Highly enantioselective access to α-dibenzylamino ketones from chiral nonracemic α-bromo α′-sulfinyl ketones by dynamic kinetic resolution: Synthesis of (2R,1′S)-2-[1-(dibenzylamino)alkyl]oxiranes

Article abstract of DOI:10.1002/ejoc.201001403

A novel and efficient synthesis of enantiomerically pure α-dibenzylamino α′-sulfinyl ketones starting from a mixture of both epimers of α-bromo α′-(R)-sulfinyl ketone has been realized through combined in situ substitution-epimerization in a so-called Dynamic Kinetic Resolution (DKR). The scope of the reaction has been examined, and four differently substituted α-(S)-dibenzylamino α′-(R)- sulfinyl ketones were obtained in good yields with excellent diastereoselectivities. The utility of these derivatives was further illustrated with a highly stereoselective synthesis of syn-(2R,1′S)-2-(1- dibenzylaminoalkyl)oxiranes.

Full text of DOI:10.1002/ejoc.201001403

FULL PAPER
DOI: 10.1002/ejoc.201001403
Highly Enantioselective Access to α-Dibenzylamino Ketones from Chiral
Nonracemic α-Bromo αЈ-Sulfinyl Ketones by Dynamic Kinetic Resolution:
Synthesis of (2R,1ЈS)-2-[1-(Dibenzylamino)alkyl]oxiranes
Pierre-Yves Géant,[a] Jean Martínez,[a] and Xavier J. Salom-Roig*[a]
Dedicated to the memory of Professor Jean-Marc Kern
Keywords: Amino ketones / Amino alcohols / Chiral sulfoxides / Epoxidation / Kinetic resolution / Template synthesis /
Chirality
A novel and efficient synthesis of enantiomerically pure α-
dibenzylamino αЈ-sulfinyl ketones starting from a mixture of
tuted α-(S)-dibenzylamino αЈ-(R)-sulfinyl ketones were ob-
tained in good yields with excellent diastereoselectivities.
both epimers of α-bromo αЈ-(R)-sulfinyl ketone has been real- The utility of these derivatives was further illustrated with a
ized through combined in situ substitution–epimerization in
a so-called Dynamic Kinetic Resolution (DKR). The scope of
the reaction has been examined, and four differently substi-
highly stereoselective synthesis of syn-(2R,1ЈS)-2-(1-dibenz-
ylaminoalkyl)oxiranes.
philes that often results in racemization at the halogenated
chiral centre.[6] Accordingly, flexible strategies permitting
access to both (R) and (S) α-amino ketone enantiomers are
of great interest in terms of developing practical processes.
This paper summarizes our studies on a new, highly ster-
eoselective strategy that allows the recovery of enantiopure
α-(S)-dibenzylamino ketones from chiral nonracemic α-
bromo αЈ-(R)-sulfinyl ketones (Scheme 1). The reaction
mechanism is discussed. Our approach involved nucleo-
philic displacement of the more reactive bromine epimer by
dibenzylamine and epimerization of the less reactive epimer.
The sulfoxide group is solely responsible for the diastereo-
selectivity observed and it is this process that transfers the
chiral information to the substituents at the α-bromo car-
bon center. To the best of our knowledge, the sequence used
here for the synthesis of α-amino ketones is the first exam-
ple of dynamic kinetic resolution of α-halo ketones by am-
ination so far reported.[7] Chiral sulfoxides have also not
been used for this proposal.[8] An additional advantage of
our strategy is the presence of the sulfoxide group in the
resulting α-amino ketones, which allows further synthetic
exploitation. As an application, we describe the highly dia-
stereoselective transformation of α-(S)-dibenzylamino αЈ-
Introduction
α-Amino ketones are well-known as versatile precursors
of many physiologically important compounds and useful
intermediates for organic synthesis. Indeed, various syn-
thetic approaches to the asymmetric synthesis of optically
active α-amino ketones have been reported in recent years.
The most common procedure for the synthesis of these
valuable moieties involves the use of a natural α-amino acid
as chiral pool.[1] However, with side chains not found in
natural α-amino acids, this route requires additional steps,
making the procedure long and inefficient. Electrophilic
amination of chiral enolates is one of the most important
and general strategies, and many examples of amination of
lithium enolates, enamines, and enolsilanes have been docu-
mented.[2] It is only rather recently that enantioselective
catalytic asymmetric variants of ketone amination using
azodicarboxylates as nitrogen source have been re-
ported.[3,4] The SN2 halogen displacement in α-halo ketones
by nitrogen nucleophiles is another alternative that requires
not readily accessible enantiopure α-halo ketones.[5] This
latter methodology generally involves two-step azide dis-
placement followed by reduction of the azide group, avoid-
ing the potentially problematic use of amines as nucleo-
[a] Institut de Biomolécules Max Mousseron (IBMM), UMR
5247, Université Montpellier I et II, CNRS,
Place Eugène Bataillon, 34095 Montpellier, France
Fax: +33-4-67144866
Scheme 1. Synthesis of α-(S)-dibenzylamino αЈ-(R)-sulfinyl ketones
and their transformation into syn-(2R,1ЈS)-2-(1-dibenzylamino-
alkyl)oxiranes.
E-mail: salom-roig@univ-montp2.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001403.
1300
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1300–1309

Synthesis of (2R,1ЈS)-2-(1-Dibenzylaminoalkyl)epoxides
(R)-sulfinyl ketones into syn-(2R,1ЈS)-2-[1-(dibenzylamino)- Table 1. Synthesis of enantiopure α-(S)-dibenzylamino αЈ-(R)-sulf-
inyl ketones.
alkyl]oxiranes, which are particularly valuable moieties in
the total synthesis of biologically active compounds
(Scheme 1).
Results and Discussion
The required chiral nonracemic α-bromo αЈ-(R)-sulfinyl
ketones, optically pure only at the sulfur atom, were pre-
pared by the conventional method described by Bravo.[9]
Nucleophilic addition at –78 °C of the lithiated anion of
Entry Substrate
Reaction
time
Yield [%]
Diastereomeric
ratio[c]
(+)-(R)-(methyl p-tolyl sulfoxide) (1) to the (Ϯ)-(methyl 2-
bromo esters) 2a–d[10] was performed and it was found that
the reaction occurred regioselectively on the carboxyl group
of α-bromo esters (Scheme 2). Use of one equivalent excess
of the nucleophile led to the corresponding α-bromo αЈ-
sulfinyl ketone 3a–d[11] by virtue of their acidity. The prod-
ucts were obtained in 73–91% yield after purification by
column chromatography on silica gel. 1H NMR spectro-
scopic analysis of the crude reaction mixtures showed
clearly that, in each case, an approximate 1:1 mixture of
diastereomers was obtained.
1
2
3
4
3a
3b
3c
3d
5 h
12 d
3 d
84[a]
68[b]
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
55[b][d]
74[b]
10 d
[a] Yield after washing the crude solid with diethyl ether. [b] Yield
after purification by chromatography on silica gel. [c] Determined
1
by 300 MHz H NMR and HPLC analyses. [d] Compound 5 was
also obtained in 35% isolated yield.
creased the reaction yields. In the case of substrate 3c
(Table 1, entry 3), the desired product 4c was accompanied
by the formation of α,β-unsaturated ketone 5, which was
isolated in 35% yield.
At this point, the absolute configuration of the new car-
bon bearing the nitrogen atom was not known. The stereo-
chemistry of the major diastereomer formed in this reaction
was unambiguously established as S by X-ray crystallo-
graphic analysis of the α-dibenzylamino αЈ-(R)-sulfinyl
ketone 4a (Figure 1).[14]
Scheme 2. Condensation of lithiated (+)-(R)-(methyl p-tolyl sulfox-
ide) carbanion with α-bromo esters.
Exposure of the epimeric mixture of α-bromo ketone 3a
to 2.5 equiv. of sterically hindered dibenzylamine in tetra-
hydrofuran (THF) was then examined at room temperature.
1
Surprisingly, both the H NMR and 13C NMR spectra of
the crude reaction mixture after 5 h showed the presence of
exclusively one of the two possible diastereomeric α-dibenz-
ylamino αЈ-(R)-sulfinyl ketones. Thus, compound 4a was
isolated as a single diastereoisomer[12] in 84% yield, after
washing the solid crude material with diethyl ether (Table 1,
entry 1). The influence of solvent on the stereoselectivity
and reaction time was then studied. The use of acetone,
acetonitrile, or methanol instead of THF did not affect the
excellent diastereoselectivity of the reaction, but no im-
Figure 1. X-ray structure of compound 4a.
