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Building Blocks for the Synthesis of Enantiomerically Pure Jasmonoids Synthesis of (+)-Methyl Epijasmonate.

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C 0M M U N I CA T 1 0 N S
able large quantities of enantiomerically pure, structurally
diverse cis jasmonoids in a stereoselective fashion. Although
several syntheses of nonracemic compounds of the trans series are known,[7a1only two unselective syntheses of rac-1 a
have been
1. cyrlo-C,H,
2. LiOH
-3. .KI3
'ROOCP , O R *
Building Blocks for the Synthesis of
Enantiomerically Pure Jasmonoids:
Synthesis of (+)-Methyl Epijasmonate **
By Giinter Helmchen,* Andreas Goeke, Gilbert Lauer,
Matthias Urmann, and Jiirgen Fries
Jasmonoids of type 1 (n = 1,3,5) and their reduction products are widespread in the plant world.['"] The best-known
compound is ester 1, n = 1, X = OCH,, a valued fragrance,["] found in jasmine and rosemary oil. This ester and
the corresponding carboxylic acid (I, n = 1, X = OH) are
endogenous growth regulators in plants.[1a1
a : n = 1 , X=OCH3, 2.3-cis
b: n = 1, X=OCH3, 2,3-trans
Recent investigations raised the question as to the rt-ative
configuration of the biologically active substances. Thus,
Acree and Nishida et al. obtained the pure stereoisomers
1 a, b and their enantiomers by tedious separation procedures.'" Only 1 a (methyl epijasmonate), which readily isomerizes to 1 b (methyl jasmonate), is fragrant.!'] The abovementioned plant oils contain only 5 YOof 1a together with 1 b
(equilibrium mixture). Furthermore, l a acts as a pheromone, whereas 1 b is inactive.[,] Finally, cyclopentanes with
cis configuration have been shown to be the biogenetic precursors of j a s r n o n ~ i d s ; [notably,
this also holds true for all
reduced compounds such as lactone Zrs1and cucurbic acid
(3),16]neither of which can undergo epimerization at C-2. We
have now developed a synthetic strategy that makes avail[*] Prof. Dr. G. Helmchen. DiplLChem. A. Goeke, DipLChem. G. Lauer,
Dip].-Chem. M . Urmann, DipLChem. J. Fries
Organisch-chemisches Institut der Universitit
Im Neuenheimer Feld 270, D-6900 Heidelberg (FRG)
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen lndustrie. The results were presented at the
1lth International Symposium Synthesis in Organic Chemistry (Oxford,
June 26. 1989). We thank Dr. J. Weetmon and 7: Lohreyer for preliminary
studies and Prof. K Weinges. whose group independently carried out a
synthesis of ( + ) - I a. for exchanging information.
f> VCH Vurlu~.s~e.sell.s~hufr
mbH. 0-6940 Wrinheim,1990
Our starting point is the asymmetric Diels-Alder reaction.
Several years ago, we found that the uncatalyzed reactions of
the fumarates of (8-ethyl lactate and (R)-pantolactone proceed with high diastereosele~tivity.~~~
For example, ester 4,
readily available in kilogram quantities, and cyclopentadiene
react with a diastereoselectivity of 98:2. The crude product
is hydrolyzed with LiOH in THF/water to give the salt of
5-norbornene-2,3-dicarboxylicacid, which is then converted
directly, without purification, into the iodolactone 5. Recrystallization affords enantiomerically pure['] 5 in 70-80 Yo
yield. Heating a solution of the dried K salt of 5 in dimethyl
sulfoxide (DMSO) (9 h, 175 "C) gives lactone 6 in 84% yield.
We assume that this new cyclization is a decarboxylative 1,3
Conversion of 6 to the ketocarboxylic acid 7 [m.p. 123.5124.5 "C, [a];' = 95.5 (c = 3, 95 % EtOH)] is accomplished
in 91 YOyield by oxidation with RuO, (cat.)/NaIO,.["' In
analogy to the C-7 epimer, a key intermediate in prostaglandin synthesis,["] 7 can be selectively opened a t the cyclopropane ring with mineral acids."'] Heating with concentrated hydrogen iodide leads to 5-iodonorbornanecarboxylic
acid (8a, 84%0), which can be reduced with zinc (THF/
KH,PO, buffer) to give the ketocarboxylic acid 8 b (93 YO).
