Novel routes to the kainates: Stereoselectivity in addition reactions to pyrrole [1,2c]-oxazol-3-one

Article abstract of DOI:10.1055/s-2004-829076

This paper describes the addition of a range of electrophiles to 1. An unusual and unpredicted stereochemistry of addition has been observed in line with our original photochemical observations.

Full text of DOI:10.1055/s-2004-829076

LETTER
1589
Novel Routes to the Kainates: Stereoselectivity in Addition Reactions to
Pyrrole [1,2c]-oxazol-3-one
N
ovel Routes to th
.
e
K
ainates J. Murray, P. J. Parsons,* E. S. Greenwood, E. M. E. Viseux
Department of Chemistry, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QJ, UK
E-mail: P.J.Parsons@sussex.ac.uk
Received 20 February 2004
We have also observed this apparent reversal of selectivi-
ty in hydroxylation reactions3 and we now wish to report
on our other findings in this area together with molecular
modelling studies for the facial selectivity observed.
Abstract: This paper describes the addition of a range of electro-
philes to 1. An unusual and unpredicted stereochemistry of addition
has been observed in line with our original photochemical observa-
tions.
Key words: electrophilic attack, photochemical addition, kainates, The oxazolidine 14 was synthesised from the alcohol 5
(Scheme 3).5
oxazolidinone, ab initio calculations, molecular modelling
i
We have been involved in the synthesis of kainic acid and
N
N
the family of excitatory amino acids.1 We recently report-
ed that the photochemical addition of the oxazolidine 1 to
the enone 2 resulted in the formation of the cyclobutane 3
with unexpected stereochemical outcome (Scheme 1).
Boc
OH
O
O
5
1
Reagents: i. Et2NSF3, CH2Cl2, 75%.
Scheme 3
O
O
Me
O
The enantiomerically pure oxazolidine 1 was reacted with
a series of electrophilic reagents and other activated re-
agents to give products with unexpected stereochemistry
(Table 1).
H
H
O
i
H
O
O
N
O
N
O
Of note, the approach of electrophiles on alkene 1 in all
entries is directed on the endo face. The observed regio-
chemistry and diastereoselectivity of the nucleophilic at-
tack of hydroxide or chloride nucleophiles on the
activated iodonium and episulfonium ionic intermediates
in entries 4 and 5 suggest that the reaction proceeds under
steric control, with delivery made on the least hindered
carbon.
O
2
1
O
3
Reagents: i. hν / EtOAc, 38%.
Scheme 1
A recent paper by Pyne and co-workers has described the
dihydroxylation of alkene 1 in which they also observed
the unexpected diol 4 (Scheme 2).2
Treatment of the iodohydrin 7 with base gave the enantio-
merically pure epoxide 9 (Scheme 4).
OH
HO
I
HO
O
i
N
N
i
O
O
N
N
O
O
O
O
O
O
1
4
7
9
Reagents: i. OsO4 (cat.), NMO, (CH3)2CO/H2O, 7 h, 83%.
Reagents: i. KOH, EtOAc, 45%.
Scheme 2
Scheme 4
Hadjiarapoglou previously reported on the stereoselectiv-
ity of the epoxidation of alkenes by DMDO. It was pro-
posed that hydrogen bonding between the dioxirane and
the substrate (Figure 1) accounted for the observed facial
selectivity.7 However, stabilisation of the transition state
SYNLETT 2004, No. 9, pp 1589–1591
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829076; Art ID: D04504ST
© Georg Thieme Verlag Stuttgart · New York
2
2.
0
7.
2
0
0
4

