A direct catalytic aldol route to protected β-hydroxy-α-amino acids

Article abstract of DOI:10.1055/s-2002-34241

The combination of triethylamine, magnesium(II) perchlorate and bipyridine generates a catalyst system for the efficient combination of ethyl isothiocyanatoacetate and a range of aromatic aldehydes. The products of these reactions are synthetically valuab

Full text of DOI:10.1055/s-2002-34241

LETTER
1625
A Direct Catalytic Aldol Route to Protected -Hydroxy- -amino Acids
A
Direct Catalytic
A
ld
i
ol
R
ou
c
te toProtec
h
ted -Hydrox
a
y- -amino
eAcids l C. Willis,* Vincent J.-D. Piccio
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
E-mail: M.C.Willis@bath.ac.uk
Received 24 June 2002
hol functionality in an oxazolidinethione unit the metal
chelating ability of the products would be reduced
(Scheme 2).
Abstract: The combination of triethylamine, magnesium(II) per-
chlorate and bipyridine generates a catalyst system for the efficient
combination of ethyl isothiocyanatoacetate and a range of aromatic
aldehydes. The products of these reactions are synthetically valu-
able protected -hydroxy -amino acids.
In designing a catalyst we chose to employ a two-compo-
nent system involving the combination of a Lewis acid
and a weak amine base. In doing so we hoped that simple
commercially available components could be combined
to create an effective catalyst system. One important con-
sideration when selecting the individual components to
generate a catalyst system was to avoid the irreversible
complexation of amine and Lewis acid; literature prece-
dent suggested several trialkyl amines should bind revers-
ibly to a range of metal triflate salts and thus generate
active catalysts.6
Keywords: catalysis, amino acids, aldol reaction, Lewis acid
Non-proteinogenic -hydroxy- -amino acids are consti-
tuents in a number of important natural products including
vancomycin, cyclosporine A, the polyoxins and the cyclo-
marins.1 The wide variety of biological properties dis-
played by these important amino acids has resulted in a
variety of syntheses being reported in the literature.2 One
of the most attractive routes to these compounds involves
the direct, catalyst controlled addition of a protected gly-
cine equivalent to an aldehyde fragment (Scheme 1).
We elected to study the addition of the commercially
available ethyl isothiocyanatoacetate 1 to benzaldehyde 2
as our test reaction and evaluated a range of potential cat-
alyst combinations against this system (Table 1). Our ini-
tial reaction conditions involved combining 1.0
equivalent of isothiocyanate-substituted ester 1 with 1.1
equivalents of benzaldehyde in THF at room temperature.
Catalysts generated from Cu(OTf)2, Zn(OTf)2 or
Sn(OTf)2 in combination with Et3N failed to deliver any
of the desired aldol adduct 3, even after extended reaction
times (entries 1–3). However the combination of
Mg(OTf)2 (10 mol%) and Et3N (20 mol%) delivered thio-
oxazolidone 3 in 26% yield (entry 4). Either increasing or
decreasing the amine basicity resulted in lower yields (en-
tries 5 and 6). The use of stoichiometric amounts of both
Mg(OTf)2 and Et3N delivered the desired product in 76%
yield and suggested that poor catalyst turnover may be re-
sponsible for the low yields obtained using sub-stoichio-
metric catalyst loadings (entry 7). Accordingly we
investigated the effect of various additives with the hope
of expediting catalyst release: The addition of isopropanol
or trifluoroethanol increased product yields slightly but
extended reaction times were still required (entries 8 and
O
OH
R2
O
O
catalyst
R1O
+
H
NP2
R1O
R2
NP2
Scheme 1
Several examples of such a bond construction have been
documented, although in the majority of examples a pre-
formed enolate or an enolate equivalent such as an enol si-
lane is employed.3 Imperative in our design of such a
reaction system was the desire to involve the catalyst in
both the formation of the enolate and in the addition of the
enolate to the aldehyde.4 One potential problem in devel-
oping a catalytic variant of the above reaction is that the
amino-alcohol functionality present in the products could
coordinate to any metal catalyst and cause product inhibi-
