Synthesis of homochiral propargyl amines from W-(Boc)-tetrahy dro-2#-l,3-oxazines

Article abstract of DOI:10.1039/a902671a

The functionalisation of homochiral N-(Boc)-tetrahydro-2//-l,3-oxazines with the Grignard reagent of (trimethylsilyl)acetylene under Lewis acidic conditions is described. This leads directly to homochiral propargyl amines in good yields, under mild condit

Full text of DOI:10.1039/a902671a

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Synthesis of homochiral propargyl amines from N-(Boc)-
tetrahydro-2H-1,3-oxazines
Alastair Rae,a José L. Castrob and Alethea B. Tabor*a
a Department of Chemistry, University College London, 20 Gordon Street, London,
UK WC1H 0AJ
b Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow,
Essex, UK CM20 2QR
Received (in Cambridge) 6th April 1999, Accepted 10th May 1999
The functionalisation of homochiral N-(Boc)-tetrahydro-2H-1,3-oxazines with the Grignard reagent of
(trimethylsilyl)acetylene under Lewis acidic conditions is described. This leads directly to homochiral
propargyl amines in good yields, under mild conditions, and with moderate to good enantioselectivities.
The stereochemistry of the major enantiomer was determined to be (R) by correlation, and a mechanism
for the ring opening reaction has been proposed on this basis.
Introduction
Results and discussion
The stereoselective synthesis of amines by ring-opening of
N,O-acetals (aminals) by organometallic reagents has recently
received attention from a number of groups.1 For example,
2-aliphatic2 and 2-aryl2,3 1,3-oxazolidines 1 have been treated
with aliphatic Grignard and other organometallic reagents, fol-
lowed by cleavage via hydrogenolysis or oxidative methods to
afford homochiral aliphatic and benzyl amines in moderate to
good enantiomeric excesses (ee). Bicyclic N-benzyl-tetrahydro-
2H-1,3-oxazines 2 derived from (ϩ)-pulegone have also been
Ring opening of tetrahydro-2H-1,3-oxazines with acetylenic
nucleophiles
In the preceding paper,5 we reported the synthesis of a series
of N-(Boc)-tetrahydro-2H-1,3-oxazines 3 from (S)-N-(Boc)-3-
aminobutan-1-ol and appropriate diethyl acetals. We also
determined the structure, and the unusual conformation,
adopted by these aminals, as the configuration at the 2-position
is crucial to understanding the mechanism of the subsequent
ring-opening reaction.
A few groups have previously reported reactions between
aminals and a variety of acetylenic nucleophiles. Aminals
derived from formaldehyde have been converted to simple
propargyl amines with acetylenic Grignard reagents,6 lithiated
acetylenes,7 or via cuprate catalysed acetylene addition.8
Alkynyllithiums, in the presence of BF3ؒEt2O, have been used
to ring-open achiral tetrahydro-2H-1,3-oxazines9 in moderate
yields, and acyclic aminals have been amidoalkylated with (tri-
methylsilyl)acetylenes in the presence of TiCl4,10 and (tributyl-
stannyl)acetylenes in the presence of BF3.11 A considerable
amount of work on the ring-opening of homochiral acetals by
bis(trimethylsilyl)acetylene in the presence of TiCl4 has also
been carried out.12 We therefore explored the reaction of
a number of acetylenic nucleophiles and Lewis acids with
N-(Boc)-tetrahydro-2H-1,3-oxazines 3.
H
H
R'
N
N
R
O
R
Ph
O
Ph
2
1
reacted with Grignard and organoaluminium reagents;4 sub-
sequent treatment with P2O5, followed by hydrogenolysis, also
led to homochiral aliphatic amines in high ee. However, these
methods have not been used to access homochiral propargylic
(prop-2-ynyl) amines, probably because the harsh conditions
required for removal of the chiral auxiliary and the amine
protecting groups would be incompatible with the sensitive
functionality.
Ring opening reactions of aminal 3a were initially attempted
with bis(trimethylsilyl)acetylene, using either TiCl4 or SnBr4 as
the Lewis acid. In both cases, cyclohexanecarbaldehyde and
N-(Boc)-3-aminobutan-1-ol were recovered in high yield. These
results suggest that complexation of the aminal to the Lewis
acid occurs, giving iminium ion 6; however, the insufficient
nucleophilicity of bis(trimethylsilyl)acetylene means that no
further reaction takes place. On aqueous workup, the iminium
ion is hydrolysed to give the observed products (Scheme 2).
Further combinations of nucleophile and Lewis acid were
attempted (Table 1). Although many of these had been previ-
ously reported to react with aminals or acetals,13–15 the reactions
with aminal 3a were unsuccessful. The failure of alkynyl-
lithiums to give the desired ring opened product in the presence
of BF3ؒEt2O was particularly surprising, as a similar reaction
has recently been described.9
We wish to report a novel method for the synthesis of homo-
chiral propargyl amines via the functionalisation of chiral
N-(Boc)-tetrahydro-2H-1,3-oxazines 3. Our approach (Scheme
1) involves ring-opening of the tetrahydrooxazines with an
Me
BocN
R1
OH
NHBoc
Me
BocN
R2
M
R1
O
R2
Lewis acid
R1
3
R2
5
4
Scheme 1
appropriate acetylenic nucleophile. This is followed by a mild,
two step procedure which simultaneously removes the chiral
directing group and the nitrogen protecting group, followed by
reprotection of the amine.
As aminals have previously been successfully functionalised
with alkyl and aryl Grignard reagents,2,3,4 we next investigated
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948
1943

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the use of acetylenic Grignard reagents. Pridgen2a has shown
that the reaction of Grignard reagents with 2-aryl-1,3-oxazol-
idines requires 2.5–3 equivalents of Grignard reagent, presum-
ably leading to the formation of the Lewis acidic MgBr2. We
therefore treated aminals 3a–f with an excess of the Grignard
reagent derived from trimethylsilylacetylene, in the presence of
BF3ؒEt2O (Scheme 3), to give the required ring opened alcohols
4a–f in good yields (Table 2). Surprisingly, the 2-benzyl aminal
3g failed to give any of the required product, giving only
decomposition products. This may be due to deprotonation at
the benzylic position by the Grignard reagent, leading to elim-
ination giving unknown by-products. This problem is probably
enhanced by the relatively high temperatures required for the
reaction.
