Desymmetrisation of (4R,5S)-4,5-diphenylimidazolidine-2-thione using pentafluorophenyl active esters

Article abstract of DOI:10.1016/j.tetlet.2010.01.019

(4R,5S)-4,5-Diphenylimidazolidine-2-thione is efficiently desymmetrised by stereorandom deprotonation with NaHMDS, followed by kinetic resolution of the resulting racemic intermediate with an enantiomerically pure pentafluorophenyl active ester. The levels of diastereocontrol were found to be excellent (86-92% de at ～30% conversion). This desymmetrisation reaction is an example of a masked resolution.

Full text of DOI:10.1016/j.tetlet.2010.01.019

Tetrahedron Letters 51 (2010) 1423–1425
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Tetrahedron Letters
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Desymmetrisation of (4R,5S)-4,5-diphenylimidazolidine-2-thione using
pentafluorophenyl active esters
b
a
b
Anna Andreou a, Jason Eames a, , Majid Motevalli , Timothy J. Prior , Michael Watkinson
*
a Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
b School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
(4R,5S)-4,5-Diphenylimidazolidine-2-thione is efficiently desymmetrised by stereorandom deprotona-
tion with NaHMDS, followed by kinetic resolution of the resulting racemic intermediate with an enanti-
omerically pure pentafluorophenyl active ester. The levels of diastereocontrol were found to be excellent
(86–92% de at ꢀ30% conversion). This desymmetrisation reaction is an example of a masked resolution.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 December 2009
Revised 22 December 2009
Accepted 8 January 2010
Available online 13 January 2010
Since 2000, we have been interested in the kinetic, mutual and
parallel kinetic resolutions of pentafluorophenyl active esters, such
as (rac)-2, using 4-phenyl-oxazolidin-2-(thi)ones, such as (S)-1
(Scheme 1).1–3 Treatment of 4-phenyl-oxazolidin-2-thione (S)-1
in THF with n-BuLi at ꢁ78 °C followed by the addition of pentaflu-
orophenyl 2-(6-methoxynaphthalen-2-yl)propanoate (rac)-2 gave
after 2 h the corresponding oxazolidin-2-thione adduct (R,S)-syn-
3 in 30% yield with high levels of diastereoisomeric control
(Scheme 1).3 The resolved active ester, (S)-2, was recovered in
50% yield with 44% ee.3
with excellent levels of diastereocontrol (92% de) (measured by
400 MHz 1H NMR spectroscopy)6 (Scheme 2).
The stereochemical outcome of this process was identical to
that of our previous kinetic, mutual and parallel kinetic resolution
studies;1 the level of molecular recognition between the (S)-enan-
tiomer of active ester 2 and the C(4)–carbon atom of the thiourea 4
bearing the (R)-stereocentre/phenyl group was excellent (92% de).
The stereochemistry of the major diastereoisomeric 4,5-dipheny-
limidazolidine-2-thione (S,R,S)-syn,syn-5 was confirmed by X-ray
crystallography (Fig. 1).7
We now report a novel application of this methodology for the
desymmetrisation of meso-thioureas using enantiomerically pure
pentafluorophenyl active esters. We first chose to investigate
the desymmetrisation of 4,5-diphenylimidazolidine-2-thione
(R,S)-meso-44,5 due to its structural resemblance to 4-phenyl-oxaz-
olidin-2-thione (S)-1 (Schemes 1 and 2). Treatment of 4,5-dipheny-
limidazolidine-2-thione (R,S)-meso-4 in THF with NaHMDS at
ꢁ78 °C followed by the addition of pentafluorophenyl 2-(6-meth-
oxynaphthalen-2-yl)propanoate (S)-2 gave after 2 h the substituted
With this information at hand, we next investigated the desym-
metrisation of 4,5-diphenylimidazolidine-2-thione (R,S)-meso-4
using three structurally related pentafluorophenyl active esters
(S)-6, (R)-7 and (R)-8 (Fig. 2).
These active esters behaved similarly to active ester (S)-2 giving
the corresponding substituted thioureas (S,R,S)-syn,syn-9 {½a D20
ꢂ
+64.7 (c 3.4, CHCl3)}, (R,S,R)-syn,syn-10 {½a D20
ꢁ24.5 (c 2.2, CHCl3)}
ꢂ
and (R,S,R)-syn,syn-11 {½a D20
ꢁ32.4 (c 1.8, CHCl3)} in 30–35% yields
ꢂ
with good levels of diastereocontrol (84–92% de) (Scheme 3). The
levels of diastereocontrol were higher for the more sterically
thiourea (S,R,S)-syn,syn-5 {½a D20
ꢂ
+173.2 (c 3.2, CHCl3)} in 32% yield
MeO
S
S
O
1. n-BuLi
THF, -78 o
C
N
O
HN
Ph
O
MeO
2.