tion. In an attempt to avoid this issue we chose to use
isothiocyanate substituted esters as our glycine equiva-
lents;5 we reasoned that by incorporating the amino-alco-
O
O
R2
R2
O
NCS
R1O
R1O
O-
R1O
catalyst
+
O
S
N
O
HN
C
S
H
R2
Scheme 2
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1625,1628,ftx,en;D13702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1626
M. C. Willis, V. J.-D. Piccio
LETTER
9).7 Attempts to increase catalyst turnover via silylation of equiv); in order to avoid the formation of byproducts all
the oxazolidinethione resulted in no product formation reactions were conducted at 0 °C in THF.12 The benzalde-
(entry 10).8 Pleasingly, a modest increase in yield (39%) hyde derived adduct was obtained in 84% yield as a 65:35
was observed with the addition of a catalytic amount of mixture of diastereomers in favour of the syn aldol isomer
the ligand bipyridine (entry 11). Using these modified (entry 1). Electron poor aldehydes such as p-NO2- and p-
conditions we chose to vary the metal counterion; both CN-benzaldehydes resulted in good yields of the aldol ad-
MgBr2 and MgI2 performed similarly to Mg(OTf)2, how- ducts with the diastereoselectivities remaining similar
ever the use of Mg(ClO4)2 as the Lewis acid furnished the (entries 2 and 3).13 Inductively electron-withdrawing bro-
desired product in 94% yield after 24 hours reaction (en- mine substituents had little effect on the reaction efficien-
tries 12 to 14). Further experiments confirmed that all cy with ortho-, meta- and para-bromobenzaldehydes
three components: amine base, Lewis acid and ligand, delivering adducts in 84%, 88% and 84% yields respec-
were necessary to generate an active catalyst system.9 The tively (entries 4–6). Pleasingly, sterically hindered 2,6-
reason for the increase in catalyst activity upon the addi- dichlorobenzaldehyde also performed well furnishing the
tion of bipyridine is not clear;10 one possible explanation product in 89% yield as a 60:40 mix of diastereomers.
is that the added ligand allows easier dissociation of a Electron rich aldehydes such as para-anisaldehyde (67%)
counterion from the metal centre and thus allows more and 2-naphthaldehyde (89%) are also tolerated well (en-
facile complexation of the substrate to the Lewis acid.
tries 8 and 9).
Table 1 Lewis Acid and Base Combinations for the Addition of 1
to 2a
Table 2 Variation in Aldehyde Componenta
Entry
R
Time (h)
20
Syn:Antib
65:35
70:30
75:25
65:35
65:35
70:30
60:40
60:40
60:40
Yield (%)c
Entry Lewis Acid
(mol%)
Baseb
(mol%)
Additivec (mol%) Time Yield
(h) (%)
1
2
3
4
5
6
7
8
9
C6H5
84
70
85
84
88
84
89d
67
89
1
2
Cu(OTf)2 (10) Et3N (20)
Zn(OTf)2 (10) Et3N (20)
–
–
–
–
–
–
–
63
48
45
0
0
0
4-NO2-C6H4
4-CN-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
2,6-di-Cl-C6H4
4-OMe-C6H4
2-naphth
25
22
3
Sn(TOf)2 (10)
Et3N (20)
23
4
Mg(OTf)2 (10) Et3N (20)
Mg(OTf)2 (10) DBU (20)
Mg(OTf)2 (10) NEP (20)
Mg(OTf)2 (110) Et3N (110)
95 26
21
5
138 15
21
6
45
9
21
7
100 76
71 14
23
8
Mg(OTf)2 (10) Et3N (20) i-PrOH (100)
21
9
Mg(OTf)2 (10) Et3N (20) CF3CH2OH (100) 71
16
0
a All reactions: ester (1.0 equiv), aldehyde (1.1. equiv).
b Diastereomer ratios measured by 1H NMR.
c Combined yield of the isolated diastereomers.
d Diastereomers not separable.
10
11
12
13
14
Mg(OTf)2 (10) Et3N (20) TMS-Cl (100)
Mg(OTf)2 (10) Et3N (20) bipy (10)
72
103 39
116 31
65 35
24 94
MgBr2 (10)
MgI2 (10)
Et3N (20) bipy (10)
Et3N (20) bipy (10)
In summary, we have demonstrated that a catalyst system
generated from three commercially available components
can be used to catalyse the addition of ethyl isothiocyana-
toacetate, a commercially available glycine equivalent, to
a range of aromatic aldehydes. The products of these reac-
tions are synthetically useful protected -hydroxy- -ami-
no acids. Finally, we note the significance of the need for
an added external ligand (bipyridine) to generate an active
catalyst system; this observation is encouraging for the
development of an asymmetric version of this process uti-
lizing enantiomerically enriched ligands. Studies towards
this goal, and to expand the range of the process, will be
reported in due course.
