Tandem oxime formation-epoxide ring opening sequences for the preparation of oxazines related to the trichodermamides

Article abstract of DOI:10.1016/j.tetlet.2007.05.145

A mild and straightforward method for the preparation of 4H-5,6-dihydro-1,2-oxazines from keto-epoxides via cyclisation of the intermediate oximes is reported, as is a preparative route to 3-amino-7,8-dimethoxychromen-2-one; these procedures were then emp

Full text of DOI:10.1016/j.tetlet.2007.05.145

Tetrahedron Letters 48 (2007) 5201–5204
Tandem oxime formation—epoxide ring opening sequences for
the preparation of oxazines related to the trichodermamides
James R. Donald, Michael G. Edwards and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 23 April 2007; revised 14 May 2007; accepted 24 May 2007
Available online 31 May 2007
Abstract—A mild and straightforward method for the preparation of 4H-5,6-dihydro-1,2-oxazines from keto-epoxides via cyclisa-
tion of the intermediate oximes is reported, as is a preparative route to 3-amino-7,8-dimethoxychromen-2-one; these procedures
were then employed to prepare a novel analogue of trichodermamide natural products.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Trichodermamides 1 and 2 and the aspergillazines 3–7
(Fig. 1) are a family of highly modified heterocyclic
dipeptides reported in 2003 and 2005.1,2 Trichoderm-
amides 1 and 2 were isolated from the marine fungus
Trichoderma virens by Clardy and colleagues and shown
to contain the unusual 4H-5,6-dihydro-1,2-oxazine (O-
alkyl oxime) unit annelated to a highly functionalised
cyclohexene ring.1 Subsequently, Capon et al. isolated
the related aspergillazines 3–7 from the fungus Aspergil-
lus unilateralis.2 Aspergillazine A 3 has a tricyclic East-
ern portion based on a highly substituted, fused
tetrahydrothiophene-tetrahydro-1,2-oxazine-cyclohexene
containing the unusual S–C–N–O connectivity and four
contiguous stereocentres.
Given the structural novelty of these compounds, toge-
ther with their interesting and only partially explored
biological activities, we decided to develop routes for
their synthesis. We were particularly interested in the
synthesis of trichodermamides 1 and 2 and aspergillazine
A 3. To the best of our knowledge, there were no
reported synthetic endeavours in this area until the
´
recent publication by Wan, Doridot and Joullie on
model studies towards trichodermamides.3 We therefore
present our own preliminary studies in this Letter.
OH
OH
OH
OH
X
Our synthetic approach is illustrated retrosynthetically
in Scheme 1 using the trichodermamides 1 and 2. Amide
disconnection generates amino-coumarin 8 and a bicy-
clic dihydro-1,2-oxazine carboxylic acid 9 containing
four stereocentres.
O
S
O
HN
N
H
N
H
N
O
O
MeO
O
O
MeO
O
O
OMe
OMe
Trichodermamide A (X = OH), 1
Trichodermamide B ( X = Cl), 2
Aspergillazine A 3
OH
O
N
NH
O
2
H
N
OH
OH
OH
OH
OH
HO
S
HO
H N
2
MeO
O
H N
2
H
N
O
X
H
N
MeO
O
O
OMe
+
2
8
2
OMe
Trichodermamide A (X = OH), 1
Trichodermamide B ( X = Cl), 2
O
O
O
MeO
O
O
MeO
O
O
OMe
OMe
OH
Aspergillazines B and C (C2-epimers)
Aspergillazines D and E (C2-epimers)
O
O
OH
4, 5
N
6, 7
N
OH
X
OH
HO C
2
R
Figure 1. The trichodermamides and aspergillazines.
X
10
9
*
Scheme 1.
Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.145

5202
J. R. Donald et al. / Tetrahedron Letters 48 (2007) 5201–5204
Many methods have been reported for the preparation
of 4H-5,6-dihydro-1,2-oxazines, the majority of which
fall into two general classes: (i) pericyclic reactions such
as hetero-Diels–Alder cycloadditions4,5 or the 1,2-oxaza-
Cope rearrangement6 and (ii) the O-alkylation of oximes
by an internal electrophile such as iodonium ions,7 sele-
niranium ions8 or alkyl chlorides.9 We were interested
in developing a variant of the latter category in which
oxazine formation is achieved by the intramolecular
opening of epoxides by an adjacent oxime (e.g.,
10 ! 9, Scheme 1). When we commenced this project,
there were only two reports of dihydro-1,2-oxazine prep-
oxime 19 proved problematic with a best yield of
<20%. For this reason, subsequent studies involved the
oximination of keto-esters with amide formation at a
later stage.