1590
A. J. Murray et al.
LETTER
Table 1 Reaction of 1 with a Series of Electrophilic Reagents
calculated with MM+ set) and molecular orbitals of the
most stable conformer using the 6-31G* polarisation basis
set. Of note, the model predicts that the lone pair of elec-
trons of the nitrogen atom in the oxazolidinone ring is out
of conjugation with the carbonyl functionality. Indeed, the
observed IR stretch frequency of the C=O bond is at the
higher end (1751 cm–1) for an N-alkyl substituted oxazo-
lidinone. The HOMO reveals an unsymmetrical p bond
with a higher electronic density on the endo face of the bi-
cyclic system, partially accounting for the exceptional
endo diastereoselectivity of the electrophilic attack of
DMDO and osmium tetroxide observed on our system.
Though Furstoss observed endo approach of the p-system
on the lactone analogue 10 (Figure 3),8 only partial selec-
tivity was observed. This electrophilic attack of the cyclo-
pentene cannot be rationalised from hyperconjugative
electron release from an axial hydrogen atom (the Cieplak
effect),9 as there is no activation by a neighbouring carbo-
nyl group. Once again, the stabilising effect by hydrogen
bonding postulated by Hadjiarapoglou does not explain
the observed endo selectivity in the case of the lactone
analogue.
Entry Starting
material
Reagent
Product
Yield
33%
1
m-CPBA
O
N
O
N
O
O
1
O
2
3
1
1
DMDO6
OsO4
6
80%
83%
OH
HO
HO
Cl
N
O
O
4
4
5
1
1
60%
65%
O
N
O
I
I
N
O
O
7
PhSCl
SPh
N
O
O
8
could not account for the facial discrimination observed
on our system, as this would lead to an approach of the
b-face leading to epoxide 9. Pyne discordantly invokes a
stereoelectronic shielding of pseudo-axial protons H5b
and H7a, favouring the endo selectivity.2
Figure 2 6-31G* representation of the HOMO of oxazolidinone 1
O
O
O
H
H
10
O
O
O
O
H
H
O
Figure 3
Interestingly, it was noticed when modelling the lactone
analogue that the pseudoaxial protons exert a different
shielding effect on the convex face of the alkene to the one
in our oxazolidinone. Indeed, the replacement of a nitro-
gen atom by a carbon atom has a tremendous impact on
the conformation of the bicyclic system. The access to the
concave face of the lactone is therefore much more
restricted, due to a more folded butterfly shape. These
observations could account for the lower facial selectivity
of the epoxidation of the lactone (Figure 4).
Figure 1 Hadjiarapoglou’s proposed transition state for the epoxi-
dation of cyclic alkenes
A quantitative theoretical characterisation of the origin of
the complete diastereoselection of both the electrophilic
dihydroxylation and the electrophilic epoxidation of the
alkene 1 was accomplished by locating the most stable
conformer by molecular mechanics conformational
searching and ab initio studies at the 6-31G* level.
Figure 2 shows plots of the preferred conformation (as
Synlett 2004, No. 9, 1589–1591 © Thieme Stuttgart · New York

