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Highly Alkylated 1-Oxyallyl Anions from N N-Dialkylcarbamic Acid Allyl Esters -Hydroxyalkylation (Homoaldol Reaction).

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tively upon heating to give the new compounds (8) and
(16). respectively. Moreover, since (4) and (6) are very reactive towards C, N, 0, and S nucleophiles, they constitute
valuable synthons for introducing. -CF3 and -CCI3
groups, respectively, into various substrates as shown in
the synthesis of compounds (9), (11) and (12) as well as of
(15)). (17) and (18)[51(Schemes 1 and 2).
The rearrangement product (14) cannot be isolated since
it eliminates HCI to give trichloroenamine (16).
In order to gain some insight into the mechanism, we
measured the kinetics of rearrangement of (4) in benzene,
dioxane, and nitrobenzene at different temperatures. The
plots show that the process is unimolecular and does not
depend upon the polarity of the solvent. This precludes
polar pathways and confirms that the process is intramolecular. Although no radicals have been detected to date
by ESR spectroscopy, v e consider %homolysis leading to a
tight radical pair [CF3CCIN(CH3)2CI]as very likely; a concerted process cannot, however, be excluded.
Table I . Kinetics of the 1,3-CI/H exchange (4)-+(8).
Solvent
Benzene
D i ox ane
Nitrobenzene
T
I"C1
k x lo5
Is-']
72.5
81
91
72.5
81.5
92.5
98.5
74
82.5
91.5
1.14
3.57
10.40
1.74
4.98
17.50
34.30
2.64
6.88
19.60
A x lo-"
Is - 'I
Ed
[kcal/mol]
7.9
29.76
6.02
29.32
3.82
28.9
0; (8). 79770-13-1; (9). 312-73-2; (10). 79770-14-2; (11). 79770-15-3: (12).
79770-16-4; (13). 79770-17-5; (15a). 79770-18-6; (15b). 79770- 19-7 ; (16).
79770-20-0: ( I 7). 79770-22-2; (18). 79770-23-3.
[ I ] F. Huys. R . Merenyi, 2. Junousek. L. Stella. H. G. Viehe. Angew. Chem.
91, 650 (1979); Angew. Chem. Int. Ed. Engl. 18. 615 (1979).
[2] Z . Janousek. F. Huys. L. Rent. M. Musquelier, L. Stella. R . Merenyi, H .
G . Viehe. Angew. Chem. 91, 651 (1979); Angew. Chem. Int. Ed. Engl. 18.
616 (1979).
[3] F. Huys. Dissertation, Universite Louvain-la-Neuve 1979.
141 Y. L. Yagupolskij. 5. K. Kerzhner, L. M. Yagupolskij, Zh. Org. Khim. 12,
2213 (1976): J. Org. Chem. USSR 12, 2148 (1976).
151 All the new compounds were characterized by MS, 'H- and "C-NMR.
Highly Alkylated 1-Oxyallyl Anions
from N,N-Dialkylcarbamic Acid Ally1 Esters:
y-Hydroxyalkylation (Homoaldol Reaction)[**'
By Dieter Hoppe, Rudolf Hanko, Alfons Bronneke, and
Florian Lichtenberg"'
Dedicated to Professor Oskar Glemser on the occasion
of his 70th birthday
I-Oxyallyl anions (3). R = alkyl['], aryl"] or trialkylsilyl[2.31are synthetic equivalents of the unknown aldehydeand ketone-homoenolates (I); their scope of application,
however, is very limited: 1) Anions of type (3) are indeed
selectively y-alkylated to enol ethers (4); however, on addition of carbonyl compounds the a-adducts (5) predominate''.2.41.2) Because of inadequate acidity only those ally1
ethers (2) which bear at most one alkyl group can be deprotonated (in the absence of stabilizing M-substituents)",". 3) Wittig rearrangements and related reactions
often take place, even at low temperature^[^.^^.
