Stereocontrolled synthesis of 1,3-amino alcohols by reduction of substituted 2-{1-[(tert-butylsulfinyl)amino]alkyl}cyclohexanones

Article abstract of DOI:10.1055/s-0029-1216821

Assembly of diethylzinc, cyclohex-2-en-1-one, and a chiral N-tert-butylsulfinyl imine in the presence of an appropriate phosphoramidite ligand yields a β-sulfinylamino cyclohexanone, which on reduction with sodium borohydride or lithium triethylborohydrid

Full text of DOI:10.1055/s-0029-1216821

SPECIAL TOPIC
2083
Stereocontrolled Synthesis of 1,3-Amino Alcohols by Reduction of Substituted
2-{1-[(tert-Butylsulfinyl)amino]alkyl}cyclohexanones
1
, 3-Amino
o
A
lcohols sé C. González-Gómez,* Francisco Foubelo,* Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: josecarlos.gonzalez@ua.es; E-mail: foubelo@ua.es
Received 10 March 2009
Dedicated to Professor Yoshinori Yamamoto on the occasion of his 65th birthday
OH NH2
O
Me
Abstract: Assembly of diethylzinc, cyclohex-2-en-1-one, and a
chiral N-tert-butylsulfinyl imine in the presence of an appropriate
phosphoramidite ligand yields a b-sulfinylamino cyclohexanone,
which on reduction with sodium borohydride or lithium triethyl-
borohydride provides access to a wide range of enantiomerically
pure N-tert-butylsulfinyl 1,3-amino alcohols with five stereogenic
centers.
Me
Me
Me
3 steps
(a)
Me
Me
(+)-pulegone
O
(–)-8-aminomenthol
H
H
S
*
Key words: amino alcohols, ketones, reduction, phosphoramidites,
multicomponent reaction, stereoselectivity
O
N
*
t-Bu
OH NH2
H
R2
R2
*
*
2 steps
(b)
R1
R1
( )n
( )n
I
II
Chiral amino alcohols are useful as building blocks in
asymmetric synthesis, where they can function as ligands
or auxiliaries. Although less common than 1,2-amino al-
cohols, 1,3-amino alcohols have been used extensively in
asymmetric synthesis.1
n = 0, 1, 2
R1, R2 = alkyl, aryl
Scheme 1 Stereoselective synthesis of b-amino cycloalkanols
After the seminal contribution of He and Eliel in 1987,2
more work has been published on the chemistry of (–)-8-
and sulfinimine 2 (or its enantiomer ent-2) for the sake of
simplicity in this study. In our previous study, we used the
phosphoramidite ligand L2, because it permits the gener-
ation of highly enantioenriched enolates (ee > 98%)
through a copper-catalyzed addition of dialkylzinc re-
agents to cyclic enones.6 We decided to re-examine the
tandem reaction by using phosphoramidite ligand L1, in
which the binaphthyl moiety is the sole source of chirality,
and which has been reported to afford only modest enan-
tioselectivity (60% ee) in the conjugate addition.7
aminomenthol
[(1S,2S,5R)-2-(2-aminopropan-2-yl)-5-
methylcyclohexanol] and its derivatives than on any other
single 1,3-amino alcohol.3 This is probably because such
compounds can be readily prepared in three steps from
natural (+)-pulegone (Scheme 1, a). To the best of our
knowledge, and despite the prevalence of (–)-8-amino-
menthol as a source of chirality in asymmetric synthesis,
no work on any other stereoisomer has been reported. Un-
doubtedly, this is because of the lack of affordable enan-
tiomerically pure precursors and routes for the efficient
syntheses of these chiral building blocks.4
Our studies in which we used ligand L1 in the tandem
copper-catalyzed addition of diethylzinc to cyclohex-2-
en-1-one and Mannich reaction with sulfinimine 2 (or ent-
2) are summarized in Table 1. Interestingly, better diaste-
reoselection was obtained when the (RS)-sulfinimine 2
was added before the conjugate addition occurred (entries
1 and 3), and the opposite was observed with ent-2 (en-
tries 2 and 4). A greater excess of the enolate afforded
similar results, suggesting that kinetic resolution of the
homochiral enolate is not a good explanation for this
matched/mismatched combination. It is more likely that
the (RS)-sulfinimine 2 cooperates with phosphoramidite
Sa-L1 in the copper-catalyzed addition of diethylzinc;
however, we lack firm evidence to support this hypothe-
sis. Importantly, diastereoisomers 3a and 3b could be eas-
ily separated by normal flash chromatography (FC).