Mg(ClO4)2 (10) Et3N (20) bipy (10)
a All reactions: ester (1.0 equiv), aldehyde (1.1 equiv).
b NEP = N-ethyl piperidine.
c bipy = bipyridine.
With optimised conditions in hand, the range of aldehydes
that could be successfully employed in the reaction was
investigated (Table 2).11 The catalyst system generated
from Mg(ClO4)2 (10 mol%), bipy (10 mol%) and Et3N (20
mol%) was used to promote the combination of ester 1
(1.0 equiv) with a range of aromatic aldehydes (1.1
Synlett 2002, No. 10, 1625–1628 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Direct Catalytic Aldol Route to Protected -Hydroxy- -amino Acids
1627
recrystallisation from dichloromethane/petroleum spirit 40–
60 °C.
(12) Small amounts of a by-product originating from the addition
of a second equivalent of ester 1 to the initially formed aldol
adduct could be isolated in several experiments when
conducted at r.t.
Acknowledgement
We thank the EPSRC, AstraZeneca (strategic research fund) and
Pfizer for funding. The EPSRC Mass Spectrometry Service at the
University of Wales Swansea is also thanked for their assistance.
(13) All new compounds were fully characterised. Selected data
for novel compounds:
References
(4R*,5R*)-Ethyl 5-(4-nitrophenyl)-2-thioxo-oxazolidine-
4-carboxylate. 1H NMR (400 MHz, CDCl3): = 8.28–8.24
(2 H, m), 7.71 (1 H, s), 7.57–7.54 (2 H, m), 6.19 (1 H, d, J =
9.8 Hz), 5.00 (1 H, d, J = 9.8 Hz), 3.87 (1 H, app. dq, J = 10.8
and 7.2 Hz), 3.72 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.89 (3
(1) (a) Vancomycin: Glycopeptide Antiobiotics; Nagarajan, R.,
Ed.; Marcel Dekker: New York, 1994. (b) Cyclosporine A:
Wenger, R. M. Prog. Chem. Org. Nat. Prod. 1986, 50, 123.
(c) Polyoxins : Isono, K.; Suzuki, S. Heterocycles 1979, 13,
333. (d) Cyclomarins: Renner, M. K.; Shen, Y.-C.; Cheng,
X.-C.; Jensen, P. R.; Frankmoelle, W.; Kauffman, C. A.;
Fenical, W. E.; Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc.
1999, 121, 11273.
H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
=
189.5, 166.6, 148.8, 140.2, 128.1, 124.0, 83.9, 62.9, 62.8,
14.1.
(4R*,5R*)-Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.72–
7.46 (4 H, m), 7.36 (1 H, s), 6.12 (1 H, d, J = 9.8 Hz), 4.94
(1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq, J = 10.7 and 7.2 Hz),
3.72 (1 H, app. dq, J = 10.7 and 7.2 Hz), 0.88 (3 H, app. t, J
(2) For selected recent examples, see: (a) MacMillan, J. B.;
Molinski, T. F. Org. Lett. 2002, 4, 1883. (b) Loncaric, C.;
Wulff, W. D. Org. Lett. 2001, 3, 3675. (c) DeMong, D. E.;
Williams, R. M. Tetrahedron Lett. 2001, 42, 183. (d) Kim,
I. H.; Kirk, K. L. Tetrahedron Lett. 2001, 42, 8401.
(3) For example: (a) Horikawa, M.; Busch-Petersen, J.; Corey,
E. J. Tetrahedron Lett. 1999, 40, 3843. (b) Kobayashi, S.;
Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(4) For the use of isocyanoacetates in direct catalytic aldol
additions, see: Ito, Y.; Sawamura, M.; Hayashi, T. J. Am.
Chem. Soc. 1986, 108, 6405.
(5) (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108,
6757. (b) Volkmann, R. A.; Davis, J. T.; Meltz, C. N. J. Am.
Chem. Soc. 1983, 105, 5946. (c) Hoppe, D.; Follmann, R.
Chem. Ber. 1976, 109, 3047.
(6) For examples, see: (a) Ji, J.; Barnes, D. M.; Zhang, J.; King,
S. A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc.
1999, 121, 10215. (b) Frantz, D. E.; Fassler, R.; Carreira, E.
