and 6.0 Hz, 1H), 2.73 (bs, 1H), alcohol was isolated as a colorless oil (96% yield) and er = 96.7:3.4
2.23 (m, 1H), 1.92 (m, 1H), 1.66 (m, 1H); 13CNMR (150 MHz): δ 159.0, determined by HPLC analysis using CHIRALCEL® OJ-H, hexane/i-
152.9, 142.9, 142.5, 131.8, 130.4, 129.4, 129.2, 129.0, 128.6, 128.4, PrOH= 90/10, 1mL min-1, 230nm, 25 °C: minor isomer tr= 40.0 min
23
128.1, 127.0, 126.6, 126.4, 125.7, 123.3, 123.0, 122.9, 119.2, 114.6, and major isomer tr= 43.8 min; [α]D +2.2 (c 2.27, CHCl3); 1H NMR
113.6, 83.3, 72.5, 68.2, 55.2, 53.8, 42.3, 30.7, 28.8.
(400 MHz) δ: 7.30-7.22 (m, 4H), 7.21-7.13 (m, 3H), 6.87 (m, 2H), 4.43
(s, 2H), 3.79 (s, 3H), 3.61-3.53 (m, 2H), 3.48-3.42, (m, 2H), 2.94 (bs,
Hydrolysis of diastereoisomerically enriched naphthoxazines 5a-e: 1H), 2.67 (dd, J = 13.7 and 7.3 Hz,m 1H), 2.52 (dd, J = 13.7 and 7.5 Hz,
genaral procedure. To a suspension of diastereoisomerical enriched 1H), 1.95 (m, 1H), 1.75-1.59 (m, 2H); 13C NMR (100 MHz, CDCl3) δ:
naphthoxazines 5a-f in THF (4 mL mmol-1),33 washed-dried20 Dowex 159.2, 140.4, 129.8, 129.3, 129.1, 128.2, 125.8, 113.7, 72.7, 68.3,
50WX8-100 (1.2 g mmol-1), AcOH (0.25 mL mmol-1) and 0.06 M
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 11
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
65.0, 55.1, 41.4, 38.0, 31.6; IR (film) cm-1: 3417.9, 2932.2, 2863.46, Heck’s methodology.24 After flash chromatography, on silica gel, and
View Article Online
1612.6, 1513.3, 1247.2, 1173.8, 1087.3, 1033.0, 818.8, 738.8, 700.2. bulb to bulb distillation, 3.62 g (62%) of aldehyde 9 were isolated as
DOI: 10.1039/C6OB02765B
1
a colorless oil. H NMR (600 MHz, CDCl3): δ 9.62 (d, J = 1.6 Hz, 1H),
(–)-2-(4-Fluorobenzyl)-4-((4-methoxybenzyl)oxy)butan-1-ol, (–)-6b. 7.25 (m, 2H), 7.09 (m, 2H), 3.05 (dd, J = 13.8 and 6.2 Hz, 1H), 2.66 (m,
The alcohol was isolated as a colorless oil (81% yield) and er = 1H), 2.58 (dd, J = 13.8 and 8.2 Hz, 1H), 1.62 (q, J = 7.4 Hz, 2H), 1.26 (s,
97.3:2.7 determined by HPLC analysis using Lux-Cellulose 2®, n- 6H), 1.08 (d, J = 7.0 Hz, 3H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (150
hexane/i-PrOH = 94/6, 0.7 mL/min, 230 nm, 20 °C: minor isomer tr MHz, CDCl3): δ 204.6, 147.6, 135.5, 128.6, 126.1, 48.0, 37.6, 36.8,
= 26.3 and major isomer tr = 27.6 min; [α]D23 –2.7 (c 1.58, CHCl3); 1H- 36.1, 28.4, 13.3, 9.1.
NMR (600 MHz) δ: 7.23 (m, 2H), 7.09 (m, 2H), 6.94 (m, 2H), 6.87 (m,
(1S,3R,SR)-3-(1-(4-(tert-Pentyl)phenyl)propan-2-yl)-1-phenyl-2,3-
dihydro-1H-naphtho[1,2-e][1,3]oxazine, 10d. In a round-bottomed
flask, (S)-1-(α-Amminobenzyl)-2-naphthol [(S)-1] (4.44 g, 17.8 mmol)
was suspended in MeOH (50 mL) then the aldehyde 9 (3.9 g, 17.8
mmol) was added. The suspension was stirred for 120 min, and the
1:1 diastereoisomeric mixture of naphthoxazines 10d (7.8 g, 97%),
was collected by filtration. The two isomers were separated by flash-
chromatography on silica gel (5% EtOAc in hexanes, Rf = 0.31 and Rf
= 0.26):
2H), 4.42 (s, 2H), 3.78 (s, 3H), 3.57-3.53 (m, 2H), 3.47-3.40 (m, 2H),
3.00 (bs, 1H), 2.64 (dd, J = 13.8 and 7.6 Hz, 1H), 2.49 (dd, J = 13.8 and
7.3 Hz, 1H), 1.89 (m, 1H) e 1.65 (m, 2H); 13C-NMR (150 MHz) δ:
161.2(d, J = 244 Hz), 159.3, 136.0(d, J = 3.2 Hz), 130.4(d, J = 8.1 Hz),
129.7, 129.4, 114.9(d, J = 21.1 Hz), 113.8, 72.8, 68.2, 64.8, 55.2, 41.2,
37.1, 31.6; IR (film) cm-1: 3418.1, 2931.9, 2856.2, 1612.6, 1509.2,
1248.6, 1220.4, 1088.4, 1034.3, 818.3. HR-MS (ESI): calculated for
C19H23FO3: [M+Na]+ 341.1529. Found: m/z 341.1530
(R)-2-(2-((4-Methoxybenzyl)oxy)ethyl)pent-4-en-1-ol, (R)-6c. The
alcohol was isolated as a colorless oil (89% yield) and er = 92.6:7.4
determined by HPLC analysis using CHIRALCEL® OD-H, n-hexane/i-
PrOH = 95/5, 1 mL/min, 230 nm, 20 °C: major isomer tr = 11.6 and
minor isomer tr = 13.5 min; [α]D24 –7.5 (c 1.26, CHCl3); 1H-NMR (400
MHz, CDCl3): δ 7.24 (m, 2H), 6.87 (m, 2H), 5.77 (m, 1H), 5.06-4.98 (m,
2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.61-3.53 (m, 2H), 3.51-3.43 (m, 2H),
2.81 (bs, 1H), 2.15-1.98 (m, 2H), 1.77-1.57 (m, 3H); 13C-NMR (100
MHz, CDCl3): δ 159.2, 136.8, 129.8, 129.4, 116.3, 113.8, 72.8, 68.3,
65.6, 55.2, 39.0, 36.2, 31.74. IR (film) cm-1: 3417.6, 2923.1, 2868.1,
1607.7, 1511.7, 1245.6.
