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Bicyclic Acetals from Oxacarbenes.

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(14%), respectively, are found. For 3c, the Diels-Alder adduct rac-9a (60%) is preferably formed under Lewis acid
catalysis, while only 29% of the ene product rac-5c is obtained. The amount of cis-substituted cyclohexane derivatives is always less than 1%; for 3 a ; no cis-fused ene product was detected. The alkylidene compound 3d, though,
behaves differently; in both the thermal and the Lewisacid-catalyzed reaction, rac-9b and not the corresponding
ene compound is formed[’] (Table 1).
Table I . Thermal and Lewis-acid-catalyzed reactions of 3 a - 3 d .
Main product
(yield [“YO]) [a]
5 : 7 [b]
(yield [%])[a]
ZnBrz, room temp.
rac-5a (73)
rac-5b (71)
rac-5c (89)
rap-9b (80)
(88) 6a (4)
(68) rac-8 (14)
(29) rac-9a (60)
5 : 7 [b]
> 99 : 1
. O F o H
> 99 : 1
Received: July 29, 1985;
revised: September 3, 1985 [Z 1402 IE]
German version: Angew. Chem. 97 (1985) 1067
[ I ] a) H. M . R. Hoffmann, Angew. Chem. 81 (1969) 597; Angew. Chem. I n / .
Ed. Engl. 8 (1969) 556; b) W. Oppolzer, V. Snieckus, ibid. 90 (1978) 506
and 17 (1978) 476: c) B. B. Snider, Acc. Chern. Res. 13 (1980) 426; d) W.
Oppolzer, Angew. Chem. 96 (1984) 840: Angew. Chem. I n t . Ed. Engl. 23
(1984) 876; e) D. F. Taber: Intramolecular Diels-Alder and Alder Ene
Reaction.?. Springer, Berlin 1984.
[2] L. F. Tietze in W. Bartmann, B. M. Trost (Ed.): Selectivity-a G o a l f o r
Synthetic Efficiency, Verlag Chemie, Weinheim 1984, p. 299; L. F. Tietze,
G. von Kiedrowski, Tetrahedron Lett. 22 (1981) 219: L. F. Tietze, G. von
Kiedrowski, B. Berger, Angew. Chem. 94 (1982) 222; Angew. Chem. Int.
Ed. Engl. 21 (1982) 22 I;L. F. Tietze, H. Stegelmeier, K. Harms, T. Brumby, ihid. 94 (1982) 868 and 21 (1982) 863; L. F. Tietze, S. Brand, T. Pfeiffer, ibid. 97 (1985) 790 and 24 (1985) 784.
[3] The selectivity of the reactions was determined by HPLC, GC-MS, and
I3C-NMR spectroscopy of the crude product mixture.
[4] With other terms suggested for the non-induced and induced diastereoselective reaction such as ”internal asymmetric induction” and “relative
asymmetric induction” (P. A. Bartlett, Tetrahedron 36 (1980) 3) or “simple
diastereuselection” (C. H. Heathcock in J . D. Morrison (Ed.): Asymmetric
Synthesi.5. Vul. 3. Academic Press, New York 1984; M. T. Reetz, Angew.
Chem. 96 (1984) 542: Angew. Chem. Int. Ed. Engl. 23 (1984) 556) the
meanings of the terms may not so easily be inferred. Further advantages
of the pair of terms inducedlnon-induced lie in the possibility of differentiating between externally and internally inducing elements of chirality
as well as their number and-in the case of internally induced reactions- their position relative to the reaction center.
151 The aldehyde 2 was synthesized by Wittig reaction of methyl 5-formylpentanoale, available through a technical process, and its subsequent reduction (LiAIH,) and oxidation (dimethylsulfoxide, (COCI),), in a n overall yield of 95% L. F. Tietze, s. Brand, unpublished.
161 rac-5c: ‘H-NMR (200 MHz, C,D,): S=0.84-1.8 (m; 8 H , ring protons),
1.42 (m; 3 H, CHI=C-CH,), 1.94 (tt, J = 3 and I 1 Hz; 1 H, I-H), 2.11 (dt,
J = 3 and I I Hz; I H, 2-H), 3.18 (s; 3 H , COICH3), 3.39 (d, J = 3 Hz; 1 H,
NC-CH-C02CH3), 4.72 and 4.93 (m; 2H, H,C-C=CH,).
[7] W. Oppolzcr. S. Mirza, Helu. Chim. Acta 67 (1984) 730.
[81 In addition. small amounts of a decalin derivative were detected, which
may have been formed via a tandem ene reaction.
