New β-amino thiols as efficient catalysts for highly enantioselective alkenylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2004.11.093

A series of new optically active β-amino thiols and thiolacetates prepared from the simple natural amino acid, (S)-(-)-valine, were found to be effective catalysts for the enantioselective addition of alkenylzinc to aldehydes and thereby providing an effi

Full text of DOI:10.1016/j.tetasy.2004.11.093

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 773–782
New b-amino thiols as efficient catalysts for highly enantioselective
alkenylzinc addition to aldehydes
Shi-Liang Tseng and Teng-Kuei Yang*
Department of Chemistry, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung, 40227, Taiwan, ROC
Received 1 September 2004; accepted 8 November 2004
Abstract—A series of new optically active b-amino thiols and thiolacetates prepared from the simple natural amino acid, (S)-(ꢀ)-
valine, were found to be effective catalysts for the enantioselective addition of alkenylzinc to aldehydes and thereby providing an
efficient route for chiral (E)-allylic alcohols with ees of up to >99% in the presence of 7a (1 mol %).
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
aldehydes with high enantioselectivities. Dahmen and
Bra¨se also demonstrated a paracyclophane based keti-
mine ligand with excellent performance for enantioselec-
tive alkenylation of R-branched aliphatic aldehydes.3
However, b-amino thiols are relatively much less ex-
plored as ligands for similar types of reactions.4 On
the other hand Wipf et al.5 reported a method for hydro-
zirconation of alkynes with Cp2ZrHCl (Schwartz
reagent) then through in situ transmetalation of
alkenylzirconocenes to give alkenylzinc reagents; how-
ever a relatively high catalyst loading is required in this
case.
Over the past two decades, great progress has been
realized in the catalytic asymmetric alkyl addition to
aldehydes for the generation of enantiomerically pure
secondary alcohols with very high enantiomeric excess.1
However, the enantioselective alkenyl addition to alde-
hydes still remains a challenge as indicated by only a
few reports in the literature. The importance of alkenyl
addition of aldehydes could be well understood as enan-
tiopure allyl alcohols are enormously useful key inter-
mediates for synthesizing a wide variety of natural
products and biologically active compounds.2 Recently
Pu and Yu reviewed the results of organozinc additions
to carbonyl compounds using approximately 600 indi-
vidual catalysts during the last decade or so.1a Amino
alcohols have been the choice invariably for the ligand
design of many asymmetric catalytic reactions due to
their excellent enantioselectivity obtainable, especially
in the organozinc addition to the carbonyl compounds.
Chan et al. reported a new one-step procedure for the
synthesis of optically active tertiary amino naphthol
with high purity in the alkenylation of aldehydes but
at 15 mol % of ligand to substrate.6 In the reaction path-
way, a zinc-based chiral Lewis acid-amino alcohol com-
plex was first formed as an intermediate, which then
adds to the aldehyde to afford the alkenylated product.
While moderate to excellent stereoselectivities were
achieved in the enantioselective alkenylation, the cata-
lytic loading demands a bigger L/S ratio, which make
it less attractive.
In the pioneering work of Oppolzer and Radinov,2a the
reaction of terminal alkynes with dicyclohexylborane
followed by boron–zinc exchange in the presence
of b-amino alcohol, 3-exo-dimethylaminoisobornenol
(DAIB, NoyoriÕs ligand), as a chiral ligand was em-
ployed either in the case of intermolecular2a or intra-
molecular2b alkenylation of aromatic and aliphatic
During our ongoing research, we understood that amino
thiol structures serve as better alternative to amino alco-
hols in asymmetric alkenylzinc additions to aldehydes.
Herein, we report the ability of new chiral b-amino thiol
based catalytic systems for the highly effective enantiose-
lective alkenylation with higher yields over conventional
systems. It is also important to note that the L/S ratio
has been reduced drastically to as low as 0.5 mol % with
*
Corresponding author. Tel.: +886 4 2285 6603; fax: +886 4 2285
6597; e-mail addresses: tk@wisdompharma.com; tkyang@mail.
nchu.edu.tw; zsl007@pchome.com.tw
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.11.093

774
S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
a still very high enantioselectivity. The softness of the
sulfur atom in the thiol functional group invigorates
the chelation effect with the zinc better than to the oxy-
gen atom of the amino alcohol. To the best of our
knowledge this is the first report on the usage of b-ami-
no thiol ligands for the asymmetric alkenylzinc addition
to aldehydes.
2. Synthesis of the chiral ligands
A typical synthetic sequence for the preparation of these
chiral amino thiols is illustrated below in Scheme 1.
Adopting the method of Reetz et al.,7 N,N-dialkylation
of (S)-(ꢀ)-valine was initially carried out using benzyl
chloride in the presence of NaOH to give the N,N-di-
benzylamino benzyl ester, which was reduced by lithium
aluminum hydride to afford the optically active amino
primary alcohols. After Swern oxidation of the N,N-di-
benzylamino alcohols, alkylmagnesium bromide was
added to the corresponding aldehydes 1 to give the ami-
no alcohols 2 in high diastereoselectivity. Figure 1 shows
the X-ray structure of 20. The protecting benzyl group
was cleaved by hydrogenolysis using either Pd/C or
Pd(OH)2 under hydrogen (1 atm). The dialkylation of
the nitrogen in 4 was then carried out with various alkyl
dihalides [bis(2-bromoethyl) ether, 1,5-dibromopentane
and 1,4-dibromobutane] to produce tertiary amino alco-
hol 5. The hydroxyl group in 5 was transformed into the
mesylate for further in situ intramolecular nucleophilic
attack by the neighboring tertiary nitrogen atom thus
furnishing the aziridinium ion as an intermediate with
Figure 1. X-ray structure of 20 (R0 = Ph).
an inversion of configuration.8 This aziridium ion then
undergoes regiospecific ring-opening at the benzylic po-
sition via a thiolacetate to produce the amino thiolac-
eate 6 with an inversion of configuration. Figure 2
shows the X-ray structure of 6h. Then the thiolacetate
group was reduced to the amino thiol 7 and the whole
process carried out in a highly stereocontrolled fashion.
H
O
R'
R'
i
+
Bn2N
Bn2N
OH
Bn2N
OH
3
1
5
6
2
ii
R'
R'
iii
R"2N
OH
H2N
OH
4
iv
R'
R'
v
R"2N
SAc
R"2N
SH
7
Scheme 1. Reagents and conditions: (i) R0MgX, THF, 0 ꢁC, 1 h; (when
R0 = iPr; 2/3 = 96/4, yield = 56%), (when R0 = Ph; 20/30 = 91/9,
yield = 69%). Diastereomeric ratio was determined by 1H NMR
(400 MHz, Varian Mercury 400) spectroscopy; (ii) H2, Pd/C, MeOH,
1 atm, rt, 8 h, 92%; (iii) R00Br, K2CO3, CH3CN, reflux, 18 h, 82–89%;
(iv) MeSO2Cl, NEt3, CH2Cl2, 0 ꢁC, 1 h then removed CH2Cl2, and
added AcSH, NEt3, benzene, reflux, 8 h, 62–69%; (v) LAH, Et2O, 0 ꢁC,
1 h, 92%. (1R,2S)-1,2-Diphenyl-2-amino-1-ethanol is commercially
available.
Figure 2. X-ray structure of 6h (R0 = Ph, R200 = –(CH2)5–).
3. Results and discussion
According to the protocol of Oppolzer and Radinov, the
terminal alkyne was hydroborated with freshly prepared
dicyclohexylborane to produce (E)-1-alkenylborane,

S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
775
which was then treated with diethylzinc to generate alken-
ylzinc reagents.2a As suggested by Dahmen and Bra¨se,
we employed toluene as the solvent for hydroboration to
improve the solubility of substrates.3 In general, we used
1.5 equiv of alkenylzinc reagent relative to the aldehyde
in the presence of 2 mol % of ligands and the desired chi-
ral allylic alcohols were obtained in good yields with
high stereoselectivity. In agreement with Bra¨seÕs report,
we found that 2 equiv of diethyl zinc and 1.5 equiv of
dicyclohexylborane were essential to ensure good chem-
ical conversion during the addition. Otherwise, the alde-
hyde would not be completely consumed as against the
original OppolzerÕs stoichiometry. The results of asym-
metric alkenyl addition to various aldehydes in the pres-
ence of chiral amino thiol ligands 7a and 7b are
summarized in Table 1.
to Dahmen and Bra¨seÕs ligands,3 we observed that ami-
no thiol catalyzed reactions afforded highly enantiomer-
ically enriched products from aromatic aldehydes rather
than aliphatic aldehydes. It was also found that aromat-
ics substituted with electron withdrawing group resulted
in slightly lower selectivities than those of electron rich
aromatics (entries 9, 12, and 13). For the aliphatic alde-
hydes, the aliphatic chain on the alkyne when elongated
from butyl to hexyl resulted in the highest enantioselec-
tivity (entry 18 vs 11), while a bulky substitution on the
alkyne did not have any influence (entry 4 vs 6).9
In Table 2, we made a parallel comparison of the compe-
tency between amino alcohols 5 and amino thiols 7 as the
chiral ligands for asymmetric alkenylation of aldehydes.