Nevertheless, the use of the phosphoramidite ligand L2 is
still more practical, because compound 3a is obtained as a
single isomer (entry 5). Unfortunately, a rather low selec-
tivity was observed when the combination of ligand L2
We have recently reported that enantiomerically pure b-
amino cycloalkanones can be readily prepared by trapping
by chiral N-tert-butylsulfinyl imines of the chiral enolates
formed by asymmetric conjugate addition of dialkylzinc
reagents to cycloalkanones.5 These enantiomerically pure
b-amino cycloalkanones, which contain three consecutive
stereogenic centers, offer a good platform for the stereo-
selective synthesis of syn- and anti-1,3-amino alcohols
(Scheme 1, b).
Although a broad range of substrates could be used for the
preparation of b-aminocycloalkanones by our tandem
procedure, we selected diethylzinc, cyclohex-2-en-1-one,
SYNTHESIS 2009, No. 12, pp 2083–2088
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.05.2009
DOI: 10.1055/s-0029-1216821; Art ID: C01009SS
© Georg Thieme Verlag Stuttgart · New York

2084
J. C. González-Gómez et al.
SPECIAL TOPIC
and sulfinimine ent-2 was used, compounds ent-3b and The absolute configuration of compound 4a was deter-
ent-3c being obtained as an inseparable 71:29 mixture mined by single-crystal X-ray analysis. The observed ste-
(entry 6).8
reochemistry was consistent with an axial hydride
delivery from sodium borohydride to the diequatorial con-
former of cyclohexanone 3a (Figure 1).
The stereochemical information present in cyclohex-
anones 3 suggests that a stereoselective reduction is pos-
sible. However, because control can be exerted by the
cyclohexanone moiety as well as by the sulfinylamino
group, the stereochemical outcome was not completely
apparent at the outset of this work. Moreover, the repul-
sive gauche interaction between the C(2) and C(3) substit-
uents of the cyclohexanone moiety could favor the diaxial
conformer over the usual diequatorial one, further compli-
cating the result.9
Reduction of compound 3a with sodium borohydride
gave the crystalline amino alcohol 4a exclusively in al-
most quantitative yield. When the 71:29 mixture of com-
pounds 3b and 3c was reduced by sodium borohydride,
diastereoisomers 4c and 4d were isolated as pure com-
pounds after FC. To confirm the stereochemical assign-
ment, the sulfinyl group in compounds 4a and 4d was
oxidized with 3-chloroperoxybenzoic acid to give the sul-
fonamides 4f and ent-4f, respectively. This result clearly
supports the view that the formation of the minor b-amino
cycloalkanone 3c is a consequence of poor diastereocon-
trol in the reaction of the chiral enolate with the chiral
sulfinimine (Scheme 2).
Figure 1 X-ray crystal structure of compound 4a
Importantly, because both enantiomers of the phosphor-
amidite ligand and tert-butylsulfinamides were available,
enantiomers of amino alcohols 4a–e were also prepared
from ent-L2 and ent-2 (see below). Moreover, the N-sulfi-
nyl group can be easily oxidized to a sulphonamide group
(e.g., 4f) or removed with methanolic hydrogen chloride
to give the free amine, which can be further alkylated. We
hope that this ability to modify the electronic nature of the
amino group could be useful in finding future applications
Interestingly, reduction of 3a with lithium triethylborohy-
dride at –78 °C gave the syn-amino alcohol 4b, whereas
anti-amino alcohols are formed preferentially by reduc-
tion of acyclic N-sulfinyl b-amino ketones.10 More sur-
prisingly, when the mixture of compounds 3b + 3c was
submitted to reduction under the same conditions, syn-
amino alcohols 4c and 4e were isolated after FC
(Scheme 2).
Table 1 Syntheses of 2-{[(tert-Butylsulfinyl)amino]methyl}cyclohexanone 3a–c
O
S
O
S
O
O
S
O
H
H
H
H
O
H
H
S
S
Cu(OTf)2 cat.
L1 (or L2)
Et2Zn
O
N
t-Bu
Ph
O
N
t-Bu
Ph
N
t-Bu
O
N
t-Bu
Ph
N
t-Bu
Ph
Ph
ent-2
2
+
ent-3a
ent-3b
+
+
CH2Cl2, –20 °C
CH2Cl2, –20 °C
Et
Et
Et
1
3a
3b
ent-3c
Entry
Ligand
L1
Method
Imine
2
Products (ratio)c
1
2
3
4
5
6
Aa
A
Bb
B
3a + 3b (77:23)
Me
N
O
R
R
L1
ent-2
2
ent-3a + ent-3b + ent-3c (27:67:6)
3a + 3b (86:14)
P
L1
O
Me
L1
ent-2
2
ent-3a, ent-3b, ent-3c (49:48:3)
3a (>98)
L1 (R = Me)
L2 (R = Ph)
L2
B
L2
B
ent-2
ent-3b + ent-3c (71:29)
a Method A: The sulfinimine (2 or ent-2) was added 5 h after the addition of Et2Zn.
b Method B: Et2Zn was added to the mixture of cyclohex-2-en-1-one, ligand, Cu(OTf)2, and sulfinimine 2.
c Relative amounts of each diasteromeric product as determined by 1H NMR of the crude reaction mixture.