M. J. Am. Chem. Soc. 1999, 121, 11245; ref. 5a.
= 7.2 Hz). 13C NMR (100 MHz, CDCl3–CD3OD, 66:33):
=
189.6, 167.0, 138.9, 132.2, 127.5, 118.0, 113.1, 83.7, 63.0,
62.1, 13.6.
(4S*,5R*)-Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 8.09
(1 H, s), 7.75–7.54 (4 H, m), 6.03 (1 H, d, J = 6.2 Hz), 4.44
(1 H, d, J = 6.2 Hz), 4.41–4.29 (2 H, m), 1.37 (3 H, app. t,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): = 188.2, 167.2,
141.6, 132.8, 126.1, 117.9, 113.4, 84.0, 64.4, 63.4, 14.2.
(4R*,5R*)-Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.58
(1 H, s), 7.53–7.50 (2 H, m), 7.23–7.18 (2 H, m), 6.04 (1 H,
d, J = 9.8 Hz), 4.90 (1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq,
J = 10.7 and 7.2 Hz), 3.74 (1 H, app. dq, J = 10.7 and 7.2 Hz),
0.89 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 189.8, 166.9, 132.4, 132.0, 128.6, 124.2, 84.7, 62.9, 62.7,
14.0.
(7) For an example of alcohol additives aiding catalyst turnover,
see: Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M.
C. J. Am. Chem. Soc. 2001, 123, 4480.
(4S*,5R*)-Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.95
(1 H, s), 7.58–7.55 (2 H, m), 7.31–7.26 (2 H, m), 5.93 (1 H,
d, J = 6.2 Hz), 4.43 (1 H, d, J = 6.2 Hz), 4.39–4.27 (2 H, m),
1.35 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 188.4, 167.5, 135.6, 132.2, 127.2, 123.6, 84.8, 64.5, 63.2,
14.2.
(4R*,5R*)-Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.54–
7.47 (3 H, m), 7.29–7.27 (2 H, m), 6.04 (1 H, d, J = 9.8 Hz),
4.91 (1 H, d, J = 9.8 Hz), 3.86 (1 H, app. dq, J = 10.8 and 7.2
Hz), 3.76 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.90 (3 H, app.
t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): = 189.8,
166.8, 135.5, 133.0, 130.5, 130.0, 125.5, 122.8, 84.4, 62.9,
62.8, 14.0.
(4S*,5R*)-Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.78
(1 H, s), 7.57–7.53 (2 H, m), 7.37–7.29 (2 H, m), 5.94 (1 H,
d, J = 6.2 Hz), 4.45 (1 H, d, J = 6.2 Hz), 4.41–4.28 (2 H, m),
1.36 (3 H, app. t, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3):
= 188.7, 167.7, 139.1, 132.9, 131.0, 128.8, 124.4, 123.4,
84.8, 64.8, 63.6, 14.6.
(4R*,5R*)-Ethyl 5-(2-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.58–
7.23 (5 H, m), 6.41 (1 H, d, J = 9.0 Hz), 5.00 (1 H, d,
J = 9.0 Hz), 3.80 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.66
(1 H, app. dq, J = 10.7and 7.2 Hz), 0.82 (3 H, app. t, J = 7.2
Hz). 13C NMR (100 MHz, CDCl3): = 189.8, 166.9, 132.6,
132.3, 130.7, 127.8, 127.7, 122.1, 84.5, 62.2, 61.2, 13.6.
(8) For impressive recent examples of TMSCl being employed
as an additive in diastereoselective MgCl2 catalysed aldol
reactions, see: (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
(b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S.
Org. Lett. 2002, 4, 1127.
(9) A reaction using only Et3N (no metal salt or bipyridine)
provided an 8% yield of the aldol adducts after 48 h at r.t.
Reactions excluding Et3N provided no product.
