Practical one-step synthesis of ethynylglycine synthon from Garner's aldehyde

Article abstract of DOI:10.1016/S0040-4020(02)00438-6

A simple, efficient and practical synthesis of (R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine (ethynylglycine synthon) is described. The method involves in situ formation of dimethyl 1-diazo-2-oxopropyl phosphonate from dimethyl 2-oxopropyl phosphonate and 4-acetamidobenzene sulfonyl azide and one-pot reaction on Garner's aldehyde. The reaction has been extended to other aminoaldehydes.

Full text of DOI:10.1016/S0040-4020(02)00438-6

TETRAHEDRON
Pergamon
Tetrahedron 58'2002) 5159±5162
Practical one-step synthesis of ethynylglycine synthon from
Garner's aldehyde
a,p
Patrick Meffre, S e bastien Hermann, Philippe Durand, Gianna Reginato and Antonella Riu
a
b
c
c
a
UMR 7573-CNRS, ENSCP, 11 rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France
b
UPR 2301-CNRS, ICSN, F-91198 Gif-sur Yvette, France
Dipartimento di Chimica Organica `Ugo Schiff', Centro CNR di studio per la Chimica e Struttura dei Composti Eterociclici e loro
Applicazioni, Firenze, via della Lastruccia 13, I-50019, Sesto Fiorentino, Italy
c
Received 28February 2002; accepted 22 April 2002
AbstractÐA simple, ef®cient and practical synthesis of 'R)-2,2-dimethyl-3-'tert-butoxycarbonyl)-4-ethynyloxazolidine 'ethynylglycine
synthon) is described. The method involves in situ formation of dimethyl 1-diazo-2-oxopropyl phosphonate from dimethyl 2-oxopropyl
phosphonate and 4-acetamidobenzene sulfonyl azide and one-pot reaction on Garnerꢀs aldehyde. The reaction has been extended to other
aminoaldehydes. q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
problems and conversion to the alkyne using compound 3
requires stronger reaction conditions 't-BuOK, 2788C,
THF). On the other hand, dimethyl 1-diazo-2-oxopropyl
'R)-2,2-dimethyl-3-'tert-butoxycarbonyl)-4-ethynyl-oxazo-
lidine 1a 'ethynylglycine synthon) is a valuable chiral
1
4
phosphonate 4 is easier to prepare and alkyne formation
1
2
synthon. It is easily functionalized: alkylation or acylation
under basic conditions, oxidative homocoupling by CuCl,
'K CO , rt, MeOH) avoids the use of strong bases, low
2 3
1
2
15
temperature and tolerates various functional groups. Using
3
palladium catalysed couplings, hydrostannylation followed
1b
diazophosphonate 3, we obtained alkyne 1a in 60% yield
while using 4 we and others obtained yields ranging
75±80%.
3
by Stille couplings, stannylcupration, silylcupration,
a
3c
4
5
cycloaddition, have been recently reported.
1b,1d,2,3a,8b
Ohira reagent 4 is usually prepared in 80±90% yield accord-
ing to the literature by reaction of dimethyl 2-oxopropyl
phosphonate 5 and potentially explosive tosyl azide
This compound has been prepared from Garnerꢀs aldehyde
2
mediate 'Corey±Fuchs strategy)
6
a either by a two steps sequence via dibromovinyl inter-
'60±80% yield
from 2a) or via direct aldehyde-to-alkyne one-carbon homo-
'TsN ) using NaH in benzene followed by chromatographic
puri®cation.
3
1
0,14
1
a,3b,3c,5,7
1
b,1d,2,3a,8
In an attempt to increase the simplicity, ef®ciency and safety
of the method, we now report that Garnerꢀs aldehyde 2a and
the threonine derivative 2b can be transformed in good
yields to the ethynyloxazolidines 1a and 1b, respectively,
using a safe and ef®cient one-pot multicomponent process.
logation 'diazo strategy).
is known to be milder and compatible with sensitive func-
This latter transformation
1
b,9,10
tionalities
and implies the preparation of the diazo-
phosphonates 3 'Seyferth±Colvin±Gilbert reagent) or 4
1
1
1
2,13
'
Ohira reagent).
Synthesis of diazophosphonate 3 is
lengthy '®ve steps starting from phthalimide) and the
yield of the ®nal step including the vaccum distillation is
not satisfactory. Moreover, this compound presents stability
2. Results and discussion
The method involves in situ formation of dimethyl 1-diazo-
Keywords: ethynyloxazolidine; diazo compounds; aldehydes; alkynes.
Corresponding author. Tel.: 133-1-44-27-67-25; fax: 133-1-43-25-79-
p
2-oxopropyl phosphonate
available dimethyl 2-oxopropyl phosphonate 5
4
from
commercially
and
75; e-mail: patmeffr@ext.jussieu.fr
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'02)00438-6