For the possible mechanism of this transformation, we
provement in reaction time was observed.[13] The use of speculated that the reaction took place through a combined
N,N-dimethylformamide (DMF) accelerated the reaction SN2-displacement[15]–epimerization process that constitutes
(2.5 h) but reduced the diastereoselectivity (91:9).
a dynamic kinetic asymmetric transformation concept,
The reaction with α-bromo ketones 3b–d in THF was which has its origin in the 1,4-stereoinduction of the chiral
then assessed. Longer reaction times were needed for more sulfoxide group.[16]
sterically hindered side chains (Table 1, entries 2–4), but the
We ensured first that the enantiopure α-(S)-dibenz-
size of the R substituent had no significant influence on the ylamino αЈ-(R)-sulfinyl ketones obtained were configura-
stereoselectivity. Compounds 4b–d were isolated as single tionally stable and were not the result of an interconversion
diastereoisomers in yields ranging from 55 to 74%, after between the two possible diastereomeric products under the
purification by column chromatography of the correspond- reaction conditions. To test this proposal, we synthesized a
ing crude oils, as summarized in Table 1. Partial product racemic mixture of both epimers of 4a by condensing
degradation was observed during purification, which de- methyl (Ϯ)-2-(dibenzylamino)propionate (6) with the lithi-
Eur. J. Org. Chem. 2011, 1300–1309
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1301

P.-Y. Géant, J. Martínez, X. J. Salom-Roig
FULL PAPER
ated anion of (R)-1 according to Scheme 3. By treating 4a vity by ketones,[22a] nitriles,[22b,22c] thiols,[22d] carboxylic
with 1 equiv. of Bn2NH in THF for 18 h, no variation in acids,[22e] and organolithium compounds[22f,22g] was recently
the 4a epimer ratio was observed.
reported by Concellón and co-workers. DBAE have also
been used as precursors for the synthesis of oxazolidin-
ones,[23a]
4-(1-dibenzylaminoalkyl)-2-oxo-1,3-dioxol-
anes,[23b] 2,5-disubstituted-1,4-dioxanes with C2 sym-
metry,[23c] and cis- or trans-3,4-disubstituted 1,2,3,4-tetra-
hydroisoquinolines.[23d]
Initial attention focused upon the preparation of vicinal
threo- or syn-amino alcohols, which would lead to the pro-
jected DBAE by stereoselective reduction of the carbonyl
of α-(S)-dibenzylamino αЈ-(R)-sulfinyl ketones. Various
synthetic approaches to vicinal syn-amino alcohols have
been reported in the literature.[24] Among them, it is well-
documented that ketones having a dibenzylamino group α
to the carbonyl can be reduced to give syn-rich products.[25]
In our case, the stereochemical outcome of the reduction
could be controlled by the dibenzylamino group but also
by the chiral sulfinyl functionality.[26]
As depicted in Table 2, we initially proceeded by reacting
4a–d with NaBH4 in anhydrous MeOH at –15 °C (entries
1, 4, 7, and 10). In all cases the syn stereoisomer was the
major product with the highest selectivity (Ͼ95:5) for 4d;
the diastereomerically pure material was isolated in 77%
yield after column chromatography. We examined the use
diisobutylaluminum hydride (DIBAL-H) at –78 °C in the
presence of 1.5 equiv. of ZnI2. An excess of DIBAL-H
(2.5 equiv.) was required to achieve complete transforma-
tion of the starting materials. The reductions proceeded
Scheme 3. Synthesis of an epimeric mixture of α-dibenzylamino αЈ-
(R)-sulfinyl ketone (4a).
As depicted in Scheme 4, we therefore proposed that the
starting material epimers (CS,SR) and (CR,SR) adopt a con-
formation in which the C=O and S=O bonds are aligned in
opposition to minimize carbonyl–sufoxide dipole interac-
tions,[17] and are in equilibrium under the reaction condi-
tions. In the transition state, the C–Br bond is perpendicu-
lar to the carbonyl because this conformation permits the
halogen displacement to take place much more rapidly (π*
C=O).[18] The slightly less stable and faster reacting epimer
(CR,SR) leads to displacement of the bromide ion by the
bulky nucleophile dibenzylamine, which approaches from
the less hindered, opposite side to the p-tolyl sulfoxide sub-
stituent, providing exclusively the (S)-dibenzylamino
ketone. In addition, simultaneous in situ epimerization of
the slower reacting epimer (CS,SR) into (CR,SR) allows the
yield to increase to more than 50% in the transformation.
Table 2. Stereoselective reduction of α-(S)-dibenzylamino αЈ-(R)-
sulfinyl ketones to vicinal amino alcohols.
Entry Substrate Conditions
Yield
[%][a]
Ratio[b]
syn-7/anti-7
1
2
4a
4a
NaBH4, MeOH, –15 °C
DIBAL/ZnI2
90
86
90:10
Ͼ95:5
THF, –78 °C
3
4
5
4a
4b
4b
DIBAL,THF, –78 °C
NaBH4, MeOH, –15 °C
DIBAL/ZnI2
72
84
77
35:65
90:10
Ͼ95:5
Scheme 4. Proposed mechanism for the SN2-DKR process involv-
ing α-bromo αЈ-(R)-sulfinyl ketones and dibenzylamine.
THF, –78 °C
6
7
8
4b
4c
4c
DIBAL,THF, –78 °C
NaBH4, MeOH, –15 °C
DIBAL/ZnI2
87
77
88
30:70
85:15
Ͼ95:5
To illustrate the utility of the α-(S)-dibenzylamino αЈ-
(R)-sulfinyl ketone intermediates, we planned to bring
about their transformation into syn-(2R,1ЈS)-2-[1-(dibenz-
ylamino)alkyl]epoxides (DBAE), which are very useful
moieties in organic synthesis[19] that have been used to pre-
pare a large number of biologically active natural and syn-
thetic compounds, such as hydroxyethylene dipeptide iso-
steres[20] and other pharmacologically important com-
THF, –78 °C
9
10
11
4c
4d
4d
DIBAL,THF, –78 °C
NaBH4, MeOH, –15 °C
DIBAL/ZnI2
THF, –78 °C
DIBAL,THF, –78 °C
70
77
86
15:85
Ͼ95:5
Ͼ95:5
12
4d
87
Ͼ5:95
[a] Yield after purification by chromatography on silica gel. [b] De-
pounds.[21] Ring opening of DBAE with total regioselecti- termined by 300 MHz H NMR and HPLC analyses.
1302 Eur. J. Org. Chem. 2011, 1300–1309
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of (2R,1ЈS)-2-(1-Dibenzylaminoalkyl)epoxides
with high diastereoselectivity for each substrate, and dia-
stereomerically pure syn-7a–d products were obtained in
high yields (Table 2entries 2, 5, 8, and 11). Alternatively,
reduction of 4a–d using DIBAL-H alone provided the anti-
7d product with excellent yield and higher stereoselectivity
(Ͼ5:95; Table 2, entry 12) and anti-7a–c with lower dia-
stereoselectivity (35:65 to 15:85; Table 2, entries 3, 6, and
9).
Figure 2. Proposed transition states for hydride transfer in DIBAL-
H/ZnI2 and DIBAL-H reductions.
Configurational assignment of the resulting hydroxyl car-
1
bon atoms was deduced from the H NMR spectroscopic
fluxing chloroform,[29] followed by methylation, without
further purification, of the resulting β-sulfenyl derivatives
with trimethyl oxonium tetrafluoroborate in anhydrous
CH2Cl2 and treatment of the corresponding sulfonium salts
with aqueous K2CO3. Epoxides 8a–c (Scheme 5) were ob-
tained after purification by column chromatography in 45–
67% yields from 7a–c. The spectroscopic and physical data
of these compounds were in accordance with the reported
literature values.[30]
data for the methylene protons α to the sulfinyl group.
Thus, the syn-7 isomers exhibited lower Janti and larger
Jgauche values than those of their corresponding anti-7 epi-
mers. It has been established in previous studies with related
systems[17b,26a,27] that these data are indicative of a (CR,SR)
relative configuration in syn-7 and a (CS,SR) relative config-
uration in anti-7. The assignment was in agreement with
predictions made on the basis of the stereochimical model
proposed in the literature to explain the DIBAL-H and
DIBAL-H/ZnI2 reduction of β-keto sulfoxides. The abso-
lute configuration of 7a–c was confirmed by comparison of
the optical rotation of epoxides 8a–c to the literature values.
