Total synthesis and configurational assignment of pasteurestin A and B

Article abstract of DOI:10.1002/anie.200703457

(Figure Presented) Fresh pasture for the [2+2+2] cycloaddition: The two sesquiterpenoids pasteurestin A and B, which exhibit strong and selective antibacterial activity against Pasteurella haemolytica, have been prepared in a synthesis relying on a [2+2+2] Vollhardt enediyne cycloaddition. The previously unknown absolute and relative configurations were established, and the biological profile was specified more precisely.

Full text of DOI:10.1002/anie.200703457

Communications
DOI: 10.1002/anie.200703457
Natural Product Synthesis
Total Synthesis and Configurational Assignment of Pasteurestin A
and B**
Marion Kögl, Lothar Brecker, Ralf Warrass, and Johann Mulzer*
The isolation and biological properties of two novel basidio-
mycete sesquiterpenoids, pasteurestin A (1) and pasteures-
tin B (2), were recently reported in a Japanese patent.[1] Both
Scheme 1. Retrosynthetic analysis for pasteurestin A (1)and B ( 2).
TBDPS=tert-butyldiphenylsilyl; TBS=tert-butyldimethylsilyl.
compounds were obtained by fermentation of Agrocybe
aegeritta and are of considerable interest for veterinary
applications, as they exhibit strong and selective antibacterial
activities against some strains of Mannheimia haemolytica, a
pathogen for bovine respiratory disease (BRD).[2]
in four steps.[6] Swern oxidation gave the a,b-unsaturated
aldehyde 10, which was subjected to a tin(II) Reformatsky
addition with bromide 11,[7,8c] SnCl2, and LiAlH4.[8] At ꢀ788C,
The carbon skeleton of both compounds is identical to
that of other members of the protoilludane family such as
illudol (3).[3,4] However, the absolute and relative configu-
rations of 1 and 2 are unknown, since only 1H and 13C NMR,
IR, and mass spectra as well as optical rotations have been
published. The relative configurations at C-4a, C-7a, and C-7b
were assumed to be the same as in other protoilludanes,[3] but
those at C-4 and C-6 in 1 and C-4 and C-7 in 2, respectively,
and the absolute configurations had to be established by total
synthesis, all the more so as we were unable to procure
authentic samples of 1 and 2.
Retrosynthetically, a Vollhardt [2+2+2] cycloaddition[4c,5]
of enediynes 4 and 5 should lead to the tricyclic intermediates
6 and 7, which contain virtually the full carbon skeleton of 1
and 2 (Scheme 1). It was an open question how the
stereogenic centers in 4 and 5 would influence the stereo-
chemical course of the cycloaddition.
The synthesis of pasteurestin B (2) started from allylic
alcohol 8, easily available from geranyl acetate (9; Scheme 2)
[*] M. Kögl, Dr. L. Brecker, Prof. J. Mulzer
Institut für Organische Chemie
Universität Wien
Währingerstrasse 38, 1090 Wien (Austria)
Fax: (+43)1-4277-9521
E-mail: johann.mulzer@univie.ac.at
Scheme 2. Reagents and conditions: a) mCPBA, NaOAc, CH2Cl2,
ꢀ218C, 98%; b)HIO 4·2H2O, THF/Et2O, 08C, 82%; c)K 2CO3, dimethyl
1-diazo-2-oxopropylphosphonate, MeOH, 238C, 90%; d)1) nBuLi,
TMSCl, THF, ꢀ788C, 2)HCl 2 n, 238C, 95%; e)(COCl) 2, DMSO,
DIPEA, CH2Cl2, ꢀ788C, 89%; f)SnCl 2, LiAlH4, THF, 238C then 11,
then ꢀ788C, then 10, 78%; g)SnCl 2, LiAlH4, THF, 238C then 11, then
10, 82%; h)TBSOTf, 2,6-lutidine, CH 2Cl2, 08C, 95%; i) nBuLi, EtSH,
THF, 08C, 89%; j)DIBAL-H, CH 2Cl2, ꢀ788C, 75% (+15% alcohol).
Bn=benzyl; Ln=ligand; mCPBA=meta-chloroperbenzoic acid;
TMS=trimethylsilyl; DIPEA=diisopropylethylamine; Tf=trifluorome-
thanesulfonate; DIBAL-H=diisobutylaluminum hydride.
