An (E)-selective synthesis of trisubstituted (E)-α, β-unsaturated acid derivatives

Article abstract of DOI:10.1039/b304213h

Potassium alkoxides of N-acyloxazolidin-2-one derived synaldolates undergo a novel tandem intramolecular cyclisation elimination reaction to afford trisubstituted (E)-α,β-unsaturated amides in high d.e., which may be converted into their corresponding acids or oxazolines in good yield.

Full text of DOI:10.1039/b304213h

An (E)-selective synthesis of trisubstituted (E)-a,b-unsaturated acid
derivatives†
Fred J. P. Feuillet, Diane E. J. E. Robinson and Steven D. Bull*
Department of Chemistry, University of Bath, Bath, UK BA2 7AY. E-mail: s.d.bull@bath.ac.uk
Received (in Cambridge, UK) 16th April 2003, Accepted 26th June 2003
First published as an Advance Article on the web 24th July 2003
Potassium alkoxides of N-acyloxazolidin-2-one derived syn-
aldolates undergo a novel tandem intramolecular cyclisation
elimination reaction to afford trisubstituted (E)-a,b-un-
saturated amides in high d.e., which may be converted into
their corresponding acids or oxazolines in good yield.
carbonyl groups.10 Consequently, it was proposed that the high
diastereoselectivities observed for the formation of (E)-a,b-
unsaturated amides 3a–h in this reaction could be explained by
invoking an intramolecular endocyclic cleavage mechanism.
Thus, potassium alkoxide 4 initially undergoes intramolecular
attack at the oxazolidin-2-one carbonyl resulting in O–O
carbonyl migration, to afford 1,3-oxazinane-2,4-dione alkoxide
5. Subsequent anion equilibration of alkoxide 5 to enolate 6
would then enable stereoselective elimination of carbon dioxide
to occur to afford the trisubstituted secondary amide (E)-3 in
high d.e. (Fig. 1).
It has been reported previously that reaction of the Zn enolate
of a-bromo-N-acyl-oxazolidin-2-one 7 with benzaldehyde did
not afford the expected aldolate product, but instead gave a
mixture of rearranged 1,3-oxazinane-2,4-dione diastereoisom-
ers 8 and 9 in good yield (Scheme 2).11 Since this implied that
Zn alkoxides of b-hydroxy-N-acyloxazolidin-2-ones underwent
rearrangement to their corresponding 1,3-oxazinane-2,4-diones,
we treated syn-aldolate 2f with 10 mol% of Et2Zn in CH2Cl2 at
room temperature to cleanly afford its corresponding 1,3-ox-
azinane-2,4-dione 10 in 88% yield.12 Subsequent treatment of
10 with KHMDS in THF at 278 °C gave (E)-3f in > 90% d.e.,
thus providing good evidence that the potassium alkoxide of
There are currently few general methods available for the
diastereoselective synthesis of (E)-a,b-unsaturated acids/esters/
amides that are substituted at both their a- and b-positions.1
These types of trisubstituted a,b-unsaturated acid derivatives
are important targets because they serve as versatile substrates
for a wide range of synthetic methodology,2 and for the
construction of a wide range of natural products.3,4 Previously,
(E)-acid derivatives of this type have been prepared using
Wittig,3 or Horner–Emmons4 methodology, however alter-
5
native diastereoselective protocols employing excess SmI2 or
CrCl26 to effect the reductive elimination of a-halo-b-hydroxy-
esters or amides have recently been described. We now report
an alternative approach towards this class of acid fragment, that
employs syn-b-hydroxy-N-acyloxazolidin-2-ones as substrates
for a novel intramolecular cyclisation/elimination reaction to
afford trisubstituted (E)-a,b-unsaturated amides in high d.e.
In the course of our synthetic studies we prepared nine
racemic syn-aldolates 2a–i in high d.e. via reaction of the boron
enolates of N-acyloxazolidin-2-ones 1a–d (1a R = Me; 1b R =
iPr; 1c R = Ph, 1d R = PhCH2–) with a series of aldehydes
according to well established literature precedent.7 It was found
that treatment of these syn-aldolates 2a–h with 1.5 equivalents
of KHMDS in THF at 278 °C resulted in a clean elimination
reaction to afford the corresponding a,b-unsaturated amides
(E)-3a–h in 67–99% isolated yield, and in > 90% d.e.8 in all
cases.9 It is noteworthy that this simple elimination method-
ology is general in scope, with linear and branched R-
substituents being tolerated at the a-position of the syn-
aldolates 2a–h, and with aliphatic, unsaturated, and aromatic
(neutral and electron rich) R1-substituents being tolerated at the
b-position (Scheme 1, Table 1). The only limitation of this
methodology occurred during elimination of 2i (R = Ph, R1 =
Et) which gave 3i in a lower 47% isolated yield as a result of a
competing retro-aldol reaction which gave (N-phenylacetyl)ox-
azolidin-2-one 1c (R = Ph) and propionaldehyde (not isolated)
as competing side-products in 32% yield.
Table 1 Synthesis of (E)-a,b-unsaturated amides 3a–h
Entry Aldolate
R
R1
Product d.e.a % Yieldb
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Ph
Et
3a
3b
3c
3d
> 95 89
> 95 67
92 99
PhCH2– Me(CH2)6–
iPr
iPr
iPr
iPr
iPr
Ph
cyclohexyl
(E)-Ph(CHNCH)– 3e
Et
Ph
p-MeOPh–
Et
93 76
> 95 95
> 95 99
92 94
90 79
> 95 47
3f
3g
3h
3i
a All diastereoselectivities were determined via 1H NMR spectroscopic
analysis (300 MHz) of the crude reaction product. b Yields are for pure (E)-
diastereoisomers isolated after chromatographic purification.
It is well known that sterically unhindered N-acyloxazolidin-
2-ones can undergo endocyclic ring cleavage via either inter- or
intramolecular attack of nucleophiles at their oxazolidin-2-one
i
Scheme 1 Reagents and conditions: (i) 9-BBNTf, Pr2NEt, CH2Cl2, 0 ?
278 °C; R1CHO, CH2Cl2; (ii) KHMDS (1.5 eq.), THF, 278 °C.
† Electronic supplementary information (ESI) available: synthesis and
spectroscopic details for compounds 3a and 12a. See http://www.rsc.org/
suppdata/cc/b3/b304213h/
Fig. 1 Intramolecular cyclisation/elimination mechanism for the formation
of (E)-a,b-unsaturated amides 3.
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CHEM. COMMUN., 2003, 2184–2185
This journal is © The Royal Society of Chemistry 2003