The secondary amine plays a crucial role in the stereose-
lectivity of the reduction with the non-chelating agent
NaBH4, with the external hydride being delivered to the less
hindered face of the carbonyl group according to the Fel-
kin–Anh model.[25] In contrast, in the reaction with
DIBAL-H/ZnI2, the transition state involves a conforma-
tionally rigid six-membered cyclic intermediate originating
from the chelation of the Lewis acid to the sulfinyl and
carbonyl oxygen atoms (Figure 2, A). The approach of the
electrophilic hydride is then directed by complexation with
the lone electron pair of the sulfoxide or the pseudo-axial
halogen.[28] Finally, in the diastereoselective reduction with
DIBAL-H alone, where the opposite stereoselectivity was
observed, dibenzylamine and the chiral sulfoxide operate in
opposite directions, and a predominant role of the sulfinyl
group in the stereoselectivity was clearly observed. The
product was derived from an intramolecular hydride trans-
fer through a six-membered cyclic transition state after for-
mation of an O–Al bond with the basic sulfinyl oxygen
(Figure 2, B). Thus, the anti stereoisomer was the major
product obtained. However, even if the selectivity of the
reduction is primarily controlled by the chiral sulfoxide
group, the nitrogen atom is able to compete with the sulfinyl
oxygen to chelate the metal and cause some interference,
which explains why the reduction is less stereoselective and
gives a mixture of epimers. These interferences became less
important with increased steric hindrance on the carbon
bearing the nitrogen (compare Table 2, entries 3, 6, 9, and
12).
Scheme 5. Three-step sequence leading to syn-(2R,1ЈS)-2-(1-di-
benzylaminoalkyl)epoxides 8a–c from the corresponding vicinal
syn-dibenzylamino alcohols.
Conclusions
We have developed a conceptually new and synthetically
efficient route to α-(S)-dibenzylamino αЈ-(R)-sulfinyl
ketones from α-bromo αЈ-(R)-sulfinyl ketones, exploiting a
combined in situ substitution–epimerization process. The
absolute stereochemistry at the carbon bearing the nitrogen
atom of the isomer obtained was of S configuration when
(+)-(R)-(methyl p-tolyl sulfoxide) was used as starting mate-
rial. The X-ray structure of derivative 4a permitted un-
equivocal confirmation of the structural assignment.
Changing the absolute configuration on the sulfoxide SS
would provide the R epimers using the same strategy. These
derivatives were shown to be excellent precursors for the
synthesis of enantiopure vicinal syn-amino alcohols
through a highly stereoselective ketone reduction. The sulf-
inyl group controlled the stereochemical course of both the
amination and ketone reduction steps. Finally, three useful
syn-amino epoxides derived from alanine, leucine, and
phenylalanine have been synthesized. Current investigations
will expand the scope of these combined in situ substitu-
tion–epimerization processes.
We finally turned our attention to the preparation of
three DBAE compounds 8a–c that could be correlated with
those derived from natural alanine, leucine, and phenyl-
alanine and that have been described in the literature.
Having amino alcohols 7a–c in hand, conversion into the
corresponding oxiranes 8a–c was achieved by a three-step
Experimental Section
General Information: All reagents and solvents were purchased
from commercial sources. THF was dried by distillation from so-
sequence involving sulfinyl reduction with tBuBr in re- dium/benzophenone. Diisopropylamine was distilled from KOH.
Eur. J. Org. Chem. 2011, 1300–1309
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1303

P.-Y. Géant, J. Martínez, X. J. Salom-Roig
FULL PAPER
Reactions were conducted in flame- or oven-dried glassware under
an argon atmosphere. 1H NMR and 13C NMR spectra were re-
corded at 300 and 75 MHz, respectively, in either CDCl3 or [D6]-
acetone. Chemical shifts are given in ppm and are reported relative
to the residual solvent peak (CHCl3: δ = 7.26 and 77.16 ppm or
[D6]acetone: δ = 2.05 and 205.87 ppm). Data are reported as fol-
lows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), coupling constants, and inte-
gration. Analytical TLC was performed on silica gel 60F254 plates.
Column chromatography was carried out on silica gel 60 (63–
200 μm). High-resolution mass spectra (HRMS) were measured
using electrospray ionization (ESI) and Q-Tof detection. Melting
points were measured with a Büchi apparatus and are uncorrected.
Optical rotations values were measured with a Perkin–Elmer appa-
ratus at 20 °C, 589 nm (sodium D-line), and concentrations are
given in g/100 mL. HPLC analyses were performed with a Waters
2796 instrument with a variable detector [column: monolith C18;
50ϫ4.6 mm; flow: 3 mL/min; eluent: H2O (TFA 0.1%)/CH3CN
(TFA 0.1%); gradient 0–100% (4 min)].
3.23 (dd, J = 7.1, 14.1 Hz, 1 H, CHaHbPh) ppm. 13C NMR
(75 MHz, CDCl3):
δ = 170.1 (C=O), 136.9 (Carom.), 129.4
(CHarom.), 128.9 (CHarom.), 127.6 (CHarom.), 53.1 (CH), 45.3 (CH2),
41.3 (CH3) ppm. ESIMS: m/z = 243.0 [M + H]+. HRMS: calcd.
+
for C10H12BrO2 243.0021; found 243.0029.
Methyl 2-Bromo-3-cyclohexylpropanoate (2d): To a mixture of 3-
cyclohexylpropanoic acid (3.4 mL, 19.8 mmol) and phosphorus tri-
bromide (1.95 mL, 20.7 mmol), was slowly added bromine (2.1 mL,
41 mmol). The system was heated at 80 °C for 1.5 h and then al-
lowed to cool to room temperature. Supplementary bromine
(0.5 mL, 9.8 mmol) was then added and heating at 80 °C was con-
tinued overnight. MeOH (8 mL) was cautiously added before heat-
ing at reflux for an additional 2 h. The reaction mixture was hy-
drolyzed by adding ice water (50 mL). The phases were separated
and the aqueous layer was extracted with Et2O (3ϫ 50 mL). The
combined organic layers were dried with MgSO4 and concentrated
under reduced pressure. 2b was obtained as a yellowish oil (5.9 g,
quantitative) and was used without further purification. Rf = 0.7
1
(cyclohexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ = 4.32
Methyl 2-Bromo-4-methylpentanoate (2b): To a mixture of 4-meth-
ylpentanoic acid (2.5 mL, 20 mmol) and phosphorus tribromide
(1.95 mL, 20.7 mmol), was slowly added bromine (2.1 mL,
41 mmol). The system was heated at 80 °C for 1.5 h and then al-
lowed to cool to room temperature. Supplementary bromine
(0.5 mL, 9.8 mmol) was then added and the mixture was heated at
80 °C overnight. The solution was cautiously treated with MeOH
(8 mL) and heated to reflux for an additional 2 h before adding ice
water (50 mL). The phases were separated and the aqueous layer
was extracted with Et2O (3ϫ 50 mL). The combined organic layers
were dried with MgSO4 and concentrated under reduced pressure.
Product 2b was obtained as a yellowish oil (4.49 g, quantitative)
and was used without further purification. Rf = 0.75 (cyclohexane/
EtOAc, 9:1). 1H NMR (CDCl3, 300 MHz): δ = 4.28 (t, J = 7.7 Hz,
1 H, CHBr), 3.77 (s, 3 H, OCH3), 1.98–1.86 (m, 2 H, CH2CHBr),
1.83–1.68 [m, 1 H, CH(CH3)2], 0.95 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 0.90 (d, J = 6.5 Hz, 3 H, CH3CHCH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.8 (C=O), 53.1 (CH), 44.5 (CH2),
43.7 (CH3), 26.6 (CH), 22.6 (CH3), 21.8 (CH3) ppm. ESIMS: m/z
= 209.1 [M + H]+. HRMS: calcd. for C7H14BrO2+ 209.0177; found
209.0180.
(t, J = 7.7 Hz, 1 H, CHBr), 3.78 (s, 3 H, OCH3), 1.97–1.89 (m, 2
H, CH2CHBr), 1.72–1.64 (m, 5 H), 1.52–1.36 (m, 1 H), 1.30–1.12
(m, 3 H), 1.03–0.82 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.9 (C=O), 53.1 (CH), 44.1 (CH2), 42.4 (CH3), 35.8 (CH),
33.3 (CH2), 32.4 (CH2), 26.5 (CH2), 26.2 (CH2), 26.1 (CH2) ppm.
