Stereodefined N,O-acetals: Pd-catalyzed synthesis from homopropargylic amines and utility in the flexible synthesis of 2,6-substituted piperidines

Article abstract of DOI:10.1021/ja2116298

We developed a conceptually new synthetic strategy which exploits the stereochemical information of labile acyclic N,O-acetals. The key to this strategy, chemo- and stereoselective synthesis of N,O-acetals, was achieved by the Pd-catalyzed addition of sulfonyl-protected homopropargylic amines to alkoxyallene. The N,O-acetals generated in this way were combined with Au-catalyzed cycloisomerization to give an access to 2,6-disubstituted piperidines with stereochemical flexibility.

Full text of DOI:10.1021/ja2116298

Supporting Information
Stereodifined N,O-acetals: Pd-catalyzed Synthesis from
Homopropargylic Amines and Utility in the Flexible Synthesis of
2
,6-Substituted Piperidines
Haejin Kim and Young Ho Rhee*
S1

page
S3
1
2
. General Information
. Tables for the optimization
S3
S5
3
4
. Synthesis of n-pentoxyallene
. Synthesis of Homopropargylic Amine Substrates
S5
S9
4
4
-1. Synthesis of substrate 2, 7-9, 11, ent-11
-2. Synthesis of substrate 10
5
. Synthesis of Stereodefined N,O-acetals
5
5
5
-1. Synthesis of N,O-acetals via Pd-catalyzed stereoselective hydroamination
-2. Synthesis of N,O-acetal from achiral substrate
S13
S23
S25
S29
S36
-3. Synthesis of desilylaed N,O-acetals
6
7
8
. Au-catalyzed Cycloisomerization of N,O-acetals
. Synthesis of Piperidin-4-ones
. Structure Determination and X-ray Crystallographic Data
8
8
8
-1) Structure determination of N,O-acetal 18a
-2) Structure determination of compound 25b
-3) X-ray crystallographic data
S43
S43
S44
S46
S47
9
1
. References
1
13
0. H and C-NMR Spectra for New Compounds
S2

1
. General Information
Air and moisture sensitive reactions were carried out in oven-dried glassware sealed with rubber
septa under a positive pressure of nitrogen. Similarly all solvents were dried and distilled according to
the standard methods before use, then were transferred via syringe. Reactions were stirred using
+
-
Teflon-coated magnetic stir bars. Pd(OAc)
2
, Au (CH
3
CN)[(tert-Butyl)
2
P((o-Ph)Ph)]SbF
6
were
purchased from Aldrich Chemical and stored in a dry-keeper. Chiral Trost ligands were purchased
from Strem Chemical Inc. and stored in glove box. Reactions were monitored by thin-layer
chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as a
visualizing agent and acidic p-anisaldehyde, and heat as developing agent. Flash chromatography was
carried out on Merck 60 silica gel (230-400 mesh). 1H and 13C NMR spectra were recorded on
3
Bruker (300 MHz) spectrometer. 1H NMR spectra were referenced to CDCl (7.26 ppm), and
reported as follows; chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, apt=
apparent triplet, m = multiplet, br = broad). Chemical shifts of the 13C NMR spectra were measured
relative to CDCl3 (77.23 ppm). Infrared spectra were recorded on a Shimadzu IR-470 spectrometer.
Specific rotation data were measured on JASCO P-1020 Polarimeter. HPLC was performed with a
SpectaSERIES UV100 equipped with a SpectraSYSTEM P1000 pump. Melting points were measured
on Electrothermal 9100. Mass spectral data were obtained from the Korea Basic Science Institute
(Daegu) on a Jeol JMS 700 high resolution mass spectrometer.
2
. Tables for the optimization
1
) Solvent and concentration effect
a, b
Entry R
equiv)
Solvent
CH Cl
THF
Toluene
Temp
(ºC)
Conc.
(M)
Rxn time
(h)
Yield (%)
(a:b)
c
(
1
2
3
CH
3
3
3
(30)
(30)
(30)
2
2
rt
0.1
0.1
0.1
40
40
40
78 (5.5:1)
CH
CH
rt
rt
82 (1.7:1)
d
70 (3.6:1)
S3

4
5
6
7
CH
CH
CH
3
3
3
(30)
(30)
(70)
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
rt
rt
rt
rt
rt
0.05
0.01
0.05
0.05
0.15
40
40
20
13
10
92 (6.2:1)
34 (3:1)
92 (10:1)
98 (24:1)
98 (25:1)
n-C
5
5
H
H
11 (70)
11 (70)
8
n-C
a
2
Typical procedure: a mixture of substrate, alkoxyallene, Pd(OAc) (5 mol%), (R,R)-3 (10 mol%), and
b
c
1
Et
3
N (1.5 eq) was reacted in CH
2
Cl
2
at rt. Isolated yield. Determined by the integration of H NMR
data.
-
Summary:
1
2
) Among the solvents tested, methylene chloride showed the optimal result.
) Dilution of the reaction lowered the stereoselectivity. On the other hand, concentration had little
effect on the result.
2
) Temperature effect
a, b
Entry R Solvent
Temp
(ºC)
Conc.
(M)
Rxn time
(h)
Yield (%)
(a:b)
c
(equiv)
1
2
n-C H (70)
CH
2
2
Cl
Cl
2
2
rt
0.05
0.05
0.05
13
26
1.5
98 (24:1)
5
11
n-C H (70)
5
11
CH
10
95 (5.3:1)
98 (7.7:1)
3
n-C H (70)
1,2-Dichloroethane 80
5
11
a
2
Typical procedure: a mixture of substrate, alkoxyallene, Pd(OAc) (5 mol%), (R,R)-3 (10 mol%), and
b
c
1
Et
3
N (1.5 eq) was reacted in CH
2
Cl
2
at rt. Isolated yield. Determined by the integration of H NMR
data.
-
Summary: Both lowering and increasing temperature decreased the selectivity
3
) Using neat pentoxyallene
a, b
Entry R
equiv)
Solvent
CH Cl
Neat
Temp
(ºC)
Conc.
(M)
Rxn time
(h)
Yield (%)
(a:b)
c
(
1
n-C H (70)
2
2
rt
rt
0.05
0.05
13
10
98 (24:1)
97 (21:1)
5
11
2
5
n-C H
11
a
2
Typical procedure: a mixture of substrate, alkoxyallene, Pd(OAc) (5 mol%), (R,R)-3 (10 mol%), and
b
c
1
Et
3
N (1.5 eq) was reacted in CH
2
Cl
2
at rt. Isolated yield. Determined by the integration of H NMR
data.
-
Summary: Comparable result was seen.
S4

1
3
. Synthesis of Pentoxyallene (1-(propa-1,2-dien-1-yloxy)pentane)
.
OC H
5
11
2
A literature procedure was modified. To a solution of powdered KOH (17.0 g, 302.9 mmol) in
o
DMSO (80 mL) was added propargyl alcohol (10 mL, 169.3 mmol) at 0 C. After stirring for 10min,
the reaction mixture was allowed to warm to rt over 1h. Then 1-bromopentane (24.6 mL, 203.14
o
mmol) was added to the reaction mixture at 0 C. After stirring for 3h at rt, the resulting brown
suspension was diluted with ether and washed with water. The aqueous layer was extracted with ether
2 4
and then the combined organic layer was dried over anhydrous Na SO . The resulting yellow solution
was concentrated under diminished pressure at low temperature and purified by Kugelrohor
3
distillatioin under diminished pressure at low temperature to afford propargyl ether as a colorless to a
pale yellow liquid, which was used for the next step without further purification.
To a solution of the propargyl ether in THF (70mL) was added potassium t-butoxide (5.7 g, 50.8
mmol) at room temperature. The resulting dark brown suspension was stirred for 4h at rt, then filtered
through a pad of celite and washed with ether. Combined solution was concentrated under diminished
pressure at low temperature, then the concentrated crude was filtered through a short column of silica
gel. The combining solution was again concentrated under diminished pressure at low temperature
and the residue was purified by Kugelrohor distillation under diminished pressure to afford the
desired compound (14.7g, 116.5 mmol, 68% yield over two steps) as a colorless to a light yellowish
liquid.
1
R
f
0.95 (hexane/EtOAc = 80:20) ; H NMR (300 MHz, CDCl
3
) δ 6.72 (t, J =10.5 Hz, 1H), 5.42 (d, J
=
6.0 Hz, 2H), 3.55 (t, J = 6.6 Hz, 2cH), 1.71-1.58 (m, 2H), 1.40-1.29 (m, 4H), 0.93 (t, J = 6.9 Hz,
1
3
3
2
3
H); C NMR (75 MHz, CDCl ) δ 201.7, 121.8, 90.5, 69.1, 29.1, 28.4, 22.7, 14.2; IR (NaCl) ν 2958,
-1
934, 1733, 1468 cm .
4
. Synthesis of Homopropargylic Amine Substrates
-1. Synthesis of substrate 2, 7-9, 11, ent-11
4
S5

Ts
NH2
N
1) TsCl, NEt , CH Cl
3
2
2
2
) NaOH, THF
OH
R
R
TMS-acetylene
or
TMS-acetylene, HMPA
3
R = n-C H7
3
7
8
9
R = i-Pr
R = CH3
R = Ph
Ts
R
Ts
NH
TMS
NH
H
or
11 R = CH Ph
2
R
4
Aziridines were prepared following the literature.
Representative procedure for the preparation of substrate 2
(R)-4-methyl-N-(1-(trimethylsilyl)hept-1-yn-4-yl)benzenesulfonamide (2)
Ts
NH
TMS
A solution of n-BuLi (13.5 mL of 1.3 M solution in Hexane, 17.6 mmol, 3 equiv) was added to a
solution of (trimethylsilyl)acetylene (2.47 mL, 17.8 mmol, 3 equiv) in THF (30 mL) under nitrogen at
o
o
-
78 C. The reaction mixture was stirred for 30 min at -78 C. To this solution the (R)-2-propyl-1-
5
tosylaziridine (1.40 g, 5.86 mmol, 1equiv) in THF (5 mL) was added to the reaction mixture then it
o
was allowed to warm up to room temperature and stirred for 26 hr. After cooling to 0 C and the
reaction quenched by adding the saturated NH
4
Cl (15 mL). Aqueous layer was extracted with ether
and washed with brine and dried over Na SO
2
4
. Solvent was removed under reduced pressure and
crude was purified by flash column chromatography on silica gel (eluted with hexane/EtOAc = 90:10)
to give compound 2 (1.30 g, 3.87 mmol, 66% yield) as a white solid.
2
0
1
Rf 0.42 (hexane/EtOAc = 80:20) ; Mp. 65-67 ˚C; [α] +102.1 (c 1.31, CH Cl ); H NMR (300 MHz,
D
2
2
CDCl
3
) δ 7.76 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.65 (d, J = 9.0 Hz, 1H), 3.40-3.28 (m,
1
1
1
1
H), 2.43 (s, 3H), 2.25 (dd, J = 17.1, 4.2 Hz, 1H), 2.23 (dd, J = 17.1, 5.7 Hz, 1H), 1.57-1.45 (m, 2H),
1
3
.38-1.18 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H), 0.14 (s, 9H); C NMR (75 MHz, CDCl
3
) δ 143.6, 138.3,
29.9, 127.2, 101.9, 88.6, 51.7, 36.5, 26.3, 21.7, 18.9, 13.8, 0.2; IR (NaCl) ν 3280, 2960, 2177, 1329,
-1
+
250, 1163 cm ; HRMS (FAB) calcd for C H NO SSi (MH ) 338.1610, found 338.1611.
17
28
2
(S)-4-methyl-N-(2-methyl-6-(trimethylsilyl)hex-5-yn-3-yl)benzenesulfonamide (7)
S6