Dr. R. Warrass
Intervet Innovation GmbH
Zur Propstei, 55270 Schwabenheim (Germany)
[**] M. K. gratefully acknowledges financial support from Intervet
Innovation GmbH. We thank S. Felsinger for NMR spectra, M. Zinke
for HPLC analysis, and C. Wilhelm for MIC determinations.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
the desired 3S adduct 12 was obtained in > 99% de under
complete retention of the E configuration of the alkene unit.
This result was surprising, as such aldol additions have been
reported to be 3R-selective.[8b,c] The discrepancy with our
result must arise from the reaction temperature, as we
performed the aldehyde addition at ꢀ788C, whereas ambient
temperature had been used in the literature.[8] This remark-
able temperature effect might be interpreted in terms of a
fully complexed transition state 13 (Nerz–Stormes–Thornton
model) at low temperature[9] and an uncomplexed Pridgen-
type transition state 14 at ambient temperature.[10] Under
these conditions, the primary aldol adduct 15 was unstable
and isomerized to the 1,3-oxazine-2,6-dione 16,[11] presumably
owing to a gem-dimethyl effect. Protection of 3S adduct 12,
removal of the chiral auxiliary, and reduction of the thioester
17[12] led to aldehyde 18.
The 3S configuration in 18 was confirmed by an unam-
biguous synthesis (Scheme 3) from aldehyde 19, which is
readily available from (R)-pantolactone in three steps.[13] The
Scheme 4. Reagents and conditions: a)MeOCHPPh 3Cl, nBuLi, 08C,
then 2m HCl, 238C, 60%; b)K 2CO3, dimethyl 1-diazo-2-oxopropyl-
phosphonate, MeOH, 238C, 93%; c)[CoCp(CO) 2], toluene, hn, reflux,
then CuCl2·2H2O, DME, 238C, 40%; d)Li (excess), NH 3, tBuOH, THF,
ꢀ788C, 85%; e)BH 3, THF, 238C, then K2CO3, H2O2, THF/H2O, reflux,
78%; f)DMP, CH 2Cl2, 238C, 95%; g)LDA, HMPA, THF, ꢀ788C, then
CO2 (excess), ꢀ588C, then 1n HCl, 238C, then TMSCHN2, 08C, 45%,
75% (brsm); h) LDA, PhSeCl, THF, ꢀ788C, 63%; i)NH 4Cl, H2O2,
H2O/CH2Cl2, 08C, 72%; j)NaBH 4, CeCl3·7H2O, MeOH, 238C, 90%;
k)HF·Py, THF, 23 8C; l)LiOH, H 2O/THF, 238C, 59%; Cp=cyclopenta-
dienyl; DME=1,2-dimethoxyethane; HMPA=hexamethylphosphor-
amide; brsm=based on recovered starting material.
Scheme 3. Reagents and conditions: a)2-propenylMgBr, THF, 0 8C,
92%; b)Ac 2O, NEt3, DMAP, CH2Cl2, 238C, 87%; c)LDA, TMSCl,
ꢀ788C!238C, 69%; d)DIC, NEt 3, MeHNOMe·HCl, CH2Cl2, 238C,
98%; e)DIBAL-H, THF, ꢀ788C, 95%; f)K 2CO3, dimethyl 1-diazo-2-
oxopropylphosphonate; g) nBuLi, TMSCl, THF, ꢀ788C, 95%; h)80%
AcOH, THF, 99%; i)TBSOTf, 2,6-lutidine, CH 2Cl2, 08C, 92%; j)HF·Py,
THF, 238C, 65%; k)DMP, CH 2Cl2, 238C, 92%. PMP=para-methoxy
phenyl; DMAP=4-dimethylaminopyridine; LDA=lithium diisopropyl-
amide; DIC=N,N’-diisopropylcarbodiimide; Py=pyridine;
DMP=Dess–Martin periodinane.
and subsequent methylation with trimethylsilyldiazomethane.
The b-ketoester was treated with 2.5 equiv of LDA and
phenylselenyl chloride. Under these conditions diastereomers
25a,b equilibrated to give exclusively the epimer with a cis
ring juncture between the five- and six-membered rings.
