Stereoselective synthesis of enantioenriched acetylenic 1,2-amino alcohols

Article abstract of DOI:10.1055/s-2007-965989

The stereoselective synthesis of enantioenriched anti-and syn-4-aminoalk-1-yn-3-ols is described. Initial reaction of racemic 3-(methoxymethoxy)allenylzinc with enantiopure Ellman's (S_S)-(tert- butylsulfinyl)imines was shown to give straightfor

Full text of DOI:10.1055/s-2007-965989

PAPER
1235
Stereoselective Synthesis of Enantioenriched Acetylenic 1,2-Amino Alcohols
S
tereoselectiv
a
e
S
ynthesis
b
of Enantioen
r
riched A
i
cetyle
c
e
A
lcohols Chemla, Franck Ferreira,* Xavier Gaucher, Laëtitia Palais
Université Pierre et Marie Curie–Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire (FR 2769),
case 183, 4 place Jussieu, 75252 Paris Cedex 05, France
Fax +33(0)144275571; E-mail: franck.ferreira@upmc.fr
Received 14 December 2006
pounds. We have shown that acetylenic 1,2-amino alco-
Abstract: The stereoselective synthesis of enantioenriched anti-
hols can be obtained through the highly regio- and
and syn-4-aminoalk-1-yn-3-ols is described. Initial reaction of race-
stereoselective ring opening of N-(tert-butylsulfinyl)azir-
mic 3-(methoxymethoxy)allenylzinc with enantiopure Ellman’s
(SS)-(tert-butylsulfinyl)imines was shown to give straightforward
idines by water under acidic conditions.16 This method ap-
and highly stereoselective access to anti-(SS,3S,4R)-3-(methoxy- pears to be synthetically useful with a wide range of N-
methoxy)-4-sulfinamidoalk-1-ynes. Upon treatment with dry meth-
anolic hydrochloric acid at reflux, the latter led to the corresponding
enantioenriched anti-(3S,4R)-4-aminoalk-1-yn-3-ols. Regarding
Furthermore, aziridines with a quaternary carbon at the
the syn-diastereomeric (3R,4R)-4-aminoalk-1-yn-3-ols, they were
obtained by ring opening of the corresponding cis-N-(tert-butyl-
(tert-butylsulfinyl)aziridines but failed when applied to
aziridines substituted with vinylic or aromatic side chains.
propargylic position give the corresponding 1,2-amino al-
cohols with quite low stereoselectivity. We envisioned the
development of another method applicable to unsaturated
and hindered N-(tert-butylsulfinyl)aziridines employing a
3-alkoxyallenylzinc reagent.
sulfinyl)aziridines by water under acidic conditions.
Key words: amino alcohols, asymmetric synthesis, chiral auxilia-
ries, sulfoxides, zinc
Thus, in the course of our studies, we found that enan-
tioenriched anti-4-aminoalk-1-yn-3-ols 4 can be prepared
by a two-step procedure from enantiopure Ellman’s N-
(tert-butylsulfinyl)imines 2 (readily prepared in large
amounts with >99% ee from commercially available and
inexpensive tert-butyl disulfide) via the corresponding 3-
(methoxymethoxy)-4-sulfinamidoalk-1-ynes 3 (Scheme 1).
1,2-Amino alcohols constitute interesting building blocks
for the synthesis of biologically active compounds. They
have been found in a number of bioactive natural
products1 such as alkaloids,2 aminosugars,3 enzyme inhib-
itors,4 and antibiotics.5 For instance, sphingosines,
phytosphingosines, and sphinganines, which represent the
three main classes of the sphingoid bases of sphingolipids,
all contain a 1,2-amino alcohol unit.6 Recently, simple
1,2-amino alcohol containing compounds were shown to
exhibit in vitro activity against the cloned strain of human
plasmodium falciparum.7 Also, they are frequently em-
ployed in asymmetric synthesis as chiral auxiliaries or
chiral catalysts.8 The biological importance of numerous
compounds containing the 1,2-amino alcohol pattern has
meant that methods for their stereoselective preparation
have been the subject of frequent publications.9
Initially, reaction of racemic 3-(methoxymethoxy)alle-
nylzinc ( )-1 with N-(tert-butylsulfinyl)imines 2a–h in
diethyl ether at –80 °C for one hour gave 3-(meth-
oxymethoxy)-4-sulfinamidoalk-1-ynes 3a–h with high
stereoselectivity providing that 4.0 equivalents of ( )-1
were used in the presence of a catalytic amount of
N,N,N¢,N¢-tetramethylethylenediamine (Scheme 1, step
1).17 In all cases, the reaction was highly stereoselective,
anti-3-(methoxymethoxy)-4-sulfinamidoalk-1-ynes 3a–h
were formed with high diastereoselectivity (anti/syn
>20:1). It is noteworthy that when the imines 2a–c were
used which had low levels of steric hindrance, high levels
of selectivity (>20:1) were obtained only when the imines
were added slowly (over a period of 45 min via syringe
pump) to allenylzinc ( )-1. However, slow addition was
not required for hindered or unsaturated imines 2d–h.
Further purification by flash chromatography (silica gel)
allowed the major anti-ethers 3a–f to be isolated in dia-
stereo- and enantiomerically enriched forms in excellent
yields ranging (70–87%, Table 1, entries 1–7). Ether 3h,
synthesized from ketimine 2h, was isolated in lower yield
(41%), albeit with high stereoselectivity, due to the forma-
tion of unidentified byproducts (Table 1, entry 8).
Surprisingly, and despite they great synthetic potential,
relatively few syntheses of highly functionalized acety-
lenic 1,2-amino alcohols have been reported. However,
some interesting syntheses have been described including
the condensation of a tin(II) enolate of glycinate onto an
acetylenic ketone,10 the reduction of an acetylenic a-ami-
no ketone,11 the addition of a propargylmetal to an a-ami-
no aldehyde,12 and the addition of an allenylmetal to an a-
alkoxybenzylimine.13 Over the past ten years our efforts
have focused on elaborating new synthetic methods for
the stereoselective preparation of acetylenic halohy-
drins,14 oxiranes,14 and aziridines14a,15 through the addi-
tion of 3-heterosubstituted allenylzinc reagents to various
carbon–heteroatom multiple-bond-containing com-
Acetylenic anti-ethers 3 were converted into the corre-
sponding anti-1,2-amino alcohols 4 by treatment with dry
methanolic hydrochloric acid at reflux (Scheme 1, step 2).
