Microwave-enhanced α-functionalisation of tetramates

Article abstract of DOI:10.1055/s-2008-1078253

Bicyclic tetramic acids may be efficiently allylated or arylated either directly or via the corresponding triflate, using a microwave-enhanced protocol; under these conditions, the yield and diastereoselectivity are very high. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078253

LETTER
2107
Microwave-Enhanced a-Functionalisation of Tetramates
a-Functionalisation of
aTetramatesrk G. Moloney,* Muhammad Yaqoob
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
Fax +44(1865)285002; E-mail: mark.moloney@chem.ox.ac.uk
Received 9 July 2008
Dedicated to Professor Sir Jack Baldwin on the occasion of his 70th birthday
by the formation of a soft enolate with a high propensity
for O-alkylation,15,16 especially in substrates already con-
taining an a-substituent or by solubility issues related to
the highly polar tetramate nucleus.12 We report here the
development of a reliable protocol for such a process. Fur-
thermore, access to these compounds gave us the opportu-
nity to examine the inherent antibacterial activity of
substituted tetramates. This complements a recent study
which has established that simple mimics of oxazolomy-
cin containing a 3-hydroxy-2,2-dimethylpropanamide
moiety are indeed antibacterial, and suggest that it is this
function, rather than the lactam unit, which is responsible
for the observed bioactivity of this class of natural prod-
uct.17
Abstract: Bicyclic tetramic acids may be efficiently allylated or
arylated either directly or via the corresponding triflate, using a mi-
crowave-enhanced protocol; under these conditions, the yield and
diastereoselectivity are very high.
Key words: allylations, arylations, antibiotics
Tetramic acid derivatives comprise the structural core of
a variety of natural products which exhibit a wide spec-
trum of biological activities, including antiviral, antibiot-
ic, and antifungal properties.1 For this reason, they have
found application as a key building block in combinatorial
libraries,2–5 and our interest has been the development of
rapid and effective synthesis of enantiopure tetramates6–9
of relevance to the oxazolomycin, isatisine, and equisetin
classes. Key to the success of our strategy for tetramate
synthesis has been the application of Seebach’s ‘self re-
generation of stereocentres’ concept10 to enantioselective
ring-closing reactions leading to [3.3.0]-bicyclic systems.
We became interested in the direct C-allylation of tetra-
mates in particular to enable efficient routes for the syn-
thesis of a range of natural products, by using the vinylic
group for functional-group manipulation. Although a stra-
tegically direct route to functionalised tetramates by
conventional11,12 or more novel13,14 approaches, the direct
a-alkylation of the b-dicarbonyl function is complicated
When we examined the reaction of tetramate 3 (Figure 1),
prepared by the method reported previously,7 we found
that allylation products 4a,b could be obtained but only in
moderate yield under conventional conditions (Et3N–
THF, 0 °C to r.t., 24 h), with the products obtained only as
single diastereomers; this is presumably a result of the rel-
atively hindered b-dicarbonyl unit of the bicyclic system.