According to the HSAB rule, due the sulfur atom in the
amino thiols being soft base, it prefers to associate
strongly to the soft zinc metal than the oxygen atom of
the amino alcohols. Therefore, a more stable transition
state of the addition complex from the amino thiol rela-
tive to the amino alcohols would be expected. Thus, ami-
no thiols showed much higher enantioselectivities than
the corresponding amino alcohols in these asymmetric
alkenyl addition processes under similar conditions.
We also found that the size increment of R0 in thiols im-
proved the enantioselectivity from phenyl to isopropyl
group, which probably due to more steric congested
transition state (entry 7–9 vs 16–18) (Fig. 3).
In general, we obtained good chemical conversion and
much higher enantioselectivity with the amino thiol
ligands in comparison with the corresponding amino
alcohol ligands. In the stoichiometric study of 7a we
found that from 5 to 0.5 mol % catalyst loading only
1.1% ee variation (entries 1–5), and the temperature
effect was significant as lowering the reaction tempera-
ture from ꢀ10 to ꢀ20 ꢁC resulted in an increase of
7% ee (entry 16 vs 17). However, further lowering reac-
tion temperature to ꢀ40 ꢁC did not have any influence
on optical selectivity (entries 17, 18, and 19). In contrast
Table 1. Asymmetric alkenyl addition to aldehydes
O
OH
1. Chiral ligand
2. NaHCO3 (sat)
R'
+
ZnEt
R
H
R'
R
N
SH
N
SH
7a
______________________________________________________________________________________________________________________________
Entry R aldehyde R' Ligand Mol % of ligand Solvent Temp (ºC) Yield (%)
Ee (%)a
7b
______________________________________________________________________________________________________________________________
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
tert-Bu
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
0.1
0.5
1
2
5
2
2
2
2
2
5
2
2
1
2
5
5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–30
–10
–20
–30
–40
–30
–30
62
69
80
88
90
86
72
81
84
80
94
90
86
90
92
89
94
94
94
94
90
59.4(R)
98.4(R)
99.1(R)
99.5(R)
99.5(R)
99.0(R)
66.5(S)
69.8(R)
99.0(R)
99.0(R)
99.4(R)
98.1(R)
92.6(R)
94.3(R)
94.5(R)
91.3(R)
98.3(R)
98.2(R)
98.3(R)
99.5(R)
98.1(R)
Cyclohexyl
(E)-PhCH=CH
Ph
Ph
Ph
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
CH3(CH2)3
9
10
11
12
13
14
15
16
17
18
19
20
21
Ph
4-MeO-Ph
2-Cl-Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
5
15
5
2-Cl-Ph
______________________________________________________________________________________________________________________________
a Determined by HPLC (Chiracel OD-H column, flow rate : 0.7 ml/min, hexane : IPA = 97:3).

776
S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
Table 2. Alkenylation to benzaldehyde with various chiral ligands
5. Experimental
OH
Ph
O
1. Chiral Ligand
2. NaHCO3(sat)
ZnEt
+
Starting materials were obtained from commercial sup-
pliers and used without further purification unless
otherwise stated. All reactions were performed in
flame-dried apparatus under an atmosphere of nitrogen
at room temperature unless otherwise stated. All reac-
tions were conducted under a nitrogen atmosphere. All
chemicals and solvents were used as received unless
otherwise stated. THF (Na, benzophenone), CH2Cl2
(CaH2), methanol (Mg), and toluene (Na) were dis-
tilled from the drying agents indicated. Flash chroma-
tography was carried out using Merck silica gel 60, 70–
230 mesh ASTM. Melting points are uncorrected.
Optical rotations were measured on PERKIN ELMER
241 polarimeter. Infrared spectra were recorded on
HITACHI 270-30 Infrared Spectrophotometer. NMR
spectra were recorded on Varian Mercury 400 or Var-
ian INOVA 600. The chemical shift are reported as d
value in parts per million relative to TMS (d = 0)
C6H13
C6H13
Ph
H
Entry
Ligand
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
5a
5b
5c
6a
6b
6c
7a
7b
7c
5d
5e
5f
6d
6e
6f
7d
7e
7f
5g
5h
5i
6g
6h
6i
7g
7h
7i
55
86
63
86
60
63
88
84
88
48
55
50
86
55
77
89
92
88
65
55
53
83
77
85
82
93
83
51.1(R)
74.6(R)
71.8(R)
92.3(R)
78.8(R)
81.6(R)
99.5(R)
99.0(R)
99.3(R)
21.7(R)
46.5(R)
30.7(R)
93.3(R)
15.8(R)
53.3(R)
95.1(R)
98.6(R)
98.4(R)
86.7(R)
58.9(R)
78.7(R)
96.5(R)
93.2(R)
96.8(R)
98.1(R)
98.4(R)
97.3(R)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1
was used as internal standard in CDCl3 for H NMR
spectra and the center peak of CDCl3 (d = 77.0 ppm)
was used as internal standard in 13C NMR spectra.
FAB-mass spectra were collected on JMS-700 double
focusing Mass Spectrometer. Elemental analyses were
collected on Foss Heraeus CHN-O-RAPID Elemental
Analyzer.
5.1. (3R,4S)-4-(Dibenzylamino)-2,5-dimethyl-
hexan-3-ol, 2
To a vigorously stirred solution of 1 (10.4 g, 35 mmol) in
35 mL THF at 0 ꢁC by an ice bath, to the resulting solu-
tion was added 35 mL of isopropyl magnesium chloride
(2.0 M, in THF) stirred for 1 h and then warmed to
room temperature and quenched with NH4Cl (aq).
The aqueous solution was extracted with ethyl acetate
(3 · 200 mL), dried over MgSO4, and concentrated in
vacuo to give the crude product, which was purified
All reactions are carried out with 1.5 equiv organozinc in the presence
of 2 mol % chiral ligand at ꢀ30 ꢁC and enantiomeric excess determined
by HPLC (Chiracel OD-H column, flow rate: 0.7 mL/min, hexane/
IPA = 97:3, retention time: 10–11 min (R), 14–15 min (S) and detected
by UV irradiation at k = 254 nm).
4. Conclusion
through column chromatography on silica gel to afford
25
2 (6.1 g, 56%) as a colorless oil; ½aꢁ ¼ ꢀ20:4 (c 5.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.73 (d,
J = 7.2 Hz, 3H, CH3), 0.86 (d, J = 6.8 Hz, 3H, CH3),
1.02 (d, J = 7.2 Hz, 3H, CH3), 1.12 (d, J = 6.8 Hz, 3H,
CH3), 2.12–2.00 (m, 1H, CHCN), 2.34–2.20 (m, 1H,
CHCO), 2.38 (dd, J = 5.2, 5.2 Hz, CHN), 3.54 (d,
J = 13.6 Hz, CH2Ph), 3.70 (s, 1H, CHO), 3.75 (d,
J = 13.6 Hz, CH2Ph), 7.07–7.25 (m, 10H, ArH); 13C
In summary, we have developed a new class of efficient
amino thiol ligands for asymmetric alkenyl addition to
aldehydes affording enantioselectivity as high as 99.1%
ee with very low catalytic loading of 1 mol % (Table 1,
entry 3). Further understanding of the hard–soft concept
of these ligands and extended utilization of these thiols as
ligands in preference to alcohols is currently underway.
X=OH
X=SH
X=SAc
5a: R" = -(CH2)4
5b: R" = -(CH2)5
-
-
7a: R" = -(CH2)4
7b: R" = -(CH2)5
-
-
6a: R" = -(CH2)4
6b: R" = -(CH2)5
-
-
R"2N
R"2N
X
5c: R" = -(CH2)2 -O-(CH2)2
-
7c: R" = -(CH2)2 -O-(CH2)2 -
6c: R" = -(CH2)2 -O-(CH2)2
-
5d: R" = -(CH2)4
5e: R" = -(CH2)5
5f: R" = -(CH2)2 -O-(CH2)2
-
-
7d: R" = -(CH2)4
7e: R" = -(CH2)5
7f: R" = -(CH2)2 -O-(CH2)2 -
-
-
Ph
6d: R" = -(CH2)4
6e: R" = -(CH2)5
6f: R" = -(CH2)2 -O-(CH2)2
-
-
X
-
-
5g: R" = -(CH2)4
5h: R" = -(CH2)5
-
-
7g: R" = -(CH2)4
7h: R" = -(CH2)5
-
-
Ph
Ph
X
6g: R" = -(CH2)4
6h: R" = -(CH2)5
-
-
R"2N
5i: R" = -(CH2)2 -O-(CH2)2
-
7i: R" = -(CH2)2 -O-(CH2)2 -
6i: R" = -(CH2)2 -O-(CH2)2
-
Figure 3.

