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C-Acylation under Virtually Neutral Conditions.

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General Synthesis of Potentially Antiviral a-Adamantyl
Carbonyl Compounds[**]
By Manfred 7: Reetz, Wilhelm F. Muier, Komad Schwrllnus,
and Ioarinis Clzatiiiosifitlis[*]
Recently, it was discovered['] that certain a-adamantyl carbony1 compounds are considerably more active as antiviral
agents and a great deal less toxic than 1 -aminoadamantane[2'.
The multistep syntheses which were described in are based
on phenols as starting materials, and are therefore restricted
to the cyclohexanone framework. We wish to report that
our method of a-tert-alkylation of carbonyl compounds can
be applied generally to the introduction of 1 -adamantyl
Silylenol ethers (2a)-(2k),
which are easily
obtained from ketones (1 a)-(1 I I ) [ ~ ~react
smoothly with
1 -bromoadamantane in the presence of titanium tetrachloride
at -40°C to - 50°C to afford the desired a-adamantyl ketones
(3) in good yields (Table 1). Table 1 shows that structurally
According to Dubois et a/.['] it is possible to convert bulky
carboxylic acid esters into ketones ria the corresponding acid
chlorides on using Grignard reagents in the presence of copper
salts. Combination of the methods allows the synthesis of
ketones having adamantyi groups in specific positions.
Concerning the antiviral activity of the compounds ( 3 ) ,
in ritro tests with viruses of the Newcastle disease show that
for example 2-(1 -adamantyl)-4-methylcyclohexanone (3 e ) is
about three times more active and half as toxic as l-aminoadamantane"].
Synthesis of 2-( 1 -adamantyl)cyclohexanone (3 b ) : A cooled
solution (- 50°C) of 3.8 g (20mmol) titanium tetrachloride
in 10ml dry methylene chloride is added within two minutes
to a cooled mixture (- 50°C) of 3.5 g (20 mmol) l-trimethylsiloxycyclohexene and 4.5 g (20.9 mmol) 1-bromoadamantane
in 60 ml of dry methylene chloride. The reaction mixture
is stirred for 30 minutes, hydrolyzed, and the solvent of the
organic phase evaporated off. Recrystallization of the residue
from methanol affords 3.5 g of pure 2-(1-adamantyl)cyclohexanone as well as 1.Og from the mother liquor: yield 8 9 % ;
m.p. 86°C; 'H-NMR (CCI,): b=l.72 (s, ISH), 1.42-2.4 (m,
9H); IR (KBr): 2960, 2930. 2895, 2840, 1695, 1445, 1345,
1310, 1205, 1130, 1120, 1110, 1065cm-'.
Received: June 19. 1978 [ Z 114 IE]
Publication delayed at authors' request
German version: Angew. Chem. 91, 7X (1979)
Table 1 . a-Adamantylation of ketones ( / o ) - ( / h ) (A: triethylamine; 8 :
TiCI4: -40 to -50°C) and carboxylic esters ( I i ) - ( / I ) ( A : lithium diisopropylamide: B: catalytic amounts of ZnC1,: room temperature).
[ y , ][a]
66 (78)
x9 (95)
73 (90)
62 (75)
72 (80)
75 (80)
8 1 (89)
70 (XO)
quite different ketones can be alkylated. Also noteworthy
is the smooth adamantylation of diisopropyl ketone (1 d ) ,
which affords the derivative (3 d) having two neighboring
quaternury carbon atoms.
In a similar manner carboxylic acid alkyl esters ( 1 i)-(l / I )
can be adamantylated ria the corresponding ketene ketals
(2i)-(2/jL5], using catalytic amounts of zinc chloride as
Lewis acid at room temperature. Compounds containing two
tertiary groups on one carbon atom can also be prepared,
e. g. (3 I ) .
[*] Doz. Dr. M. T. Reetz, Dipl.-Chem. W. F. Maier, K . Schwellnus, 1.
Fachbereich Chemle der Universitiit
Lahnberge. D-3550 Marburg (Germany)
Present address:
lnstitut fur Organische Chemie und Biochemie der Universitit
Gerhard-Domagk-StraBe I , D-5300 Bonn (Germany)
[a] The yields are based on isolated products in the reaction ( 2 ) + ( 3 ) ;
the values in brackets were determined by 'H-NMR spectroscopy. [b] I-Trimetbylsiloxy-4-methyI-3,4-dihydronaphthalene (2/1)t2-(l-adamantyl)-4methyl-1-tetralone (311). [c] Yield (il)+ ( 2 1 ) : 84%.