(1S,3R)-3-((R)-1-(4-(tert-Pentyl)phenyl)propan-2-yl)-1-phenyl-2,3-
dihydro-1H-naphtho[1,2-e][1,3]oxazine, (1S,3R,R)-10d.36
First
eluted isomer was crystallized from isopropyl alcohol (yield 78%); mp
= 113-114 °C; [α]D23 –92.5 (c 0.94, CH2ClCH2Cl); 1H NMR (600 MHz,
CDCl3): δ 7.73-7.69 (m, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.33-7.16 (m, 8H),
7.07 (d, J = 9.0 Hz, 1H), 6.98 (m, 2H), 6.75 (m, 2H), 5.49 (s, 1H), 4.49
(d, J = 3.8 Hz, 1H), 2.68 (dd, J = 13.5 and 8.2 Hz, 1H), 2.44 (dd, J = 13.5
and 7.0 Hz, 1H), 2.40 (bs, 1H), 2.18 (m, 1H), 1.55 (q, J = 7.4 Hz, 2H),
1.20 (s, 6H), 1.00 (d, J = 7.0 Hz, 3H), 0.61 (t, J = 7.4 Hz, 3H); 13C NMR
(150 MHz, CDCl3): δ 153.0, 146.5, 142.9, 136.9, 131.7, 129.5, 128.9,
128.6, 128.8, 128.4, 128.1, 127.1, 126.4, 125.6, 123.0, 122.9, 119.2,
114.5, 83.6, 53.8, 39.1, 38.2, 27.4, 36.8, 28.40, 28.36, 19.6, 9.1.
(+)-(E)-2-(2-((4-Methoxybenzyl)oxy)ethyl)-5-phenylpent-4-en-1-ol,
(+)-6d. The alcohol was isolated as a colorless oil (92% yield) and er =
97.2:2.8 determined by HPLC analysis using Lux-Cellulose 2® n-
hexane/i-PrOH = 90/10, 1 mL/min, 230 nm, 20 °C: major isomer tr =
(1S,3R)-3-((S)-1-(4-(tert-Pentyl)phenyl)propan-2-yl)-1-phenyl-2,3-
dihydro-1H-naphtho[1,2-e][1,3]oxazine, (1S,3R,S)-10d.37 Second
eluted isomer was crystallized from isopropyl alcohol (yield 98%); mp
21
12.8 and minor isomer tr = 14.1 min; [α]D +7.0 (c 1.08, CHCl3); 1H
23
1
= 163-164 °C; [α]D +39.6 (c 1.06, CH2ClCH2Cl); H NMR (600 MHz,
CDCl3): δ 7.76-7.72 (m, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.34-7.18 (m, 8H),
7.15-7.12 (m, 3H), 7.00 (m, 2H), 5.49 (bs, 1H), 4.50 (d, J = 3.7 Hz, 1H),
2.92 (dd, J = 13.4 and 4.7 Hz, 1H), 2.46 (dd, J = 13.4 and 9.2 Hz, 1H),
2.45 (bs, 1H), 2.05 (m, 1H), 1.55 (q, J = 7.4 Hz, 2H), 1.23 (s, 6H), 0.94
(d, J = 6.7 Hz, 3H), 0.61 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ 152.9, 146.8, 142.9, 136.9, 131.7, 129.3, 129.0, 128.9, 128.6, 128.4,
128.1, 127.1, 126.4, 125.6, 123.0, 122.8, 119.3, 114.5, 84.5, 53.9,
39.3, 37.6, 37.5, 36.9, 28.44, 28.41, 13.6, 9.2.
NMR (400 MHz) δ: 7.34-7.22 (m, 6H), 7.22-7.16 (m, 1H), 6.90-6.85
(m, 2H), 6.38 (d, J = 15,7 Hz, 1H), 6.17 (dt, J = 15.7 and 7.3 Hz, 1H),
4.45 (s, 2H), 3.79 (s, 3H), 3.65-3.56 (m, 2H), 3.54-3,46 (m, 2H), 2,90
(bs, 1H), 2.31-2.23 (m, 1H), 2.22-2.13 (m, 1H), 1.87-1.61 (m ,3H); 13
C
NMR (100 MHz) δ: 159.3, 137.5, 131.6, 129.9, 129.4, 128.6, 128.5,
127.0, 125.9, 113.8, 72.8, 68.4, 65.7, 55.2, 39.6, 35.4 e 31.9. IR (film)
cm-1: 3418.59, 3025.35, 2931.14, 28458.15, 1612.78, 1513.51,
1248.43, 1088.96, 1035.27, 967.73, 820.71, 742.75, 693.95.