+
ESIMS: m/z = 248.04 [M + H]+. HRMS: calcd. for C10H18BrO2
249.0490; found 249.0488.
3-Bromo-1-[(R)-p-tolylsulfinyl]butan-2-one (3a): Diisopropylamine
(2.9 mL, 20.6 mmol) was dissolved in THF (30 mL) and n-butyl-
lithium (1.6 m in hexane, 12.9 mL, 20.6 mmol) was added dropwise
at –78 °C. The system was stirred at –78 °C for 1 h before adding
a solution of (R)-1 (3.16 g, 20.5 mmol) in THF (20 mL). After stir-
ring for 30 min at –78 °C, 2a (1.1 mL, 9.85 mmol) in THF (10 mL)
was added. The reaction mixture was stirred for an additional
30 min at –78 °C, and then quenched with saturated aqueous
NH4Cl (50 mL). The phases were separated, and the aqueous layer
was extracted with EtOAc (3ϫ 50 mL). The combined organic lay-
ers were dried with MgSO4 and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
on silica gel (cyclohexane/EtOAc, 3:2) to give a 55:45 dia-
stereomeric mixture of 3a as a yellowish oil (2.60 g, 91%). Rf =
0.45 and 0.35 (cyclohexane/EtOAc, 1:1). 1H NMR [300 MHz, [D6]-
acetone]: δ = 7.64 (d, J = 8.2 Hz, 1 H, ArH, diast. A), 7.58 (d, J =
8.2 Hz, 1 H, ArH, diast. B), 7.44–7.40 (m, 2 H, ArH, 2 diast), 4.75–
7.63 (m, 1 H, CHBr, 2 diast), 4.47 (d, J = 14.2 Hz, 0.55 H,
CHaHbSO, diast. A), 4.29–4.18 (m, 0.8 H, CHaHbSO, and
CHaHbSO, diast. B), 4.05 (d, J = 14.2 Hz, 0.45 H, CHaHbSO, diast.
A), 2.42 (s, 3 H, CH3 pTol, 2 diast), 1.67 (d, J = 6.7 Hz, 1.35 H,
CH3CH, diast. B), 1.61 (d, J = 6.7 Hz, 1.65 H, CH3CH, diast.
B) ppm. 13C NMR [75 MHz, [D6]acetone]: δ = 197.0 (C=O), 196.4
(C=O), 143.3 (Carom.), 143.1 (Carom.), 142.6 (Carom.), 141.8 (Carom.),
131.4 (CHarom.), 131.3 (CHarom.), 125.5 (CHarom.), 66.8 (CH2), 65.3
(CH2), 50.8 (CH), 49.7 (CH), 21.9 (CH3), 20.2 (CH3), 19.9
(CH3) ppm. ESIMS: m/z = 288.9 [M + H]+, 576.9 [2M + H]+.
HRMS: calcd. for C11H14BrO2S+ 288.9898; found 288.9883.
Methyl 2-Bromo-3-phenylpropanoate (2c): d,l-Phenylalanine (10 g,
60.5 mmol) and sodium bromide (21.8 g, 211.9 mmol) were dis-
solved in H2SO4 (2.5 m, 80 mL). A solution of sodium nitrite (5.2 g,
75.4 mmol) in H2O (20 mL) was then added dropwise at 0 °C and
the system was stirred at 0 °C for 1 h, and at room temperature for
6 h. The phases were separated and the aqueous layer was extracted
with EtOAc (3ϫ 75 mL). The combined organic layers were
washed with brine (2ϫ 25 mL), dried with MgSO4, and concen-
trated under reduced pressure. The resulting oil was cooled to 0 °C
to precipitate the unreacted phenylalanine, which was filtered off.
The crude product (9.75 g, 42.6 mmol) was then cautiously treated
with a solution of H2SO4 (95%, 1.3 mL, 23 mmol) in MeOH
(80 mL). The mixture was heated at reflux for 3 h, allowed to cool
to room temperature, and MeOH was then evaporated under re-
duced pressure. The resulting oil was dissolved in Et2O (150 mL),
washed with an aqueous solution of 5% KHCO3 (3ϫ 50 mL), and
with brine (2ϫ 50 mL). The organic layer was dried with MgSO4
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (cyclohexane/
EtOAc, 98:2) to afford 2c as a pure pale-yellow oil (7.22 g, 49%).
Rf = 0.2 (cyclohexane/EtOAc, 95:5). 1H NMR (300 MHz, CDCl3):
δ = 7.33–7.18 (m, 5 H, ArH), 4.39 (dd, J = 7.1, 8.3 Hz, 1 H, CHBr),
3.71 (s, 3 H, OCH3), 3.45 (dd, J = 8.4, 14.1 Hz, 1 H, CHaHbPh),
3-Bromo-5-methyl-1-[(R)-p-tolylsulfinyl]hexan-2-one (3b): Prepared
from 2b (3.46 g, 16.5 mmol; reaction time: 1.5 h) as described for
3a. Purification of the crude product by column chromatography
on silica gel (cyclohexane/EtOAc, 3:2) provided a 50:50 dia-
stereomeric mixture of 3b as a yellowish oil (4.02 g, 74%). Rf =
1
0.70 (cyclohexane/EtOAc, 2:1). H NMR (300 MHz, CDCl3): δ =
7.57 (d, J = 8.2 Hz, 1 H, ArH, diast. A), 7.51 (d, J = 8.2 Hz, 1 H,
ArH, diast. B), 7.37–7.26 (m, 2 H, ArH, 2 diast), 4.34–4.23 (m, 2
1304
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1300–1309

Synthesis of (2R,1ЈS)-2-(1-Dibenzylaminoalkyl)epoxides
H, CHBr, 2 diast. and CHaHbSO, 2 diast), 3.96–3.88 (m, 1 H, 3.62 [d, J = 13.4 Hz, 2 H, N(CHaHbPh)2], 3.33 [d, J = 13.4 Hz, 2
CHaHbSO, 2 diast), 2.42 (s, 3 H, CH3 pTol, 2 diast), 1.78–1.57 [m,
3 H, CH2CHBr, 2 diast. and CH(CH3)2, 2 diast], 0.94–0.83 [m, 6
H, N(CHaHbPh)2], 2.83 (q, J = 6.6 Hz, 1 H, CHN), 2.36 (s, 3 H,
CH3 pTol), 0.99 (d, J = 6.6 Hz, 3 H, CH3CH) ppm. 13C NMR
H, CH(CH3)2, 2 diast] ppm. 13C NMR (75 MHz, CDCl3): δ = (75 MHz, CDCl3): δ = 203.1 (C=O), 142.1 (Carom.), 140.1 (Carom.),
195.1 (C=O), 194.7 (C=O), 142.7 (Carom.), 142.7 (Carom.), 140.1
138.7 (Carom.), 130.1 (CHarom.), 127.2 (CHarom.), 128.8 (CHarom.),
(Carom.), 139.3 (Carom.), 130.5 (CHarom.), 130.4 (CHarom.), 124.4 127.8 (CHarom.), 124.5 (CHarom.), 66.3 (CH2), 63.6 (CH), 55.0
(CHarom.), 124.3 (CHarom.), 66.3 (CH2), 64.5 (CH2), 53.5 (CH), 53.4 (CH2), 21.6 (CH3), 6.0 (CH3) ppm. ESIMS: m/z = 406.3 [M +
(CH), 40.9 (CH), 40.9 (CH), 26.1 (CH3), 26.0 (CH3), 22.9 (CH3), H]+. HRMS: calcd. for C25H28NO2S+ 406.1841; found 406.1850.
21.7 (CH3), 21.5 (CH3), 21.5 (CH3) ppm. ESIMS: m/z = 331.1 [M
CCDC-787067 contains the supplementary crystallographic data
for this compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
+ H]+, 661.1 [2M + H]+. HRMS: calcd. for C14H20BrO2S+
331.0367; found 331.0376.
ac.uk/data_request/cif.
