A rapid synthesis of racemic brevioxime

Article abstract of DOI:10.1055/s-2001-10769

Racemic brevioxime has been synthesised starting from N-propionyl-2-pyrroline by intramolecular cyclisation of a β-ketoamide using nitrosyl chloride.

Full text of DOI:10.1055/s-2001-10769

LETTER
257
A Rapid Synthesis of Racemic Brevioxime
Philip J. Parsons,a* Burhan Karadogan,a Jacqueline A. Macritchieb
aThe Chemical Laboratories, School of Chemistry, Physics & Environmental Science, University of Sussex, Falmer, Brighton,
BN1 9QJ, UK
bBiofocus plc Chesterford Park Saffron Walden, Essex CB10 2XL, UK
Fax +44+1273 677196; E-mail: P.J.Parsons@sussex.ac.uk
Received 27 November 2000
HO
N
Abstract: Racemic brevioxime has been synthesised starting from
N-propionyl-2-pyrroline by intramolecular cyclisation of a -keto-
amide using nitrosyl chloride.
O
N
Key words: brevioxime, -ketoamide, N-propionyl-2-pyrroline, ni-
O
trosyl chloride
1
O
O
C7H13
(H2C)4
O
Brevioxime 1 (Figure 1) is a novel juvenile hormone bio-
synthesis inhibitor which was isolated from Penicillium
brevicompactum by Primo-yufera and co-workers1 in
1997. The related compounds 2 and 3 have also been de-
rived from the same fungus. The important nature of 1 has
encouraged research groups to synthesise and investigate
the biological activity of brevioxime and related analogs.
Two syntheses of racemic brevioxime have recently been
published,2, 3 which are significantly longer than the one
presented here. More recently Clark4 has reported the first
synthesis of (-)brevioxime via epoxidation of acyl enam-
ine 2.
+
N
N
N
N
O
2
4
5
Scheme 1
The synthesis of N-propionyl-2-pyrroline 4 was achieved
as shown in Scheme 2 using the method of Kraus and
Neuenschwender.5 Pyrrolidine 6 was oxidised to pyrro-
line 7 using sodium persulfate and sodium hydroxide in
the presence of a catalytic amount of silver nitrate. Pyrro-
line 7 underwent rapid trimerisation at room temperature
to the triazine 8 which had to be cracked in boiling THF
to give the monomer which was then co-distilled with
THF and trapped at -78 °C. This was immediately trapped
with Et3N and propionyl chloride to obtain the crude, pro-
tected enamine which was purified by column chromatog-
raphy to yield 4 in 15% overall yield.
HO
N
O
N
O
1
O
O
O
O
N
N
N
N
i
NH
N
2
3
N
N
6
8
7
Figure 1
N
N
ii
iii
We wish to report a very short route to racemic
brevioxime 1. Our synthetic strategy, which is based on
intramolecular cyclisation of -keto amide 2 utilising ni-
trosyl chloride, is shown in Scheme 1. We reasoned that
pyrrolidine could be readily transformed into N-propio-
nyl-2-pyrroline 4 which could then be acylated with 6-
octenoyl imidazolide 5 to obtain the key -ketoamide 2.
Finally, reaction of 2 with nitrosyl chloride should afford
the bicyclic brevioxime 1.
N
N
O
8
7
4
Reagents and conditions: i, Na2S2O8, NaOH, cat.AgNO3, H2O;
ii, Crack in THF, trap monomer at -78 °C; iii, NEt3, CH3CH2COCl,
-78 °C, (15% overall).
Scheme 2
Synlett 2001 No. 2, 257–259 ISSN 0936-5214 © Thieme Stuttgart · New York