Experimental
(4) and (6): Solutions of (3)l4]and (5) in CH2C12are chlorinated by passing a rapid stream of chlorine through the
solutions until the exothermic reaction has subsided. (4) is
a colorless liquid b.p.=25 "C/12 torr; 'H-NMR (CDC13):
6=2.66 ppm; I9F-NMR (CDCI3): 6 = -73.5 ppm.-Solid
(6) is obtained by evaporation of the CH2Cl, and is purified by sublimation at 65 "C/0.02 torr. 'H-NMR (CDCl3):
6= 2.83.
(8): (4) is heated to 100°C over 4 h and distilled at
55"C/10 torr. 'H-NMR (CDCI,): 6=2.66 (s, 3 H), 5.03 (s,
2 H) and 5.36 (q, 1 H).
(16): A solution of (6) in CHCl3 is refluxed for 18 h.
Crude (16) is purified by Kugelrohr distillation 35 " U 0 . 2
torr. 'H-NMR (CDCI,): 6=2.76 (s, 3H) and 5.15 (s, 2H).
When the transformation is performed in the presence of
CI2, (18) is obtained.
Kinetic Measurements
A solution of 0.1 g of (4) in 0.5 mL of the solvent was
prepared in a NMR tube, which is then heated in a thermostated bath for a definite time. The rate constants were
determined at various temperatures by 'H-NMR spectroscopy. An Arrhenius plot gives the values for the A factor
and the activation energy E,, in each solvent.
Received: June 16, 1981 [z 919 IE]
German version: Angew. Chem. 93, 1091 (1981)
CAS-Registry numbers:
(3). 79770-08-4; (41, 79770-09-5; (5). 631-67-4; (6), 79770-10-8; (7). 79770-12-
1024
0 Verlag Chernie GrnbH. 6940 Weinheim. 1981
R2
14)
R2
R2
i 2)
131
151
El
R4 0-R'
R4
0-R'
We report here on a novel type of I-oxyallyl anionsi6]
which does not suffer these limitations: N ,N-dialkylcar-
['I
R.
priv.-Doz. Dr. D. Hoppe,
Dipl.-Chem. A. Branneke, DipLChem. F. Lichtenberg
Oranisch-chemisches Institut der UniversitBt
Tammannstrasse 2, D-3400 Gattingen (Germany)
Metalated Nitrogen Derivatives of Carbonic Acid in Organic Synthesis,
Part 20. This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. Delivered in part at the
Chemiedozenten-Tagung in Tiibingen, March 25, 1981.-Part 19: R.
Hanko. D. Hoppe, Angew. Chem. 93, 1 I5 (1981); Angew. Chem. Int. Ed.
Engl. 20, 127 (1981).
-
[**I
0570-0833/81/1212-1024$ 02.50/0
Angew. Chem. Int. Ed. Engl. 20 (t98l) No. 12
raphy (Table 1). With exception of E-(9e) ( ' H - N M R
(CCI,): 3 J , , 2 =13 Hz) and (Sg), Z-enol esters are obtained
[(9a).(9d) and Z-(9e): 3 J , , 2 = 6 Hz; (9b) and (Pc): 4J,,,2=1.1
Hz""~]. Thus, whenever it is sterically suitable the reacting
species (7) prefers the I-Z-configuration"Z'.
We presume that (7) is present as tight ion pair, in which
the lithium cation is held at the a - C atom by the complexing carbamoyl oxygen (Fig. la): as a result the carbonyl
compound (8) reacts with (7), via a six-membered transi(Fig. Ib), in the y-position.
tion
Solvolysis of (9) with TiCI,/H20 or CH30H affords the
6-hydroxycarbonyl compounds (homoaldols) (I 1 ) as lac-
bamic acid allyl esters (6)-prepared from allyl alcohols
and N.N-dialkylcarbamoyl chloride~~'~-arerapidly deprotonated to the lithium compounds (7) with n-butyllithium
in diethyl ether/N,N.N',N'-tetramethylethylenediamine
(TMEDA) at -78°C (Table 1). The carbamoyl group of
(6) is not attacked by butyllithium, even in the case of the
1,2,3-trialkylated allyl ester
Solutions of (7) are stable
up to ca. -50°C. Hence, highly substituted I-oxyallyl anions with a large variety of structural features are now accessible for the first time.
