Enantiopure guanidine bases for enantioselective enone epoxidations: 2, cyclic guanidines

Article abstract of DOI:10.1055/s-2003-37107

A range of structurally and functionally varied enantiopure cyclic and bicyclic guanidines has been prepared and evaluated in the enantioselective epoxidation of 3-tert-butoxycarbonylamino-4,4-dimethoxycyclohexa-2,5-dien-1-one 1 using tert-butylhydroperoxide. Encouraging enantiomeric excesses were observed (up to 60%). Low enantiomeric excesses were also observed with 2-methylnaphthoquinone and trans-chalcone.

Full text of DOI:10.1055/s-2003-37107

LETTER
369
Enantiopure Guanidine Bases for Enantioselective Enone Epoxidations:
2, Cyclic Guanidines
E
nantiopu
u
re
G
uanidine
l
Bases
i
for Ena
e
ntioselective
E
no
C
ne
E
poxidations. McManus,a Thorsten Genski,a John S. Carey,b Richard J. K. Taylor*a
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
b
GlaxoSmithKline Pharmaceuticals, Leigh, Tonbridge, Kent TN11 9AN, UK
Received 20 December 2002
Abstract: A range of structurally and functionally varied enan-
tiopure cyclic and bicyclic guanidines has been prepared and eval-
uated in the enantioselective epoxidation of 3-tert-
butoxycarbonylamino-4,4-dimethoxycyclohexa-2,5-dien-1-one
1
using tert-butylhydroperoxide. Encouraging enantiomeric excesses
were observed (up to 60%). Low enantiomeric excesses were also
observed with 2-methylnaphthoquinone and trans-chalcone.
Key words: enantioselective, epoxidation, enones, guanidines,
stereoselectivity
There have been a number of recent advances concerning
the enantioselective epoxidation of electron-deficient al-
kenes but the epoxidation of cyclic enones has presented
particular problems.1 As discussed in more detail in the
accompanying paper,2 we have investigated the use of
asymmetric phase-transfer epoxidation,3 and asymmetric
epoxidations using sugar-derived hydroperoxides.4 We
have also reported t-butylhydroperoxide (TBHP)-mediat-
ed epoxidation reactions effected by enantiopure
guanidines (Scheme 1).2,5 We employed 3-tert-butoxycar-
Scheme 1
bonylamino-4,4-dimethoxycyclohexa-2,5-dien-1-one
1
ion-exchange chromatography on Amberlite® resin. Us-
ing this procedure, a range of functionally varied, enan-
tiopure monocyclic guanidines 6a–g were prepared as
free bases.9
with tert-butylhydroperoxide as the test system as the
product epoxide 2 is a versatile synthetic intermediate for
the preparation of manumycin and related natural prod-
ucts.6
Of the enantiopure guanidine-catalysts prepared in these
earlier studies, the best enantiomeric excesses (ee) ob-
served were using compounds 3,5 42 and 52 (Scheme 1),
but despite optimisation studies the reactions were slow
and the maximum ee was 35%. Given that the best ee was
obtained using the bicyclic guanidine 3, we decided to in-
corporate greater conformational rigidity into the
guanidines and investigate the monocyclic and bicyclic
systems 6–8 (Scheme 1).
We also attempted the N-methylation of these monocyclic
bases but only produced complex mixtures. In addition,
the reduction of the Boc-derivatives 11 to the correspond-
ing N-methyl analogues proved unsuccessful. We there-
fore explored an alternative route to N-methylated
systems based on chloroamidine chemistry (Scheme 3).
Chloroamidine 12 has been developed as an amidine
transfer agent.10 Generation of 12 followed by treatment
with (R)-α-methylbenzylamine successfully gave guan-
idine 7a (Scheme 3). Unfortunately, the attempted exten-
sion of this methodology to prepare the corresponding 6-
membered ring systems 13 and 14 proved problematic.11
We first studied the preparation of monocyclic guanidines
6 as shown in Scheme 2. The novel guanylating agent 10
was prepared from commercially available 97 using the
Mitsunobu protocol shown in Scheme 2.8 Reaction of 10
with chiral primary amines gave Boc-protected
guanidines 11. Deprotection was then carried out by treat-
ment with 3 M anhydrous methanolic HCl followed by
The final series of enantiopure guanidines investigated in
this study were 8a–c. The synthesis of the C2-symmetric
guanidine 8a has been reported in the literature where it
has been used as an anion receptor.12 The route described
by Schmidtchen’s group,12b commencing from L-aspar-
agine and L-methionine, was successfully employed to
prepare diol 8a, and by minor modification, the silylated
guanidines 8b and 8c (Figure 1).
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2002,0,02,0369,0371,ftx,en;D23602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