The conversion of oximes into oxazines proved to be
more facile than expected (Scheme 3). Oxime 13 under-
went spontaneous cyclisation on standing at room tem-
perature to give oxazine 20 in quantitative yield; oxazine
20 was identified by comparison with published 13C
NMR data (dC 155.2, C@N), lit.10b (dC 155.1).
aration by epoxide ring opening,10 although the Joullie
´
OH
O
N
OH
group employed an intramolecular example in their
recent publication.3
N
i
O
To commence this study, c,d-epoxy-oximes were
required in order to test the oxazine formation process
(Scheme 2). Phenyl ketone 1111 was chosen as the initial
model system as it was assumed that oxime formation
would favour the desired E-oxime isomer on steric
grounds. In addition, oxazine 20 derived from oxime
13 is a known compound.10b After much experimenta-
tion, epoxide 1212 was obtained by the conversion of
alkene 11 into the corresponding bromohydrin followed
by treatment with caesium carbonate.13 Epoxide 12 was
found to be rather unstable and its conversion to oxime
13 proved problematic under a range of classical oxi-
mination conditions. However, on treatment with
hydroxylamine hydrochloride in buffered acetic acid,14
oxime 13 was obtained in a best yield of 39% as what
appeared to be a single isomer, although the reaction
was capricious.
20
13
OH
O
N
N
OH
ii or iii
EtO
EtO
O
O
O
21
16
Scheme 3. Reagents and conditions: (i) Standing, quantitative; (ii)
K2CO3, EtOH, rt, 14 h, 80%; (iii) SiO2, EtOAc, reflux, 6 h, 75%.
Oxime 16 proved to be more stable but treatment with
K2CO3 in ethanol, or heating in a slurry of silica gel,
gave oxazine 21 in good yield. It should be noted that
these cyclisation conditions are extremely mild com-
pared to published examples, which employed strong
bases.3,10
Given the success with oxazine formation we hoped to
combine the oximination and cyclisation to achieve a
one-pot approach to oxazines (Scheme 4).
a-Keto-ester 1415 was efficiently epoxidised using
DMDO and product 15 could be purified by Kugelrohr
distillation. Epoxide 15 readily underwent condensation
with hydroxylamine in aqueous acetonitrile16 to give
oxime 16 in good yield (as a single isomer according
to 1H NMR spectroscopy).17 Amide 17 was readily pre-
pared18 and epoxidised using DMDO in a similar man-
ner. However, the conversion of a-keto-amide 18 into
H NOH.HCl
2
O
or H NOTBS
O
2
N
OH
EtO
EtO
O
rt , 16 h
O
O
21
15
(i) H NOH.HCl, 1.1 eq. K2CO3, DMF
2
14%
OH
O
O
(ii) H NOH.HCl, 1.1 eq K2CO3, EtOH
2
64%
60%
N
i, ii
iii
O
O
(iii) H2NOTBS, EtOH then TBAF
12
11
13
Scheme 4.
OH
O
O
N
N
This tandem approach was successful with oxazine 21
being obtained from keto-epoxide 15 in up to 64% yield
on a 0.1 mmol scale. However, the efficiency diminished
on scale up and at present the two step procedure is gen-
erally preferred.
v
iv
vi
EtO
EtO
EtO
O
O
O
O
O
O
O
16
14
15
OH
O
O
vii
PhNH
PhNH
PhNH
O
O
At this point, the success of the model studies provided
encouragement to prepare analogues more closely re-
lated to the trichodermamides. To achieve this, the novel
amino-coumarin 8 was first prepared (Scheme 5).
