Stereoselective synthesis of 2-hydroxymorpholines and aminodiols via a three-component boro-Mannich reaction

Article abstract of DOI:10.1016/j.tet.2006.02.023

The three-component coupling of an 1,2-aminoalcohol, a 1,2-dicarbonyl compound and a boronic acid was investigated. The reaction is supposed to proceed through the formation of a heterocyclic iminium species followed by the addition of the organoboron derivative. The diastereoselectivity of this process is discussed. Best results were observed when the probable intermediate was generated from a preformed 3-phenylthiomorpholin-2-ol. Products of this three-component boro-Mannich could be readily converted to the corresponding aminodiols by reduction with lithium aluminium hydride.

Full text of DOI:10.1016/j.tet.2006.02.023

Tetrahedron 62 (2006) 4027–4037
Stereoselective synthesis of 2-hydroxymorpholines and aminodiols
via a three-component boro-Mannich reaction
a,
b
Fabienne Berree, AbdelMajid Debache, Yohann Marsac, Beatrice Collet,
a
a
*
´
´
Pascale Girard-Le Bleiza and Bertrand Carbonia
a
´
Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes 1, Bat 10 A, Campus de Beaulieu, 35042 Rennes CEDEX, France
b
´
´
Institut de chimie, Universite de Constantine, 25000 Constantine, Algerie
Received 3 January 2006; revised 7 February 2006; accepted 9 February 2006
Available online 6 March 2006
Abstract—The three-component coupling of an 1,2-aminoalcohol, a 1,2-dicarbonyl compound and a boronic acid was investigated. The
reaction is supposed to proceed through the formation of a heterocyclic iminium species followed by the addition of the organoboron
derivative. The diastereoselectivity of this process is discussed. Best results were observed when the probable intermediate was generated
from a preformed 3-phenylthiomorpholin-2-ol. Products of this three-component boro-Mannich could be readily converted to the
corresponding aminodiols by reduction with lithium aluminium hydride.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Based on the NMR structure of the complex between the
antibiotic paromomycin and the A-site ribosomal RNA, a set
of analogs 3 possessing a morpholino moiety was designed
and synthesized.4 In addition to their antioxidant activities,
nitric esters 4 appeared to release NO that can be exploited for
the inhibition of artherogenic mechanism (Fig. 2).5
The 2-hydroxymorpholine structural core is found as a basic
skeleton in a wide range of biologically active compounds.1
For example, Aprepitant 1, an orally active NK1 receptor
antagonist, shows potent and promising activities for the
treatment of chemotherapy-induced emesis and depression.2
(3,5-Difluorophenyl)morpholinol 2 selectively inhibits nor-
epinephrine uptake with antidepressant properties (Fig. 1).3
OH
O
HO
HO
NH2
O
N
NH2
O
HO
O
O
CF3
NH2
O
NH2
O
HO
F
N
R
3
4
CF3
F
Figure 2.
O
N
O
O
OH
Besides these remarkable pharmacological properties,
2-hydroxymorpholines are also direct precursors of mor-
pholine-2-ones, their oxidation products. These hetero-
cycles have proven to be versatile intermediates in
asymmetric synthesis, as it was amply demonstrated in the
stereocontrolled access to a-aminoacids.6
N
H
H
N
O
N
HN
1
2
Figure 1.
Few stereoselective preparations of 2-hydroxymorpholines
and derivatives have been hitherto reported. Main procedures
include the condensation of an 1,2-aminoalcohol with
a-halogeno-ketone,7 the reaction of an amine with an epoxide
Keywords: 2-Hydroxymorpholine; Multicomponent reaction; Boro-
Mannich condensation; Boronic acid; Chiral aminodiol.
8
and the reduction of morpholin-2-ones.9 Addition of
*
Corresponding author. Tel.: C33 2 23 23 57 35; fax: C33 2 23 23 69 39;
e-mail: fabienne.berree@univ-rennes1.fr
organometallicreagentstoN-cyanomethyl-1,3-oxazolidines10
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.023

´
F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4028
or 2-hydroxy-3-phenylthiomorpholines11 have been also
successfully used in non-racemic series. However, these
previous approaches are limited in versatility and restrict the
number of accessible structures.
2. Results and discussion
2.1. Synthesis of 2-hydroxymorpholines from achiral 1,2-
aminoalcohols
Using N-methylaminoethanol (R1ZR2ZH, R3ZMe), phe-
nylboronic acid (R4ZPh) and glyoxal (R5ZH) as models
reagents, we first screened several solvents including
ethanol, acetonitrile, toluene, tetrahydrofuran and methyl-
ene chloride. Of these, ethanol gave best results in terms of
yields and reproducibility. The subsequent reactions were
therefore carried out by simple mixing equimolar amounts
of the aminoalcohol, 1,2-dicarbonyl compound and boronic
acid in ethanol for 12 h at room temperature. With aryl and
alkenyl boronic acids, the formation of the expected
2-hydroxymorpholines 8 proceeded readily with satisfac-
tory yields and was compatible with the presence of various
substituents in different positions of the morpholine core
(Table 1). Owing to ring-chain tautomerism, all these
compounds were obtained as mixtures of diastereoisomers
with a ratio depending on R3–R5. In the case of MeB(OH)2,
glyoxal and N-benzylaminoethanol, the only identified
product was the tricyclic compound 10 (see Scheme 3) as
previously reported when the reaction was conducted in the
absence of the methyl boronic acid.17 We were also unable
to isolate any 2-hydroxy-1,4-oxazepane from N-methyl-
aminopropanol instead of N-methylaminoethanol.
Multicomponent methodologies are still attracting consider-
able interest due to their high flexibility, selectivity and
convergence.12 Among them, the boro-Mannich reaction,
widelydevelopedbyPetasisandco-workers,hasdrawnalotof
attentionfortheconstructionofnitrogen-containingsystems.13
With this in mind, we decided to study the three-component
condensationofa1,2-aminoalcool5,aboronicacid6anda1,2-
dicarbonylcompound7(Scheme 1).14 Theuseoforganoboron
compoundsisespeciallyvaluedduetotheireasilyaccessibility
or commercial availability, their tolerance for a broad range of
functional groups, and their air and water stability compared
withusualorganometallicsreagents.Weherepresentadetailed
study of the scope and limitations of this reaction, as well as its
stereochemical course in the case of chiral C-substituted
aminoalcohols. Furtherreduction ofthe resultingproduct8 led
to the corresponding aminodiols 9, some useful ligands in
asymmetriccatalysis.15 Duringthecourseofourwork,Pyeand
co-workers,fromMerckLaboratories,reportedanasymmetric
versionbasedontheuseofachiralgroupatthenitrogenatomof
thestartingaminoalcoholanditsapplication tothe synthesisof
Aprepitant 1.16
R1
R2
OH
O
O
R5
H
+
2.2. Mechanistic hypothesis
R5
OH
R1 R5
R1
R2
NH
R3
O
OH
R4
HO
R2
5
7
With regard to mechanism, the most plausible hypothesis
involves the initial reaction of the amino group of the 1,2-
aminoalcohol 5 with the aldehyde function of 7 to give the
key intermediate 11. The coordination between the hydroxyl
function of this cyclic iminium species and the boron atom
of 6 leads to the formation of a tetracoordinate boron
N
R4
N
R3
9
4
+
R
B(OH)2
R3
8
6
Scheme 1.
Table 1. One-pot three-component boro-Mannich reaction with achiral 1,2-aminoalcohols (R1ZR2ZH)
Entry
1
Product
R3
R4
R5
Yield (%)a
62
drb
8a
Me
Ph
H
95/5
O
2
8b
Me
H
65
70/30
OCH3
3
4
8c
Me
H
H
80
70
90/10
85/15
8d
PhCH2
Ph
5
8e
PhCH2
H
50
80/20
H3CO
S
6
7
8f
PhCH2
PhCH2
PhCH2
H
H
65
67
75/25
60/40
(E)
8g
Bu
Bu
8
9
8h
8i
Ph
Ph
(E)
H
75
57
75/25
85/15
Me
10
11
8j
PhCH2
PhCH2
Me
Ph
59
58
55/45
90/10
8k
Ph
a Yield of isolated product after purification by column chromatography.
b Determined by 1H NMR in CDCl3 solution.

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4029
derivative 12 that evolves via an irreversible transfer of the
R4 group to afford the 2-hydroxymorpholine 8 (Scheme 2).
Similar intramolecular migrations have been already
suggested in the case of 3-hydroxypyrrolidines or
salicylaldehyde.18
2.4. Synthesis of 2-hydroxymorpholines from chiral 1,2-
aminoalcohols
Having developed an efficient method for the preparation of
substituted 2-hydroxymorpholines, we then turned our
attention to the diastereoselectivity of this process with
chiral aminoalcohols. We first chose (1R)-N-methylphenyl-
glycinol and phenylboronic acid as model reagents. As
previously reported, the reaction was carried out in ethanol
at room temperature without any special precaution.
Compound 8m was isolated as a mixture of four
diastereoisomers (24/69/2/5) in a 86% yield after purifi-
cation by column chromatography. Stereoselectivity at the
new stereocenter C-3 was determined after conversion to the
corresponding aminodiols by reduction with LiAlH4. A
mixture of two epimers 90m and 900m was obtained in a 93/7
ratio (Scheme 4).
OH
R5
R5
O
OH
O
O
+
N
R3
NH
R3
5
8
7
11
4 B(OH)2
R
6
R5
O
O
OH
OH
B
R4
N
R3
The stereochemistry of the minor isomer 900m, and therefore
of the major one 90m, was determined by treatment of the
crude mixture resulting from the boro-Mannich reaction
with DBU at 60 8C for 24 h. Under these conditions,
epimerisation at C3 was complete to give the more stable
diequatorial compound, that was confirmed after reduction
with LiAlH4. Compound 900m has indeed an [a]DZ0. By
comparison, the other epimer 90m, which was synthesised
from the corresponding thioether 13a as described further in
Scheme 7 (Table 3, entry 1), has an [a]D C86.5 (c 1.35,
CH2Cl2). (Scheme 5).
12
Scheme 2.
2.3. Synthesis of 2-hydroxymorpholines from
an activated alkenylboronic ester
No expected 2-hydroxymorpholine was obtained in the one
pot procedure from an activated alkenyl boronic acid 5 (R4Z
CH]CH–CO2Me), which may be due to a competitive
Michael addition of the amine to the activated double bond.