Unlike (3) the lithium compounds (7) take up aldehydes
and ketones (8) predominantly at the y-position to give the
6-hydroxyenolcarbamates (9); small amounts of the less
polar ally1 isomers (10)are easily separated by chromatog-
(6a.
Fig. I . a) f7) as tight ion pair. b) Transition state of the addition o f carbonyl
compounds to (7).
Table I . Addition of aldehydes and ketones (8)to I-oxyallyl anions f7) generated from (6). R=iPr.
R'
R'
H
H
(6)
R3
H
Yield pl
(91 : ( l o )[cl
f
"1
(v:@
[hl
i9aj
79
93 :7
0.25
/9h,
93
97:<3
1
60
83:17
I
(9) la1
(8)
R4
R'
Rh
H
CH,
CH,
OC b
CH,
H
H
H
(CHW
CH,
H
H
H
(CH I)lC=-CH
&
OC b
XLy
(*<I
OC b
KO
H
H
CH,
H
(CH,),C
17
97: < 3
I
H
H
CH,
CH,
C6H5
75
95: <5
I
42
95: <s
1.5
65
95:cs
5
+CH&-
19f1
Ii H
CHI
[a] Structure secured by 'H-NMR and IR spectra and by CH analysis; Cb=C(=-O)N(iPr)l. [b] Pure (9) after chromatography. [c] Determined by isolation of the
compounds or 'H-NMR spectroscopically. [dl rhreo-(9d) :eryfhro-(9d)-85 :IS, cf. [9].,[e]Contains co. 5% Z-(9e) ('H-NMR: 21,.l=6Hz). [q Prepared from (-)-myrtenol. [gl Cb=C(=-O)NEt:; (3S.5S)f9g):(3R.59)-(99/=92:8, determined by "C-NMR spectroscopy.
Angew. Chem. In[. Ed. Engl. 20 (1981) No. 12
0 Verlag Chemie GmbH. 6940 Weinheim, 1981
057~0833/81/1212-1025 S 02.50/0
1025
tols (12) or as lactol ethers (13). After protection of the hydroxy group in (9), deblocking leads to preparatively useful homoaldol derivatives with free carbonyl groups. Thus,
the acetate of (9b) gives the y-acetoxyketone (14) in 94%
yield.
Procedure
(9): All operations must be carried out under N2 with
of butylrigorous exclusion of moisture. A 1 . 6 0 solution
~
lithium (3.40 mL, 5.50 mmol) in hexane is transferred
within 15 min at - 7 8 ° C through a syringe cooled with
dry-ice into a solution of (6)l7] (5.00 mmol) and TMEDA
(0.83 mL, 5.50 mmol) in diethyl ether (15 mL). After 0.25-5
h (Table I), a solution of (8) (5.30 mmol, 1.06 equiv.) in a
few mL of ether is added to the mixture at -78 to -70°C;
after 2 hours stirring at this temperature the mixture is neutralized with glacial acetic acid (0.90 g, 15 mmol), allowed
to warm, and worked-up in the usual way with etherlwater. Chromatography on ca. 60 g silica gel with ether/petroleum ether (1 : 1) furnishes pure (9). Rf=0.1-0.3 [(lo):
R = 0.3 -0.51.
Received: July 31, 1981 [Z 920 IE]
German version: Angew. Chem. 93. 1106 (1981)
CAS Registry numbers:
(6a). 74562-19-9; (66). 79792-70-4; (6c). 79792-71-5; (6d). 79792-72-6; (6e).