In the case of simple allylation, the desired product 4a was
accompanied with a significant amount of the alternative
O-allyl product 5a (Scheme 1). However, if the reaction
was conducted using microwave irradiation under very
mild conditions (Et3N–THF, 75 W, 60 °C, 10 min, 13.8
bar), the yields of 4a,b improved significantly to 83% and
N
O
HO
O
MeO
O
O
Me
N
N
H
OH
OH
O
1 oxazolomycin A
OH
O
H
H
H
HO
HO
N
O
O
O
HO
N
O
CH2OH
N
Me
2 equisetin
3 isatisine A
Figure 1
SYNLETT 2008, No. 14, pp 2107–2110
2
2
.0
8
.2
0
0
8
Advanced online publication: 05.08.2008
DOI: 10.1055/s-2008-1078253; Art ID: D26008ST
© Georg Thieme Verlag Stuttgart · New York

2108
M. G. Moloney, M. Yaqoob
LETTER
O
O
R
O
O
CO2Me
CO2Me
O
N
+
O
N
Me
Me
R
Br
t-Bu
t-Bu
O
Et3N–THF
0 °C, 3 d
CO2Me
4
5
Yield (%)*
O
N
18
–
a R = H
44 (83)
33 (87)
O
t-Bu
b R = Ph
Et3N–THF
0 °C, 1 h
NO2
3
* thermal (MW)
NO2
O
NO2
O2N
CO2Me
F
O
Me
N
O
t-Bu
6 44% (32%)
Scheme 1
87%, respectively, with no formation of O-allyl products. O-acetylation (8a,b), although in the case of cinnamyl
This process could even be used to access the a-aryl ad- bromide a good yield (63%) only of product 4c was ob-
duct 6 in moderate yield, but in this case the arylation re- tained (Scheme 2). However, if the reaction of 7 with allyl
action was slightly worse off using microwave irradiation, bromide was conducted with microwave irradiation, near
giving only 32% of the product. The stereochemistry of quantitative yields of the allyl product 5a were obtained
the products was readily ascertained by NOE analysis, in (97%). Control experiments which omitted the allylic ha-
which enhancements across the bicyclic system indicated lide but conserved all other reaction parameters indicated
that allylation/arylation had proceeded to the exo- (less that triflate 7 was converted into the parent tetramate 3 in
hindered) face of the convex bicyclic system (Figure 2).18 high yield, suggesting that the allylation process proceeds
by formation of a reactive palladium enolate species; fur-
thermore, in the absence of palladium(II), the reaction
Although b-trifloxyacrylates have been successfully used
for palladium-mediated cross-coupling,19–21 their hydrol-
failed both with and without microwave irradiation. One
ysis under mild basic conditions to the corresponding di-
route for the formation of the enolate would be by direct
carbonyl has also been reported,22 and since palladium23,24
triflate hydrolysis, but the formation of enol acetate sug-
and other transition-metal25 enolates have recently been
gests an alternative pathway might involve initial addi-
found to be efficient nucleophiles for conjugate addition
tion–elimination of acetate, followed by acetate ester
reactions, it was of interest to investigate the combination
of these two steps in a one-pot synthesis of the allyl tetra-
hydrolysis.28
mate. The starting triflate 726 was readily obtained from Of interest is that bioassay of tetramates 4b and 6 gave
tetramate 3 by treatment with Tf2O, Et3N, CH2Cl2 in 73% only weak activity, and 4a and 7 gave no bioactivity,
yield as a colourless oil.27 Reaction of triflate 7 with allyl against S. aureus at 3–4 mg/mL,29 suggesting that the ob-
and crotyl bromides under thermal conditions served antibacterial activity of oxazolomycin and equise-
[Pd(II)OAc2, Et3N, THF, r.t., overnight) gave mixtures of tin does not reside solely in their lactam portions; this is
products of a-allylation (4a,b), O-allylation (5a,b), and consistent with the low levels of antibacterial activity of
Me
NO2
Me
Me
O
O
O
O
O
O
O
O2N
H
H
O
O
O
O
Ph
H
H
H
H
O
O
O
N
H
Me
N
Me
N
Me
H
O
t-Bu
t-Bu
H
t-Bu
H
4a
4c
6
Figure 2
Synlett 2008, No. 14, 2107–2110 © Thieme Stuttgart · New York

LETTER
a-Functionalisation of Tetramates
2109
(14) Schobert, R.; Gordon, G. J.; Mullen, G.; Stehle, R.
Tetrahedron Lett. 2004, 45, 1121.
(15) Huang, P. Q. Synlett 2006, 1133.
(16) Huang, P. Q.; Deng, J. Synlett 2004, 247.
(17) Bagwell, C. L.; Moloney, M. G.; Thompson, A. Bioorg.
Med. Chem. Lett. 2008, in press.