Synthesis 2009, No. 12, 2083–2088 © Thieme Stuttgart · New York

SPECIAL TOPIC
1,3-Amino Alcohols
2085
O
O
S
O
O
O
H
H
H
S
H
H
H
H
H
H
S
H
H
H
S
O
N
t-Bu
Ph
O
N
t-Bu
Ph
O
N
t-Bu
Ph
O
N
t-Bu
Ph
m-CPBA
+
CH2Cl2, –20 °C
Et
Et
Et
Et
m-CPBA
ent-4f
4c (44%)
4d (21%)
4f (75%)
4a (96%)
CH2Cl2, –20 °C
O
S
Cu(OTf)2 cat.
1) NaBH4, EtOH
2) FC separation
NaBH4, EtOH
O
N
t-Bu
ent-L2
L2
3b/3c (71:29)
(68% combined yield)
3a (89%)
Ph
CH2Cl2, –20 °C
CH2Cl2, –20 °C
2
Et2Zn
1
1) LiBHEt3, THF, –78 °C
2) FC separation
LiBHEt3, THF, –78 °C
O
O
H
H
H
S
H
H
H
S
O
N
t-Bu
O
N
t-Bu
Ph
Ph
+
4c (45%)
Et
4b (84%)
Et
4e (24%)
Scheme 2 Synthesis of N-protected 1,3-amino alcohols 4a–f
–40 °C. A 1.0 M soln of Et2Zn in toluene (9.0 mL, 9 mmol) was add-
ed dropwise and the mixture was allowed to reach –20 °C while be-
ing stirred for 5 h. A soln of sulfinimine 2 (482 mg, 2.00 mmol) in
CH2Cl2 (6.0 mL) was then added dropwise, and the mixture was
stirred overnight at –20 °C. The reaction was quenched at –20 °C by
addition of a sat. soln of NH4Cl in 1:1 H2O–MeOH (3.0 mL), and
the mixture was stirred for 15 min at r.t.. The resulting precipitate
was filtered off on a short pad of Celite and, after evaporation of sol-
vents, the crude sample was analyzed by 1H NMR spectroscopy to
determine the imine conversion and the diastereomeric ratio of the
products. The sample was then purified by column chromatography
(silica gel, EtOAc–hexane, 75:25 to 70:30) to give pure 3a5b and 3b
as colorless oils; yield: 3a: 474 mg (66%); 3b: 144 mg (20%).
Compound 3b: [a]D20 –30.7 (c 2.5, CHCl3).
IR (KBr): 2957, 2868, 1698, 1454, 1069 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26 (m, 2 H), 7.15 (m, 3 H), 4.71
(d, J = 7.2 Hz, 1 H), 3.40 (m, 1 H), 2.83 (m, 1 H), 2.55 (m, 1 H),
2.30 (m, 4 H), 2.10 (m, 1 H), 1.92 (m, 1 H), 1.80–1.60 (m, 3 H), 1.40
(m, 2 H), 1.26 (s, 9 H), 0.87 (t, J = 7.2 Hz, 3 H).
for these chiral 1,3-amino alcohols in asymmetric synthe-
sis.
In conclusion, the stereoselective reduction of easily
available
hexanones with sodium borohydride or lithium triethyl-
borohydride gives access to wide range of
2-{1-[(tert-butylsulfinyl)amino]alkyl}cyclo-
a
enantiomerically pure 1,3-amino alcohols. Only two syn-
thetic operations are required to build these amino alco-
hols, which have five stereogenic centers.
TLC was performed on Merck silica gel 60 F254, using aluminum
plates and visualized by staining with phosphomolybdic acid. Flash
chromatography (FC) was carried out on hand-packed columns of
Merck silica gel 60 (0.040–0.063 mm) with hexane–EtOAc as the
eluent. IR spectra were recorded on a Nicolet Impact 510 P-FT
Spectrometer. Melting points were recorded on an OptiMelt (Stan-
ford Research Systems) apparatus using open glass capillaries and
1
are reported without corrections. H NMR spectra were recorded
13C NMR (75 MHz, CDCl3): d = 9.46 (CH3), 23.1 (CH3), 25.1
(CH2), 25.6 (CH2), 26.4 (CH2), 33.1 (CH2), 38.5 (CH2), 41.4 (CH),
43.0 (CH2), 55.2 (CH), 56.4 (q), 58.8 (CH), 125.9 (CH), 128.3
(CH), 128.4 (CH), 141.6 (q), 215.0 (q).