Removal of the chiral directing group to give chiral propargyl
amines
It was envisaged that removal of the chiral auxiliary could be
effected by oxidation of the ring opened alcohol to the aldehyde
followed by a retro-Michael β-elimination to reveal the required
amine. Having introduced the acetylenic moiety, it was import-
ant that the chiral auxiliary could be removed without
damaging both the triple bond and the new chiral centre; it
was therefore desirable that strongly oxidising, basic or acidic
conditions be avoided.
Me
BocN
OL.A.
The Parikh–Doering variant16 of the Swern reaction gave
smooth conversion of the alcohols to the aldehydes 7a–f. All
attempts to remove the chiral directing group under basic con-
ditions12 were unsuccessful, as was treatment with piperidinium
acetate17 or acidic ion exchange resin. However, reaction of
7a–f with aqueous 2 M HCl in THF at reflux for 3 hours
allowed smooth cleavage of the auxiliary (Scheme 4), with con-
Me
Boc
TiCl4 or
SnBr4
N
O
3a
6
Me3Si
SiMe3
H2O
Me
BocN
OH
Me
BocN
R
CHO
CHO
(i)
Me
OH
R
TMS
TMS
BocHN
4a-f
7a-f
Scheme 2
(ii), (iii)
Me
BocN
Me
BocN
OH
(i)
O
NHMTPA
NHBoc
(iv), (v)
R
R
R
R
TMS
TMS
TMS
4a-f
3a-g
8a-e
5a-f
a R = cyclohexyl e R = ((CH3)2CH)3SiOCH2CH2CH2CH2CH2
4a, 5a, 7a, 8a R = cyclohexyl
4b, 5b, 7b, 8b R = n-hexyl
4c, 5c, 7c, 8c R = n-propyl
4d, 5d, 7d, 8d R = iso-propyl
b R = n-hexyl
c R = n-propyl
d R = iso-propyl
f R = ((CH3)2CH)3SiOCH2CH2CH2
g R = CH2Ph
4e, 7e R = ((CH3)2CH)3SiOCH2CH2CH2CH2CH2
4f, 7f R = ((CH3)2CH)3SiOCH2CH2CH2
5e, 8e R = HOCH2CH2CH2CH2CH2
5f R = HOCH2CH2CH2
᎐
Scheme 3 Reagents and conditions: (i) Me3SiC᎐CMgBr (4 equiv.),
᎐
BF3ؒOEt2 (1.2 equiv.), THF, 30 ЊC, 45 min.
Table 1
Scheme 4 Reagents and conditions: (i) DMSO, Et3N, SO3ؒpyridine,
THF, N2, 45 min; (ii) HCl (2 M), reflux, 3 h; (iii) Et3N, (tBuOCO)2O,
CH2Cl2, 0 ЊC, 18 h; (iv) CF3COOH, MeOH; (v) pyridine, (S)-MTPA-
Cl, CH2Cl2, rt, 1 h.
Lewis
acid
Yield
(%)
Aminal
Nucleophile
Reference
᎐
3a
3a
3a
3a
3a
TMSC᎐CLi
TiCl4
BF3ؒEt2O
SnCl4
5
—
9
13
14
15
᎐
comittant removal of the TIPS group from 7e and 7f. The
amine hydrochloride salts were immediately reprotected as their
Boc derivatives (5a–f), as unprotected propargyl amines have
been shown to be unstable and prone to decomposition.18 The
ee of 5a–e were measured by removal of the Boc group
and conversion to the (S)-Mosher’s amides 8a–e (Table 2).19
0a
0a
0b
0b
᎐
TMSC᎐CLi
᎐
᎐
TMSC᎐CH
᎐
Ϫ
ϩ
᎐
(TMSC᎐C) (AlMe3Li)
—
᎐
᎐
TMSC᎐CSnMe3
BF3ؒEt2O
᎐
a Starting material was consumed. b Starting material was recovered.
Table 2
Aminal
de (%)5
Alcohol
Yield (%)
Boc amine
Yield (%)
Mosher’s amide
ee (%)
3a
3b
3c
3d
3e
3f
96
72
72
78
80
100
100
4a
4b
4c
4d
4e
4f
65
63
63
48
55
46
—
5a
5b
5c
5d
5e
5f
69
65
46
60
31
77
—
8a
8b
8c
8d
8e
11
—
40
60
64
86
95
52
—
3g
—
—
1944
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948

View Article Online
Propargyl amine 5f was converted to phthalimide 9 prior to
forming the (S)-Mosher’s amide 10 (Scheme 5).
tetrahydro-2H-1,3-oxazines by Grignard reagents showed un-
ambiguously that attack occurred from the face of the nitrogen
atom, in an SN2-manner.4b An equivalent stereochemical out-
come was also reported by Takahashi for the ring-opening of
N-methyl-1,3-oxazolidines by various organometallics, possibly
indicating a similar mechanism.3 By contrast, Pridgen showed
that the ring-opening of 1,3-oxazolidines without substituents
on the nitrogen atom resulted in the opposite stereochemistry at
the newly formed chiral centre;2a this was attributed to equili-
bration of the 1,3-oxazolidine to the tautomeric imino alcohol,
followed by attack of the nucleophile to a highly ordered,
chelation complex resulting from the imino alcohol. The
hypothesis that these unsubstituted 1,3-oxazolidines react via
the imino alcohol is reinforced by studies on related imino
ethers by Takahashi,3c in which the stereochemical outcome is
identical to that reported by Pridgen and opposite to that seen
for the N-methyl-1,3-oxazolidines.
As the ring-opening reactions reported in this paper give
the opposite stereochemistry to that reported by Pedrosa, and
in addition, require an excess of the Grignard reagent, it is
reasonable to assume that the reactions proceed via initial ring-
opening to give an iminium ion, in line with the results reported
by Pridgen. Furthermore, as the presence of one equivalent of
BF3ؒEt2O is essential for ring opening to occur, it is possible
NHBoc
O
(i)
NHR
HO
N
TMS
O
TMS
5f
9 R = Boc
10 R = MTPA
(ii), (iii)
Scheme 5 Reagents and conditions: (i) Ph3P, DEAD, phthalimide,
THF, N2, 18 h; (ii) CF3COOH, MeOH; (iii) pyridine, (S)-MTPA-Cl,
CH2Cl2, rt, 1 h.