Subsequent oxidation gave 26, and diastereoselective reduc-
tion under Luche conditions[17] delivered alcohol 27, which
was deprotected with HF·pyridine and hydrolyzed to pasteur-
estin B (2), whose analytical data matched those of the
natural product.[1]
For the synthesis of pasteurestin A (1), butyrolactone 28
was prepared in two steps from (R)-glycidol.[18] a-Allylation
with bromide 29 furnished lactone 30 with d.r. 98:2,[19] which
was elaborated into aldehyde 31 (Scheme 5). C1-Homologa-
tion and deprotection gave enediyne 4 in 45% yield over six
steps, which was cyclized to give a 4:3 mixture of 6a and 6b.
Birch reduction and desilylation followed by HPLC separa-
tion furnished diastereomerically pure 32 (Scheme 6). The
endgame was performed in analogy to the synthesis of
pasteurestin B (2). Thus, conversion of the epimeric mixture
of 33a and 33b furnished 34a and 34b in a 1:3 ratio. This
mixture was processed through to pasteurestin A (1), whose
analytical data were in accord with those reported.[1]
key step in this sequence was the Claisen–Ireland rearrange-
ment[14] of the epimeric alcohols 20. The rearranged com-
pound was converted to aldehyde 18,[15] which is identical in
all respects to the material obtained above.
C1-homologation of 18 was accomplished by Wittig
reaction and subsequent hydrolysis (Scheme 4). The resulting
aldehyde was treated with the Bestmann–Ohira reagent[16] to
give enediyne 5. Subsequent [CoCp(CO)2]-mediated cycliza-
tion (Cp = cyclopentadienyl) delivered diene 7 in a highly
diastereoselective manner. Regioselective Birch reduction of
ꢀ
the C2a C3 p bond to give cis bicyclo[4.2.0]octane 23 and
subsequent hydroboration–oxidation of the remaining double
bond followed by Dess–Martin oxidation of the newly formed
alcohol furnished a 2:1 mixture of the syn/anti isomers 24a,b.
Functionalization of C-3 in 24 was accomplished by carbox-
ylation of the kinetically favored enolate with carbon dioxide
In conclusion, pasteurestin A (1) was prepared in 22 linear
steps with an overall yield of 0.5%, and the synthesis of
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Communications
to continue with biological testing and the synthesis of
suitable analogues.
Received: July 31, 2007
Published online: October 2, 2007
Keywords: antibacterial activity · asymmetric synthesis ·
.
cycloaddition · sesquiterpenoids · total synthesis
[1] T. Takeuchi, H. Iinuma, I. Momose, S. Matsui (Jpn. Kokai
Tokkyo Koho), JP 2001–9452 20010117, 2002.
[2] G. C. Duff, M. L. Galyean, J. Anim. Sci. 2006, 85, 823.
[3] a) K. Yoshikawa, A. Kaneko, Y. Matsumoto, H. Hama, S.
Arihara, J. Nat. Prod. 2006, 69, 1267; b) A. Arnone G. Candiani,
G. Nasini, R. Sinisi, Tetrahedron 2003, 59, 5033; c) T. C.
McMorris, A. Kashinatham, R. Lira, H. Rundgren, P. K.
Gantzel, M. J. Kelner, R. Dawe, Phytochemistry 2002, 61, 395;
d) M. Clericuzio, M. Mella, L. Toma, P. Vita-Finzi, G. Vidari,
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Rossi, P. Vita-Finzi, Tetrahedron Lett. 1998, 39, 1957; f) W. A.
Ayer, L. M. Browne, Tetrahedron 1981, 37, 2199.
[4] Total syntheses of illudol: a) T. Matsumoto, K. Miyano, S.
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Johnson, K. P. C. Vollhardt, J. Am. Chem. Soc. 1991, 113, 381.
[5] For a general review on [2+2+2] cycloadditions see: S. Kotha, E.
Brahmachary, K. Lahiri, Eur. J. Org. Chem. 2005, 4741.
[6] M. Rychlet Elliott, A. L. Dhimane, L. Hamon, M. Malacria, Eur.
