Diastereocontrolled strecker reaction using (S)-5-phenylmorpholin-2-one

Article abstract of DOI:10.1039/b104052a

Iminium ions derived from (S)-5-phenylmorpholin-2-one 1 undergo diastereoselective Strecker reactions using copper(I) cyanide and anhydrous hydrochloric acid; the major adducts may be degraded to D-α-amino acids.

Full text of DOI:10.1039/b104052a

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Diastereocontrolled Strecker reaction using (S)-5-phenylmorpholin-
2-one
Laurence M. Harwood,*a Michael G. B. Drew,a David J. Hughesb and Richard J. Vickersa
1
a Department of Chemistry, University of Reading, Whiteknights, Reading, UK RG6 6AD.
E-mail: l.m.harwood@reading.ac.uk; Fax: 44 (0)1189 316782; Tel: 44 (0)1189 318449
b Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, UK RG42 6EY.
E-mail: dave.hughes@syngenta.com; Fax: 44 (0)1344 41373 9; Tel: 44 (0)1344 414962
Received (in Cambridge, UK) 9th May 2001, Accepted 1st June 2001
First published as an Advance Article on the web 27th June 2001
Iminium ions derived from (S)-5-phenylmorpholin-2-one 1
undergo diastereoselective Strecker reactions using
copper(I) cyanide and anhydrous hydrochloric acid; the
major adducts may be degraded to D-α-amino acids.
Introduction
(S)-5-Phenylmorpholin-2-one 1† has proven to be a highly
Scheme 2 Reagents and conditions: CuCN, HCl (anhyd.), Na2SO4
versatile template for the induction of stereocontrol during
diastereoselective reactions of azomethine ylides in the syn-
thesis of proline derivatives,1 β-hydroxy-α-amino acids,2 and
α,β-diamino acids.3 In addition, we have revealed that the 3,4-
didehydro derivatives undergo diastereocontrolled alkylation.4
Furthermore, iminium species generated in situ from 1 undergo
diastereoselective Mannich reactions with 2-furylboronic acid
and subsequent chemical manipulation of the adducts has
yielded a range of enantiopure α-amino acids.5a,b
(anhyd.), RCHO, THF.
Table 1 Isolated yields of Strecker adducts
R
3
4
Diastereoisomeric ratio 3 : 4
iPr
nBu
iBu
PhCH2CH2
Ph
4-(NO2)C6H4
Cyclopropyl
Me
79
77
76
76
64
58
38
42
6
5
6
6
5
5
13.2 : 1a
15.4 : 1a
12.5 : 1a
12.7 : 1a
12.8 : 1a
11.6 : 1a
2.2 : 1b
Results and discussion
17
19
In efforts to extend the diastereoselective Mannich protocol,
our attention turned to alternative nucleophiles that would
demonstrate increased atom efficiency over the furan nucleus as
a carboxy equivalent and, to this end, attention focused on
attempts to develop a diastereocontrolled Strecker reaction.6
Reagents previously used as cyanide sources, such as TMS-
CN,6a,e KCN,6b and EtAl2CN,6c did not promote the desired
reaction, but it was found that copper() cyanide in the presence
of aqueous hydrochloric acid and paraformaldehyde furnished
the desired parent adduct 2 in 78% yield (Scheme 1).
2.2 : 1b
a Reaction carried out in refluxing THF. b Reaction carried out at room
temperature.
The reaction protocol successfully accommodated both aryl
and alkyl aldehydes, although attempts with ketones met with
failure, and electron-rich aryl aldehydes, such as anisaldehyde,
gave low yields of adducts. In the cases of cyclopropylcarb-
aldehyde and acetaldehyde, the necessity of conducting the
reaction at room temperature led to the lower diastereoisomeric
ratios, although yields of adducts were acceptable.