Me
CO2C6F5
Me
Ph
(rac)-2
(R,S)-syn-3
30%; 86% de
(S)-1
Scheme 1. Resolution of active ester (rac)-2 using 4-phenyl-oxazolidin-2-thione (S)-1.
* Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410.
E-mail address: j.eames@hull.ac.uk (J. Eames).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.019

1424
A. Andreou et al. / Tetrahedron Letters 51 (2010) 1423–1425
S
1. NaHMDS
THF, -78 oC
HN
NH
2. (S)-2
Ph
Ph
(R,S)-meso-4
OMe
MeO
S
S
O
O
HN
N
N
NH
Ph
Me
Me
Ph
(R,S,S)-syn,anti-5
32%; 92% d.e
Ph
Ph
96:4
(S,R,S)-syn,syn-5
Scheme 2. Desymmetrisation of 4,5-diphenylimidazolidine-2-thione (R,S)-meso-4 using active ester (S)-2.
demanding pentafluorophenyl 2-phenylbutanoate (R)-8. It is wor-
thy of note that the use of active esters (R)-7 and (R)-8 allows the
access to two similar quasi-enantiomeric 4,5-diphenylimidazoli-
dine-2-thiones (R,S,R)-syn,syn-10 and (R,S,R)-syn,syn-11; in addi-
tion their specific rotations have the expected opposite sign of
rotation [compared to (S,R,S)-syn,syn-9].
We next turned our attention towards a parallel desymmetrisa-
tion of 4,5-diphenylimidazolidine-2-thione (R,S)-meso-4 using a
pair of quasi-enantiomeric active esters (S)-2 and (R)-7 (Scheme
4). Deprotonation of (R,S)-meso-4 using NaHMDS in THF at
ꢁ78 °C followed by the addition of a solution of quasi-enantiomeric
active esters (S)-2 and (R)-7 in THF gave after 2 h a mixture of two
diastereoisomeric thioureas (S,R,S)-syn,syn-5 (in 25% yield) and
(R,S,R)-syn,syn-10 (in 29% yield) with >90% de. These adducts 5
and 10 were easily separable by column chromatography due to
the more polar 6-methoxynaphthalen-2-yl group in 5 {
petroleum ether/diethyl ether (1:1)] = ꢀ0.10}.
DRf [light
Figure 1. ORTEP diagram of 3-[2-(6-methoxynaphthalen-2-yl)propionyl]-4,5-
diphenyl-imidazolidine-2-thione (S,R,S)-syn,syn-5. Displacement ellipsoids are
drawn at 50% probability level.
This overall desymmetrisation procedure is an example of a
masked resolution as stereorandom deprotonation of 4,5-dipheny-
limidazolidine-2-thione (R,S)-meso-4 with NaHMDS leads to a
racemic8 sodiated thiourea 4-Na (Scheme 5). Parallel resolution9
of this sodiated thiourea (rac)-4-Na using an equimolar amount
of active esters (S)-2 and (R)-7 gives complementary 4,5-dipheny-
limidazolidine-2-thiones (S,R,S)-syn,syn-5 and (R,S,R)-syn,syn-10,
respectively, in a near equal amount.
Ph
CO2C6F5
CO2C6F5
Ph
CO2C6F5
Me
(R)-7
Et
(R)-8
Me
(S)-6
In conclusion, we have shown that a series of structurally related
pentafluorophenyl active esters (S)-2, (S)-6, (R)-7 and (R)-8 can be
used to efficiently desymmetrise 4,5-diphenylimidazolidine-2-
Figure 2. Pentafluorophenyl active esters (S)-6, (R)-7 and (R)-8.
S
S
S
O
O
1. NaHMDS
THF, -78 o
2. (S)-6
1. NaHMDS
THF, -78 oC
Ph
C
HN
Ph
(R,S,R)-syn,syn-10; 35%; 84% de
N
N
NH
Ph
HN
Ph
NH
Ph
2. (R)-7
Me
Me
Ph
Ph
(S,R,S)-syn,syn-9; 31%; 84% de
(R,S)-meso-4
1. NaHMDS
THF, -78 o
2. (R)-8
C
S
O
Ph
HN
N
Et
Ph
Ph
(R,S,R)-syn,syn-11; 30%; 92% de
Scheme 3. Desymmetrisation of 4,5-diphenylimidazolidine-2-thione (R,S)-meso-4 using active esters (S)-6, (R)-7 and (R)-8.