258
P. J. Parsons et al.
LETTER
Having prepared N-propionyl-2-pyrroline 4, the next step any acid-catalysed side reactions. When 2 was treated
was to perform an acylation of 4 with 5 which can be ob- with nitrosonium tetrafluoroborate in the presence of 2,6-
tained from 6-octenoic acid 9. The acid 9 was prepared by di-tert-butylpyridine decomposition occured. Hence sev-
Hara’s method6 starting from commercially available 1,4- eral other nitroso compounds were investigated in order to
hexadiene. With N-propionyl-2-pyrroline 4 and 6-octeno- introduce the oxime at C-3. Using N-nitrosopyridinium
ic acid 9 in hand, we were ready to do the acylation reac- salts7 also led to the formation of the cyslised product 3 in
tion of N-propionyl-2-pyrroline 4 to obtain our key 70% yield. At this stage we decided to prepare the more
intermediate 2. Therefore we first converted 6-octenoic reactive nitrosyl chloride in situ and react it with our key
acid6 9 into the corresponding acyl imidazole. Treatment intermediate 2. Nitrosyl chloride was prepared according
of N, N’-carbonyldiimidazole with 6-octenoic acid 9 gave to the method of Weib and Wagner8. Subsequent addition
the desired acylimidazole 5 in situ. Subsequent reaction of a solution of the ketoamide 2 in DCM led to forma-
with the enolate of 4 prepared by treatment with LDA at tion of racemic brevioxime in 22% yield9 (Scheme 5). We
-78 °C gave the desired -ketoamide 2 in 30% yield with also obtained a mixture of uncyclised anti-10 and syn-11
35% recovered starting material (Scheme 3).
oxime in 15% and 10% yields respectively. The uncyc-
lised oxime 10 could be independently converted to race-
mic brevioxime in 48% yield by refluxing in toluene with
a catalytic amount of PPTS. The spectral data of the reac-
tion product was identical with that reported for racemic
brevioxime.2,4
N
OH
N
i
9
O
5
O
N
O
N
O
i
N
O
O
2
O
3
Reagents and conditions: i, CDI, THF, 4h, rt.; ii, LDA, 4, THF,
-78 °C, 1h, 30%.
O
2
Reagents and conditions: i, Nitrosonium tetrafluoroborate, THF, rt,
50%;
Scheme 3
Scheme 4
Following the preparation of -ketoamide 2, the next step
was the introduction of the oxime at C-3, to obtain
brevioxime. Therefore we treated 2 with nitrosonium tet- In conclusion, we have discovered a very short synthesis
rafluoroborate, but this led to formation of the cyclised of racemic brevioxime, in 6.6% overall yield, from N-pro-
product 3 in 50% yield, rather than brevioxime 1. pionyl-2-pyrroline 4. We are currently investigating ways
(Scheme 4). Presumably this product is due to an alterna- to improve the yield of the nitrosyl chloride cyclisation re-
tive pathway mediated by HBF4 present in the reaction action and the synthesis of brevioxime anologs.
mixture. At this stage we thought it would be prudent to
use 2,6-di-tert-butylpyridine as a hindered base to prevent
O
N
O
2
i
OH
HO
N
N
Brevioxime
+
+
1 (22%)
O
N
O
N
O
O
ii
10 (15%)
C7H13
11 (10%)
C7H13
O
O
Reagents and conditions: i, iso-Amylnitrite, TMSCl, DCM, 22%;
ii, PPTS, toluene reflux, 1h, 48%.
Scheme 5
Synlett 2001, No. 2, 257–259 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Rapid Synthesis of Racemic Brevioxime
259
(8) Weib, K.; Wagner, K. Chem. Ber. 1984, 117, 1973.
Acknowledgement
(9) Preparation of 1: A mixture of TMSCl (0.05 ml, 0.4 mmol)
and iso-amyl nitrite (0.053 ml, 0.4 mmol) was refluxed for 30
min and then cooled to room temperature. A solution of -
ketoamide 2 (50 mg, 0.2 mmol) in DCM (2 ml) was then
added and the mixture was stirred at room temperature for 2 h.
After evaporation of the solvent, the residue was purified by
flash column chromatography (silica, 50% petroleum ether/
diethyl ether) to afford brevioxime as a white solid: mp 135-
140 °C (12 mg, 22%). H (300 MHz, CDCl3, Me4Si) 8.1 (br, s,
1H), 5.6 (s, 1H), 5.30-5.40 (m, 2H), 4.10-4.20 (m, 1H), 3.40-
3.60 (m, 1H), 2.80-3.00 (m, 2H), 2.30-2.40 (m, 2H), 1.80 (m,
3H), 1.65-1.35 (m, 7H), 1.30-1.40 (m, 2H) ppm; C (75 MHz,
CDCl3, Me4Si) 10.5, 18.3, 24.1, 26.7, 29.5, 31.1, 32.6, 42.0,
84.5, 107.4, 125.6, 131.2, 158.3, 163.7, 164.3 ppm; max (film)
3256, 2951, 1641, 1447 cm-1; LRMS: m/z 278 (M+, 30%), 261
(15); HRMS (EI) Calcd for C15H22N2O3 (M+): 278.1630;
Found: 278.1628.
We are extremely grateful to the Turkish Ministry of Education for
funding B. Karadogan and to AgrEvo for funding this research.
References and Notes
(1) (a) Primo-Yufera, E.; Moya, P.; Castillo, M.; Primo, J.;
Miranda, M. J. Org.Chem. 1997, 62, 8544. (b) Primo-Yufera,
E.; Moya, P.; Cantin, A.; Castillo, M.; Primo, J.; Miranda, M.
J. Org. Chem. 1998, 63, 8530. (c) Primo-Yufera, E.; Moya, P.;
Cantin, A.; Castillo, M.; Primo, J.; Miranda, M. Eur. J. Org.
Chem. 1999, 221.
(2) Nishimura, Y.; Kithara T. Heterocycles. 2000, 52, 553.
(3) Clive, D. L. J.; Hisaindee, S. Chem. Commun. 1999, 2251.
(4) Clark, D. Tetrahedron. 2000, 56, 6181.
(5) Kraus, G. A.; Neuenschwander, K. J. Org. Chem. 1981, 46,
4791.
(6) Hara, S.; Kishimura, K.; Suzuki, A. J. Org. Chem. 1990, 55,
6356.
(7) Olah, G. A.; Olah, J.A.; Overchuk, N. A. J. Org. Chem. 1965,
30, 3373.
Article Identifier:
1437-2096,E;2001,0,02,0257,0259,ftx,en;L19800ST.pdf
Synlett 2001, No. 2, 257–259 ISSN 0936-5214 © Thieme Stuttgart · New York