370
J. C. McManus et al.
LETTER
Figure 1
Table 1 Asymmetric Epoxidation of Enone 1 Using Chiral Guani-
dine Basesa
Guanidine
Yield (%)
RSMb (%)
ee 2c (%)
39 (–)
60 (+)
40 (+)
38 (–)
50 (+)
44 (+)
41 (+)
26 (+)
–
i
6a
6b
6c
6d
6e
6e
6f
49
34
56
45
50
67d
37
52
0
0
41
0
ii
iii
iv
v
37
0
vi
vii
viii
ix
x
0
0
6g
7a
8a
8b
8c
0
–
74e
45
10
0
48 (–)
0
xi
0
xii
0
0
a 2 Equiv TBHP, 1 equiv base, 5% IPA in toluene, r.t., 7 d.
b RSM = recovered starting material 1.
c The sign in brackets indicates which enantiomer of 2 was formed;
ee was determined by chiral HPLC.13
Scheme 2
d Reaction stopped after 24 h.
e Reaction was complete after 48 h.
All of the enantiopure guanidines described were evaluat-
ed in the epoxidation of enone 1; the results are sum-
marised in Table 1.
It is immediately noticeable that these cyclic and bicyclic and bicyclic structural types are viable. However, it is the
guanidines give much higher ee than previously ob- 60% ee achieved with the phenylglycinol-derived guan-
served.2,5 The 50% ee achieved with monocyclic guan- idine 6b (entry ii) that is of greatest note. In addition, the
idine 6e (entry v) and the 48% ee with bicycle 8a (entry x) ineffectiveness of guanidine 7a as an epoxidation media-
are particularly interesting, showing that both monocyclic tor (entry ix) is rather surprising.
Scheme 3
Synlett 2003, No. 3, 369–371 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Enantiopure Guanidine Bases for Enantioselective Enone Epoxidations
371
Within the series of monocyclic guanidines 6, there is a
good correlation between the absolute stereochemistry of
the original amine and the predominant enantiomer of ep-
oxide 2: thus, 6a and 6d give a predominance of (–)-2, in
contrast to the other members of the series which favour
formation of (+)-2. By comparison of the results obtained
with 6b and 6c (entries ii and iii, respectively), it can be
noted that the free alcohol functionality improves the
enantioselectivity but decreases the yield of the reaction
(as observed before).2 In contrast to the earlier study,2
however, the enantioselectivity of this series of
guanidines appears to be improved by introduction of a
larger aryl group adjacent to the chiral centre (compare
entries i and v). Guanidines 6e and 8a were notable in that
the epoxidation reaction was complete in 24–48 hours
(entries vi and x).
References
(1) For a review see: Porter, M. J.; Skidmore, J. Chem. Commun.
2000, 1215.
(2) McManus, J. C.; Carey, J. S.; Taylor, R. J. K. Synlett 2003,
365.
(3) Macdonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 5433.
(4) Dwyer, C. L.; Gill, C. D.; Ichihara, O.; Taylor, R. J. K.
Synlett 2000, 704.
(5) (a) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor,
R. J. K. Synlett 1999, 795. (b) Genski, T.; Macdonald, G.;
Wei, X.; Lewis, N.; Taylor, R. J. K. Arkivoc 2000, 1, 266.
(6) Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron 1999, 55, 3707; and references therein.
(7) Baker, T. J.; Tomioka, M.; Goodman, M. Org. Synth. 2000,
78, 91.
(8) All new compounds were fully characterised by 1H NMR,
13C NMR and IR, plus HRMS or elemental analysis.
(9) Preparation of 6b. HCl salt: (a) (R)-(–)-2-Phenylglycinol
(189 mg, 1.38 mmol) was added to a solution of di-tert-
butyl-2-[(trifluoromethanesulfonyl)imino]dihydro-
1,3(2H,4H)-pyrimidinecarboxylate 10 (300 mg, 0.69 mmol)
and diisopropyl(ethyl)amine (0.24 cm3, 1.38 mmol) in
CH2Cl2 (4 cm3), under a nitrogen atmosphere. The solution
was stirred at r.t. for 18 h before the solvent was removed
under reduced pressure and the residue purified by flash
silica chromatography (CH2Cl2:MeOH, 50:1) to afford di-