HRMS–MALDI: m/z [M + Na]+ calcd for C21H33NNaO2S:
386.2130; found: 386.2139.
with a Bruker AC-300 using CDCl3 (d = 7.27) or CD3OD (d = 4.84)
as the solvent and internal standard. 13C NMR spectra were record-
1
ed with H-decoupling on a BRUKER 75-MHz spectrometer, and
DEPT-135 experiments were performed to assign the CH, CH2 and
CH3 protons. Optical rotations were measured on a Perkin Elmer
341 polarimeter. HRMS (EI) were recorded on a Finnigan MAT
95S. N-Sulfinyl imine 211 and phosphoramidite ligands L1 and L212
were prepared according to the reported procedures. The properties
of known compounds matched those reported in the corresponding
references.
(RS)-N-{(1R)-1-[(1R,2S)-2-Ethyl-6-oxocyclohexyl]-3-phenylpro-
pyl}-2-methylpropane-2-sulfinamide (3a); Typical Procedure B
Cu(OTf)2 (22 mg, 0.06 mmol), phosphoramidite L2 (66 mg, 0.12
mmol), enone 1 (230 mg, 240 mL, 2.40 mmol) and sulfinimine 2
(482 mg, 2.00 mmol) were suspended in CH2Cl2 (14.0 mL) and
stirred at r.t. for 15 min before cooling to –40 °C. A 1.0 M soln of
Et2Zn in toluene (9.0 mL, 9 mmol) was added dropwise and the
mixture was allowed to reach –20 °C while being stirred overnight
(12 h). Quenching and purification were carried out as described
above to give pure 3a5b as a colorless oil; yield: 640 mg (89%).
(RS)-N-{(1R)-1-[(1R,2S)-2-Ethyl-6-oxocyclohexyl]-3-phenylpro-
pyl}-2-methylpropane-2-sulfinamide (3a) and (RS)-N-{(1R)-1-
[(1R,2R)-2-Ethyl-6-oxocyclohexyl]-3-phenylpropyl}-2-methyl-
propane-2-sulfinamide (3b); Typical Procedure A
Cu(OTf)2 (22 mg, 0.06 mmol), phosphoramidite L1 (66 mg, 0.12
mmol), and enone 1 (230 mg, 240 mL, 2.40 mmol) were suspended
in CH2Cl2 (8.0 mL) and stirred at r.t. for 15 min before cooling to
Synthesis 2009, No. 12, 2083–2088 © Thieme Stuttgart · New York

2086
J. C. González-Gómez et al.
SPECIAL TOPIC
(RS)-N-{(1R)-1-[(1R,2S,6R)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (4a); Typical
Procedure for Reduction with NaBH4
1H NMR (300 MHz, CD3OD): d = 7.26 (m, 2 H), 7.15 (m, 3 H), 4.23
(m, 1 H), 3.45 (m, 1 H), 2.75 (dt, J = 13.3, 5.9 Hz, 1 H), 2.56 (dt,
J = 13.3, 8.2 Hz, 1 H), 1.85–1.65 (m, 6 H), 1.50 (m, 1 H), 1.40 (m,
2 H), 1.20 (s, 9 H), 1.15–0.80 (m, 3 H), 0.74 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CD3OD): d = 9.9 (CH3), 20.5 (CH2), 23.6
(CH3), 25.9 (CH2), 31.6 (CH2), 33.4 (CH), 33.9 (CH2), 35.6 (CH2),
39.7 (CH2), 47.9 (CH), 57.45 (q), 57.50 (CH), 67.8 (CH), 126.9
(CH), 129.5 (CH), 129.9 (CH), 143.2 (q).
NaBH4 (100 mg, 2.6 mmol) was added to a soln of 3a (492 mg, 1.36
mmol) in 95% EtOH (7 mL) at 0 °C, and the mixture was stirred at
0 °C for 2 h (TLC monitoring; hexane–EtOAc, 1:1). Sat. aq NH4Cl
was then carefully added (5 mL). When gas evolution ceased, the
mixture was partitioned between EtOAc (50 mL) and H2O (20 mL).