79792-73-7; (6fl, 79792-74-8; (8) (R'. R'=CH,), 67-64-1 ; (8) (RS=(CH3),C,
R'=H), 630-19-3; (8) (RS=(CH3)2C=CH, R"=H), 107-86-8; (8) (R'=ChHS,
Re=H), 100-52-7; (8) (R', R6=(CH2),), 120-92-3; (Z)-(9a), 79792-75-9; (9(9b). 79792-76-0; ( 9 4 9 6 ) acetate, 79792-77-1 ; (Z)-(9c),79792-78-2; (3-threo(9d), 79792-79-3; (Z)-erythro-(9d). 79792-80-6; (E)-(9e),79792-81-7 ; (Z)49e).
79792-82-8; (Z)-(9fl. 79792-83-9; (3S,5S)-(9g), 79792-84-0: ( 3 R , 5S)-(9g),
79814-95-2; (IOa), 79792-85-1 ; (IOc), 79792-86-2; (14). 79792-87-3
[ I j a) D. A. Euans. C.C.Andrews. B. Buckwalter, J. Am. Chem. SOC. 96, 5560
(1974); b) D. A. Evans. D. 1. Baillargeon. J . V. Nelson, ibid. 100. 2242
(1978); c) W . Oppolzer. P. H . Briner. R. L. Snowden. Helv. Chim. Acta 63.
967 ( 1 980); df J. Uartmann, R. Muthukrishnan. M. Schlosser. ibid. 57.
2261 (1974).
[2] By deprotonation: a) W. C. Still. T. L. Macdonald, J. Am. Chem. SOC.96.
5561 (1974); b) J. Org. Chem. 41, 3620 (1976).
(31 From acylsilanes: A. Hosomi, H . Hashimoto. H. Sakurai. J. Org. Chem.
43, 2551 (1978); b) I. Kuwajima, M. Kato, J. Chem. SOC.Chem. Commun.
1979. 708; c) H. J. Reich, R. E. Olson, M . C. Clark, J. Am. Chem. SOC.
102. 1423 (1980).
[4j For an exception cf. M. Yamaguchi. T. Mukaiyama, Chem. Lett. 1979.
1279.
[S] a) Wittig rearrangement: V. Rautenstrauch. G. Biichi. H . Wiisi. J. Am.
Chem. SOC. 96, 2576 (1974). and references cited therein; b) Brook rearrangement: Ref. 131 and A. G. Brook, Acc. Chem. Res. 7. 77 (1974); b)
rearrangement of (aroy1oxy)allyl anions: P. Beak, L. G. Carter, J. Org.
Chem. 46, 2363 (1981).
[6] Detection and use of anions (7) generated in situ: D. Hoppe. R. Hanko, A.
Bronneke. Angew. Chem. 92,637 (1980); Angew. Chem. Int. Ed. Engl. 19.
625 (1980).
171 With 1.5 equiv. pyridine (without solvent, 5-12 h, 80-100°C) o r [(6fl]
from the lithium alkoxide according to: L. E. Ouerman, C. B. Campbell.
F. M. Knoll, J. Am. Chem. SOC.100. 4822 (1978).
181 Analogous to the aldol reaction of lithium E- and Z-enolates, cf. W. A .
Kleschick. C. T. Buse, C. H . Heathcock. J. Am. Chem. SOC. 99. 247
(1977).
191 For the threo-selective homoaldol reaction with dialkylaluminum compounds see: D. Hoppe. F. Lichtenberg. Angew. Chem., in press.
1026
0 Verlag Chemie GmbH, 6940 Weinheim. 1981
Total Synthesis of Zizyphin A
and N-Acetylzizyphin B"*'
By UIrich Schmidt, Albrecht Lieberknecht. Hilrnar Bokens,
and Helmut Griesser['I
Until now, attempts to synthesize ansapeptides have
only been partially successful"'. Over the last ten years cu.