This failure was successfully overcome by using perhydro-
4,8-dibenzyl-4,8-diaza-1,5,9,10-tetraoxoanthracene 10 as an
iminium precursor in accordance with the suggested mechan-
ism (Scheme 3).19 By way of comparison with the one pot
process, 8d (R4ZPh) was obtained from phenylboronic acid
in a better yield by this approach.
To expand the scope and utility of the sequence described in
Scheme 4, we envisioned using other boronic acids and 1,2-
aminoalcohols. The results of these three-component boro-
Mannich reactions followed by the reductive morpholine
ring opening are summarized in Table 2 (Scheme 6).
Whatever R1 and R2, the control of the configuration at C3 is
definitely more efficient for R4ZPh than for R4Zalkenyl
(entries 1 and 3, 4 and 5, 8 and 9). The replacement of
R2ZPh (entry 1) by R2ZiPr (entry 6) did not induce any
significant modification of the diastereoisomeric ratio.
Similarly, the same conclusion can be drawn when 5 was
substituted at a position a to the oxygen (R1ZMe or Ph,
entries 7–9), although it was less significant when the
phenyl group is located in a to the oxygen of the starting
material. The configuration of the new stereogenic center a
to the nitrogen for compounds 90p20 and 900t21 were
established from their 1H NMR spectra by comparison
CH2Ph
O
N
OH
OH
R4
O
N
O
O
N
O
N
R4B(OH)2
Et O,BF
2
3
6
(Z)
O
CH2Ph
CH2Ph
CH2Ph
10
R4
Ph
Compound
Yd (%)
d.r.
8d
84
76
75/25
CO2Me
60/40
8l
Scheme 3.
OH
O
O
H
H
O
OH
Ph
O
OH
Ph
+
+
Ph B(OH)2
+
Ph
NH
Me
86%
Ph
N
Ph
N
Me
8'm
Me
8"m
HO
Ph
OH
Ph
HO
Ph
OH
LiAlH4
68%
+
N
N
Ph
Me
Me
9'm/9"m = 93/7
9"m
9'm
Scheme 4.

´
F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4030
HO
Ph
OH
Ph
O
OH
Ph
R4
OH
OH
O
OH
Ph
LiAlH
4
DBU
89%
B
45%
Ph
N
N
O
Ph
N
O
N
R2
Me
R3
Me
Me
12
R1
8'm + 8"m
Scheme 5.
8"m
9''m
Figure 3.
with literature. For other aminodiols, it was done by analogy
with 90m, 90p or 90t. From a stereochemical point of view,
the formation of the major compound could be ascribed to a
preferred axial attack of the boron derivative that could be
favoured by the formation of the tetracoordinate boron
complex 12 (Fig. 3).
OH
O
OH
O
H
H
R4B(OH)2
BF3-Et2O
PhSH
+
Ph
NH
R3
5
Ph
N
R3
SPh
O
13a R3=Me
87%
To improve the stereoselectivity of this reaction, we decided
to generate the iminium intermediate from the correspond-
ing 5-phenyl-3-phenylthiomorpholin-2-ols 13, as previously
reported by Agami and co-workers.19 Compounds 13a and
13b, selected as examples, were first prepared by
condensation of the aminoalcools 5, with glyoxal and
thiophenol (Scheme 7).
13b R3=CH2Ph 60%
O
OH
R4
HO
Ph
OH HO
+
OH
R4
LiAlH4
R4
Ph
N
R3
Ph
N
R3
N
R3
As expected, the addition of a boronic acid in dichloro-
methane at K78 8C in presence of BF3–etherate led to the
corresponding 2-hydroxymorpholines 8 in good isolated
yields (Table 3). Reduction with LiAlH4 in ether gave the
corresponding aminoalcohols with good to excellent
8'+8"
Scheme 7.
9'
9"
Table 2. One-pot three-component boro-Mannich reaction/LiAlH4 reduction
Entry
2-Hydroxy-
morpholine
R1
R2
R3
R4
Ph
80C800
90C900
Yield (%)a,b
86
Yield (%)a
68
dec
86
1
2
8m
8n
H
H
Ph
Ph
Me
Me
47
56
40
Br
3
4
8o
8p
H
H
Ph
Ph
Me
75
76
78
66
4
Bu
Ph
PhCH2
Ph
Ph
72
5
6
8q
8r
H
H
Ph
PhCH2
Me
77
74
63
63
4
iPr
82
7
8
8s
8t
Me
Ph
H
H
Ph
Ph
43
66
76
75
60
80
PhCH2
PhCH2
9
8u
8v
Ph
H
H
56
51
72
—
50
—
Bu
10
Ph
PhCH2
Me
Me
a Yield of isolated product after purification by column chromatography.
b All the reactions were performed with optically pure products except 8s.
c Determined by 1H NMR.
1
1
1
1
R
O
N
OH
R
OH
NH
R
OH OH
glyoxal
R
OH OH
LiAlH
4
+
4
2
2
4
2
4
B(OH)
2
4
R
R
R
R
2
R
N
3
R
R
N
R
3
3
3
R
R
R
R
8' + 8"
9'
9"
Scheme 6.

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4031
Table 3. 2-Hydroxymorpholines 8 and aminodiols 9 from thioethers 13
4.2. 1-Synthesis of 2-hydroxymorpholines 8a–k
from achiral 1,2-aminoalcohols
R3
R4
8
90C900
Entry 2-Hydroxy-
morpholine
Yield Yield deb
General procedure. A mixture of 1,2-aminoalcohol 5
(1 mmol), boronic acid 6 (1 mmol) and 1,2-dicarbonyl
compound 7 (1 mmol) in ethanol (5 mL) was stirred at room
temperature for 12 h. The solvent was removed in vacuo to
give crude 8, which was purified by flash chromatography
(silica gel, ethyl acetate/heptane).
(%)a
(%)a
1
2
8m
8w
Me
Me
Ph
71
82
96
92
O98%
O98%
3
8o
Me
61
72
94
Bu
4
5
8p
8x
PhCH2 Ph
PhCH2
65
77
66
72
96
94
4.2.1. 4-Methyl-3-phenylmorpholin-2-ol 8a. Yield 62%,
mp 115–17 8C (diisopropylether). Major epimer: H NMR
1
a Yield of isolated product after purification by column chromatography.
1
b Determined by H NMR.
(300 MHz, CDCl3) d 1.99 (s, 3H), 2.42 (td, JZ4.1, 11.6 Hz,
1H), 2.71 (d, JZ11.7 Hz, 1H), 2.79 (d, JZ7.3 Hz, 1H),
3.80–3.94 (m, 2H), 4.51 (br s, 1H), 4.66 (d, JZ7.4 Hz, 1H),
7.27–7.35 (m, 5H). 13C NMR (75 MHz, CDCl3) d 43.2,
54.2, 63.9, 74.4, 97.0, 127.7, 128.3, 128.7, 138.3. Minor
epimer (characteristic signals): 1H (300 MHz, CDCl3) d
2.04 (s, 3H), 4.93 (br s, 1H). 13C NMR (75 MHz, CDCl3) d
43.8, 56.1, 58.7, 72.8, 92.9. Anal. Calcd for C11H15NO2: C,
68.37; H, 7.82; N, 7.25. Found: C, 68.39; H, 7.78; N, 7.40.
diastereoisomer excesses from 94 to O98%. This highlights
the fact that a modification of the iminium generation can
greatly improve the stereoselectivity of the reaction (entries
1, 3 and 4; Tables 2 and 3). The exact origin of this
significant amelioration remains unclear for the moment.
4.2.2. 3-(2-Furyl)-4-methylmorpholin-2-ol 8b. Yield
65%, mp 130–32 8C (diisopropylether). Major epimer: H
1
3. Conclusion
NMR (500 MHz, CDCl3) d 2.18 (s, 3H), 2.41 (ddd, JZ3.4,
9.0, 12.0 Hz, 1H), 2.78 (dq, JZ3.8, 11.8 Hz, 1H), 3.18 (d,
JZ5.9 Hz, 1H), 3.77 (br s, 1H), 3.87 (ddd, JZ2.9, 9.0,
11.8 Hz, 1H), 4.04 (dt, JZ3.8, 11.8 Hz, 1H), 4.99 (d, JZ
5.9 Hz, 1H), 6.39–6.41 (m, 2H), 7.45 (d, JZ0.9 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 43.2, 52.8, 63.0, 66.2, 94.4,
109.7, 110.2, 142.3, 150.9. Minor epimer (characteristic
In conclusion, the preparation of 2-hydroxymorpholines
was achieved, either in a one-pot process from aminoalco-
hol, glyoxal and boronic acid or from a preformed
3-phenylthiomorpholin-2-ol. Better results in term of
diastereoselectivity were obtained in the last case. More-
over, the corresponding chiral aminodiols were prepared by
reduction with lithium aluminium hydride. Further studies
focusing on the use of 2-hydroxymorpholines in the
synthesis of more elaborated substrates are underway in
our laboratory.
1
signals): H NMR (500 MHz, CDCl3) d 2.13 (s, 3H), 2.45
(ddd, JZ3.6, 9.5, 12.9 Hz, 1H), 3.58 (d, JZ1.3 Hz, 1H),
3.71 (dt, JZ3.8, 11.7 Hz, 1H), 4.22 (ddd, JZ3.0, 9.5,
12.1 Hz, 1H), 5.03 (s, 1H). 13C NMR (75 MHz, CDCl3) d
43.4, 53.1, 60.4, 64.8, 92.4, 110.0, 110.3, 142.5, 150.1.
Anal. Calcd for C9H13NO3: C, 59.00; H, 7.15; N, 7.65.
Found: C, 59.02; H, 7.29; N, 7.62.
4. Experimental
4.2.3. 3-(4-Methoxyphenyl)-4-methylmorpholin-2-ol 8c.