5160
P. Meffre et al. / Tetrahedron 58 ꢀ2002) 5159±5162
and comparison with literature values. It has been extended
to two other a-amino aldehydes 2cd in yields comparable
with the classical method using prepared diazophosphonate
4
'40%) and with good enantiomeric purity as determined
by NMR analysis of Mosherꢀs derivatives. It offers the
advantage of low cost, safety, ease of manipulation and
could be good way for parallel synthesis.
Scheme 1.
4. Experimental
4.1. General
4-acetamidobenzene sulfonyl azide 6 and clean one-pot
reaction of this intermediate on aldehydes 2 'Scheme 1).
1
6
All solvents and reagents were used as purchased.
Aldehydes 2 are commercially available or are easily
Chloroform was chosen as solvent in the diazophosphonate
formation stage because the sulfonamide formed in the reac-
tion is not soluble in this solvent, decreasing the possible
reaction with the aldehyde in the second stage of the reac-
tion. However, ®ltering sulfonamide before addition of the
aldehyde did not increase the yield. Performing the reaction
at 40±508C diminishes reaction time 'yield is not affected)
but leads to some loss of enantiopurity as observed by opti-
cal rotation measurements. Although the reaction seems to
be slower with 4-acetamidobenzene sulfonyl azide 6
6
synthesized following literature procedures. 4-Acetamido-
benzene sulfonyl azide 6 was prepared according to the
literature.
18a,c
Puri®cations by ¯ash column chromatography
were performed using silica gel 60, 0.04±0.063 mm
230±400 Mesh) 'Merck re: 9385), and TLC using silica
1
7
'
gel 60F254, layer thickness 0.2 mm on aluminum sheets.
Optical rotation were measured on a Perkin±Elmer 241
polarimeter in a 1 cm cell. IR spectra were obtained using
1
13
a Nicolet 205 FT-IR spectrometer. H and C NMR spectra
were recorded on a Bruker AM 200 spectrometer. Chemical
shifts are reported as d values 'ppm) relative to internal
tetramethylsilane.
comparing to TsN , the former was prefered as diazo trans-
3
fert reagent. Being a crystalline solid, it is more convenient
to manipulate, is easier to prepare in a pure form and is
1
8
known to not exhibit impact properties. In fact, prepara-
tion of TsN when performed in ethanol lead to the
1
9
Caution: although 4-acetamido benzenesulfonyl azide
exhibited no impact properties, proper caution should be
exercised with all azide compounds.
3
1
contamination of product with up to 5% ' H NMR) of
ethyl 4-toluene sulfonate.
The reaction has also been extended to two other a-amino
aldehydes 2c and 2d derived from natural occurring phenyl-
alanine and leucine, leading to the corresponding
propargylic amines 1c and 1d, respectively. The latter
compound has been for the ®rst time fully characterized.
In both cases, aldehydes were completely converted into
the corresponding propargylamines which were recovered
in 40% yield after ¯ash chromatography. Parallel experi-
ments showed that yields of ®nal compounds are similar
when the present one-pot procedure is used instead of
isolated diazophosphonate 4. The enantiomeric purity of
4.2. General procedure for the preparation of alkynes 1
from aldehydes 2
In a three-necked round bottomed ¯ask equiped with argon
inlet and outlet and a pressure equalizing dropping funnel
are placed dimethyl 2-oxopropylphosphonate 5 '538mg,
3.2 mmol, 3.4 equiv.) in CHCl '8mL) under an argon
3
atmosphere. The mixture is ef®ciently stirred under argon
at 08C 'ice bath). 4-Acetamido benzene sulfonyl azide 6
'771 mg, 3.2 mmol, 3.4 equiv.) and K CO '453 mg,
2
3
3.3 mmol, 3.5 equiv.) are added in one portion. The mixture
is ef®ciently stirred under argon in an ice-water bath
'temperature ,108C) for 48h 'TLC analysis indicates the
reaction is complete). A ®ne white suspension is formed.
K CO '210 mg, 1.5 mmol, 1.6 equiv.) is added to the reac-
unprecedently reported compound 1d was established as
9
1
2% by H NMR analysis of the diastereomeric Mosher
amides prepared by reaction of 'S)-'1)-a-methoxy-a-
tri¯uoromethyl)phenylacetyl choride 'MTPACl) with the
primary amine in turn obtained by removal of the Boc
'
2
3
tion mixture and a solution of aldehyde 2 '0.95 mmol) in
MeOH '8mL) is added dropwise 'slow addition) to the
reaction mixture, under argon, at 08C 'ice bath). The reac-
tion mixture becomes thick-yellow. After 24 h in an ice-
water bath 'maximum temperature: 108C), TLC examina-
protective group in the presence of Me SiI.
3
tion shows that the reaction is ®nished. Saturated aq. NH Cl
4
solution '25 mL) is added. The biphasic solution obtained is
®ltered in a separatory funnel. The organic phase is washed
with a sat. aq. NH Cl solution '25 mL) then with water
.
4
'
2£25 mL). Each aqueous phase is extracted with CHCl
3
3. Conclusions
'10 mL). The combined organic phase is dried over
Na SO and evaporated. Crude product is puri®ed by silica
2
4
This procedure constitutes an expedious route to alkynes
ab from aldehydes 2ab in good yields '70%) with no
loss of optical purity as determined by optical rotations
gel ¯ash chromatography '10 g, diameter 20 mm, cyclo-
hexane/ethyle acetate 95/5) to obtained pure alkyne 1 as a
clear oil.
1