Assignment of stereochemistry at the newly formed chiral centre
Assignment of the dominant absolute stereochemistry at
the newly formed chiral centre of the amines 5a–f was achieved
by correlation to literature compounds. Amine 5d was treated
with 6 M HCl in order to remove the TMS and Boc groups;
reprotection with Boc gave 11 in low yield. Comparison of the
optical rotation with the literature values for this compound20
indicated that the predominant enantiomer was the (R)-form.
O
that the reacting species is either an alkynylboron, for example,
᎐
M = TMSC᎐CBF , or an alkynylboronate, for example, M =
Ph
᎐
2
NHBoc
HN
ϩ
TMSC᎐CBF MgBrϪ. This would therefore lead us to con-
᎐
᎐
3
OMe
sider some form of co-ordination mechanism, where the in-
coming nucleophile would be delivered by the oxygen to the
iminium ion formed via initial ring opening. If this were the
case then either conformer A (the immediate product of ring-
opening) or conformer B (arising from rapid equilibration to
the most stable allylic conformation)22 would furnish the
observed major diastereomer (Scheme 7). A mechanism where
(R)-11
(R, S)-12
For confirmation, amine 5c was also deprotected with 6 M HCl,
and the resulting amine converted to the mandelamide 12 with
(S)-(ϩ)-α-methoxyphenylacetic acid. Comparison of the
optical rotation of 12 with the literature value21 again indicated
that the predominant enantiomer of amine 5c was the (R)-
form.
R
Me
BocHN
R
N
H
H
MO
TMS
Boc
A
Mechanism of ring opening
Boc
Two factors control the stereochemistry of the newly formed
chiral centre of the amines 5a–f: the configuration of the chiral
centre at C2 of the N-(Boc)-tetrahydro-2H-1,3-oxazines, and
the direction of attack of the incoming nucleophile during the
reaction with the Grignard reagents. The configuration at C2 is
known from the structural work described in the preceding
paper.5 The absolute stereochemistry of the amines described
above, therefore, enables us to predict that the nucleophile pre-
dominantly attacks from the face of the oxygen atom, rather
than the face of the nitrogen atom (Scheme 6).
BocHN
R
Me
N
R
MO
H
H
TMS
TMS
B
BocHN
R
H
Me
N
H
R
MO
Boc
C
Previous work by Pedrosa on the ring-opening of N-benzyl-
Scheme 7
Me
BF3ؒEt2O alone is acting as the Lewis acid and then directing
the nucleophile by chelation is less likely, due to saturation of
the coordination sphere of boron. Although the minor enan-
tiomer could be accounted for by ring-opening of the minor
tetrahydrooxazine diastereoisomer C (Scheme 7), the de of the
tetrahydrooxazine appears to be unrelated to the ee of the
resulting amine (Table 2).5 This may suggest equilibration
between major and minor tetrahydrooxazine diastereoisomers
during the course of the reaction, or some other factor may be
operational. Further studies, to elucidate the mechanism of this
novel ring-opening reaction and to increase the enantioselectiv-
ity, are ongoing.
R
H
N
Boc
O
H
X
attack from
attack from
oxygen face
nitrogen face
(SN2)
Me3Si
OH
C
C
OH
BocN
BocN
H
H
R
R
SiMe3
SiMe3
predominant isomer
Experimental
Unless otherwise indicated, reagents were obtained from com-
mercial suppliers and were used without further purification.
Scheme 6
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948
1945

View Article Online
᎐
THF was distilled from sodium–benzophenone. CH2Cl2 was
distilled from P2O5 and stored over 4 Å molecular sieves.
DMSO, triethylamine and pyridine were distilled from CaH2
and stored over 4 Å molecular sieves. Hexane is described as the
fraction boiling between 67–70 ЊC unless otherwise stated.
Flash column chromatography23 was carried out using silica gel
(particle size 40–63 mm) purchased from BDH. NMR spectra
were recorded on Bruker AC 250 and Bruker AC 300 spectro-
ane); νmax (CHCl3)/cmϪ1 3456 (O–H), 2963, 2934, 2171 (C᎐C),
᎐
1682 (C᎐O), 1251 (R–SiMe ); δ (250 MHz; CDCl ) 0.10 (9H, s,
᎐
3
H
3
Si(CH3)3), 0.89 (3H, t, J 7.2, CH3CH2), 1.25–1.67 (4H, m, ali-
phatic), 1.28 (3H, d, J 6.8, CH3CH2), 1.44 (9H, s, C(CH3)3),
1.70–1.95 (3H, m, CH2CH2OH and CH3CH), 3.49–3.65 (3H,
᎐
m, CH CH OH and CHC᎐C); δ (75 MHz; CDCl3) 0.0,
᎐
2
2
C
13.8, 19.3, 19.9, 28.3, 28.6, 32.5, 37.6, 48.5, 60.5, 80.4, 105.3,
155.7; m/z (FAB) 342.2450 (M ϩ 1ϩ. C18H36NO3Si requires
342.2464) (ESϩ), 342 (M ϩ 1, 9%), 286 (M Ϫ tBu, 100%), 242
(M Ϫ Boc, 94%).
1
meters operating at 250 and 300 MHz for H; 75 and 90 MHz
for 13C and 392 and 325.8 MHz for 19F. Chemical shift (δ) values
are measured in parts per million relative to the residual
(undeuterated) solvent peak as an internal standard for 1H and
13C and relative to CFCl3 for 19F. J-Values are measured in Hz.
Nominal and high resolution mass spectra were taken on a VG
ZAB-SE spectrometer with sources for FAB and EIϩ. IR spec-
tra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer.
Optical rotations of chiral compounds were measured on a
JASCO 600 spectrophotometer and an Optical Activity
POLAAR 2000 polarimeter using sucrose as a standard and are
given in units of 10Ϫ1 deg cm2 gϪ1. All rotations were taken as
solutions in CHCl3 unless otherwise stated.
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
isopropylprop-2-ynyl]amino}butan-1-ol 4d. 48% (viscous yellow
oil); [α]D ϩ16.85 (c 5.5 mg cmϪ3); RF 0.23 (20% EtOAc in hex-
ane); νmax (CHCl3)/cmϪ1 3456 (O–H), 2967, 2172 (C᎐C), 1682
᎐
᎐
(C᎐O), 1250 (R–SiMe ); δ (300 MHz; CDCl3) 0.09 (9H, s,
Si(CH3)3), 0.84 (3H, d, J 6.7, (CH3)2CH), 0.98–1.01 (3H, m,
(CH3)2CH), 1.28 (3H, d, J 6.7, CH3CH), 1.42 (9H, s, (CH3)3C),
1.81–2.18 (3H, m, (CH3)2CH and CH2CH2OH), 3.41–3.85
(4H, m, CH CH OH and CHC᎐C and CH CH); δ (75 MHz;
CDCl3) Ϫ0.3, 19.4, 19.7, 20.7, 28.3, 32.2, 37.1, 47.6, 55.7, 58.6,
79.8, 84.8, 105.6, 155.6; m/z (FAB) 342.2450 (M ϩ 1ϩ.