(-)-4-((4-methoxybenzyl)oxy)-2-(thiophen-2-ylmethyl)butan-1-ol,
(–)-6f. The alcohol was isolated as a colorless oil (91% yield) and er =
96.6:3.4 determined by HPLC analysis using CHIRALCEL® OD-H n-
hexane/i-PrOH = 95/5, 1 mL/min, 230 nm, 25 °C: major isomer tr =
24.9 and minor isomer tr = 27.1 min; [α]D24 –2.8 (c 1.10, CHCl3); 1H
NMR (600 MHz) δ: 7.24 (m, 2H), 7.11 (dd, J = 5.1 and 1.2 Hz, 1H), 6.90
(dd, J = 5.1 and 3.3 Hz, 1H), 6.87 (m, 2H), 6.77 (m, 1H), 4.43 (s, 2H),
3.78 (s, 3H), 3.62 – 3.55 (m, 2H), 3.51 -3.45 (m, 2H), 2.93 (m, 1H), 2.88
(dd, J = 15.0 and 7.1 Hz, 1H), 2.77 (dd, J = 15.0 and 7.4 Hz, 1H), 1.96
(m, 1H), 1.77 – 1.71 (m, 1H), 1.69 – 1.62 (m, 1H); 13C NMR (100 MHz)
δ: 159.2, 143.0, 129.8, 129.4, 126.7, 125.3, 123.3, 113.8, 72.8, 68.2,
64.9, 55.2, 41.6, 31.9, 31.5. HR-MS (ESI): calculated for C17H22O3S:
[M+Na]+ 329.1187. Found: m/z 329.1190.
Hydrogenolysis of naphthoxazines 10a-d to amino alcohols 11a-d:
general procedure. The naphthoxazines (10a-d) in anhydrous THF (5
mL mmol-1) was added to a cooled equimolar suspension of LiAlH4 in
anhydrous THF (1 mL, mmol-1) in 45 min, then heated to reflux. After
2 hours, the suspension was cooled to -10 °C and the reaction
quenched with a saturated aqueous NH4Cl solution (3 mL) and left
under stirring for two hours. The suspension was filtered and the
solid washed with CH2Cl2 and THF. The filtrate fractions were
concentrated dried under reduced pressure, the residue dissolved in
CH2Cl2, dried on Na2SO4 and the solvent distilled under reduced
pressure.
1-((S)-(((R)-3-(Benzo[d][1,3]dioxol-5-yl)-2-methylpropyl)amino)
(phenyl)methyl)naphthalene-2-ol, (+)-11a. The crude, obtained
from 10a was crystalized from isopropanol (25 ml mmol-1), (S,R)-11a
was isolated (80% yield) as white solid, dr = 50:1;38 mp = 122-123 °C;
[α]D20 +101.0 (c 1.2, CHCl3); 1H NMR (600 MHz, CDCl3): δ ppm 13.60
(bs, 1H), 7.77-7.67 (m, 3H), 7.41-7.37 (m, 2H), 7.32 (m, 1H), 7.26 (m,
2-Methyl-3-(4-(tert-pentyl)phenyl)propanal, 9. In a flask charged
with Pd(OAc)2 (90 mg, 0.39 mmol), 1-iodo-4-(tert-pentyl)benzene25
(4.866 g, 17.7 mmol), 2-methyl-2-propen-1-ol (1.63 g, 22.2 mmol),
Et3N (5.77 mL) in MeCN (5.8 mL) were left to react following the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
Journal Name
2H), 7.23-7.19 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), (q, J = 7.3 Hz, 2H), 1.59 (bs, 1H), 1.25 (s, 6H), 0.91 (d, J = 6.7 Hz, 3H),
View Article Online
6.60 (d, J = 1.5 Hz, 1H), 6.54 (dd, J = 7.9 and 1.6 Hz, 1H), 5.86 (dd, J = 0.64 (t, 7.4 Hz, 3H); 13C NMR (150 MHz, CDClD)O: δI: 1105.160.739, 1/C467O.1B,0124716.56B,
3
8.6 and 1.4 Hz, 2H), 5.57 (s, 1H), 2.77 (dd, J = 11.8 and 5.6 Hz, 1H), 136.7, 132.6, 129.6, 129.1, 128.8, 128.59, 128.56, 128.1, 127.8,
2.64 (m, 1H), 2.50 (dd, J = 13.8 and 6.7 Hz, 1H), 2.38 (dd, J = 13.8 and 126.4, 125.9, 122.3, 121.1, 120.1, 113.4, 64.4, 55.2, 40.6, 37.5, 36.9,
7.6 Hz, 1H), 1.79 (m, 1H), 1.61 (bs, 1H), 0.96 (d, J = 6.7 Hz, 3H); 13C 34.7, 28.4, 17.9, 9.1.
NMR 150 MHz (CDCl3): δ 156.6, 147.5, 145.8, 141.5, 133.8, 132.6,
129.6, 129.0, 128.8, 128.6, 128.0, 127.6, 126.4, 122.3, 121.8, 121.1,
120.1, 113.3, 109.2, 108.1, 100.7, 64.3, 55.3, 41.5, 35.4, 18.3.