Ts
NH
TMS
Using the representative procedure, 7 was obtained from (R)-2-isopropyl-1-tosylaziridine (1.50 g,
6
.28 mmol) as a white solid (1.43 g, 4.24 mmol) in 67% isolated yield.
2
0
1
Rf 0.46 (hexane/EtOAc = 80:20); Mp. 99-101 ˚C; [α] +150.1 (c 1.00, CH Cl ); H NMR (300 MHz,
D
2
2
CDCl
3
) δ 7.76 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.70 (d, J = 9.0 Hz, 1H), 3.12-3.00 (m,
1
0
1
1
H), 2.42 (s, 3H), 2.35 (dd, J = 17.3, 3.4 Hz, 1H), 2.17 (dd, J = 17.1, 6.0 Hz, 1H), 1.97-1.84 (m, 1H),
13
.86 (d, J = 7.2 Hz, 3H), 0.83 (d, J = 7.8 Hz, 3H), 0.13 (s, 9H); C NMR (75 MHz, CDCl ) δ 143.5,
3
38.2, 129.8, 127.3, 102.0, 88.5, 57.3, 31.1, 24.0, 21.7, 19.4, 18.3, 0.2; IR (NaCl) ν 3289, 2962, 2176,
-1
+
330, 1250, 1162 cm ; HRMS (FAB) calcd for C H NO SSi (MH ) 338.1610, found 338.1608.
17
28
2
(R)-4-methyl-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (8)
Ts
NH
TMS
6
Using the representative procedure, 8 was obtained from (R)-2-methyl-1-tosylaziridine (3.34 g,
1
5.81 mmol, in THF 16 mL) as a white solid (4.11 g, 13.28 mmol) in 84% isolated yield.
2
0
1
R
f
0.38 (hexane/EtOAc = 80:20); Mp. 144-146 ˚C; [α]
D 2 2
+52.7 (c 1.9, CH Cl ); H NMR (300 MHz,
CDCl
3
) δ 7.76 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.77 (d, J = 8.1 Hz, 1H), 3.55-3.40 (m,
13
1
H), 2.42 (s, 3H), 2.32-2.27 (m, 2H), 1.63 (d, J = 6.6 Hz, 3H), 0.14 (s, 9H); C NMR (75 MHz,
3
CDCl ) δ 143.6, 138.1, 129.9, 127.2, 101.9, 88.6, 48.1, 28.3, 21.7, 20.8, 0.2. IR (NaCl) ν 3274, 2960,
-1
+
2
3
177, 1331, 1250, 1163 cm ; HRMS (FAB) calcd for C15
2
H24NO SSi (MH ) 310.1297 found
10.1295.
(S)-4-methyl-N-(1-phenylbut-3-yn-1-yl)benzenesulfonamide (9)
Ts
NH
H
Ph
7
The representative procedure was modified. To a solution of n-BuLi (7.2 mL of 1.6 M solution in
Hexane, 11.4 mmol) was added to a solution of (trimethylsilyl)acetylene (1.84 mL, 13.3 mmol) in
o
o
THF (10 mL) under nitrogen at -78 C. The reaction mixture was stirred for 30 min at -78 C. To this
S7

solution the (R)-2-phenyl-1-tosylaziridine (1.04 g, 3.80 mmol) in THF (10 mL) and HMPA (861 μL,
4
.95mmol) in THF (10 mL) was added to the reaction mixture then it was allowed to warm up to rt
o
and stirred for 9 hr. After cooling to 0 C and the reaction quenched by adding the saturated NH
4
Cl
(
20 mL). Aqueous layer was extracted with ether and washed with brine and dried over Na SO .
2 4
Solvent was removed under reduced pressure and crude was purified by flash column chromatograghy
on silica gel (eluted with hexane/EtOAc=10:90) to give the TMS-protected compound ((S)-4-methyl-
N-(1-phenyl-4-(trimethylsilyl)but-3-yn-1-yl)benzenesulfonamide, 456 mg, 1.23 mmol) as a yellowish
solid in 32% isolated yield. Further elution (eluted with hexane/EtOAc = 85:15) furnished the desired
product 9 (530 mg, 1.77 mmol, 47% yield) as a yellowish solid.
2
0
1
R
f
0.20 (pentane/ether = 70:30); Mp. 125.5-127.5 ˚C; [α]
D 2 2
-70.9 (c 0.94, CH Cl ); H NMR (300
MHz, CDCl ) δ 7.62(d, J = 8,4 Hz, 2H), 7.35-7.11 (m, 7H), 5.27 (d, J = 8.6 Hz, 1H), 4.50 (dd, J =
3
13
1
3.2, 6.0 Hz 1H), 2.64 (dd, J = 6.0, 2.4 Hz, 2H), 2.38 (s, 3H), 1.97 (t, J = 2.6 Hz, 1H); C NMR (75
3
MHz, CDCl ) δ 143.5, 139.4, 137.5, 129.7, 128.6, 128.1, 127.4, 126.8, 79.3, 72.4, 55.9, 27.5, 21.7; IR
-1
+
(
NaCl) ν 3298, 3263, 1320, 1164 cm ; HRMS (FAB) calcd for C H NO S (MH ) 300.1058, found
17 18 2
3
00.1056.
(R)-4-methyl-N-(1-phenyl-5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (11)
Ts
NH
TMS
Bn
8
Using the representative procedure, 11 was obtained from (R)-2-benzyl-1-tosylaziridine ( 430 mg,
1
.64 mmol) as a white solid (399 mg, 1.03 mmol) in 63 % isolated yield. Further elution (eluted with
hexane/EtOAc = 85:15) furnished the TMS-deprotected compound ((S)-4-methyl-N-(1-phenylpent-4-
yn-2-yl)benzene-sulfonamide, 90.4 mg, 0.288 mmol, 17% yield) as a white solid.
2
0
1
R
f
0.49 (hexane/EtOAc = 80:20); Mp. 65-67 ˚C; [α]
CDCl ) δ 7.65(d, J = 8,4 Hz, 2H), 7.29-7.03(m, 2H), 4.72 (d, J = 8.4 Hz, 1H), 3.60-3.48 (m, 1H), 2.88
dd, J = 13.7, 7.4 Hz, 1H), 2.82 (dd, J = 13.7, 6.5 Hz, 1H), 2.42 (s, 3H), 2.34 (dd, J = 17.0, 4.4 Hz,
D 2 2
+26.3 (c 1.03, CH Cl ); H NMR (300 MHz,
3
(
1
3
1
1
2
3
H), 2.26 (dd, J = 17.0, 6.2 Hz, 1H), 0.19 (s, 9H); C NMR (75 MHz, CDCl
3
) δ 143.5, 137.7, 136.9,
29.9, 129.5, 128.8, 127.2, 127.0, 101.9, 89.1, 53.3, 40.1, 25.5, 21.7, 0.3; IR (NaCl) ν 3277, 2958,
-1
+
176, 1330, 1250, 1161 cm ; HRMS (FAB) calcd for C H NO SSi (MH ) 386.1610, found
2
1
28
2
86.1612.
S8

(S)-4-methyl-N-(1-phenyl-5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (ent-11)
Ts
NH
TMS
Bn
Using the representative procedure, ent-11 was obtained from (S)-2-benzyl-1-tosylaziridine (1.50
gm, 5.23 mmol) as a white solid (1.30 g, 3.37 mmol) in 64% isolated yield.
2
0
All spectral data matched a compound 11 except for the sign of specific rotation: [α] -27.8 (c
D
0
.36, CH Cl )
2
2
4
-2. Synthesis of substrate 10
OH
H
BnO
5
ee 97%
1
0a'
K CO /MeOH
2
3
N3
TMS
OH
TMS
OMs
TMS
NaN3
MsCl
BnO
5
BnO
BnO
5
5
10c
10a
10b
K CO /MeOH
2
3
Ts
N3
H
NH
H
i) LAH
ii) TsCl
BnO
BnO
5
5
10
10d
(S)-10-(benzyloxy)-1-(trimethylsilyl)dec-1-yn-4-ol (10a)
OH TMS
BnO
To a stirred solution of trimethylsilylacetylene (3.8 ml, 26.8 mmol) in THF (90 ml) was slowly
added n-BuLi (15 ml of 1.6M solution in hexane, 24.4 mmol) under nitrogen at -78 ˚C. The resulting
3 2
mixture was stirred for 0.5 h at -78 ˚C, then BF •OEt was added slowly. After stirring for 0.5 h at -78
9
˚
C, (S)-2-(6-(benzyloxy)hexyl)oxirane (2.9 g, 12.2 mmol) in THF (20 ml) was slowly added at -78
˚
C. The reaction mixture was stirred at -78 ˚C for 8 h. After the reaction was completed, saturated
Cl (70 mL) was added to the mixture, and it was extracted with ethyl acetate. The organic layer
was dried by anhydrous Na SO and evaporated under reduced pressure. The residue was purified by
NH
4
2
4
S9