Under these acidic conditions, the removal of the tert-
butylsulfinyl group on the nitrogen is concomitant with
SYNTHESIS 2007, No. 8, pp 1235–1241
x
x
.
x
x
.2
0
0
7
Advanced online publication: 23.03.2007
DOI: 10.1055/s-2007-965989; Art ID: Z26006SS
© Georg Thieme Verlag Stuttgart · New York

1236
F. Chemla et al.
PAPER
O
TMS
ZnBr
•
O
S
MOMO
( )-1
H2N
HN
R2
R1
R2
R1
TMS
S
N
TMS
(4 equiv)
HCl, MeOH
3
4
3
4
TMEDA (0.4 equiv)
Et2O, –80 °C, 1 h
(step 1)
reflux, 1 h
(step 2)
R2
(SS)-2
R1
OH
OMOM
(SS,3S,4R)-3, >20:1 er
(3S,4R)-4, >20:1 er
Scheme 1 Two-step synthesis of anti-(3S,4R)-3-(methoxymethoxy)-4-sulfinamidoalk-1-ynes 4 by reaction of racemic 3-(methoxymeth-
oxy)allenylzinc ( )-1 with N-(tert-butylsulfinyl)imines (SS)-2.
deprotection of the ether function. In all cases, only traces chloro-1-(trimethylsilyl)prop-1-yne, and the same (SS)-
1
(<5%) of 1,2-amino ethers were observed by H NMR imines.16
analysis of the crude mixtures suggesting that removal of
the tert-butylsulfinyl auxiliary on the nitrogen atom oc-
At this time, we reasoned that using hexamethylphos-
phoramide as a co-solvent in the first step could result in
curred first followed by the deprotection of the meth-
reversal of the stereoselectivity of the reaction in favor of
oxymethyl ether moiety. Crude anti-4-aminoalk-1-yn-3-
the syn-isomer, as earlier observed in the reaction of N-
ols 4 were obtained with high purity (>90%). They were
(tert-butylsulfinyl)imines with the analogous 3-chloroal-
further isolated in good to excellent yields (66–87%) as
lenylzinc reagent.15a Unfortunately, when 3-(methoxy-
diastereo- and enantioenriched products after flash chro-
methoxy)allenylzinc ( )-1 was reacted with N-(tert-
butylsulfinyl)imines 2 in the presence of an excess of
matography over silica gel (Table 1).
Under the above acidic conditions, 4-tert-butyldimethyl- hexamethylphosphoramide (1.5 equiv) at –80 °C in dieth-
siloxy-substituted 3-(methoxymethoxy)-4-sulfinamido- yl ether, the sole products were the anti-ethers 3. This sur-
alk-1-yne 3c (R1 = OCH2TBS and R2 = H; Scheme 1, prising difference between the 3-chloro- and 3-(meth-
step 2) gave the corresponding 2-amino-1,3-diol 4c oxymethoxy)allenylzinc reagents still remains unclear to
(R1 = CH2OH and R2 = H; Scheme 1, step 2) in two hours us and indicates that the syn-isomers of ethers 3 could not
in 81% yield after flash silica gel chromatography; it re- be readily prepared from ( )-1. Thus, using our methodol-
sulted from deprotection of the silyl ether moiety concom- ogy, syn-(3R,4R)-4-aminoalk-1-yn-3-ols 6 were obtained
itant to the N- and O-deprotections. Thus, acetylenic anti- only through the regio- and stereoselective ring opening
(3S,4R)-4-aminoalk-1-yn-3-ols 4 were obtained in two of cis-(SS,3S,4R)-N-(tert-butylsulfinyl)aziridines 5 by wa-
steps with good to excellent overall yields (from 36–75%) ter under acidic conditions (Scheme 2).16
from racemic 3-(methoxymethoxy)allenylzinc ( )-1 and
enantiopure (SS)-N-(tert-butylsulfinyl)imines. It is note-
With the aim of using the ethers 3 synthetically, we then
attempted selective deprotection of either the nitrogen or
worthy that anti-1,2-amino alcohols 4 are enantiomeric to
the oxygen. Removal of the tert-butylsulfinyl group on
those previously obtained by ring opening with water of
the nitrogen atom was successfully performed by treat-
N-(tert-butylsulfinyl)aziridines arising from the reaction
ment of ether 3d with methanolic hydrochloric acid (8
between the 3-chloroallenylzinc species, derived from 3-
Table 1 Synthesis of anti-(3S,4R)-4-Aminoalk-1-yn-3-ols 4 from N-(tert-Butylsulfinyl)imines (SS)-2 (Scheme 1)
Entry
R1
R2
H
Imine
2ac
Ether
3a
Yielda (%)
1,2-Amino alcohol
Yieldb (%)
1
2
3
4
5
6
7
8
Pr
82
78
70
81
83
77
87
41
4a
4b
4cd
4d
4e
78
66
81
86
81
73
86
87
(CH2)2Ph
H
2bc
2cc
3b
3c
CH2OTBS
H
Cy
H
2de
2ee
3d
3e
i-Pr
H
(E)-CH=CHMe
H
2fe,f
2ge
3ff
3g
4ff
4g
4h
Ph
Ph
H
Me
2he
3h
a Yields of purified 3 from 2.
b Yields of purified 4 from 3.
c Slow addition of 2 over a period of 45 min via syringe pump.
d The reaction was performed at reflux for 2 h to give the 2-amino-1,3-diol (R1 = CH2OH and R2 = H for 4c).
e Rapid addition of 2 over a period of 2 min.
f Obtained as an E/Z mixture (20:1).
Synthesis 2007, No. 8, 1235–1241 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Enantioenriched Acetylenic 1,2-Amino Alcohols
1237
anhyd Et2O. Commercial s-BuLi was titrated with 1 M s-BuOH in
toluene in the presence of 2,2¢-biquinoline. All other reagents and
solvents were of commercial quality and were used without purifi-
cation. Flash column chromatographic separations were carried out
over silica gel (0.015–0.040 mm). 1H NMR spectra were recorded
at 400 MHz and 13C NMR spectra at 100 MHz with an internal stan-
TMS
NH2
TMS
R
MeCN, H2O
PTSA
3
4
3
4
R
N
S
reflux, 20 h
OH
O
1
dard of residual CHCl3 (d 7.27 for H NMR and d 77.1 for 13C
(3R,4R)-6, >20:1 er
NMR). IR spectra were recorded with an ATR Diamand spectro-
photometer. Melting points were not corrected.