O
19
18
17
Scheme 2. Reagents and conditions: (i) NBS, THF/H2O, rt, 16 h, 73%;
(ii) Cs2CO3, MeCN, rt, 3 h, 86%; (iii) H2NOHÆHCl, KOAc, AcOH
buffered to pH 6, rt, 26 h, 39%; (iv) DMDO, Me2CO, rt, 6 h, 95%; (v)
H2NOHÆHCl, NaOAc, MeCN/H2O (3:1), rt, 2.5 h, 76%; (vi) DMDO,
Me2CO, rt, 6 h, 86%; (vii) H2NOHÆHCl, NaOAc, EtOH, n, 2 h, 19%.
Thus, following a literature protocol,19 2,3,4-trimeth-
oxybenzaldehyde was converted into coumarin 22.

J. R. Donald et al. / Tetrahedron Letters 48 (2007) 5201–5204
5203
CHO
OMe
CO2H
under forcing conditions, presumably due to the low
reactivity of the amine. We therefore converted acid 28
into the corresponding acid chloride using the mild
chloro-enamine reagent developed by Ghosez et al.25
Amino-coumarin 8 was then deprotonated using n-butyl-
lithium and the lithioamide added directly to the freshly
prepared acid chloride. Desilylation of the product gave
the requisite amide 29, which was fully characterised, in
an unoptimised yield of 18% over the three steps.
i,ii
iii
MeO
MeO
O
O
OMe
OMe
22
H
N
O
NH2
O
iv
O
O
O
O
MeO
MeO
OMe
OMe
In summary, we have developed a mild and straightfor-
ward method for the preparation of 4H-5,6-dihydro-
1,2-oxazines from keto-epoxides via cyclisation of the
intermediate oximes, and a preparative route to amino-
coumarin 8; these procedures were then employed to
prepare the novel trichodermamide analogue 29. It
should also be noted that the current procedure is
successful at the a-keto-ester oxidation level delivering
the required carboxylate-substituted oxazines, in con-
trast to the alternative approach, which produces
hydroxymethyl-substituted oxazines.3
23
8
Scheme 5. Reagents and conditions: (i) Meldrum’s acid, ZnO, 80 ꢁC,
4.5 h, 83%; (ii) concd HCl, 0 ꢁC, 20 min, 76%; (iii) DPPA, Et3N,
toluene, reflux, 1.25 h, t-BuOH, reflux, 1.25 h, 43%; (iv) 10% HCl (aq),
MeOH, reflux, 45 min, 76%.
Reaction of coumarin 22 with diphenylphosphoryl azide
(DPPA) followed by trapping the isocyanate intermedi-
ate with t-BuOH gave carbamate 23 in modest
yields.20,21 Deprotection of compound 23 with acid then
produced the required amino-coumarin 8 in 76% yield
(mp 177–180 ꢁC; 21% overall yield from 2,3,4-
trimethoxybenzaldehyde).
We are currently optimising the above methodology
with a view to completing the total synthesis of the
trichodermamide and aspergillazine natural products.
Finally, we combined the oxazine and amino-coumarin
methodology to prepare analogues of trichodermamide
(Scheme 6). The known a-keto-ester 2422 was epoxidised
with DMDO in a non-stereoselective manner to produce
a separable mixture of epoxides (88%, cis:trans = 1.7:1
Acknowledgements
We thank the University of York for studentship sup-
port (JRD), Elsevier for postdoctoral funding (MGE)
and Dr. T. Dransfield (University of York) for assis-
tance with mass spectrometry.
1
by H NMR spectroscopy). The trans-isomer 25 was
oximinated and silica-mediated cyclisation gave the
bicyclic oxazine 26 in 72% over two steps.23
In order to facilitate the final amide coupling, alcohol 26
was converted into silyl ether 27, which in turn was
saponified using TMSOK24 in quantitative yield. Based
on model studies we established that the direct coupling
of acid 28 with amino-coumarin 8 was not viable even
References and notes
1. Garo, E.; Starks, C. M.; Jensen, P. R.; Fenical, W.;
Lobkovsky, E.; Clardy, J. J. Nat. Prod. 2003, 66, 423–426;
Trichodermamide A is identical to the previously reported
penicillazine although the structure of the latter was
misassigned: Lin, Y.; Shao, Z.; Jiang, G.; Zhou, S.; Cai, J.;
Vrijmoed, L. L. P.; Jones, E. B. G. Tetrahedron 2000, 56,
9607–9609.