Structure determination via X-ray crystallographic analysis
of adduct 3a confirmed the relative configurations of the major
isomers as having the (R)-configuration at the newly formed
exocyclic stereocentre (Fig. 1).¶
It appears that the major diastereoisomers 3 are favoured
both thermodynamically and kinetically, although our mne-
monic for predicting stereocontrol holds true for each case
(Fig. 2).
Scheme 1 Reagents and conditions: CuCN, HCl, (CH2O)n, THF, rt.
Disappointingly, when aldehydes other than paraformalde-
hyde were subjected to these conditions, only low yields of the
desired adducts were observed. However, exposure of 1 to a
range of aldehydes in the presence of CuCN and anhydrous
sodium sulfate in THF containing anhydrous HCl, led to the
isolation of diastereoisomeric Strecker adducts 3 and 4 in good
combined yield, reaction being complete within a few minutes
at room temperature (Scheme 2).
Unfortunately, diastereocontrol over the reaction was poor
with the ratio of diastereoisomers 3 : 4 being approximately
2.5 : 1. However, by conducting the reaction in THF at reflux
for 2 hours it was found that the diastereomeric ratio improved
to around 12 : 1 in favour of isomer 3 (Table 1); the isomers
being readily separated by column chromatography.‡§
With a series of adducts in hand, attention focused on
removal of the template and hydrolysis of the nitrile to release
the desired α-amino acids. Although we have reported a tem-
plate degradation protocol that could have been adapted to the
present system,5b we desired a more expedient route. Reduction
of the lactone 3a with DIBAL-H furnished lactol 5 in quantita-
tive yield as a 1 : 2 mixture of anomers. Dehydration to furnish
enamine 6 in 54% yield was achieved with acetic anhydride in
7
the presence of excess of BF3ؒOEt2 (Scheme 3). Attempts at
hydrolysis of the enamine 6 failed and thus a one-pot oxidative
procedure was developed. A DCM solution of enamine 6
and MCPBA was stirred for 10 hours before the addition of
periodic acid and water. After stirring for a further 10 hours
DOI: 10.1039/b104052a
J. Chem. Soc., Perkin Trans. 1, 2001, 1581–1583
This journal is © The Royal Society of Chemistry 2001
1581

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Scheme 4
aryl and alkyl aldehydes and template degradation has been
illustrated with adduct 3a to release (R)--valine in 32% overall
yield. During the course of the template degradation crude
reaction mixtures can be carried through the process without
detrimental effects.
Fig. 1 X-Ray structure of major adduct 3a.
Experimental
Typical experimental procedure for preparation of adducts 3 and
4
To a rapidly stirred solution of morpholinone 1 (1 mmol,
1.0 equiv.) in THF (18 mL) under a nitrogen atmosphere were
added sequentially HCl (4 M in 1,4-dioxane, 275 µL, 1.1 equiv.),
CuCN (2 mmol, 2.0 equiv.) and anhydrous Na2SO4 (890 mg).
The requisite aldehyde (5 mmol, 5.0 equiv.) was then added and
the mixture heated to reflux for 2 hours before Et3N (0.89 mL)
was added. The suspension was then cooled to room tempera-
ture before diethyl ether (18 mL) was added and the reaction
filtered through a short silica pad. The pad was washed with
ether and, following solvent removal under reduced pressure,
the residual oil was purified by flash column chromatography
on silica, typically eluting with 1 : 1 diethyl ether–petrol to
separate the diastereoisomeric products.
Fig. 2 Stereochemical rationale.
Selected data
Compound 3a. Colourless solid, mp 91–93 ЊC; [α]D ϩ75.0
(c 0.56, CHCl3); νmax (Nujol) 1760 cmϪ1; δH (250 MHz, CDCl3)
7.31–7.27 (5H, m), 4.30–4.20 (2H, m), 3.82 (1H, dd, J 4.1,
JЈ 10.0 Hz), 3.73 (1H, d, J 17.5 Hz), 3.43 (1H, d, J 17.5 Hz),
2.95 (1H, d, J 11.2 Hz), 1.95–1.80 (1H, m), 0.92 (6H, d, J 6.6
Hz); δC (69.2 MHz, CDCl3) 166.8, 134.5, 130.1, 130.0, 128.8,
115.9, 72.8, 61.7, 60.7, 49.2, 28.6, 20.5, 19.1; C15H19N2O2
(MHϩ) requires 259.1447, found 259.1440.