3-Bromo-4-phenyl-1-[(R)-p-tolylsulfinyl]butan-2-one (3c): Prepared
from 2c (3.50 g, 14.4 mmol; reaction time: 1.5 h) as described for
3a. Purification of the crude product by column chromatography
on silica gel (cyclohexane/EtOAc, 3:2) provided a 55:45 dia-
stereomeric mixture of 3c as a yellowish oil (4.30 g, 82%). Rf =
0.20 (cyclohexane/EtOAc, 95:5). 1H NMR (300 MHz, CDCl3): δ =
7.38–7.01 (m, 9 H, ArH, 2 diast), 4.39–4.32 (m, 1 H, CHBr, 2 di-
ast), 4.23 (d, J = 13.3 Hz, 0.55 H, CHaHbSO, diast. A), 4.06 (d, J
= 13.6 Hz, 0.45 H, CHaHbSO, diast. B), 3.70 (m, 1 H, CHaHbSO,
2 diast), 3.26 (dd, J = 6.1, 14.7 Hz, 0.45 H, CHaHbPh, diast. B),
3.14 (dd, J = 6.4, 14.6 Hz, 0.55 H, CHaHbPh, diast. A), 3.00–2.88
(m, 1 H, CHaHbPh, 2 diast), 2.28, 2.27 (2s, 3 H, CH3 pTol, 2 di-
ast) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.6 (C=O), 194.1
(C=O), 142.7 (Carom.), 142.5 (Carom.), 139.9 (Carom.), 138.9 (Carom.),
136.8 (Carom.), 136.7 (Carom.), 130.5 (CHarom.), 130.4 (CHarom.),
129.6 (CHarom.), 129.5 (CHarom.), 128.8 (CHarom.), 128.8 (CHarom.),
127.3 (CHarom.), 127.3 (CHarom.), 124.3 (CHarom.), 124.2 (CHarom.),
66.4 (CH2), 64.1 (CH2), 54.4 (CH), 54.2 (CH), 38.6 (CH2), 21.7
(CH3) ppm. ESIMS: m/z = 365.0 [M + H]+, 729.1 [2M + H]+.
HRMS: calcd. for C17H18BrO2S+ 365.0211; found 365.0209.
(S)-3-(Dibenzylamino)-5-methyl-1-[(R)-p-tolylsulfinyl]hexan-2-one
(4b): Prepared from 3b (400 mg, 1.207 mmol; reaction time: 12 d)
as described for 4a. The crude product was purified by column
chromatography on silica gel (cyclohexane/EtOAc, 4:1) to give 4b
(368 mg, 68%) as a colorless oil. Rf = 0.45 (cyclohexane/EtOAc,
2:1); [α]D = +3.3 (c = 1.205, acetone). 1H NMR (300 MHz, CDCl3):
δ = 7.41–7.09 (m, 14 H, ArH), 4.20 (d, J = 13.1 Hz, 1 H,
CHaHbSO), 4.11 (d, J = 13.1 Hz, 1 H, CHaHbSO), 3.61 [d, J =
13.4 Hz, 2 H, N(CHaHbPh)2], 3.33 [d, J = 13.4 Hz, 2 H,
N(CHaHbPh)2], 2.71 (dd, J = 2.4, 9.8 Hz, 1 H, CHN), 2.34 (s, 3 H,
CH3 pTol), 1.66 (ddd, J = 3.6, 9.9, 13.4 Hz, 1 H, CHaHb-CHN),
1.17 (m, 1 H, CHaHb-CHN), 1.02 [m, 1 H, CH(CH3)2], 0.82 (d, J
= 6.5 Hz, 3 H, CH3 CHCH3 ), 0.46 (d, J = 6.4 Hz, 3 H,
CH3CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.9 (C=O),
142.4 (Carom.), 139.9 (Carom.), 138.9 (Carom.), 130.1 (CHarom.), 129.4
(CHarom.), 128.7 (CHarom.), 127.7 (CHarom.), 124.9 (CHarom.), 66.7
(CH2), 66.0 (CH), 54.9 (CH2), 30.3 (CH2), 25.5 (CH), 23.8 (CH3),
21.9 (CH3), 21.6 (CH3) ppm. ESIMS: m/z = 448.3 [M + H]+.
HRMS: calcd. for C28H34NO2S+ 448.2310; found 448.2301.
(S)-3-(Dibenzylamino)-4-phenyl-1-[(R)-p-tolylsulfinyl]butan-2-one
(4c): Prepared from 3c (502 mg, 1.37 mmol; reaction time: 3 d) as
described for 4a. The crude product contained a mixture of 4c and
5, which were separated by column chromatography on silica gel
(cyclohexane/EtOAc, 4:1) to give 4c (360 mg, 55%) as a yellowish
oil. Rf = 0.5 (cyclohexane/EtOAc, 3:2); [α]D = –52.2 (c = 0.69, ace-
tone). 1H NMR (300 MHz, CDCl3): δ = 7.24–6.69 (m, 19 H, ArH),
3.91 (s, 2 H, CH2SO), 3.57 [d, J = 13.3 Hz, 2 H, N(CHaHbPh)2],
3.28 [d, J = 13.4 Hz, 2 H, N(CHaHbPh)2], 2.87–2.63 (m, 3 H,
CH2Ph and CHN), 2.13 (s, 3 H, CH3 pTol) ppm. 13C NMR
(75 MHz, CDCl3): δ = 200.8 (C=O), 141.8 (Carom.), 139.5 (Carom.),
139.1 (Carom.), 138.5 (Carom.), 130.0 (CHarom.), 129.7 (CHarom.),
129.3 (CHarom.), 128.8 (CHarom.), 128.5 (CHarom.), 127.8 (CHarom.),
126.2 (CHarom.), 124.2 (CHarom.), 70.1 (CH), 66.7 (CH2), 55.0
(CH2), 28.4 (CH2), 21.6 (CH3) ppm. ESIMS: m/z = 482.1 [M +
H]+. HRMS: calcd. for C31H32NO2S+ 482.2154; found 482.2159.
3-Bromo-4-cyclohexyl-1-[(R)-p-tolylsulfinyl]butan-2-one (3d): Pre-
pared from 2d (1.029 g, 4.09 mmol of 2d; reaction time: 45 min) as
described for 3a. Purification of the crude product by flash
chromatography on silica gel (cyclohexane/EtOAc, 85:15 to 60:40)
provided a 55:45 diastereomeric mixture of 3c as a yellowish oil
(1.157 g, 76%). Rf = 0.57 and 0.53 (cyclohexane/EtOAc, 2:1). 1H
NMR (300 MHz, CDCl3): δ = 7.58–7.32 (m, 4 H, ArH, 2 diast),
4.35–4.22 (m, 2 H, CHBr, 2 diast. and CHaHbSO, 2 diast), 3.93 (d,
J = 5.1 Hz, 0.55 H, CHaHbSO, diast. A), 3.89 (d, J = 5.4 Hz, 0.45
H, CHaHbSO diast. B), 2.41 (s, 3 H, CH3, 2 diast), 1.79–0.68 (m,
13 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 195.2 (C=O), 194.7
(C=O), 142.7 (Carom.), 142.6 (Carom.), 140.0 (Carom.), 139.2 (Carom.),
130.4 (CHarom.), 130.4 (CHarom.), 124.4 (CHarom.), 124.3 (CHarom.),
66.1 (CH2), 64.3 (CH2), 52.8 (CH), 52.8 (CH), 39.6 (CH2), 35.3
(CH), 35.1 (CH), 33.5 (CH2), 32.3 (CH2), 32.2 (CH2), 26.5 (CH2),
26.5 (CH2), 26.2 (CH2), 26.2 (CH2), 26.1 (CH2), 26.0 (CH2), 21.7
(CH3) ppm. ESIMS: m/z = 373.1 [M + H]+, 741.2 [2M + H]+.
HRMS: calcd. for C17H24BrO2S+ 371.0680; found 371.0689.