J. Org. Chem. 2000, 155, and references therein.
Scheme 5. Reagents and conditions: a)CBr 4, PPh3, CH2Cl2, 08C, 85%;
b) 28, LDA, HMPA, THF, ꢀ788C, then 29, 90%; c)DIBAL-H, THF,
ꢀ788C, 95%; d)TBDPSCl, DMAP, NEt 3, CH2Cl2, 238C, 90%;
e)Et 2AlCl, CH2Cl2, ꢀ788C, 87%; f)Pb(OAc) 4, CH2Cl2, 238C, 95%;
g)K 2CO3, MeOH, dimethyl 1-diazo-2-oxopropylphosphonate, 238C,
71%; h)[CoCp(CO) 2], toluene, hn, reflux, then CuCl2·2H2O, DME,
238C, 46%; Tr=triphenylmethyl.
[7] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127.
[8] a) T. Harada, T. Mukaiyama, Chem. Lett. 1982, 161; b) A. S.
Kende, K. Kawamura, R. J. DeVita, J. Am. Chem. Soc. 1990, 112,
4070; c) A. S. Kende, K. Kawamura, M. J. Orwat, Tetrahedron
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[9] a) S. Fukuzawa, H. Matsuzawa, S. Yoshimitsu, J. Org. Chem.
2000, 65, 1702; b) S. Fukuzawa, M. Tatsuzawa, K. Hirano,
Tetrahedron Lett. 1998, 39, 6899; c) M. Nerz-Stormes, E. R.
Thornton, J. Org. Chem. 1991, 56, 2489.
[10] A. Abdel-Magid, L. N. Pridgen, D. S. Eggleston, I. Lantos, J. Am.
Chem. Soc. 1986, 108, 4595.
[11] The configuration at C-6 has not been determined.
[12] R. E. Damon, G. M. Coppola, Tetrahedron Lett. 1990, 31, 2849.
[13] P. Lavallꢀe, R. Ruel, L. Grenier, M. Bissonnette, Tetrahedron
Lett. 1986, 27, 679.
[14] For a review see: Y. Chai, S.-P. Hong, H. A. Lindsay, C.
McFarland, M. C. McIntosh, Tetrahedron 2002, 58, 2905.
[15] a) D. A. Evans, J. R. Gage, J. L. Leighton, J. Am. Chem. Soc.
1992, 114, 9434.
Scheme 6. Reagents and conditions a)Li (excess), NH 3, tBuOH, THF,
ꢀ788C, 85%; b)TBAF, THF, 23 8C, 95%; HPLC separation; c)TBSCl,
imidazole, DMF, 238C, 90%; d)BH 3, THF, 238C, then K2CO3, H2O2,
reflux, 78%; e)DMP, CH 2Cl2, 238C, 95%; f)LDA, HMPA, THF,
ꢀ788C, then CO2 (excess), ꢀ588C, then 1n HCl, 238C, then
TMSCHN2, 08C, 55%, 75% (brsm); g) LDA, PhSeCl, THF, ꢀ788C,
55%; h)NH 4Cl, H2O2, H2O/CH2Cl2, 08C, 72%; i)NaBH 4, CeCl3·7H2O,
MeOH, 87%; j)HF·Py, THF, 23 8C; k)LiOH, H 2O/THF, 238C, 55%
over two steps. TBAF=tetrabutylammonium fluoride.
pasteurestin B required 20 steps with an overall yield of 0.8%.
The [2+2+2] cycloaddition was completely diastereoselective
in the synthesis of pasteurestin B (2), owing to the neighbor-
ing stereocenter in 5, whereas the stereocenter in 4 is too
remote to have any influence on the stereochemical outcome.
Screening against a wide variety of bacteria showed that 1
exhibits micromolar activity and high selectivity for some very
versatile pathogenic strains of Pasteurella multocida.[20] Other
bacteria tested such as Escherichia coli and Mannheimia
haemolytica remained unaffected.[21] These results prompt us
[16] G. J. Roth, B. Liepold, S. G. Mꢁller, H. J. Bestmann, Synthesis
2004, 59.
[17] J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226.
[18] For the synthesis of 28 see: R. M. Hanson, Chem. Rev. 1991, 91,
437.
[19] a) K. Tomioka, Y.-S. Cho, F. Sato, K. Koga, J. Org. Chem. 1988,
53, 4094; b) S. Takano, M. Yonaga, M. Morimoto, K. Ogasawara,
J. Chem. Soc. Perkin Trans. 1 1985, 305.
[20] M. Harper, J. D. Boyce, B. Adler, FEMSMicrobiol. Lett. 2006,
265, 1.
[21] For minimum inhibitory concentrations see the Supporting
Information.
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