flash column chromatography (eluted with hexane/EtOAc = 90:10) to give 3.2 g (9.6 mmol, 78%
yield) of the desired alcohol 10a as a colorless oil.
2
0
1
R
f
0.43 (hexane/EtOAc = 80:20); [α]
D 3 3
+5.3 (c 0.65, CHCl ); H NMR (300 MHz, CDCl ) δ 7.35-
7
5
.26 (m, 5H), 4.50 (s, 2H), 3.72 (dt, J = 11.4, 5.9 Hz, 1H), 3.47 (t, J = 6.6 Hz, 2H), 2.40 (qd, J = 17.7,
13
.8 Hz, 2H), 1.67-1.58 (m, 2H), 1.55-1.49 (m, 2H), 1.43-1.35 (m, 6H), 0.17 (s, 9H); C NMR (75
MHz, CDCl
3
) δ 138.9, 128.6, 127.8, 127.7, 103.5, 87.8, 73.1, 70.6, 70.0, 36.4, 29.9, 29.6, 29.1, 26.3,
-
1
+
2
5.7, 0.3; IR (NaCl) ν 3435, 2934, 2857, 2715 cm ; HRMS (FAB) calcd for C20
33.2250, found 333.2247.
33 2
H O Si (MH )
3
(S)-10-(benzyloxy)dec-1-yn-4-ol (10a’)
OH
H
BnO
To a solution of 10a (20 mg, 0.06 mmol) in methanol (0.3 mL) was added K
2
3
CO (8 mg, 0.07
mmol) at room temperature. After stirring for 6 h at rt, the solvent was removed under reduced
pressure. The mixture was purified by flash column chromatography (eluted with hexane/ether =
9
5:5) to give desilylated product 10a’ (13 mg, 0.05 mmol, 80%) as a yellowish oil. The enantiomeric
excess (97% ee) determined by HPLC on a chiral column (Chiralcel OD-H, n-hexane/2-propanol =
9
5/5; flow rate = 1.0 mL/min; UV = 254 nm); retention times = 15.1 min (major), 17.9 min (minor).
2
0
1
R
f D 3 3
0.33 (hexane/EtOAc = 80:20); [α] +10.1 (c 0.45, CHCl ); H NMR (300 MHz, CDCl ) δ 7.35-
7
2
1
1
2
.27 (m, 5H), 4.50 (s, 2H), 3.75 (dt, J = 11.4, 5.9, 1H), 3.46 (t, J = 6.6, 2H), 2.43 (ddd, J = 16.6, 4.6,
.5, 1H), 2.47-2.26 (m, 2H), 2.31 (ddd, J = 16.8, 6.6, 2.4, 1H), 2.05 (t, J = 2.4, 1H), 1.87-1.80 (m, 1H),
13
.64-1.58 (m, 2H), 1.57-1.49 (m, 2H), 1.45-1.29 (m, 6H); C NMR (75 MHz, CDCl
3
) δ 138.9, 128.6,
27.9, 127.71, 81.1, 73.1, 71.0, 70.6, 70.1, 36.4, 29.9, 29.6, 27.6, 26.4, 25.8; IR (NaCl) ν 3397, 3310,
-1
+
926, 2855 cm ; HRMS (EI) calcd for C H O (M ) 260.1776, found 260.1779.
1
7
24
2
HPLC data for compound 10a’
S10

OH
H
BnO
5
1
0a' racemic
( )
OH
H
BnO
5
1
0a'
(S)-10-(benzyloxy)-1-(trimethylsilyl)dec-1-yn-4-yl methanesulfonate (10b)
OMs
TMS
BnO
To a solution of 10a (2.1 g, 6.4 mmol) dissolved in CH
2
2
Cl (18 mL) were slowly added methane
sulfonylchloride (1.0 mL, 13.4 mmol) and triethylamine (1.8 mL, 12.8 mmol) at 0 ˚C. The reaction
mixture was warmed to room temperature and stirred for 5 h. After the reaction was completed, 20mL
2 2
of water was added to the mixture, and it was extracted with CH Cl . The combined organic layer was
dried by anhydrous Na SO and evaporated under reduced pressure. The residue was purified by flash
2
4
S11

column chromatography (eluted with hexane/EtOAc = 95:5) to give mesylate compound 10b (2.5 g, 6
mmol, 94%) as a colorless oil.
2
0
1
R
f
0.43 (hexane/EtOAc = 80:20); [α]
.26 (m, 5H), 4.72 (tt, J = 6.1, 6.1 Hz, 1H), 4.50 (s, 2H), 3.46 (t, J = 6.5 Hz, 2H), 3.05 (s, 3H), 2.64
dd, J = 6.1, 3.7 Hz, 2H), 1.78 (q, J = 7.0 Hz, 2H), 1.61 (q, J = 6.8 Hz, 2H), 1.44-1.33 (m, 6H), 0.15 (s,
D 3 3
-11.4 (c 1.69, CHCl ); H NMR (300 MHz, CDCl ) δ 7.35-
7
(
1
3
9
H); C NMR (75 MHz, CDCl
3
) δ 138.9, 128.5, 127.8, 127.7, 101.5, 88.2, 81.0, 73.1, 70.5, 38.9, 34.3,
-1
2
9.8, 29.2, 26.4, 26.2, 24.9, 0.1; IR (NaCl) ν 2937, 2859, 2719, 1362 cm .
(R)-(4-azido-10-(benzyloxy)dec-1-ynyl)trimethylsilane (10c)
N3 TMS
BnO
To a solution of sodium azide (1.9 g, 29.3 mmol) in DMF (18 mL) was added 10b (3 g, 7.3 mmol).
The reaction mixture was stirred at 50 ˚C overnight. The mixture was cooled to room temperature and
diluted with water (30 mL). It was extracted with ethyl acetate, and the combined organic extracts
2 4
were washed with water. The organic layer was dried over anhydrous Na SO and evaporated under
reduced pressure. The residue was purified by flash column chromatography ( hexane/EtOAc = 96:4)
to give the compound 10c (1.9 g, 5.3 mmol, 72 %) as a pale yellow oil.
2
0
1
R
f
0.55 (hexane/EtOAc = 80:20); [α]
D 3 3
+14.2 (c 1.1, CHCl ); H NMR (300 MHz, CDCl ) δ 7.35-
7
1
1
2
.26 (m, 5H), 4.51 (s, 2H), 3.47 (t, J = 6.5 Hz, 2H), 3.45-3.41 (m, 1H), 2.47 (d, J = 6.2 Hz, 2H), 1.65-
13
.58 (m, 4H), 1.43-1.32 (m, 6H), 0.17 (s, 9H); C NMR (75 MHz, CDCl ) δ 138.9, 128.6, 127.8,
3
27.7, 102.6, 88.0, 73.1, 70.6, 61.1, 33.7, 29.9, 29.3, 26.5, 26.3, 26.1, 0.1; IR (NaCl) ν 2936, 2858,
-1
+
120, 2102 cm ; HRMS (FAB) calcd for C H ON Si (MH ) 358.2315, found 358.2319.
20
32
3
(R)-((7-azidodec-9-ynyloxy)methyl)benzene (10d)
N3
H
BnO
To a solution of 10c (1.4 g, 3.9 mmol) in methanol (10 mL) was added potassium carbonate (805
mg, 5.8 mmol) at rt. After stirring for 6 h at room temperature, the solvent was removed under
reduced pressure. The mixture was purified by flash column chromatography (eluted with
hexane/ether = 96 : 4) to give desilylated product 10d (910 mg, 3.2 mmol, 81%) as a yellowish oil.
S12

2
0
1
R
f
0.69 (hexane/EtOAc = 80:20); [α]
D 3 3
+16.8 (c 1.0, CHCl ); H NMR (300 MHz, CDCl ) δ 7.36-
7
1
7
.28 (m, 5H), 4.51 (s, 2H), 3.50-3.44 (m, 3H), 2.44 (dd, J = 6.1, 2.7 Hz, 2H), 2.08 (t, J = 2.6 Hz, 1H),
13
.66-1.59 (m, 4H), 1.46-1.34 (m, 6H); C NMR (75 MHz, CDCl
3
) δ 138.9, 128.5, 127.8, 127.7, 80.1,
-1
3.1, 71.2, 70.5, 61.0, 33.6, 29.8, 29.3, 26.2, 26.0, 24.8; IR (NaCl) ν 3305, 2933, 2858, 2102 cm .
(R)-N-(10-(benzyloxy)dec-1-yn-4-yl)-4-methylbenzenesulfonamide (10)
Ts
NH
H
BnO
To a solution of LiAlH
4
(48.7 mg, 1.30 mmol) in ether (1 mL) was carefully added the compound
o
1
0d (310 mg, 1.09 mmol) in ether (2.6 mL) at 0 C. The reaction mixture was slowly warmed to room
temperature and stirred for 3h. The mixture was quenched with small amount of water and filtered
through celite. The residue oil was dreied over anhydrous Na2SO4 and evaporated under the reduced
pressure. The residue was (278.7 mg, 1.07 mmol) of desired amine as a yellowish oil.
To p-toluenylsulfonyl chloride (306.0mg, 1.61 mmol) were slowly added a solution of amine
o
(
278.7 mg, 1.07 mmol) in CH
2
Cl
2
(5 mL) and triethylamine (0.18 mL, 1.28 mmol) at 0 C. The
reaction mixture was warmed to room temperature and stirred for overnight. The reacton mixture was
extracted with ether (20 mLx3). The organic was dried over anhydrous Na SO and evaporated under
2
4
the reduced pressure. The residual oil was purified by flash column chromatography (eluted with
hexane/EtOAc = 90:10) to give the desired compound 10 (424.8 mg, 1.03 mmol, 96% yield) as a
white solid.
2
0
1
R
f
0.17 (hexane/EtOAc = 80:20); Mp. 76-78 ˚C: [α]
CDCl ) δ 7.76 (d, J = 8.1 Hz, 2H), 7.37-7.25 (m, 7H), 4.67 (d, J = 9.0 Hz, 1H), 4.49 (s, 2H), 3.43 (t, J
6.6 Hz, 2H), 3.40-3.27 (m, 1H), 2.41 (s, 3H), 2.30-2.22 (m, 2H), 1.97 (t, J = 2.4 Hz, 1H), 1.61-1.43
D 2 2
+34.4 (c 0.875, CH Cl ); H NMR (300 MHz,
3
=
1
3
(
m, 4H), 1.34-1.08 (m, 6H); C NMR (75 MHz, CDCl )δ 143.6, 138.8, 138.2, 129.8, 128.5, 127.8,
3
1
2
4
27.7, 127.2, 79.6, 73.0, 71.7, 70.5, 51.9, 34.1, 29.8, 29.1, 26.1, 25.6, 25.2, 21.7; IR (NaCl) 3288,
1
+
934, 2858, 1327, 1160, 1094 cm- ; HRMS (FAB) calcd for C24
H32NO
3
S (MH ) 414.2103 found
14.2106.
5
. Synthesis of Stereodefined N,O-acetals
5
-1. Synthesis of N,O-acetals via Pd-catalyzed stereoselective hydroamination
S13