(SS,3S,4R)-5
5a R = Me
5b R = Pr
6a, 66%
6b, 71%
6c, 66%
5c R = hept
(SS)-N-(tert-Butylsulfinyl)imines 2; General Procedure
Ellman’s procedure was followed starting from enantioenriched
(SS)-2-methylpropane-2-sulfinamide19 (>99% ee). Sulfinimines
2a,b,d–h exhibited spectral data and optical rotations in accordance
with those previously reported.15a,b,20
Scheme 2 Synthesis of syn-(3R,4R)-4-aminoalk-1-yn-3-ols 6 from
cis-(SS,3S,4R)-N-(tert-butylsulfinyl)aziridines 5.
equiv) at 0 °C for one hour; N-deprotected 1-cyclohexyl-
2-(methoxymethoxy)-4-(trimethylsilyl)but-3-yn-1-amine
(7) was obtained as a pure compound in high yield (94%)
after basic workup and did not require further purification
(Scheme 3). We attempted selective deprotection of the
methoxymethyl ether moiety to give 1-(tert-butanesulfi-
namido)but-3-yn-2-ol 8. Conditions involving the use of
Lewis acids such as boron trifluoride–diethyl ether or
magnesium bromide–diethyl ether in diethyl ether or
dichloromethane in the presence of an excess of
ethanethiol17 failed; no reaction was observed at 0 °C and
full deprotection occurred at reflux, giving 1,2-amino al-
cohol 4d (Scheme 3).18
(+)-(SS,E)-N-[2-(tert-Butyldimethylsiloxy)ethylidene]-2-methyl-
propane-2-sulfinamide (2c)
Under an argon atmosphere, a suspension of (SS)-2-methylpropane-
2-sulfinamide (605 mg, 5.00 mmol), the appropriate aldehyde21
(1.74 g, 10.00 mmol), PPTS (65 mg, 0.25 mmol), and anhyd MgSO4
(3.00 g, 25.00 mmol) in CH2Cl2 (8 mL) was stirred at r.t. for 24 h.
The mixture was filtered through a pad of Celite and concentrated
in vacuo. The residual oil was purified by flash chromatography
(silica gel, 0–30% Et2O–pentane) to yield enantioenriched 2c as a
clear colorless oil; yield: 933 mg (67%).
[a]D20 +189 (c 0.78 CHCl3).
IR (ATR diamant): 2169 (w), 1628 (m), 1254 (m), 834 (s), 777
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 8.08 (t, J = 3.0 Hz, 1 H, HC=N),
4.57 (d, J = 3.0 Hz, 2 H, CH2O), 1.23 [s, 9 H, (CH3)3CS], 0.94 [s, 9
H, (CH3)3CSi], 0.12 [s, 6 H, (CH3)2Si].
13C NMR (100 MHz, CDCl3): d = 168.6, 65.5, 56.7, 25.7, 22.3, 18.3,
–5.4.
In summary, we have developed a straightforward and
concise stereoselective preparation of enantioenriched
acetylenic anti- and syn-1,2-amino alcohols. The reaction
of racemic 3-(methoxymethoxy)allenylzinc ( )-1, derived
from methoxymethyl 3-(trimethylsilyl)prop-2-ynyl ether
with enantiopure Ellman’s (SS)-N-(tert-butylsulfinyl)imi-
nes gives, in two steps, the corresponding acetylenic anti-
(3S,4R)-3-alkoxy-4-sulfinamidoalk-1-ynes as enantio-
enriched compounds. The syn-(3R,4R)-isomers were ob-
tained by ring opening of the corresponding cis-N-(tert-
butylsulfinyl)aziridines by water under acidic conditions.
Our efforts are now focused on the synthetic use of this
method. The synthesis of naturally occurring compounds
of biological interest is currently under investigation in
our group and will be reported in due course.
HRMS: m/z [M + H]+ calcd for C12H28NO2SSi: 278.1605; found:
278.1604.
(+)-N-[(1R,2S)-2-(Methoxymethoxy)-1-propyl-4-(trimethylsi-
lyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3a); Typical
Procedure
Under a N2 atmosphere, at –80 °C, to a stirred soln of methoxy-
methyl 3-(trimethylsilyl)prop-2-ynyl ether (760 mL, 4.00 mmol)
and TMEDA (60 mL, 0.40 mmol) in anhyd Et2O (40 mL) was added
dropwise 1.3 M s-BuLi in hexane–cyclohexane (3.10 mL, 4.00
mmol). The resulting clear pale orange mixture was stirred at
–80 °C for 1 h and then 1 M ZnBr2 in Et2O (4.00 mL, 4.00 mmol)
was added. After stirring at –80 °C for 15 min, a soln of (SS)-imine
2a (175 mg, 1.00 mmol) in anhyd Et2O (2 mL) was slowly added
dropwise over a period of 45 min via a syringe pump to the pale
orange mixture. The mixture was stirred at –80 °C for 1 h and then
quenched by the addition of aq 1 M HCl (40 mL) and warmed to r.t.
The layers were separated and the aqueous layer was extracted with
Et2O (3 × 20 mL). The combined organic layers were washed with
sat. aq NaHCO3 (10 mL), H2O (20 mL), and brine (20 mL), dried
Experiments involving organometallics were carried out in dried
glassware under a positive pressure of dry N2. Liquid N2 was used
as a cryoscopic fluid. A four-necked, round-bottomed flask
equipped with an internal thermometer, a septum cap, a nitrogen in-
let and a mechanic stirring was used. Et2O was freshly distilled from
sodium benzophenone ketyl prior to use. ZnBr2 (98%) was melted
under dry N2 and, immediately after cooling to r.t., was dissolved in
O
O
S
NH2
BF3⋅OEt2
or
MgBr2⋅OEt2
S
TMS
HN
HN
TMS
TMS
HCl, MeOH
0 °C, 1 h
MOMO
7, 94%
EtSH
CH2Cl2 or Et2O
MOMO
OH
3d
0 °C to reflux
8
Scheme 3 Monodeprotection of 4-(tert-butanesulfinamido)-3-(methoxymethoxy)but-1-yne 3d.
Synthesis 2007, No. 8, 1235–1241 © Thieme Stuttgart · New York

1238
F. Chemla et al.
PAPER
(anhyd MgSO4), and concentrated in vacuo to give an orange oil.
Flash chromatography (silica gel, 0–50% Et2O–pentane) yielded
enantioenriched 3a as a yellow oil that crystallized as a sticky solid
upon standing; yield: 284 mg (82%).
(+)-N-[(1R,2S)-1-Cyclohexyl-2-(methoxymethoxy)-4-(trimeth-
ylsilyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3d)
Following the typical procedure using (SS)-imine 2d (215 mg, 1.00
mmol), which was added rapidly dropwise over a period of 2 min.
Flash chromatography (0–50% Et2O–pentane) yielded enantio-
enriched 3d as a pale yellow oil; yield: 311 mg (81%).