80 of these "peptide alkaloids", which complex with alkali
earth metal ions and function as ionophores in plants,
have been isolated and characterized"]. Most peptide alkaloids show activity against gram-positive bacteria and
lower funghi. Some inhibit energy transfer processes in
chloroplasts.- We report here the first total synthesis of
two peptide alkaloids-zizyphin A (I) and N-acetylzizyphin B (2) from Zizyphus oen~plia[~I-witha 13-membered
ring having a 10-membered "handle", using a cyclization
method previously developed by
By means of the route worked out for the preparation of
trans-3-pheno~yproline[~],
the methyl ester of 3-bromodehydroproline was reacted with sodium 3-tert-butoxycarbonyI-4-metho~yphenolate[~],
the methoxycarbonyl group
was saponified, and the dehydroproline derivative was reduced with dimethylaminoborane. The resulting mixture
of cis- and trans-phenoxyproline derivatives could be separated by recrystallization. The trans-compound (3) was
acylated at the proline nitrogen and finally converted into
the methyl ester (4) by diazomethane. After cleavage of
both tert-butyl groups and acylation of the proline nitrogen to give (5) [yield 21% relative to the methyl ester of
bromodehydroproline], we synthesized the aminoacetyl
group from the aromatic carboxy group.
R e a ~ t i o n ' ~of] the imidazolide of (5) with the magnesium
salt of monobenzyl malonate led to the benzyl acetylacetate (6) [yield 97% from (5)]; oximation of (6) to (7) [yield
9I%], followed by catalytic hydrogenation of the oxime
group, simultaneous catalytic debenzylation of the ester
and decarboxylation of the keto acid formed the amino ketone (S), which upon treatment with N-benzyloxycarbonylproline hydroxysuccinimide produced the diastereomeric
amides (9a) and (96) [yield 56% from (7)J. Reduction of the
carbonyl group on C-I with NaB(CN)H, to give
[I00
% yield], saponification of the methyl ester [yield 95%] and
formation of a mixture of the four diastereomeric pentafluorophenyl esters ( f l u - d ) [pentafluorophenob'dicyclohexylcarbodiimide; yield 83Y0]yielded the starting material
for the ring-closure step which, after 5 h catalytic hydrogenation on palladium/charcoal using dilution techn i q u e ~ ' ~produced
],
the four diastereomeric alcohols (12ad) in 80% yield.
It should be possible to form the double bond between
C-I and C-2 from the corresponding bromides via an elimination step. To preserve the acid-sensitive Boc protecting
group, we reacted the mixture of alcohols (12a-d) with 1 bromo-N, N-2-trimethyIpr0penylamine[~~
to produce a mixture of the diastereomeric bromides ( 1 3 ~ - d ) .Even this re-
['] Prof. Dr. U. Schmidt, Dr. A. Lieberknecht, DipLChem. H. Bakens, H.
Griesser
lnstitut fiir Organische Chemie, Biocbemie und lsotopenforschung der
Universitst
Pfaffenwaldring 55, D-7000 Stuttgan 80 (Germany)
["I Synthesis of Peptide Alkaloids, Part 4; Amino Acids and Peptides, P a n
33. This work was supported by the Fonds der Chemischen Industrie, by
BASF AG, and by the Deutsche Forschungsgemeinschaft. We thank Dr.
J. M. Muller (Ciba-Geigy) and Dr. G.Eckhurdt for providing samples of
zizyphin A, Dr. W. Rozdzinski for recording numerous mass spectra, and
Dr. K.-D. Jany for determining allo-isoleucine.- Pans 3 and 32, respectively: Tetrahedron Lett., 1981, 4949.
0570-0833/81/1212-1026 $02.50/0
Angew. Chem. Ini. Ed. Engl 20 (1981) No. 12
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acid, ally, oxyallyl, reaction, dialkylcarbamoyl, hydroxyalkylation, esters, homoaldol, alkylated, anion, highly
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