The aqueous phase was extracted with more EtOAc (2 × 20 mL),
and the combined organics extracts were washed with brine (10
mL) and dried (MgSO4). The filtered soln was concentrated in
vacuo to give pure 4a as a colorless solid; yield: 471 mg (96%); mp
175–178 °C; [a]D20 –5.2 (c 1.00, EtOH).
MS (EI, 70 eV): m/z (%) = 91.0 (72), 117.0 (100), 181.0 (42), 227
(20), 309 (21) [M – C4H8]+.
Compound 4d: [a]D20 –96.7 (c 0.65, EtOH).
IR (KBr): 3374, 3222, 2928, 1455, 1362, 1033 cm–1.
IR (KBr): 3374, 3222, 2928, 1455, 1362, 1033 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.25 (m, 5 H), 3.56 (td, J = 10.3,
4.4 Hz, 1 H), 3.25 (m, 1 H), 2.89 (dt, J = 13.8, 6.0 Hz, 1 H), 2.78 (dt,
J = 13.8, 8.4 Hz, 1 H), 1.80 (m, 3 H), 1.60 (m, 1 H), 1.50 (m, 1 H),
1.25 (m, 4 H), 1.20 (s, 9 H), 1.15–0.80 (m, 4 H), 0.60 (t, J = 7.2 Hz,
3 H).
13C NMR (75 MHz, CD3OD): d = 9.7 (CH3), 23.2 (CH3), 25.0
(CH2), 25.7 (CH2), 31.8 (CH2), 33.3 (CH2), 34.6 (CH2), 37.6 (CH2),
39.7 (CH), 54.1 (CH), 57.2 (q), 58.4 (CH), 73.1 (CH), 126.9 (CH),
129.4 (CH), 130.1 (CH), 143.4 (q).
1H NMR (400 MHz, CD3OD): d = 7.26 (m, 2 H), 7.15 (m, 3 H), 3.56
(td, J = 10.1/3.9 Hz, 1 H), 3.36 (m, 1 H), 2.83 (dt, J = 13.3, 5.9 Hz,
1 H), 2.55 (dt, J = 13.3, 8.2 Hz, 1 H), 1.75 (m, 3 H), 1.65–1.45 (m,
3 H), 1.27 (m, 2 H), 1.24 (s, 9 H), 1.15–0.80 (m, 4 H), 0.67 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CD3OD): d = 9.9 (CH3), 23.5 (CH3), 25.1
(CH2), 25.6 (CH2), 30.7 (CH2), 31.9 (CH2), 33.5 (CH2), 37.5 (CH2),
40.0 (CH), 53.7 (CH), 57.3 (q), 58.3 (CH), 73.6 (CH), 127.0 (CH),
129.5 (CH), 129.9 (CH), 143.2 (q).
MS (EI, 70 eV): m/z (%) = 91.0 (68), 117.0 (100), 181.0 (44), 227
(7), 309 (54) [M – C4H8]+.
MS (EI, 70 eV): m/z (%) = 91.0 (68), 117.0 (100), 181.0 (44), 227
(7), 309 (54) [M – C4H8]+.
HRMS–EI: m/z [M – C4H8]+ calcd for C17H27NO2S: 309.1762;
found: 309.1781.
(SS)-N-{(1R)-1-[(1R,2R,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (ent-4c) and
(SS)-N-{(1S)-1-[(1R,2R,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (ent-4d)
By following the typical procedure, a 2.4:1 mixture of ent-3b and
ent-3c (500 mg) was reduced with NaBH4 (120 mg). After FC (hex-
ane–EtOAc, 3:2 to 1:1), pure ent-4c and ent-4d were obtained as
colorless foams; ent-4c; yield: 201 mg (40%); [a]D20 +74.0 (c 0.85,
MeOH), ent-4d; yield: 103 mg (20%); [a]D20 +95.0 (c 0.65, MeOH).