[**I This
K. rligurni, Y Ifranloto, N . Zrkorrhi, K . H o r i o r i , J . Med. Chem. I X , 713
Reviews: R. C . Bimqhrmz, P. I,. R. S ~ h l e ! ~Fortschr.
Chem. Forsch.
18, 83 (1971); J. S. WishiioL. J. Chem. Educ. 5 0 . 780 (1973).
M. T Rert;, W F. Muier, Angew. Chem. YO. 50 (197X): Angew. Chem.
Int. Ed. Engl. I7,48 ( 1 978); see also T H . Cham I . P O ~ U W I J.
I . Pbisorinairlt.
Tetrahedron Lett. IY77. 4183.
H . 0.Hotis<,, L. J . Cxhli, M . GrilI, H . D. Olinsrrirrl. J . Org. Chem.
34. 2324 (1969).
M. T R w l z , K. S ~ / I I V ~ ~Tetrahedron
/ I I I ~ . S , Lett. IY78, 1455.
C. Lion, J. E . Duboi.5. I: Borrzouyou, J . Chem. Research (S) lY78. 46.
work was supported by the Fonds der Chemlschen Industrie.
C-Acylation under Virtually Neutral ConditionsP*]
By Dee W. Brooks, Linda D.-L. Lu, and Satoru Masuniune[*l
During the course of studies directed toward the total synthesis of macrolide antibiotics, the pressing need for an efficient
method of C-acylation on acid- and base-sensitive synthetic
intermediates became evidenti1].We wish to describe here
a practical solution of this fundamental problem.
The method is operationally very simple; it involves successive addition of two reagents to a carboxylic acid ( I ) in
tetrahydrofuran (THF) [reaction (a)]. Carbonyldiimidazole
converts the acid ( I ) into the corresponding imidazolide
(2)12], which, without isolation, is treated with the neutral
magnesium salt of a malonic or methylmalonic acid half thiol
ester of type (3) or ( 4 ) . The condensation proceeds in excellent
yields and under mild conditions (see Table 1). The B-ketothiol
esters of type ( 7 ) and ( 8 ) which are obtained are apparently
1'3, Ms. L. D.-L. Lu ['I. and Professor Dr. S.
Masarnune ['I
Department of Chemistry. Unibersity of Alberta, Edmonton. Alberta
T6G 2G2 (Canada)
[ '1 Present address: Department of Chemistry. Massachusetts Institute of
Technology, Cambridge, Massachusetts 021 39 (USA)
This work n a s supported by the National Research Council of Canada.
[*] Dr. D. W. Brooks
A n q n v . Chml. I f i t . Ed. Engl. I R ( 1 9 7 9 ) No. I
not complexed with magnesium and are readily isolated, either
directly by thin layer chromatography or by aqueous workup.-The reaction can also be carried out with the neutral
magnesium salts of the esters (5) and (6) [Reaction (b);
Table I].
turn was allowed to react with 1.2mmol ( 4 a ) or ( 4 h ) . Methanolysis in the presence of sodium acetate (25°C for 2h)
afforded them-hydroxy-p-ketothioester in 90 yield [reaction
(8i), R3
(8k). R3
Im =
Table 1 . Conversion of carboxylic acids ( 1 ) into P-ketoesters ( ? j - - ( I O )
ria reactions ( a ) and (b).
No. Carbox- R 1
conditions [a]
Prod- Yield
[a] Condirions A: 4h, 25°C; B: ISh, 25°C; C: 6 h , 35°C; D: 24h. 35°C.
[b] Yield of isolated, pure product. [c] Formula, see above; cf. R. Aiiliker,
D. D ~ o r n i k ,K . Guhler, H. Hrusser, V Prelog. Helv. Chim. Acta 39. 1785
(1956); C . D j m s s i , J . A . Zderic, J . Am. Chem. SOC.78, 9390 (1958): synthesis:
S. Ma.wrnutir. C . L'. Kim, K . E. Wilson, G. 0. Spessrrrd, P. E . G~.orghiou,
G. Batch. ibid. 97. 3512(1975); new synthesis: S. Musumtine et a/., unpublished.
Because of the slightly enhanced reactivity of a primary
hydroxy group toward carbonyldiimidazole as compared with
a secondary hydroxy group, the above method requires modification when applied to w-hydroxycarboxylic acids. Thus, treatment of 8-hydroxyoctanoic acid (2 i) (1.Ommol) in 4 ml THF
with excess imidazole (4.4 mmol) and trifluoroacetic acid
anhydride (2.1 mmol) gave the imidazolide ( I Z ) , which in
Aiigtw. Chern. 1111.E d . Engl. 18 ( 1 9 7 9 ) N u . 1
= C2Hs
= (CH,),C
The efficient C-acylation resulting from reaction of the new
tral magnesium compounds of type (3) or ( 4 ) with an acid
imidazolide (2) is surprising and offers distinct advantages
in many respects over an earlier, superficially similar method
which involves reaction of the basic magnesium enolate ( I I )
with an acid chloride or imidazolider3! With this earlier
method, e. 9.. the acid derivatives of (1 d ) and ( I e ) provided,
at best, 25-32 % yields of the corresponding products listed
in Table 1 . Protection of the hydroxy group is normally
required before the reaction with ( 1 1 ) (cf. entries 12 and
14 in Table 1). Furthermore, the present C-acylation proceeds
unaffected by the presence of 1 equivalent of cyclohexanecarboxaldehyde, which is recovered intact.
The use of malonic acid half thiol esters patterns the scheme
proposed for a similar process involved in the biosynthesis
of fatty acids[4].Early and recent model studies for the enzymatic process[51have aided us in developing the present synthetically useful procedure.
Synthesis of ( 4 a ) : Magnesium ethoxide (0.49 g, 5 mmol)
is added to a solution of methyl malonic acid half ethanethiol
ester (1.62g, IOmmol) in T H F (25ml) and the mixture is
stirred for 1 h. The solvent is removed at reduced pressure
(25"C/O.I torr) to give a slightly hygroscopic white salt which
is used directly.
Synthesis of (8u) (Table 1, entry 7): Carbonyldiimidazole
(180mg, 1.1 mmol) is added to a solution of levulinic acid
( 1 d ) (116 mg, 1 .O mmol) in T H F ( 5 ml). After stirring at room
temperature for 6 h, the magnesium salt ( 4 a ) prepared above
(380mg, 1.1 mmol) is added. The mixture is stirred for 18h
at 25°C and then the solvent is removed at reduced pressure.
The residue is partitioned between ether (20 ml) and aqueous
0.5 N HCI (20 ml) and the layers are separated. The aqueous
phase is further extracted with ether (10ml). The combined
ether extracts are washed with aqueous saturated N a H C 0 3
(20ml), dried over anhydrous Na2S04, and filtered. The solvent is evaporated at reduced pressure to give 185 mg (85 %)
of the P-ketoester ( a d ) ; 'H-NMR (CDCI3): 6=1.26 (t, 3H,
J=7.5Hz), 1.38 (d, 3H, J=7.0Hz), 2.16 (s, 3H), 2.75 (m,
4H), 2.91 (q, 2H, J=7.5Hz), 3.82 (q, I H , J=7.0Hz); MS:
m/e= 21 6.0819 = C l OH1603S( M ' ) .
Received: October 19. 1978 [Z I 1 7 IE]
German version: Angew Chem. Y I . 76 (1979)
For a concise review of acylation of active methylene compounds, see
H. 0. House: Modern Synthetic Reactions. Benjamin, Menlo Park 1972,
Chap. 1 1 ; For the use of Meldrum's acid for acylation. see Y. Oikuiw.
K . Sugano. 0. Yonemitsu, J. Org. Chem. 43, 2087 (19781, and references
cited therein.
H . A . Staab, M . Liikiiig, F. H . Diiry, Chem. Ber. 95, 1275 (1962).
R. E. Ireland, J . A. Murc.hall, J . Am. Chem. Soc. 81, 2907 (1959); G .
h u m , M . Vilkas. Bull. Soc. Chim. Fr. 1964, 945.
F . L y n m in R. M . S. Smellre- Chemical Reactivity and Biological Role
of Functional Groups in Enzymes. Academic Press, New York 1970,
p. Iff.: K.-I. Arnsradr, G. Schindlbeck, F. Lynen, Eur. J. Biochem. .55.
561 (1975), and references cited therein
a) G. E. Lienhard, W P. Jencks. J. Am. Chem. Soc. 87, 3863 (1965);
b) H . Wetick, M . Schalties, Helv. Shim. Acta 56, 3059 (1973); c) Y
Kobuke, J . Yoshida, Tetrahedron Lett. 1978, 367. Reaction (a) described
herein resembles in some respects the enzyme model reaction described
by these authors which appeared during the course of our present study.