Hydrogenolysis of arylamines 11a-d to amines hydrochloride
12a-d·HCl: general procedure. To the arylamines 11a-d, dissolved in
MeOH (15-25 mL mmol-1) were added 10% Pd on carbon (20% w/w)
and HCO2NH4 (4 eq). The suspension was kept at reflux and the
1-((S)-(((R)-2-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl-
butyl)amino)(phenyl)methyl)naphthalene-2-ol, (+)-11b. From the reaction was monitored by TLC. After 18-24 hours, the catalyst was
naphthoxazine 10b, with dr = 99.5:0.5, the amine (S,R)-11b (98% separated by filtration with Celite®. The filtrate was concentrated,
24
yield) was isolated as a sticky material; [α]D +122.8 (c 1.0, CHCl3); the crude product was dissolved in anhydrous CH2Cl2, dried on
1H NMR (600 MHz, CDCl3): δ 13.55 (bs, 1H), 7.72-7.66 (m, 3H), 7.36- Na2SO4 and concentrated. The crude product was then dissolved in
7.31 (m, 3H), 7.29-7.24 (m, 2H), 7.23-7.20 (m, 2H), 7.11 (d, J = 8.8 Hz, anhydrous Et2O (4 mL mmol-1) and the solution was cooled with an
1H), 6.73 (d, J = 8.2 Hz, 1H), 6.69 (m, 1H), 6.66 (dd, J = 8.2 and 1.8 Hz, ice bath. HCl 2M in Et2O was slowly added (2 eq) under nitrogen and
1H), 5.54 (s, 1H), 4.04 (m, 2H), 3.81 (s, 3H), 3.56 (t, J = 6.2 Hz, 2H), stirring. After 40 minutes, the hydrochloride salt was collected by
3.35 (s, 3H), 2.74 (m, 2H), 2.68 (dd, J = 14.1 and 6.4 Hz, 1H), 2.49 (dd, filtration, washed with anhydrous Et2O and dried under reduced
J = 14.1 and 8.3 Hz, 1H),2.08 (m, 2H), 1.83-1.74 (m, 2H), 1.62 (bs, 1H), pressure.
1
0.88 (d, J = 2.7 Hz, 3H), 0.87 (d, J = 2.7 Hz, 3H); H NMR (600 MHz,
(R)-3-(Benzo[d][1,3]dioxol-5-yl)-2-methylpropane-1-amine
CDCl3): δ 156.7, 148.4, 147.7, 141.5, 133.4, 132.5, 129.6, 129.0,
128.8, 128.6, 128.0, 127.7, 126.3, 122.3, 121.1, 120.9, 120.1, 114.0,
113.6, 111.9, 69.4, 66.1, 64.1, 58.6, 56.4, 49.8, 45.9, 35.8, 29.6, 28.6,
19.6, 18.9.
hydrochloride, (–)-[12a·HCl]. The ammine hydrochloride (–)-
[12a·HCl] (86% yield) was crystallized from isopropanol; mp = 180-
181 °C; [α]D21 –1.1 (c 1.0, MeOH); 1H NMR (600 MHz, CD3OD): δ 6.74
(d, J = 7.9 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J = 7.9 Hz, 1H), 5.89 (s, 2H),
1-((S)-(((S)-3-(4-(tert-Butyl)phenyl)-2-methylpropyl)amino)(phenyl) 2.92 (dd, J = 12.8 and 5.5 Hz, 1H) , 2.75 (dd, J = 12.8 and 8.5 Hz, 1H),
methyl)naphthalene-2-ol, (+)-11c. From naphthoxazine (S,R,S)-10c, 2.67 (dd, J = 13.6 and 6.4 Hz, 1H), 2.42 (dd, J = 13.6 and 8.3 Hz, 1H),
with dr = 94:6,39 the amine (S,S)-11c (78% yield) was isolated, from 2.07 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDOD3): δ
the crude, by crystallization from n-hexane with dr
= 96:4 150.0, 148.4, 135.1, 124.0, 111.1, 109.9, 103.0, 46.8, 41.9, 36.0, 18.0.
(determined by NMR) as a white solid; [α]D24 +167.1 (c 1.24, CHCl3);
1H NMR (600 MHz, CDCl3): δ 13.60 (bs, 1H), 7.73-7.67 (m, 3H), 7.43
(m, 2H), 7.35-7.19 (m, 7H), 7.16 (d, J = 8.7 Hz, 1H), 7.05 (m, 2H), 5.62
(s, 1H), 2.81 (bs, 1H), 2.71 (dd, J = 13.8 and 5.8 Hz, 1H), 2.67 (dd, J =
11.8 and 6.6 Hz, 1H), 2.39 (dd, J = 13.8 and 8.7 Hz, 1H), 2.07 (m, 1H),
1.96 (bs, 1H), 1.28 (s, 9H), 0.91 (d, J = 6.7 Hz, 3H); diagnostic signals:
(S,S)-isomer δ 5.62 and δ 5.59 (S,R)-isomer; 13C NMR 150 MHz
(CDCl3): δ 156.7, 148.8, 141.6, 136.9, 132.6, 129.6, 129.1, 128.8,
128.64, 128.60, 128.1, 127.7, 126.4, 125.2, 122.3, 121.1, 120.1,
113.5, 64.4, 55.2, 40.6, 34.7, 34.7, 31.4, 17.9.
(R)-2-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutane-
1-amine hydrochloride, (+)-[12b·HCl]. The amine hydrochloride (+)-
[12b·HCl] (88% yield) was isolated as a semisolid material; [α]D
23
+14.7 (c 1.25, CD3OD); 1H NMR (600 MHz, CD3OD): δ 6.89 (d, J = 7.6
Hz, 1H), 6.84(s, 1H), 6.77 (d, J = 7.6 Hz, 1H), 4.07(m, 2H), 3.80(s, 3H),
3.57(m, 2H), 3.34(s, 3H), 2.95(m,1H), 2.79(m,1H), 2.66(m, 1H),
2.48(m, 1H), 2.02(m, 2H), 1.93(m, 1H), 1.85(m, 1H), 1.01(d, J = 6.6 Hz,
3H), 0.95(d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDOD3): δ 150.7,
150.3, 134.6, 123.5, 116.6, 114.5, 71.1, 68.1, 59.8, 57.6, 46.6, 42.1,
35.2, 31.4, 28.8, 19.9, 19.3.