Representative procedure for the synthesis of 5a and 5b
4
-Methyl-N-((S)-1-(pentyloxy)allyl)-N-((R)-1-(trimethylsilyl)hept-1-yn-4-yl)benzenesulfonamide
(5a)
Ts
N
OC H
5
11
TMS
A solution of Pd(OAc)
2
(3.3 mg, 14.8 μmol) and (R,R)-3 (20.4 mg, 0.03 mmol), triethylamine (61.9
(4.9 mL) was added to 2 (100 mg, 0.296 mmol) in CH Cl (1.0 mL) in a 10
μL, 0.44mmol) in CH Cl
2
2
2
2
mL pressure tube equipped with a magnetic stir bar, and sealed with aluminium crimp top cap under
7
nitrogen. Then, pentoxyallene (2.62 g, 20.74 mmol) was added to a reaction mixture. The resulting
mixture was stirred for 13 hr at rt until TLC indicated complete conversion of the starting material.
Then remaining pentoxyallene(2.28 g, 18.1 mmol) was recovered using Kugelrohr distillation under
diminished pressure and the resulting crude residue was purified by flash column chromatography
(eluted with hexane/EtOAc = 97:3), afforded the compound 5a as a yellowish oil (134 mg, 0.289
1
mmol, 98% yield) in a diasteromeric ratio of 24:1 (measured by the integration of H NMR data).
2
0
1
R
f
0.65 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-75.4 (c 0.73, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.74 (d,
J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.76 (ddd, J = 16.8, 10.5, 4.8 Hz, 1H), 5.40 (ddd, J = 16.8,
1
3
3
0
1
.5, 1.5 Hz, 1H), 5.36 (ddd, J = 4.8.1.5, 1.5 Hz, 1H), 3.55 (dt, J = 9.6, 6.6 Hz, 1H), 3.58-3.43 (m, 1H),
.36 (dt, J = 9.6, 6.6 Hz, 1H), 2.80 (dd, J = 16.8, 9.6 Hz, 1H), 2.56 (dd, J = 16.8, 4.4 Hz, 1H), 2.41 (s,
H), 1.80 (m, 2H), 1.52 (tt, J = 6.9, 6.6 Hz, 2H), 1.28 (m, 4H), 1.08 (m, 2H), 0.89 (t, J = 6.9 Hz, 3H),
13
.74 (t, J = 7.5 Hz, 3H), 0.12 (s, 9H); C NMR (75 MHz, CDCl
3
) δ 143.2, 139.8, 133.5, 129.6, 127.4,
18.4, 105.4, 87.7, 86.5, 68.7, 56.7, 35.2, 29.3, 28.5, 27.5, 22.7, 21.7, 20.6, 14.2, 13.9, 0.2; IR (NaCl)
-1
+
ν 2959, 2176, 1343, 1250, 1161cm ; HRMS (FAB) calcd for C H NO SSiNa (MNa ) 486.2474,
2
5
41
3
found 486.2476.
4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((R)-1-(trimethylsilyl)hept-1-yn-4-yl)benzenesulfonamide
(5b)
Ts
N
OC H
5
11
TMS
S14

A solution of Pd(OAc)
2
(3.3 mg, 14.8 μmol) and (S,S)-3 (20.4 mg, 0.03 mmol), triethylamine (61.9
μL, 0.44mmol) in CH Cl
2
2
(5.9 mL) was added to 2 (100 mg, 0.296 mmol) in a 10 mL pressure tube
equipped with a magnetic stir bar, and sealed with aluminium crimp top cap under nitrogen. Then,
pentyloxyallene (2.62 g, 20.74 mmol) was added to a reaction mixture. The resulting mixture was
stirred for 13 hr at rt until TLC indicated complete conversion of the starting material. The remaining
allene was removed by Kugelrohr distillation under diminished pressure. The resulting crude residue
was purified by flash column chromatography (eluted with hexane/EtOAc = 97:3), afforded the
compound 5b as a yellowish oil (136 mg, 0.293 mmol, 99 % yield) in a diasteromeric ratio of 24:1
1
(
measured by the integration of H NMR data).
2
0
1
R
f D 2 2 3
0.65 (hexane/EtOAc = 80:20); [α] +16.7 (c 0.59, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.76 (d,
J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.76 (ddd, J = 17.1, 10.5, 4.2 Hz, 1H), 5.38 (ddd, J = 17.1,
.5, 1.5 Hz, 1H), 5.32 (ddd, J = 4.2, 1.5, 1.5 Hz, 1H), 5.20 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 3.61 (dt, J
9.3, 6.6 Hz, 1H), 3.55-3.45 (m, 1H), 3.37 (dt, J = 9.3, 6.6 Hz, 1H), 2.70 (dd, J = 17.3, 7.1 Hz, 1H),
.61 (dd, J = 17.1, 7.5 Hz, 1H), 2.40 (s, 3H), 1.97-1.75 (m ,2H), 1.57-1.48 (m, 2H), 1.35-1.21 (m, 6H),
1
=
2
0
1
1
1
3
.88 (t, J = 6.6 Hz, 3H), 0.86 (t, J = 7.5 Hz, 3H), 0.08 (s, 9H) ; C NMR (75 MHz, CDCl
3
) δ 143.2,
39.6, 135.4, 129.6, 127.5, 118.3, 105.3, 87.5, 86.4, 69.0, 56.9, 37.7, 29.3, 28.5, 25.6, 22.7, 21.7, 20.8,
-1
4.2, 14.0, 0.1; IR (NaCl) ν 2959, 2177, 1343, 1250, 1161cm ; HRMS (FAB) calcd for
+
C H NO SSiNa (MNa ) 486.2474, found 486.2471.
2
5
41
3
4
-Methyl-N-((S)-2-methyl-6-(trimethylsilyl)hex-5-yn-3-yl)-N-((S)-1-
(pentyloxy)allyl)benzenesulfonamide (12a)
Ts
N
OC H
5
11
TMS
2
Using the representative procedure, 7 (103.0 mg, 0.305 mmol) was reacted with Pd(OAc) (3.4 mg,
0
.0151 mmol) and (R,R)-3 (21.0 mg, 0.0304 mmol) , pentyloxyallene (2.65 g, 68.8 mmol) and
triethylamine (65.5 μL, 0.470 mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 12a as a yellowish oil (140.0 mg, 0.302 mmol, 99% yield) in a diasteromeric
ratio of 21:1.
2
0
1
R
f
0.65 (hexane/EtOAc = 80:20); [α]
D 2 2 3
+39.1 (c 0.48, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.81 (d,
J = 8.4 Hz, 2H), 7.24 (d, J = 8,4 Hz, 2H), 6.20 (ddd, J = 16.8, 10.5, 6.9 Hz, 1H), 5.26 (d, J = 10.5 Hz,
1
H), 5.23 (d, J = 16.8 Hz, 1H), 5.19 (d, J = 6.9 Hz, 1H), 3.41-3.28 (m, 3H), 2.47 (dd, J = 17.7, 4.8,
S15

1
H), 2.41 (s, 3H), 2.33 (dd, J = 17.7, 4.8 Hz, 1H), 2.17-2.09 (m, 1H), 1.54-1.43 (m, 2H), 1.33-1.19
13
(
m, 4H), 1.01 (d, J = 6.6Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 0.12 (s, 9H); C
NMR (75 MHz, CDCl ) δ 143.0, 139.5, 136.9, 129.3, 128.1, 117.9, 104.8, 88.6, 87.3, 68.1, 62.2, 31.4,
9.4, 28.5, 24.2, 22.7, 21.6, 21.2, 20.1, 14.2, 0.1; IR (NaCl) ν 2960, 2932, 2873, 2175, 1345, 1250,
3
2
1
1
+
163 cm- ; HRMS (FAB) calc for C H NO SSiNa (MNa ) 486.2474 found 486.2472.
2
5
41
3
4
-methyl-N-((S)-2-methyl-6-(trimethylsilyl)hex-5-yn-3-yl)-N-((R)-1-
pentyloxy)allyl)benzenesulfonamide (12b)
Ts
N
OC H
5
11
TMS
2
Using the representative procedure, 7 (99.2 mg, 0.294 mmol) was reacted with Pd(OAc) (3.3 mg,
0
.0147 mmol) and (S,S)-3 (20.5 mg, 0.0297 mmol) , pentyloxyallene (2.60 g, 20.6 mmol) and
triethylamine (61.5 μL, 0.441 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 12b as a yellowish oil (129.7 mg, 0.279 mmol, 95% yield) in a
diastereomeric ratio of >25:1.
2
0
1
R
f
0.65 (hexane/EtOAc = 80:20); [α]
d, J = 8.1 Hz, 2H), 7.26 (d, J = 8,1 Hz, 2H), 5.90 (ddd, J = 17.1, 10.5, 4.8 Hz, 1H), 5.40 (ddd, J =
7.1, 1.5, 1.5 Hz, 1H), 5.32 (ddd, J = 4.8, 1.5, 1.2 Hz, 1H), 5.22 (ddd, J = 10.5, 1.5, 1.2 Hz, 1H), 3.54
dt, J = 9.3, 6.6 Hz, 1H), 3.36 (ddd, J = 9.3, 6.9, 6.9 Hz, 1H), 3.25 (dt, J = 9.3, 5.9 Hz, 1H), 2.69 (dd,
J = 17.7, 6.0 Hz, 1H), 2.55 (dd, J = 17.7, 6.0 Hz, 1H), 2.41 (s, 3H), 2.31-2.19 (m, 1H), 1.59-1.47 (m,
D 2 2 3
+ 22.4 (c 0.63, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.77
(
1
(
2
0
6
1
H), 1.36-1.23 (m ,4H), 1.02 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.3 Hz, 3H),
1
3
.87 (s, 9H); C NMR (75 MHz, CDCl
3
) δ 143.2, 139.3, 135.4, 129.6, 127.8, 118.5, 105.8, 87.8, 87.1,
9.2, 63.2, 33.4, 29.2, 28.5, 24.9, 22.7, 21.7, 21.6, 20.8, 14.2, 0.1; IR (NaCl) ν 2960, 2873, 2177, 1342,
1
+
250, 1161 cm- ; HRMS (FAB) calc for C H NO SSiNa (MNa ) 486.2474 found 486.2475.
2
5
41
3
4
-methyl-N-((S)-1-(pentyloxy)allyl)-N-((R)-5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide
(13a)
S16

Ts
N
OC H
5
11
TMS
Using the representative procedure, 8 (101 mg, 0.326 mmol) was reacted with Pd(OAc)
2
(3.6 mg,
0
.016 mmol) and (R,R)-3 (22.3 mg, 0.033 mmol) , pentyloxyallene (2.85 g, 22.62 mmol) and
triethylamine (67.5 μL, 0.48mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 13a as a yellowish oil (142.0 mg, 0.323 mmol, 99% yield) in a diasteromeric
ratio of 19:1
2
0
1
R
f
0.60 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-104.4 (c 0.58, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.72
(d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.61 (ddd, J = 17.6, 10.5, 3.6 Hz, 1H), 5.39 (dd, J = 17.6,
1
1
2
0
.5, 1.5 Hz, 1H), 5.22 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 3.66-3.58 (m, 1H), 3.60 (dt, J = 9.6, 6.6 Hz,
H), 3.49 (dt, J = 9.6, 6.6 Hz, 1H), 2.98 (dd, J = 16.5, 10.8 Hz, 1H), 2.57 (dd, J = 16.5, 4.2 Hz, 1H),
.41 (s, 3H), 1.57-1.52 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H) 1.32-1.27 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H),
1
3
.14 (s, 9H) ; C NMR (75 MHz, CDCl
3
) δ 143.3, 139.8, 134.7, 129.7, 127.4, 118.8, 105.0, 87.5, 86.5,
-
6
8.4, 51.9, 29.2, 28.6, 28.5, 22.7, 21.7, 18.9, 14.2, 0.3; IR (NaCl) ν 2958, 2176, 1344, 1250, 1161 cm
1
+
;
HRMS (FAB) calcd for C23
H37NO
3
SSiNa (MNa ) 458.2161, found 458.2164.
4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((R)-5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide
(13b)
Ts
N
OC H
5
11
TMS
Using the representative procedure, 8 (105 mg, 0.339 mmol) was reacted with Pd(OAc) (3.7 mg,
2
0
.016 mmol) and (S,S)-3 (23.7 mg, 0.034 mmol) , pentyloxyallene (2.89 g, 22.92 mmol) and
triethylamine (70.9 μL, 0.51 mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 13b as a yellowish oil (144 mg, 0.331 mmol, 98% yield) in a diasteromeric
ratio of 16:1.
2
0
1
R
f
0.60 (hexane/EtOAc = 80:20); [α]
D 2 2 3
+36.6 (c 0.95, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.75 (d,
J = 8.1 Hz, 2H), 7.26 (d, J = 8,1 Hz, 2H), 5.71 (ddd, J = 16.8, 10.5, 4.2 Hz, 1H), 5.39 (ddd, J = 16.8,
1
.5, 1.5 Hz, 1H), 5.35 (ddd, J = 4.2, 1.5, 1.5 Hz, 1H), 5.21 (ddd, 10.5, 1.5, 1.5 Hz, 1H), 3.75-3.64
S17