(R,E)-4-Phenyl-1-(p-tolylsulfinyl)but-3-en-2-one (5): Obtained as by
product with 4c as a white solid (137 mg, 35%). Rf = 0.2 (cyclohex-
1
ane/EtOAc, 3:2); [α]D = +275 (c = 0.8, CHCl3); m.p. 85–88 °C. H
(S)-3-(Dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-2-one (4a): Com-
pound 3a (1.00 g, 5.49 mmol) was dissolved in THF (25 mL) and
dibenzylamine (1.7 mL, 13.6 mmol) was added. The reaction mix-
ture was stirred for 5 h at room temperature and treated with satu-
rated aqueous KHCO3 (50 mL). The phases were separated and
the aqueous layer was extracted with EtOAc (3ϫ 75 mL). The com-
bined organic layers were washed with an aqueous solution of 10%
KHSO4 (2ϫ 50 mL), dried with MgSO4, and concentrated under
reduced pressure. The residue was washed with Et2O (3ϫ 10 mL)
NMR (300 MHz, CDCl3):
δ = 7.46–7.13 (m, 10 H, ArH,
PhCH=CH), 6.58 (d, J = 16.2 Hz, 1 H, PhCH=CH), 4.05 (d, J =
13.2 Hz, 1 H, CHaHbSO), 3.88 (d, J = 13.2 Hz, 1 H, CHaHbSO),
2.25 (s, 3 H, CH3 pTol) ppm. 13C NMR (75 MHz, CDCl3): δ =
190.7 (C=O), 146.0 (C=C), 142.4 (Carom.), 140.0 (Carom.), 134.1
(Carom.), 131.4 (C=C), 130.3 (CHarom.), 129.2 (CHarom.), 128.9
(CHarom.), 126.0 (CHarom.), 124.5 (CHarom.), 67.3 (CH2), 21.6
(CH3) ppm. ESIMS: m/z = 285.1 [M + H]+, 569.2 [2M + H]+.
HRMS: calcd. for C17H17O2S+ 285.0949; found 285.0946.
to afford 4a as a white solid (1.185 g, 84%). Rf = 0.60 (cyclohexane/
1
EtOAc, 2:1); [α]D = +13.61 (c = 1, acetone); m.p. 89 °C. H NMR (S)-4-Cyclohexyl-3-(dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-2-
(300 MHz, CDCl3): δ = 7.37–7.12 (m, 14 H, ArH), 4.20 (d, J = one (4d): Prepared from 3d (503 mg, 1.35 mmol; reaction time:
13.2 Hz, 1 H, CHaHbSO), 4.10 (d, J = 13.2 Hz, 1 H, CHaHbSO),
10 d) as described for 4a. The crude product was purified by col-
Eur. J. Org. Chem. 2011, 1300–1309
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1305

P.-Y. Géant, J. Martínez, X. J. Salom-Roig
FULL PAPER
umn chromatography on silica gel (cyclohexane/EtOAc, 5:1) to give
4d (490 mg, 74%) as a white solid. Rf = 0.40 (cyclohexane/EtOAc,
2:1); [α]D = –101.0 (c = 1.04, CHCl3); [α]D = –20.5 (c = 1.03, ace-
added to dry ZnI2 (123 mg, 0.385 mmol) and the system was stirred
at room temperature for 30 min. DIBAL-H (1.5 m in toluene,
0.4 mL, 0.60 mmol) was added dropwise at –78 °C and the reaction
mixture was stirred for 1 h. The solution was treated with MeOH
(10 mL) and was allowed to reach the room temperature. The sol-
vents were evaporated under reduced pressure and the resulting
solid crude material was treated with EtOAc (25 mL) and saturated
1
tone); m.p. 82–86 °C. H NMR (300 MHz, CDCl3): δ = 7.32–7.16
(m, 12 H, ArH), 7.02 (d, J = 8.3 Hz, 2 H, ArH), 4.16 (d, J =
13.2 Hz, 1 H, CHaHbSO), 4.03 (d, J = 13.2 Hz, 1 H, CHaHbSO),
3.52 [d, J = 13.3 Hz, 2 H, N(CHaHbPh)2], 3.24 [d, J = 13.4 Hz, 2
H, N(CHaHbPh)2], 2.64 (dd, J = 2.3, 9.8 Hz, 1 H, CHN), 2.25 (s, aqueous potassium sodium tartrate (25 mL). The system was then
3 H, CH3 pTol), 1.57–0.50 (m, 13 H) ppm. 13C NMR (75 MHz, stirred overnight. The phases were separated and the aqueous layer
CDCl3): δ = 202.1 (C=O), 142.3 (Carom.), 139.9 (Carom.), 138.8 was extracted with EtOAc (3ϫ 25 mL). The combined organic lay-
(Carom.), 130.0 (CHarom.), 129.3 (CHarom.), 128.6 (CHarom.), 127.6 ers were washed with brine (2ϫ 25 mL), dried with MgSO4 and
(CHarom.), 124.9 (CHarom.), 66.5 (CH), 65.3 (CH2), 54.8 (CH2), 34.6 concentrated under reduced pressure. The crude product was puri-
(CH), 34.3 (CH2), 32.6 (CH2), 28.9 (CH2), 26.5 (CH2), 26.3 (CH2), fied by column chromatography on silica gel (cyclohexane/EtOAc,
26.2 (CH2), 21.6 (CH3) ppm. ESIMS: m/z = 488.3 [M + H]+.
3:2) to afford syn-7a as a colorless oil (87 mg, 86%). Rf = 0.5 (cy-
clohexane/EtOAc, 1:1); [α]D = –9.3 (c = 0.53, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.46 (d, J = 8.2 Hz, 2 H, ArH), 7.27–7.14
(m, 12 H, ArH), 4.37 (br. s, 1 H, OH), 3.66 [d, J = 13.3 Hz, 2 H,
N(CHaHbPh)2], 3.44 (td, J = 3.0, 8.6 Hz, 1 H, CHOH), 3.23 [d, J
= 13.3 Hz, 2 H, N(CHaHbPh)2], 2.93 (dd, J = 8.0, 12.9 Hz, 1 H,
CHaHbSO), 2.81–2.68 (m, 2 H, CHaHbSO and CHN), 2.32 (s, 3 H,
CH3 pTol), 0.93 (d, J = 6.7 Hz, 3 H, CH3CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 141.6 (Carom.), 140.8 (Carom.), 138.6 (Carom.),
129.9 (CHarom.), 129.0 (CHarom.), 128.6 (CHarom.), 127.4 (CHarom.),
124.5 (CHarom.), 67.7 (CH), 62.4 (CH2), 57.9 (CH), 53.6 (CH2),
21.5 (CH3), 8.3 (CH3) ppm. ESIMS: m/z = 408.2 [M + H]+, 815.5
[2M + H]+. HRMS: calcd. for C25H30NO2S+ 408.1997; found
408.1991.
HRMS: calcd. for C31H38NO2S+ 488.2623; found 488.2631.
Methyl 2-(Dibenzylamino)propanoate (6): Compound 2a (0.16 mL,
1.43 mmol) was dissolved in THF (10 mL) and dibenzylamine
(0.7 mL, 3.53 mmol) was added. The reaction mixture was heated
under microwave irradiation at 100 °C for 4 h, allowed to cool to
room temperature and stirred until no starting material was de-
tected (10 d) by HPLC analysis. A saturated aqueous solution of
KHCO3 (50 mL) was added, the phases were separated, and the
aqueous layer was extracted with EtOAc (3ϫ 50 mL). The com-
bined organic layers were washed with an aqueous solution of 10%
KHSO4 (2ϫ 50 mL), dried with MgSO4 and concentrated under
reduced pressure. The crude product was used without further puri-
fication for the next step (155 mg, 38%). Rf = 0.7 (cyclohexane/
EtOAc, 2:1). 1H NMR (300 MHz, CDCl3): δ = 7.32–7.12 (m, 10
H, ArH), 3.76 [d, J = 14.0 Hz, 2 H, N(CHaHbPh)2], 3.66 (s, 3 H,
OCH3), 3.56 [d, J = 14.0 Hz, 2 H, N(CHaHbPh)2], 3.44 (q, J =
7.1 Hz, 1 H, CHN), 1.25 (d, J = 7.1 Hz, 3 H, CH3CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 174.4 (C=O), 140.0 (Carom.), 128.8
(Carom.), 128.4 (CHarom.), 127.1 (CHarom.), 56.3 (CH), 54.6 (CH2),
51.4 (CH3), 15.3 (CH3) ppm.
(2R,3S)-3-(Dibenzylamino)-5-methyl-1-[(R)-p-tolylsulfinyl]hexan-2-
ol (syn-7b): Obtained from 4b (156 mg, 0.349 mmol; reaction time:
1 h) as described for syn-7a. The crude product was purified by
column chromatography on silica gel (cyclohexane/EtOAc, 4:1) to
give pure syn-7b as a white solid (120 mg, 77%). Rf = 0.25 (cyclo-
hexane/EtOAc, 2:1); [α]D = +25 (c = 1, acetone); m.p. 118–121 °C.