[a]D20 +158 (c 1.04 CHCl3).
IR (ATR diamant): 3228 (w), 2171 (w), 1250 (m), 1025 (s), 840 (s),
[a]D20 +156 (c 1.10 CHCl3).
759 cm–1 (m).
IR (ATR diamant): 3256 (w), 2171 (w), 1250 (m), 1024 (s), 840 (s),
759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.94 (d, J = 6.8 Hz, 1 H, OCH2O),
4.60 (d, J = 6.8 Hz, 1 H, OCH2O), 4.32 (d, J = 3.3 Hz, 1 H, OCH),
3.40 (s, 3 H, CH3O), 3.46–3.37 (m, 2 H, NH, NCH), 1.80–1.71 (m,
1 H, CH2), 1.67–1.51 (m, 2 H, CH2), 1.52–1.41 (m, 1 H, CH2), 1.25
[s, 9 H, (CH3)3CS], 0.97 (t, J = 7.2 Hz, 3 H, CH3), 0.19 [s, 9 H,
(CH3)3Si].
1H NMR (400 MHz, CDCl3): d = 4.93 (d, J = 6.8 Hz, 1 H, OCH2O),
4.57 (d, J = 6.8 Hz, 1 H, OCH2O), 4.43 (d, J = 3.8 Hz, 1 H, OCH),
3.48 (d, J = 8.8 Hz, 1 H, NH), 3.39 (s, 3 H, CH3O), 3.20 (ddd,
J = 8.8, 6.3, 3.8 Hz, 1 H, NCH), 2.03–1.99 (m, 1 H, H-cyclohexyl),
1.82–1.59 (m, 5 H, H-cyclohexyl), 1.26 [s, 9 H, (CH3)3CS], 1.33–
1.14 (m, 4 H, H-cyclohexyl), 1.10–1.01 (m, 1 H, H-cyclohexyl),
0.19 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 101.4, 94.2, 92.5, 70.2, 60.0, 56.2,
55.7, 34.5, 22.6, 19.0, 13.7, –0.3.
Anal. Calcd for C16H33NO3SSi: C, 55.29; H, 9.57; N, 4.03. Found:
C, 55.22; H, 9.53; N, 4.23.
13C NMR (100 MHz, CDCl3): d = 101.7, 93.8, 92.9, 68.3, 65.0, 56.7,
55.7, 40.4, 30.2, 29.0, 26.2, 26.1, 26.0, 22.8, –0.2.
(+)-N-[(1R,2S)-2-(Methoxymethoxy)-1-phenethyl-4-(trimethyl-
silyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3b)
Following the typical procedure using (SS)-imine 2b (237 mg, 1.00
mmol). Flash chromatography (0–50% Et2O–pentane) yielded
enantioenriched 3b as a pale yellow oil that crystallized upon stand-
ing; yield: 320 mg (78%); mp 53–55 °C.
HRMS: m/z [M + H]+ calcd for C19H38NO3SSi: 388.2342; found:
388.2343.
(+)-N-[(1R,2S)-1-Isopropyl-2-(methoxymethoxy)-4-(trimethyl-
silyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3e)
Following the typical procedure using (SS)-imine 2e (175 mg, 1.00
mmol) which was rapidly added dropwise over a period of 2 min.
Flash chromatography (0–50% Et2O–pentane) yielded enantio-
enriched 3e as a pale yellow oil that crystallized as a sticky solid
upon standing; yield: 289 mg (83%).
[a]D20 +218 (c 0.52 CHCl3).
IR (ATR diamant): 3239 (w), 2170 (w), 1603 (w), 1249 (m), 1024
(s), 840 (s), 759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.31–7.24 (m, 4 H, H-Ar), 7.23–
7.19 (m, 1 H, H-Ar), 4.93 (d, J = 6.8 Hz, 1 H, OCH2O), 4.59 (d,
J = 6.8 Hz, 1 H, OCH2O), 4.34 (d, J = 3.6 Hz, 1 H, OCH), 3.49 (d,
J = 8.6 Hz, 1 H, NH), 3.44–3.40 (m, 1 H, NCH), 3.38 (s, 3 H,
CH3O), 2.99–2.91 (m, 1 H, CH2), 2.89–2.80 (m, 1 H, CH2), 2.22–
2.13 (m, 1 H, CH2), 2.00–1.90 (m, 1 H, CH2), 1.26 [s, 9 H,
(CH3)3CS], 0.19 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 141.2, 128.7, 128.4, 125.9, 101.4,
94.3, 92.8, 70.5, 59.7, 56.3, 55.8, 33.7, 31.5, 22.7, –0.2.
HRMS: m/z [M + H]+ calcd for C21H36NO3SSi: 410.2185; found:
410.2198.
[a]D20 +168 (c 1.33 CHCl3).
IR (ATR diamant): 3341 (w), 2176 (w), 1249 (m), 1026 (s), 841 (s),
761 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.93 (d, J = 6.8 Hz, 1 H, OCH2O),
4.58 (d, J = 6.8 Hz, 1 H, OCH2O), 4.40 (d, J = 3.8 Hz, 1 H, OCH),
3.48 (d, J = 8.8 Hz, 1 H, NH), 3.39 (s, 3 H, CH3O), 3.20 (ddd,
J = 8.8, 6.8, 3.8 Hz, 1 H, NCH), 1.98 (octet, J = 6.8 Hz, 1 H, CH),
1.27 [s, 9 H, (CH3)3CS], 1.06 (d, J = 6.8 Hz, 6 H, 2 CH3), 0.18 [s, 9
H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 101.7, 93.8, 92.9, 68.5, 65.6, 56.7,
55.7, 30.5, 22.7, 19.9, 18.6, –0.3.
(+)-N-{(1R,2S)-1-[(tert-Butyldimethylsiloxy)methyl]-2-(meth-
oxymethoxy)-4-(trimethylsilyl)but-3-ynyl}-2-methylpropane-2-
sulfinamide (3c)
Following the typical procedure using (SS)-imine 2c (277 mg, 1.00
mmol). Flash chromatography (0–40% Et2O–pentane) yielded
enantioenriched 3c as a pale yellow oil; 314 mg (70%).
Anal. Calcd for C16H33NO3SSi: C, 55.29; H, 9.57; N, 4.03. Found:
C, 55.73; H, 9.98; N, 4.15.
(+)-N-[(1R,2S,E)-2-(Methoxymethoxy)-1-prop-1-enyl-4-(tri-
methylsilyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3f)
Following the typical procedure using (SS)-imine 2f (173 mg, 1.00
mmol), which was rapidly added dropwise over a period of 2 min.