1-((S)-(((R)-2-Methyl-3-(4-tert-pentyl)phenyl)propyl)amino(phenyl)
methyl)naphthalene-2-ol, (1S,2R)-11d. From naphthoxazine (S,R,R)-
10c the amine (1S,2R)-11d (95% yield) was isolated as a non-
(S)-3-(4-(tert-Butyl)phenyl)-2-methylpropane-1-amine
hydrochloride, (+)-[12c·HCl]. The ammine hydrochloride (+)-
[12c·HCl] (80% yield) was crystallized from isopropanol; mp = 162-
164 °C; [α]D21 +1.6 (c 1.0, CD3OD); 1H NMR (600 MHz, CD3OD): δ 7.33
(m, 2H), 7.14 (m, 2H), 2.93 (dd, J = 12.6 and 5.5 Hz, 1H), 2.76 (dd, J =
12.6 and 8.4 Hz, 1H), 2.71 (dd, J = 13.4 and 6.5 Hz, 1H), 2.48 (dd, J =
13.4 and 8.2 Hz, 1H), 2.11 (m, 1H), 1.30 (s, 9H), 0.99 (d, J = 6.7 Hz,
3H); 13C NMR (150 MHz, CD3OD): δ 151.2, 138.2, 130.7, 127.2, 46.9,
41.8, 36.1, 35.8, 32.7, 18.1.
24
1
crystallizable glassy material; [α]D +114.4 (c 1.95, CHCl3); H NMR
(600 MHz, CDCl3): δ 13.61 (bs, 1H), 7.73-7.69 (m, 3H), 7.40 (m, 2H),
7.33 (m, 1H), 7.29-7.20 (m, 4H), 7.18 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H),
7.03 (m, 2H), 5.62 (s, 1H), 2.82 (dd, J = 11.9 and 5.6 Hz, 1H), 2.70-2.63
(m, 1H), 2.58 (dd, J = 13.8 and 6.7 Hz, 1H), 2.44 (dd, J = 13.8 and 7.6
Hz, 1H), 2.06 (m, 1H), 1.93 (bs, 1H), 1.59 (q, J = 7.3 Hz, 2H), 1.23 (s,
6H), 0.99 (d, J = 6.7 Hz, 3H), 0.64 (t, 7.3 Hz, 3H); 13C NMR (150 MHz,
CDCl3): δ 156.7, 147.2, 141.6, 136.8, 132.6, 129.6, 129.1, 128.8,
128.6, 125.5, 128.0, 127.7, 126.4, 125.9, 122.3, 121.1, 120.1, 113.4,
64.3, 55.5, 41.3, 37.5, 36.9, 35.1, 28.4 (2 C’s), 18.4, 9.1.
(R)-2-Methyl-3-(4-(tert-pentyl)phenyl)propane-1-amine
hydrochloride, (–)-[12d·HCl]. The hydrochloride salt of (–)-[12d·HCl],
was isolated by filtration as a white solid (yield 95%); mp = 161-164
°C; [α]D24 –0.6 (c 1.0, MeOH); 1H NMR (600 MHz, CD3OD): δ 7.31 (m,
2H), 7.17(m, 2H), 2.96 (dd, J = 12.6 and 5.4 Hz, 1H), 2.79 (dd, J = 12.6
and 8.5 Hz, 1H), 2.73 (dd, J = 13.6 and 6.4 Hz, 1H), 2.51 (dd, J = 13.6
and 8.3 Hz, 1H), 2.14 (m, 1H), 1.68 (q, J = 7.4 Hz, 2H), 1.29 (s, 6H),
1.02 (d, J = 6.7 Hz, 3H), 0.69 (t, J = 7.5 Hz, 3H); 13C NMR (150 MHz,
CD3OD): δ 149.4, 138.1, 130.7, 128.0, 46.9, 41.8, 39.4, 38.7, 35.9,
29.8 (2 C’s), 18.1, 10.3.
1-((S)-(((S)-2-Methyl-3-(4-tert-pentyl)phenyl)propyl)amino(phenyl)
methyl)naphthalene-2-ol (1S,2S)-11d. From naphthoxazine (S,R,S)-
10d the amine (1S,2S)-11d (89% yield) was isolated as a non-
24
1
crystallizable glassy material; [α]D +166.5 (c 1.18, CHCl3); H NMR
(600 MHz, CDCl3): δ 13.61 (bs, 1H), 7.70 (m, 3H), 7.43 (m, 2H), 7.34-
7.27 (m, 3H), 7.25-7.21 (m, 2H), 7.20 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H),
7.05 (m, 2H), 5.61 (s, 1H), 2.80 (m, 1H), 2.71 (dd, J = 13.7 and 6.1 Hz,
1H), 2.67 (m, 1H), 2.39 (dd, J = 13.7 and 8.6 Hz, 1H), 2.09 (m, 1H), 1.60
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
(S)-2-Methyl-3-(4-(tert-pentyl)phenyl)propane-1-amine
137.8, 128.8, 125.6, 71.72, 71.69, 65.0, 60.1, 59.8, 40.8, 37.5, 36.9,
hydrochloride, (+)-[12d·HCl]. The hydrochloride salt of (+)-[12d·HCl], 32.0, 28.4, 19.2, 18.0, 9.1. ESI-Ms [M+1]+ 31D8OmI:/1z01.10003V%9ie/,Cw[6MAOrt+iBc2l0e]2+O7n36l1i5nB9e
was isolated by filtration as a white solid (yield 92%) ; mp = 162-164 m/z, [M+Na]+ 23%, 340 m/z 1.5%, [M+K]+ 356 m/z 1%.