Scheme 3 Reagents and conditions: (i) DIBAL-H, THF, Ϫ78 ЊC; (ii)
Ac2O, BF3ؒOEt2, MeCN, rt; (iii) MCPBA, DCM; (iv) H5IO6; (v) EtOH,
TiCl4, rt; (vi) Pb(OAc)4, MeOH–DCM, 0 ЊC; (vii) conc. HCl.
Compound 4a. Colourless solid, mp 126–131 ЊC; [α]D ϩ183.0
(c 0.94, CHCl3); νmax (Nujol) 1752 cmϪ1; δH (250 MHz, CDCl3)
7.27–7.31 (5H, m), 4.47 (1H, dd, J 4.3, JЈ 11.8 Hz), 4.30 (1H,
dd, J 6.2, JЈ 11.8 Hz), 4.10 (1H, dd, J 4.3, JЈ 6.2 Hz), 3.79 (1H,
d, J 16.1 Hz), 3.64 (1H, d, J 16.1 Hz), 3.10 (1H, d, J 10.3 Hz),
1.45–1.50 (1H, m), 0.91 (3H, d, J 6.6 Hz), 0.72 (3H, d, J 6.6 Hz);
δC (69.2 MHz, CDCl3) 168.6, 138.1, 129.4, 129.2, 128.1, 117.4,
71.4, 65.0, 59.8, 52.5, 30.2, 20.3, 20.0; C15H19N2O2 (MHϩ)
requires 259.1447, found 259.1451.
7 was isolated in 84% yield and this was most efficiently
deformylated by stirring in ethanol in the presence of TiCl4,
delivering the amino alcohol 8 in 95% yield. Following a
procedure developed by Chakraborty,8 the amino alcohol 8
was oxidized with lead() acetate to the imine, which, with-
out isolation, was subjected to reflux in concentrated HCl.
Following purification by ion-exchange chromatography, -
valine 9 was isolated in 74% yield (32% overall yield from
3a). On the basis of the specific rotation {[α]2D0 Ϫ25.9 (c 4.0, 6 M
HCl), lit.6b [α]2D0 Ϫ26.02 (c 4.0, 6 M HCl)} the final amino acid
had been obtained without compromising the integrity of the
stereocentre of 3a during degradation.
Acknowledgements
We thank Syngenta for a CASE studentship to R.J.V.
Alternative attempts at ozonolytic cleavage of 6 furnished 7
in only 23% yield with the major product being 3a, isolated in
48% yield. Lactone 3a could arise via 1,2-shift of H-2 of the
molozonide to carbon (or oxygen via intermediacy of the enol)
with concomitant loss of molecular oxygen (Scheme 4).
Notes and references
† The trivial morpholinone nomenclature is used in this report for the
1,4-oxazinan-2-one ring system.
‡ All novel compounds in this report gave spectroscopic and analytical
data in accord with their assigned structures.
§ The product ratios were based on isolated yields and, where resolution
permitted, were found to be in close agreement with analysis of signal
intergrations in the 1H NMR of the crude reaction mixtures.