Flash chromatography (0–50% Et2O–pentane) yielded enantio-
enriched 3f as a pale yellow oil; yield: 267 mg (77%).
[a]D20 +66 (c 0.93 CHCl3).
IR (ATR diamant): 3279 (w), 2166 (w), 1250 (m), 1026 (s), 836 (s),
760 cm–1 (m).
[a]D20 +144 (c 1.22 CHCl3).
1H NMR (400 MHz, CDCl3): d = 4.94 (d, J = 6.6 Hz, 1 H, OCH2O),
4.62 (d, J = 6.6 Hz, 1 H, OCH2O), 4.48 (d, J = 6.6 Hz, 1 H, OCH),
3.98 (ABX system, J = 10.1, 3.3 Hz, 1 H, CH2OSi), 3.89 (d, J = 9.1
Hz, 1 H, NH), 3.78 (ABX system, J = 10.1, 5.4 Hz, 1 H, CH2OSi),
3.54–3.47 (m, 1 H, NCH), 3.40 (s, 3 H, CH3O), 1.26 [s, 9 H,
(CH3)3CS], 0.92 [s, 9 H, (CH3)3CSi], 0.17 [s, 9 H, (CH3)3Si], 0.12
(s, 3 H, CH3Si), 0.09 (s, 3 H, CH3Si).
IR (ATR diamant): 3219 (w), 2173 (w), 1250 (m), 1026 (s), 840 (s),
759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 5.91–5.84 (m, 1 H, HC=C), 5.67–
5.61 (m, 1 H, HC=C), 4.93 (d, J = 6.8 Hz, 1 H, OCH2O), 4.63 (d,
J = 6.8 Hz, 1 H, OCH2O), 4.38 (d, J = 3.8 Hz, 1 H, OCH), 3.98–
3.93 (m, 1 H, NCH), 3.67 (d, J = 8.4 Hz, 1 H, NH), 3.40 (s, 3 H,
CH3O), 1.78 (m, 3 H, CH3), 1.24 [s, 9 H, (CH3)3CS], 0.19 [s, 9 H,
(CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 102.0, 94.3, 92.1, 66.2, 62.6, 60.9,
56.3, 55.7, 25.8, 22.7, 18.1, –0.2, –5.4, –5.6.
13C NMR (100 MHz, CDCl3): d = 129.9, 128.0, 101.1, 94.2, 92.9,
70.2, 61.7, 56.2, 55.7, 22.5, 17.9, –0.3.
Anal. Calcd for C20H43NO4SSi2: C, 53.41; H, 9.64; N, 3.11. Found:
C, 53.38; H, 9.43; N, 3.07.
Anal. Calcd for C16H31NO3SSi: C, 55.61; H, 9.04; N, 4.05. Found:
C, 55.36; H, 9.29; N, 4.25.
Synthesis 2007, No. 8, 1235–1241 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Enantioenriched Acetylenic 1,2-Amino Alcohols
1239
(–)-N-[(1R,2S)-2-(Methoxymethoxy)-1-phenyl-4-(trimethyl-
silyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3g)
Following the typical procedure using (SS)-imine 2g (209 mg, 1.00
mmol), which was rapidly added dropwise over a period of 2 min.
Flash chromatography (0–50% Et2O–pentane) yielded enantio-
enriched 3g as a pale yellow solid; yield: 333 mg (87%); mp 50–
51 °C.
Anal. Calcd for C10H21NOSi: C, 60.24; H, 10.62; N, 7.03. Found: C,
60.18; H, 10.85; N, 6.76.
(–)-(3S,4R)-4-Amino-6-phenyl-1-(trimethylsilyl)hex-1-yn-3-ol
(4b)
Following the typical procedure using ether 3b (204 mg, 0.50
mmol). Flash chromatography (0–8% MeOH–CH2Cl2) yielded
enantioenriched 4b as a pale yellow oil that crystallized as a sticky
solid upon standing; yield: 86 mg (66%).
[a]D20 –94 (c 1.04 CHCl3).
IR (ATR diamant): 3293 (m), 3065 (w), 3035 (w), 2171 (w), 1247
(m), 1033 (s), 838 (s), 758 cm–1 (m).
[a]D20 –35 (c 0.84 CHCl3).
IR(ATR diamant): 3062 (w), 2166 (m), 1586 (m), 1249 (m), 838 (s),
759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.45–7.42 (m, 2 H, H-Ar), 7.38–
7.30 (m, 3 H, H-Ar), 4.91 (d, J = 6.8 Hz, 1 H, OCH2O), 4.61–4.56
(m, 3 H, OCH2O, OCH, NCH), 4.08 (d, J = 6.5 Hz, 1 H, NH), 3.25
(s, 3 H, CH3O), 1.26 [s, 9 H, (CH3)3CS], 0.17 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 138.6, 128.2, 128.0, 127.9, 101.1,
94.2, 93.6, 70.4, 62.1, 56.6, 55.7, 22.6, –0.3.
1H NMR (400 MHz, CDCl3): d = 7.33–7.28 (m, 2 H, H-Ar), 7.29–
7.20 (m, 3 H, H-Ar), 4.31 (br d, J = 4.0 Hz, 1 H, OCH), 2.85–2.78
(m, 2 H, NCH, CH2), 2.74–2.67 (m, 1 H, CH2), 2.45–2.07 (m, 3 H,
OH, NH2), 1.95–1.86 (m, 1 H, CH2), 1.78–1.68 (m, 1 H, CH2), 0.20
[s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 141.7, 128.5, 128.4, 126.0, 103.9,
91.0, 66.2, 54.9, 35.8, 32.5, –0.0.
Anal. Calcd for C19H31NO3SSi: C, 59.80; H, 8.19; N, 3.67. Found:
C, 59.83; H, 8.31; N, 3.57.
(+)-N-[(1R,2S)-2-(Methoxymethoxy)-1-methyl-1-phenyl-2-(tri-
methylsilyl)but-3-ynyl]-2-methylpropane-2-sulfinamide (3h)
Following the typical procedure using (SS)-imine 2h (223 mg, 1.00
mmol), which was rapidly added dropwise over a period of 2 min.
Flash chromatography (0–40% Et2O–pentane) yielded enantio-
enriched 3h as a pale yellow oil that crystallized upon standing;
yield: 152 mg (41%); mp 66–67 °C.
Anal. Calcd for C15H23NOSi: C, 68.91; H, 8.87; N, 5.36. Found: C,
69.06; H, 8.75; N, 5.17.