°C; [α]D24 +1.0 (c 1.05, MeOH); 1H and 13C NMR spectra were identical
(2S,6S)-2,6-Dimethyl-4-((S)-2-methyl-3-(4-(tert-pentyl)phenyl)
to (–)-12d.
propyl)morpholine, (–)-(2S,6S,S)-22. The title product was obtained
24
Preparation of the morpholines derivatives 21 and 22: general with 86% yield, as a colorless oil; [α]D –10.5 (c 1.75, CHCl3); NMR
procedure. To a solution of amine in dry MeCN (2.5 mL mmol-1), (600 MHz, CDCl3): δ 7.22 (m, 2H), 7.07 (m, 2H), 4.00 (m, 2H), 2.75
K2CO3 (2 eq) and diiodo derivative 20 (1.1 eq) were consecutively (dd, J = 13.4 and 5.0 Hz, 1H), 2.41 (m, 2H), 2.32 (dd, J = 13.4 and 8.2
added. The reaction was heated to 70 °C and monitored by TLC. After Hz, 1H), 2.13-2.09 (m, 3H), 2.05 (dd, J = 12.0 and 7.7 Hz, 1H), 1.94 (m,
20 h, the reaction was cooled and CH2Cl2 (6 volumes) was added. In 1H), 1.62 (q, J = 7.4 Hz, 2H), 1.27 (s, 6H), 1.23 (d, J = 6.6 Hz, 6H), 0.85
a separator funnel the reaction mixture was washed with water (d, J = 6.6 Hz, 3H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3):
(twice) and brine, dried on Na2SO4 and concentrated. The product δ 146.7, 137.7, 128.8, 125.7, 66.8(2 C’s), 65.0(2 C’s), 59.2, 40.7, 37.5,
was purified by flash chromatography:
36.9, 32.1, 28.4, 18.2, 17.8, 9.1. ESI-Ms [M+1]+ 318 m/z 100%, [M+2]+
319 m/z 22%, [M+Na]+ 340 m/z 32%, [M+K]+ 356 m/z 8%. HR-MS
(ESI): calculated for C21H35NO: [M+H]+ 318.2791. Found: m/z
318.2800.
cis
4-((S)-3-(4-(tert-Butyl)phenyl)-2-methylpropyl)-2,6-dimethyl
morpholine, cis-(–)-21. The title product was obtained with 82%
25
1
yield, as a light yellow oil; [α]D –1.2 (c 1.3, CHCl3); H NMR (600
MHz, CDCl3): δ 7.28 (m, 2H), 7.08 (m, 2H), 3.67 (m, 2H), 2.76 (dd, J = cis 2,6-Dimethyl-4-((R)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)
13.4 and 4.7 Hz, 1H), 2.70 (m, 1H), 2.66 (m, 1H), 2.28 (dd, J = 13.4 and morpholine, cis-(+)-22. The title product was obtained with 83%
8.6 Hz, 1H), 2.18 (dd, J = 12.2 and 7.2 Hz, 1H), 2.09 (dd, J = 12.2 and yield, as a colorless oil; [α]D24 +0.61 (c 3.70, CHCl3); NMR (600 MHz,
7.5 Hz, 1H), 1.97 (m, 1H), 1.69 (m, 1H), 1.66 (m, 1H), 1.31 (s, 9H), CDCl3): δ 7.22 (m, 2H), 7.07 (m, 2H), 3.67 (m, 2H), 2.76 (dd, J = 13.5
1.150 (d, J = 6.2 Hz, 3H), 1.147 (d, J = 6.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, and 4.7 Hz, 1H), 2.70 (m, 1H), 2.66 (m, 1H), 2.28 (dd, J = 13.5 and 8.8
3H); 13C NMR (150 MHz, CDCl3): δ 148.4, 137.9, 128.8, 124.9, 71.73, Hz, 1H) 2.18 (dd, J = 12.1 and 7.4 Hz, 1H), 2.10 (dd, J = 12.1 and 7.5
71.69, 65.0, 60.1, 59.8, 40.7, 34.3, 32.0, 31.4, 19.2(2 C’s), 18.0. ESI- Hz, 1H), 1.96 (m, 1H), 1.69 (m, 1H), 1.65 (m, 1H), 1.62 (q, J = 7.3 Hz,
Ms [M+1]+ 304 m/z 100%, [M+2]+ 305 m/z 19%, [M+Na]+ 326 m/z 2H), 1.27 (s, 6H), 1.15 (d, J = 2.1 Hz, 3H), 1.14 (d, J = 2.1 Hz, 3H), 0.85
22%, [M+K]+ 342 m/z 2%.
(d, J = 6.6 Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ 146.7, 137.8, 128.8, 125.6, 71.73, 71.69, 65.0, 60.1, 59.8, 40.8, 37.5,
36.9, 32.0, 28.4, 19.2, 18.0, 9.1. ESI-Ms [M+1]+ 318 m/z 100%, [M+2]+
319 m/z 22%, [M+Na]+ 340 m/z 15%, [M+K]+ 4 m/z 8%.