Whereas C-3 undergoes migration in norbornanones with
syn (relative to the carbonyl group) halogen or alkyl substituents at position 7,[',] C-I migrates when the carboxylic
acid 8b is treated with rn-chloroperbenzoic acid (MCPBA)[14]or peracetic acid. Reaction of the resulting lactone 9
(83 YO)with oxalyl chloride followed by Rosenmund reduction and treatment of the resulting aldehyde with the phos-
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Angen. Chem. h i . Ed. Engl. 29 (1990) No. 9
- HI
8a: X = I
8b: X = H
1. (C0Cl)Z
2. H2/ Pd (BaS04)
10: R = CH=CHOCH3
11 : R = CHzCHO
phorane PPh,CHOCH, affords enol ether 10 (66%) as a
Z / E mixture. Hydrolysis of 10 (THF/H,O/CH,COOH
1 :1:3) leads to aldehyde 11. Reaction of unpurified 11 with
propylidenetriphenylphosphorane in a “salt-free’’ Wittig reaction results in highly selective[’51formation of lactone 2,
[a];’ = -73.0 (c = 3.0, CHC13)J161in 72% yield.
Hydrolysis (NaOH) of 2 followed by esterification of the
resulting hydroxy acid (CH,N,) gives ester 12 (95 %). The
absence of epimerization had to be ensured for both the
oxidation of 12 to the target compound la and the subsequent analysis. HPLC analysis using silica gel columns[’71
proved suitable, but gas chromatography on capillary
columns did not.[’*] The best oxidation results were obtained
with pyridinium dichromate in CH,CI, (1 a:l b = 99.4:0.6,
70% yield). The optical rotation [a];’ = 57.3 (c = 2.5,
CH,OH) of HPLC-pure la agrees with the literature value.[’] Whereas a very intense, typical “jasmonate fragrance”
is found for 1 a, HPLC-pure 1 b is odorless (cf. Ref. [7a]).
The method described here allows methyl epijasmonate (1 a)
to be prepared on a multigram scale and thus makes it available for investigations in plant physiology. Furthermore,
intermediates 8 and 11 are building blocks for the EPC synthesis of almost all jasmonoids (about 20 compounds).
Received: December 29. 1989 [Z 3711 IE]
German version: Angew. Chem. 102 (1990) 1079
CAS Registry numbers
1 a, 95722-42-2; 2. 54595-10-7; 4, 111293-23-3; 5, 128777-68-4; 6.6169-95-5; 7.
128777-69-5; 8a, 128777-70-8; 8b, 60133-54-2; 9, 128685-21-2; 10 (isomer l),
128685-22-3: 10 (isomer 2). 128777-73-1; 11, 128777-71-9, 12, 128777-72-0;
cyclo-C,H,, 542-92-7; Ph,PCHOMe, 20763-19.3; propylidenetriphenylphosphorane, 16666-78-7.
[l] a) G. Sembdner, C. Klose, Biol. Rundsch. 23 (1985) 29-40; b) E. Demole
in E. T. Theimer (Ed.): Fragrance Chemistry, Academic, New York 1982,
pp. 349-396.
[2] T. E. Acree. R. Nishida, H. Fukami, J: Agric. Food Chem. 33 (1985) 425427.
(31 T. C. Baker, R. Nishida, W. L. Roelofs, Science (Washington D . C . ) 214
(1981) 1359-1361.
[4] L. Crombie, K. M. Mistry, J. Chem. Soc. Chem. Commun. 1988, 539.
[5] This compound, called “6-Jasmonsaurelacton” by its discoverers, was isolated from the oil of jasmine flowers: R. Kaiser, D. Lamparsky, Tetrahedron Lert. 1974, 3413-3416. However, this paper gives the formula of the
enantiomer of 2 (presumably arbitrarily).
[6] H. Fukui, K. Koshimizu, Y. Yamazaki, S . Usuda, Agric. Biol. Chem. 41
(1977) 189-194.
[7] a)Syn/orm 1 (1983) 33-63; ibid. 3 (1985) 125-133; recent work: K.
Weinges, H. Gethoffer, U. Huber-Patz, H Rodewald, H. Irngartinger,
Liehigs Ann. Chem. 1987,361 -366; F.-P. Montforts, 1. Gesing-Zibulak, W.