(+)-(2R,3S)-2-Amino-5-(trimethylsilyl)pent-4-yne-1,3-diol (4c)
Following the typical procedure using ether 3c (180 mg, 0.40
mmol), but stirring at reflux for 2 h. Flash chromatography (0–25%
MeOH–CH2Cl2) yielded enantioenriched anti-2-amino-1,3-diol 4c
as a pale yellow solid; yield: 60 mg (81%); mp 75–78 °C.
[a]D20 +21 (c 0.93 CHCl3).
[a]D20 +11 (c 0.77 CHCl3).
IR (ATR diamant): 3278 (m), 3060 (w), 3035 (w), 2165 (w), 1251
(m), 1064 (s), 839 (s), 760 cm–1 (m).
IR (ATR diamant): 3347 (m), 3285 (w), 3035 (w), 2168 (w), 1250
(m), 1038 (m), 837 (s), 760 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.52–4.27 (m, 1 H, OCH), 3.83–
3.64 (m, 2 H, CH2O), 3.64–3.33 (m, 4 H, 2 OH, NH2), 3.07–2.75 (m,
1 H, NCH), 0.18 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 104.2 (br), 91.4, 64.4 (br), 62.9
(br), 56.6 (br), –0.1.
1H NMR (400 MHz, CDCl3): d = 7.54 (d, J = 8.1 Hz, 2 H, H-Ar),
7.38–7.30 (m, 3 H, H-Ar), 4.80 (d, J = 6.8 Hz, 1 H, OCH2O), 4.56
(s, 1 H, OCH), 4.32 (d, J = 6.8 Hz, 1 H, OCH2O), 4.17 (s, 1 H, NH),
2.85 (s, 3 H, CH3O), 1.95 (s, 3 H, CH3), 1.25 [s, 9 H, (CH3)3CS],
0.22 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 141.2, 128.1, 127.9, 127.6, 101.4,
94.1, 93.8, 74.3, 62.6, 56.4, 55.3, 22.7, 22.6, –0.2.
HRMS: m/z [M + H]+ calcd for C8H18NO2Si: 188.1101; found:
Anal. Calcd for C20H33NO3SSi: C, 60.72; H, 8.41; N, 3.54. Found:
C, 60.67; H, 8.32; N, 3.59.
188.1100.
(–)-(1R,2S)-1-Amino-1-cyclohexyl-4-(trimethylsilyl)but-3-yn-2-
ol (4d)
Following the typical procedure using ether 3d (193 mg, 0.50
mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yielded
enantioenriched 4d as a pale yellow oil; yield: 102 mg (86%).
(–)-(3S,4R)-4-Amino-1-(trimethylsilyl)hept-1-yn-3-ol (4a); Typ-
ical Procedure
Under N2, to a stirred soln of ether 3a (173 mg, 0.50 mmol) in
MeOH (10 mL) was added at r.t. 4 M anhyd HCl in 1,4-dioxane
(0.62 mL, 2.5 mmol). The soln was refluxed for 1 h and, after cool-
ing to r.t., sat. aq NaHCO3 soln (5 mL) was added to the vigorously
stirred mixture, followed by anhyd MgSO4. The mixture was stirred
at r.t. for 10 min and then the solvents were removed in vacuo. The
residue was taken up in Et2O (50 mL), dried (anhyd MgSO4), and
concentrated in vacuo to give an orange oil. Flash chromatography
(silica gel, 0–6% MeOH–CH2Cl2) yielded enantioenriched 4a as a
pale yellow oil that crystallized as a sticky solid upon standing;
yield: 77 mg (78%).
[a]D20 –24 (c 0.67 CHCl3).
IR (ATR diamant): 3164 (w), 2166 (m), 1586 (m), 1249 (m), 838
(s), 758 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.42 (d, J = 4.6 Hz, 1 H, OCH),
2.47 (dd, J = 8.6, 4.5 Hz, 1 H, NCH), 2.40–2.25 (m, 3 H, OH, NH2),
2.02–1.98 (m, 1 H, H-cyclohexyl), 1.80–1.66 (m, 4 H, H-cyclohex-
yl), 1.39–1.14 (m, 4 H, H-cyclohexyl), 1.04–0.94 (m, 2 H, H-cyclo-
hexyl), 0.18 [s, 9 H, (CH3)3Si].
[a]D20 –16 (c 0.80 CHCl3).
13C NMR (100 MHz, CDCl3): d = 104.1, 90.3, 63.5, 60.4, 42.1, 29.9,
29.6, 26.4, 26.1, 0.0.
IR (ATR diamant): 3344 (w), 3324 (w), 3287 (w), 2166 (m), 1590
(m), 836 (s), 758 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.28 (d, J = 4.3 Hz, 1 H, OCH),
2.84–2.79 (m, 1 H, NCH), 2.10–1.97 (m, 3 H, OH, NH2), 1.56–1.43
(m, 2 H, CH2), 1.40–1.35 (m, 2 H, CH2), 0.96 (d, J = 6.8 Hz, 3 H,
CH3), 0.20 [s, 9 H, (CH3)3Si].
Anal. Calcd for C13H25NOSi: C, 65.21; H, 10.52; N, 5.85. Found: C,
64.87; H, 10.62; N, 5.73.
(–)-(3S,4R)-4-Amino-5-methyl-1-(trimethylsilyl)hex-1-yn-3-ol
(4e)
Following the typical procedure using ether 3e (173 mg, 0.50
mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yielded
enantioenriched 4e as a pale yellow oil that crystallized as a sticky
solid; yield: 80 mg (81%).
13C NMR (100 MHz, CDCl3): d = 104.2, 90.6, 66.0, 55.3, 35.8, 19.3,
14.1, –0.1.
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1240
F. Chemla et al.
PAPER
[a]D20 –19 (c 0.72 CHCl3).
13C NMR (100 MHz, CDCl3): d = 144.7, 128.0, 126.9, 125.9, 104.6,
91.1, 70.7, 59.1, 26.0, –0.3.
IR (ATR diamant): 3151 (w), 2166 (m), 1587 (m), 1249 (m), 838
(s), 759 cm–1 (m).
HRMS m/z [M + H]+ calcd for C14H22NOSi: 248.1471; found:
248.1469.
1H NMR (400 MHz, CDCl3): d = 4.08 (d, J = 4.6 Hz, 1 H, OCH),
2.92–2.83 (dd, J = 8.7, 4.6 Hz 1 H, NCH), 2.30–1.90 (m, 3 H, OH,
NH2), 1.65 (m, 1 H, CH), 1.04 (d, J = 6.8 Hz, 3 H, CH3), 0.96 (d,
J = 6.8 Hz, 3 H, CH3), 0.19 [s, 9 H, (CH3)3Si].