Crystal Structure:13 C21H35NO2S, M = 365.57; triclinic,
a = 9.5123(11) Å, b = 9.7013(11) Å, c = 13.3331(15) Å,
a = 94.474(2), b = 110.126(2), g = 105.743(2); V = 1091.8(2) Å3;
space group P1; Z = 2; Dc = 1.112 Mg m–3; l = 0.71073 Å;
m = 0.161 mm–1; F(000) = 400; T = 23 1 °C. Data collection was
performed on a Bruker Smart CCD diffractometer, based on three
w-scan runs (starting = –34°) at values f = 0°, 120°, and 240° with
the detector at 2q = –32°. For each of these runs, 606 frames were
collected at 0.3° intervals and 20 s per frame. An additional run at
f = 0° of 100 frames was collected to improve redundancy. The
diffraction frames were integrated by using the program SAINT,14a
and the integrated intensities were corrected for Lorentz polariza-
tion effects with SADABS.14b The structure was solved by direct
(RS)-N-{(1R)-1-[(1S,2S,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (4b); Typical
Procedure for Reduction with LiBHEt3
A 1 M soln of LiBHEt3 in THF (9 mL, 9 mmol) was added dropwise
from a syringe to a soln of 3a (530 mg, 1.50 mmol) in anhyd THF
(24 mL) at –78 °C under argon, and the mixture was stirred for 3 h
at –78 °C (TLC monitoring; hexane–EtOAc, 1:2). 1:1 MeOH–aq
NH4Cl (10 mL) was added and the mixture was stirred for an addi-
tional 15 min while the temperature increased to r.t. and gas evolu-
tion ceased. The mixture was partitioned between EtOAc (50 mL)
and H2O (20 mL), and the aqueous phase was extracted with addi-
tional EtOAc (2 × 20 mL). The combined organics extracts were
washed with brine (10 mL) and dried (MgSO4). The filtered soln
was concentrated in vacuo to give crude 4b, which was triturated
with hexane (10 mL) to give a precipitate that was filtered off to
give pure 4b as a colorless solid; yield: 445 mg (82%); mp 152–155
°C; [a]D20 +51.0 (c 0.60, EtOH).
2
methods and refined to all 7190 unique Fo by full-matrix least-
squares.14c All the hydrogen atoms were placed at idealized posi-
tions and refined as rigid atoms. Final wR2 = 0.1448 for all data and
467 parameters; R1 = 0.0613 for 4885 Fo > 4s(Fo).
(SS)-N-{(1R)-1-[(1R,2S,6R)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (ent-4a)
By following the typical procedure starting from ent-3a (616 mg,
1.70 mmol) and NaBH4 (120 mg), pure compound ent-4a was ob-
tained as a colorless solid; yield: 565 mg (92%); [a]D20 +5.0 (c 1.00,
EtOH).
IR (KBr): 3208 (br), 2956, 1456, 1355, 1025 cm–1.
(RS)-N-{(1R)-1-[(1R,2R,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (4c) and (RS)-
N-{(1S)-1-[(1R,2R,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-phenyl-
propyl}-2-methylpropane-2-sulfinamide (4d)
By following the typical procedure, a 2.4:1 mixture of 3b and 3c
(550 mg, 1.50 mmol) was reduced by NaBH4 (110 mg, 2.9 mmol).
After solvent evaporation, the residue was purified by FC (hexane–
EtOAc, 3:2 to 1:1) to give pure compounds 4c and 4d as colorless
foams; yield: 4c: 244 mg (44%); 4d: 116 mg (21%).
1H NMR (300 MHz, CD3OD): d = 7.26 (m, 2 H), 7.15 (m, 3 H), 4.20
(m, 1 H), 3.38 (m, 1 H), 2.75 (dt, J = 13.3, 5.9 Hz, 1 H), 2.53 (dt,
J = 13.3, 8.2 Hz, 1 H), 1.90 (m, 1 H), 1.80 (m, 1 H), 1.60 (m, 2 H),
1.50 (m, 2 H), 1.40 (m, 2 H), 1.23 (s, 9 H), 1.15 (m, 1 H), 0.80 (m,
3H), 0.64 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CD3OD): d = 10.3 (CH3), 20.9 (CH2), 23.4
(CH3), 25.5 (CH2), 32.2 (CH2), 34.7 (CH2), 34.8 (CH2), 35.2 (CH),
51.2 (CH), 57.8 (q), 59.9 (CH), 67.2 (CH), 126.9 (CH), 129.4 (CH),
129.8 (CH), 143.3 (q).
Compound 4c: [a]D20 –76.5 (c 0.65, EtOH).
IR (KBr): 3374, 3222, 2928, 1455, 1362, 1033 cm–1.
MS (EI, 70 eV): m/z (%) = 91.0 (72), 117.0 (100), 181.0 (42), 227
(20), 309 (21) [M – C4H8]+.
Synthesis 2009, No. 12, 2083–2088 © Thieme Stuttgart · New York

SPECIAL TOPIC
1,3-Amino Alcohols
2087
HRMS–EI: m/z calcd for C17H27NO2S [M – C4H8]+: 309.1762;
found: 309.1780.
MS (EI, 70 eV): m/z (%) = 57.1 (24), 91.1 (25), 134.1 (100), 156.1
(23), 254.1 (24) [M – C8H15O]+, 381.2 (1) [M]+.