Grammenos, M. Schneider, K. Laumen, Helv. Chim. Acta 72 (1989) 18521859 (these authors generated, via 2, a 6:4 mixture of 1 a and 1 b and
Org. Chem. 40 (1975) 462isomerized it to 1 b), b) H. Tanaka, S. Torii, .
465; T. Kitahara, K. Miura, Y. Warita, Y Takagi, K . Mori, Agric. Biol.
Chem. 51 (1987) 1129-1133.
Angeu. Chem. In!. Ed. Engl. 29 (1990) No. 9
[S] H. Hartmann, A. F.Abdel Hady, K. Sartor, J. Weetman, G. Helmchen,
A q e w . Chem. 99(1987) 1188-1189; Angew. Chem. In!. Ed. Engl. 26(1987)
1143-1 145.
[9] In order to determine the enantiomeric purity. 5 was treated with l(1napbthy1)ethylamine to give diastereomeric amides, which were analyzed
by HPLC.
[lo] R. M. Moriarty, C. C. Chien, T. B. Adams. J. Org. Chem. 44 (1979) 22062210.
[ l l ] a) N. R. A. Beeley, R. Peel, J. K. Sutherland. J. J. Holohan, K . B. Mallion.
G . J. Sependa, Tetrahedron 37 (Supplement No. I) (1981) 41 1-420; b) J. S.
Bindra, A. Grodski,T. K. Schaaf, E. J. Corey, J: Am. Chem. Soc. 95(1973)
7522 - 7523.
[12] Analogous derivatives 8, X = C1, Br, OH, are also readily available in
yields of about 80% by heating with aqueous mineral acids.
[13] G. R. Krow, Tetrahedron 37(1981) 2697-2724.
[14] Paricularly good results were obtained with a “solid-phase variant”: F.
Toda, M. Yagi, K. Kiyoshige, J. Chem. SOC.Chem. Commun. 1988 958959.
[IS] A Z / E selectivity of >96:4 was achieved. Pure Z isomer. isolated by
MPLC, was used in all further reactions.
1161 Ref. [ 5 ] gives a value of [.]go = -47.4 (c = 0.775, CHCI,) for natural
material of only 85% purity.
[I71 50-cm column, Merck silica gel 60.5 p; eluent, n-hexanelethyl acetate 9: 1;
refractometer detector.
[18] Capillary columns, Hewlett Packard HP-5 (25 m) and HP-1 ( 5 m): temperature of injector, 220 and 18O”C, respectively; temperature of column,
120-180 and 80°C. respectively.
Peptide Synthesis under High Pressure
By Joachim Gante,* Ulrike Kalthof, Frank-Gerrit Klarner,*
and Thomas Weber
Dedicated to Professor Wolfgang Kirmse on the occasion
of his 60th birthday
A long-cherished wish of peptide chemists is to carry out
peptide couplings with nonactivated amino acid alkyl esters
as partners in the reaction 1 + 2 -+ 3 (Scheme 1). The advantages of this reaction would include a simplified procedure,
more readily accessible and more inexpensive starting materials, and the easy removal of byproducts (volatile alcohols).
o 3
Scheme 1. AS’, ASZ = amino acid residues
Up to now, a practical procedure of this kind could not be
developed owing to the low degree of activation of the alkyl
esters.[’’ Only the addition of large amounts of activating
substances-like imidazole as solvent (80 “C!)[’] or complexforming metal salts[3x41-has made possible such a reaction,
which requires considerable preparative work.
We have now found a solution to this problem by the use
of high pressure (10-kbar range). High pressure has already
proved useful in many areas of organic chemistry and has
allowed reactions that, under normal conditions, can be carried out only inadequately or not at all.151The preparation of
[‘I Priv.-Doz. Dr. J. Gante, T. Weber
E. Merck, Pharmaforschung
Frankfurter Strasse 250, D-6100 Damstadt (FRG)
Prof. Dr. F.-G. Klarner, DipLChem. U. Kalthof
Fakultlt fur Chemie der Universitat
Postfach 10 21 48, D-4630 Bochum 1 (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0 VCH Verlagsgesellschafr mbH, 0-6940
Weinheim, 1990
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methyl, block, synthesis, enantiomerically, building, jasmonoids, pure, epijasmonate
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