Yield 80%, mp 168–170 8C (diethylether/pentane). Major
epimer: 1H NMR (500 MHz, CDCl3) d 1.82 (br s, 1H), 2.07
(s, 3H), 2.45 (dt, JZ3.5, 11.5 Hz, 1H), 2.78 (d, JZ7.2 Hz,
1H), 2.81 (d, JZ11.7 Hz, 1H), 3.83 (s, 3H), 3.94 (dt, JZ1.7,
11.3 Hz, 1H), 4.01 (d, JZ11.3 Hz, 1H), 4.71 (d, JZ7.2 Hz,
1H), 6.92 (d, JZ8.6 Hz, 2H), 7.32 (d, JZ8.4 Hz, 2H). 13C
NMR (75 MHz, CDCl3) d 43.3, 54.3, 55.2, 64.2, 73.8, 97.4,
113.9, 129.7, 130.3, 159.3. Minor epimer (characteristic
4.1. General comments
1H NMR spectra (300 MHz) and 13C NMR (75 MHz) were
recorded on a Bruker AC 300 spectrometer, 1H NMR
spectra (200 MHz) and 13C NMR (50 MHz) on a Bruker
ARX 200 spectrometer, in CDCl3 solutions with Me4Si as
internal reference. Chemical shifts are given in parts per
million and coupling constants J in Hertz. Diethylether and
tetrahydrofuran were distilled from Na/benzophenone under
N2, dichloromethane from P2O5 under N2. Elemental
analyses were performed by the Microanalytical Laboratory
of the Centre National de la Recherche Scientifique, Gif sur
Yvette. High-resolution mass (HRMS) data spectrum was
recorded on a Varian MAT 311 spectrometer from the
Centre Regional de Mesures Physiques de l’Ouest.
Analytical thin-layer chromatography was performed on
Merck Silica Gel 60 F254 plates. Aminoalcohols 5 and
boronic acids 6 are commercially available, except the
precursor of 8l, whose preparation is described further.
Thioethers 13a and 13b were prepared as described by
Agami and co-workers.19
1
signals): H NMR (500 MHz, CDCl3) d 2.13 (s, 3H), 2.51
(dt, JZ3.6, 11.8 Hz, 1H), 2.90 (d, JZ11.7 Hz, 1H), 3.28 (s,
1H), 3.70 (d, JZ8.3 Hz, 1H), 4.32 (dt, JZ2.7, 11.7 Hz, 1H),
4.94 (d, JZ1.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 44.1,
55.4, 59.0, 72.0, 93.3, 113.8, 130.0. MS (EI) calcd for
C12H17NO3 [M]C: 223.1208. Found: 223.1206.
4.2.4. 4-Benzyl-3-phenylmorpholin-2-ol 8d.22 Yield 70%,
mp 148–150 8C. Major epimer: 1H NMR (300 MHz,
CDCl3) d 2.34 (td, JZ4.0, 10.8 Hz, 1H), 2.76 (dt, JZ2.0,
11.8 Hz, 1H), 2.98 (d, JZ13.4 Hz, 1H), 3.17 (d, JZ7.2 Hz,
1H), 3.40–4.24 (m, 4H), 4.78 (d, JZ7.2 Hz, 1H), 7.21–7.60
(m, 10H). 13C NMR (75 MHz, CDCl3) d 50.4, 58.7, 64.4,
72.8, 97.6, 126.9, 128.2, 128.3, 128.5, 128.7, 128.9, 138.3,
138.7. Minor epimer (characteristic signals): 1H NMR

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4032
(300 MHz, CDCl3) d 2.88 (d, JZ11.6 Hz, 1H), 4.16 (t, JZ
12.6 Hz, 1H), 5.01 (d, JZ6.8 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d 51.7, 59.1, 70.9, 93.3. MS (EI) calcd for
C17H19NO2 [M]C: 269.1416. Found: 269.1418.
(characteristic signals): 1H NMR (300 MHz, CDCl3) d 2.46
(dt, JZ3.7, 11.8 Hz, 1H), 2.98 (d, JZ11.8 Hz, 1H), 3.13 (d,
JZ4.8 Hz, 2H), 3.27 (dd, JZ5.1, 13.8 Hz, 1H), 3.56 (d, JZ
1.8 Hz, 1H), 3.64 (dd, JZ1.8, 12.0 Hz, 1H), 4.28 (dt, JZ
2.5, 11.8 Hz, 1H), 5.00 (d, JZ1.3 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 51.5, 57.5, 58.6, 70.7, 92.7. MS (EI)
calcd for C10H12NO2 [MKC3H5]C: 178.0868. Found:
178.0852.
4.2.5. 4-Benzyl-3-(2-methoxyphenyl)morpholin-2-ol 8e.
Yield 50%, mp 159–160 8C (diisopropylether). Major
1
epimer: H NMR (200 MHz, CDCl3) d 2.35 (td, JZ3.8,
11.5 Hz, 1H), 2.79 (dt, JZ1.9, 11.8 Hz, 1H), 2.99 (d, JZ
13.5 Hz, 1H), 3.48 (d, JZ8.9 Hz, 1H), 3.78 (s, 1H), 3.83 (d,
JZ5.6 Hz, 1H), 3.84–4.00 (m, 2H), 3.93 (s, 3H), 4.66 (dd,
JZ7.4, 8.8 Hz, 1H), 6.98 (d, JZ8.2 Hz, 1H), 7.10 (td, JZ
1.0, 7.5 Hz, 1H), 7.26–7.38 (m, 6H), 7.80 (dd, JZ1.7,
7.5 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 50.8, 55.6, 58.5,
63.9, 64.4, 98.6, 110.7, 121.2, 126.8, 127.9, 128.1, 128.4,
128.6, 128.7, 138.4, 158.1. Minor epimer (characteristic
signals): 1H NMR (200 MHz, CDCl3) d 2.81 (d, JZ13.6 Hz,
1H), 4.96 (br s, 1H). 13C NMR (50 MHz, CDCl3) d 52.2,
55.2, 58.9, 91.8, 120.7, 125.3, 157.2. Anal. Calcd for
C18H21NO3: C, 72.21; H, 7.07; N, 4.68. Found: C, 72.03; H,
7.24; N, 4.43.
4.2.9. 4-Benzyl-2-methyl-3-phenylmorpholin-2-ol 8i.
Yield 57%, mp 178–180 8C (diisopropylether). Major
1
epimer: H NMR (300 MHz, CDCl3) d 1.15 (s, 3H), 2.34
(dt, JZ4.0, 12.4 Hz, 1H), 2.77–2.83 (m, 1H), 2.84 (d, JZ
10.1 Hz, 1H), 3.38 (s, 1H), 3.59–3.67 (m, 1H), 3.79 (d, JZ
13.4 Hz, 1H), 4.08 (dt, JZ2.8, 12.4 Hz, 1H), 4.41 (br s, 1H),
7.20–7.56 (m, 10H). 13C NMR (75 MHz, CDCl3) d 25.1,
52.3, 59.2, 59.5, 75.7, 95.7, 127.0, 127.8, 127.9, 128.2,
128.4, 128.7, 137.5, 138.1. Minor epimer (characteristic
1
signals): H NMR (300 MHz, CDCl3) d 1.26 (s, 3H), 3.19
(d, JZ13.6 Hz, 1H), 3.46 (d, JZ13.6 Hz, 1H), 5,20 (s, 1H).
MS (EI) calcd for C18H21NO2 [M]C: 283.1572. Found:
283.1569.
4.2.6. 4-Benzyl-3-(2-thienyl)morpholin-2-ol 8f. Yield
65%, mp 100–102 8C (diisopropylether). Major epimer:
1H NMR (300 MHz, CDCl3) d 2.25 (td, JZ3.5, 11.8 Hz,
1H), 2.67 (ddd, JZ1.3, 3.0, 11.9 Hz, 1H), 3.05 (d, JZ
13.4 Hz, 1H), 3.54 (d, JZ5.8 Hz, 1H), 3.64–4.02 (m, 4H),
4.76 (d, JZ5.8 Hz, 1H), 6.93–7.29 (m, 8H). 13C NMR
(50 MHz, CDCl3) d 49.2, 58.8, 62.9, 66.4, 96.4, 125.7,
126.5, 127.2, 127.7, 128.3, 128.8, 137.9, 140.2. Minor
epimer (characteristic signals): 1H NMR (300 MHz, CDCl3)
d 3.09 (d, JZ13.1 Hz, 1H), 5.06 (br s, 1H). 13C NMR
(50 MHz, CDCl3) d 64.9, 93.6, 126.3, 126.8, 128.9. Anal.
Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09. Found:
C, 65.26; H, 6.26; N, 5.08.
4.2.10.
4-Benzyl-3-[(1E)-hex-1-en-1-yl]-2-methyl-
morpholin-2-ol 8j. Yield 59%, oil. Major epimer: 1H
NMR (200 MHz, CDCl3) d 0.96 (t, JZ7.0 Hz, 3H), 1.33–
1.47 (m, 4H), 1.36 (s, 3H), 2.12–2.24 (m, 2H), 2.81 (d, JZ
9.4 Hz, 1H), 3.00 (d, JZ13.6 Hz, 1H), 3.54 (dd, JZ13.1,
22.7 Hz, 2H), 3.93 (dd, JZ3.0, 12.1 Hz, 2H), 4.17 (d, JZ
13.4 Hz, 1H), 4.57 (br s, 1H), 5.41 (ddt, JZ1.3, 9.3,
15.4 Hz, 1H), 5.81 (dt, JZ5.1, 15.4 Hz, 1H), 7.29–7.41 (m,
5H). 13C NMR (50 MHz, CDCl3) d 13.8, 22.2, 24.7, 31.2,
32.1, 51.4, 58.7, 59.7, 73.8, 95.5, 127.0, 128.2, 128.4, 128.8,
137.5, 138.4. Minor epimer (characteristic signals): 1H
NMR (200 MHz, CDCl3) d 1.25 (s, 3H), 2.45 (dd, JZ3.7,
11.8 Hz, 1H), 2.66 (ddd, JZ1.2, 3.0, 11.7 Hz, 2H), 2.94 (d,
JZ10.7 Hz, 1H), 3.72 (dd, JZ3.8, 11.8 Hz, 1H), 4.04 (dd,
JZ3.8, 8.3 Hz, 1H), 4.14 (d, JZ11.8 Hz, 1H), 5.22 (s, 1H),
5.61 (dt, JZ6.3, 15.5 Hz, 1H). 13C NMR (50 MHz, CDCl3)
d 13.8, 22.1, 24.2, 31.4, 32.3, 45.1, 58.7, 59.9, 67.6, 95.2,
121.1, 127.2, 127.4, 128.3, 137.7, 138.9. MS (EI) calcd for
C18H27NO2 [M]C: 289.2042. Found: 289.2040.
4.2.7. 4-Benzyl-3-[(1E)-hex-1-en-1-yl]morpholin-2-ol 8g.