HRMS–EI: m/z [M – C8H15O]+ calcd for C13H20NO2S: 254.1215;
found: 254.1211.
(SS)-N-{(1R)-1-[(1S,2S,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (ent-4b)
By following the typical procedure, ent-3a (556 mg, 1.53 mmol)
was reduced by a 1 M soln of LiBHEt3 in THF (9 mL, 9 mmol) to
give pure ent-4b; yield: 444 mg (80%); [a]D –55.0 (c 0.90,
MeOH).
N-{(1S)-1-[(1R,2R,6S)-2-Ethyl-6-hydroxycyclohexyl]-3-phenyl-
propyl}-2-methylpropane-2-sulfonamide (ent-4f)
By following the typical procedure from 4d (55 mg, 0.15 mmol) and
MCPBA (70%, 55 mg, 0.23 mmol), pure ent-4f was isolated as a
colorless foam; yield: 39 mg (71%); [a]D20 –29.0 (c 2.5, CH2Cl2).
20
(RS)-N-{(1S)-1-[(1R,2R,6R)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (4e)
By following the typical procedure, a 2.4:1 mixture of 3b and 3c
(570 mg, 1.57 mmol) was reduced with a 1 M soln of LiBHEt3 in
THF (10 mL, 10 mmol). After aqueous workup and solvent evapo-
ration, the residue was purified by FC (hexane–EtOAc, 3:2 to 1:1)
to give pure 4c and 4e as colorless foams; yield: 4c: 256 mg (45%);
4e: 139 mg (24%).
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; Consolider Ingenio 2010-CSD2007-
00006 and CTQ-2007-65218).
Compound 4e: [a]D20 –124.0 (c 0.50, EtOH).
IR (KBr): 3471, 3415, 2927, 1454, 1362, 1035 cm–1.
References
(1) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007,
107, 767.
1H NMR (300 MHz, CD3OD): d = 7.26 (m, 4 H), 4.19 (m, 1 H), 3.37
(m, 1 H), 2.85 (m, 1 H), 2.58 (m, 1 H), 1.90 (m, 2 H), 1.75–1.35 (m,
5 H), 1.30 (m, 1 H), 1.20 (s, 9 H), 0.90 (m, 3 H), 0.70 (m, 1 H), 0.65
(m, 3 H).
13C NMR (75 MHz, CD3OD): d = 10.2 (CH3), 20.9 (CH2), 23.3
(CH3), 25.3 (CH2), 32.1 (CH2), 33.9 (CH2), 34.7 (CH2), 34.8 (CH),
35.5 (CH2), 52.4 (CH), 57.0 (q), 58.6 (CH), 66.7 (CH), 126.8 (CH),
129.3 (CH), 130.0 (CH), 143.6 (q).
(2) (a) He, X.-C.; Eliel, E. L. Tetrahedron 1987, 43, 4979.
(b) Eliel, E. L.; He, X.-C. J. Org. Chem. 1990, 55, 2114.
(3) For selected examples, see: (a) Alberola, A.; Andrés, C.;
Nieto, J.; Pedrosa, R. Synlett 1990, 763. (b) Pedrosa, R.;
Andrés, C.; Iglesias, J. M. J. Org. Chem. 2001, 66, 243.
(c) Pedrosa, R.; Andrés, C.; Iglesias, J. M.; Pérez-Encabo, A.
J. Am. Chem. Soc. 2001, 123, 1817. (d) Pedrosa, R.;
Andrés, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
(e) Villaplana, M. J.; Molina, P.; Arques, A.; Andrés, C.;
Pedrosa, R. Tetrahedron: Asymmetry 2002, 13, 5.
(f) Pedrosa, R.; Andrés, C.; Nieto, J.; del Pozo, S. J. Org.
Chem. 2003, 68, 4923. (g) Pedrosa, R.; Andrés, C.; Nieto, J.;
Rosón, C. J. Org. Chem. 2005, 70, 4332. (h) Pedrosa, R.;
Sayalero, S.; Vicente, M.; Maestro, A. J. Org. Chem. 2006,
71, 2177.
MS (EI, 70 eV): m/z (%) = 91.0 (72), 117.0 (100), 181.0 (42), 227
(20), 309 (21) [M – C4H8]+.
(SS)-N-{(1S)-1-[(1R,2R,6R)-2-Ethyl-6-hydroxycyclohexyl]-3-
phenylpropyl}-2-methylpropane-2-sulfinamide (ent-4e)
By following the typical procedure, a 2.4:1 mixture of ent-3b and
ent-3c (489 mg, 1.35 mmol) was reduced with a 1 M soln of
LiBHEt3 in THF (9 mL, 9 mmol). After aqueous workup and sol-
vent evaporation, the residue was purified by FC (hexane–EtOAc,
3:2 to 1:1) to give pure ent-4c and ent-4e as colorless foams; yield:
ent-4c: 280 mg (57%); ent-4e: 180 mg (36%); [a]D20 +115.0 (c 1.00,
MeOH).