Table 2 Yields of (E)-a,b-unsaturated acids 12a–e and (E)-oxazoline 13
Entry
Amide
R
R1
Product % Yield
1
2
3
4
5
6
3a
3b
3c
3d
3e
3b
Me
Me
Ph
Et
12a
12b
12c
12d
99
91
99
99
99
88
PhCH2– Me(CH2)6–
iPr
iPr
Me
cyclohexyl
(E)-Ph(CHNCH)– 12e
Et 13
Scheme 2 Reagents and conditions: (i) Zn, THF, 278 °C, PhCHO.
conversion of 3b to its corresponding trisubstituted-a,b-
unsaturated oxazoline (E)-13 on treatment with thionyl chloride
in 88% yield (Scheme 5, Table 2, entry 6).15
In conclusion, we have demonstrated that treatment of easily
prepared N-acyloxazolidone-syn-aldolates with KHMDS af-
fords an alkoxide intermediate which undergoes a stereo-
selective base mediated elimination reaction to afford trisub-
stituted (E)-a,b-unsaturated amides in high d.e.
Scheme 3 Reagents and conditions: (i) Et2Zn (10 mol%), CH2Cl2, 0 °C; (ii)
KHMDS, THF, 278 °C.
We would like to thank the EPSRC (DEJER), the University
of Bath (FJPF) and the Royal Society (SDB) for funding, and
the Mass Spectrometry Service at the University of Wales,
Swansea for their assistance.
1,3-oxazinane-2,4-dione 5 is a key intermediate in controlling
diastereoselectivity during stereoselective elimination of the
potassium alkoxides of syn-aldolates 2a–h (Scheme 3).
We next explored elimination of the corresponding anti-
aldolate 11 which was prepared via treatment of 1a with MgCl2,
TMSCl, Et3N and benzaldehyde in EtOAc according to Evans’
recently published procedure.13 Treatment of anti-aldolate 11
with KHMDS in THF at 278 °C afforded amide (E)-3a in
> 95% d.e. identical to that observed previously for elimination
of syn-2a under the same conditions (Scheme 4). This is
consistent with the key elimination step of both syn-2a and anti-
11 occurring via an E1cB-type mechanism, to afford a common
enolate intermediate 6 that decomposes to afford a,b-un-
saturated amide (E)-3a in high d.e.
Notes and references
1 For a recent review on the synthesis of carboxylic acids and esters see
A. S. Franklin, J. Chem. Soc., Perkin Trans. 1., 1999, 3537 and
references therein.
2 (a) For examples see S. G. Davies, O. Ichihara and I. A. S. Walters, J.
Chem. Soc., Perkin Trans. 1, 1994, 1141; (b) M-J. Villa and S. Warren,
J. Chem. Soc., Perkin Trans. 1, 1994, 1569.
3 (a) For recent examples using Wittig methodology see R. J. Anderson,
J. E. Coleman, E. Priers and D. J. Wallace, Tetrahedron Lett., 1997, 38,
317; (b) A. B. Smith III and B. M. Brandt, Org. Lett., 2001, 3, 1685.
4 For recent examples using Horner–Emmons methodology see (a) M. B.
Andrus, E. L. Meredith, B. L. Simmons, B. B. V. Soma and E. J. Hicken,