Yield 67%, oil. Major epimer: 1H NMR (300 MHz, CDCl3)
d 0.93 (t, JZ6.6 Hz, 3H), 1.28–1.48 (m, 4H), 2.10–2.17 (m,
2H), 2.28 (dt, JZ3.5, 8.2 Hz, 1H), 2.67 (dt, JZ3.4, 12.3 Hz,
1H), 2.80 (dd, JZ4.6, 8.8 Hz, 1H), 3.28 (d, JZ13.3 Hz,
1H), 3.63–3.71 (m, 1H), 3.86 (d, JZ13.3 Hz, 1H), 3.94–
4.02 (m, 1H), 4.70 (d, JZ4.6 Hz, 1H), 5.61 (dd, JZ8.8,
15.6 Hz, 1H), 5.75 (dt, JZ6.5, 15.5 Hz, 1H), 7.29–7.37 (m,
5H). 13C NMR (75 MHz, CDCl3) d 13.7, 22.0, 31.1, 32.1,
48.6, 58.4, 62.1, 68.2, 95.0, 125.4, 126.8, 128.0, 128.8,
137.4, 138.2. Minor epimer (characteristic signals): 1H
NMR (300 MHz, CDCl3) 2.73 (dd, JZ3.1, 6.5 Hz, 1H),
3.05 (dd, JZ2.0, 9.2 Hz, 1H), 3.16 (d, JZ13.4 Hz, 1H),
4.86 (d, JZ1.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 31.1,
32.0, 49.7, 58.6, 60.4, 68.2, 93.7, 126.9, 137.3, 137.6. MS
(EI) calcd for C17H25NO2 [M]C: 275.1885. Found:
275.1897.
4.2.11. 4-Benzyl-2,3-diphenylmorpholin-2-ol 8k. Yield
58%, mp 112–114 8C (diethylether/pentane). Major epimer:
1H NMR (200 MHz, CDCl3) d 2.51 (td, JZ3.8, 12.2 Hz,
1H), 2.85–2.95 (m, 2H), 3.53 (s, 1H), 3.81 (dd, JZ3.7,
12.0 Hz, 1H), 3.88 (d, JZ13.4 Hz, 1H), 4.31 (td, JZ2.8,
12.3 Hz, 1H), 4.58 (br s, 1H), 7.11–7.19 (m, 15H). 13C NMR
(50 MHz, CDCl3) d 52.4, 59.4, 59.9, 76.8, 97.3, 126.2,
127.1, 127.3, 127.4, 127.5, 127.6, 127.8, 128.3, 128.8,
136.4, 138.0, 141.0. Minor epimer (characteristic signals):
1H NMR (200 MHz, CDCl3) d 3.16 (d, JZ13.2 Hz, 1H),
4.08 (dd, JZ3.7, 11.3 Hz, 1H). 13C NMR (50 MHz, CDCl3)
d 52.7, 58.9, 60.2, 70.5, 96.4. Anal. Calcd for C23H23NO2:
C, 79.97; H, 6.71; N, 4.05. Found: C, 79.82; H, 6.67; N,
4.35.
4.2.8. 4-Allyl-3-phenylmorpholin-2-ol 8h. Yield 75%, oil.
Major epimer: 1H NMR (300 MHz, CDCl3) d 2.38 (dt, JZ
3.3, 11.6 Hz, 1H), 2.58 (dd, JZ8.1, 13.8 Hz, 1H), 2.87 (dt,
JZ1.8, 11.9 Hz, 1H), 3.09 (d, JZ7.1 Hz, 2H), 3.85 (dt, JZ
2.2, 11.4 Hz, 1H), 3.97 (d, JZ11.0 Hz, 1H), 4.41 (br s, 1H),
4.72 (d, JZ7.1 Hz, 1H), 5.09 (d, JZ11.6 Hz, 1H), 5.14 (d,
JZ4.4 Hz, 1H), 5.68–5.81 (m, 1H), 7.28–7.58 (m, 5H). 13C
NMR (75 MHz, CDCl3) d 50.2, 57.2, 63.9, 72.0, 97.1,
118.1, 127.6, 128.3, 128.9, 134.0, 138.1. Minor epimer
4.3. 2-Synthesis of 2-hydroxymorpholine 8l starting
from the tetraoxoanthracene 10
4.3.1. Perhydro-4,8-dibenzyl-4,8-diaza-1,5,9,10-tetraoxo
anthracene 10.19 To a solution of glyoxal (22 mmol, 40%

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4033
in water) in water (3 mL) was added dropwise N-benzyl-
ethanolamine (20 mmol) at 0 8C. The solution was stirred at
room temperature for 3 h and extracted with dichloro-
methane (3!20 mL). The organic phase was dried over
MgSO4, filtered and concentrated in vacuo. The residue was
washed with diethylether to give 10 as a white solid (yield
51.6, 59.2, 62.4, 67.2, 94.3, 125.9, 127.2, 128.3, 128.8,
137.3, 144.6, 166.1. Minor epimer (characteristic signals):
1H NMR (200 MHz, CDCl3) d 2.72 (td, JZ1.2, 4.5 Hz, 1H),
4.90 (d, JZ2.3 Hz, 1H), 6.07 (d, JZ16.1 Hz, 1H), 7.03 (d,
JZ1.6, 9.6 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 49.2,
59.3, 60.7, 66.7, 93.3, 125.4, 127.3, 128.9, 137.0, 165.9. MS
(EI) calcd for C15H19NO4 [M]C: 277.1314. Found:
277.1317.
1
70%), mp 190 8C. H NMR (200 MHz, CDCl3) d 2.18 (dd,
JZ1.6, 11.3 Hz, 2H), 2.86 (dt, JZ3.6, 11.5 Hz, 2H), 3.71
(dt, JZ2.7, 11.45 Hz, 4H), 3.72 (d, JZ13.8 Hz, 2H), 3.92
(dd, JZ2.8, 11.3 Hz, 4H), 3.95 (d, JZ13.8 Hz, 2H), 7.20–
7.34 (m, 10H). 13C NMR (50 MHz, CDCl3) d 42.8, 57.4,
65.2, 79.0, 94.1, 127.2, 128.3, 128.8, 138.2.
4.4. 3-One-pot synthesis of 2-hydroxymorpholines
8m–8v from chiral 1,2-aminoalcohols
4.4.1. (3R,5R)-4-Methyl-3,5-diphenylmorpholin-2-ol
1
4.3.2. [(1E)-3-Methoxy-3-oxoprop-1-en-1-yl]boronic
acid. At K10 8C, under N2, borane–methylsulfide complex
(6.6 mL, 66 mmol) was added dropwise to a solution of
a-pinene (22.6 mL, 141.2 mmol) in dry THF (20 mL). The
mixture was kept at 0 8C for 1 h and then allowed to reach
room temperature by removing the cold bath (formation of a
white suspension of diisopinocampheylborane). After 2 h,
the suspension of (Ipc)2BH was cooled to K30 8C. A
solution of methyl propiolate (6.25 mL, 70 mmol) in dry
THF (10 mL) was added dropwise. After 1 h at K30 8C, the
reaction mixture was allowed to warm to room temperature
(limpid solution). Five hours later, the mixture was cooled
to 0 8C and freshly distilled acetaldehyde (43.5 mL,
700 mmol, 10 equiv) was added dropwise. The solution
was kept at room temperature for 18 h and then 1 h at 40 8C.
The excess of acetaldehyde and about half of the solvent
were removed by distillation (15 mmHg). A mixture of
THF/water (5 mL/5 mL) was added. The mixture was
stirred overnight. After removing most of the solvent
under reduced pressure, 30 mL of pentane were added
give a solid, which was filtered and washed several times
with pentane. Yields varied from 30 to 55%. The boronic
acid is only soluble in DMSO that gives an ill-resolved
NMR spectrum. It was best characterized as its pinacol
derivative, obtained by addition of 1 equiv of pinacol in
diethylether in the presence of 2 equiv of methanol during
one night. Pinacol derivative.23 EbZ80–85 8C/0.1 mmHg
80m. From thioether 13a, yield 71%. Major epimer: H
NMR (200 MHz, CDCl3) d 1.84 (s, 3H), 3.66–4.12 (m, 5H),
5.19 (d, JZ2.6 Hz, 1H), 7.24–7.56 (m, 10H). 13C NMR
(50 MHz, CDCl3) d 39.6, 60.7, 65.7, 67.5, 93.9, 127.9,
128.0, 128.2, 128.3, 128.8, 130.3, 135.4, 138.3. Minor
epimer (characteristic signals): 1H NMR (200 MHz, CDCl3)
d 1.81 (s, 3H), 5.27 (d, JZ3.0 Hz, 1H). 13C NMR (50 MHz,
CDCl3) d 39.7, 60.2, 68.0, 71.2, 95.4, 133.6, 138.5. MS (EI)
calcd for C17H19NO2 [M]C: 269.1416. Found: 269.1415.
[a]2D0 C78.5 (c 0.9, CH2Cl2).
4.4.2. (3S,5R)-4-Methyl-3,5-diphenylmorpholin-2-ol
800m. From epimerisation, yield 89%, mp 150–52 8C
(diethylether/pentane). Major epimer: H NMR (300 MHz,
1
CDCl3) d 1.82 (s, 3H), 3.07 (d, JZ7.5 Hz, 1H), 3.06 (dd,
JZ3.0, 10.4 Hz, 1H), 3.45 (br s, 1H), 3.68 (dd, JZ10.5,
11.8 Hz, 1H), 3.87 (dd, JZ3.3, 11.7 Hz, 1H), 4.79 (d, JZ
7.5 Hz, 1H), 7.24–7.50 (m, 10H). 13C NMR (50 MHz,
CDCl3) d 40.8, 67.4, 70.8, 74.0, 97.9, 127.8, 127.9, 128.0,
128.4, 128.6, 128.8, 139.1. Minor epimer (characteristic
signals): 1H NMR (300 MHz, CDCl3) d 1.91 (s, 3H), 5.03 (s,
1H). 13C NMR (50 MHz, CDCl3) d 41.2, 64.6, 69.1, 72.1,
93.3. Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N,
5.20. Found: C, 75.96; H, 7.05; N, 5.12.
4.4.3.
(5R)-3-(4-Bromophenyl)-4-methyl-5-phenyl-
morpholin-2-ol 80nD800n. Yield 47%. Major diastereo-
isomer: RMN H (300 MHz, CDCl3) d 1.78 (s, 3H), 3.56
1
1
(Kugelrohr). H NMR (300 MHz, CDCl3) d 1.28 (s, 12H),
3.76 (s, 3H), 6.63 (d, JZ18.3 Hz, 1H), 6.76 (d, JZ18.3 Hz,
1H). 13C NMR (75 MHz, CDCl3) d 24.7, 51.6, 84.3, 134.4,
138.2, 166.4.