A. Andreou et al. / Tetrahedron Letters 51 (2010) 1423–1425
1425
MeO
S
O
N
NH
Ph
Me
Ph
1. NaHMDS
THF, -78 oC
(S,R,S)-syn,syn-5; 25%; >90% de
(R,S)-meso-4
2. (S)-2 +
(R)-7
S
O
Ph
HN
N
Me
Ph
Ph
(R,S,R)-syn,syn-10; 29%; >90% de
Scheme 4. Parallel desymmetrisation of 4,5-diphenylimidazolidine-2-thione (R,S)-meso-4 using two active esters (S)-2 and (R)-7.
diphenylimidazolidine-2-thione (R,S,R)-anti,syn-5, the PhCHNC@O doublet
appeared at 5.69 ppm (1 H, d, J = 9.1).
7. The crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre (reference number: CCDC 756360).
8. This comprises of an equimolar mixture of (R,S)-4-Na and (S,R)-4-Na.
9. For reviews on parallel kinetic resolutions, see: (a) Eames, J. Angew. Chem., Int.
Ed. 2000, 39, 885–888; (b) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–
370.
SNa
NH
SNa
N
S
NaHMDS
THF, -78 o
N
HN
Ph
HN
Ph
NH
Ph
C
Ph
Ph
(rac)-4-Na
Ph
(R,S)-meso-4
10. Representative experimental procedure: Synthesis of (2S,4R,5S)-3-[2-(6-
methoxynaphthalen-2-yl)propionyl]-4,5-diphenyl-imidazolidine-2-thione (S,R,S)-
syn,syn-5: Sodium bis(trimethylsilyl)amide (0.22 mL, 1 M in THF, 0.22 mmol)
was added to a stirred solution of 4,5-diphenylimidazolidine-2-thione (R,S)-
meso-4 (50 mg, 0.20 mmol) in THF (1.5 mL) at ꢁ78 °C. After stirring for 1 h, a
solution of pentafluorophenyl 2-(6-methoxynaphthalen-2-yl)propanoate (S)-2
(86 mg, 0.22 mmol) in THF (1 mL) was added. The resulting mixture was
stirred for 2 h at ꢁ78 °C. The reaction was quenched with H2O (10 mL). The
organic layer was extracted with CH2Cl2 (2 ꢃ 10 mL), dried (MgSO4) and
evaporated under reduced pressure to give a mixture of diastereoisomeric 4,5-
diphenylimidazolidine-2-thione syn,syn- and syn,anti-5 [ratio 94:6 syn-:anti-].
The crude residue was purified by flash chromatography on silica gel eluting
with light petroleum ether (bp 40–60 °C)/Et2O (8:2) to give (2S,4R,5S)-3-[2-(6-
methoxynaphthalen-2-yl)propionyl]-4,5-diphenyl-imidazolidine-2-thione (S,R,S)-
syn,syn-5 (29 mg, 32%) as a white flaky solid; Rf [light petroleum ether (bp
Scheme 5. Formation of racemic sodiated 4,5-diphenylimidazolidine-2-thione
(rac)-4-Na.
thione (R,S)-meso-4 in good yields.10 The levels of diastereocontrol
were found to be excellent (84–92%) favouring the formation of the
corresponding (R*,S*,R*)-syn,syn-thiourea adducts 5, 9, 10 and 11.