(4) Synthetic (–)-pulegone is about ten times more expensive
than its natural enantiomer.
(5) (a) González-Gómez, J. C.; Foubelo, F.; Yus, M.
Tetrahedron Lett. 2008, 49, 2343. (b) González-Gómez, J.
C.; Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74, 2547.
(6) For leading references on the use of ligands L1 and L2, see:
(a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.;
de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36,
2620. (b) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(c) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221. (d) Alexakis, A.; Backwall, J. E.; Krause, N.; Pamies,
O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
(7) De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2374.
(8) Closely related examples are described in references 5a and
5b; attempts to improve the diastereoselectivity by using an
excess of Et2Zn were unsuccessful.
(9) For conformations of aldols derived from cyclohexanone,
see: Kitamura, M.; Nakano, K.; Miki, T.; Okada, M.;
Noyori, R. J. Am. Chem. Soc. 2001, 123, 8939.
(10) Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org.
Chem. 2008, 73, 9619.
(11) Sulfinimines 2 and ent-2 were prepared from
phenylpropanal and (RS)- and (S S)-2-methylpropane-2-
sulfinamide (>99% ee) by using CuSO4 as described in: Liu,
G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278.
N-{(1R)-1-[(1S,2S,6R)-2-Ethyl-6-hydroxycyclohexyl]-3-phenyl-
propyl}-2-methylpropane-2-sulfonamide (4f); Typical Proce-
dure for Oxidation of the tert-Butylsulfinyl Group
MCPBA (70%, 55 mg, 0.23 mmol) was add at 0 °C to a soln of com-
pound 4a (55 mg, 0.15 mmol) in CH2Cl2 (2 mL), and the mixture
was stirred for 30 min at 0 °C until the starting material was con-
sumed (TLC; hexane–EtOAc, 3:1). A soln of Na2SO3 (600 mg) in
H2O (10 mL) was added and the mixture was stirred for 10 min
more. The mixture was then extracted with EtOAc (3 × 10 mL) and
the combined organic extracts were washed with sat. aq NaHCO3
and brine, then dried (MgSO4). The filtered soln was concentrated
in vacuo, and the residue was purified by FC (hexane–EtOAc, 4:1)
to give 4f as a colorless foam; yield: 41 mg (75%); [a]D20 +31.0 (c
2.7, CH2Cl2).
IR (KBr): 3522 (br), 2922, 1459, 1306, 1122 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25 (m, 5 H), 5.79 (br s, 1 H,
NH), 3.79 (m, 1 H, CHN), 3.70 (td, J = 10.4, 4.1 Hz, 1 H, CHO),
3.03 (m, 1 H), 2.66 (m, 1 H), 2.00–1.60 (m, 7 H), 1.43 (s, 9 H), 1.30–
0.90 (m, 5 H), 0.82 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 10.4 (CH3), 23.8 (CH2), 24.4
(CH3), 24.9 (CH2), 30.6 (CH2), 32.9 (CH2), 33.3 (CH2), 36.9 (CH2),
39.2 (CH), 53.2 (CH), 54.4 (CH), 59.3 (q), 73.2 (CH), 125.8 (CH),
128.3 (CH), 128.5 (CH), 142.3 (q).
(12) Phosphoramidites L1, ent-L1, L2, and ent-L2 were prepared
according the procedure described in: Polet, D.; Alexakis,
Synthesis 2009, No. 12, 2083–2088 © Thieme Stuttgart · New York

2088
J. C. González-Gómez et al.
SPECIAL TOPIC
A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.
Eur. J. 2006, 12, 3596.
(14) (a) SAINT Area-Detector Integration Software (Version
6.02A); Siemens Industrial Automation, Inc.: Madison
(USA), 1995. (b) Sheldrick, G. M. SADABS Area-Detector
Absorption Correction; Göttingen University: Germany,
1996. (c) Sheldrick, G. M. SHELX97 [Includes SHELXS97,
SHELXL97 and CIFTAB] – Programs for Crystal Structure
Analysis (Release 97-2); Institüt für Anorganische Chemie
der Universität: Göttingen (Germany), 1998.
(13) Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 723111. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: +44(1223)336033;
e-mail: deposit@ccdc.cam.ac.uk].
Synthesis 2009, No. 12, 2083–2088 © Thieme Stuttgart · New York