191 B. B. Snider, D. M. Roush, T. A. Killinger, J. A m . Chem. Soc. I01 (1979)
Angew>.Chem Int. Ed. Engl. 24 (1985) No. 12
By Michael Pirrung*
The photochemical ring expansion of cyclobutanones to
2-tetrahydrofuranylidenes has been extensively studied
mechanistically“] but synthetic applications are few. A
proposed mechanism involves a-cleavage followed by the
establishment of a n equilibrium between the singlet acylalkyl biradical and the oxacarbene, but a concerted mechanism may also operate.[21Accordingly, the formation of
products may be explained by the known reactions of the
biradical or the carbene. We report here on the intramolecular trapping of photochemically generated oxacarbenes
to provide bicyclic acetals.
> 99 : I
The trans-arrangement of the substituents in the ene
products rac-5a-5c was shown by ‘H-NMR and I3C-NMR
spectroscopy. Thus, for rac-5c a value of 1 1 Hz is found
for 3Ji.F,,
2.H as is usual with trans-diequatorially substituted cyclohexane derivatives.[61 The good yields and the
high selectivity of the ene reaction of the 1,7-dienes are
surprising since analogous triply activated compounds decompose upon heating.[’]
Bicyclic Acetals from Oxacarbenes**
Compounds 1 ( 3 : l mixture of diastereomers) and 3
were prepared by Ikeda’s route.[31 Compounds 5 and 7
were prepared by modifying this method in order to begin
with 2-hydro~y-3-methylcyclopentenone.~~~
4-Hydroxyethylcyclobutanone 1 provides a stringent
test of this methodology, since (considering the stability of
the resulting acyl-alkyl biradicals) either a-bond could be
expected to cleave. In fact, irradiation (0.02 M CH,CI2 solution, 450-W Hanovia lamp, Pyrex filter) results in complete conversion of 1 into 2 within two hours. Examination of the ’H-NMR spectrum of the crude reaction mixture shows only two products (3 : l), which may be isolated
by chromatography ( I : 1 EtOAdhexanes). Their structures were assigned from spectral data, particularly MS
and ‘H-NMR, and comparison with literature data for ajugareptansin.[’] The major isomer shows data essentially
identical to those of this diterpene natural product. In
ether the reaction is extremely sluggish. The importance of
the intramolecular trapping reaction is emphasized by the
irradiation of the acetate of 1 in methanol. Complete consumption of starting material requires 24 h, and at least
five products are observed by ‘H-NMR. Compound 1 is
also consumed very slowly in methanol, producing 2 and a
complex mixture of methyl acetals. These data suggest that
an important control element may be the intramolecular
hydrogen bonding evident in the IR spectrum of 1.161
yield, while only 30% at room temperature, increases to
50% at -60”, consistent with the findings of Miller et al.
that 1,4-acyl-alkyl diradicals undergo e-cleavage more
readily at higher temperatures.l’I
With compounds 3 and 5 , no ambiguity exists regarding
the preferred direction of bond cleavage, and irradiation at
room temperature provides the bicyclic acetals 4 and 6 in
45 and 70% yield, respectively. The homothromboxane
ring system[’] is embodied in the former structure. Finally,
in order to provide an entry into the more highly oxidized
skeletons of the aflatoxinslgi and caryoptins,””’ cyanohy[*I
Prof. Dr. M. Pirrung
Department of Chemistry, Stanford University
Stanford, CA 94305 (USA)
[**I This work was supported by a grant from the National Science Foundation (USA).
0 VCH Verlagsgesellschaft mbH. D-6940 Weinheim, 1985
0570-0833/85/12/2-1043$ 02.S0/0
Cyclopropyl-Substituted Aminocyclopropane
Carboxylic Acid (Cyclopropyl-ACC)
-an Investigation of the Mechanism of
Ethylene Biosynthesis**
By Michael Pirrung* and Gerard M. McGeehan
We report here the synthesis of 1-amino-2-cyclopropylcyclopropane carboxylic acid (cyclopropyl-ACC) 3 and its
use in investigating the mechanism of ethylene biosynthesis in plants. The application of the SchBlZkopf'] procedure
to 1,2-dibromides has proven the method of choice for synthesis of ACC analogues.[z1In this case, ethyl isocyanoacetate reacts with 1',2'-dibromoethylcyclopropane 1 l 3 I in the
presence of NaH in ether/dimethylsulfoxide (DMSO) to
give the protected bis-cyclopropane 2 in 20-27% yield. A
two-step hydrolysis procedure and ion-exchange chroma-,
tography gives cyclopropyl-ACC 314]as a mixture of stereoisomers (> 7 : 1) in 85-95% yield. The structure shown
was assigned to the major isomer by comparison of its I3CNMR spectra with those of the known methyl-ACCIZ1and
by bioassay.
i OAc
-n/ co2"
1) HCI
2) KOH
drin 7 was prepared from 5 . Irradiation in this case provides a mixture of cyanides such as 8 (51%).