(–)-(3R,4R)-4-Amino-1-(trimethylsilyl)pent-1-yn-3-ol (6a);
Typical Procedure
A stirred soln of cis-aziridine 5a (202 mg, 0.78 mmol) and PTSA
monohydrate (150 mg, 0.78 mmol) in MeCN (30 mL) and H2O (4.3
mL) was refluxed for 20 h. After cooling to r.t., sat. aq NaHCO3 soln
(30 mL) and CH2Cl2 (30 mL) were added and the resulting mixture
was stirred at r.t. for 15 min. The layers were then separated and the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The com-
bined organic layers were washed with sat. aq NaHCO3 (30 mL),
dried (anhyd Na2SO4), and concentrated in vacuo. The residual
brownish oil was purified by flash chromatography (0–15%
MeOH–CH2Cl2) yielding enantioenriched syn-alcohol 6a as a
sticky solid; yield: 88 mg (66%).
13C NMR (100 MHz, CDCl3): d = 104.2, 90.3, 64.1, 61.6, 32.0, 19.6,
19.4, –0.1.
HRMS: m/z [M + H]+ calcd for C10H22NOSi: 200.1471; found:
200.1465.
(–)-(3S,4R,E)-4-Amino-1-(trimethylsilyl)hept-5-en-1-yn-3-ol
(4f)
Following the typical procedure using ether 3f (172 mg, 0.50
mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yielded
enantioenriched 4f as a pale yellow solid; yield: 71 mg (73%); mp
74–77 °C.
[a]D20 –13 (c 0.75 CHCl3).
[a]D20 –47 (c 0.84 CHCl3).
IR (ATR diamant): 3342 (m), 3271 (m), 3188 (w), 2170 (m), 1614
(m), 835 (s), 759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.05 (br d, J = 3.6 Hz, 1 H, OCH),
3.12–3.00 (m, 1 H, NCH), 2.25–1.93 (m, 3 H, OH, NH2), 1.21 (d,
J = 6.5 Hz, 3 H, CH3), 0.19 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 105.5 (br), 90.1, 67.2 (br), 52.0
(br), 18.9 (br), 0.0.
IR (ATR diamant): 3355 (w), 3291 (w), 3035 (w), 3024 (w), 2169
(w), 1249 (m), 1048 (m), 840 (s), 760 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 5.79–5.63 (m, 1 H, HC=C), 5.57–
5.46 (m, 1 H, HC=C), 4.40–4.17 (m, 1 H, OCH), 3.52–3.35 (m, 1 H,
NCH), 2.70–2.25 (m, 3 H, OH, NH2), 1.74 (br d, J = 6.1 Hz, 3 H,
CH3), 0.19 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 130.6 (br), 128.2, 104.0, 90.9,
66.3 (br), 57.8 (br), 17.9, –0.1.
HRMS: m/z [M + H]+ calcd for C10H20NOSi: 198.1309; found:
HRMS: m/z [M + H]+ calcd for C8H18NOSi: 172.1152; found:
172.1152.
(–)-(3R,4R)-4-Amino-1-(trimethylsilyl)hept-1-yn-3-ol (6b)
Following the typical procedure using cis-aziridine 5b (230 mg,
0.81 mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yield-
ed enantioenriched syn-alcohol 6b as a pale yellow oil that crystal-
lized as a sticky solid upon standing; yield: 114 mg (71%).
198.1309.
(–)-(1R,2S)-1-Amino-1-phenyl-4-(trimethylsilyl)but-3-yn-2-ol
(4g)
Following the typical procedure using ether 3g (190 mg, 0.50
mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yielded
enantioenriched 4g as a pale yellow oil that crystallized as a sticky
solid upon standing; yield: 100 mg (86%).
[a]D20 –8 (c 0.35 CHCl3).
IR (ATR diamant): 2168 (m), 1589 (m), 1249 (m), 838 (s), 758
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.08 (br d, J = 5.0 Hz, 1 H, OCH),
2.92–2.83 (m, 1 H, NCH), 2.30–1.90 (s, 3 H, OH, NH2), 1.67–1.61
(m, 1 H, CH2), 1.60–1.27 (m, 3 H, CH2), 0.96 (d, J = 7.2 Hz, 3 H,
CH3), 0.19 [s, 9 H, (CH3)3Si].
[a]D20 –60 (c 0.45 CHCl3).
IR (ATR diamant): 3352 (w), 3299 (w), 3061 (w), 2167 (w), 1249
(m), 1071 (m), 837 (s), 759 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.40–7.30 (m, 5 H, H-Ar), 4.66 (br
d, J = 4.0 Hz, 1 H, OCH), 4.24 (br d, J = 4.0 Hz, 1 H, NCH), 4.21–
3.87 (m, 3 H, OH, NH2), 0.11 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 138.7, 128.2, 127.9, 127.4, 102.9,
92.4, 66.5, 59.5, –0.3.
13C NMR (100 MHz, CDCl3): d = 105.5, 90.2, 65.8, 56.1, 35.3, 19.4,
14.2, 0.0.
Anal. Calcd for C10H21NOSi: C, 60.24; H, 10.62; N, 7.03. Found: C,
60.65; H, 10.41; N, 6.15.
HRMS: m/z [M + H]+ calcd for C13H20NOSi: 234.1314; found:
(+)-(3R,4R)-4-Amino-1-(trimethylsilyl)undec-1-yn-3-ol (6c)
Following the typical procedure using cis-aziridine 5c (381 mg,
1.11 mmol). Flash chromatography (0–10% Et2O–pentane) yielded
enantioenriched syn-alcohol 6c as a yellow oil that crystallized as a
sticky solid upon standing; yield: 185 mg (66%).
234.1313.
(–)-(3S,4R)-4-Amino-4-phenyl-1-(trimethylsilyl)pent-1-yn-3-ol
(4h)
Following the typical procedure using ether 3h (118 mg, 0.30
mmol). Flash chromatography (0–10% MeOH–CH2Cl2) yielded
enantioenriched 4h as a pale yellow solid; yield: 65 mg (87%); mp
69–72 °C.
[a]D20 +3 (c 1.10 CHCl3).
IR (ATR diamant): 2169 (w), 1588 (w), 1249 (m), 839 (s), 759
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.08 (d, J = 5.3 Hz, 1 H, OCH),
2.90–2.79 (m, 1 H, NCH), 2.28–1.95 (m, 3 H, OH, NH2), 1.68–1.63
(m, 1 H, CH2), 1.45–1.22 (m, 11 H, CH2), 0.90 (t, J = 6.9 Hz, 3 H,
CH3), 0.19 [s, 9 H, (CH3)3Si].
[a]D20 –20 (c 0.50 CHCl3).