(2S,S)-4-((S)-3-(4-(tert-Butyl)phenyl)-2-methylpropyl)-2,6-dimethyl
morpholine, (–)-(2S,6S,S)-21. The title product was obtained with
90% yield, as a colorless oil; [α]D25 –11.8 (c 1.4, CHCl3); 1H NMR (600
MHz, CDCl3): δ 7.28 (m, 2H), 7.08 (m, 2H), 4.00 (m, 2H), 2.75 (dd, J = (2S,6S)-2,6-Dimethyl-4-((R)-2-methyl-3-(4-(tert-pentyl)phenyl)
13.5 and 4.9 Hz, 1H), 2.42 (m, 2H), 2.32 (dd, J = 13.5 and 8.2 Hz, 1H), propyl)morpholine, (–)-(2R,6S,R)-22. The title product was obtained
2.15-2.08 (m, 3H), 2.05 (m, 1H), 1.94 (m, 1H), 1.31 (s, 9H), 1.23 (d, J = with 83% yield, a colorless oil; [α]D24 –1.2 (c 1.85, CHCl3); NMR (600
6.5 Hz, 6H), 0.86 (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ MHz, CDCl3): δ 7.22 (m, 2H), 7.07 (m, 2H), 4.03 (m, 2H), 2.86 (dd, J =
148.4, 137.9, 128.9, 124.9, 66.7(2 C’s), 65.0 (2 C’s), 59.2, 40.7, 34.3, 13.5 and 4.3 Hz, 1H), 2.41 (m, 2H), 2.24 (dd, J = 13.5 and 8.9 Hz, 1H),
32.1, 31.4, 18.2, 17.8; ESI-Ms [M+1]+ 304 m/z 53%, %, [M+2]+ 305 m/z 2.18-2.12 (m, 3H), 2.03 (dd, J = 12.0 and 6.5 Hz, 1H), 1.91 (m, 1H),
18%, [M+Na]+ 326 m/z 100%, [M+1+Na]+ 327 m/z 26%, [M+K]+ 342 1.62 (q, J = 7.4 Hz, 2H), 1.27 (s, 6H), 1.25 (d, J = 6.4 Hz, 6H), 0.83 (d, J
m/z 4%. HR-MS (ESI): calculated for C20H33NO: [M+H]+ 304.2635. = 6.7 Hz, 3H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ
Found: m/z 304.2640.
146.7, 137.9, 128.8, 125.0, 66.8(2C’s), 64.9(2C’s), 59.2, 40.4, 37.5,
36.9, 32.3, 28.4, 18.3, 17.8, 9.1. ESI-Ms [M+1]+ 318 m/z 100%, [M+2]+
319 m/z 23%, [M+Na]+ 340 m/z 11%, [M+K]+ 356 m/z 2%.
cis-2,6-Dimethyl-4-((S)-2-methyl-3-(4-(tert-pentyl)phenyl)propyl)
morpholine, cis-(–)-22. The title product was obtained with 86%
yield, as a colorless oil; [α]D –2.0 (c 1.35, CHCl3); NMR (600 MHz,
24
CDCl3): δ 7.22 (m, 2H), 7.07 (m, 2H), 3.67 (m, 2H), 2.76 (dd, J = 13.4
and 4.9 Hz, 1H), 2.70 (m, 1H), 2.66 (m, 1H), 2.28 (dd, J = 13.4 and 8.6
Hz, 1H) 2.18 (dd, J = 12.1 and 7.2 Hz, 1H), 2.09 (dd, J = 12.1 and 7.5
Hz, 1H), 1.97 (m, 1H), 1.71-1.63 (m, 2H), 1.62 (q, J = 7.3 Hz, 2H), 1.27
(s, 6H), 1.15 (d, J = 2.0 Hz, 3H), 1.14 (d, J = 2.0 Hz, 3H), 0.85 (d, J = 6.5
Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 146.7,
Acknowledgements
This work was financially supported by the University of Bologna
(FARB Project “Catalytic transformation of biomass-derived
materials into high added-value chemicals” and RFO-2014
funds).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 11
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB02765B
1
2
3
4
5
6
7
Y. Tanabe, E. Sato, N. Nakajima, A. Ohkubo, O. Ohno and K. 22 N. Lee, Y.-W. Kim, Y. Chang, H. K. Kim, S. S. Jew, D.-K. Kim,
Suenaga, Org. Lett., 2014, 16, 2858-2861 Tetrahedron Lett., 1996, 37, 2429-2432
M. Kunitake, T. Oshima, K. Konoki, M. Ebine, K. Torikai, M. 23 A structural search (SciFinder®) of the 2-alkyl-3-aryl-propan-
Murata and T. Oishi, J. Org. Chem., 2014, 79, 4948-4962
K. Kobayashi, Y. Fujii, Y. Hirayama, S. Kobayashi, I. Hayakawa
and H. Kigoshi, Org. Lett., 2012, 14, 1290-1293
J. L.-Y. Chen and M. A. Brimble, J. Org. Chem., 2011, 76, 9417-
9428
H. Fuwa, K. Ishigai, T. Goto, A. Suzuki and M. Sasaki, J. Org.
Chem., 2009, 74, 4024-4040
1-amine moiety, Figure 1, returned over 6000 substances.
Over 2000 were related to biological applications, among
which anti-tumoral, anti-infective and central nervous
system related studies stood out.
24 S. A. Buntin and R. F. Heck, Organic Syntheses, coll. Vol. 7,
1990, 361
25 J.-G. Boiteau, B. Musicki, Patent EP1842848 A1, 2007
S. W. Goltein, L. E. Overman and M. H. Rabinowitz, J. Org. 26 The CIDT on 1:1 diastereoisomeric mixture of 10d (5% AcOH
Chem., 1992, 57, 1179-1190
MeOH, 5 mL mmol-1) at 60 °C for 30 hrs gave a 2.5:1
diastereoisomeric ratio, and around 60% of chemical yield
27 Hu’s group has performed a double hydrogenolysis with H2-
Pd/C, in MeOH or CH2Cl-CH2Cl, of the naphthoxazine
obtained from (d,l)-Betti base and 2,2-dimetoxy-
acetaldehyde: B. Liu, D. Su, G. Cheng, H. Liu, X. Wang and Y.