C18H35NO3Si requires 342.2464), 342 (M ϩ 1, 40%), 241
(M Ϫ Boc, 70%), 198 (100%).
᎐
3
H
᎐
᎐
2
2
3
C
General procedure for the ring-opening of tetrahydro-2H-1,3-
oxazines 3a–f
To a stirred solution of EtMgBr (3 M in THF, 0.79 ml, 2.4
mmol) in anhydrous THF (2.5 ml) at 0 ЊC under N2 was added
trimethylsilylacetylene (0.33 ml, 2.42 mmol, 4.03 equiv.). A
brown precipitate was formed which dissolved on heating to
30 ЊC. After 15 min a solution of the appropriate tetrahydro-
2H-1,3-oxazine 3 (0.6 mmol) in THF (0.5 ml) was added, fol-
lowed by BF3ؒEt2O (0.1 ml, 0.7 mmol, 1.17 equiv.). After 45 min
the reaction was quenched with saturated NH4Cl solution (5
ml) and extracted with EtOAc (3 × 25 ml). The combined
organic layers were dried over Na2SO4 and the solvents
removed in vacuo to give a viscous brown oil. Flash column
chromatography over silica using the eluants indicated gave the
required compounds.
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
(5-triisopropylsilyloxy-pentyl)prop-2-ynyl]amino}butan-1-ol 4e.
55% (viscous yellow oil); [α]D ϩ15.7 (c 3.89 mg cmϪ3); RF 0.23
(20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3457 (O–H), 2940,
᎐
2866, 2172 (C᎐C), 1682 (C᎐O), 1250 (R–SiMe ), 1113 (RO–Si);
᎐
᎐
3
δH (300 MHz; CDCl3) 0.12 (9H, s, Si(CH3)3), 1.03 (21H, s,
OSi(CH(CH3)2)3), 1.10–1.59 (8H, m, aliphatic), 1.30 (3H, d,
J 6.9, CH3CH), 1.44 (9H, s, (CH3)3C), 1.60–2.05 (3H, m,
CH2CH2OH and CH3CH), 3.52–3.74 (3H, m, CH2CH2OH and
᎐
CHC᎐C), 3.64 (2H, t J 7.0, CH OSi), 4.12 (1H, br s, OH);
᎐
2
δC (75 MHz; CDCl3) Ϫ0.18, 11.92, 17.94, 19.05, 25.27, 25.33,
26.40, 28.44, 32.82, 35.28, 47.44, 48.34, 63.16, 80.20, 105.15,
᎐
155.43, either 1 × C᎐C or (CH ) CO missing; m/z (FAB)
᎐
3
3
564.3860 (M ϩ Naϩ. C29H59NO4Si2Na requires 564.3880), 564
(M ϩ Na, 12%), 442 (M Ϫ Boc, 100%).
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
cyclohexylprop-2-ynyl]aminobutan-1-ol 4a. 65% (viscous yel-
low oil); [α]D ϩ28.2 (c 4.89 mg cmϪ3); RF 0.20 (20% EtOAc in
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
(3-triisopropylsilyloxypropyl)prop-2-ynyl]amino}butan-1-ol 4f.
46% (yellow oil); [α]D ϩ16.9 (c 7.5 mg cmϪ3); RF 0.27 (20%
hexane); νmax (CHCl3)/cmϪ1 3620 (O–H), 3020, 2153 (C᎐C),
᎐
᎐
1677 (C᎐O), 1271 (R–SiMe ); δ (250 MHz; CDCl ) 0.18 (9H, s,
᎐
3
H
3
Si(CH3)3), 1.10–1.20 (3H, m, cyclohexyl), 1.21–1.30 (2H, m,
cyclohexyl), 1.38 (3H, d, J 6.8, CH3CH), 1.47 (9H, s, C(CH3)3),
EtOAc in hexane); νmax (CHCl3)/cmϪ1 3471 (O–H), 2943, 2867,
᎐
2172 (C᎐C), 1693 (C᎐O), 1250 (R–SiMe ), 1114 (RO–Si);
᎐
᎐
3
1.61–1.81 (6H, m, cyclohexyl), 1.98–2.12 (3H, m, CH2CH2OH
δH (300 MHz; CDCl3) 0.19 (9H, s, Si(CH3)3), 1.14 (21H, s,
OSi(CH(CH3)2)3), 1.28–1.35 (2H, m, aliphatic), 1.33 (3H, d,
᎐
and CH CH), 3.52–3.74 (3H, m, CH CH OH and CHC᎐C);
᎐
3
2
2
δC (75 MHz; CDCl3) 0.4, 20.3, 27.0, 29.2, 30.8, 32.1, 38.0, 42.4,
50.2, 55.5, 60.4, 61.3, 80.7, 81.4, 156.3; m/z (FAB) 382.2760
(M ϩ 1ϩ. C21H40NO3Si requires 382.2777), 382 (M ϩ 1, 33%),
326 (M Ϫ tBu, 94%), 282 (M Ϫ Boc, 100%).
J 6.8, CH3CH), 1.52 (9H, s, (CH3)3C), 1.57–1.81 (2H, m, CH2-
᎐
CHC᎐C), 1.98–2.01 (3H, m, CH CH OH and CH CH), 3.57–
᎐
2
2
3
᎐
3.67 (2H, m, CH CH OH), 3.70–3.81 (3H, m, CHC᎐C and
᎐
2
2
CH2OSi); δC (75 MHz; CDCl3) Ϫ0.18, 11.92, 17.94, 19.05,
26.40, 28.44, 32.82, 35.28, 47.44, 48.34, 62.77, 80.15, 104.95,
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
hexylprop-2-ynyl]amino}butan-1-ol 4b. 63% (viscous yellow oil);
[α]D ϩ23.4 (c 3.98 mg cmϪ3); RF 0.23 (20% EtOAc in hexane);
t
᎐
155.48, either 1 × C᎐C or BuCO missing; m/z (FAB) 536.3580
᎐
(M ϩ Naϩ. C27H55NO4Si2Na requires 536.3567), 536 (M ϩ Na,
11%), 414 (M Ϫ Boc, 100%).