This desymmetrisation process is a masked kinetic resolution as it
proceeds via the formation and resolution of an intermediate
racemic sodiated thiourea (rac)-4-Na. Enantioselective desymmet-
risation of meso-compounds11 such as alkenes,12 amines,13 anhy-
drides,14 diols15 and epoxides16 is very well documented. The
nearest analogy to our study is Fu’s desymmetrisation of meso-
1,5-diols using an enantiomerically pure acyl transfer reagent.17
40–60 °C)/Et2O (1:1)] 0.50; ½a D20
þ 173:2 (c 3.2, CHCl3); mp 97–100 °C; mmax
ꢂ
(CHCl3) 1705 (C@O) and 1216 (C@S) cmꢁ1; dH (400 MHz; CDCl3) 7.57 (1H, d,
J = 8.4 Hz, CH; Ar), 7.45 (1H, d, J = 9.7 Hz, CH; Ar), 7.37 (1H, s, CH; Ar), 7.33 (1H,
dd, J = 8.4 and 1.7 Hz, CH; Ar), 7.02–6.88 (6H, m, 6 ꢃ CH; Ar and Ph), 6.75–6.68
(4H, m, 4 ꢃ CH; Ph), 6.63 (1H, br s, NH), 6.41 (2H, d, J = 7.4 Hz, 2 ꢃ CH; Ph), 6.32
(1H, q, J = 6.8 Hz, ArCHCH3), 5.92 (1H, d, J = 9.2 Hz, PhCHNC@O), 5.22 (1H, d,
J = 9.2 Hz, PhCHN), 3.85 (3H, s, OCH3) and 1.45 (3H, d, J = 6.8 Hz, ArCHCH3); dC
(100 MHz; CDCl3) 181.8 (C@S), 175.1 (C@O), 157.5 (i-CO; Ar), 135.5 (i-C; Ar),
134.5 (i-C; Ph), 134.1 (i-C; Ph), 133.5 (i-C; Ar), 129.4 (CH; Ar), 128.8 (i-C; Ar),
128.3 (CH; Ph), 128.2 (2C, 2 ꢃ CH; Ph), 128.0 (CH; Ar), 127.8 (2C, 2 ꢃ CH; Ph),
127.6 (CH; Ph), 127.0 (2C, 2 ꢃ CH; Ph), 126.8 (CH; Ar), 126.7 (2C, 2 ꢃ CH; Ph),
126.6 (CH; Ar), 118.5 (CH; Ar), 105.5 (CH; Ar), 67.5 (PhCHNC@O), 61.8 (PhCHN),
55.3 (OCH3), 43.8 (ArCHCH3) and 19.7 (ArCHCH3). (Found MH+, 467.1787;
C29H27N2O2S requires MH+, 467.1788.)
Acknowledgement
We are grateful to the EPSRC National Mass Spectrometry Ser-
vice (Swansea) for accurate mass determinations.
References and notes
1. Yohannes, Y. PhD Thesis, University of London, 2004.; (b) Coumbarides, G. S.;
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2005, 46, 2897–2902; (c) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
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Chavda, S.; Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Motevalli, M.; Northen, J.; Yohannes, Y. Tetrahedron: Asymmetry 2007, 18,
2515–2530.
2. For resolution of racemic 1-phenylethanol using related pentafluorophenyl
active esters; see: (a) Coulbeck, E.; Eames, J. Synlett 2008, 333–338; (b)
Coulbeck, E.; Eames, J. Tetrahedron Lett. 2009, 50, 4449–4451.
11. Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765–1784.
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Chem. Soc. 1987, 109, 1525–1529; (b) Hodgson, R.; Majid, T.; Nelson, A. J. Chem.
Soc., Perkin Trans. 1 2002, 1631–1643; (c) Lorenz, J. C.; Frohn, M.; Zhou, X.;
Zhang, J.-R.; Tang, Y.; Burke, C.; Shi, Y. J. Org. Chem. 2005, 70, 2904–2911.
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Gotor-Fernandez, V.; Montejo-Bernardo, J.; Garcia-Granda, S.; Gotor, V. Org.
Lett. 2007, 9, 4203–4206.
14. (a) Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 142–146; (b) Evans, A.
ˇ
C.; Longbottom, D. A.; Matsuoka, M.; Davies, J. E.; Turner, R.; Franckevicius; Ley,
S. V. Org. Biomol. Chem. 2009, 7, 747–760.
15. Review Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965–2983.
16. Review Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361–
14384.
3. Al-Shaye, N.; Broughton, T.; Coulbeck, E.; Eames, J. Synlett 2009, 960–964.
4. Ali, M. I.; El-Sayed, A. A.; Hammouda, H. A. J. Prakt. Chem. 1976, 318, 168–172.
5. 4,5-Diphenylimidazolidine-2-thione
(R,S)-meso-4
can
be
efficiently
synthesised from meso-1,2-diphenylethane-1,2-diamine and carbon disulfide.
For a representative procedure, see: Davies, S. G.; Mortlock, A. A. Tetrahedron
1993, 49, 4419–4438.
17. Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794–2795.
6. For 4,5-diphenylimidazolidine-2-thione (S,R,S)-syn,syn-5, the PhCHNC@O
doublet appeared at 5.92 ppm (1 H, d, J = 9.2). In comparison, for 4,5-