P. Meffre et al. / Tetrahedron 58 ꢀ2002) 5159±5162
5161
4
.2.1. ꢀR)-2,2-Dimethyl-3-ꢀtert-butoxycarbonyl)-4-ethynyl-
NMR '200 MHz, CDCl ): 'S,S): 3.43 'q, 3H, J ˆ1.3 Hz,
3
H±F
2
0
20
oxazolidine 1a. Yield: 154 mg '72%), [a]D ˆ2998 'c
OCH ) 'major diastereoisomer); 'R,S): 3.46 'q, 3H,
3
1
b
20
3a
0
.96, CHCl ). [lit. [a]D ˆ296.58 'c 1.23, CHCl ), lit.
JH±Fˆ1.3 Hz, OCH ) 'minor diastereoisomer).
3
3
3
2
0
1d
20
D
[
a]D ˆ281.38 'c 2.43, CHCl ), lit. [a] ˆ288.28 'c
3
3
c
20
1
loss of optical purity was observed as determined by optical
.05, CHCl ), lit. [a] ˆ273.58 'c 1.01, CHCl )]. No
4.2.7. Dimethyl 1-diazo-2-oxopropyl phosphonate 4. To a
solution of phosphonate 5 '332 mg, 2 mmol) and TsN
3
3
D
3
rotations measurements of 1a and ent-1a 'see below).
'394 mg, 2 mmol) in acetonitrile '5 mL) at 08C is added
K CO '276 mg, 2 mmol). The mixture is left under stirring
2
3
Alkyne 1a has been fully characterised previously by us and
others and our present data are consistent with those
reported before.
at 08C to rt for 5 h. TLC analysis shows that reaction is
complete. The mixture is evaporated to dryness, triturated
in CHCl and 4-toluene sulfonamide is ®ltered off. Evapora-
3
1
b,3c
tion of the solvent leaves crude diazophosphonate 4 as an oil
'332 mg, 86%). H NMR analysis is consistent with the
1
4.2.2. ꢀS)-2,2-Dimethyl-3-ꢀtert-butoxycarbonyl)-4-ethynyl-
oxazolidine ꢀent-1a). This was synthesized from ent-2a
structure of 4 contaminated with 4-toluene sulfonamide.
Crude 4 is puri®ed by ¯ash chromatography on silica gel
as described in the literature.
on 10 mmol scale using the same procedure. Yield: 1.55 g
'
2
0
14
69%), [a]D ˆ11028 'c 1.02, CHCl3).
4
.2.3. ꢀR,R)-2,2,5-Trimethyl-3-ꢀtert-butoxycarbonyl)-4-
ethynyloxazolidine 1b. This was synthesized from 2b on
mmol scale using the same procedure. Yield: 162 mg
Acknowledgements
1
2
0
'
aldehyde, a longer reaction time '72 h) for second stage may
69%), [a]D ˆ293.18 'c 1.06, CHCl ). In the case of this
We are grateful to Centre National de la Recherche
Scienti®que 'CNRS, France) and Consiglio Nazionale
delle Ricerche 'CNR, Italy) for ®nancial support in this
collaboration.
3
2
be needed. IR 'neat): 2100, 3255 cm ; H NMR '200 MHz,
1 1
CDCl ): 1.35 'd, 3H, Jˆ6.0 Hz, CH CHO), 1.48's, 9H,
3
3
Boc), 1.52, 1.57 '2s, 6H, 2CH ), 2.32 'bs, 1H, CCH), 3.97
3
1
3
'
NMR '50.3 MHz, CDCl ): 18.1 'CH CHO), 24.9, 26.7
m, 1H, CHN), 4.19 'dq, 1H, Jˆ6.0, 7.3 Hz, CH CHO); C
3
3
3
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7
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'
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2
1
1
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3
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1
1
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3
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3
in
1
2
3
1
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1
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1
1
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1
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