IR (ATR diamant): 3359 (w), 3298 (w), 3074 (w), 2169 (w), 1246
(m), 1076 (s), 837 (s), 757 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.48 (d, J = 8.6 Hz, 2 H, H-Ar),
7.36 (d, J = 8.6 Hz, 2 H, H-Ar), 7.30–7.22 (m, 1 H, H-Ar), 4.43 (s,
1 H, OCH), 2.50–2.18 (m, 3 H, OH, NH2), 1.57 (s, 3 H, CH3), 0.07
[s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 105.9, 89.7, 65.6, 56.2, 32.8, 31.8,
29.5, 29.1, 26.1, 22.6, 14.1, –0.1.
Synthesis 2007, No. 8, 1235–1241 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Enantioenriched Acetylenic 1,2-Amino Alcohols
1241
Anal. Calcd for C14H29NOSi: C, 65.82; H, 11.45; N, 5.48. Found: C,
65.42; H, 11.34; N, 5.71.
Takeuchi, T. J. Antibiot. 1976, 29, 97. (d) Umezawa, H.;
Aoyagi, T.; Morishima, H.; Matsuzaki, M.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1970, 23, 259.
(+)-(1R,2S)-1-Cyclohexyl-2-(methoxymethoxy)-4-(trimethylsi-
lyl)but-3-yn-1-amine (7)
(5) (a) Iwamoto, R. H.; Lim, P.; Bhacca, N. S. Tetrahedron Lett.
1968, 9, 3891. (b) Arcamone, F.; Cassinelli, G.; Orezzi, P.;
Franceschi, G.; Mondelli, R. J. Am. Chem. Soc. 1964, 86,
5334.
(6) Howell, A. R.; So, R. C.; Richardson, S. T. Tetrahedron
2004, 60, 11327.
(7) Howarth, J.; Lloyd, D. G. J. Antimicrob. Chemother. 2000,
46, 625.
(8) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De Jesús,
M.; Espinosa, S.; Ortiz, L. Tetrahedron: Asymmetry 2006,
17, 112.
(9) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
(10) Gridley, J. J.; Coogan, M. P.; Knight, D. W.; Malik, K. M.
A.; Sharland, C. M.; Singkhonrat, J.; Williams, S. Chem.
Commun. 2003, 2550.
Under a N2 atmosphere, at 0 °C, to a stirred soln of anti-ether 3d
(234 mg, 0.60 mmol) in MeOH (5 mL) was added dropwise 4 M
HCl in 1,4-dioxane (1.2 mL, 4.80 mmol). The resulting mixture was
stirred at 0 °C for 1 h and was quenched with sat. aq NaHCO3 (10
mL). After removal of MeOH in vacuo, the aqueous layer was ex-
tracted with Et2O (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL) and brine (10 mL), and dried (anhyd
MgSO4). Removal of the solvent in vacuo yielded enantioenriched
anti-ether 7 as a viscous yellow oil that needed no purification;
yield: 159 mg (94%).
[a]D20 +88 (c 0.99 CHCl3).
IR (ATR diamant): 2169 (w), 1250 (m), 1025 (s), 840 (s), 760
cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 4.92 (d, J = 6.8 Hz, 1 H, OCH2O),
4.61 (d, J = 6.8 Hz, 1 H, OCH2O), 4.50–4.45 (m, 1 H, OCH), 3.35
(s, 3 H, CH3O), 2.93–2.75 (m, 1 H, NCH), 2.07–1.97 (m, 1 H, H-
cyclohexyl), 1.85–1.64 (m, 6 H, NH2, H-cyclohexyl), 1.34–1.06 (m,
6 H, H-cyclohexyl), 0.16 [s, 9 H, (CH3)3Si].
13C NMR (100 MHz, CDCl3): d = 100.5, 94.3, 93.4, 68.1 (br), 59.0,
55.9, 39.2, 30.1, 28.9, 26.2, 26.0, –0.2.
(11) (a) Alemany, C.; Bach, J.; Farràs, J.; Garcia, J. Org. Lett.
1999, 1, 1831. (b) Dondoni, A.; Perrone, D.; Turturici, E. J.
Org. Chem. 1999, 64, 5557.
(12) (a) Andrés, J. M.; Pedrosa, R.; Pérez-Encabo, A.
Tetrahedron Lett. 2006, 47, 5317. (b) Ohno, H.; Takemoto,
Y.; Fujii, N.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1999,
2979.
(13) Poisson, J.-F.; Normant, J. F. Org. Lett. 2001, 3, 1889.
(14) (a) Chemla, F.; Ferreira, F. Curr. Org. Chem. 2002, 6, 539.
(b) Chemla, F.; Bernard, N.; Ferreira, F.; Normant, J.-F. Eur.
J. Org. Chem. 2001, 3295.
HRMS: m/z [M + H]+ calcd for C15H30NO2Si: 284.2040; found:
284.2039.
(15) (a) Ferreira, F.; Audouin, M.; Chemla, F. Chem. Eur. J.
2005, 11, 5269. (b) Chemla, F.; Ferreira, F. J. Org. Chem.
2004, 69, 8244. (c) Chemla, F.; Ferreira, F. Synlett 2004,
983. (d) Ferreira, F.; Denichoux, D.; Bejjani, J.; Chemla, F.
Synlett 2004, 2051. (e) Chemla, F.; Ferreira, F.; Hebbe, V.;
Stercklen, E. Eur. J. Org. Chem. 2002, 1385.
(16) Palais, L.; Chemla, F.; Ferreira, F. Synlett 2006, 1039.
(17) Chemla, F.; Ferreira, F. Synlett 2006, 2613.
(18) Kieczykowski, G. R.; Schlessinger, R. H. J. Am. Chem. Soc.
1978, 100, 1938.
Acknowledgment
The authors would like to thank Dr Alejandro Pérez-Luna for fruit-
ful discussions.
References
(1) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (b)Reetz,
M. T. Chem. Rev. 1999, 99, 1121.
(2) (a) Yokomatsu, Y.; Yuasa, Y.; Shibuya, S. Heterocycles
1992, 33, 1051. (b) Ohfune, Y. Acc. Chem. Res. 1992, 25,
360. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30,
1531.
(19) (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(b) Cogan, D. A.; Liu, J.; Kim, K.; Backes, B. J.; Ellman, J.
A. J. Am. Chem. Soc. 1998, 120, 8011.
(20) Liu, J.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
(3) Golebiowski, A.; Jurczak, J. Synlett 1993, 241.
(4) (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(b) Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1978, 31, 636.
(c) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.;
119, 9913.
(21) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.;
O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005,
70, 150.
Synthesis 2007, No. 8, 1235–1241 © Thieme Stuttgart · New York