(
m ,1H), 3.59 (dt, J = 9.3, 6.6 Hz, 1H), 3.35 (dt, J = 9.6, 6.6 Hz, 1H), 2.70 (dd, J = 16.8, 8.4 Hz, 1H),
.62 (dd, J = 16.8, 6.6 Hz, 1H), 2.41 (s, 3H), 1.61-1.48 (m, 2H), 1.46 (d, J = 6.9 Hz, 3H), 1.39-1.19
2
13
(
m ,4H), 0.89 (t, J = 6.6 Hz, 3H), 0.09 (s, 9H) ; C NMR (75 MHz, CDCl
3
) δ 143.2, 139.7, 135.3,
1
29.7, 127.4, 118.4, 104.8, 87.4, 86.6, 68.7, 52.2, 29.3, 28.5, 27.2, 22.7, 21.7, 21.0, 14.2, 0.2; IR
-1
+
(
NaCl) ν 2958, 2177, 1343, 1161 cm ; HRMS (FAB) calcd for C H NO SSiNa (MNa ) 458.2161,
23 37 3
found 458.2165.
4
-methyl-N-((S)-1-(pentyloxy)allyl)-N-((R)-1-phenyl-4-(trimethylsilyl)but-3-yn-1-
yl)benzenesulfonamide (14a)
Ts
Ph
N
OC H
5
11
H
Using the representative procedure, 9 (85.6 mg, 0.286 mmol) was reacted with Pd(OAc)
2
(3.2 mg,
0
.0142 mmol) and (R,R)-3 (19.6 mg, 0.0286 mmol) , pentyloxyallene (2.51 g, 19.9 mmol) and
triethylamine (59.4 μL, 0.426 mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 14a as a yellowish oil (116.5 mg, 0.274 mmol, 96% yield) in a diasteromeric
ratio of 25:1
2
0
1
R
f
0.55 (hexane/EtOAc = 80:20); [α]
.12 (m, 5H), 7.06-6.92 (m, 4H), 5.68 (ddd, J =17.4, 10.2, 3.6 Hz, 1H), 5.56-5.45 (m, 2H), 5.35 (d, J
10.2, 1H), 4.76 (dd, J = 11.7, 3.9 Hz, 1H), 3.79 (dt, J = 9.6, 6.6 Hz, 1H), 3.64 (ddd, J = 16.8, 12.0,
.7 Hz, 1H), 3.55 (dt, J = 9.6, 6.6 Hz, 1H), 2.86 (ddd, J = 16.8, 3.6, 3.0 Hz, 1H), 2.31 (s, 3H), 1.87
D 2 2 3
-152.9 (c 0.77, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.38-
7
=
2
1
3
(
apt, J = 2.4 Hz, 1H), 1.72-1.58 (m, 2H), 1.47-1.25 ( m, 4H), 0.94 (t, J = 6.6 Hz, 3H); C NMR (75
MHz, CDCl
3
) δ 142.5, 139.3, 135.8, 135.5, 130.1, 129.1, 127.9, 127.8, 126.5, 119.2, 88.1, 81.7, 70.9,
1
6
8.6, 57.5, 29.3, 28.5, 24.2, 22.7, 21.5, 14.2; IR (NaCl) ν 3296, 2932, 2872, 1340, 1161 cm- ; HRMS
+
(
FAB) calcd for C H NO S (MH ) 426.2103, found 426.2106.
25 32 3
4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((R)-1-phenylbut-3-yn-1-yl)benzenesulfonamide ) (14b)
Ts
Ph
N
OC H
5
11
H
S18

Using the representative procedure, 9 (87.5 mg, 0.293 mmol) was reacted with Pd(OAc)
2
(3.3 mg,
0
.0147 mmol) and (S,S)-3 (20.6 mg, 0.0298 mmol) , pentyloxyallene (2.55 g, 20.2 mmol) and
triethylamine (60.0 μL, 0.430 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 14b as a yellowish oil (118.8 mg, 0.279 mmol, 95% yield) in a diasteromeric
ratio of 21:1.
2
0
1
R
f
0.55 (hexane/EtOAc = 80:20); [α]
.41 (m, 2H), 7.31-7.20 (m, 5H), 7.11- 7.04 (m, 2H), 5.80 (ddd, J = 17.1, 10.5, 4.5 Hz, 1H), 5.50 (ddd,
J = 17.1, 1.5, 1.5 Hz, 1H), 5.37 (ddd, J = 4.2, 1.5, 1.5 Hz, 1H), 5.30 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H),
.80 (dd, 11.4, 4.8 Hz, 1H), 3.55 (ddd, 17.1, 11.4, 2.7 Hz, 1H), 3.05 (td, J = 6.6, 2.1 Hz, 2H), 2.92
ddd, J = 17.1, 4.5, 2.7 Hz, 1H), 2.34 (s, 3H), 1.89 (apt, J = 2.7 Hz, 1H), 1.51-1.33 (m, 2H), 1.31-1.07
D 2 2 3
-18.6 (c 1.14, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.49-
7
4
(
(
1
3
m, 4H), 0.87 (t, J = 6.9 Hz, 3H) C NMR (75 MHz, CDCl
3
) δ143.0, 138.8, 137.1, 134.8, 130.0,
1
29.2, 128.0, 127.9, 127.3, 118.6, 87.6, 81.6, 70.9, 69.1, 58.0, 29.0, 28.3, 24.1, 22.5, 21.6, 14.2; IR
1
(
3
NaCl) ν 3308, 3026, 2926, 1653, 1493, 1453, 1341, 1161 cm- ; HRMS (FAB) calcd for C25H32NO S
+
(
MH ) 426.2103, found 426.2101.
N-((R)-10-(benzyloxy)dec-1-yn-4-yl)-4-methyl-N-((S)-1-(pentyloxy)allyl)benzenesulfonamide
15a)
(
Ts
N
BnO
OC H
5
11
H
Using the representative procedure, 10 (123.5 mg, 0.299 mmol) was reacted with Pd(OAc)
2
(3.4 mg,
0
.0151 mmol) and (R,R)-3 (20.4 mg, 0.0296 mmol) , pentyloxyallene (2.61 g, 20.73 mmol) and
triethylamine (61.9 μL, 0.444 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 15a as a yellowish oil (158.8 mg, 0.294 mmol, 99% yield) in a diastereomeric
ratio of >25:1
2
0
1
R
f
0.56 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-63.5 (c 0.87, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.73 (d,
J = 8.4 Hz, 2H), 7.38-7.22 (m, 7H), 5.78-5.64 (m, 1H), 5.49-5.38 (m, 2H), 5.24 (ddd, J = 10.5, 1.5,
1
3
2
1
1
.5 Hz, 1H), 4.89 (s, 2H), 3.61 (dt, J =9.3, 6.6 Hz, 1H), 3.53-3.42 (m, 1H), 3.41 (t, J = 6.6 Hz, 2H),
.37 (dt J = 9.3, 6.6 Hz, 1H), 2.75 (ddd, J = 16.8, 9.3, 2.7 Hz, 1H), 2.59 (ddd, J = 16.8, 4.5, 2.7, 1H),
.39 (s, 3H), 1.95 (apt, J = 3.0 Hz, 1H), 1.91-1.70 (m, 2H), 1.59-1.45 (m, 4H), 1.38-1.25 (m, 5H),
13
3
.25-1.12 (m, 3H), 1.12-0.99 (m, 2H), 0.89 (t, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl ) δ 143.3,
39.8, 138.9, 135.3, 129.6, 128.5, 127.8, 127.7, 127.3, 118.6, 87.7, 82.7, 73.0, 70.6, 70.0, 68.8, 57.0,
S19

3
3.0, 29.9, 29.4, 29.2, 28.5, 27.4, 26.2, 22.7, 21.6,14.2; IR (NaCl) ν 3309, 2933, 2860, 1342, 1160
1
+
cm- ; HRMS (FAB) calcd for C H NO SNa (MNa ) 562.2967 found 562. 2969.
32
45
4
N-((R)-10-(benzyloxy)dec-1-yn-4-yl)-4-methyl-N-((R)-1-(pentyloxy)allyl)benzenesulfonamide
15b)
(
Ts
N
BnO
OC H
5
11
H
Using the representative procedure, 10 (123.8 mg, 0.299 mmol) was reacted with Pd(OAc)
2
(3.3 mg,
0
.0148 mmol) and (S,S)-3 (20.4 mg, 0.0296 mmol) , pentyloxyallene (2.66 g, 21.08 mmol) and
triethylamine (62.0 μL, 0.445 mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 15b as a yellowish oil (159.3 mg, 0.295 mmol, 99% yield) in a diastereomeric
ratio of >1:25.
2
0
1
f D 2 2 3
R 0.56 (hexane/EtOAc = 80:20); [α] +29.2 (c 0.81, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.75 (d,
J = 8.4 Hz, 2H), 7.39-7.22 (m, 7H), 5.78 (ddd, J =17.1, 10.5, 4.5 Hz, 1H), 5.40 (ddd, J =17.1, 1.5, 1.2
Hz, 1H), 5.35 (ddd, J = 4.5, 1.5, 1.5 Hz, 1H) 5.24 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 4.50 (s, 2H), 3.57-
3
2
2
.53 (m, 1H), 3.52 (dt, J =9.3, 6.6 Hz, 1H), 3.44 (t, J = 6.6 Hz, 2H), 3.32 (dt, J = 9.3, 6.6 Hz, 1H),
.66 (dd, J = 16.8, 8.4, 2.7 Hz, 1H), 2.57 (ddd, J = 16.8, 6.0, 2.7 Hz, 1H), 2.40 (s, 3H), 1.90 (apt, J =
13
.4 Hz, 1H), 1.93-1.82 (m, 2H), 1.65-1.45 (m, 4H), 1.39-1.15 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H); C
) δ 143.3, 139.4, 138.9, 135.1, 129.6, 128.5, 127.8, 127.7, 127.6, 118.4, 87.5,
2.5, 73.0, 70.6, 70.2, 69.1, 57.1, 34.4, 29.9, 29.4, 29.2, 28.5, 27.4, 26.3, 25.1, 22.7, 21.6, 14.2; IR
NMR (75 MHz, CDCl
3
8
1
+
(
NaCl) ν 3308, 2933, 2859, 1341, 1161 cm- ; HRMS (FAB) calcd for C H NO SNa (MNa )
32 45 4
5
62.2967 found 562. 2967.
4
-methyl-N-((S)-1-(pentyloxy)allyl)-N-((R)-1-phenyl-5-(trimethylsilyl)pent-4-yn-2-
yl)benzenesulfonamide (16a)
Ts
Bn
N
OC H
5
11
TMS
S20

