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Diastereo- and Enantioselective Synthesis of (1R 3R)-Caronaldehyde Acid Methyl Ester and (1R 3R)-Chrysanthemic Acid Methyl Ester from (R)-Glycerinaldehyde Acetonide.

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[3] A. E. Liitzow, J. R. Vercellotti, J. Chem. SOC.C1967, 1750.
[S] a) H. Kunz, H. Kauth, Angew. Chem. 93 (1981) 918; Angew. Chem. In,.
Ed. Engl. 20 (1981) 895; b) Liebigs Ann. Chem.. in press.
[7] a) S. Hanessian, J. Banoub, Carbohydr. Res. 52 (1977) 26.
(81 L. A. Carpino, N. Y. Han, J. Org. Chem. 37 (1972) 3404.
[ I 11 B. Belleau, G. Malek, J. Am. Chem. SOC.90 (1968) 1651.
B z l = Benzyl
Bz 0
OB z
4: R = -CHz-OBz,
5: R = -H, 7070
The value of the Fmoc groupL8]in glycopeptide synthesis
is demonstrated by the highly selective deblocking of 4 using morpholine, to give 6 in essentially quantitative yield.
H-Se r-OB zl F moc-A sn-Leu-S e r-OB zl
Bz 0
11, 81%
Neither aminolysis of the ester groups nor p-elimination
of the glyconic moiety[31is observed. The composition and
structure of 6 are confirmed by 'H-NMR spectroscopy.
The free amino group of 6 can be coupled with Fmoc
amino acids as well as with Fmoc dipeptide 9 in presence
(EEDQ)" 'I. The protected glycotripeptide 11 so obtained
in good yield will serve in our investigations as model substance for 0- N transglycosylations.
The amino protecting group can be selectively removed
in high yield with morpholine from both the Fmoc glycodipeptide ester, which is formed by condensation of 6 with
Fmoc-leucine, and from fully protected glycotripeptide
NH B z o L O
r-OB zl
OB z
13, 8370
15, 62%
After hydrogenolysis of the benzyl group in 13, the benzoyl groups can be removed so smoothly with hydrazine
hydrate in methanol at room temperature that the sensitive
0-glycosidic bond is wholly preserved. The structure of
the free glucotripeptide 15 is confirmed by NMR.
Thus, the Fmoc group is a valuable tool for directed N terminal chain elongation of sensitive O-glycopeptides,
whereby the carboxy group of the glycopeptides remains
reversibly protected as benzyl ester.
Received: September 16, 1982 [Z 147 IE]
supplemented: November 10, 1982
German version: Angew. Chem. 95 (1983) 64
The complete manuscript of this communication appears in:
Angew. Chem. Suppl. 1983. 39-46
Angew. Chem. Inr. Ed. Engl. 22 (1983) No. I
Diastereo- and Enantioselective Synthesis of
(lR,3R)-Caronaldehyde Acid Methyl Ester and
(lR,3R)-Chrysanthernic Acid Methyl Ester from
(R)-Glycerinaldehyde Acetonidex*
By Johann Mulzer* and MichaeI Kappert
Certain esters of the (lR,3R)-chrysanthemic acid 1 and
its cis-dibromovinyl analogue 2, which are generally
known as pyrethroids, have found widespread application
as insecticides[']. Remarkably, their physiological activity
is closely associated with the (1R)-configuration; the (IS)enantiomers of 1 and 2 are many times less effective[']. For
this reason suitable routes to optically active 1 and 2 are
being intensively investigated. The (1R,3R)-caronaldehyde
acid methyl ester 3 plays a key role in many of these syntheses'''. We report here on a rational synthesis of optically
pure 3 and the conversion of this intermediate into
(1R,3R)-chrysanthemic acid methyl ester 4.
1, X = Ch1ez, R = H
3 , X = 0 , 11 = M e
4, X = CMe2, R = Me
As shown in Scheme 1, (R)-glycerinaldehyde acetonide
5 can be converted without separation of diastereomers
with 86% ee into 3 (total yield 55% in 5 steps) and 4 (39%
in 6 steps). Optically pure 3 and 4 are obtained by hydrolysis of the mixed cyclopropanecarboxylates 8a/ b to the
corresponding acids 9a/b, from which pure 9a can be isolated by crystallization and then reesterified to 8a. Further
reaction according to Scheme 1 affords 3 (total yield 36%)
and 4 (24%) with > 99% ee. Remarkably, the enantioselectivity of the cyclopropanation increases considerably if the
corresponding methyl ester is employed in place of (E)-6.
The diastereomeric ratio at the stage of 8 in this case rises
to > 98 :2;alkaline hydrolysis furnishes diastereomerically
pure 9a in quantitative yield. In this way, 5 is converted
into optically pure 4 in 35% total yield without any separation of isomers. Esters other than 8 can also be prepared
from 9a via the acid chloride, which opens an entry to a
variety of optically pure pyrethroids. This finding is not
trivial, as the hydrolysis of 4 to 1 causes 23% racemization,
even under mild conditions (5% KOH, MeOH, 22 "C, 14
[*] Dr. J. Mulzer, M. Kappert
Institut fur Organische Chemie der Universitat
Karlstrasse 23, D-8000 Miinchen 2 (Germany)
Present address:
Institut fur Organische Chemie der Universiat
Universitatsstrasse I, D-4000 Dusseldorf (Germany)
This work was supported by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and BASF Ludwigshafen.