νmax (CHCl3)/cmϪ1 3456 (O–H), 2960, 2930, 2172 (C᎐C), 1682
᎐
᎐
(C᎐O), 1250 (R–SiMe ); δ (300 MHz; CDCl3) 0.13 (9H, s,
᎐
3
H
General procedure for the synthesis of Boc-protected amines 5a–f
Si(CH3)3), 0.87 (3H, m, CH3CH2), 1.19–1.30 (10H, m, ali-
phatic), 1.28 (3H, d, J 6.8, CH3CH), 1.45 (9H, s, C(CH3)3),
1.48–1.95 (3H, m, CH2CH2OH and CH3CH), 3.59–3.76 (3H,
To a solution of alcohol 4 (1.94 mmol) in anhydrous THF (1.5
ml) under N2 were added DMSO (13 ml) and triethylamine
(1.94 ml). The SO3ؒpyridine complex (5.82 mmol; 3 equiv.)
was added over 10 min. The reaction was stirred for 45 min,
after which it was cooled to 0 ЊC, acidified with HCl (1 M; ca.
pH = 4) and extracted with EtOAc–hexane (1:1; 3 × 20 ml).
The combined organic layers were washed with water (40 ml)
and dried over Na2SO4. The solvents were removed in vacuo
to give a clear oil. Column chromatography gave the desired
aldehyde as a clear oil.
᎐
m, CH CH OH and CHC᎐C); δ (90 MHz; CDCl ) Ϫ0.2, 13.9,
᎐
2
2
C
3
19.1, 22.4, 26.4, 28.4, 31.6, 35.1, 37.0, 47.4, 48.3, 58.6, 59.4,
80.1, 80.7, 105.2, 155.4; m/z (FAB) 384.2950 (M ϩ 1ϩ. C21H42-
NO3Si requires 384.2934) (ESϩ), 384 (M ϩ 1, 10%), 328
(M Ϫ tBu, 100%), 284 (M Ϫ Boc, 16%).
(3S)-3-{N-(tert-Butoxycarbonyl)-N-[(1R)-3-trimethylsilyl-1-
propylprop-2-ynyl]amino}butan-1-ol 4c. 63% (viscous yellow
oil); [α]D ϩ37.4 (c 4.55 mg cmϪ3); RF 0.21 (20% EtOAc in hex-
To a solution of the aldehyde (0.08 mmol) in THF (0.5 ml)
1946
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948

View Article Online
was then added HCl (2 M; 1.5 ml). The solution was heated at
reflux for 3 hours, whereupon a brown precipitate was seen to
form and TLC indicated the complete consumption of starting
material. The solvents were removed in vacuo to give an off-
white solid. This was dissolved in CH2Cl2 (1 ml) and cooled to
0 ЊC. Triethylamine (0.03 ml, 0.2 mmol, 2.53 equiv.) was added
followed by a solution of di-tert-butyl dicarbonate (52.3 mg,
0.24 mmol, 3.0 equiv.) in CH2Cl2 (0.5 ml). The mixture was
stirred overnight, then poured into water (2 ml) and extracted
with CHCl3 (3 × 2 ml). The combined organic layers were dried
over Na2SO4 and the solvent removed in vacuo to give a yellow
oil. Flash column chromatography over silica using the eluants
indicated gave the required product. Yields are quoted over 3
steps.
The ee’s of the Boc-protected amines 5a–e were determined
by conversion to the Mosher’s amides, as follows. To a solution
of 5 (1 mmol) in wet methanol (0.7 ml) was added trifluoro-
acetic acid (7 ml). The mixture was stirred until no starting
material was detectable by TLC. Et2O (10 ml) was added and
the solvents were removed in vacuo to give an off-white solid.
The solid was dissolved in CH2Cl2 (3 ml) and the solution was
cooled to 0 ЊC. Pyridine (6 ml) was added followed by (S)-
methoxytrifluoromethylphenylacetyl chloride (0.24 ml, 1.4
mmol, 1.4 equiv.). The mixture was stirred for 1 h, then poured
into saturated NaHCO3 solution (5 ml) and extracted with
CH2Cl2 (3 × 5 ml). The combined organic layers were dried over
Na2SO4 and the solvents removed to give the required Mosher’s
amides 8a–e.
missing; m/z (FAB) 270.1870 (M ϩ Hϩ. C14H28NO2Si requires
270.1889), 270 (M ϩ 1, 9%), 256 (80%), 214 (100%).
Mosher’s amide derivative. δH (300 MHz; CDCl3) 0.15 (9H,
s, Si(CH3)3), 0.89–0.98 (3H, m, CH2CH3), 1.44–1.65 (4H, m,
CH2CH2CH3 and CH2CH2CH3), 3.56 (3H, s, OCH3), 4.80 (1H,
᎐
m, CHC᎐C), 7.31–7.44 (5H, m, Ph); δ (325.8 MHz; CDCl3)
᎐
F
Ϫ69.07 (82%), Ϫ69.22 (18%).
(3R)-N-(tert-Butoxycarbonyl)-1-trimethylsilyl-4-methylpent-
1-yn-3-ylamine 5d. 60% (viscous oil); [α]D ϩ18.6 (c 5.15 mg
cmϪ3); RF 0.50 (20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3448
᎐
(N–H), 2963, 2930, 2254 (C᎐C), 1708 (C᎐O), 1250 (R–SiMe );
᎐
᎐
3
δH (300 MHz; CDCl3) 0.14 (9H, s, Si(CH3)3), 0.95 (6H, d, J 6.9,
CH(CH3)2), 1.44 (9H, s, C(CH3)3), 1.87 (1H, octet, J 6.6,
᎐
CH(CH ) ), 4.29 (1H, m, CHC᎐C), 4.77 (1H, br s, NH); δ (75
᎐
3
2
C
MHz; CDCl3) Ϫ0.2, 17.3, 18.6, 28.2, 33.0, 49.2, 88.1, 103.8,
154.8; m/z (FAB) 270.1880 (M ϩ Hϩ. C14H28NO2Si requires
270.1889), 270 (M ϩ 1, 14%), 214 (100%), 170 (M Ϫ Boc, 75%).