¶ X-Ray crystal data: 3a, C15H18N2O2, M = 258.31, monoclinic, space
group P21, Z = 2, a = 9.599(12), b = 6.542(8), c = 12.017(14), β =
99.61(10)Њ, U = 744 Å3, ρ = 1.153 g cmϪ3, 1584 independent reflections
were collected with MoKα radiation on the MARresearch Image Plate
Conclusions
We have demonstrated that Strecker adducts can be prepared
in high yield with good diastereocontrol using (S)-5-phenyl-
morpholin-2-one 1, aldehydes, copper() cyanide and
anhydrous HCl. The reaction successfully accommodates both
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L. M. Harwood, D. J. Hughes, R. W. A. Luke and R. J. Vickers,
J. Chem. Soc., Perkin Trans. 1, 2000, 2982.
system. Data analysis was carried out with the XDS program;9 the
structure was solved by direct methods using SHELX8610 and refined
on F2 using SHELX11 to R 1 0.0686, wR 2 0.1937 on 1112 observed
data. Atomic co-ordinates, bond lengths and angles and thermal
parameters have been deposited with the Cambridge Crystallographic
Data Centre. CCDC reference number 163541. See http://www.rsc.org/
suppdata/p1/b1/b104052a/ for crystallographic files in .cif or other
electronic format.
6 For other examples of asymmetric Strecker reactions in the
synthesis of α-amino acids see: (a) H. Kunz and W. Sager,
Angew. Chem., Int. Ed. Engl., 1987, 26, 557; H. Kunz, H. W. Sager,
W. Pfrengle and D. Schanzenbach, Tetrahedron Lett., 1988, 29, 4397;
(b) T. Inaba, I. Kozono, M. Fujita and K. Ogura, Bull. Chem. Soc.
Jpn., 1992, 65, 2359; (c) F. A. Davies and D. L. Fanelli, J. Org.
Chem., 1998, 63, 1981; (d ) K. Saito and S. Harada, Tetrahedron
Lett., 1989, 30, 4535; (e) T. K. Chakraborty, K. Hussain and
G. V. Reddy, Tetrahedron, 1995, 33, 9179; ( f ) M. S. Iyer,
K. M. Gigstad, N. D. Namdev and M. Lipton, J. Am. Chem. Soc.,
1996, 118, 4910; (g) C. A. Krueger, K. W. Kuntz, C. D. Dzeiebra,
W. G. Wirschum, J. D. Gleason, M. L. Snapper and A. H. Hoveyda,
J. Am. Chem. Soc., 1999, 121, 4284.
1 A. S. Anslow, L. M. Harwood and I. A. Lilley, Tetrahedron: Asym-
metry, 1995, 6, 2465; L. M. Harwood, A. C. Manage, S. Robin,
S. F. G. Hopes, D. J. Watkin and C. E. Williams, Synlett, 1993, 777;
L. M. Harwood and I. A. Lilley, Tetrahedron: Asymmetry, 1995,
6, 1557.
2 D. Alker, G. Hamblett, L. M. Harwood, S. M. Robertson, D. Watkin
and C. E. Williams, Tetrahedron, 1998, 54, 6089; L. M. Harwood
and S. M. Robertson, Chem. Commun., 1998, 2641.
7 R. M. Williams and Y. Aoyagi, Tetrahedron, 1998, 54, 10419.
8 T. K. Chakraborty, G. V. Reddy and K. Azharttursein, Tetrahedron
Lett., 1991, 32, 7579.
3 D. Alker, L. M. Harwood and C. E. Williams, Tetrahedron Lett.,
1998, 39, 475.
9 W. Kabsch, J. Appl. Crystallogr., 1988, 21, 916.
4 L. M. Harwood, S. N. G. Tyler, A. S. Anslow, I. D. MacGilp and
M. G. B. Drew, Tetrahedron: Asymmetry, 1997, 8, 4007.
5 (a) L. M. Harwood, G. S. Currie, M. G. B. Drew and R. W. A. Luke,
Chem. Commun., 1996, 1953; (b) G. S. Currie, M. G. B. Drew,
10 G. M. Sheldrick, Acta Crystallogr., Sect. A: Fundam. Crystallogr.,
1990, 46, 467.
11 G. M. Sheldrick, 1993, Program for crystal structure refinement,
University of Göttingen.
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