TfO
O
O
CO2Me
CO2Me
Me
O
N
O
N
t-Bu
O
t-Bu
7
3
(18) General Method without Microwave
To a solution of tetramic acid 3 (50 mg, 0.20 mmol) in dry
THF [5 mL; or dry CH2Cl2 (5 mL)] was added the allyl
bromide (0.22 mmol) and Et3N (0.22 mmol) at 0 °C and the
mixture stirred for 3 d at r.t. The reaction was monitored by
TLC, and when complete it was quenched with sat. aq
NH4Cl solution, extracted with EtOAc (3 × 20 mL), washed
with brine (10 mL), dried over MgSO4, and the solvent was
evaporated in vacuo. Column chromatography with PE–
EtOAc gave the product.
Br
Pd(OAc)2
Et3N–THF
r.t., overnight
Ac
O
O
R
O
O
CO2Me
CO2Me
CO2Me
O
N
+
+
Me
O
Me
O
Me
N
N
O
t-Bu
General Method with Microwave
t-Bu
O
t-Bu
8
To a solution of tetramic acid 3 (100 mg, 0.37 mmol) in dry
THF (2 mL) in a microwave reaction tube was added allyl
bromide (0.1 mL, 0.40 mmol) and Et3N (0.1 mL, 0.40 mmol)
and stirred at 60 °C for 10 min at 13.8 bar under microwave
power of 75 W. The solvent was evaporated the product
obtained by column chromatography.
(3R,6R,7aR)-Methyl 6-Allyl-3-tert-butyl-6-methyl-5,7-
dioxohexahydropyrrolo[1,2-c]oxazole-7a-carboxylate
(4a) and (3R,7aR)-Methyl 7-(Allyloxy)-3-tert-butyl-6-
methyl-5-oxo-1,3,5,7a-tetrahydropyrrolo[1,2-c]oxazole-
7a-carboxylate (5a)
4
5
Yield (%)
4
5
8
26
63
21
22
–
–
44
–
30
a R = H
b R = Ph
c R = Me
Scheme 2
Product 4a: Rf = 0.65 (PE–EtOAc, 4:1); [a]D24 +93 (c 1,
CHCl3). IR (neat): nmax = 2960 (m), 1780 (m), 1750 (s), 1720
(s), 1484 (w), 1280 (s), 1015 (m) cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.92 [9 H, s, C(CH3)3], 1.22 (3 H, s, CH3), 2.63
(2 H, m, CH2CH=CH2), 3.42 (1 H, d, J = 8.9 Hz, CH2O),
3.83 (3 H, s, CO2CH3), 4.85 (1 H, d, J = 8.9 Hz, CH2O), 5.06
(1 H, s, CHt-Bu), 5.16 (2 H, m, CH2CH=CH2), 5.75 (1 H, m,
CH2CH=CH2). 13C NMR (100 MHz, CDCl3): d = 17.1
(CH3), 24.7 [C(CH3)3], 35.3 (C), 40.9 (CH2), 53.5
(CO2CH3), 54.7 (C), 69.3 (CH2O), 78.6 (C), 99.0 (CH),
120.1 (CH2), 130.5 (CH), 167.1 (CO), 179.8 (CO), 204.1
(CO). HRMS (microTOF): m/z calcd for C16H23NO5Na:
332.1474; found: 332.1468 [M + Na]+.
other simple spirocyclic bislactams derived from pyro-
glutamic acid.30
In conclusion, we have shown that a bicyclic tetramate
can be successfully reacted at the a-position of the dicar-
bonyl unit directly or via its derived triflate either using
microwave-mediated conditions, and that the derived
products show low levels of antibacterial activity.
Acknowledgment
This work was supported by EPSRC grant GR/T20380/01.
Product 5a: Rf = 0.3 (PE–EtOAc, 4:1); [a]D24 +96 (c 0.83,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.91 (9 H, s, t-Bu),
1.90 (3 H, s, CH3), 3.39 (1 H, d, J = 8.4 Hz, CH2O), 3.78 (3
H, s, CO2CH3), 4.68 (1 H, s, CHt-Bu), 4.72 (1 H, m,
OCH2CH=CH2), 4.82 (1 H, d, J = 8.4 Hz, CH2O), 5.30 (2 H,
References and Notes
(1) Royles, B. J. L. Chem. Rev. 1996, 95, 1961.
(2) Edwards, P. Drug Discov. Today 2007, 12, 345.