Mosher’s amide derivative. δH (300 MHz; CDCl3) 0.21 (9H,
s, Si(CH3)3), 1.01 (6H, d, J 7.0, CH(CH3)2), 2.01 (1H, m,
᎐
CH(CH ) ), 3.62 (3H, s, OCH ), 4.66 (1H, m, CHC᎐C), 7.35–
᎐
3
2
3
7.69 (5H, m, Ph); δF (325.8 MHz; CDCl3) Ϫ76.29 (93%),
Ϫ76.32 (7%).
(6R)-6-[(tert-Butoxycarbonyl)amino]-8-trimethylsilyloct-7-
yn-1-ol 5e. 31% (viscous oil); [α]D ϩ36.7 (c 1.2 mg cmϪ3); RF
0.27 (20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3620 (O–H),
᎐
3450 (N–H), 2961, 2929, 2254 (C᎐C), 1708 (C᎐O), 1250 (R–
᎐
᎐
SiMe3); δH (300 MHz; CDCl3) 0.16 (9H, s, Si(CH3)3), 1.41 (9H,
(1R)-N-(tert-Butoxycarbonyl)-3-(trimethylsilyl)-1-cyclohexyl-
prop-2-yn-1-ylamine 5a. 69% (viscous oil); [α]D ϩ35.9 (c 2.9 mg
s, C(CH3)3), 1.49–1.70 (6H, m, aliphatic), 1.78–1.82 (2H, m,
᎐
CH CHC᎐C), 3.50 (1H, br s, OH), 3.58 (2H, t, J 6.5, CH OH),
᎐
2
2
cmϪ3); RF 0.52 (20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3619
᎐
4.34 (1H, m, CHC᎐C), 4.92 (1H, br d, J 8.2, NH); δ (75 MHz;
᎐
C
᎐
(N-H), 3020, 2931, 2171 (C᎐C), 1679 (C᎐O), 1215; δ (300
᎐
᎐
H
CDCl3) Ϫ0.2, 25.1, 28.3, 32.5, 36.0, 36.4, 43.3, 62.6, 70.9, 105.3,
154.8; m/z (FAB) 314.2140 (M ϩ Hϩ. C16H32NO3Si requires
314.2151), 314 (M ϩ 1, 15%), 258 (100%), 214 (M Ϫ Boc,
30%).
Bis-Mosher’s amide derivative. δH (300 MHz; CDCl3) 0.18
(9H, s, Si(CH3)3), 1.47–1.53 (6H, m, aliphatic), 1.65–1.82 (2H,
MHz; CDCl3) 0.17 (9H, s, Si(CH3)3), 1.00–1.41 (6H, m, cyclo-
hexyl), 1.46 (9H, s, C(CH3)3), 1.62–1.93 (5H, m, cyclohexyl),
᎐
4.35 (1H, m, CHC᎐C), 4.72 (1H, m, NH); m/z (FAB) 332.2010
᎐
(M ϩ Naϩ. C17H31NO2SiNa requires 332.2022), 308.2030
(M Ϫ Hϩ. C17H30NO2Si requires 308.2046) 332 (M ϩ Na), 308
(M Ϫ 1).
m, aliphatic), 3.66 (6H, s, OCH3), 4.35 (2H, t, J 8.0, CH2OH),
Mosher’s amide derivative. δH (300 MHz; CDCl3) 0.14 (9H, s,
᎐
4.76 (1H, m, CHC᎐C), 7.30–7.67 (10H, m, Ph); δ (325.8 MHz;
᎐
F
CDCl3) {Ϫ75.20 (95%), Ϫ75.26 (5%)} (C1F3), Ϫ75.88 (100%)
Si(CH3)3), 1.40–1.78 (11H, m, cyclohexyl), 3.56 (3H, s, OCH3),
᎐
(C2F3).
4.78 (1H, m, CHC᎐C), 7.38–7.48 (5H, m, Ph); δ (325.8 MHz;
᎐
F
CDCl3) Ϫ69.13 (60%), Ϫ69.19 (40%).
(4R)-4-[(tert-Butoxycarbonyl)amino]-6-trimethylsilylhex-5-
yn-1-ol 5f. 77% (viscous oil); [α]D ϩ11.7 (c 62 mg cmϪ3); RF 0.25
(3R)-N-(tert-Butoxycarbonyl)-1-(trimethylsilyl)non-1-yn-3-yl-
amine 5b. 65% (viscous oil); [α]D ϩ23.0 (c 5 mg cmϪ3); RF 0.53
(20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3621 (O–H), 3448
(20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3448 (N–H), 2961,
᎐
(N–H), 2961, 2929, 2254 (C᎐C), 1708 (C᎐O), 1250 (R–SiMe );
᎐
᎐
3
᎐
2929, 2254 (C᎐C), 1708 (C᎐O), 1250 (R–SiMe ); δH (300 MHz;
᎐
᎐
3
δH (300 MHz; CDCl3) 0.14 (9H, s, Si(CH3)3), 1.44 (9H, s,
C(CH3)3), 1.60–1.80 (4H, m, CH2CH2CH2OH and CH2CH2-
CDCl3) 0.18 (9H, s, Si(CH3)3), 0.92 (3H, t, J 7.0, CH2CH3),
1.23–1.40 (4H, m, CH2CH2CH3 and CH2CH2CH3), 1.49 (9H,
CH2OH), 2.10 (1H, br s, OH), 3.61–3.78 (2H, m, CH2OH),
s, C(CH3)3), 1.58–1.62 (6H, m, CH aliphatic), 4.41 (1H, m,
᎐
4.43 (1H, m, CHC᎐C), 4.88 (1H, br d, J 6.2, NH); δ (75
᎐
C
᎐
CHC᎐C), 4.70 (1H, br s, NH); δ (75 MHz; CDCl3) 0.0,
᎐
C
MHz; CDCl3) Ϫ0.4, 27.6, 32.4, 47.5, 64.3, 66.4, 81.7, 104.6,
154.6; m/z (FAB) 286.1850 (M ϩ Hϩ. C14H28NO3Si requires
286.1838), 308 (M ϩ Na, 20%), 286 (M ϩ 1, 25%), 230 (100%),
186 (M Ϫ Boc, 30%).
13.7, 14.1, 18.9, 22.6, 25.6, 28.4, 28.2, 29.8, 31.7, 36.5, 105.8,
154.7; m/z (FAB) 312.2370 (M ϩ Hϩ. C17H34NO2Si requires
312.2359), 312 (M ϩ 1, 10%), 256 (100%).