Using the representative procedure, 11 (92.8 mg, 0.241 mmol) was reacted with Pd(OAc)
2
(2.7 mg,
0
.0120 mmol) and (R,R)-3 (16.6 mg, 0.0241 mmol) , pentyloxyallene (2.27 g, 16.9 mmol) and
triethylamine (50.3 μL, 0.361 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 16a as a yellowish oil (118.2 mg, 0.231 mmol, 96% yield) in a diasteromeric
ratio of up to >25:1.
2
0
1
f D 2 2 3
R 0.57 (hexane/EtOAc = 80:20); [α] -68.2 (c 0.76, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.84 (d,
J = 8.1 Hz, 2H), 7.34-7.08 (m, 7H), 5.55 (ddd, J = 17.1, 9.9, 3.6 Hz, 1H), 5.41 (ddd, J = 17.1, 1.8, 1.8
Hz, 1H), 5.30 (ddd, J = 3.6, 1.8, 1.8 Hz, 1H), 5.15 (ddd, J = 9.9, 1.8, 1.8 Hz, 1H), 3.87-3.77 (m, 1H),
3
.48 (dt, J = 9.6, 6.6 Hz, 1H), 3.22-3.16 (m, 3H), 2.87 (dd, J = 17.1, 6.9, 1H), 2.78 (dd, J = 17.1, 7.5
13
Hz, 1H), 2.45 (s, 3H), 1.69-1.58 (m, 2H), 1.49-1.17 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H), 0.12 (s. 9H); C
NMR (75 MHz, CDCl ) δ 143.5, 139.3, 139.1, 135.1, 129.7, 129.6, 128.4, 127.9, 126.6, 118.3, 105.2,
7.2, 86.8, 68.9, 58.5, 40.6, 29.1, 28.4, 25.9, 22.7, 21.7, 14.2, 0.2; IR (NaCl) ν 3028, 2958, 2932, 2872,
3
8
2
5
1
+
176, 1340, 1249, 1160 cm- ; HRMS (FAB) calc for C29
3
H41NO SSiNa (MNa ) 534.2474 found
34.2476.
4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((R)-1-phenyl-5-(trimethylsilyl)pent-4-yn-2-
yl)benzenesulfonamide (16b)
Ts
Bn
N
OC H
5
11
TMS
Using the representative procedure, 11 (114.6 mg, 0.297 mmol) was reacted with Pd(OAc)
2
(3.2 mg,
0
.0142 mmol) and (S,S)-3 (22.3 mg, 0.0323 mmol) , pentyloxyallene (2.62 g, 20.8 mmol) and
triethylamine (62.1 μL, 0.446 mmol). Column chromatography (eluted with hexane/EtOAc = 97:3)
afforded the compound 16b as a yellowish oil (150.5 mg, 0.294 mmol, 99% yield) in a diasteromeric
ratio of >25:1.
2
0
1
R
f
0.57 (hexane/EtOAc = 80:20); [α]
D 2 2 3
+54.4 (c 2.22, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.86 (d,
J = 8.1 Hz, 2H), 7.34-7.19 (m, 7H), 5.79 (ddd, J = 17.1, 10.5, 3.6 Hz, 1H), 5.49 (ddd. J = 17.1, 1.8,
1
1
2
4
1
.5 Hz, 1H), 5.42 (ddd, J = 3.6, 1.8, 1.5 Hz, 1H), 5.23 (ddd, J = 10.5, 1.8, 1.5 Hz, 1H), 3.81-3.70 (m,
H), 3.72 (dt, J = 9.6, 6.6, 1H), 3.49 (dt, J = 9.6, 6.6, 1H), 3.28 (d, J = 6.3, 1H), 3.25 (d, J = 8.1, 1H),
.96 (dd, J = 17.4, 9.9, 1H), 2.48 (dd, J = 17.4, 4.8, 1H), 2.44 (s, 3H), 1.63-1.54 (m, 2H), 1.41-1.29 (m,
13
3
H), 0.92 (t, J = 6.9, 3H), 0.47 (s, 9H) ; C NMR (75 MHz, CDCl ) δ 143.2, 139.6, 139.5, 135.5,
29.7, 129.5, 128.7, 127.5, 126.6, 118.4, 105.1, 87.7, 86.3, 69.1, 58.6, 43.0, 29.4, 28.5, 23.1, 22.7,
S21

1
2
1.7, 14.2, 0.0; IR (NaCl) ν 2957, 2933, 2872, 2179, 1645, 1343, 1249, 1161 cm- ; HRMS (FAB) calc
+
for C H NO SSiNa (MNa ) 534.2474 found 534.2477.
2
9
41
3
N-((S)-1-methoxyallyl)-4-methyl-N-((R)-1-phenyl-5-(trimethylsilyl)pent-4-yn-2-
yl)benzenesulfonamide (17a)
Ts
Bn
N
OMe
TMS
Using the representative procedure, 11 (103.1 mg, 0.267 mmol) was reacted with Pd(OAc)
2
(3.0 mg,
1
3.4 μmol) and (R,R)-3 (11.5 mg, 0.0167 mmol), methoxyallene (1.60 mL, 18.9 mmol) and
triethylamine (56.0 μL, 0.40 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 17a as a yellowish oil (120.4 mg, 0.264 mmol, 99% yield) in a diasteromeric
ratio of 14:1
2
0
1
R
f
0.68 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-67.1(c 2.39, CH Cl ); H NMR (CDCl , 300 MHz) δ 7.83 (d,
J = 8.1 Hz, 2H), 7.31-7.04 (m, 7H), 5.65 (ddd, J = 17.1, 10.2, 3.9 Hz, 1H), 5.44 (ddd, 17.1, 1.5, 1.5
Hz, 1H), 5.22 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 5.20-5.16 (m, 1H), 3.81-3.69 (m, 1H), 3.18 (s, 3H),
3
.22-3.09 (m, 2H), 2.95 (dd, J = 17.4, 9.9 Hz, 1H), 2.66 (dd, J = 17.4, 6.6 Hz, 1H), 2.42 (s, 3H), 0.07
1
3
(
s, 9H); C NMR (CDCl
3
, 75 MHz) δ 143.6, 139.2, 138.2, 134.6, 129.7, 129.6, 128.6, 127.9, 126.7,
1
18.6, 105.3, 88.9, 86.6, 58.6, 56.9, 41.0, 25.1, 21.7, 0.2; IR (NaCl) 3028, 2177, 1343, 1249, 1160
1
+
cm- ; HRMS (FAB) calcd for C H NO SSi (MH ) 456.2029, found 456.2031.
25
34
3
N-((R)-1-methoxyallyl)-4-methyl-N-((R)-1-phenyl-5-(trimethylsilyl)pent-4-yn-2-
yl)benzenesulfonamide (17b)
Ts
Bn
N
OMe
TMS
Using the representative procedure, 11 (102.4 mg, 0.266 mmol) was reacted with Pd(OAc) (3.1 mg,
2
1
3.8 μmol) and (S,S)-3 (12.3 mg, 0.0178 mmol), methoxyallene (1.69 mL, 19.96 mmol) and
triethylamine (60.0 μL, 0.430 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
S22

afforded the compound 17b as a white solid (119.5 mg, 0.262 mmol, 99 % yield) in a diasteromeric
ratio of 13:1.
2
0
D
1
Rf 0.55 (hexane/EtOAc = 80:20); Mp.77-79 ˚C; [α] +45.7 (c 0.925, CH Cl ); H NMR (300 MHz,
2
2
CDCl
3
) δ 7.81 (d, J = 8.4 Hz, 2H), 7.34-7.16 (m, 7H), 5.73 (ddd, J = 17.1, 10.5, 3.9 Hz, 1H), 5.42
ddd, J = 17.1, 1.5, 1.5 Hz, 1H), 5.32-5.25 (m, 1H), 5.21 (ddd, J = 10.5, 1.5, 1.,5 Hz, 1H), 3.78-3.65
m, 1H), 3.32 (s, 3H), 3.28-3.18 (m, 2H), 2.86 (dd, J = 17.4, 9.3 Hz, 1H), 2.49 (dd, J = 17.4, 5.4 Hz,
(
(
1
3
1
1
2
4
H), 2.41 (s, 3H), 0.02 (s, 9H) ; C NMR (75 MHz, CDCl
3
) δ 143.3, 139.6, 139.5, 135.0, 129.7,
29.7, 128.7, 127.6, 126.7, 118.7, 105.0, 89.3, 86.6, 58.8, 56.6, 42.8, 23.5, 21.7, 0.1; IR (NaCl) 3029,
1
+
958, 2117, 1342, 1249, 1160 cm- ; HRMS (FAB) calcd for C25
H34NO
3
SSi (MH ) 456.2029, found
56. 2031.
N-((S)-1-methoxyallyl)-4-methyl-N-((S)-1-phenyl-5-(trimethylsilyl)pent-4-yn-2-
yl)benzenesulfonamide (18a)
Ts
Bn
N
OMe
TMS
2
Using the representative procedure, ent-11 (43.2 mg, 0.112 mmol) was reacted with Pd(OAc) (1.3
mg, 5.79 μmol) and (R,R)-3 (7.73 mg, 0.0112 mmol), methoxyallene (663.9 μL, 7.84 mmol) and
triethylamine (23.4 μL, 0.168 mmol). Column chromatography (eluted with hexane/EtOAc = 98:2)
afforded the compound 18a as a yellowish solid (48.6 mg, 0.107 mmol, 95% yield) in a diasteromeric
ratio of 13:1. The solid was recrystallized with pentane at 0 ˚C and suitable crystals were subjected to
an X-ray structure determination (for the detailed information, see the additional supporting
information below, section 6).
2
0
All spectral data matched a compound 17b except for the sign of specific rotation: [α]
.245, CH Cl ).
D
-56.9 (c
1
2
2
5
-2. Synthesis of N,O-acetal from achiral substrate
(S)-N-cyclohexyl-N-(1-methoxyallyl)-4-methylbenzenesulfonamide (32)
S23