(10) For a recent example of Lewis acid catalysed reaction in
which the addition of an external ligand was needed to
achieve reaction, see ref.6a
(11) The Preparation of 3 Serves as a Typical Procedure:
Mg(ClO4)2 (31 mg, 0.138 mmol) and bipyridine (22 mg,
0.138 mmol) were stirred for 10 min in dry THF (5.5 mL)
under nitrogen at r.t. Triethylamine (39 L, 0.276 mmol)
was then added and the mixture was cooled at 0 °C. After 10
min ethyl isothiocyanatoacetate (170 L, 1.38 mmol) and
benzaldehyde (150 L, 1.52 mmol) were added. After 20 h
at 0 °C, the reaction was quenched with a sat. aq ammonium
chloride solution (5 mL). The organic layer was separated
and the aq layer was extracted with dichloromethane (3 10
mL). The organic portions were washed with a sat. aq copper
sulphate solution (5 mL) and with brine (5 mL), dried
(MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2,
EtOAc–DCM, 2:98) to give a mixture of the syn- and anti-
oxazolidinethiones, 3 (290 mg, 84%, syn:anti = 65:35), as a
viscous oil. Analytical samples were prepared by
Synlett 2002, No. 10, 1625–1628 ISSN 0936-5214 © Thieme Stuttgart · New York

1628
M. C. Willis, V. J.-D. Piccio
LETTER
(4S*,5R*)-Ethyl 5-(2-bromophenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 8.00
(1 H, s), 7.62–7.25 (4 H, m), 6.34 (1 H, d, J = 4.7 Hz), 4.46
(1 H, d, J = 4.7 Hz), 4.37–4.27 (2 H, m), 1.35 (3 H, app. t,
J = 7.3 Hz). 13C NMR (100 MHz, CDCl3): = 188.8, 167.4,
135.5, 133.3, 130.8, 128.1, 127.6, 120.9, 84.6, 64.0, 63.0,
14.2.
(4R*,5R*)-Ethyl 5-(4-methoxyphenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.51
(1 H, s), 7.25–7.21 (2 H, m), 6.90–6.86 (2 H, m), 6.04 (1 H,
d, J = 9.8 Hz), 4.86 (1 H, d, J = 9.8 Hz), 3.84 (1 H, app. dq,
J = 10.7 and 7.2 Hz), 3.80 (3 H, s), 3.73 (1 H, app. dq, J =
10.7 and 7.2 Hz), 0.88 (3 H, app. t, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): = 189.9, 167.1, 160.7, 128.3, 125.4,
114.1, 85.5, 63.0, 62.5, 55.7, 14.0.
3.82 (1 H, s), 1.34 (3 H, app. t, J = 7.0 Hz). 13C NMR (100
MHz, CDCl3): = 188.6, 167.7, 160.4, 128.5, 127.3, 114.4,
85.8, 64.4, 62.9, 55.4, 14.2.
(4R*,5R*)-Ethyl 5-(2-naphthyl)-2-thioxo-oxazolidine-4-
carboxylate. 1H NMR (400 MHz, CDCl3): = 7.86–7.83
(4 H, m), 7.55–7.50 (3 H, m), 7.39–7.36 (1 H, m), 6.26 (1 H,
d, J = 9.8 Hz), 4.97 (1 H, d, J = 9.8 Hz), 3.64 (1 H, app. dq,
J = 10.4 and 7.2 Hz), 3.48 (1 H, app. dq, J = 10.4 and 7.2 Hz),
0.55 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 189.7, 166.7, 133.5, 132.5, 130.3, 128.4, 128.1, 127.6,
126.9, 126.7, 126.4, 123.3, 85.4, 62.8, 62.2, 13.4.
(4S*,5R*)-Ethyl 5-(2-naphthyl)-2-thioxo-oxazolidine-4-
carboxylate. 1H NMR (400 MHz, CDCl3): = 7.92–7.85
(5 H, m), 7.55–7.53 (2 H, m), 7.48–7.46 (1 H, m), 6.14 (1 H,
d, J = 6.2 Hz), 4.56 (1 H, d, J = 6.2 Hz), 4.42–4.29 (2 H, m),
1.38 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
= 189.1, 168.1, 134.1, 133.8, 133.1, 129.7, 128.5, 128.0,
127.3, 127.1, 125.6, 122.6, 86.1, 64.9, 63.4, 14.6.
(4S*,5R*)-Ethyl 5-(4-methoxyphenyl)-2-thioxo-oxazoli-
dine-4-carboxylate. 1H NMR (400 MHz, CDCl3): = 7.71
(1 H, s), 7.34–7.32 (2 H, m), 6.96–6.92 (2 H, m), 5.90 (1 H,
d, J = 6.2 Hz), 4.47 (1 H, d, J = 6.2 Hz), 4.37–4.25 (2 H, m),
Synlett 2002, No. 10, 1625–1628 ISSN 0936-5214 © Thieme Stuttgart · New York