(3) Terrett, N. Drug Discov. Today 1998, 3, 563.
(4) Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1998, 39,
4369.
m, OCH2CH=CH2), 5.90 (1 H, m, OCH2CH=CH2). 13
C
NMR (100 MHz, CDCl3): d = 8.37 (CH3), 24.6 [C(CH3)3],
35.1 (C), 53.0 (CO2CH3), 70.1 (CH2O), 71.8
(5) Matthews, J.; Rivero, R. A. J. Org. Chem. 1998, 63, 4808.
(6) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. Synlett
1996, 612.
(7) Andrews, M. D.; Brewster, A. G.; Crapnell, K. M.; Ibbett, A.
J.; Jones, T.; Moloney, M. G.; Prout, K.; Watkin, D. J. Chem.
Soc., Perkin Trans. 1 1998, 223.
(OCH2CH=CH2), 74.0 (C), 96.7 (CHt-Bu), 105.4 (C), 118.4
(OCH2CH=CH2), 131.9 (OCH2CH=CH2), 166.7 (C), 169.2
(C), 179.7 (C). HRMS (microTOF): m/z calcd for
C16H23NO5Na: 332.1474; found: 332.1468 [M + Na]+.
(3R,6R,7aR)-Methyl 3-tert-Butyl-6-cinnamyl-6-methyl-
5,7-dioxohexahydropyrrolo[1,2-c]oxazole-7a-
(8) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. J. Chem.
Soc., Perkin Trans. 1 2002, 80.
(9) Anwar, M.; Moloney, M. G. Tetrahedron Lett. 2007, 48,
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(10) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708.
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Chem. Int. Ed. 2007, 46, 7488.
carboxylate (4b)
Rf = 0.56 (PE–EtOAc, 4:1); [a]D24 +81.0 (c 0.4, CHCl3). IR
(neat): nmax = 3485 (w), 3030 (s), 2960 (s), 1715 (s), 1600
(w), 1485 (s), 1450 (s), 1280 (s), 1100 (s), 750 (s) cm–1. 1H
NMR (400 MHz, CDCl3): d = 0.92 [9 H, s, (C(CH3)3], 1.27
(3 H, s, CH3), 2.79 (2 H, d, J = 7.6 Hz, CH2CHCHPh), 3.45
(1 H, d, J = 8.9 Hz, CH2O), 3.73 (3 H, s, CO2CH3), 4.86 (1
H, d, J = 8.9 Hz, CH2O), 5.03 (1 H, s, CHt-Bu), 6.13 (1 H, s,
m, CH2CHCHPh), 6.46 (1 H, d, J = 15.7 Hz, CH2CHCHPh),
7.22–7.38 (5 H, m, Ph). 13C NMR (100 MHz, CDCl3): d =
17.9 (CH3), 24.8 [C(CH3)3], 35.3 [C(CH3)3], 40.2
(CH2CHCHPh), 53.6 (CO2CH3), 55.0 (C), 69.3 (CH2O),
Synlett 2008, No. 14, 2107–2110 © Thieme Stuttgart · New York

2110
M. G. Moloney, M. Yaqoob
LETTER
78.7 (C), 99.2 (CHt-Bu), 122.0 (CH), 126.4 (CH), 127.7
(CH), 128.5 (CH), 134.9 (CH), 136.8 (C), 167.1 (CO), 180.0
(CO), 204.3 (CO). MS (ES+): m/z (%) = 444.28 (60) [M +
59]+, 277.3 (100). HRMS (microTOF): m/z calcd for
C22H27NO5Na: 408.1787; found: 408.1781 [M + Na]+.
(3R,6R,7aR)-Methyl 3-tert-Butyl-6-(2,4-dinitrophenyl)-
6-methyl-5,7-dioxohexahydro-pyrrolo-[1,2-c]oxazole-
7a-carboxylate (6)
pyrrolo[1,2-c]oxazole-7a-carboxylate (7)
To a solution of tetramic acid 3 (100 mg, 0.37 mmol), dry
Et3N (0.16 mL, 1.16 mmol, 3 equiv) in dry CH2Cl2 (2 mL) at
0 °C was added Tf2O (0.19 mL, 1.13 mmol, 3 equiv) via
syringe and stirred for 1 h. The solvent was evaporated in
vacuo and the residue purified by flash column
chromatography in PE (40–60)–EtOAc (4:1) to give the
product 7 (110 mg, 73%) as a colourless oil.