O
O
O
i
ii iii
EtO
EtO
O
O
25
24
2. Capon, R. J.; Ratnayake, R.; Stewart, M.; Lacey, E.;
Tennant, S.; Gill, J. H. Org. Biomol. Chem. 2005, 3, 123–
129.
OH
OTBS
O
O
N
iv
N
v
EtO
EtO
´
3. Wan, X.; Doridot, G.; Joullie, M. M. Org. Lett. 2007, 9,
O
977–980.
O
26
27
4. Davies, D. E.; Gilchrist, T. L.; Roberts, T. G. J. Chem.
Soc., Perkin Trans. 1 1983, 1275–1281.
5. Naruse, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
1994, 35, 595–598.
6. Zakarian, A.; Lu, C.-D. J. Am. Chem. Soc. 2006, 128,
5356–5357, it should be noted that these authors com-
mented on the suitability of the oxaza-Cope rearrange-
ment for the preparation of trichodermamide-like
structures.
7. Dondas, H. A.; Grigg, R.; Hadjisoteriou, M.; Markandu,
J.; Kennewell, P.; Thornton-Pett, M. Tetrahedron 2001,
57, 1119–1128.
OH
O
OTBS
N
H
N
O
vi, vii
viii
N
HO
O
MeO
O
O
O
OMe
29
28
Scheme 6. Reagents and conditions: (i) DMDO, Me2CO, rt, 1 h 88%
(1.7:1 dr); chromatography gave 25 (16%) and cis-isomer (44%); (ii)
H2NOHÆHCl, NaOAc, MeCN/H2O, rt, 12 h; (iii) SiO2, EtOAc, rt, 8 h,
72% (two steps); (iv) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 1 h, 88%; (v)
TMSOK, THF, rt, 1 h then 10% HCl, quant.; (vi) Me2C@C(Cl)NMe2,
THF, rt, 2 h, (vii) 8/n-BuLi, THF, 0 ꢁC to rt, 5.5 h, 25%; (vii) TBAF,
THF, rt, 6 h, 72%.
8. Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu,
J. J. Chem. Soc., Chem. Commun. 1992, 1537–1538.

5204
J. R. Donald et al. / Tetrahedron Letters 48 (2007) 5201–5204
9. Ellames, G. J.; Hewkin, C. T.; Jackson, R. F. W.; Smith,
0.60 mmol, 1.25 equiv) in water (1 mL) was prepared
and added via a pipette to a stirred solution of epoxy-
ketone 25 (102 mg, 0.48 mmol, 1.0 equiv) in MeCN (3 mL)
at rt. The resulting colourless solution was stirred at rt for
12 h and then carefully concentrated to remove the
acetonitrile present. The remainder was partitioned
between EtOAc (20 mL) and water (10 mL), the layers
separated and the aqueous further extracted with EtOAc
(2 · 10 mL). The combined organic extracts were then
washed with brine (25 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The residue was dissolved in
EtOAc (10 mL) and SiO2 (5 g) added in a single portion.
The slurry was stirred vigorously at rt for 4 h before the
addition of an extra 5 g of SiO2 and 10 mL of EtOAc.
After 8 h of stirring at rt the reaction was judged to be
complete by TLC. The mixture was filtered to remove
SiO2, the solids washed with EtOAc (50 mL) and the
filtrate concentrated in vacuo. The crude material was pre-
adsorbed onto SiO2 and purified by flash column chro-
matography (SiO2, 30 g, 7 cm · 35 mm B, 1:1 petrol/
EtOAc) to afford oxazine 26 (78 mg, 72%, over two steps)
as a colourless oil; Rf 0.29 (1:1, petrol/EtOAc); mmax(film)/
cmꢀ1 3425 (OH), 1721 (C@O), 1597 (C@N); dH
(400 MHz; CDCl3) 4.29 (2H, q, J 7.5, OCH2), 3.89–3.93
(2H, m, CHOH and CHO–N@C), 2.44 (1H, dd, J 19.0,
7.0, CHaHbC@N–O), 2.37 (1H, br s, OH), 2.30–2.36
D. I.; Standen, S. P. Tetrahedron Lett. 1989, 30, 3471–
3472.