0 Verlag Chemie GmbH. 6940 Wernheim, 1983
0570-0833/83/0101-0063 $02.50/0
The key step of our reaction sequence is the enantioand diastereoselective cyclopropanation of the acrylate
derivative (Q-6 with isopropylidene-triphenylphosphane
7@l.A rationalization of the high stereoselection in favor
of the (1R)-isomer is presented in Scheme 2. The assump-
[ I ] Review: D. Arlt, M. Jautelat, R. Lantrsch, Angew. Chem. 93 (1981) 719;
Angew. Chem In/. Ed. E n y / . 20 (1981) 703
.[2] J . Martel, DOS 1935386 (1970), Roussel-ticlaf.
161 A. Knef, DOS 2615 I60 (1976), Roussel-Uclaf: M. J. Devos, L. Hevesi,
P. Bayet, A. Krief, Tetrahedron Lett. 1976, 3911.
1171 a) T. Ardtani, Y . Yoneyoshi, T. NagdSe, Tetrahedron Letr. 1977. 2599; b)
M. Franck-Neumann. I>. Martina, M. P. Hem. ihid. 23 (1982) 3493.
ZH-l,5Benzodioxepin and 3-Halo Derivatives
By Gerald Guillaumet, Gerard Coudert*, and
Bernard Loubinoux
Scheme I . a: NaH, MeO,CCH,P(O)(OEt),, dimethoxyethane, 22 "C, I h,
%%.-b: Me2C=PPh, 7, tetrahydrofuran (THF), -78"C, 1 h, I O T , 2 h,
6O%-c: 5% KOH in MeOH, 2 2 T , 24 h, quant.-d: CH2Nz,ether, 22 "C, 5
min, quant.-e: NalO,, 2 N H,S04/THF, 2 2 T , 24 h, 9 9 - f : 7, THF,
-30 "C, 1 h, 64%.
tion of a transoid conformation in E - ( 6 ) seems plausible; 7
attacks CL3anti
to 0-3-which could be explained in terms of
an electrostatic repulsion between C , and 0 - 3 . The zwitterion 10 cyclizes to give 8a with retention of configuration.
Formally (E)-6 thus corresponds to a chiral fumaraldehyde ester-equivalent, in which attack at the C=C bond
shows a significant degree of diastereo face control.
Up to the present, very few benzodioxepin derivatives
have been isolated[']; thus, 2H-1,5-benzodioxepin 1 and its
3-halo derivatives 2a and 2b were hitherto unknown.
These compounds should offer a simple means of preparing 2,3-disubstituted 1,5-benzodioxepins and 3,4-dihydro1,5-2H-benzodioxepins.
We have now prepared the gem-dihalocyclopropane
derivatives 4aL3]
and 4b in 95% yields from the readily accessible 1,4-benzodioxine 3Ir1 by carbene-addition under
"liquid-liquid" phase-transfer catalysis conditions.
Sa, X = C1
Sb, X = B r
4a, X = C1
3 b X = Br
Scheme 2
In order to prepare optically pure compounds the crucial question always is: Can the enantioselective synthesis
(defined as "asymmetric induction under the influence of
optically active centers, which on further reaction are
either eliminated or are converted into achiral centers")
compete with other methods such as resolutiqn, isolation
from natural sources, o r chiral-pool synthesis (defined as
"synthesis of an optically active target compounds from an
optically active natural product, so that at least one chiral
center of the starting material either remains unchanged o r
is transformed in a stereochemically unambiguous way")?
For 1 , 3, and 4 sufficient data are available"' to permit a
conclusive answer, at least for this particular case: The enantioselective synthesis-whether according to our variant
o r that of other a~thors["~-affords chemical and optical
yields comparable to those obtained by optical resolution,
whereas the "chiral pool" syntheses starting from 3-carene,
pantolactone o r a-pinene, clearly appear to be inferior. AIthough such a comparison is not quite conclusive-one
would have to repeat all the reported syntheses under optimized conditions-the results obtained so far emphasize
the efficiency of the enantioselective approach.
Received: September 21, 1982 [Z 151 IE]
revised: October 25, 1982
German version: Angew. Chem 95 (1982) 60
The complete manuscript of this communication appears in Angew. Chem.
Suppl. 1983, 23-33
0 Verlag Chemie GmbH. 6940 Weinherm. 1983
4a and 4b are heated at 185 "C for 5 h and 170 "C for 25
min, respe~tively'~~.
The compounds 5a and 5b thus obtained are not isolated but immediately reduced to 2 and
1 , r e s p e c t i ~ e l y(Table
~ ~ ] 1).
Table 1. Some data for the synthesis of 1 as well as 2a and Zb. (THF=tetrahydrofuran, HMPT= hexamethylphosphoric triamide).
LiAIH, [a]
LiAIH, [b]
N a B H K N [c]
LiAIH, pa]
2a [5b]
1 [5a]
Zb [5cl
1 [5a]
[%I [el
[a] LiAIH,:5=2: I. (b] LiAiH,:Sa = 4 : I . (c] N a B H 3 C N : 5 b = 8 : I . Id] 5 mL
per mmol of substrate. [el Yield referred to 4a and 4b.
Received: November 17, 1980 [ Z 407 IE]
revised: October 19, 1982
German version: Angew Chem. 95 (1983) 50
CAS Registry numbers:
1, 265-19-0: Za, 83968-1 1-0; Zb, 83968-12-1; 3, 255-37-8: 4a, 65041-40-9;
4b, 83968-08-5: 5a, 83968-09-6; 5b, 83968-10-9; HCCI,, 67-66-3; HCBr3, 7525-2
(*] Dr. G. Coudert, Dr. G. Guillaumet, Dr. B. Loubinoux
Universite d e Nancy I-Faculte des Sciences-B.P. no 239
F-54 506 Vandeuvre-les-Nancy Ctdex (France)
OS70-0833/83/0101-0064 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 22 (1983) No. I
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acid, methyl, synthesis, glycerinaldehyde, caronaldehyde, acetonide, esters, chrysanthemum, enantioselectivity, diastereo
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