LETTER
Novel Routes to the Kainates
1591
Acknowledgement
We thank the EPSRC, the Royal Commission for the Exhibition of
1851 and Tocris Cookson Ltd for grants. We wish to thank Dr. A.
G. Avent and Dr. A. K. Sada for performing NMR and mass
spectroscopy experiments. We thank Dr. C. Penkett for very useful
discussions.
References
Figure 4 MM+ representations of the lactone analogue 10 (left) and
oxazolidinone 1 (right)
(1) Greenwood, E. S.; Parsons, P. J. Tetrahedron 2003, 18,
3307.
(2) Davis, A. S.; Gates, N. J.; Lindsay, K. B.; Tang, M.; Pyne, S.
G. Synlett 2004, 49.
(3) Murray, A. Third Year Report; University of Sussex: UK,
2002.
(4) Greenwood, E. S. D. Phil Thesis; University of Sussex: UK,
2001.
With the epoxide 6 in hand, we next studied the addition
of nucleophiles to it in order to prepare kainate analogues.
Addition of isopropenylmagnesium bromide to 6 in the
presence of cuprous bromide dimethyl sulfide complex
gave the alcohol 11 as the major product (Scheme 5).10
(5) (a) Schumacher, K. K.; Jiang, J.; Joullie, M. M.
Tetrahedron: Asymmetry 1998, 9, 47. (b) Abraham, D. J.;
Mokotoff, M.; Sheh, L.; Simmons, J. C. J. Med. Chem. 1983,
26, 549. (c) Zhao, H.; Thurkauf, A. Synlett 1999, 1280.
(6) Typical Experimental Procedure:11
OH
O
H
O
H
i
(5R,6S,7R)-1-aza-3-oxa-6,7-epoxybicyclo[3,3,O]-octan-2-
one (6).
N
N
O
To a stirred solution of oxazolidinone 1 (4.00 g, 32 mmol) in
dimethoxymethane (130 mL) and MeCN (260 mL) were
added tetrabutylammonium hydrogen sulfate (0.43 g, 1.28
mmol), acetone (71 mL, 960 mmol) and K2CO3 (0.1 M in
water, 64 mL). A solution of EDTA (4 × 10–4 M in water,
341 mL) acidified with enough HOAc to dissolve the
insoluble solid was added to oxone® (78.7 g, 992 mmol). The
resulting solution and a solution of K2CO3 (87.2 g, 631.5
mmol) in water (341 mL) were concomitantly added to the
initial solution of oxazoline 1 over 5 h. The reaction mixture
was then extracted with EtOAc (3 × 100 mL) and washed
with brine (100 mL) and water (100 mL). The combined
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. The resulting oil was purified by
flash column chromatography (60% EtOAc–petroleum
ether) to give epoxide 6 as a white crystalline solid (3.60 g,
80%); mp (uncorrected) 60–63 °C; [a]23D –8.6 (c = 1.91,
CHCl3). IR (film): 3059, 2922, 1748 (s), 1410 (s), 1199,
1075 (s) cm–1. 1H NMR (500 MHz, C6D6): d = 3.95 (dd,
J = 8.7, 3.6 Hz, 1 H), 3.87 (apparent t, J = 8.7 Hz, 1 H), 3.80
(d, J = 13.2 Hz, 1 H), 3.08 (dd, J = 8.7, 3.6 Hz, 1 H), 2.97 (d,
J = 2.8 Hz, 1 H), 2.91 (d, J = 2.8 Hz, 1 H), 2.50 (d, J = 13.2
Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 163.2, 64.5, 58.4,
55.7, 55.5, 48.9. HRMS: m/z [M+] calcd for C6H7NO3:
141.0426; found: 141.0420.
O
O
6
11
Reagents: i.
, CuBr·S(CH3)2, THF/Et2O/(CH3)2S, 78%.
MgBr
Scheme 5
The chemistry shown in Scheme 5 is very pleasing as it
allows a facile entry into the kainate ring system. The al-
cohol 11 was converted into its triflate ester 12. Displace-
ment of the triflate group in 12 with thiophenol in the
presence of base gave the oxazolidinone 13 (Scheme 6).
OSO2CF3
ii
OH
O
SPh
i
N
N
N
O
12
O
O
O
O
11
13
Reagents: i. (CF3SO2)2O, pyridine, CH2Cl2, 92%;
ii. NaH, PhSH, THF, 62%.
(7) Asouti, A.; Hadjiarapoglou, L. P. Synlett 2001, 1847.
(8) Andrau, L.; Lebreton, J.; Viazzo, P.; Alphand, V.; Furstoss,
R. Tetrahedron Lett. 1997, 38, 825.
Scheme 6
(9) (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
(b) Katagiri, N.; Ito, Y.; Kitano, K.; Toyota, A.; Kaneko, C.
Chem. Pharm. Bull. 1994, 42, 2653. (c) Mahmodian, M.;
Baines, B. S.; Dawson, M. J.; Lawrence, G. C. Enzyme
Microb. Technol. 1992, 14, 911.
Application of the chemistry described in Scheme 6 to the
total synthesis of kainic acid and its analogues will be
reported in the near future.
(10) The addition of 2-propenylmagnesium bromide in the
presence of Cu(I) gave a 6:1 mixture of regioisomers in
favour of desired alcohol 10 as determined by high field
NMR (500 MHz).
(11) Modification of the procedure described in: Shi, Y.; Whang,
Z.; Froha, M. J. Org. Chem. 1998, 63, 6425.
Synlett 2004, No. 9, 1589–1591 © Thieme Stuttgart · New York