Org. Lett., 2002, 4, 3549; (b) Y. Hayashi, J. Kanayama, J. Yamaguchi
and M. Shoji, J. Org. Chem., 2002, 67, 9443.
In order to demonstrate the synthetic utility of this method-
ology, a range of diastereomerically pure trisubstituted secon-
dary amides (E)-3a–e were hydrolysed to their parent acids
12a–e by refluxing in 6 M HCl for two hours in 91–99% yield.†
Importantly, no evidence of any products resulting from double
5 J. M. Concellón, J. A. Pérez-Andrés and H. Rodríguez-Solla, Angew.
Chem. Int. Ed., 2000, 39, 2773; J. M. Concellón, J. A. Pérez-Andrés and
H. Rodríguez-Solla, Chem. Eur. J., 2001, 7, 3062.
6 D. K. Barma, A. Kundu, H. Zhang, C. Mioskowski and J. R. Flack, J.
Am. Chem. Soc., 2003, 125, 3218.
1
bond migration were observed in the H NMR spectra of the
crude hydrolysis products of 3a–e (Scheme 5, Table 2, entries
1–5).14 The potential synthetic versatility of this methodology
arising from the presence of the N-hydroxyalkyl substituent of
a,b-unsaturated amides 3a–e was also demonstrated via
7 S. Caddick, N. J. Parr and M. C. Pritchard, Tetrahedron Lett., 2000, 41,
5963.
8 Treatment of (E)-2a in THF with KHMDS at 0 °C afforded amide (E)-
3a in an inferior 80% d.e.
9 The (E)-stereochemistry of amide 3d was confirmed via X-ray
crystallographic analysis.
10 For further discussion see (a) S. D. Bull, S. G. Davies, S. Jones and H.
J. Sanganee, J. Chem. Soc., Perkin Trans. 1, 1999, 387; (b) S. P. Bew,
S. D. Bull, S. G. Davies, E. D. Savory and D. J. Watkin, Tetrahedron,
2002, 58, 9387.
11 See Reference 11 in Y. Ito and S. Terashima, Tetrahedron, 1991, 47,
2821.
Scheme 4 Reagents and conditions: (i) MgCl2, Et3N, TMSCl, PhCHO,
EtOAc, rt; (ii) KHMDS, THF, 278 °C.
12 For examples where metal enolates of a,a-disubstituted-N-acylox-
azolidin-2-ones gave rearranged 1,3-oxazinane-2,4-diones see (a) A. S.
Kende, K. Kawamura and M. J. Orwat, Tetrahedron Lett., 1989, 30,
5821; (b) T. Kamino, Y. Murata, N. Kawai, S. Hosokawa and S.
Kobayashi, Tetrahedron Lett., 2001, 42, 5249.
13 D. A. Evans, J. S. Tedrow, J. T. Shaw and C. W. Downey, J. Am. Chem.
Soc., 2002, 124, 392.
14 For an alternative five step synthesis of acid (E)-12a from a chiral N-
acyl-oxazolidin-2-one-syn-aldolate see J. Palaty and F. S. Abbott, J.
Med. Chem., 1995, 38, 3398.
15 (a) Oxazolines are easily converted into their corresponding acids,
esters, aldehydes or alcohols; see J. A. Frump, Chem. Rev., 1971, 71,
483; (b) A. I. Meyers, R. J. Himmelsbach and M. Reuman, J. Org.
Chem., 1983, 48, 4053.
Scheme 5 Reagents and conditions: (i) 6 M HCl, D; (ii) SOCl2, rt.
CHEM. COMMUN., 2003, 2184–2185
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