(dd, JZ3.7, 8.5 Hz, 1H), 3.69 (d, JZ2.7 Hz, 1H), 3.78 (dd,
JZ3.9, 11.8 Hz, 1H), 3.85 (br s, 1H), 4.05 (dd, JZ8.6,
11.8 Hz, 1H), 5.06 (d, JZ2.8 Hz, 1H), 7.21–7.44 (m, 9H).
RMN 13C (50 MHz, CDCl3) d 39.6, 60.6, 65.8, 66.7, 93.9,
122.1, 128.0, 128.3, 128.7, 131.2, 132.0, 133.1, 138.0.
Minor diastereoisomer (characteristic signals): RMN 1H
(300 MHz, CDCl3) d 1.76 (s, 3H), 5.24 (d, JZ3.0 Hz, 1H).
RMN 13C (50 MHz, CDCl3) d 39.7, 60.1, 67.2, 71.1, 95.3,
122.5, 138.2. MS (EI) calcd for C17H18NO2Br [M]C:
347.0521. Found: 347.0526.
4.3.3. Methyl-(2E)-3-(4-benzyl-2-hydroxymorpholin-3-
yl)acrylate 8l. To a solution of perhydro-4,8-dibenzyl-4,8-
diaza-1,5,9,10-tetraoxoanthracene 10 (1 mmol) and [(1E)-
3-methoxy-3-oxoprop-1-en-1-yl]boronic acid (2 mmol) in
dry methylene chloride (20 mL) was added dropwise BF3–
etherate (4.5 mmol) at K78 8C. The solution was stirred at
K78 8C for 0.5 h, warmed to room temperature and stirred
overnight. After addition of a saturated solution of NaHCO3
(15 mL) at K78 8C, the mixture was extracted with
methylene chloride (3!30 mL). The organic phases were
dried over MgSO4, filtered and concentrated in vacuo. Flash
chromatography using 30% ethyl acetate in heptane
4.4.4. (3R,5R)-3-[(1E)-Hex-1-en-1-yl]-4-methyl-5-phe-
nylmorpholin-2-ol 80o. From thioether 13a, yield 61%.
1
Major epimer: H RMN (300 MHz, CDCl3) d 0.92 (t, JZ
7 Hz, 3H), 1.36–1.38 (m, 4H), 2.02 (s, 3H), 2.14 (q, JZ
7.2 Hz, 2H), 3.27 (dd, JZ1.3, 9.3 Hz, 1H), 3.55–4.03 (m,
3H), 4.40 (br s, 1H), 4.67 (d, JZ7.6 Hz, 1H), 5.73 (dd, JZ
8.8, 15.5 Hz, 1H), 5.83 (dt, JZ8.7, 15.5 Hz, 1H), 7.29–7.36
(m, 5H). RMN 13C (75 MHz, CDCl3) d 13.8, 22.1, 31.2,
32.5, 39.5, 61.6, 64.5, 67.3, 93.3, 121.8, 128.4, 128.5, 128.6,
138.7, 141.9. Minor epimer (characteristic signals): RMN
(300 MHz, CDCl3) d 2.02 (s, 3H), 2.18 (q, JZ7.3 Hz, 2H),
1
afforded 8l as an oil (yield 76%). Major epimer: H NMR
(200 MHz, CDCl3) d 2.24 (td, JZ3.3, 8.6 Hz, 1H), 2.66 (td,
JZ1.5, 4.3 Hz, 1H), 2.94 (dd, JZ5.3, 8.8 Hz, 1H), 3.20 (br
s, 1H), 3.56–4.04 (m, 4H), 3.75 (s, 3H), 4.68 (d, JZ5.4 Hz,
1H), 6.16 (d, JZ15.9 Hz, 1H), 7.03 (d, JZ1.5, 8.8 Hz, 1H),
7.24–7.33 (m, 5H). 13C NMR (50 MHz, CDCl3) d 48.6,

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4034
3.33 (dt, JZ2.4, 6.8 Hz, 1H), 5.03 (d, JZ2.5 Hz, 1H). RMN
13C (75 MHz, CDCl3) d 22.2, 31.3, 32.3, 39.8, 61.1, 66.6,
71.2, 94.4, 119.4, 138.0, 138.2. MS (EI) calcd for
C17H25NO2 [M]C: 275.1885. Found: 275.1883.
RMN 13C (50 MHz, CDCl3) d 16.2, 19.8, 25.9, 38.8, 58.6,
59.5, 67.6, 93.0, 127.8, 130.0, 131.5, 135.7. Second
diastereoisomer (characteristic signals): 1H NMR
(200 MHz, CDCl3) d 0.79 (d, JZ6.8 Hz, 3H), 1.98 (s,
3H), 2.46–2.52 (m, 1H), 3.70 (dd, JZ3.0, 11.4 Hz, 1H),
5.25 (br s, 1H). RMN 13C (50 MHz, CDCl3) d 15.0, 19.6,
25.6, 57.2, 64.5, 68.3, 94.9, 133.9. Third diastereoisomer
(characteristic signals): 1H RMN (200 MHz, CDCl3) d 1.00
(d, JZ4.1 Hz, 3H), 1.00 (d, JZ4.1 Hz, 3H), 1.03 (d, JZ
4.0 Hz, 3H), 2.01 (s, 3H), 2.21–2.35 (m, 2H), 2.97 (d, JZ
7.6 Hz, 1H), 3.68 (t, JZ11.5 Hz, 1H), 3.97 (dd, JZ3.0,
11.6 Hz, 1H), 4.61 (d, JZ7.6 Hz, 1H). RMN 13C (50 MHz,
CDCl3) d 15.1, 19.5, 26.2, 38.9, 64.2, 64.9, 74.1, 97.7,
127.6, 128.3, 128.8, 140.2. MS (EI) calcd for C14H21NO2
[M]C: 235.1572. Found: 235.1572.
4.4.5. (3S,5R)-3-[(1E)-Hex-1-en-1-yl]-4-methyl-5-phenyl-
1
morpholin-2-ol 800o. Major epimer: H RMN (200 MHz,
CDCl3) d 0.88 (t, JZ6.5 Hz, 3H), 1.29–1.39 (m, 4H), 2.04
(s, 3H), 2.07 (q, JZ7.2 Hz, 2H), 3.22 (dd, JZ3.7, 10.7 Hz,
1H), 3.52 (dd, JZ3.8, 12.1 Hz, 1H), 3.79 (dd, JZ3.6,
11.8 Hz, 1H), 3.97–4.23 (m, 2H), 4.69 (d, JZ7.6 Hz, 1H),
5.36 (dd, JZ9.0, 15.5 Hz, 1H), 5.75 (dt, JZ6.7, 15.4 Hz,
1H), 7.25–7.36 (m, 5H). RMN 13C (50 MHz, CDCl3) d 13.9,
22.2, 31.1, 32.1, 40.2, 64.7, 69.2, 70.7, 93.8, 127.6, 127.7,
128.0, 128.6, 135.9, 138.6. Minor epimer (characteristic
signals): RMN (200 MHz, CDCl3) d 1.99 (s, 3H), 4.94 (d,
JZ1.8 Hz, 1H). RMN 13C (75 MHz, CDCl3) d 14.1, 22.7,
31.2, 32.2, 40.5, 67.6, 70.5, 72.5, 96.3, 137.2, 139.0. MS
(EI) calcd for C17H25NO2 [M]C: 275.1885. Found:
275.1870.
4.4.10. 4-Allyl-2-hydroxy-6-methyl-3-phenylmorpholine
80sD800s. Prepared from racemic 1-(allylamino)propan-2-
ol, yield 43%. Major diastereoisomer: 1H NMR (300 MHz,
CDCl3) d 1.33 (d, JZ6.5 Hz, 3H), 2.43–2.49 (m, 2H), 2.79
(dd, JZ6.2, 13.8 Hz, 1H), 3.02 (dd, JZ6.3, 13.9 Hz, 1H),
3.65 (d, JZ2.3 Hz, 1H), 4.28–4.38 (m, 1H), 5.15–5.22 (m,
3H), 5.76–5.89 (m, 1H), 7.34–7.56 (m, 5H). RMN 13C
(75 MHz, CDCl3) d 18.5, 51.9, 57.3, 65.7, 66.8, 92.9, 118.0,
127.8, 128.0, 130.2, 135.2, 135.3. Minor diastereoisomer
(characteristic signals): 1H NMR (300 MHz, CDCl3) d 1.36
(d, JZ7.3 Hz, 3H), 2.67 (dd, JZ6.7, 13.4 Hz, 1H), 3.91 (d,
JZ3.1 Hz, 1H), 3.96–4.06 (m, 1H). Anal. Calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.00;
H, 8.16; N, 6.01.
4.4.6. (3R,5R)-4-Benzyl-3,5-diphenylmorpholin-2-ol 80p.
From thioether 13b, yield 65%. Major epimer (character-
istic signals): 1H NMR (300 MHz, CDCl3) d 2.87 (br s, 1H),
3.00 (d, JZ14.3 Hz, 1H), 3.59 (d, JZ14.3 Hz, 1H), 3.88–
4.28 (m, 3H), 5.20 (d, JZ2.8 Hz, 1H), 7.28–7.57 (m, 15H).
13C NMR (50 MHz, CDCl3) d 52.3, 58.7, 63.1, 66.3, 94.6,
127.1, 128.1, 128.3, 128.4, 128.6, 128.7, 128.8, 128.9,
130.5, 138.4, 138.7, 138.9. Minor epimer (characteristic
signals): RMN (300 MHz, CDCl3) d 2.98 (d, JZ14.4 Hz,
1H), 5.32 (br s, 1H). 13C NMR (50 MHz, CDCl3) d 52.9,
59.1, 62.8, 71.8, 95.8. [a]2D0 K78.2 (c 1.1, CH2Cl2).
4.4.11. (6R)-4-Benzyl-2-hydroxy-3,6-diphenylmorpho-
line 80tD800t. Yield 66%, mp 157–58 8C (diethylether/
pentane). Major diastereoisomer: 1H NMR (300 MHz,
CDCl3) d 2.28 (t, JZ11.2 Hz, 1H), 2.83 (d, JZ5.2 Hz,
1H), 2.98 (d, JZ13.4 Hz, 2H), 3.23 (d, JZ7.4 Hz, 1H), 3.82
(d, JZ13.4 Hz, 1H), 4.88 (dd, JZ1.8, 10.5 Hz, 1H), 5.00
(dd, JZ5.3, 7.0 Hz, 1H), 7.24–7.63 (m, 15H). RMN 13C
(75 MHz, CDCl3) d 57.6, 58.6, 72.1, 76.1, 99.1, 126.3,
127.0, 127.9, 127.95, 128.2, 128.3, 128.6, 128.7, 128.9,
138.0, 138.8, 139.0. Second diastereoisomer (characteristic
4.4.7. (3S,5R)-4-Benzyl-3,5-diphenylmorpholin-2-ol 800p.