Received: August 5, 1985 [Z 1418 IE]
German version: Angew. Chem. 97 (1985) 1073
(I] D. Morton, N. Turro, J . Am. Chem. SOC. 95 (1973) 3947; Adu. Photo-
chem. 9 (1974) 197.
[2] W. D. Stohrer, G . Weich, G. Quinkert, Angew. Chem. 86 (1974) 200; Angew. Chem. Int. Ed. Engl. 13 (1974) 200, and the directly preceding communications.
131 M, Ikeda, M. Takahashi, T. Uchino, K. Ohno, Y. Tamura, M. Kido, J.
Org. Chem. 48 (1983) 4241. The preparation of 1 by this procedure involves as the final step methanolysis of a tricyclic lactone. The reaction
conditions cause epimerization of the rrans-2,4-disubstituted cyclobutanone to different extents from experiment to experiment. A better procedure involves hydrolysis (1 equiv. NaOH/THF) and methylation
(CHZNz)to preserve the stereochemistry ( > 5 :I).
141 Treatment of the enone with 3-butene-1-01 @-TsOH, benzene, reflux,
67%, b.p. =70"/0.5 t o r ) followed by intramolecular [2 +2] photocycloaddition (acetone, 450-W Hanovia lamp, Pyrex, 16 h, 92%) gave exclusively the fused-ring tricyclic adduct. Baeyer-Villiger oxidation (mchloroperbenzoic acid, CHICI2,room temperature, 12 h, 83% after chromatography) and methanolysis (or hydrolysis/methylation) yielded 5
(93%). Oxidation with pyridinium dichromate (2 equiv., CHzCI2, followed by 2 equiv. Et,N; 54%) and KCN/AcOH treatment gave 7 (quantitative). All new compounds reported herein gave satisfactory NMR,
IR, and mass-spectral data.
(51 F. Camps, J. Coll, A. Cortel, A. Messeguer, Terrahedron Lett. 1979,
[6] There is no significant solvent effect on the n d x * UV absorption band
of 1.
[7] R. Miller, P. Golitz, I. Janssen, J. Lemmens, J. Am. Chem. Soc. 106
(1984) 7277.
181 T. K. Schaaf, D. L. Bussolotti, M. J. Parray, E. J. Corey, J. Am. Chem.
Soc. 103 (1981) 6502.
[9] J. Heathcote, J. Hibbert: Aflatoxins: Chemical and Biological Aspecfs, Elsevier, Oxford 1978.
[lo] P. Zanno, 1. Miura, K. Nakanishi, D. Eider, J. Am. Chem. SOC.97(1975)
1975; S. Hosozawa, N. Kato, K. Munakata, Phyrochemistry 13 (1974)
308; N. Kato, M. Shibayama, K. Munakata, J. Chem. SOC.Perkin Trans.
I 1973. 712.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim, 1985
Yang et al. have established that in alkyl-ACC derivatives the alkyl and carboxyl groups must be in trans positions to be metabolized by plant
The trans-methylACC serves as a good inhibitor of ethylene production
( K , = 0.5 mM) and is a substrate for propylene production
in mungbean hypocotyl segments.['] A Dixon analysis of
the inhibition of ethylene biosynthesis in mungbean by cyclopropyl-ACC 3 shows a K , of 1.5 mM.[61The bulkier cyclopropyl group probably makes it more difficult for 3 to
penetrate to the active center of ethylene biosynthesis.
Based on the previously proposed mechanism of ethylene biosynthe~is,[~'
it was anticipated that the radical 5 , in
Scheme I.
[*] Prof. Dr. M. C. Pirrung, Dipl.-Chem. G. M. McGeehan
Department of Chemistry, Stanford University
Stanford, CA 94305 (USA)
[**I Ethylene Biosynthesis, Part 4. This work was supported by the US.Israel Binational Agricultural Research and Development Fund.-Part
3: Bioorg. Chem. 13 (1985) 219.
0570-0833/85/1212-1044 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 24 (1985) No,I 2
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oxacarbenes, bicyclic, acetals
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