1H NMR (300 MHz, CDCl3): δ = 7.43 (d, J = 8.2 Hz, 2 H, ArH),
7.24–7.12 (m, 12 H, ArH), 4.25 (br. s, 1 H, OH), 3.77 [d, J =
13.3 Hz, 2 H, N(CHaHbPh)2], 3.67–3.63 (m, J = 7.0 Hz, 1 H,
CHOH), 3.31 [d, J = 13.4 Hz, 2 H, N(CHaHbPh)2], 3.06 (dd, J =
9.2, 12.7 Hz, 1 H, CHaHbSO), 2.54 (m, 2 H, CHaHbSO and CHN),
2.33 (s, 3 H, CH3 pTol), 1.67–1.54 [m, 1 H, CH(CH3)2], 1.45–1.36
(m, 1 H, CHaHbCHN), 1.26–1.18 (m, 1 H, CHaHbCHN), 0.84–
0.80 [m, 6 H, CH(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ =
141.8 (Carom.), 140.8 (Carom.), 139.7 (Carom.), 130.1 (CHarom.), 129.2
(CHarom.), 128.5 (CHarom.), 127.3 (CHarom.), 124.5 (CHarom.), 68.6
(CH), 62.4 (CH2), 60.1 (CH), 54.8 (CH2), 34.6 (CH2), 25.9 (CH),
23.5 (CH3), 22.8 (CH3), 21.6 (CH3) ppm. ESIMS: m/z = 450.3 [M
+ H]+. HRMS: calcd. for C28H36NO2S+ 450.2453; found 450.2464.
3-(Dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-2-one (4a rac): Diiso-
propylamine (0.16 mL, 1.148 mmol) was dissolved in THF (3 mL)
and cooled to –78 °C before adding, dropwise, n-butyllithium
(1.6 m in hexane, 0.7 mL, 1.12 mmol). The system was stirred at
–78 °C for 45 min and then (R)-1 (172 mg, 1.115 mmol), dissolved
in THF (3 mL), was added. After 75 min at –78 °C, a solution of
6 (150 mg, 0.529 mmol) in THF (4 mL) was added. The reaction
mixture was stirred for 1 h at –78 °C and quenched with saturated
aqueous NH4Cl (10 mL). The phases were separated, and the aque-
ous layer was extracted with EtOAc (3ϫ 10 mL). The combined
organic layers were dried with MgSO4 and concentrated under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (cyclohexane/EtOAc, 3:2) to give a
55:45 diastereomeric mixture of 4a as a colorless oil (188 mg, 88%).
Rf = 0.40 and 0.45 (cyclohexane/EtOAc, 2:1). 1H NMR (300 MHz,
CDCl3): δ = 7.32–7.03 (m, 28 H, ArH), 4.14–3.74 (m, 4 H, CH2SO,
2 diast), 3.55–3.18 [m, 9 H, N(CH2Ph)2, 2 diast. and CHN, diast.
A], 2.74 (q, J = 6.6 Hz, 1 H, CHN, diast. B), 2.28 (s, 3 H, CH3
pTol, diast. B), 2.26 (s, 3 H, CH3 pTol, diast. A), 1.03 (d, J =
6.6 Hz, 3 H, CH3CH, diast. B), 0.91 (d, J = 6.6 Hz, 3 H, CH3CH,
diast. A) ppm. 13C NMR (75 MHz, CDCl3): δ = 203.5 (C=O),
203.0 (C=O), 142.1 (Carom.), 142.0 (Carom.), 140.5 (Carom.), 140.0
(Carom.), 138.6 (Carom.), 130.1 (CHarom.), 130.0 (CHarom.), 129.1
(CHarom.), 128.9 (CHarom.), 128.7 (CHarom.), 127.7 (CHarom.), 127.6
(CHarom.), 124.4 (CHarom.), 124.4 (CHarom.), 66.2 (CH2), 63.8 (CH),
63.5 (CH), 54.9 (CH2), 54.8 (CH2), 21.6 (CH3), 6.2 (CH3), 6.0
(CH3) ppm.
(2R,3S)-3-(Dibenzylamino)-4-phenyl-1-[(R)-p-tolylsulfinyl]butan-2-
ol (syn-7c): Obtained from 4c (303 mg, 0.63 mmol; reaction time:
2 h) as described for syn-7a. The crude product was purified by
column chromatography on silica gel (cyclohexane/EtOAc, 4:1) to
give pure syn-7c as a colorless oil (267 mg, 88%). Rf = 0.45 (cyclo-
hexane/EtOAc, 3:2); [α]D = +37.1 (c = 0.97, acetone). 1H NMR
(300 MHz, CDCl3): δ = 7.29–7.07 (m, 19 H, ArH), 4.25 (br. s, 1 H,
OH), 3.88 [d, J = 13.3 Hz, 2 H, N(CHaHbPh)2], 3.78–3.74 (m, 1 H,
CHOH), 3.25 [d, J = 13.3 Hz, 2 H, N(CHaHbPh)2], 2.99–2.85 (m,
2 H, CHaHbSO and CHaHbPh), 2.78–2.66 (m, 2 H, CHaHbSO and
CHN), 2.28 (s, 3 H, CH3 pTol), 2.19 (dd, J = 1.6, 13.2 Hz, 1 H,
CHaHbPh) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.8 (Carom.),
141.1 (Carom.), 139.8 (Carom.), 139.6 (Carom.), 130.2 (CHarom.), 129.6
(CHarom.), 129.2 (CHarom.), 128.9 (CHarom.), 128.6 (CHarom.), 127.4
(CHarom.), 126.5 (CHarom.), 124.3 (CHarom.), 68.4 (CH), 63.8 (CH2),
62.3 (CH), 55.0 (CH2), 30.9 (CH2), 21.7 (CH3) ppm. ESIMS: m/z =
(2R,3S)-3-(Dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-2-ol
(7a-
syn): A solution of 4a (102 mg, 0.25 mmol) in THF (5 mL) was
1306
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1300–1309

Synthesis of (2R,1ЈS)-2-(1-Dibenzylaminoalkyl)epoxides
484.3 [M + H]+, 967.5 [2M + H]+. HRMS: calcd. for C31H34NO2S+
484.2310; found 484.2316.
were dried with MgSO4 and concentrated under reduced pressure
by heating simultaneously at 70 °C to remove the methyl-p-tolyl
sulfide. The crude product was purified by column chromatography
on silica gel (cyclohexane/EtOAc, 10:1) to afford 8a as a colorless
(2R,3S)-4-Cyclohexyl-3-(dibenzylamino)-1-[(R)-p-tolylsulfinyl]but-
an-2-ol (syn-7d): Obtained from 4d (400 mg, 0.82 mmol; reaction
time: 1 h) as described for syn-7a. The crude product was purified
by column chromatography on silica gel (cyclohexane/EtOAc, 3:1)
to give pure syn-7d as a white solid (345 mg, 86%). Rf = 0.30 (cyclo-
hexane/EtOAc, 2:1); [α]D = +13.40 (c = 0.97, CHCl3); m.p. 97–
oil (183 mg, 56%). Rf = 0.45 (cyclohexane/EtOAc, 10:1); [α]D
=
+5.7 (c = 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.17
(m, 10 H, ArH), 3.80 [d, J = 13.8 Hz, 2 H, N(CHaHbPh)2], 3.67
[d, J = 13.8 Hz, 2 H, N(CHaHbPh)2], 3.08 (ddd, J = 2.8, 4.0, 6.0 Hz,
1 H, CHO), 2.83–2.74 (m, 1 H, CHN), 2.66 (dd, J = 4.2, 4.9 Hz,
1 H, CHaHbO), 2.49 (dd, J = 2.7, 5.0 Hz, 1 H, CHaHbO), 1.04 (d,
J = 6.9 Hz, 3 H, CH3CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
140.5 (Carom.), 128.8 (CHarom.), 128.4 (CHarom.), 127.0 (CHarom),
54.8 (CH), 54.6 (CH2), 54.0 (CH), 44.1 (CH2), 11.4 (CH3) ppm.
ESIMS: m/z = 268.1 [M + H]+. HRMS: calcd. for C18H22NO+
268.1701; found 268.1705.