10. (a) Al-Qawasmeh, R. A.; Al-Tel, T. H.; Abdel-Jalil, R. J.;
Voelter, W. Chem. Lett. 1999, 541–542; See also: (b) Dang,
T. T.; Albrecht, U.; Gerwein, K.; Siebert, M.; Langer, P. J.
Org. Chem. 2006, 71, 2293–2301.
11. Hok, S.; Schore, N. E. J. Org. Chem. 2006, 71, 1736–1738.
12. All novel products were fully charactersied by NMR and
IR spectroscopy, as well as HRMS or elemental analysis.
`
13. Cribiu, R.; Allevi, P.; Anastasia, M. Tetrahedron: Asym-
metry 2005, 16, 3059–3069, the use of caesium carbonate
proved much superior to the published procedure for the
preparation of 12 from the corresponding bromohydrin
using NaOH; (see: Crotti, P.; Di Bussolo, V.; Favero, L.;
Macchia, F.; Pineschi, M.; Napolitano, E. Tetrahedron
1999, 55, 5853–5866).
14. Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107,
256–257.
15. Macritchie, J. A.; Silcock, A.; Willis, C. L. Tetrahedron:
Asymmetry 1997, 8, 3895–3902.
16. Markandu, J.; Dondas, H. A.; Frederickson, M.; Grigg,
R. Tetrahedron 1997, 53, 13165–13176.
17. Attempts to determine the oxime geometry by NOE (as
per Imoto, H.; Imamiya, E.; Momose, Y.; Sugiyama, Y.;
Kimura, H.; Sohda, T. Chem. Pharm. Bull. 2002, 50, 1349–
1357) were unsuccessful.
(1H, m, CHCH2C@N–O), 2.22, (1H, dd,
J 19.0,
18. The known acid (Berryhill, S. R.; Price, T.; Rosenblum,
M. J. Org. Chem. 1983, 48, 158–162) was converted into
amide 17 using aniline and 2-propanephosphonic anhy-
dride; (T3P Wissmann, H.; Kleiner, H.-J. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 133–134).
19. Rouessac, F.; Leclerc, A. Synth. Commun. 1993, 23, 2709–
2715.
20. Bonsignore, L.; Loy, G. J. Heterocycl. Chem. 1998, 35,
117–119.
21. Attempts to trap the isocyanate with water and produce
amine 8 directly gave only intractable mixtures.
22. Bien, S.; Segal, Y. J. Org. Chem. 1977, 42, 1685–1688, we
employed a more efficient route to compound 24 involving
addition of (cyclohexenyl)methylmagnesium bromide to
diethyl oxalate (see Ref. 15).
23. Representative experimental—preparation of oxazine 26: A
solution of hydroxylamine hydrochloride (42 mg,
0.60 mmol, 1.25 equiv) and sodium acetate (49 mg,
6.0, CHaHbC@N–O), 1.83–1.91 (m, 1H, CH(OH)-
CHaHbCH2), 1.64 (1H, m, CH(OH)CH2CHaHbCH2),
1.38–1.59 (4H, m, CH2CHCH2C@N–O, CH(OH)CH2-
CHaHbCH2 and CH(OH)CHaHbCH2), 1.34 (3H, t, J
7.5, OCH2CH3); dC (100 MHz; CDCl3) 163.4 (C@O),
149.2 (C@N), 78.5 (HCO–N@C), 66.0 (HCOH), 61.9
(OCH2CH3), 29.4 (CH(OH)CH2CH2CH2CH), 27.1
(CH(OH)CH2CH2CH2CH), 25.3 (HCCH2C@N–O), 24.1
(H2CC@N–O), 18.5 (CH(OH)CH2CH2CH2CH), 14.0
(OCH2CH3); m/z (ESI): 228 ([MH]+, 100) [HRMS (ESI):
Calcd for C11H18NO4 [MH]+, 228.1230; found, 228.1241
(4.7 ppm error)].
24. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25,
5831–5834.
25. Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens,
A.; Ghosez, L. Chem. Commun. 1979, 1180–1181; Have-
aux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.;
Ghosez, L. Org. Synth. 1980, 59, 26–34.