Mosher’s amide derivative. δH (300 MHz; CDCl3) 0.14 (9H, s,
Si(CH3)3), 0.84–0.94 (3H, m, CH2CH3), 1.20–1.38 (6H, m, ali-
(3R)-N-(tert-Butoxycarbonyl)-1-(trimethylsilyl)-6-phthalimido-
hex-1-yn-3-ylamine 9
phatic), 1.53–1.72 (4H, m, aliphatic), 3.56 (3H, s, OCH3), 4.80
᎐
(1H, m, CHC᎐C), 7.41–7.52 (5H, m, Ph); δ (325.8 MHz;
᎐
F
CDCl3) Ϫ69.07 (80%), Ϫ69.22 (20%).
To a solution of (4R)-4-[(tert-butoxycarbonyl)amino]-6-tri-
methylsilylhex-5-yn-1-ol 5f (0.135 g, 0.5 mmol), triphenyl-
phosphine (0.150 g, 0.55 mmol, 1.1 equiv.) and phthalimide
(0.082 g, 0.55 mmol, 1.1 equiv.) in THF (5 cm3) was added
diethyl azodicarboxylate (0.11 cm3, 0.66 mmol, 1.32 equiv.)
dropwise over 5 min. The mixture was stirred overnight (16 h)
and then the solvents were removed in vacuo. Column chrom-
atography (silica gel; 50% EtOAc in hexane; RF 0.68) gave the
title compound as a pale yellow solid (0.122 g; 60%); [α]D ϩ12.7
(3R)-N-(tert-Butoxycarbonyl)-1-(trimethylsilyl)hex-1-yn-3-
ylamine 5c. 46% (viscous oil); [α]D ϩ25.2 (c 4.7 mg cmϪ3); RF
0.50 (20% EtOAc in hexane); νmax (CHCl3)/cmϪ1 3448 (N–H),
᎐
2963, 2931, 2254 (C᎐C), 1708 (C᎐O), 1250 (R–SiMe ); δ (300
᎐
᎐
3
H
MHz; CDCl3) 0.18 (9H, s, Si(CH3)3), 0.97 (3H, t, J 7.0,
CH2CH3), 1.23–1.36 (2H, m, CH2CH2CH3), 1.45 (9H, s,
C(CH3)3), 1.58–1.65 (2H, m, CH2CH2CH3), 4.40 (1H, m,
CHC᎐C), 4.70 (1H, br s, NH); δ (75 MHz; CDCl3) 0, 13.70,
(c 39 mg cmϪ3); νmax (CHCl3)/cmϪ1 3619 (N–H), 3020, 2400
᎐
᎐
C
t
᎐
᎐
18.93, 28.43, 31.75, 67.16, 105.76, 154.68 BuCO and 1 × C᎐C
(C᎐C), 1711 (C᎐O), 1520 (C᎐C, Ar), 1216 (R–SiMe ); δ (300
᎐
᎐
᎐
᎐
3
H
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948
1947

View Article Online
MHz; CDCl3) 0.14 (9H, s, Si(CH3)3), 1.43 (9H, s, C(CH3)3),
m, CH2CH2CH3 and CH2CH2CH3), 2.26 and 2.30 (1H, 2 × d
᎐
᎐
1.63–1.75 (2H, m, C᎐C–CHCH ), 1.78–1.87 (2H, m,
(major and minor diastereoisomers), J 2.3, C᎐CH), 3.38 (3H, s,
᎐
᎐
2
᎐
᎐
CH CH N), 3.73 (2H, t, J 7.0, CH CH N), 4.10 (1H, m, C᎐C–
OCH ), 4.6 (1H, s, CHOCH ), 4.65 (1H, m, C᎐C–CHCH ),
᎐
᎐
2
2
2
2
3
3
2
CHCH2), 4.49 (1H, br s, NH), 7.72 (2H, m, Ph), 7.84 (2H, m,
Ph); δC (75 MHz; CDCl3) Ϫ0.2, 24.9, 28.3, 33.6, 37.5, 43.3, 79.8,
87.9, 104.7, 123.2, 132.1, 133.8, 154.6, 168.2; m/z (FAB)
437.1860 (M ϩ Naϩ. C22H30N2O4SiNa requires 437.1873), 437
(M ϩ Na).
6.90 (1H, br m, NH), 7.25–7.44 (5H, m, Ph).
Acknowledgements
We thank the EPSRC and Merck, Sharp and Dohme for a
CASE Studentship (to A. R.). We also thank Dr Tam Bui,
Dr Giuliano Siligardi and the EPSRC National Chiroptical
and ULIRS Spectroscopy Centres, King’s College London,
for the optical rotation measurements, and the ULIRS Mass
Spectrometry Facility at the University of London School of
Pharmacy for the high resolution mass spectra.
This was converted to the Mosher’s amide 10 by the method
described above; δH (300 MHz; CDCl3) 0.18 (9H, s, Si(CH3)3),
᎐
1.65–1.97 (4H, m, C᎐C–CHCH and CH2CH2N), 3.10–3.15
᎐
2
(2H, m, CH2CH2N), 3.74 (3H, s, OCH3), 4.18 (1H, m, J 8.5,
᎐
C᎐C–CHCH ), 7.30–7.47 (5H, m, Ph), 7.50–7.60 (2H, m, Ph),
᎐
2
7.81–7.90 (2H, m, Ph); δF (392 MHz; CDCl3) Ϫ69.33 (76%),
Ϫ69.45 (24%).
References
Correlation of the stereocentre of Boc-protected amine 5d by
conversion to (3R)-N-(tert-butoxycarbonyl)-4-methylpent-1-yn-
3-ylamine 11
1 D. Enders and U. Reinhold, Tetrahedron: Asymmetry, 1997, 8, 1895.
2 (a) M.-J. Wu and L. N. Pridgen, J. Org. Chem., 1991, 56, 1340;
(b) M. K. Mokhallalati, K. R. Muralidharan and L. N. Pridgen,
Tetrahedron Lett., 1994, 35, 4267.
3 (a) K. Higashiyama, H. Inoue, T. Yamauchi and H. Takahashi,
J. Chem. Soc., Perkin Trans. 1, 1995, 111; (b) K. Higashiyama,
K. Nakagawa and H. Takahashi, Heterocycles, 1995, 41, 2007;
(c) K. Higashiyama, H. Fujikura and H. Takahashi, Chem. Pharm.