Rf = 0.33 [PE (40–60)–EtOAc, 4:1]; [a]D21 +121.0 (c, 0.33,
CHCl3). IR (neat): nmax = 3425 (w), 3110 (s), 2960 (s), 1715
(s), 1615 (s), 1540 (s), 1480 (s), 1350 (s), 1065 (s), 740 (s)
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.93 (9 H, s, t-Bu),
1.49 (3 H, s, CH3), 3.57 (1 H, d, J = 8.6 Hz, CH2O), 3.90 (3
H, s, CO2CH3), 4.75 (1 H, s, CHt-Bu), 4.83 (1 H, d, J = 8.6
Hz, CH2O), 7.44 (1 H, d, J = 9.1 Hz, CHAr), 8.51 (1 H, dd,
Rf = 0.6 [PE (40–60)–EtOAc, 4:1]; [a]D23 +91 (c 0.7 in
CHCl3). IR (neat): nmax = 2960 (m), 1730 (m), 1295 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.94 [9 H, s, C(CH3)3], 1.94
(3 H, s, CH3), 3.51 (1 H, d, J = 8.9 Hz, H-4endo), 3.83 (3 H, s,
CO2CH3), 4.74 (1 H, s, H-2), 4.83 (1 H, d, J = 8.9 Hz, H-
4
exo). 13C NMR (100 MHz, CDCl3): d = 8.2 (CH3), 24.7
[C(CH3)3], 35.1 [C(CH3)3], 53.6 (CO2CH3), 70.6 (C-4), 74.2
(C-5), 96.7 (C-2), 127.2 (C-7), 154.9 (C-6), 166.7
(CO2CH3), 173.8 (C-8). HRMS (CI+): m/z calcd for
C14H19NO7F3S: 402.0834; found: 402.0831 [M + H]+.
(28) Allylations of Triflate 7 (with MW) in the Presence of
Pd(OAc)2 – General Method
J = 2.7, 9.1 Hz, CHAr), 8.87 (1 H, d, J = 2.7 Hz, CHAr). 13
NMR (100 MHz, CDCl3): d = 8.3 (CH3), 24.6 [C(CH3)3],
C
35.1 [C(CH3)3], 53.5 (CO2CH3), 70.1 (CH2O), 73.8 (C), 80.5
(C), 96.9 (CHt-Bu), 121.4 (CH, Ar), 122.1 (CH, Ar), 127.8
(CH, Ar), 140.3 (C, Ar), 143.9 (C, Ar), 151.6 (C, Ar), 168.1
(CO), 176.5 (CO), 198.0 (CO). MS (ES–): m/z (%) = 434.26
(20) [M – H]+, 568.13 (100). HRMS (microTOF): m/z calcd
for C19H22N3O9: 436.1351; found: 436.1351 [M + H]+.
To a solution of the enol triflate 7 (20 mg, 0.05 mmol) in dry
THF (2 mL) was added allyl bromide (0.2 mL, 2.3 mmol),
Pd(OAc)2 (35 mg, 0.16 mmol), and Et3N (0.2 mL, 1.44
mmol) under N2. The reaction tube was inserted in
microwave reactor, and the reaction was carried out for 10
min at 50 °C under 100 W microwave power. The reaction
course was monitored by TLC. When the reaction was
complete, it was diluted with EtOAc (20 mL), quenched with
sat. aq NH4Cl (10 mL), washed with brine (5 mL), dried over
MgSO4, and the solvent was evaporated in vacuum. Column
chromatography with PE–EtOAc (4:1) afforded the product.
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compounds to be tested (4 mg/mL) were loaded into wells in
bioassay plates, and incubated overnight at 37 °C. The
diameters of the resultant inhibition zones were measured,
and relative potency estimated by reference to standards
prepared with Cephalosporin C.
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