1
Major epimer (characteristic signals): H NMR (300 MHz,
CDCl3) d 4.78 (d, JZ7.5 Hz, 1H). 13C NMR (50 MHz,
CDCl3) d 51.7, 60.8, 62.9, 72.5, 98.4. Minor epimer
(characteristic signals): RMN (300 MHz, CDCl3) d 5.06
(d, JZ2.6 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 53.7.
4.4.8.
(2E,5R)-4-Benzyl-3-(2-phenylethylenyl)-2-
1
hydroxy-5-phenylmorpholine 80qD800q. Yield 77%. Mix-
ture of four diastereoisomers: 1H NMR (300 MHz, CDCl3) d
2.90–4.11 (m, 6H), 4.69 (d, JZ7.35 Hz, 1H) and 4.93 (d,
JZ1.7 Hz, 1H) and 4.98 (br s, 1H) and 5.01 (d, JZ2.2 Hz,
1H), 5.93 (dd, JZ9.3, 16.0 Hz, 1H) and 6.02 (dd, JZ8.7,
16.0 Hz, 1H) and 6.63–6.76 (m, 1HC1H), 6.40 (d, JZ
16.0 Hz, 1H) and 6.55 (d, JZ16.0 Hz, 1H) and 6.63 (d, JZ
16.0 Hz, 1H) and 6.72 (d, JZ16.1 Hz, 1H), 7.04–7.47 (m,
15H). RMN 13C (50 MHz, CDCl3) d 52.9 and 53.7 and 54.3
and 55.1, 60.1 and 60.6 and 61.2 and 62.4, 63.1 and 65.9 and
69.0 and 69.4, 65.0 and 70.8 and 72.1 and 73.2, 93.2 and
93.9 and 95.4 and 96.4, 119.6 and 122.3, 126.4–129.6, 132.9
and 134.7 and 136.8 and 139.5, 136.0 and 136.4 and 136.7
and 138.2. MS (EI) calcd for C24H23N [MKCH2O2]C:
325.18305. Found: 325.1844.
signals): H NMR (300 MHz, CDCl3) d 2.64 (dd, JZ2.8,
11.2 Hz, 1H), 3.04 (t, JZ11.0 Hz, 1H), 3.79 (d, JZ13.4 Hz,
1H), 4.05 (d, JZ13.4 Hz, 1H), 4.39 (br s, 1H), 4.72 (dd, JZ
2.6, 10.6 Hz, 1H), 5.44 (dd, JZ2.4, 9.1 Hz, 1H). RMN 13C
(75 MHz, CDCl3) d 59.1, 70.6, 93.6. Third diastereoisomer
(characteristic signals): 1H RMN (300 MHz, CDCl3) d 2.57
(dd, JZ9.3, 11.8 Hz, 1H), 3.18 (dd, JZ2.7, 11.8 Hz, 1H),
3.39 (d, JZ13.5 Hz, 1H), 4.25 (d, JZ13.4 Hz, 1H), 5.31
(dd, JZ5.7, 8.0 Hz, 1H). Anal. Calcd for C23H23NO2: C,
79.97; H, 6.71; N, 4.05. Found: C, 79.97; H, 6.97; N, 4.18.
4.4.12. (6R)-4-Benzyl-3-hexen-1-yl-2-hydroxy-6-phenyl-
morpholine 80uD800u. Yield 56%. Major diastereoisomer:
1H RMN (300 MHz, CDCl3) d 0.87 (t, JZ6.3 Hz, 3H),
1.18–1.36 (m, 4H), 1.99–2.15 (m, 3H), 2.57 (d, JZ11.0 Hz,
1H), 2.61 (d, JZ11.9 Hz, 1H), 3.10 (d, JZ9.3 Hz, 1H), 3.44
(d, JZ10.7 Hz, 1H), 3.50 (d, JZ14.8 Hz, 1H), 4.97 (br s,
1H), 5.07 (dd, JZ3.9, 10.7 Hz, 1H), 5.62 (dt, JZ6.6,
15.5 Hz, 1H), 5.83 (ddt, JZ1.2, 9.3, 15.5 Hz, 1H), 7.17–
7.32 (m, 10H). RMN 13C (50 MHz, CDCl3) d 13.8, 22.2,
31.4, 32.5, 52.2, 58.5, 63.3, 70.1, 93.6, 121.6, 126.3, 128.3,
128.4, 128.6, 128.9, 129.0, 137.6, 138.4, 139.8. Second
4.4.9. (5R)-2-Hydroxy-5-isopropyl-4-methyl-3-phenyl-
morpholine 80rD800r. Yield 74%. Major diastereoisomer:
1H NMR (200 MHz, CDCl3) d 0.81 (d, JZ7.0 Hz, 3H), 0.87
(d, JZ6.9 Hz, 3H), 1.82–1.95 (m, 1H), 2.05 (s, 3H), 2.46–
2.52 (m, 1H), 3.58–3.66 (m, 2H), 3.92 (t, JZ10.3 Hz, 1H),
4.22 (br s, 1H), 5.17 (d, JZ3.0 Hz, 1H), 7.16–7.47 (m, 5H).

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4035
diastereoisomer (characteristic signals): 1H NMR
(300 MHz, CDCl3) d 3.20 (dd, JZ2.6, 9.0 Hz, 1H), 4.73
(dd, JZ3.6, 10.3 Hz, 1H), 4.99 (d, JZ2.7 Hz, 1H). RMN
13C (50 MHz, CDCl3) d 31.5, 32.6, 52.7, 58.7, 64.2, 76.9,
94.8, 118.7, 126.1, 128.1, 128.2, 138.5, 141.9. Third
diastereoisomer (characteristic signals): 1H NMR
(300 MHz, CDCl3) d 4.71 (d, JZ10.1 Hz, 1H). RMN 13C
(50 MHz, CDCl3) d 31.2, 32.2, 69.1, 94.2, 136.7. Fourth
diastereoisomer (characteristic signals): 1H RMN
(300 MHz, CDCl3) d 5.01 (d, JZ2.6 Hz, 1H). RMN 13C
(50 MHz, CDCl3) d 75.9, 96.6, 137.9. MS (EI) calcd for
C23H29NO2 [M]C: 351.2198. Found: 351.2177.
40.1, 61.0 and 61.4, 64.8 and 71.6, 67.5 and 68.3, 93.0 and
94.5, 121.5 and 124.4, 127.9, 128.0, 128.1, 128.2, 128.5,
128.6, 129.2 and 131.2, 138.5. MS (EI) calcd for
C13H17NO2 [M]C: 219.1259. Found: 219.1244. [a]2D0
C41.9 (c 1.01, CH3OH).
4.5.2.
(5R)-4-Benzyl-2-hydroxy-5-phenyl-3-vinyl-
morpholine 80x. Yield 77%. Two epimers (50/50): 1H
NMR (500 MHz, CDCl3) d 2.91 (d, JZ11.6 Hz, 1H) and
3.19 (d, JZ11.6 Hz, 1H), 3.27 (d, JZ13.4 Hz, 1H) and 3.32
(d, JZ13.4 Hz, 1H), 3.60–3.74 (m, 2HC2H), 3.96–4.11 (m,
2HC2H), 4.49 (d, JZ10.3 Hz, 1H), 4.94 (d, JZ9.5 Hz, 1H)
and 4.98 (dd, JZ2.5, 11.5 Hz, 1H), 5.21 (dd, JZ1.7,
17.3 Hz, 1H) and 5.23 (dd, JZ1.9, 17.3 Hz, 1H), 5.53 (dd,
JZ1.8, 10.4 Hz, 1H) and 5.70 (dd, JZ7.9, 10.4 Hz, 1H),
6.25–6.40 (m, 1HC1H), 7.26–7.52 (m, 10HC10H). 13C
NMR (50 MHz, CDCl3) d 52.7 and 53.5, 58.8 and 60.0, 60.5
and 61.8, 62.9 and 63.4, 65.0 and 72.1, 93.1 and 94.8, 122.2
and 125.2, 126.9 and 127.2, 128.0, 128.1, 128.2, 128.5,
128.6, 128.65, 128.7, 128.9, 131.0, 137.8 and 138.1, 138.9
and 139.0. MS (EI) calcd for C19H21NO2 [M]C: 295.1572.
Found: 295.1567. [a]2D0 C37.2 (c 1.04, CH2Cl2).
4.4.13. (3E,5R)-4-Benzyl-2-hydroxy-3-(1-methylpropen-
1-yl)-5-phenylmorpholine 80vD800v. Yield 51%. Major
diastereoisomer: 1H RMN (300 MHz, CDCl3) d 1.67 (d, JZ
6.7 Hz, 3H), 1.83 (s, 3H), 3.09 (d, JZ14.6 Hz, 1H), 3.28 (d,
JZ5.8 Hz, 1H), 3.52 (br s, 1H), 3.71 (d, JZ14.6 Hz, 2H),
3.82 (t, JZ3.7 Hz, 1H), 4.07 (dt, JZ3.6, 11.6 Hz, 2H), 5.00
(d, JZ5.7 Hz, 1H), 5.58 (q, JZ6.6 Hz, 1H), 7.25–7.54 (m,
10H). RMN 13C (75 MHz, CDCl3) d 13.1, 13.2, 52.4, 57.4,
67.7, 68.2, 95.1, 126.6, 127.4, 127.9, 128.1, 128.2, 128.5,
129.7, 132.6, 138.6, 139.2. Second diastereoisomer (charac-
teristic signals): 1H RMN (300 MHz, CDCl3) d 1.73 (d, JZ
7.0 Hz, 3H), 1.97 (s, 3H), 3.36 (d, JZ14.1 Hz, 1H), 3.39 (d,
JZ3.15 Hz, 1H), 3.69 (d, JZ14.4 Hz, 1H), 4.11 (dt, JZ4.1,
11.5 Hz, 2H), 5.07 (d, JZ6.2 Hz, 1H), 5.40 (q, JZ6.5 Hz,
1H). RMN 13C (75 MHz, CDCl3) d 13.2, 17.0, 53.2, 60.0,
65.5, 70.3, 95.1, 126.5, 131.5, 138.8, 139.7. Third
diastereoisomer (characteristic signals): 1H RMN
(300 MHz, CDCl3) d 4.76 (d, JZ7.5 Hz, 1H), 5.78 (q, JZ
5.7 Hz, 1H). RMN 13C (75 MHz, CDCl3) d 12.6, 13.3, 53.3,
62.2, 70.7, 72.9, 95.2, 133.2, 139.0. MS (EI) calcd for
C21H25NO2 [M]C: 323.1885. Found: 323.1872.