tert-butyl-2-[(1R)-2-hydroxy-1-phenylethylimino]dihydro-
1,3(2H,4H)-pyrimidinecarboxylate 11 (208 mg, 71%) as a
clear gum, [α]D20 +18.7 (c 1.25, CHCl3) which was fully
characterised. (b) The Boc-protected guanidine 11 (200 mg,
0.48 mmol) was dissolved in approx. 3 M anhyd. methanolic
HCl (20 cm3) and was stirred at r.t., under nitrogen, for 18 h.
The solvent was then removed under reduced pressure to
afford N-[(1S)-1-phenyl-2-hydroxyethyl]-N-tetrahydro-
2(1H)-pyrimidinylideneaminehydrochloride 6b. HCl
quantitatively (124 mg) as a gum, [α]D20 –40.9 (c 1.0,
MeOH). IR(neat): νmax = 3365 (OH), 3029 and 2096 (CH),
1695 (CN3) cm-1. MS (CI): m/z = 220 (100) [MH+], 202 (21),
138 (27), 100 (25), 75 (31). HRMS (CI): Calcd for
C12H18N3O: 220.1450. Found: [MH+]: 220.1456 (–2.7 ppm
error), which gave consistent 1H and 13C NMR spectra.
(10) (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.
(b) Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahedron:
Asymmetry 1998, 9, 1729.
The C2-symmetric guanidine 8a was also extremely effec-
tive in the enantioselective epoxidation reaction giving
epoxide 2 in 74% yield and 48% ee in a relatively fast
transformation (entry x). Unfortunately, attempts to mod-
ify structure 8a in order to optimise its activity were un-
successful (entries xi, xii).
Finally, we explored the use of guanidine 6b for the ep-
oxidation of 2-methylnaphthoquinone and trans-chalcone
(Figure 2). Although these epoxidations were not opti-
mised, it was extremely encouraging to observe that
guanidine 6b gives enantioselectivity with both cyclic
enones (1 and 2-methylnaphthoquinone) as well as with
the acyclic enone, trans-chalcone.
Figure 2 Epoxidation of 2-methylnaphthoquinone and trans-chal-
cone using 6b/TBHP
(11) Rapid hydrolysis to DMPU occurred; a one-pot variant was
also unsuccessful.
In summary, we have prepared a range of novel
guanidines and demonstrated that these give encouraging
ee (up to 60%) and yields (up to 74%) in the epoxidation
of substituted cyclohexenone 1 with tert-butylhydroper-
oxide, and that either enantiomer can be obtained. We
have also established that guanidine 6b can mediate the
epoxidation of 2-methylnaphthoquinone and trans-chal-
cone. Given the ease of preparation of guanidines 6, we
are currently preparing additional analogues to optimise
ee and yield and extend the range of substrates. We are
also investigating their use in natural product synthesis
and in other guanidine-mediated asymmetric processes.
(12) (a) Echavarren, A.; Galán, A.; de Mendoza, J.; Salmeron, A.
Helv. Chim. Acta 1988, 71, 685. (b) Kurzmeier, H.;
Schmidtchen, F. P. J. Org. Chem. 1990, 55, 3749.
(c) Gleich, A.; Schmidtchen, F. P. Chem. Ber. 1988, 71, 685.
(13) Chiral HPLC was carried out using a Chiralcel OJ column
(25 cm × 4.6 mm) with hexane–isopropanol (98:2) as eluent
at a flow rate of 1 mL/min and detection at 276 nm.
(14) Michael Additions: (a) Ishikawa, T.; Araki, Y.; Kumamoto,
T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001,
245; and references therein. (b) Howard-Jones, A.; Murphy,
P. J.; Thomas, D. A.; Caulkett, P. W. R. J. Org. Chem. 1999,
64, 1039. (c) Ma, K.; Cheng, K. Tetrahedron: Asymmetry
1999, 10, 713.
(15) (a) Strecker Synthesis: Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157. (b) Henry Reaction: Chinchilla, R.; Nájera,
C.; Sánchez-Agulló, P. Tetrahedron: Asymmetry 1994, 5,
1393.
Acknowledgement
We would like to thank the EPSRC and GSK (J. McM.), and the
Deutscher Akademischer Austauschdienst (DAAD) and Elsevier
Science (T. G.) for studentship support.
Synlett 2003, No. 3, 369–371 ISSN 0936-5214 © Thieme Stuttgart · New York