Regioselective and diastereoselective phosphine-catalysed [3+2] cycloadditions to 5-methylenehydantoins: Reversal of regioselectivity using chiral N-2-butynoyl-(4S)-benzyloxazolidinone

Article abstract of DOI:10.1016/S0040-4039(02)01245-5

The phosphine-catalysed [3+2] cycloaddition of 5-methylenehydantoins 1 with the ylides 2a and 2b gives spirocyclic products with reverse regioselectivities; the latter ylide gives optically active products.

Full text of DOI:10.1016/S0040-4039(02)01245-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5953–5956
Regioselective and diastereoselective phosphine-catalysed [3+2]
cycloadditions to 5-methylenehydantoins: reversal of
regioselectivity using chiral
N-2-butynoyl-(4S)-benzyloxazolidinone
Tien Q. Pham,a Stephen G. Pyne,a,* Brian W. Skeltonb and Allan H. Whiteb
aDepartment of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
bDepartment of Chemistry, University of Western Australia, Crawley, WA 6009, Australia.
Received 6 June 2002; revised 24 June 2002; accepted 27 June 2002
Abstract—The phosphine-catalysed [3+2] cycloaddition of 5-methylenehydantoins 1 with the ylides 2a and 2b gives spirocyclic
products with reverse regioselectivities; the latter ylide gives optically active products. © 2002 Elsevier Science Ltd. All rights
reserved.
The phosphine-catalysed cycloaddition of ethyl buta-
2,3-dienoate or ethyl butynoate with an electron-
deficient alkene has been established as a useful method
for preparing substituted ethyl 1-cyclopentenecarboxy-
lates.1–8 Optically active versions of these products can
be obtained using either a chiral electron-deficient
alkene,5,8 giving spiro-heterocyclic derivatives, or a chi-
ral phosphine catalyst.6 As part of a project aimed at
preparing carbocyclic analogues (A) of the potent her-
bicide, hydantocidin9 we have examined the phosphine-
catalysed [3+2] cycloaddition of 5-methylenehydantoins
1 with the ylides 2a and 2b, that were generated in situ
from the reaction of ethyl butynoate 3a and N-(2-
butynoyl)-(4S)-benzyloxazolidinone 3b, respectively,
with tributylphosphine (TBP). Compounds 1 and 3b
have not been previously investigated as components
for these types of cycloaddition reactions. Interestingly
we have found that the ylide 2b that was generated
from 3b gives optically active products with the reverse
regioselectivity to that of the traditionally used ethyl
butynoate 3a (Scheme 1).
5-Methylenehydantoin 1 (R1=R2=Bn) and its p-
methoxybenzyl (PMB) analogue 1 (R1=R2=PMB)
were prepared using literature procedures.10 The other
5-methylenehydantoins were prepared from 5-hydroxy-
methylhydantoin by selective N-benzylation (KOBut,
BnCl, DMSO, rt, 1 h),11 followed by treatment with
Boc2O (2.1 equiv.)/DMAP (0.2 equiv.)/MeCN, at rt for
18 h or Ac2O (4 equiv.)/Et3N (2 equiv.) at rt for 8 h.
COX
HO
OH
Bu3P
O
R1
HO
O
+
R1
N
O
O
N
HN
X
N
N
NH
2
O
R2
O
R2
O
Bu3P
1
A
4
a; X = OEt
b; X =
O
O
Me
X
N
O
3
Bn
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01245-5