4.6. 6-Synthesis of aminodiols 9 from 2-hydroxymorpho-
lines 8
General procedure. A solution of 2-hydroxymorpholine 8
(1 mmol) in dry diethylether (4 mL) was added dropwise to
a suspension of LiAlH4 (3.3 mmol) in dry diethylether
(4 mL) at 0 8C. The mixture was stirred at room temperature
for 5 h, cooled to 0 8C, and quenched by carefully addition
of water (2.5 mL) and a solution of 15% NaOH (2.5 mL).
Aqueous phase was extracted with diethylether (2!10 mL).
The combined organic phases were dried over MgSO4,
filtered and concentrated to give crude aminodiol 9, which
was purified by flash chromatography using 5% methanol in
dichloromethane.
4.4.14. 4-Epimerisation of 8. To a solution of 80m and 800m
(0.5 mmol) in toluene (2 mL), was added diaza(1,3)bicyclo-
[5.4.0]undecane (1 mmol). The solution was stirred for 24 h
at 60 8C. The mixture was concentrated in vacuo. Flash
chromatography using 30% ethyl acetate in heptane
afforded 800m (yield 89%) (see above for the NMR data).
4.6.1. (1R,10R)-2,20-Dihydroxy-1,10-diphenyl-N-methyl-
diethanamine 90m. Yield 96%. 1H NMR (300 MHz,
CDCl3) d 2.25 (s, 3H), 3.52 (dd, JZ5.4, 10.4 Hz, 2H),
3.66 (dd, JZ5.4, 6.9 Hz, 2H), 3.77 (dd, JZ6.9, 10.4 Hz,
2H), 4.76 (br s, 2H), 7.10–7.30 (m, 10H). 13C NMR
(75 MHz, CDCl3) d 32.5, 62.4, 65.8, 127.6, 128.3, 128.8,
137.6. MS (EI) calcd for C17H21NO2 [M]C: 271.1572.
Found: 271.1584. [a]2D0 C86.5 (c 1.35, CH2Cl2).
4.5. 5-Synthesis of 2-hydroxymorpholines 8
from thioethers 13a and 13b
To a mixture of 13a or 13b (1 mmol) and boronic acid 6
(1 mmol) in dry dichloromethane (15 mL) was added BF3–
etherate (567 mL, 4.5 mmol) at K78 8C. The solution was
stirred at K78 8C for 0.5 h, warmed to room temperature
and stirred overnight. At K78 8C, the mixture was quenched
with saturated solution of NaHCO3 (15 mL). The aqueous
layer was extracted with dichloromethane (3!15 mL). The
combined organic phases were washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. Flash
chromatography using 30% ethyl acetate in heptane
afforded 8.
4.6.2. (1S,10R)-2,20-Dihydroxy-1,10-diphenyl-N-methyl-
diethanamine 900m. Yield 45%.1H NMR (300 MHz,
CDCl3) d 1.26 (s, 3H), 2.96 (br s, 2H), 3.89 (dd, JZ4.7,
10.3 Hz, 2H), 4.03 (dd, JZ7.8, 10.3 Hz, 2H), 4.09 (dd, JZ
4.7, 7.8 Hz, 2H), 7.23–7.35 (m, 10H). 13C NMR (75 MHz,
CDCl3) d 32.4, 62.2, 66.5, 127.6, 128.4, 128.5, 138.4. MS
(EI) calcd for C16H18NO [MKCH2OH]C: 240.1388.
Found: 240.1376. [a]2D0Z0 (c 1, CH2Cl2).
4.6.3. 2-(4-Bromophenyl)-2-[((1R)-2-hydroxy-1-phenyl-
ethyl)-N-methylamino]ethanol 90nD900n. Yield 56%.
Major diastereoisomer: 1H NMR (300 MHz, CDCl3) d
2.27 (s, 3H), 0.97 (br s, 2H), 3.57–3.70 (m, 4H), 3.78–3.88
(m, 2H), 7.04 (d, JZ8.4 Hz, 1H), 7.13–7.20 (m, 3H), 7.26–
7.31 (m, 4H), 7.43 (d, JZ8.4 Hz, 1H). 13C NMR (50 MHz,
CDCl3) d 32.6, 62.6, 65.6, 121.8, 128.0, 128.6, 128.9, 130.5,
4.5.1. (3R,5R)-3-Vinyl 4-methyl-5-phenylmorpholin-2-ol
80w. Yield 82%. Two epimers (56/44): 1H NMR (300 MHz,
CDCl3) d 2.08 (s, 3H) and 2.10 (s, 3H), 3.25–4.20 (m, 5HC
5H), 5.00 (d, JZ1.2 Hz, 1H) and 5.05 (d, JZ2.6 Hz, 1H),
5.25–5.70 (m, 2HC2H), 6.10–6.41 (m, 1HC1H), 7.21–
7.58 (m, 5HC5H). 13C NMR (50 MHz, CDCl3) d 39.7 and

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F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4036
131.6, 136.7, 137.3. Minor diastereoisomer (characteristic
6.7 Hz, 1H), 2.44 (s, 3H), 2.62 (dt, JZ4.9, 9.3 Hz, 1H), 3.16
(br s, 2H), 3.46–3.58 (m, 2H), 3.69 (dd, JZ8.4, 14.4 Hz,
1H), 3.93–4.01 (m, 2H), 7.25–7.37 (m, 5H). 13C NMR
(50 MHz, CDCl3) d 19.9, 21.7, 28.4, 33.8, 60.3, 63.5, 66.3,
68.0, 127.3, 128.1, 128.3, 140.5. Minor diastereoisomer
(characteristic signals): 1H NMR (300 MHz, CDCl3) d 2.31
(s, 3H). 13C NMR (50 MHz, CDCl3) d 60.5, 62.6, 69.8, 70.5,
140.3. MS (EI) calcd for C14H23NO2 [M]C: 237.1728.
Found: 237.1725.
1
signals): H NMR (300 MHz, CDCl3) d 2.22 (s, 3H). 13C
NMR (50 MHz, CDCl3) d 30.9, 62.4, 64.9. MS (EI) calcd
for C17H20NO2Br [M]C: 240.13884. Found: 240.1379.
4.6.4. (2R,3E)-2-[((1R)-2-Hydroxy-1-phenylethyl)-N-
methylamino]oct-3-en-1-ol 90o. 1H NMR (300 MHz,
CDCl3) d 0.78–0.85 (m, 3H), 1.18–1.28 (m, 4H), 2.02 (q,
JZ6.3 Hz, 2H), 2.25 (s, 3H), 2.35 (br s, 2H), 3.18 (dt, JZ
5.5, 8.6 Hz, 1H), 3.31 (dd, JZ5.5, 10.6 Hz, 1H), 3.50 (dd,
JZ9.1, 10.6 Hz, 1H), 3.69–3.91 (m, 3H), 5.17 (dd, JZ8.4,
15.5 Hz, 1H), 5.39 (dt, JZ6.4, 15.5 Hz, 1H), 7.18–7.33 (m,
5H). 13C NMR (75 MHz, CDCl3) d 13.8, 22.0, 31.2, 32.2,
32.7, 61.6, 62.4, 62.9, 66.7, 124.4, 127.5, 128.3, 128.6,
136.2, 138.8. MS (EI) calcd for C17H27NO2 [M]C:
277.2042. Found: 277.2041. [a]2D0 K80.2 (c 1.15, CH2Cl2).
4.6.10. 1-[Allyl((1R)-2-hydroxy-1-phenylethyl)amino]-
propan-2-ol 90sD900s. Yield 76%. Major diastereoisomer:
1H NMR (300 MHz, CDCl3) d 1.15 (d, JZ6.2 Hz, 3H), 2.21
(dd, JZ2.3, 13.3 Hz, 1H), 2.63 (dd, JZ10.2, 13.3 Hz, 1H),
2.99 (dd, JZ8.1, 14.3 Hz, 1H), 3.31 (ddt, JZ2.2, 4.6,
14.3 Hz, 1H), 3.52 (br s, 2H), 3.73 (dd, JZ10.0, 16.0 Hz,
1H), 3.85–3.95 (m, 1H), 4.04 (d, JZ3.8 Hz, 1H), 4.06 (d,
JZ2.5 Hz, 1H), 5.19 (d, JZ9.3 Hz, 1H), 5.23 (d, JZ
16.2 Hz, 1H), 5.81–5.94 (m, 1H), 7.19–7.39 (m, 5H). 13C
NMR (75 MHz, CDCl3) d 20.1, 54.4, 56.3, 61.3, 63.9, 64.4,
117.3, 127.4, 128.1, 128.5, 136.6, 136.7. Minor diastereo-
isomer (characteristic signals): 1H NMR (300 MHz, CDCl3)
d 2.45 (d, JZ9.2 Hz, 1H), 2.50 (d, JZ8.6 Hz, 1H), 2.71 (d,
JZ4.0 Hz, 1H), 5.10 (d, JZ3.2 Hz, 1H), 5.12 (d, JZ
6.7 Hz, 1H). MS (EI) calcd for C13H18NO [MKCH2OH]C:
204.1388. Found: 204.1386.
4.6.5. (2S,3E)-2-[((1R)-2-Hydroxy-1-phenylethyl)-N-
methylamino]oct-3-en-1-ol 900o. 1H NMR (300 MHz,
CDCl3) d 0.79–0.83 (m, 3H), 1.16–1.25 (m, 4H), 1.91 (dt,
JZ6.8, 5.8 Hz, 2H), 2.05 (s, 3H), 2.53 (br s, 2H), 3.44–3.52
(m, 3H), 3.74–3.94 (m, 3H), 5.23 (dd, JZ15.3, 6.4 Hz, 1H),
5.53 (dt, JZ15.5, 6.7 Hz, 1H), 7.20–7.27 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 12.9, 21.1, 30.1, 30.2, 31.3, 60.9, 61.5,
63.5, 67.5, 123.4, 126.8, 127.4, 127.8, 135.1, 138.5.