S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
777
NMR (100 MHz, CDCl3) d 16.93, 20.46, 20.52, 23.17,
25.87, 31.11, 54.57, 63.03, 75.33, 126.73, 128.05,
5.3. (3R,4S)-2,5-Dimethyl-4-(pyrrolidin-1-yl)hexan-3-ol,
5a
129.11, 140.29. IR (neat) 3606, 3505, 3061, 3028, 2958,
2872, 2799, 1492, 1455, 1380 cmꢀ1
.
To a mixture of 4 (5 mmol, 0.75 g) and potassium car-
bonate (10 mmol, 1.4 g) in 40 mL of acetonitrile was
added 1,4-dibromobutane (6 mmol, 1.3 g) and then the
solution heated to reflux for 18 h, after which TLC anal-
ysis of the reaction mixture indicated the completion of
the reaction. The resulting solution was filtered and the
acetonitrile evaporated, at which point water (30 mL)
was added, then extracted with ethyl acetate
(3 · 30 mL). The combined organic layer was dried over
MgSO4 and concentrated in vacuo to give the crude
product, which was purified through column chro-
matography on silica gel to afford 5a (0.84 g, 84%) as
5.1.1.
(1R,2S)-2-(Dibenzylamino)-3-methyl-1-phenyl-
butan-1-ol, 20. To a vigorously stirred solution of 1
(10.4 g, 35 mmol) in 35 ml THF at 0 ꢁC by ice bath, then
the resulting solution was added 35 ml of phenyl magne-
sium chloride (2.0 M, in THF) stirred for 1 h then
warmed to room temperature and quenched with
NH4Cl(aq). The aqueous solution extracted with ethyl
acetate (3 · 200 ml), dried (MgSO4) and concentrated
in vacuo to give the crude product, which was purified
through column chromatography on silica gel to afford
20 (8.7 g, 69%) as a colorless solid; d 0.93 (d,
J = 6.4 Hz, 3H, CH3), 1.18 (d, J = 6.4 Hz, 3H, CH3),
2.12 (d, J = 5.2 Hz, 1H, CHMe2), 2.23–2.40 (m, 1H,
CHNBn2), 2.78 (br, 1H, OH), 3.52 (d, 13.6 Hz, 2H,
PhCH2), 3.90 (d, J = 13.6 Hz, 2H, PhCH2), 5.12
(s, 1H, CHO), 7.20–7.40 (m, 15H, Ar); 13C NMR
(100 MHz, CDCl3) d 20.81, 22.77, 26.38, 54.99, 67.53,
71.58, 126.21, 126.84, 127.99, 128.14, 128.54, 128.95,
139.94, 144.67; HRMS(FAB): m/z calcd for C25H30NO
MH+: 360.2328; Found : 360.2325.
25
1
a colorless oil; ½aꢁ ¼ þ45:7 (c 1.21, CHCl3); H NMR
D
CDCl3)
(400 MHz,
d
0.83
(d,
J = 6.8 Hz,
3H, NCHCH(CH3)2), 0.97 (d, J = 6.8 Hz, 3H,
NCHCHCH3), 1.02 (d, J = 1.2 Hz, 3H, OCCHCH3),
1.04 (d, J = 1.2 Hz, 3H, OCCHCH3), 1.63–1.73 (m,
4H, NCH2), 1.74–1.83 (m, 1H, NCCH(CH3)2), 2.05–
2.12 (m, 1H, OCCH(CH3)2), 2.21 (dd, J = 3.2, 4.4 Hz,
1H, NCH), 2.55–2.63 (m, 2H, NCH2), 2.65–2.72 (m,
2H, NCH2), 3.41 (dd, J = 4.4, 9.2 Hz, 1H, CHO); 13C
NMR (100 MHz, CDCl3) d 19.20, 19.30, 19.62, 22.68,
23.40, 26.99, 30.59, 51.59, 68.34, 77.60; HRMS (FAB):
m/z calcd for C12H25NO MH+: 200.2014; found:
200.2011; IR (neat) 3391, 2960, 2873, 2802, 1677,
1598, 1515, 1464 cmꢀ1; Anal. Calcd for C12H25NO: C,
72.31; H, 12.64; N, 7.03. Found: C, 72.28; H, 12.73;
N, 6.99.
X-ray crystal data for 20: C25H29NO, MW = 359.49,
orthorhombic, space group P212121, a = 9.7113(14),
˚
b = 10.4909(15), c = 21.444(3) A; a = 90ꢁ, b = 90ꢁ,
3
˚
c = 90ꢁ, U = 2184.8(5) A , T = 293 K, Z = 4, Dc =
1.093 g cmꢀ1, l = 0.065 mmꢀ1, k = 0.71073 A, F(000)
˚
776, crystal size 0.22 · 0.46 · 0.47 mm3, 3857 indepen-
dent reflections (Rint = 0.0506), 11,563 reflections col-
lected; refinement method, full-matrix least-squares on
F2; goodness-of-fit on F2 = 0.788; final R indices
[I > 2r(I)] R1 = 0.0450, wR2 = 0.1142, SADABS.
5.4. (S)-(3R,4S)-2,5-Dimethyl-4-(pyrrolidin-1-yl)hexan-3-
yl ethanethioate, 6a
To a vigorously stirred solution of 5a (4.0 mmol, 0.8 g),
Et3N (12 mmol, 1.8 mL) in 30 mL anhydrous CH2Cl2 at
0 ꢁC was added MsCl (8 mmol, 0.62 mL). The resulting
solution was stirred for 1 h at 0 ꢁC, after which TLC
analysis of the reaction mixture indicated the comple-
tion of reaction; CH2Cl2 was then removed in vacuum.
To the residue was added benzene (30 mL), NEt3
(12 mmol, 1.8 mL) and thioacetic acid (8 mmol,
0.57 mL) and then heated to reflux for 8 h while moni-
toring the completion of reaction by TLC. After re-
moval of the solvent, the residued oil was purified
through column chromatography (eluent: n-hexane/
5.2. (3R,4S)-4-Amino-2,5-dimethylhexan-3-ol, 4
To a solution of 2 (6 g, 18.5 mmol) in 100 mL of
MeOH, the resulting solution was added 2 g of 10%
Pd/C. The resulting solution under an H2 balloon
(1 atm) was stirred for 8 h at room temperature. Then
resulting solution was filtered through celite and con-
centrated in vacuo to give 4 (2.5 g, 92%) as white solid;
22
D
mp = 87–88 ꢁC; ½aꢁ ¼ þ6:8 (c 2.8, EtOH) {lit.10
25
D
½aꢁ ¼ þ7:07 (c 2.05, EtOH)}; 1H NMR (400 MHz, ace-
tone-d) d 0.92 (d, J = 7.2 Hz, 3H, CH3), 0.94 (d,
J = 7.2 Hz, 3H, CH3), 1.03 (d, J = 5.2 Hz, 3H, CH3),
1.05 (d, J = 4.0 Hz, 3H, CH3), 1.90–2.04 (m, 1H,
CHMe2), 2.12–2.24 (m, 1H, CHMe2), 2.63 (dd,
J = 8.4, 3.2 Hz, 1H, NCH), 3.28 (dd, J = 8.4, 4.0 Hz,
1H, OCH), 3.37 (dd, J = 3.0, 1.6 Hz, 1H, COH), 4.9
(s, 2H, NH2); 13C NMR (100 MHz, acetone-d) d
19.15, 21.55, 22.13, 28.00, 29.20, 67.54, 83.30; 1H
NMR (400 MHz, CDCl3) d 0.89 (d, J = 6.4 Hz, 3H,
CH3), 0.90 (d, J = 6.4 Hz, 3H, CH3), 0.94 (d,
J = 6.8 Hz, 3H, CH3), 0.95 (d, J = 6.8 Hz, 3H, CH3),
1.90–2.04 (m, 1H, CHMe2), 1.86–2.06 (m, 2H,
2CHMe2), 2.59 (dd, J = 6.8, 4.0 Hz, 1H, CHN), 3.27
(dd, J = 6.8, 4.0 Hz, 1H, CHO); 13C NMR (100 MHz,
CDCl3) d 16.07, 16.10, 20.27, 20.86, 28.37, 29.09,
57.98, 77.18.
NEt3 = 100:1) on silica gel to afford 6a (0.66 g, 64%)
25
D
as a colorless oil; ½aꢁ ¼ þ53:9 (c 1.23, CHCl3); 1H
NMR (400 MHz, CDCl3) d 0.88 (d, J = 6.8 Hz, 3H,
NCHCH(CH3)2), 0.94 (d, J = 6.8 Hz, 3H, NCHCH-
(CH3)2), 0.95 (d, J = 6.4 Hz, 3H, SCHCH(CH3)2), 0.96
(d, J = 6.4 Hz, 3H, SCHCH(CH3)2), 1.66–1.71 (m, 4H,
CCH2), 1.88–2.00 (m, 1H, NCCH(CH3)), 2.01–2.12
(m, 1H, SCCHMe2), 2.34 (s, 3H, SCOMe), 2.62–2.70
(m, 2H, NCH2), 2.68 (dd, J = 5.6, 6.4 Hz, 1H, NCH),
2.71–2.77 (m, 2H, NCH2), 3.79 (dd, J = 5.2, 6.4 Hz,
1H, CHS); 13C NMR (100 MHz, CDCl3) d 18.63,
19.99, 21.11, 21.60, 24.02, 30.45, 30.55, 30.71, 49.25,
50.81, 64.74, 195.38; HRMS (FAB): m/z calcd for
C14H27NOS MH+: 258.1891; found: 258.1899; Anal.
Calcd for C14H27NOS: C, 65.32; H, 10.57; N, 5.44.
Found: C, 65.38; H, 10.60; N, 5.41.

778
S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
5.5. (3R,4S)-2,5-Dimethyl-4-(pyrrolidin-1-yl)hexane-3-
thiol, 7a
CH2Cl2 at 0 ꢁC was added followed by MsCl (8 mmol,
0.62 mL). The resulting solution was stirred for 1 h at
0 ꢁC, after which TLC analysis of the reaction mixture
indicated the completion of reaction; CH2Cl2 was then
removed in vacuum. Benzene (30 mL) and NEt3
(12 mmol, 1.8 mL) and thioacetic acid (8 mmol,
0.57 mL) were added to the residue, then heated to re-
flux for 8 h and monitoring the completion of reaction
by TLC. After removal of solvent, the residued oil was
purified through column chromatography (eluent: n-
To a suspension solution of LAH (4 mmol, 0.16 g) in
10 mL of dry Et2O in an ice bath, a solution of (S)-
(3R,4S)-2,5-dimethyl-4-(pyrrolidin-1-yl)hexan-3-yl eth-
anethioate 6a (2 mmol, 0.52 g) in 20 mL of dry Et2O
was added. After 1 h 2M aqueous NaOH (0.5 mL) was
added under nitrogen and the solution filtered. The fil-
trate was concentrated to afford our desired product
(3R,4S)-2,5-dimethyl-4-(pyrrolidin-1-yl)hexane-3-thiol
hexane/NEt3 = 100:1) on silica gel to afford 6b (0.75 g,
25
D
25
(0.37 g, 92%) 7a as a colorless oil; ½aꢁ ¼ þ13:7 (c
69%) as a colorless oil; ½aꢁ ¼ ꢀ8:85 (c 1.65, CHCl3);
D
1
0.99, CHCl3); H NMR (400 MHz, CDCl3) d 0.89 (d,
J = 6.4 Hz, 3H, NCHCH(CH3)2), 0.93 (d, J = 4.0 Hz,
3H, SCHCH(CH3)2), 0.94 (d, J = 6.4 Hz, 3H,
1H NMR (400 MHz, CDCl3) d 0.82 (d, J = 6.4 Hz,
3H, CH3), 0.89 (d, J = 2.8 Hz, 3H, CH3), 0.90 (d,
J = 2.8 Hz, 3H, CH3), 0.91 (d, J = 6.4 Hz, 3H, CH3),
1.34–1.50 (m, 6H, (CH2)2CH2(CH2)2), 1.97–2.12 (m,
1H, CHMe2), 2.30 (s, 3H, COCH3), 2.39 (dd, J = 6.8,
5.0 Hz, 1H, NCH), 2.42–2.67 (m, 4H, NCH2), 3.79
(dd, J = 6.8, 5.2 Hz, 1H, CHSAc); 13C NMR
(100 MHz, CDCl3) d 18.13, 20.75, 20.94, 21.20, 24.96,
26.86, 29.62, 30.71, 30.76, 49.00, 50.89, 70.09, 195.31;
IR (neat) 2929, 2869, 2393, 2241, 1691 cmꢀ1; Anal.
Calcd for C15H29NOS: C, 66.37; H, 10.77; N, 5.16.
Found: C, 66.35; H, 10.79; N, 5.18; MS (FAB) 272
(MH+) (100%), 228, 196, 154 (100%); HRMS (FAB):
m/z calcd for C15H29NOS MH+: 272.2048; found:
272.2039.
NHCHCH(CH3)2),
0.96
(d,
J = 4.0 Hz,
3H,
SCHCH(CH3)2), 1.62–1.72 (m, 4H, (CH2)2), 1.89–1.95
(m, 1H, NCHCH(CH3)2), 2.13–2.25 (m, 1H,
SCCHMe2), 2.52 (dd, J = 4.4, 8.0 Hz, 1H, NCH),
2.64–2.73 (m, 4H, NCH2), 2.92 (dd, J = 4.4, 7.6 Hz,
1H, CHS); 13C NMR (100 MHz, CDCl3) d 17.63,
19.57, 21.57, 21.79, 24.14, 29.40, 29.69, 48.78, 50.03,
66.20; HRMS (FAB): m/z calcd for C12H25NS MH+:
216.1786; found: 216.1742.
5.6. (3R,4S)-2,5-Dimethyl-4-(piperidin-1-yl)hexan-3-ol,
5b
To a mixture of (3R,4S)-4-amino-2,5-dimethylhexan-3-
(5 mmol, 0.75 g) and potassium carbonate
5.8. (3R,4S)-2,5-Dimethyl-4-(piperidin-1-yl)hexane-3-
thiol, 7b
ol
4
(10 mmol, 1.4 g) in 40 mL of acetonitrile was added
1,5-dibromopentane (6 mmol, 1.39 g); the solution was
then heated to reflux for 18 h, after which TLC analysis
of the reaction mixture indicated the completion of the
reaction. The resulting solution was filtered and the
acetonitrile evaporated. After removal of acetonitrile,
water (30 mL) was added and then extracted with
3 · 30 mL of ethyl acetate. The combined organic layer
was dried over MgSO4 and concentrated in vacuo to
give the crude product, which was purified through col-
According to the reduced procedure, 7b (0.39 g, 90%)
25
was obtained as a colorless oil; ½aꢁ ¼ ꢀ136 (c 0.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.84 (d,
J = 6.8 Hz, 3H, CH3), 0.94 (d, J = 6.8 Hz, 3H, CH3),
0.97 (d, J = 2.8 Hz, 3H, CH3), 0.91 (d, J = 6.4 Hz, 3H,
CH3), 1.36–1.42 (m, 2H, CH2), 1.44–1.48 (m, 4H,
CH2(CH2)2), 2.09–2.13 (m, 1H, CHMe2), 2.18–2.24 (m,
1H, CHMe2) 2.50–2.60 (m, 4H, NCH2), 2.22–2.30 (dd,
J = 4.0, 3.6 Hz 1H, NCH), 2.93 (dd, J = 4.8, 4.0 Hz
1H, CHS); 13C NMR (100 MHz, CDCl3) d 16.48,
20.75, 21.88, 25.07, 26.95, 28.81, 29.67, 47.58, 51.56,
72.16; Anal. Calcd for C13H27NS: C, 68.06; H, 11.86;
N, 6.11. Found: C, 68.01; H, 11.78; N, 6.07.
umn chromatography on silica gel to afford 5b (0.95 g,
22
89%) as a white solid; mp 46 ꢁC; ½aꢁ ¼ ꢀ7:4 (c 1.8,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.86 (d,
J = 6.8 Hz, 3H, CH3), 0.93 (d, J = 6.8 Hz, 3H, CH3),
0.95 (d, J = 6.8 Hz, 3H, CH3), 0.99 (d, J = 6.8 Hz,
3H, CH3), 1.37–1.42 (m, 2H, (CH2)2CH2(CH2)2),
1.42–1.52 (m, 4H, N(CH2CH2)2), 1.85–1.88 (m, 1H,
CHMe2), 1.90–2.10 (m, 1H, CHMe2), 2.14 (dd,
J = 4.8, 4.4 Hz, 1H, NCH), 2.47–2.59 (m, 4H, NCH2),
3.49 (dd, J = 5.2, 4.8 Hz, 1H, HCO); 13C NMR (100
MHz, CDCl3) d 16.42, 20.69, 20.86, 22.50, 24.95,
26.85, 27.00, 30.10, 51.73, 72.19, 74.52; IR (neat)
3492, 2931, 2873, 2974, 2741, 1465,1384 cmꢀ1; HRMS
(FAB): m/z calcd for C13H27NO MH+: 214.2171;
found: 214.2170; Anal. Calcd for C13H27NO: C,
73.18; H, 12.76; N, 7.50. Found: C, 73.16; H, 12.77;
N, 7.49.
5.9. (3R,4S)-2,5-Dimethyl-4-morpholinohexan-3-ol, 5c
According to the N-alkylation procedure 5c (84%) was
22
D
obtained as a white solid; mp 56–58 ꢁC; ½aꢁ ¼ ꢀ10:5
1
(c 2.28, CHCl3); H NMR (400 MHz, CDCl3) d 0.88
(d, J = 6.8 Hz, 3H, CH3), 0.92 (d, J = 6.8 Hz, 3H,
CH3), 0.98 (d, J = 13.6 Hz, 3H, CH3), 1.01 (d,
J = 13.6 Hz, 3H, CH3), 1.89–1.93 (m, 1H, CHMe2),
2.04–2.09 (m, 1H, CHMe2), 2.19 (dd, J = 6.0, 5.6 Hz,
1H, NCH), 2.52–2.65 (m, 4H, NCH2), 3.54 (dd,
J = 5.2, 5.0 Hz, 1H, CHO), 3.62 (t, J = 9.2 Hz, 4H,
OCH2); 13C NMR (100 MHz, CDCl3) 16.55, 20.42,
20.73, 22.10, 26.57, 30.56, 50.64, 67.72, 71.00, 74.42;
5.7. (S)-(3R,4S)-2,5-Dimethyl-4-(piperidin-1-yl)hexan-3-
yl ethanethioate, 6b
IR (neat) 3479 (OH), 2958, 2869, 2811, 1465 cmꢀ1
;
Anal. Calcd for C12H25NO2: C, 66.93; H, 11.70; N,
6.50. Found: C, 66.67; H, 11.53; N, 6.57; HRMS
(FAB): m/z calcd for C12H25NO2MH+: 216.8928; found:
216.8925.
According to the general procedure, 5b (4.0 mmol,
0.8 g), Et3N (12 mmol, 1.8 mL) in 30 mL anhydrous

S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
779
5.10. (S)-(3R,4S)-2,5-Dimethyl-4-morpholinohexan-3-yl
ethanethioate, 6c
127.79, 142.88 (Ph); IR (neat): 3425, 3027, 2958, 2874,
2803.1671, 1492 cmꢀ1; Anal. Calcd for C15H23NO: C,
77.21; H, 9.93; N, 6.00. Found: C, 77.11; H, 9.73; N,
6.23; HRMS (FAB): m/z calcd for C15H23NO MH+:
234.1858; found: 234.1865.
According to the general procedure, to 5c (4.0 mmol,
0.8 g) and Et3N (12 mmol, 1.8 mL) in 30 mL anhydrous
CH2Cl2 at 0 ꢁC was added MsCl (8 mmol, 0.62 mL).
The resulting solution was stirred for 1 h at 0 ꢁC, after
which TLC analysis of the reaction mixture indicated
the completion of reaction, then CH2Cl2 was removed
in vacuum. To the residue were added benzene
(30 mL), NEt3 (12 mmol, 1.8 mL), and thioacetic acid
(8 mmol, 0.57 mL) then heated to reflux for 8 h and
monitoring the completion of reaction by TLC. After
removal of solvent, the residued oil was purified
through column chromatography (eluent: n-hexane/
NEt3 = 100:1) on silica gel to afford 6c (0.72 g, 66%) as
5.13. (S)-(1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-
yl)butyl ethanethioate, 6d
According to the general procedure, 6d (62%) was ob-
25
tained as a colorless oil; ½aꢁ ¼ ꢀ240:8 (c 1.02, CHCl3);
D
1H NMR (400 MHz, CDCl3) d 0.90 (d, J = 6.8 Hz, 3H,
CCH3), 0.99 (d, J = 6.4 Hz, 3H, CCH3), 1.45–1.55 (m,
4H, (CH2)2), 1.92–2.04 (m, 1H, CH(CH3)2), 2.26 (s,
3H, SCOCH3), 2.60–2.69 (m, 4H, NCH2), 2.97 (dd,
J = 6.4, 6.0 Hz, 1H, NCH), 4.99 (d, J = 6.4 Hz, 1H,
SCH), 7.14–7.41 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3) d 19.82, 21.62, 24.31, 30.57, 30.59, 49.69,
50.42, 69.33, 126.73, 127.86, 128.70, 141.80 (Ph),
23
D
1
a light red oil; ½aꢁ ¼ ꢀ10:6 (c 2.0, CHCl3); H NMR
(400 MHz, CDCl3) d 0.83 (d, J = 6.4 Hz, 3H, CMe),
0.90 (d, J = 4.8 Hz, 3H, CMe), 0.91 (d, J = 6.4 Hz, 3H,
CMe), 0.92 (d, J = 4.8 Hz, 3H, CMe), 2.00–2.18 (m,
2H, CHMe2), 2.30 (s, 3H, COMe), 2.38 (dd, J = 6.4,
4.0 Hz, 1H, CHN), 2.50–2.2.60 (m, 2H, CH2N), 2.65–
2.2.75 (m, 2H, CH2N), 3.60 (t, J = 4.0 Hz, OCH2, 4H),
3.78 (dd, J = 5.6, 4.0 Hz, 1H, CHS); 13C NMR
(100 MHz, CDCl3) d 18.10, 20.58, 20.86, 21.00, 29.43,
29.51, 30.54, 49.65, 50.01, 67.46, 69.68, 194.66; IR (neat)
2960, 2852, 2814, 1691, 1459, 1359, 1290 cmꢀ1; Anal.
Calcd for C14H27NO2S: C, 61.50; H, 9.95; N, 5.12.
Found: C, 61.55; H, 9.90; N, 5.18; HRMS (FAB): m/z
calcd for C14H27NO2S MH+: 274.1840; found: 274.1842.
194.60 (SCOCH3); IR (neat): 2959, 1690, 1133 cmꢀ1
;
HRMS (FAB): m/z calcd for C17H25NOS MH+:
292.1735; found: 292.1733.
5.14. (1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-yl)-
butane-1-thiol, 7d
According to the reduced procedure, 7d (90%) was ob-
25
tained as a colorless oil; ½aꢁ ¼ ꢀ489:0 (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3) d 0.95 (d, J = 6.8 Hz,
3H, CHCH3), 0.99 (d, J = 6.8 Hz, 3H, CCH3), 1.37–
1.48 (m, 4H, (CH2)2), 2.06–2.15 (m, 1H, CH(CH3)2),
2.54–2.70 (m, 4H, NCH2), 3.00 (dd, J = 5.2, 7.6 Hz,
1H, NCH), 4.30 (d, J = 7.6 Hz, 1H, SCH), 7.12–7.40
(m, 5H, ArH); 13C NMR (100 MHz, CDCl3) d 18.95,
21.67, 24.46, 30.42, 50.60, 70.03, 77.20, 126.73, 127.9,
128.1, 144.57 (Ph); HRMS (FAB): m/z calcd for
C15H23NS MH+: 250.1629; found: 250.1633.
5.11. (3R,4S)-2,5-Dimethyl-4-morpholinohexane-3-thiol,
7c
According to the reduced procedure 7c (92%) was ob-
22
tained as a colorless oil; ½aꢁ ¼ ꢀ14:4 (c 1.7, CHCl3);
D
1H NMR (400 MHz, CDCl3) d 0.90 (d, J = 6.4 Hz,
3H, CH3), 1.01 (d, J = 4.8 Hz, 3H, CMe), 1.01 (d,
J = 6.4 Hz, 3H, CMe), 1.02 (d, J = 4.8 Hz, 3H, CMe),
2.07–2.20 (m, 1H, CHMe2), 2.20–2.32 (m, 1H, CHMe2),
2.26–2.35 (m, 1H, CHN), 2.58–2.73 (m, 4H, NCH2),
2.98 (td, J = 8.0, 4.0 Hz, 1H, CHS), 3.62 (t, J = 4.4 Hz,
4H, CH2O); 13C NMR (100 MHz, CDCl3) d 16.83,
20.68, 21.72, 21.79, 28.73, 29.66, 29.93, 47.17, 50.64,
67.67, 71.52; IR (neat) 2958, 2929, 2852, 2811, 1458,
1374, 1290 cmꢀ1; Anal. Calcd for C12H25NOS: C,
62.29; H, 10.89; N, 6.05. Found: C, 62.30; H, 10.84;
N, 6.10; HRMS (FAB): m/z calcd for C12H25NOS
MH+: 223.1735; found: 223.1736.
5.15. (1R,2S)-3-Methyl-1-phenyl-2-(piperidin-1-yl)butan-
1-ol, 5e
According to the N-alkylation procedure, 5e (88%) was
25
obtained as a colorless viscous oil; ½aꢁ ¼ ꢀ21:6 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.97 (d,
J = 3.0 Hz, 3H, CH3), 1.08 (d, J = 3.0 Hz, 3H, CH3),
1.36–1.45 (m, 6H, (CH2)2CH2(CH2)), 1.70–1.82 (m,
1H, CHMe2), 2.35–2.45 (m, 5H, NCH2), 4.78 (d,
J = 4.4 Hz, 1H, CHOH), 7.15–7.42 (m, 5H, ArH); 13C
(100 MHz, CDCl3) d 21.95, 22.45, 24.73, 27.13, 28.02,
52.87, 70.30, 77.32, 126.12, 126.83, 127.67, 142.86 (Ph);
IR (neat): 3441, 2930, 2852, 2804, 1493 cmꢀ1; Anal.
Calcd for C16H25NO: C, 77.68; H, 10.19; N, 5.66.
Found: C, 77.95; H, 10.18; N, 5.75; HRMS (FAB): m/z
calcd for C16H25NO MH+: 248.2014; found: 248.2011.
5.12. (1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-yl)-
butan-1-ol, 5d
According to N-alkylation procedure 5d (82%) was ob-
25
tained as a colorless viscous oil; ½aꢁ ¼ ꢀ41:3 (c 1.38,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.80 (d,
J = 6.8 Hz, 3H, CCH3), 0.96 (d, J = 6.8 Hz, 3H,
CCH3), 1.62–1.70 (m, 4H, (CH2)2), 1.72–1.82 (m, 1H,
CH(CH3)2), 2.54 (dd, J = 4.4, 8.0 Hz, 1H, NCH),
2.57–2.64 (m, 2H, NCH2), 2.68–2.74 (m, 2H, NCH2),
4.92 (d, J = 4.4 Hz, 1H, CHO), 7.14–7.34 (m, 5H,
ArH); 13C NMR (100 MHz, CDCl3) d 20.28, 21.81,
23.78, 27.88, 51.47, 72.29, 72.51, 126.08, 126.62,
5.16. (S)-(1R,2S)-3-Methyl-1-phenyl-2-(piperidin-1-
yl)butyl ethanethioate, 6e
According to the general procedure 6e (62%) was ob-
25
tained as a light yellow oil; ½aꢁ ¼ ꢀ172:1 (c 1, CHCl3);
D
1H (400 MHz, CDCl3) d 0.96 (d, J = 2.0 Hz, 3H, CCH3),
1.06 (d, J = 4.0 Hz, 3H, CHCH3), 1.31–1.37 (m, 6H,
CH2(CH2)2), 1.98–2.03 (m, 1H, CH(CH3)2), 2.26 (s,

780
S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
3H, SCOCH3), 2.37–2.42 (m, 2H, NCH2), 2.43–2.55 (m,
2H, NCH2), 2.74 (dd, J = 6.0, 5.6 Hz, 1H, NCH), 4.98
(d, J = 6.0 Hz, 1H, SCH), 7.18–7.43 (m, 5H, ArH); 13C
(100 MHz, CDCl3) d 20.57, 21.79, 24.82, 26.79, 26.85,
30.18, 30.50, 49.23, 52.20, 74.69, 126.66, 127.92,
128.52, 141.987 (Ph), 194.46; IR (neat): 2930, 1690,
1447, 1380 cmꢀ1; Anal. Calcd for C21H25NOS: C,
77.77; H, 8.91; N, 4.59. Found: C, 77.75; H, 8.81; N,
4.67; MS (FAB): 306 (MH+), 262 (MꢀCOMe), 230
(MꢀSAc), 140 (100%, MꢀBnSAc); HRMS (FAB) m/z
calcd for C21H25NOS MH+: 306.1891; found: 306.1889.
(M+), 264 (MꢀAc), 232 (MꢀSAc), 142 (100%,
MꢀBnꢀSAc); HRMS (FAB) m/z calcd for C17H25NO2S
M+: 307.1606; found: 307.1600.
5.20. (1R,2S)-3-Methyl-2-morpholino-1-phenylbutane-1-
thiol, 7f
According to reduced procedure to afford 7f (91%) as a
25
D
colorless oil; ½aꢁ ¼ ꢀ80:2 (c 1, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.04 (d, J = 4.0 Hz, 3H, CHCH3),
1.13 (d, J = 4.0 Hz, 3H, CCH3), 2.07 (d, J = 3.0 Hz, 1H,
SH), 2.18–2.23 (m, 1H, CH(CH3)2), 2.49–2.59 (m, 4H,
NCH2CH2), 2.79 (dd, J = 6.0, 5.6 Hz, 1H, NCH),
3.46–3.51 (m, 4H, CH2CH2O), 4.29 (dd, J = 6.8,
7.2 Hz, 1H, SCH), 7.21–7.42 (m, 5H, ArH); 13C
(100 MHz, CDCl3) d 19.69, 21.87, 30.49, 44.54, 52.10,
67.97, 75.56, 127.30, 128.23, 128.44, 128.49, 144.36
(Ph); Anal. Calcd for C15H23NOS; C, 67.88; H, 8.73;
N, 5.28. Found: C, 67.95; H, 8.70; N, 5.30; MS (FAB)
m/z: 265 (M+), 232 (MꢀSH), 142 (100%, MꢀBnꢀSH);
HRMS (FAB) m/z calcd for C15H23NOS MH+:
266.1578; found: 266.1576.
5.17. (1R,2S)-3-Methyl-1-phenyl-2-(piperidin-1-yl)-
butane-1-thiol, 7e
According to the reduced procedure 7e (88%) was ob-
25
1
tained as a colorless oil; ½aꢁ ¼ ꢀ83:6 (c 1, CHCl3); H
D
0.91 (d, J = 6.4 Hz, 3H,
(400 MHz, CDCl3)
d
CH(CH3)2), 0.99 (d, J = 6.4 Hz, 3H, CH(CH3)2), 1.18–
1.28 (m, 6H, C(CH2CH2)2), 2.06–2.16 (m, 1H,
CH(CH3)2), 2.31–2.53 (m, 4H, N(CH2)2, 2.75 (dd,
J = 6.4, 6.8 Hz, 1H, NCH), 4.20 (d, J = 6.4 Hz, 1H,
SCH), 7.20–7.42 (m, 5H, ArH); 13C (100 MHz, CDCl3)
d 19.63, 21.69, 24.87, 26.80, 26.90, 30.21, 44.43, 52.68,
75.91, 126.66, 127.87, 128.03, 144.48 (Ph); Anal. Calcd
for C16H25NS: C, 72.95; H, 9.57; N, 5.32. Found: C,
72.90; H, 9.51; N, 5.29; HRMS (FAB) m/z calcd for
C16H25NS MH+: 264.1786; found: 264.1788.
5.21. (1R,2S)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethanol, 5g
According to the N-alkylation procedure, 5g (86%) was
25
D
obtained as a white solid; mp 113–114 ꢁC; ½aꢁ ¼ ꢀ87:5
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 1.82–1.85
(m, 4H, NCH2(CH2)2), 2.59–2.62 (m, 2H, NCH2),
2.74–2.76 (m, 2H, NCH2), 3.30 (d, J = 3.2 Hz, 1H,
NCH), 5.24 (d, J = 3.2 Hz, 1H, CHOH), 6.97–7.25 (m,
10H, ArH); 13C NMR (100 MHz, CDCl3) d 23.47,
52.94, 73.99, 77.31, 126.08, 126.70, 127.02, 127.19,
127.42, 129.25, 137.47, 140.69 (2Ph); IR (neat): 3031,
2967, 2872, 2799, 1491, 1452 cmꢀ1; Anal. Calcd for
C18H21NO: C, 80.86; H, 7.91; N, 5.24. Found: C,
80.83; H, 7.95; N, 5.21; HRMS (FAB) m/z calcd for
C18H21NO MH+: 268.1701; found: 268.1700.
5.18. (1R,2S)-3-Methyl-2-morpholino-1-phenylbutan-1-
ol, 5f
According to the N-alkylation procedure, 5f (86%) was
25
D
obtained as a white solid; mp 90–92 ꢁC; ½aꢁ ¼ ꢀ9:16
1
(c 21.9, CHCl3); H NMR (400 MHz, CDCl3) d 1.05
(d, J = 6.4 Hz, 3H, CH3), 1.12 (d, J = 6.4 Hz, 3H,
CH3), 1.85–2.0 (m, 1H, CHMe2), 2.35–2.72 (m, 5H,
CHNCH2), 3.51–3.65 (m, 4H, CH2OCH2), 4.88 (d,
J = 1.6 Hz, 1H, CHO), 7.21–7.41 (m, 5H, Ph); 13C
NMR (100 MHz, CDCl3) d 21.34, 21.53, 27.28, 51.15,
67.46, 70.23, 76.08, 125.78, 126.59, 127.58, 143.40 (Ph);
5.22. (S)-(1R,2S)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethyl
ethanethioate, 6g
IR (neat): 3436, 2956, 2856, 2816, 1450, 1384 cmꢀ1
;
Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N,
5.62. Found: C, 72.20; H, 9.25; N, 5.63; HRMS (FAB)
m/z calcd for C15H23NO2MH+: 250.1887; found:
250.1885.
According to general procedure, 6g was obtained as
a
25
D
white solid; mp 123–125 ꢁC; ½aꢁ ¼ ꢀ32:5 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) d 1.74–1.78
(m, 4H, NCH2(CH2)2), 2.28 (s, 3H, COCH3), 2.50–
2.57 (m, 4H, N(CH2)2), 3.48 (d, J = 4.8 Hz, 1H,
NCH), 5.25 (d, J = 5.2 Hz, 1H, SCH), 6.88–7.26 (m,
10H, ArH); 13C NMR (100 MHz, CDCl3) 23.33,
30.83, 52.62, 52.85, 74.99, 126.88, 127.48, 127.59,
128.88, 129.00, 138.64, 140.33 (2Ph), 196.58; Anal.
Calcd for C20H23NOS: C, 73.81; H, 7.12; N, 4.30.
Found: C, 73.55; H, 7.26; N, 4.38; HRMS (FAB) m/z
calcd for C20H23NOS MH+: 326.1578; found: 326.1580.
5.19. (S)-(1R,2S)-3-Methyl-2-morpholino-1-phenylbutyl
ethanethioate, 6f
According to the general procedure, 6f (67%) was ob-
22
D
tained as a light yellow viscous oil; ½aꢁ ¼ ꢀ187:8 (c
1
1.95, CHCl3); H NMR (400 MHz, CDCl3) d 0.86 (d,
J = 6.4 Hz, 3H, CH3), 1.00 (d, J = 6.4 Hz, 3H, CH3),
1.82–2.0 (m, 1H, CHMe2), 2.18 (s, 3H, COCH3), 2.31–
2.57 (m, 4H, CH2NCH2), 2.63 (dd, J = 4.8, 4.4 Hz, 1H,
CHN), 3.40 (t, J = 4.4 Hz, 4H, CH2OCH2), 4.89 (d,
J = 4.4 Hz, 1H, CHO), 7.05–7.4 (m, 5H, Ph); 13C
NMR (100 MHz, CDCl3) d 20.50, 21.65, 30.42, 49.16,
51.38, 67.49, 74.15, 126.95, 127.87, 128.46, 141.08,
194.08; IR (neat): 2956, 2850, 1689, 1115 cmꢀ1; Anal.
Calcd for C17H25NO2S: C, 66.41; H, 8.20; N, 4.56.
Found: C, 66.43; H, 8.18; N, 4.60; MS (FAB) m/z: 306
5.23. (1R,2S)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethanethiol,
7g
According to the reduced procedure, 7g (90%) was ob-
25
D
tained as a colorless viscous oil; ½aꢁ ¼ ꢀ162:0 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) d 1.72–1.79 (m,
4H, NCH2(CH2)2), 2.29 (s, 1H, SH), 2.45–2.51 (m, 2H,
NCH2), 2.55–2.61 (m, 2H, NCH2), 3.46 (d, J = 5.6 Hz,

S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
781
1H, NCH), 4.70 (d, J = 5.2 Hz, 1H, CHS), 6.96–7.36 (m,
10H, ArH); 13C NMR (100 MHz, CDCl3) 23.47, 48.60,
52.30, 75.70, 127.05, 127.09, 127.35, 127.72, 128.63,
129.79, 137.40, 140.85 (2Ph); Anal. Calcd for
C18H21NS: C, 76.28; H, 7.47; N, 4.94. Found: C,
76.06; H, 7.28; N, 5.23; HRMS (FAB) m/z calcd for
C18H21NS MH+: 284.1473; found: 284.1477.
7.14–7.30 (m, 10H, ArH); 13C NMR (100 MHz, CDCl3)
d 24.42, 26.12, 44.75, 50.86, 76.36, 126.84, 27.32, 127.61,
127.89, 128.03, 129.22, 135.75, 142.03 (2Ph); IR (neat):
3061, 3026, 2933, 2850, 2798, 1601 cmꢀ1; Anal. Calcd
for C19H23NS: C, 76.73; H, 7.79; N, 4.71. Found: C,
76.67; H, 7.66; N, 4.56; MS(EI) m/z: calcd for
C19H23NS M+: 264 (MꢀSH), 180, 174 (100%,
MꢀBnSH).
5.24. (1R,2S)-1,2-Diphenyl-2-(piperidin-1-yl)ethanol, 5h
According to N-alkylation procedure to afford 5h (87%)
5.27. (1R,2S)-2-Morpholino-1,2-diphenylethanol, 5i
was obtained as
a
white solid; mp 93–95 ꢁC;
According to the N-alkylation procedure 5i (90%) was
obtained as
25
D
½aꢁ ¼ ꢀ74:2 (c 1.2, CHCl3); 1H NMR (400 MHz,
a
white solid; mp 123–125 ꢁC;
25
D
CDCl3) d 1.45–1.49 (m, 2H, ((CH2)2CH2(CH2)2)),
1.55–1.62 (m, 4H, N(CH2CH2)2), 2.47–2.55 (m, 2H,
NCH2), 2.58–2.71 (m, 2H, NCH2), 3.38 (d, J = 4.0 Hz,
1H, NCH), 5.38 (d, J = 4.0 Hz, 1H, CHO), 6.98–7.26
(m, 10H, ArH); 13CNMR (100 MHz, CDCl3) d 24.60,
26.28, 52.51, 71.55, 76.42, 126.14, 126.58, 127.01,
127.42, 129.43, 136.64, 141.38 (2Ph); IR (neat): 2940,
2916, 2850, 2795, 1448, 1336 cmꢀ1; HRMS (FAB)m/z
calcd for C19H23NO MH+: 282.1858; found: 282.1857.
½aꢁ ¼ ꢀ140:7 (c 1.4, CHCl3); 1H NMR (400 MHz,
CDCl3) d 2.50–2.60 (m, 2H, NCH2), 2.61–2.72 (m, 2H,
NCH2), 3.30 (br, 1H, OH), 3.36 (d, J = 4.0 Hz, 1H,
NCH), 3.67–3.81 (m, 4H, O(CH2)2), 5.33 (d,
J = 4.0 Hz, 1H, CHO), 6.94–7.26 (m, 10H, ArH); 13C
NMR (100 MHz, CDCl3) d 51.96, 67.11, 71.18, 76.44,
126.11, 126.87, 127.40, 127.56, 127.60, 129.54, 135.56,
140.81 (2Ph); IR (neat): 2969, 2882, 2846, 2806, 2759,
2689, 1449, 1334 cmꢀ1; Anal. Calcd for C18H21NO2:
C, 76.33; H, 7.46; N,4.93. Found: C, 76.38; H, 7.36;
N, 4.90; HRMS (FAB) m/z: calcd for C18H21NO2
MH+: 284.1650; found: 284.1644.
5.25. (S)-(1R,2S)-1,2-Diphenyl-2-(piperidin-1-yl)ethyl
ethanethioate, 6h
According to the general procedure 6h (62%) was ob-
5.28. (S)-(1R,2S)-2-Morpholino-1,2-diphenylethyl
ethanethioate, 6i
22
D
tained as a white solid; mp 112–113 ꢁC; ½aꢁ ¼ ꢀ128:4
1
(c 1.3, CHCl3); H NMR (400 MHz, CDCl3) d 1.16–
1.22 (m, 2H, ((CH2)2CH2(CH2)2)), 1.22–1.31 (m, 2H,
NCH2CH2), 1.31–1.40 (m, 2H, NCH2CH2), 2.14 (s,
3H, COCH3), 2.12–2.20 (m, 2H, NCH2), 2.38–2.50 (m,
2H, NCH2), 3.82 (d, J = 10.4 Hz, 1H, NCH), 5.31 (d,
J = 10.4 Hz, 1H, SCH), 7.10–7.31 (m, 10H, ArH); 13C
NMR (100 MHz, CDCl3) d 24.42, 26.04, 30.49, 48.78,
50.71, 73.28, 126.67, 127.32, 127.59, 127.81, 128.25,
128.72, 136.03, 141.72 (2Ph); IR (neat): 2931, 1690,
1449 cmꢀ1; Anal. Calcd for C21H25NOS: C, 74.29; H,
7.42; N, 4.13; O, 4.71; S, 9.45. Found: C, 74.26; H,
7.33; N, 4.24; S, 9.61; EIMS: m/z 264 (MꢀSAc), 213,
174 (100%, MꢀBnSAc); HRMS (FAB) m/z calcd for
C21H25NOS MH+: 340.1735; found: 340.1731.
According to the general procedure, 6i (65%) was ob-
25
D
tained as light red solid; mp 128–130 ꢁC; ½aꢁ ¼ ꢀ94:3
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 2.20 (s,
3H, COCH3), 2.31–2.38 (m, 2H, N(CH2)2), 2.41–2.51
(m, 2H, N(CH2)2), 3.44–3.58 (m, 4H, O(CH2)2), 3.72 (d,
J = 8.4 Hz, 1H, NCH), 5.28 (d, J = 8.4 Hz, 1H, SCH),
7.05–7.27 (m, 10H, ArH); 13C NMR (100 MHz, CDCl3)
d 30.58, 48.88, 50.49, 66.95, 73.63, 126.93, 127.72,
127.78, 127.86, 128.43, 128.94, 135.88, 140.87 (2Ph); IR
(neat): 2956, 2852, 2813, 1689, 1450, 1353 cmꢀ1; Anal.
Calcd for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10.
Found: C, 70.85; H, 6.14; N, 4.69; HRMS (FAB) m/z:
calcd for C20H23NO2S MH+: 342.1527; found: 342.1533.
X-ray crystal data for 6h: C21H25NOS, MW = 339.48,
trigonal, space group P31, a = 9.1843(4), b = 9.1843(4),
5.29. (1R,2S)-2-Morpholino-1,2-diphenylethanethiol, 7i
˚
c = 19.6583(13) A;
U = 1446.05(13) A , T = 293 K, Z = 3, Dc = 1.178 g cm
a = 90ꢁ,
b = 90ꢁ,
c = 12ꢀ0ꢁ1,
According to the reduced procedure, 7i (90%) was ob-
25
3
˚
,
tained as a viscous liquid; ½aꢁ ¼ ꢀ113:7 (c 1, CHCl3);
D
l = 0.176 mmꢀ1, k = 0.71073 A, F(000) 546, crystal size
0.33 · 0.61 · 0.67 mm3, 3729 independent reflections
(Rint = 0.0196), 8072 reflections collected; refinement
method, full-matrix least-squares on F2; goodness-of-fit
on F2 = 0.947; final R indices [I > 2r(I)] R1 = 0.0371,
wR2 = 0.1130, SADABS. CCDC No. 261563.
1H NMR (400 MHz, CDCl3) d 1.96 (br, 1H, SH),
2.32–2.46 (m, 4H, N(CH2)2), 3.46–3.59 (m, 4H,
O(CH2)2), 3.71 (d, J = 8.4 Hz, 1H, NCH), 4.70 (d,
J = 8.4 Hz, 1H, CHS), 7.12–7.30 (m, 10H, ArH); 13C
NMR (100 MHz, CDCl3) d 44.75, 50.44, 66.95, 75.87,
127.10, 127.67, 127.94, 128.14, 129.44, 135.10, 141.24
(2Ph); HRMS (FAB) m/z: calcd for C18H21NOS MH+:
300.1422; found: 300.1429.
˚
5.26. (1R,2S)-1,2-Diphenyl-2-(piperidin-1-yl)ethanethiol,
7h
According to the reduced procedure 7h (89%) was ob-
6. Typical procedure for alkenylzinc addition to aldehydes
25
tained as a viscous liquid; ½aꢁ ¼ ꢀ128:4 (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3) d 1.16–1.39 (m, 6H,
CH2(CH2)2CN), 2.01 (br, 1H, CSH), 2.10–2.30 (m,
2H, CH2N), 2.30–2.41 (m, 2H, CH2N), 3.78 (d,
J = 9.6 Hz, 1H, NCH), 4.68 (d, J = 9.6 Hz, 1H, SCH),
6.1. (R,E)-1-Phenylnon-2-en-1-ol
To a stirring solution of dicyclohexylborane (1.5 mmol)
in toluene (0.5 mL) was added 1-octyne (0.26 mL,

782
S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 16 (2005) 773–782
1.5 mmol) and the mixture stirred for 1 h at room tem-
perature, and then cooled to ꢀ78 ꢁC. A solution of
diethyl zinc (2.0 mmol, 1.1 M in toluene) was added
slowly to this and after 1 h at ꢀ78 ꢁC, a toluene solution
of ligand (0.2 mL, 0.1 M in toluene, 0.02 mmol) was
added. The temperature was then raised to ꢀ30 ꢁC over
a period of 0.5 h and the aldehyde (1.0 mmol) added
slowly and the final mixture allowed to stir for 15 h at
ꢀ30 ꢁC. The reaction was quenched with saturated
NaHCO3 and the resulting mixture extracted with
3 · 10 mL of EtOAc, washed with brine, dried over
Na2SO4, and solvent removed in vacuo. The residue
was purified through column chromatography on silica
gel to provide the enantiomerically pure allyl alcohol.
HPLC (Chiracel OD-H, n-heptane/i-PrOH = 97:3):
5.65 (dd, 1H, J = 15.0, 6.5 Hz, CH(OH)CHCH), 5.79
(dt, 1H, J = 15.0, 7.0 Hz, CHCHCH2), 7.20 (t, 1H,
J = 7.8 Hz, HAr), 7.34–7.27 (m, 2H, HAr), 7.56 (d,
1H, J = 8.0 Hz, HAr). 13C (100 MHz, CDCl3) d 14.06,
22.35, 31.29, 32.04, 71.62, 127.23, 127.56, 128.65,
129.61, 130.29, 132.43, 133.60, 140.81 ppm.
Acknowledgements
Support from the National Science Council of the
Republic of China Taiwan (NSC 91-2113-M-005-008)
is gratefully acknowledged and very much appreciated
Dr. Shanmugam Elango for suggestions and corrections.
1
99.5% ee (R) H NMR (400 MHz, CDCl3) d 0.88 (t,
J = 6.4 Hz, 3H, CH3), 1.23–1.43 (m, 6H), 2.00–2.08
(m, 2H, CHCH2CH2), 5.15 (d, br, J = 6.6 Hz, 1H,
PhCH(OH)CH), 5.64 (ddt, J = 15.6, 6.6, 1.4 Hz, 1H,
CH(OH)CHCH), 5.75 (dt, J = 15.6, 6.6 Hz, 1H,
CHCHCH2), 7.23–7.38 (m, 5H, HAr) ppm; 13C NMR
(100 MHz, CDCl3) d 14.03, 22.47, 28.71, 29.08, 31.38,
32.11, 75.10, 125.96, 127.26, 128.25, 132.00, 132.65,
143.20 ppm; IR (neat) 2955, 2930, 2857, 1621, 1599,
1579, 1450, 1287, 1228, 697 cmꢀ1; MS (70 eV, EI), m/z
(%): 218 (1) [M+], 159, 145, 133, 120 (50), 105 (100),
77, 55.
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6.2. (R,E)-1-(4-Methoxyphenyl)non-2-en-1-ol
According to the general procedure, 1-octyne (0.260 mL,
1.5 mmol), p-methoxybenzaldehyde (0.12 mL, 1 mmol),
and diethylzinc afforded 0.22 g (90% based on the alde-
hyde) of the title compound as a colorless oil. HPLC
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1
(R) H NMR (400 MHz, CDCl3): d 0.88 (t, J = 6.4 Hz,
3H, CH3), 1.23–1.43 (m, 6H), 2.00–2.08 (m, 2H,
CHCH2CH2), 5.10 (d, br, J = 6.6 Hz, 1H, ArCH-
(OH)CH), 5.61–5.78 (m, 2H, CH(OH)CHCH), 6.88 (d,
br, J = 9.9 Hz, 3H, HAr), 7.28 (d, br, J = 9.9 Hz, 2H,
HAr) ppm; 13C NMR (100 MHz, CDCl3) d 14.09,
22.61, 28.88, 29.08, 31.70, 32.20, 55.28, 74.75, 113.84,
127.46, 132.35, 132.43, 135.73, 159.00 ppm.
5. (a) Wipf, P.; Jayasuriya, N.; Ribe, S. Chirality 2003, 208;
(b) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454.
6. Ji, J.-X.; Qiu, L.-Q.; Yip, C.-W.; Chan, A. S. C. J. Org.
Chem. 2003, 68, 1589.
6.3. (R,E)-1-(2-Chloro-phenyl)-hept-2-en-1-ol
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Chem., Int. Ed. Engl. 1987, 26, 1141; (b) Reetz, M. T.
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Chem. 1998, 63, 8067.
According to the general procedure, the reaction of 1-
hexyne (114 lL, 1 mmol), 2-chlorobenzaldehyde
(56.0 lL, 0.5 mmol), and diethylzinc afforded 100 mg
(90% yield based on the aldehyde) of (R)-1-(2-chloro-
phenyl)-hept-2-en-1-ol as a colorless oil. HPLC (Chira-
cel OD-H, n-heptane/i-PrOH = 97:3): 98.1% ee. 1H
NMR (400 MHz, CDCl3): d 0.88 (t, 3H, J = 7.0 Hz,
CH3), 1.39–1.27 (m, 4H), 2.07–2.03 (m, 2H,
CHCH2CH2), 5.56 (d, 1H, J = 7.0 Hz, ArCH(OH)CH),