5954
T. Q. Pham et al. / Tetrahedron Letters 43 (2002) 5953–5956
COX
4'
O
Bu3P
2'
5'
1'
COX
O
R1
O
+
Me
R1
+
R1
N
O
N
N
X
benzene, RT
2
N
3
N
N
O
R2
O
R2
O
R2
a; X = OEt
1
O
5
4
b; X =
N
O
Bn
Scheme 1.
The ylide 2a was generated in situ from the reaction of
ethyl butynoate (2 equiv.) and TBP (0.1 equiv.) in the
presence of 1 (R1=R2=Bn) in benzene solution at rt for
15 h. This reaction gave essentially a single regioisomer
(4a) from 1H NMR analysis of the crude reaction
mixture. Column chromatography gave pure racemic 4a
in 81% yield based on the moles of 1 (Table 1, entry 1).
The related triphenylphosphonium ylide was generated
in situ from ethyl buta-2,3-dienoate12a,b (2 equiv.) and
triphenylphosphine (0.1 equiv.) and reacted with 1 (R1=
R2=Bn) to give an 80:20 mixture of the two regioisomers
4a and 5a that were readily separated by column chro-
matography (Table 1, entry 2). Pure 4a and 5a (both
racemic) were obtained in yields of 65% and 17%,
respectively. In general, regioisomers 4a,b showed
olefinic resonances upfield (l 6.40–6.69) of the corre-
sponding resonances for 5a,b (l 7.02–7.20).13 The struc-
tures of 4a and 5a were determined by extensive 2D
NMR studies. In particular, NOESY experiments on 4a
(R1=R2=Bn) showed cross peaks between the N-2
benzyl methylenes and H2%a and H5%a. While HMBC
experiments revealed three bond-coupling between H2%b
and H5%b, consistent with the small dihedral angle
between these protons and C1.14 The related PMB
analogue 1 (R1=R2=PMB) gave a mixture of regioiso-
mers in favour of the regioisomer 4a (R1=R2=PMB).
The major regioisomer could be isolated pure in 68%
yield (Table 1, entry 3). The 1-Boc and 1-acetyl-3-benzyl-
5-methylenehydantoins 1 (R1=Boc R2=Bn) and 1 (R1=
Ac R2=Bn), respectively, also reacted with the ylide 2a
to give 4a (R1=Boc, R2=Bn) and 4a (R1=Ac, R2=Bn)
as the major regioisomers, respectively (Table 1, entries
4 and 5).
In contrast, the 5-methylenehydantoin 1 (R1=R2=Bn)
reacted with the ylide 2b, that was generated in situ from
the reaction of optically active (>98% ee) 3b15 (2 equiv.)
and TBP (0.1 equiv.), in benzene solution at rt for 15 h
to give a 11:89 mixture of 4b and 5b (R1=R2=Bn) (Table
1, entry 6). Diastereomerically pure 5b (R1=R2=Bn)
was isolated in 54% yield while 4b (R1=R2=Bn) was
obtained as a 1:1 mixture of diastereomers. The 5-
methylenehydantoins 1 (R1=R2=PMB) and 1 (R1=
Boc, R2=Bn) also reacted with the ylide 2b to give
mixtures that favoured regioisomer 5b over 4b (Table 1,
entries 7 and 8). The major regioisomers 5b (R1=R2=
PMB) and 5b (R1=Boc, R2=Bn) were obtained as single
diastereomers while the minor regioisomers 4b (R1=
R2=PMB) and 4b (R1=Boc, R2=Bn) were obtained as
1:1 mixtures of diastereomers.
Table 1. TBP-catalysed cycloaddition reactions between 5-methylene hydantoins 1 and alkynes 3a and 3b in benzene solution
at rt
Entry
Hydantoin 1
Alkyne 3
Products
Ratio 4:5h (de)i
R1
R2
Yield (%)b
1
2
3
4
5
6
7
8
Bn
Bn
PMB
Boc
Ac
Bn
PMB
Boc
Bn
Bn
PMB
Bn
Bn
Bn
PMB
Bn
3a
81
\98:B2
80:20
83:17
78:22
Allenea
3a
82c
86d
57e
43e
61f
39g
43e
3a
3a
3b
3b
80:20
11 (0%):89 (\98%)
18 (0%):82 (\98%)
5 (0%):95 (\98%)
3b
a Ethyl 2,3-butadienoate (2 equiv.) used with triphenylphosphine (0.1 equiv.).
b Combined yield of 4 and 5 after purification by column chromatography. Compounds 4a and 5a are racemic.
c Yield of 4 was 65%, yield of 5 was 17%.
d Yield of 4 was 68%, yield of 5 was 18%.
e Compounds 4 and 5 could not be separated.
f Yield of 4 was 7%, yield of 5 was 54%.
g Yield of 4 was 7%, yield of 5 was 32%.
h Determined by integration of the alkene resonances for 4 and 5.
i Determined by 1H NMR.

T. Q. Pham et al. / Tetrahedron Letters 43 (2002) 5953–5956
5955
O
Sm(OTf)3
MeOH
O
CO
N
CO2Me Ce(NH4)2(NO3)6
PMB
PMB
O
O
MeCN/H2O
RT, 45 min
N
N
reflux, 12 h
(70%)
N
N
Ph
O
O
PMB
PMB
7
5b
O
CO2Me
CO2Me
O
CO2Me
O
O
+
N
HN
O
HN
O
+
NH
NH
N
O
OMe
MeO
10 (26%)
[α]D24 -33 (c 0.45 ,CHCl3)
8 (62%)
O
9 (11%)
10% HCl
100oC 30 min
microwave
(100%)
[X-ray]
COOH
COOH
HCl.H2N
(R)-11
[α]D23 -12 (c 1.05 ,H2O)
Scheme 2.
To determine the absolute stereochemistry of 5b (R1=
R2=PMB) the chiral auxiliary was removed by treat-
ment with samarium(III) triflate in methanol16 to give
the methyl ester 7 in 70% yield (Scheme 2). Treatment
of 7 with ceric ammonium nitrate in acetonitrile/water
gave the desired N,N-dideprotected derivative 10 [([h]D24
−33 (c 0.45, CHCl3)] in 26% yield plus the mono-depro-
tected/benzylic oxidation products, the amides 8 (62%)
and 9 (11%). Compound 9 formed single crystals from
which its relative structure could be unequivocally
determined by X-ray crystallographical structural analy-
sis,17 confirming our earlier regiochemical assignments
of our cycloaddition products 5. Microwave assisted
acid hydrolysis of 8 using 1N HCl at 100°C for 30 min
gave the known amino diacid 11.8 Its optical rotation
([h]2D3 −12 (c 1.05, H2O) matched closely in magnitude
that of the (S)-enantiomer (ee 88%) of this compound
([h]2D3 +11 (c 0.4, H2O)8 and the sign of the rotation
indicated 11 had the (R) stereochemistry.
The difference in regiochemical outcomes between 2a
and 2b with 1 suggests that electronic effects are
responsible for the reversal of regiochemistry rather
than steric effects. Based on steric considerations only,
transition state B would be expected to be less sterically
crowded and favoured over transition state C for both
2a and 2b (Scheme 3). Preliminary semiempirical calcu-
lations (AM1, PC Spartan Pro) on 2a and 2b suggest
that the magnitude of the FMO coefficient of the
HOMO of 2b is significantly larger at the g-position
than that in 2a, consistent with a reversing of the
observed regiochemical outcomes.
Acknowledgements
We thank the University of Wollongong for a Ph.D.
scholarship to T.Q.P.
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T. Q. Pham et al. / Tetrahedron Letters 43 (2002) 5953–5956
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