4.6.6. (1R,10R)-N-Benzyl-2,20-dihydroxy-1,10-diphenyl-
diethanamine 90p. Mp 138–39 8C (ethylacetate) [lit.22
137.5–39 8C (ethylacetate)]. H NMR (300 MHz, CD3OD)
1
4.6.11. (1R)-2-[Benzyl(2-hydroxy-1-phenylethyl)amino]-
1-phenylethanol 90tD900t.21 Yield 75%. Major diastereo-
d 2.07 (br s, 2H), 3.51 (d, JZ14.9 Hz, 1H), 3.73 (dd, JZ4.1,
10.2 Hz, 2H), 4.02 (d, JZ9.1 Hz, 1H), 4.04–4.12 (m, 3H),
4.14 (d, JZ15.0 Hz, 1H), 7.07–7.49 (m, 15H). 13C NMR
(75 MHz, CD3OD) d 50.0, 60.9, 61.6, 124.9, 125.2, 126.2,
126.4, 126.7, 127.0, 138.3, 140.1. MS (EI) calcd for
C22H22NO [MKCH2OH]C: 316.17014. Found: 316.1698.
[a]2D0 K162 (c 1.2, CHCl3) [lit.22 K165.6 (c 1.01, CHCl3)].
1
isomer: H NMR (300 MHz, CDCl3) d 2.41 (dd, JZ2.6,
13.7 Hz, 1H), 2.95 (dd, JZ10.3, 13.7 Hz, 1H), 3.46 (d, JZ
13.9 Hz, 1H), 3.62 (dd, JZ4.4, 10.8 Hz, 1H), 3.85 (d, JZ
13.9 Hz, 1H), 3.92 (dd, JZ4.4, 10.2 Hz, 1H), 4.02 (dd, JZ
10.5, 21.2 Hz, 1H), 4.59 (dd, JZ2.5, 10.3 Hz, 1H), 7.05–
7.37 (m, 15H). 13C NMR (50 MHz, CDCl3) d 56.1, 57.4,
61.7, 64.5, 71.2, 125.8, 127.3, 127.5, 127.8, 128.4, 128.5,
128.6, 128.8, 129.0, 136.5, 139.1, 142.3. Minor diastereo-
isomer (characteristic signals): 1H NMR (300 MHz, CDCl3)
d 2.78 (dd, JZ7.8, 13.6 Hz, 1H), 2.99 (dd, JZ5.0, 13.7 Hz,
1H), 3.39 (d, JZ13.9 Hz, 1H), 3.48 (dd, JZ6.9, 13.7 Hz,
1H), 3.88 (d, JZ13.9 Hz, 1H), 4.41 (dd, JZ5.2, 7.9 Hz,
1H). 13C NMR (50 MHz, CDCl3) d 55.5, 59.4, 61.4, 66.2,
72.8. MS (EI) calcd for C16H18NO [MKPhCH2OH]C:
240.1388. Found: 240.1376.
4.6.7. (1S,10R)-N-Benzyl-2,20-dihydroxy-1,10-diphenyl-
diethanamine 900p. Characteristic signals: 1H NMR
(300 MHz, CD3OD) d 3.26 (d, JZ14.0 Hz, 1H). 13C
NMR (75 MHz, CD3OD) d 48.6, 59.7, 62.6, 138.9.
4.6.8. (3E)-2-[Benzyl((1R)-2-hydroxy-1-phenylethyl)-
amino]-4-phenylbut-3-en-1-ol 90qD900q. Yield 63%.
Major diastereoisomer: 1H NMR (300 MHz, CDCl3) d
2.59 (br s, 2H), 3.51 (d, JZ7.1 Hz, 1H), 3.63 (d, JZ
14.3 Hz, 1H), 3.67–3.81 (m, 2H), 3.75 (d, JZ15.2 Hz, 1H),
3.89 (d, JZ2.4 Hz, 1H), 4.03 (d, JZ14.7 Hz, 1H), 4.07–
4.15 (m, 1H), 6.24 (dd, JZ7.7, 16.1 Hz, 1H), 6.49 (dd, JZ
0.7, 16.1 Hz, 1H), 7.26–7.39 (m, 15H). 13C NMR (50 MHz,
CDCl3) d 49.8, 50.8, 59.2, 60.8, 65.4, 126.3, 126.9, 127.4,
127.8, 128.4, 128.5, 128.6, 128.7, 128.8, 132.3, 133.1,
138.3, 140.0, 140.4. Minor diastereoisomer (characteristic
4.6.12. (1R,3E)-2-[Benzyl(2-hydroxy-2-phenylethyl)-
amino]oct-3-en-1-ol 90uD900u. Yield 72%. Major diastereo-
1
isomer: H NMR (300 MHz, CDCl3) d 0.82 (t, JZ7.0 Hz,
3H), 1.21–1.31 (m, 4H), 1.97 (q, JZ6.1 Hz, 2H), 2.50 (dd,
JZ2.7, 13.5 Hz, 1H), 2.70 (dd, JZ10.5, 13.5 Hz, 1H), 3.08
(br s, 2H), 3.43 (dd, JZ1.6, 7.7 Hz, 1H), 3.53 (d, JZ4.0 Hz,
1H), 3.57 (br s, 2H), 3.86 (d, JZ13.5 Hz, 1H), 4.57 (dd, JZ
2.7, 10.3 Hz, 1H), 5.15 (dd, JZ9.9, 15.4 Hz, 1H), 5.63 (dt,
JZ6.7, 15.3 Hz, 1H), 7.17–7.31 (m, 10H). 13C NMR
(50 MHz, CDCl3) d 13.9, 22.1, 31.4, 32.3, 56.1, 57.3,
62.2, 63.1, 70.9, 122.9, 125.8, 126.0, 127.3, 127.5, 128.4,
128.6, 137.7, 139.2, 142.3. Minor diastereoisomer (charac-
1
signals): H NMR (300 MHz, CDCl3) d 5.69 (dd, JZ6.4,
16.3 Hz, 1H), 6.10 (d, JZ16.3 Hz, 1H). 13C NMR (50 MHz,
CDCl3) d 61.8, 62.4, 62.5, 63.5, 133.1, 136.2, 139.8. MS
(EI) calcd for C24H24NO [MKCH2OH]C: 342.1858.
Found: 342.1854.
1
teristic signals): H NMR (300 MHz, CDCl3) d 2.86 (dd,
4.6.9.
2-[((1R)-2-Hydroxy-1-phenylethyl)(methyl)-
JZ5.2, 13.5 Hz, 1H), 3.80 (d, JZ13.5 Hz, 1H), 5.28 (dd,
JZ8.3, 15.4 Hz, 1H). 13C NMR (50 MHz, CDCl3) d 56.0,
63.5, 71.8. MS (EI) calcd for C22H28NO [MKCH2OH]C:
322.2171. Found: 322.2175.
amino]-3-methylbutan-1-ol 90rD900r. Yield 63%. Major
diastereoisomer: 1H NMR (300 MHz, CDCl3) d 0.82 (d, JZ
6.5 Hz, 3H), 0.87 (d, JZ6.7 Hz, 3H), 1.67–1.75 (m, JZ

´
F. Berree et al. / Tetrahedron 62 (2006) 4027–4037
4037
8. Su, W.-Y.; LeBas, C. L.; Kopecky, A. C.; Knifton, J. F.
Tetrahedron Lett. 1992, 33, 871.
4.6.13. (2R)-2-[[(1R)-2-Hydroxy-1-phenylethyl](methyl)-
amino]but-3-en-1-ol 90w. Yield 92%. 1H NMR (300 MHz,
CDCl3) d 2.35 (s, 3H), 2.66 (br s, 2H), 3.21–4.08 (m, 6H),
5.05 (dt, JZ0.9, 17.3 Hz, 1H), 5.26 (dd, JZ1.8, 10.5 Hz,
1H), 5.58–5.79 (m, 1H), 7.27–7.46 (m, 5H). 13C NMR
(50 MHz, CDCl3) d 33.2, 61.8, 63.4, 63.5, 67.3, 119.9,
128.2, 129.0, 129.1, 134.2, 139.1. MS (EI) calcd for
C12H16NO [MKCH2OH]C: 190.12319. Found: 190.1231.
[a]2D0 K32.1 (c 0.76, CH2Cl2).
9. Hale, J. J.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.;
Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.;
MacIntyre, D. E.; Metzger, J. M. J. Med. Chem. 1996, 39,
1791.
10. Marco, J. L.; Royer, J.; Husson, H. P. Tetrahedron Lett. 1985,
26, 6345.
11. Agami, C.; Couty, B.; Prince, B.; Puchot, C. Tetrahedron
1991, 25, 4343.
12. (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (b)
4.6.14. (2R)-2-{Benzyl[(1R)-2-hydroxy-1-phenylethyl]-
amino}but-3-en-1-ol 90x. Mp 98–100 8C (ether/heptane).
1H NMR (300 MHz, CDCl3) d 2.94 (br s, 2H), 3.59 (d, JZ
14.5 Hz, 1H), 3.65–3.73 (m, 4H), 3.93–4.00 (m, 2H), 4.10
(dd, JZ10.1, 10.7 Hz, 1H), 4.88 (dd, JZ10.3, 17.6 Hz, 1H),
5.01 (d, JZ10.3 Hz, 1H), 5.30–5.38 (m, 1H), 7.28–7.48 (m,
10H). 13C NMR (75 MHz, CDCl3) d 50.7, 59.1, 61.6, 61.7,
62.5, 117.5, 127.2, 127.8, 128.5, 128.6, 128.8, 128.85,
135.0, 138.15, 140.2. Anal. Calcd for C19H23NO2: C, 76.74;
H, 7.80; N, 4.71. Found: C, 76.69; H, 7.79; N, 4.67. [a]D20
K187.8 (c 0.74, CH2Cl2).
´
Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005.
13. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445. (b) Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis,
N. A.; Olah, G. A. Org. Lett. 2000, 2, 3173. (c) Petasis, N. A.;
Patel, Z. D. Tetrahedron Lett. 2000, 41, 9607. (d) Petasis,
N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539. (e) Petasis, N.
A. in Ref. 12b, p 199. (f) Follmann, M.; Graul, F.; Schaefer, T.;
Kopec, S.; Hamley, P. Synlett 2005, 1009. (g) Chang, Y. M.;
Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M.
Tetrahedron Lett. 2005, 46, 3053. (h) Nanda, K. K.; Trotter,
B. W. Tetrahedron Lett. 2005, 46, 2025.
´
14. Preliminary communication: Berree, F.; Debache, A.; Marsac,
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