Ts
N
OCH3
1
0
Using the representative procedure, N-cyclohexyl-4-methylbenzenesulfonamide (67.7 mg, 0.267
mmol) was reacted with Pd(OAc) (3.0 mg, 0.0133 mmol) and (R,R)-3 (18.4 mg, 0.0267 mmol) ,
2
methoxyallene (1.58 mL, 18.7 mmol) and triethylamine (56.0 μL, 0.401 mmol). Column
chromatography (eluted with hexane/EtOAc = 98:2) afforded the compound 32 as a white solid (75.6
mg, 0.234 mmol, 88% yield). The enantomeric exess (88% ee) determined by HPLC on a chiral
column ((R,R)-Welk-O 1, n-hexane/2-propanol = 99.5/0.5: flow rate 1.0 mL/min: UV = 217 nm);
retention times = 14.7 min (major), 19.0 min (minor). The absolute stereochemistry was assigned by
the analogy to compound 18a.
2
0
1
R
f
0.60 (hexane/EtOAc = 80:20); Mp.50-52 ˚C; [α]
CDCl ) δ 7.73 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 5.65 (ddd, J = 17.4, 10.5, 3.9 Hz, 1H),
.34 (ddd, J = 17.4, 1.5, 1.5 Hz, 1H), 5.33 (ddd, 3.9, 1.5, 1.,5 Hz, 1H), 5.20 (ddd, J = 10.5, 1.5, 1.5 Hz,
H), 3.34 (s, 3H), 3.21 (tt, J = 12.3, 3.3 Hz, 1H), 2.41 (s, 3H), 2.13-1.97 (m, 1H), 1.98-1.83(m, 1H),
D 3
-98.2 (c 1.475, CHCl ); H NMR (300 MHz,
3
5
1
1
1
1
1
3
.81-1.65 (m, 3H), 1.62-1.47 (m, 2H), 1.30-1.03 (m, 3H); C NMR (75 MHz, CDCl
3
) δ 143.0, 140.3,
35.0, 129.6, 127.3, 118.3, 89.1, 57.7, 56.0, 33.9, 32.6, 27.0, 26.9, 25.5, 21.7; IR (NaCl) 2935, 2855,
1
+
599, 1330, 1161, 1105 cm- ; HRMS (EI) calcd for C17
H25NO
3
S (M ) 323.1555, found 323.1553.
HPLC data for compound 32
Ts
N
OCH3
2 (racemic)
3
S24

Ts
N
OCH3
32
5
-3. Synthesis of desilylated N,O-acetals
Representative procedure for desilylation of 5a
N-((R)-hept-1-yn-4-yl)-4-methyl-N-((S)-1-(pentyloxy)allyl)benzenesulfonamide (5a’)
T
s
N
OC H
5
11
H
To a solution of 5a (120.0 mg, 0.259 mmol) in methanol (1.0 mL) was added K CO (42.9 mg,
2
3
0
.311 mmol) at rt. After stirring for 6h at rt, the reaction was filtered through a pad of Celite and
concentrated under reduced pressure. The resulting residue was purified by flash column
chromatography (eluted with hexane/EtOAc = 95:5) to give the compound 5a’ a yellowish oil (96.9
mg, 0.227 mmol, 96% yield) in a diasteromeric ratio of 25:1 .
2
0
1
R
f
0.63 (hexane/EtOAc = 80:20); [α]
J = 8.4 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.71 (ddd, J = 17.1, 10.5, 4.2 Hz, 1H), 5.42 (ddd, J = 17.1,
.5, 1.5 Hz, 1H), 5.38 (ddd, J = 4.5, 1.5, 1.5 Hz, 1H), 5.24 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 3.61 (dt, J
D 2 2 3
-73.0 (c 2.08, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.73 (d,
1
=
9.6, 6.6 Hz, 1H), 3.55-3.45 (m, 1H), 3.36 (dt, J = 9.6, 6.6 Hz, 1H), 2.75 (ddd. J = 16.8, 9.3, 2.7 Hz,
S25

1
1
0
8
2
4
H), 2.59 (ddd, J =16.8, 4.8, 2.7 Hz, 1H), 2.42 (s, 3H), 1.96 (apt, J = 2.7 Hz, 1H), 1.91-1.69 (m, 2H),
.59-1.48 (m , 2H), 1.36-1.20 (m, 4H), 1.15-1.01 (m, 1H), 1.01-0.85 (m, 1H), 0.89 (t, J = 6.6 Hz, 3H),
13
.72 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl
3
) δ 143.3, 139.8, 135.3, 129.6, 127.4, 118.5, 87.7,
2.7, 70.0, 68.8, 56.8, 35.2, 29.2, 28.5, 26.2, 22.7, 21.7, 20.6, 14.2, 13.9; IR (NaCl) ν 3311, 3028,
1
+
959, 2933, 1305, 1161 cm- ; HRMS (FAB) calcd for C H NO SNa (MNa ) 414.2079, found
2
2
33
3
14.2076.
N-((R)-hept-1-yn-4-yl)-4-methyl-N-((R)-1-(pentyloxy)allyl)benzenesulfonamide (5b’)
Ts
N
OC H
5
11
H
Using the representative procedure, compound 5b (310.0 mg, 0.668 mmol) was reacted with K CO
2
3
(
110.9 mg, 0.802 mmol). Column chromatography (eluted with hexane/EtOAc = 95:5) afforded the
compound 5b’ as a yellowish oil (245.4 mg, 0.627 mmol, 94% yield) in a diastereomeric ratio of
25:1.
>
2
0
1
Rf 0.63 (hexane/EtOAc = 80:20); [α] +36.9 (c 1.72, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.75 (d,
D
2
2
3
J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 5.78 (ddd, J = 17.1, 10.5, 4.2 Hz, 1H), 5.40 (ddd, J = 17.1,
.5, 1.2 Hz, 1H), 5.35 (ddd, J = 4.2, 1.5, 1.2 Hz, 1H), 5.24 (ddd, J = 10.5, 1.5, 1.2 Hz, 1H), 3.52 (dt, J
9.3, 6.6 Hz, 1H), 3.56-3.45 (m, 1H), 3.31 (dt, J = 9.3, 6.6 Hz, 1H), 2.68 (ddd, J = 16.8, 8.1, 2.7 Hz,
H), 2.57 (ddd, J = 16.8, 6.0, 2.7 Hz, 1H), 2.42 (s, 3H), 1.90 (apt, J = 2.7 Hz, 1H), 1.91-1.83 (m, 2H),
1
=
1
1
1
3
.52-1.46 (m, 2H), 1.33-1.18 (m, 6H), 0.88 (t, J = 5.7 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H); C NMR (75
MHz, CDCl
3
) δ 143.3, 139.4, 135.2, 129.6, 127.6, 118.4, 87.5, 82.6, 70.2, 69.1, 56.8, 36.8, 29.2, 28.5,
1
2
5.1, 22.7, 21.7, 20.6, 14.2, 14.0 ; IR (NaCl) ν 3311, 2959, 1342, 1161 cm- ; HRMS (FAB) calcd for
+
C H NO S (MH ) 392.2259, found 392.2261.
2
2
34
3
4
-methyl-N-((S)-2-methylhex-5-yn-3-yl)-N-((S)-1-(pentyloxy)allyl)benzenesulfonamide (12a’)
Ts
N
OC H
5
11
H
S26

Using the representative procedure, compound 12a (133.0 mg, 0.287 mmol) was reacted with
CO (47.6 mg, 0.344 mmol). Column chromatography (eluted with hexane/EtOAc = 95:5) afforded
the compound 12b’ as a yellowish oil (106.5 mg, 0.272 mmol, 95% yield) in a diasteromeric ratio of
25:1.
K
2
3
>
2
0
1
R
f
0.65 (hexane/EtOAc = 80:20; [α]
D 2 2 3
+3.1 (c 2.90, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.80 (d,
J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.13 (ddd, J = 17.1, 10.2, 6.6 Hz, 1H), 5.29 (d, J = 17.1 Hz,
1
2
2
0
8
2
4
H), 5.26 (d, J = 10.2 Hz, 1H), 5.20 (d, J = 6.6 Hz, 1H), 3.39 (t, J = 6.6 Hz, 2H), 3.39-3.34 (m, 1H),
.51 (ddd, J = 17.4, 4.5, 2.7 Hz, 1H), 2.45-2.34(m, 1H), 2.41 (s, 3H), 2.23-2.11 (m, 1H), 1.97 (apt, J =
.7 Hz, 1H), 1.56-1.47 (m, 2H), 1.35-1,18 (m, 4H), 1.02 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H),
13
.83 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl
3
) δ 143.1, 139.5, 136.5, 129.4, 128.0, 118.2, 88.5,
2.4, 70.7, 68.4, 62.4, 31.7, 29.3, 28.5, 23.6, 22.7, 21.7, 21.3, 20.3, 14.2; IR (NaCl) ν 3310, 2960,
1
+
932, 2873, 1344, 1164 cm- ; HRMS (FAB) calcd for C22
H33NO
3
SNa (MNa ) 414.2079, found
14.2076.
4
-methyl-N-((S)-2-methylhex-5-yn-3-yl)-N-((R)-1-(pentyloxy)allyl)benzenesulfonamide (12b’).
Ts
N
OC H
5
11
H
Using the representative procedure, compound 12b (130.0 mg, 0.280 mmol) was reacted with
CO (101.5 mg, 0.259 mmol). Column chromatography (eluted with hexane/EtOAc = 95:5)
K
2
3
afforded the compound 12b’ as a yellowish oil (101.5 mg, 0.259 mmol, 93% yield) in a
diastereomeric ratio of >25:1.
2
0
1
R
f
0.65 (hexane/EtOAc = 80:20); [α]
D 2 2 3
+43.2 (c 2.34, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.78 (d,
J = 8.4 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 5.90 (ddd, J = 17.1, 10.5, 4.8 Hz, 1H), 5.40 (ddd, J = 17.1,
1
1
.2, 1.2 Hz, 1H), 5.31-5.29 (m, 1H), 5.25 (ddd, J = 10.5, 1.2, 1.2 Hz, 1H), 3.45 (dt, J = 9.3, 6.9 Hz,
H), 3.30 (dt, J = 9.3, 6.9 Hz,1 H), 3.31-3.25 (m, 1H), 2.64 (ddd, J = 17.4, 5.1, 2.7 Hz, 1H), 2.56 (ddd,
J = 17.4, 6.3, 2.7 Hz, 1H), 2.41 (s, 3H), 2.35-2.23 (m, 1H), 1.94 (apt, J = 2.7 Hz, 1H), 1.53-1.44 (m,
H), 1.34-1.20 (m, 4H), 1.03 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 2.7 Hz, 3H);
2
1
3
C NMR (75 MHz, CDCl
3
) δ 143.3, 139.2, 135.1, 129.5, 127.8, 118.7, 87.9, 83.0, 70.7, 69.2, 63.2,
3
1
3.2, 29.2, 28.4, 24.2, 22.6, 21.7, 21.6, 20.8, 14.2; IR (NaCl) ν 3310, 2960, 2933, 2873, 1599, 1342,
1
+
161 cm- ; HRMS (FAB) calcd for C H NO SNa (MNa ) 414.2079, found 414.2078.
2
2
33
3
S27