Hu, Synthesis, 2009, 3227-3232. Our attempts to run both
hydrogenolysis in one step, with H2-Pd/C in MeOH-
CH2ClCH2Cl gave mixture of products
A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky
and J. L. Gleason, J. Am. Chem. Soc., 1997, 119, 6496-6511
8
9
S. W. Roberts, J. D. Rainier, Org. Lett., 2007, 9, 2227-2230
R. Bajpai and D. P. Curran, J. Am. Chem. Soc., 2011, 133
,
20435-20443
10 N. F. Langille and J. S. Panek, Org. Lett., 2004, 6, 3203-3206
11 R. K. Jr Boeckman, J.E. Pero and D. J. Boehmler, J. Am. Chem.
Soc., 2006, 128, 11032-11033
12 X.-G. Xie, X.-W. Wu, H.-K. Lee, X.-S. Peng and H. N. C. Wong, 28 Only a small amount amines 12a-d were isolated just for a
Chem. Eur. J., 2010, 16, 6933-6941 NMR characterization, see experimental section
13 J. A. Lafontaine, D. P. Provencal, C. Gardelli and J. W. Leahy, 29 CCDC 1522373. See ESI for details
J. Org. Chem., 2003, 68, 4215-4234
30 CAS number 67564-91-4. a) S. A. Forsyth, H. Q. N.
14 J. Košmrlj, L. O. Weigel, D. A. Evans, C. W. Downey, J. Wu, J.
Am. Chem. Soc., 2003, 125, 3208-3209. For a review, see: K.
M. J. Brands, A. J. Davies, Chem. Rev., 2006, 106, 2711–2733.
For useful applications, see: W. H. J. Boesten, J.-P. G. Seerden,
B. de Lange, H. J. A. Dielemans, H. L. M. Elsenberg, B. Kaptein,
H. M. Moody, R. M. Kellogg, Q. B. Broxterman, Org. Lett.,
Guanaratne, C. Hadacre, A. McKeown and D. W. Rooney, Org.
Process Res. Dev., 2006, 10, 94-102. b) V. Vincović and V.
Šunjić, Tetrahedron, 1997, 53, 689-696. c) BASF SE Patent:
US2009/82562 A1, 2009. d) B. W. Hoffer, H. Voss, E. Schwab,
U. Rheude, G. Kaibel, M. Haake, J. Eberhardt and M. Karcher
Patent US2010/81804 A1 2010. e) Galderma S. A. Patent
WO2007/12983 A2, 2007. d) Galderma S.A. Patent
EP1935889 A1, 2008. f) BASF Aktiengesellschaft Patent
WO2006/114427 A1, 2006. f) Nihon Bayer Agrochem K.K.
Patent US5866141 A1, 1999.
2001, 3, 1121-1124; S. Karmakar, V. Byri, A. V. Gavai, R.
Rampulla, A. Mathur, A. Gupta Org. Process Res. Dev., 2016,
20, 1717–1720.
15 a) G. Rosini, C. Paolucci, F. Boschi, E. Marotta, P. Righi, F.
Tozzi, Green Chem., 2010, 12
,
1747-1757. b) M. 31 CAS number 78613-38-4. a) SYNTECO S.P.A. Patent
Srimannarayana, P. Righi, E. Marotta and C. Paolucci, Synth.
Commun., 2014, 44, 3450-3455
16 Y. Dong, R. Li, J. Lu, X. Xu, X. Wang, Y. Hu, J. Org. Chem., 2005,
70, 8617-8620
17 I. Szatmari, T. A. Martinek, L. Lazar and F. Fülöp, Tetrahedron,
2003, 59, 2877-2884
18 The cis isomers, in the naphthoxazines prepared, were 35 Racemic alcohols 6a-c, for HPLC analysis, were obtained by
US2011/301346 A1, 2011. b) ref. 28e. c) ref. 28d.
32 K. Ogasahara, K. Hirose, Y. Tobe and K. Naemura, J. Chem.
Soc., Perkin Trans. 1, 1997, 3227-3236
33 Due to its low solubility, 5e was suspended in 5.5 mL mmol-1
of THF
34 Alcohol deprotection occurs in acidic condition
presence in a range between 5 and 10%. From now on when
we talk about 2,4-substituted 1,3-naphthoxazines we always
refer to trans 2,4-subtituted
NaBH4 reduction of corresponding racemic aldehydes, as
described above. 6e come from LiAlH4 reduction of the
corresponding ester, as previously described
19 By comparing the diastereoisomeric ratio of enriched 36 About 8% of cis isomer, (1S,3S,R)-10d, is present with the
naphthoxazines (5a-d,f) with enantiomeric ratio of isolated
alcohols (6a-d,f) obtained from isolated aldehydes (4a-d,f), a
small amount of enantiomeric purity is lost during the last 37 About 6% of cis isomer, (1S,3S,S)-10d, is present with the
step, 1-5%
proton C3-H on naphthoxazinic ring at 6.78 ppm (down field
to (1S,3R,R)-isomer)
proton, on C3-H on naphthoxazinic ring at 7.00 ppm (down
field to (1S,3R,S)-isomer)
20 The commercial Dowex 50Wx8-100 was washed with
methanol, diethyl ether then dried under vacuum
21 G.P. Reid, K. W. Brear, D. J. Robins, Tetrahedron: Asymmetry,
2004, 15, 793-801
38 From 1H NMR (600 Mz), diagnostic signals: (S,R)-isomer δ
5.57 ppm and δ 5.61 (S,S)-isomer
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 11
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
39 A 85:15 diastereoisomeric mixture of 10a, VioewbtAartiincleedOnlianes
described in ref. 15, was increased by crystallization from n-
DOI: 10.1039/C6OB02765B
1
hexane (10 mL g-1) to 94:6, determined by H NMR, and the
isomeric mixture from the solvent recycled to another CIDT
process
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins