Completely diastereoselective aziridination of α,β-unsaturated acids via intramolecular reaction of 3-acetoxyaminoquinazolin-4(3H)-ones

Article abstract of DOI:10.1016/S0040-4039(02)00136-3

(R)-3-Amino-2-[1-(2-hydroxyethoxy)ethyl]quinazolin-4(3H)-one 10 was prepared in 62% yield without the need for chromatography and O-cinnamoylated; reaction with lead tetra-acetate gave aziridine 12 as a single diastereoisomer in quantitative yield which was converted into the β-amino acid ester 15 corresponding to overall enantioselective addition of ammonia to the double bond of cinnamic acid.

Full text of DOI:10.1016/S0040-4039(02)00136-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2083–2085
Completely diastereoselective aziridination of a,b-unsaturated
acids via intramolecular reaction of
3-acetoxyaminoquinazolin-4(3H)-ones
Robert S. Atkinson,a,* Richard D. Draycott,a David J. Hirst,a Martin J. Parrattb and
Tony M. Raynhamb
aDepartment of Chemistry, Leicester University, Leicester LE1 7RH, UK
bRoche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK
Received 19 November 2001; revised 10 January 2002; accepted 18 January 2002
Abstract—(R)-3-Amino-2-[1-(2-hydroxyethoxy)ethyl]quinazolin-4(3H)-one 10 was prepared in 62% yield without the need for
chromatography and O-cinnamoylated; reaction with lead tetra-acetate gave aziridine 12 as a single diastereoisomer in
quantitative yield which was converted into the b-amino acid ester 15 corresponding to overall enantioselective addition of
ammonia to the double bond of cinnamic acid. © 2002 Elsevier Science Ltd. All rights reserved.
The reaction in Scheme 1 was envisaged as a means by
which a,b-unsaturated acids could be converted into
single enantiomers of a- or b-amino acid derivatives by
the use of 3-aminoquinazolinone 1 as a chiral auxiliary/
appended pro-reagent.1
In order to determine the optimum number of addi-
tional atoms required in the tether, a series of 2-(v-
hydroxyalkyl)-3-aminoquinazolinones 4 was prepared
with n=3, 4 and 5 and each was reacted with cin-
For the conversion of 3-acetoxyaminoquinazolinone
(QNHOAc) 2 into a single diastereoisomer of lactone 3
in Scheme 1, the chiral centre in the tether must control
the face of the a,b-unsaturated ester which is
aziridinated.
Esters have previously been used as fissionable groups
in tethers, e.g. in intramolecular Diels–Alder reactions.2
When the tether including the ester comprises a limited
number of atom links (55) reaction is only feasible
from the less stable3 s-trans conformation (Scheme 2).
However, whereas a Diels–Alder reaction can if neces-
sary be heated, in the case of QNHOAc 2, its thermal
instability above 0°C4 precludes heating and means that
the s-cis-conformational preference of the ester must be
accommodated by increasing the number of connecting
atoms in the remainder of the tether to allow the
transition state (TSc) geometry of the aziridination to
become accessible.
Scheme 1.
Scheme 2.
* Corresponding author. Fax: (+44)116-252-3789; e-mail: vow@
le.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00136-3

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R. S. Atkinson et al. / Tetrahedron Letters 43 (2002) 2083–2085
Scheme 3. Reagents and conditions: (i) PhCHꢀCHCOCl (1.1 equiv.), pyridine, CH2Cl2 −40“0°C; 5 n=3, 48%; n=4, 54%; n=5,
56%; (ii) LTA (1.1 equiv.), HMDS (2 equiv.), CH2Cl2.
namoyl chloride in the presence of pyridine. In each
case, only O-acylation occurred, the nucleophilicity of
the 3-amino group being greatly reduced by the elec-
tron-withdrawing Q-group. The corresponding O-cin-
(84%) which was ring-opened quantitatively to ester 14
with sodium methoxide in methanol. Further reaction
with samarium(II) iodide in the presence of b-dimethyl-
amino ethanol gave clean reduction to a mixture of
b-amino ester 15 and QNH2 16 which was separated by
chromatography.8 Comparison of the specific rotation
of this amino ester [h]D=21 (c 0.46, CHCl3) with that
in the literature9 {[h]D=22.3 (c 1.99 CHCl3)} shows
that it is R-configured in accordance with TSc model
11.10
namoyl esters
5 were each oxidised with lead
tetra-acetate in the presence of hexamethyldisilazane
(HMDS)5 and the isolated yields of aziridines 6 deter-
mined (Scheme 3).
That ester 5, n=4 gives the highest yield of aziridine is
accounted for by the presumed TSc 7 in which the
conformation of the tether is assumed to resemble
closely that in the product aziridine 6, n=4. This TSc
model 7 reveals the following favourable features (i) an
orthogonal approach of CꢀC and QꢁN bonds con-
tained in almost parallel planes as required for the
aziridination,4 (ii) an s-cis (see above) and planar ester
functionality, (iii) a staggered conformation for the
tetramethylene segment of the tether forming a chair-
like motif and (iv) overlap of the ester carbonyl oxygen
with the Q-group, a factor believed to be mandatory for
successful intermolecular aziridination of a,b-unsatu-
rated esters with QNHOAc compounds.6 In addition,
this model strongly suggested that a substituent R on
the carbon linking the tether to the Q-group would
greatly prefer an ‘equatorial’ location on the chair
motif as shown in TSc 8, i.e. would direct aziridination
onto the face of the a,b-unsaturated ester indicated
with 1,7-chirality induction (these aziridinations are
syn-stereospecific).
We have previously described the completely
diastereoselective intermolecular aziridination of methyl
acrylate and also of electron-available alkenes, e.g.
Scheme 4. Reagents and conditions: (i) NaH (2 equiv.),
BnOCH2CH2OH, THF then (S)-MeCHBrCO2H (89%); (ii)
NaOMe (1 equiv.), MeOH“sodium salt, (COCl)2, pyridine,
benzene; (iii) methyl anthranilate (2.2 equiv.), ether (99%); (iv)
Pd/C, H2, AcOH (91%); (v) NH2NH2, EtOH, 130°C, 4 h
(78%); (vi) PhCHꢀCHCOCl (1.2 equiv.), pyridine, CH2Cl2,
−20°C“rt (62%; 91% based on recovered 9).
For ease of incorporation of the chiral centre, we
synthesised crystalline 3-aminoquinazolinone (QNH2) 9
which includes an ether linkage in the tether by the
route shown in Scheme 4 in an overall yield of 62%
without the need for chromatography at any stage.
The enantiopurity of QNH2 9 was confirmed by
derivatisation with (R)-myrtenal and comparison of the
NMR spectrum of the product with the diastereoisomer
mixture using racemic QNH2 9.
O-Cinnamoylation of QNH2 9 and then addition of
ester 10 and LTA alternately in small portions to a
stirred dichloromethane solution gave an almost quan-
titative yield of aziridine 12 as a single crystalline
diastereoisomer via, it is assumed, TSc 11 (Scheme 5).
Scheme 5. Reagents and conditions: (i) LTA (1.1 equiv.),
HMDS (2 equiv.), CH2Cl2 (>95%); (ii) SmI2, THF, ButOH
(84%); (iii) MeOH, MeONa (>95%); (iv) SmI2, THF,
Me2N(CH2)2OH (40%).
Reduction of aziridine 12 with samarium(II) iodide7
took place regiospecifically to give crystalline lactone 13

R. S. Atkinson et al. / Tetrahedron Letters 43 (2002) 2083–2085
2085
butadiene and styrene with an enantiopure QNHOAc
compound and the conversion in some cases into Q-free
chirons11 but the method is less diastereoselective with
more substituted alkenes. The present method is poten-
tially applicable to a wide variety of a,b-unsaturated
acids and is likely to be tolerant of additional sub-
stituents on the a- and on the b-positions.12 Regiocom-
plementary ring-opening of the intramolecular
aziridination products, e.g. 12 can be anticipated by
appropriate choice of reagents.13
sis (Houben-Weyl); Thieme: Stuttgart, 1996; Vol. 5, pp.
2872–2904.
3. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: Oxford, 1993; Chapter 3.
4. For a review of aziridination of alkenes using QNHOAc
compounds, see: Atkinson, R. S. Tetrahedron 1999, 55,
1519–1559.
5. Atkinson, R. S.; Barker, E.; Ulukanli, S. J. Chem. Soc.,
Perkin Trans. 1 1998, 583–589.
6. Overlap of the ester carbonyl oxygen with the CꢀO or
CꢀN of the Q-ring can occur. See: Atkinson, R. S.;
Ulukanli, S. J. Chem. Soc., Perkin Trans. 2 1999, 771–
776.
7. Molander, G. A.; Stengel, P. J. J. Org. Chem. 1995, 60,
6660–6661.
Acknowledgements
We thank the EPSRC and Roche for support.
References
8. The isolated yield of b-amino ester 15 was 40% but after
significant loss on chromatography.
9. Jiang, J.; Schumacher, K. M.; Joullie´, M. M.; Davis, F.
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10. The ester of a racemic alcohol related to 9 (Ph replacing
Me) with E-2,3-dimethylacryloyl chloride (tiglyl chloride)
similarly underwent intramolecular aziridination with
LTA and an X-ray structure determination of the
product shows it to have the same relative configuration
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oxyaminoquinazolinones, some of which were thought at
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in 45% yield.
13. Ring-opening of aziridine 12 with acid, e.g. TFA, takes
place at the benzylic position.
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1989, 45, 6203–6210; (b) Bear, B. R.; Sparks, S. M.; Shea,
K. J. Angew. Chem., Int. Ed. 2001, 40, 820–849; (c)
Gauthier, D. R.; Zandi, K. S.; Shea, K. J. Tetrahedron
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