4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((R)-1-phenylpent-4-yn-2-yl)benzenesulfonamide (16a’)
Ts
Bn
N
OC H
5
11
H
Using the representative procedure, compound 16a (109.8 mg, 0.215 mmol) was reacted with
CO (44.5 mg, 0.322 mmol). Column chromatography (eluted with hexane/EtOAc = 95:5) afforded
K
2
3
the compound 16a’ as a yellowish oil (90.2 mg, 0.205 mmol, 96% yield) in a diasteromeric ratio of
5:1.
2
2
0
1
R
f
0.54 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-60.8 (c 1.57, CH Cl );); H NMR (300 MHz, CDCl ) δ 7.81
(d, J = 8.1 Hz, 2H), 7.32-7.07 (m, 7H), 5.57 (ddd, J = 17.1, 9.6, 3.6 Hz, 1H), 5.44 (ddd, J = 17.1, 1.5,
1
1
.2 Hz, 1H), 5.30 (ddd, J = 3.6, 1.8, 1.2 Hz, 1H), 5.18 (ddd, J = 9.6, 1.8, 1.2 Hz, 1H), 3.83-3.73 (m,
H), 3.53 (dt, J = 9.0, 6.6 Hz, 1H), 3.24-3.08 (m, 3H), 2.88 (ddd, J = 17.1, 7.8, 2.1 Hz, 1H), 2.43 (ddd,
J = 17.1, 6.6, 2.1 Hz, 1H), 2.43 (s, 3H), 1.85 (apt, J = 2.7 Hz, 1H), 1.49-1.40 (m, 2H), 1.31-1.14 (m,
13
4
H), 0.86 (t, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl
3
) δ 143.6, 139.0, 139.0, 134.7, 129.6, 128.5,
1
27.9, 126.7, 118.4, 87.2, 82.4, 70.2, 69.1, 58.6, 40.9, 29.0, 28.4, 24.0, 22.6, 21.7, 14.2; IR (NaCl) ν
1
+
3
308, 2956, 2932, 2872, 1339, 1160 cm- ; HRMS (FAB) calcd for C H NO SNa (MNa ) 462.2079
26 33 3
found 462.2083.
4
-methyl-N-((R)-1-(pentyloxy)allyl)-N-((S)-1-phenylpent-4-yn-2-yl)benzenesulfonamide (16b’)
Ts
N
Bn
OC H
5
11
H
Using the representative procedure, compound 16b (dr 39.9:1, 182.8 mg, 0.357 mmol) was reacted
with K CO (59.2 mg, 0.429 mmol). Column chromatography (eluted with hexane/EtOAc = 90:10)
2
3
afforded a compound 16b’ as a yellowish oil (136.9 mg, 0.311 mmol, 87% yield) in a diasteromeric
ratio of >25:1
2
0
1
Rf 0.54 (hexane/EtOAc = 80:20); [α] +72.9. (c 1.57, CH Cl ).; H NMR (300 MHz, CDCl ) δ 7.81
D
2
2
3
(d, J = 8.4 Hz, 2H), 7.32-7.16 (m, 7H), 5.75 (ddd, J = 17.1, 10.5,3.9 Hz, 1H), 5.44 (ddd, J = 17.1, 1.5,
1
1
.5 Hz, 1H), 5.37 (ddd, J = 3.9, 1.5, 1.5 Hz, 1H), 5.23 (ddd, J = 10.5, 1.5, 1.5 Hz, 1H), 3.82-3.72 (m,
H), 3.48 (dt, J = 9.3, 6.6 Hz, 1H), 3.33 (dt, J = 9.3, 6.6 Hz, 1H), 3.28-3.12 (m, 2H), 2.80 (ddd, J =
S28

1
1
1
7.4, 9.0, 2.7 Hz, 1H), 2.51-2.38 (m, 1H), 2.41 (s, 3H), 1.72 (apt, J = 2.4 Hz, 1H), 1.51-1.40 (m, 2H),
1
3
3
.33-1,24 (m, 4H), 0.87 (t, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl ) δ 143.4, 139.6, 139.5, 135.4,
29.7, 128.8, 127.8, 126.8, 118.7, 87.8, 82.4, 70.5,69.2, 58.6, 42.5, 29.4, 28.6, 22.8, 22.7, 21.8, 14.3;
1
IR (NaCl) ν 3308, 2956, 2932, 2871, 1340, 1160 cm- ; HRMS (FAB) calcd for C H NO SNa
2
6
33
3
+
(
MNa ) 462.2079, found 462.2081.
N-((S)-1-methoxyallyl)-4-methyl-N-((R)-1-phenylpent-4-yn-2-yl)benzenesulfonamide (18a’)
Ts
Bn
N
OMe
H
Using the representative procedure, compound 18a (74 mg, 0.162 mmol) was reacted with K CO
2
3
(26.9 mg, 0.194 mmol). Column chromatography (eluted with hexane/EtOAc = 90:10) afforded a
compound 18a’ as a yellowish oil 57.4 mg, 0.150 mmol, 92% yield) in a diasteromeric ratio of 13:1.
2
0
1
R
f
0.47 (hexane/EtOAc = 80:20); [α]
D 2 2 3
-64.0 (c 0.71, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.81 (d,
J = 8.4 Hz, 2H), 7.33-7.18 (m, 7H), 5.81-5.63 (m, 1H), 5.41 (ddd, J = 17.4, 1.2, 0.9 Hz, 1H), 5.28-
5
2
.21 (m, 2H), 3.84-3.73 (m, 1H), 3.28-3.22 (m, 2H), 3.15 (s, 3H), 2.75 (ddd, J = 17.1, 8.1, 2.7 Hz, 1H),
13
.52 (ddd, J = 17.1, 6.3, 2.7 Hz, 1H), 2.42 (s, 3H), 1.79 (apt, J = 2.7 Hz, 1H); C NMR (75MHz,
CDCl
3
) δ 143.4, 139.3, 134.7, 129.7, 129.6, 128.6, 127.7, 126.6, 118.8, 89.2, 82.1, 70.5, 58.6, 56.3,
1
4
2.0, 23.0, 21.6; IR (NaCl) 3294, 3028, 2928, 1496, 1340, 1159 cm- ; HRMS (FAB) calcd for
+
C H NO SNa (MNa ) 406.1453, found 406.1450.
2
2
25
3
6
. Au-catalyzed Cycloisomerization of N,O-acetals
Representative procedure for the synthesis of 20a
(2R,6R)-4-methoxy-2-propyl-1-tosyl-6-vinyl-1,2,3,6-tetrahydropyridine (20a)
Ts
N
OC H
5
11
S29

+
-
To a solution of Au (CH
and 2,6-di-tert-butylpyridine (0.18 μL, 0.777 μmol, 0.6 mol%) in CH
added 5a’ (50.5 mg, 0.129 mmol, 25:1 diastereomeric mixture) in CH
3
CN)[(tert-Butyl)
2
P((o-Ph)Ph)]SbF
6
(3.0 mg, 0.00381 mmol, 3 mol%)
Cl (1.5 mL) under nitrogen was
Cl solution (1.1 mL) and the
2
2
2
2
resulting solution was stirred at rt for 5 min. To a reaction solution excess triethylamine was added
and stirred for 5 min. The resulting mixture was concentrated under reduced pressure and the residual
oil was purified by flash column chromatography (eluted with hexane/EtOAc = 90:10) to give
compound 20a (49.4 mg, 0.126 mmol, 98% yield) as a yellowish oil in a diasteromeric ratio of >25:1
1
(
measured by the integration of H NMR data).
2
0
1
Rf 0.60 (hexane/EtOAc = 80:20); [α] -77.5 (c 1.16, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.70 (d,
D
2
2
3
J = 8.4 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 5.69 (ddd, J = 17.1, 10.2, 6.0 Hz, 1H), 5.17 (ddd, J = 17.1,
1
3
.5, 1.2 Hz, 1H), 5.09 (ddd, J = 10.2, 1.2, 1.2 Hz, 1H), 4.98-4.91 (m, 1H), 4.42 (d, J = 4.2 Hz, 1H),
.77-3.67 (m, 1H), 3.61 (dt, J = 9.3, 6.6 Hz, 1H), 3.53 (dt, J = 9.3, 6.6 Hz, 1H), 2.40 (s, 3H), 2.02 (dd,
J = 16.5, 4.5 Hz, 1H), 1.98 (dd, J = 16.5, 8.3 Hz, 1H), 1.92-1.78 (m, 1H), 1.69-1.54 (m, 3H), 1.39-
1
3
1
1
1
3
.23 (m, 6H), 0.90 (t, J = 6.3 Hz, 1H), 0.86 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl ) δ 153.8,
43.0, 140.2, 138.7, 129.4, 127.6, 116.6, 93.8, 67.2, 57.0, 54.0, 34.7, 32.6, 28.8, 28.5, 22.6, 21.7, 20.6,
1
4.2, 14.1; IR (NaCl) ν 2958, 2933, 2872, 1668, 1336, 1162 cm- ; HRMS (FAB) calcd for
+
C H NO S (MH ) 392.2259 found 392.2261
2
2
34
3
(2R,6S)-4-(pentyloxy)-2-propyl-1-tosyl-6-vinyl-1,2,3,6-tetrahydropyridine (20b)
Ts
N
OC H
5
11
Using the representative procedure, 5b’ (60.1 mg, 0.153 mmol) was reacted with
+
-
3 6
Au (CH CN)[(tert-Butyl)P(o-BP)]SbF (3.5 mg, 0.00450 mmol) and 2,6-di-tert-butylpyridine (0.214
μL, 0.918 μmol, 0.6 mol%). Column chromatography (eluted with hexane/EtOAc = 90:10) afforded
the compound 20b as a yellowish oil (57.0 mg, 0.146 mmol, 95% yield) in a diasteromeric ratio of
>25:1.
2
0
1
R
f
0.60 (hexane/EtOAc = 80:20); [α]
d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.95 (ddd, J = 17.1, 10.2, 6.0 Hz, 1H), 5.23 (ddd, J =
7.1, 1.2, 1.2 Hz, 1H), 5.09 (ddd, J = 10.2, 1.2, 1.2 Hz, 1H), 4.98-4.90 (m, 1H), 4.49 (dd, J = 3.9, 2.1
Hz, 1H), 4.10-4.03 (m, 1H), 3.65 (dt, J = 9.3, 6.6 Hz, 1H), 3.56 (dt, J = 9.3, 6.9 Hz, 1H), 2.40 (s, 3H),
D 2 2 3
+104.8 (c 1.57, CH Cl ); H NMR (300 MHz, CDCl ) δ 7.69
(
1
2
.02 (ddd, J = 16.5, 6.9, 2.1 Hz, 1H), 1.71 (d, J = 16.5 Hz, 1H), 1.66-1.55 (m, 1H), 1.44-1.18 (m, 8H),
S30