Bull., 1995, 43, 722.
4 (a) A. Alberola, C. Andrés and R. Pedrosa, Synlett, 1990, 763; (b)
C. Andrés, J. Nieto, R. Pedrosa and N. Villamañán, J. Org. Chem.,
1996, 61, 4130.
5 A. Rae, A. E. Aliev, J. E. Anderson, J. L. Castro, J. Ker, S. Parsons,
M. Stchedroff, S. Thomas and A. B. Tabor, J. Chem. Soc., Perkin
Trans. 1, preceding paper in this issue.
6 H. Normant and R. Mantione, C. R. Seances Acad. Sci., 1964, 259,
1635.
7 J. Barluenga, P. J. Campos and G. Canal, Synthesis, 1989, 33.
8 M. F. Fegley, N. M. Bortnick and C. H. McKeever, J. Am. Chem.
Soc., 1957, 79, 4140; R. I. Kruglikova, G. R. Kalina, Y. V.
Khaetskaya and G. S. Leonova, J. Org. Chem. USSR (Engl. Transl.),
1966, 2, 1147.
(3R)-N-(tert-Butoxycarbonyl)-1-trimethylsilyl-4-methylpent-1-
yn-3-ylamine 5d (2.9 mg, 0.011 mmol) was suspended in aque-
ous HCl (6 M; 1 ml) and heated at 100 ЊC for 2 h. The solvent
was removed in vacuo and the white residue was dissolved in
CH2Cl2 (0.4 ml). Triethylamine (0.5 ml) was added followed by
a solution of di-tert-butyl dicarbonate (7.2 mg, 0.033 mmol,
3 equiv.) in CH2Cl2 (0.1 ml). The mixture was stirred for 24 h,
after which the solvents were removed in vacuo. The residue was
purified by column chromatography (silica gel; 20% EtOAc in
hexane; RF 0.45) to give the title compound as a clear oil (5 mg,
23%), spectroscopically identical with the literature.20 [α]D
ϩ24.0 (c 0.25 mg cmϪ3) [lit., for (S)-N-(tert-butoxycarbonyl)-4-
methylpent-1-yn-3-ylamine20 Ϫ45.3 (c 1.04 mg cmϪ3)]; δH (300
MHz; CDCl3) 0.98 (6H, d, J 6.8, CH(CH3)2), 1.44 (9H, s,
C(CH3)3), 1.89 (1H, octet, J 6.0, CH(CH3)2), 2.25 (1H, d, J 2.4,
᎐
᎐
C᎐CH), 4.31 (1H, m, C᎐C–CHCH ), 4.78 (1H, br s, NH).
᎐
᎐
2
9 M.-J. Wu, D.-S. Yan, H.-W. Tsai and S.-H. Chen, Tetrahedron Lett.,
1994, 35, 5003.
10 P. Renaud and D. Seebach, Angew. Chem., Int. Ed. Engl., 1986, 25,
843.
11 P. A. Jacobi and K. Lee, J. Am. Chem. Soc., 1997, 119, 3409.
12 W. S. Johnson, R. Elliot and J. D. Elliot, J. Am. Chem. Soc., 1983,
105, 2904.
13 M. Yamaguchi, A. Hayashi and M. Hirama, Chem. Lett., 1992,
2479.
14 B. H. Lipshutz and R. Tirado, J. Org. Chem., 1994, 59, 8307.
15 R. Yamaguchi, E. Hata and K. Utimoto, Tetrahedron Lett., 1988,
29, 1785.
16 J. R. Parikh and W. von E. Doering, J. Am. Chem. Soc., 1967, 89,
5505; R. Baker and J. L. Castro, J. Chem. Soc., Perkin Trans. 1, 1990,
47.
17 W. S. Johnson, C. Edington, J. D. Elliot and I. R. Silverman, J. Am.
Chem. Soc., 1984, 106, 7588.
18 P. Meffre, L. Gauzy, E. Branquet, P. Durand and F. Le Goffic,
Tetrahedron, 1996, 52, 11215.
Correlation of the stereocentre of Boc-protected amine 5c by
conversion to (2S)-N-[(3R)-hex-1-yn-3-yl]-2-methoxyphenyl-
acetamide 12
(3R)-N-(tert-Butoxycarbonyl)-1-(trimethylsilyl)hex-1-yn-3-yl-
amine 5c (4.2 mg, 0.016 mmol) was suspended in aqueous HCl
(6 M; 2 ml) and heated at 100 ЊC for 2 h. The solvent was
removed in vacuo to give the hydrochloride salt of the free
amine. To a solution of (S)-(ϩ)-α-methoxyphenylacetic acid
(5.3 mg, 0.032 mmol, 2 equiv.) in anhydrous CH2Cl2 (0.5 ml)
was added triethylamine (0.005 ml, 0.032 mmol, 2 equiv.) and
isobutyl chloroformate (0.004 ml, 0.032 mmol, 2 equiv.). The
mixture was stirred at room temperature for 30 min, and the
hydrochloride salt of the free amine and a further portion of
triethylamine (0.005 ml, 0.032 mmol, 2 equiv.) then added in
anhydrous CH2Cl2 (0.5 ml). The mixture was stirred for 24 h,
after which the solvents were removed in vacuo. The residue was
purified by column chromatography (silica gel; 20% EtOAc in
hexane; RF 0.24) to give the title compound 12 as a white solid
(1.2 mg, 31%), spectroscopically identical with the literature;21
[α]D ϩ47.9 (c 0.48 mg cmϪ3, EtOH) (lit., for N-[(S)-hex-1-yn-3-
19 J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.
20 G. Reginato, A. Mordini, F. Messina, A. Degl’Innocenti and
G. Poli, Tetrahedron, 1996, 52, 10985.
21 B. Ringdahl and R. Dahlbom, Acta Chem. Scand., Ser. B, 1976, 30,
812.
22 R. W. Hoffman, Chem. Rev., 1989, 89, 1841.
23 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
yl]-(R)-2-methoxyphenylacetamide Ϫ141.6 (c 1.0 mg cmϪ3
,
EtOH); δH (300 MHz; CDCl3) 0.90 and 0.99 (3H, 2 × t (major
and minor diastereoisomers), J 7.2, CH2CH3), 1.25–1.65 (4H,
Paper 9/02671A
1948
J. Chem. Soc., Perkin Trans. 1, 1999, 1943–1948