1
99 °C. H NMR (300 MHz, CDCl3): δ = 7.53 (d, J = 8.2 Hz, 2 H,
ArH), 7.34–7.20 (m, 12 H, ArH), 4.30 (br. s, 1 H, OH), 3.84 [d, J
= 13.3 Hz, 2 H, N(CHaHbPh)2], 3.71 (ddd, J = 2.1, 7.2, 9.2 Hz, 1
H, CHOH), 3.40 [d, J = 13.4 Hz, 2 H, N(CHaHbPh)2], 3.14 (dd, J
= 9.3, 12.8 Hz, 1 H, CHaHbSO), 2.69–2.58 (m, 2 H, CHaHbSO and
CHN), 2.43 (s, 3 H, CH3 pTol), 1.71–1.65 (m, 5 H), 1.55–1.47 (m,
1 H), 1.33–1.14 (m, 5 H), 0.94–0.81 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 141.9 (Carom.), 140.9 (Carom.), 139.8 (Carom.),
130.2 (CHarom.), 129.3 (CHarom.), 128.6 (CHarom.), 127.4 (CHarom.),
124.5 (CHarom.), 68.8 (CH), 62.5 (CH2), 59.4 (CH), 54.8 (CH2),
35.5 (CH), 34.3 (CH2), 33.7 (CH2), 33.2 (CH2), 26.7 (CH2), 26.5
(CH2), 26.4 (CH2), 21.7 (CH3) ppm. ESIMS: m/z = 490.4 [M +
H]+. HRMS: calcd. for C31H40NO2S+ 490.2780; found 490.2785.
(2R,1ЈS)-2-[1-(Dibenzylamino)-3-methylbutyl]oxirane (8b): Ob-
tained from syn-7b (424 mg, 0.94 mmol) as described for 8a. The
crude product was purified by column chromatography on silica
gel (cyclohexane/EtOAc, 6:1) to afford 8b as a colorless oil (131 mg,
45%). Rf = 0.65 (cyclohexane/EtOAc, 4:1); [α]D = –18.6 (c = 0.59,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.31–7.10 (m, 10 H,
ArH), 3.77 [d, J = 13.4 Hz, 2 H, N(CHaHbPh)2], 3.67 [d, J =
13.4 Hz, 2 H, N(CHaHbPh)2], 3.02 (ddd, J = 2.8, 4.0, 7.1 Hz, 1 H,
CHO), 2.63–2.59 (m, 1 H, CHaHbO), 2.39–2.28 (m, 2 H, CHN and
CHaHbO), 1.79–1.66 [m, 1 H, CH(CH3)2], 1.47 (ddd, J = 5.2, 9.1,
14.1 Hz, 1 H, CHaHbCHN), 0.98 (ddd, J = 5.3, 8.6, 13.9 Hz, 1 H,
CHaHbCHN), 0.73 (d, J = 6.7 Hz, 3 H, CH3CHCH3), 0.46 (d, J =
6.5 Hz, 3 H, CH3CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
140.5 (Carom.), 129.2 (CHarom.), 128.3 (CHarom.), 126.9 (CHarom.),
57.2 (CH), 54.5 (CH2), 52.7 (CH), 44.1 (CH2), 38.3 (CH2), 24.5
(CH), 23.6 (CH3), 22.0 (CH3) ppm. ESIMS: m/z = 310.3 [M +
H]+. HRMS: calcd. for C21H28NO+ 310.2171; found 310.2131.
(2S,3S)-4-Cyclohexyl-3-(dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-
2-ol (anti-7d): To a solution of 4d (160 mg, 0.328 mmol) in THF
(10 mL) was added DIBAL-H (1.5 m in toluene, 0.55 mL,
0.825 mmol), dropwise, at –78 °C. The system was stirred at –78 °C
for 75 min and treated with MeOH (15 mL). The reaction mixture
was allowed to reach room temperature and the solvents were evap-
orated under reduced pressure. The resulting crude solid was
treated with EtOAc (25 mL) and a saturated aqueous solution of
potassium sodium tartrate (25 mL). The mixture was then stirred
overnight. The phases were separated and the aqueous layer was
extracted with EtOAc (3ϫ 25 mL). The combined organic layers
were washed with brine (2ϫ 25 mL), dried with MgSO4, and con-
centrated. The crude product was purified by column chromatog-
raphy on silica gel (cyclohexane/EtOAc, 3:1) to afford anti-7d as a
colorless oil (140 mg, 87%). Rf = 0.30 (cyclohexane/EtOAc, 2:1);
(2R,1ЈS)-2-[1-(Dibenzylamino)-2-phenylethyl]oxirane (8c): Obtained
from syn-7c (460 mg, 0.95 mmol) as described for 8a. The crude
product was purified by flash chromatography on silica gel (cyclo-
hexane/AcOEt, 100:0 to 95:5) to afford 8c as a colorless oil
(220 mg, 67%). Rf = 0.35 (cyclohexane/Et2O, 10:1); [α]D = –4.9 (c
= 0.61, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.21–7.10 (m, 13
H, ArH), 6.96–6.93 (m, 2 H, ArH), 3.83–3.72 [m, 4 H, N(CH2Ph)2],
3.07 (ddd, J = 2.7, 4.2, 6.8 Hz, 1 H, CHO), 2.95–2.86 (m, 1 H,
CHaHbPh), 2.72–2.61 (m, 2 H, CHaHbPh and CHN), 2.51 (dd,
J = 4.2, 5.0 Hz, 1 H, CHaHbO), 2.12 (dd, J = 2.7, 5.1 Hz, 1 H,
CHaHbO) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.9 (Carom.),
138.2 (Carom.), 128.3 (CHarom.), 127.6 (CHarom.), 127.2 (CHarom.),
127.1 (CHarom.), 125.7 (CHarom.), 125.0 (CHarom.), 60.3 (CH), 53.3
(CH2), 51.1 (CH), 43.4 (CH2), 34.1 (CH2) ppm. ESIMS: m/z =
344.2 [M + H]+. HRMS: calcd. for C24H26NO+ 344.2014; found
344.2011.
1
[α]D = +51.61 (c = 0.62, CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.52 (d, J = 8.2 Hz, 2 H, ArH), 7.35 (d, J = 8.1 Hz, 2 H, ArH),
7.28–7.10 (m, 10 H, ArH), 4.50–4.46 (m, 1 H, CHOH), 4.12 (br. s,
1 H, OH), 3.61 [d, J = 13.7 Hz, 2 H, N(CHaHbPh)2], 3.43 [d, J =
13.7 Hz, 2 H, N(CHaHbPh)2], 2.96 (dd, J = 10.2, 13.4 Hz, 1 H,
CHaHbSO), 2.67 (d, J = 13.4 Hz, 1 H, CHaHbSO), 2.57–2.51 (m,
1 H, CHN), 2.42 (s, 3 H, CH3 pTol), 1.62 (m, 6 H), 1.41 (d, J =
15.7 Hz, 1 H), 1.20 (m, 4 H), 0.94–0.82 (m, 1 H), 0.73–0.62 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.7 (Carom.), 140.1
(Carom.), 139.6 (Carom.), 130.2 (CHarom.), 129.0 (CHarom.), 128.3
(CHarom.), 127.1 (CHarom.), 124.3 (CHarom.), 66.5 (CH), 59.3 (CH2),
58.0 (CH), 54.5 (CH2), 34.7 (CH), 34.2 (CH2), 34.0 (CH2), 33.6
(CH2), 26.8 (CH2), 26.7 (CH2), 26.4 (CH2), 21.6 (CH3) ppm. ES-
IMS: m/z = 490.4 [M + H]+. HRMS: calcd. for C31H40NO2S+
490.2780; found 490.2778.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all compounds,
chiral HPLC analysis for compounds 3a and 4a, crystallographic
data and ORTEP for compound 4a.
(2R,1ЈS)-2-[1-(Dibenzylamino)ethyl]oxirane (8a): A mixture of syn-
7a (498 mg, 1.22 mmol) and tert-butyl bromide (1.2 mL,
10.34 mmol) was heated to reflux in CHCl3 (15 mL) overnight. The
system was then allowed to cool to room temperature and the sol-
vents were evaporated under reduced pressure. The crude material
was dissolved in CH2Cl2 (10 mL) before adding trimethyloxonium
tetrafluoroborate (471 mg, 3.18 mmol), and the resulting solution
was stirred at room temperature for 5 h. The reaction mixture was
treated with saturated aqueous K2CO3 (10 mL) and stirred over-
night. The phases were separated and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ 50 mL). The combined organic layers
Acknowledgments
Thanks are expressed to Mr. Pierre Sánchez for his help in ob-
taining mass spectra and to Dr. A. Van der Lee for performing the
X-ray analysis.
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Eur. J. Org. Chem. 2011, 1300–1309
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1307

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Received: October 14, 2010
Published Online: January 11, 2011
Eur. J. Org. Chem. 2011, 1300–1309
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