Their reaction, however, proceeds rather inefficiently and is synthetically
applicable t o only the condensation of primurg carboxylic acids with malonic thiol half ester [R’ = CH2, RZ= H, R3 = reaction (a), reaction
time S7 h, yield 60 XI, d) For an intramolecular acylation reaction, see A.
I . Scott, C. J . Wirswr, S . Yoo, S . - K . Chung, J. Am. Chem. Soc. 97,
6277 (1975).
Table 1. Cyclization of phosphite derivatives of the linear oligoamides
H(NHCH2CH2CO),,0H( I ) in 0.01 M solution.
c-(NHCH,SH2CO), (2), n =
Ring atoms
Ring atoms
Ring atoms
23 ”/,
11 %
3 4:
1 % 0 5 7”
dilute solution in DEP (c= 0.1 mol/l) with o-phenylene chlorophosphite (o-phenylene phosphorochloridite) at 140°C. After
removal of the linear oligoamides (1) with ion exchangers
in aqueous solution a cycloamide mixture was obtained which
could be separated by gelchromatography (Merckogel PGM
2000/water) into a homologous series of polymeric rings with
up to 44 ring atoms [(2), n=2-11].
The assignment of
the peaks was accomplished with the aid of the synthesized
Cyclooligocondensation of Amino Acids : Macrocyclic
authentic cycloamides by plotting the elution volumes of the
Amides of P-Alanine[**l
gel chromatograms against the logarithm of the molecular
By Manfred Rothe and Dietger Miihlhausen[*]
weight (in homologous series of polymers a straight line is
obtained within a certain range), and by mass spectrometry
The formation of large ring molecules-in competition with
polymer formation-from
monomers in macrocyclization
of the isolated compounds.
Remarkably, the monomeric four-membered ring (P-propioequilibria or from polymers by degradation has recently
attracted increasing theoretical interest[’! We have investilactam) ( 2 ) , n = l , could not be detected, even at larger dilugated the system ~-alanine/cyclooligo(~-alanyls)/poly-~- tions; and also the eight-membered ring ( 2 ) , n = 2, containing
two cis-peptide bonds (detected IR spectroscopically: N H
alanine, which is of interest with respect to the industrial
3195,3080; amide I 1660; amide I1 1440; amide I11 1330cm-’)
production of fiber-forming poly-P-amides (nylon 3) from pwas formed in only moderate yields. In each case the cyclo-triIa~tams[~J.
and cyclo-tetraamide (12 and 16 ring atoms, respectively;
We first synthesized cyclic oligoamides of P-alanine
c-(NHCH2CH2CO), (2) up to the hexamer (n=2-6) in crysTable 2) were obtained as the main products.
talline form by stepwise synthesis of the linear oligoamides
H(NHCH2CHzCO),,0H ( I ), n= 2-6,
according to the
Table 2. Cyclization of p-alanine according to the phosphite method [a].
methods of peptide chemistry (via mixed anhydrides with
The yields of (2) are given in %.
isobutyl chloroformate, benzyloxycarbonyl protecting group
_--removed with HBr/glacial acetic acid) and ring closure of
c-(NHCH2CH2SO). (2), n=
( 1 ) via active esters H(NHCH2CH2CO)n SC,H5 in
- __________~._____
in diethyl phosphite (DEP)
according to the dilution principle. With the exception of
0.5 0.2 0.2
cyclo-di-~-alanyl( 2 ) , n = Y3] (m.p. 298-299Q the cyclic
[a] Conditions: see Experimental procedure b
amides (2) decompose without melting only above 350°C.
The results of the cyclization of the linear oligoamides
The formation of macrocyclic rings can be compared with
(I ) in the form of their active phosphite derivatives are listed
that of large rings containing up to 63 ring atoms during
in Table 1. These findings cannot be explained in terms of
the polymerization of caprolactam[6J. According to X-ray
a specific “doubling” resulting from antiparallel association
structure investigation^^'^ such very large rings are present-at
of two oligoamide chains with formation of hydrogen bondsc4’,
least in the nylon-6 series-as parallel chains, closed at the
but by polycondensation with subsequent cyclization, espeends. They therefore resemble the linear polymers in their
cially as an alternative reaction to formation of strained
physical properties, especially in their spectra and solubility.
medium-sized rings. Consequently, higher ring homologues
Hence their separation from the chains, and even their detecare also formed.
tion is always problematical with increasing ring size. NeverWe subsequently condensed the “monomeric” amino acid
theless, our previous studies (cf. Ref. 81) show that very large
p-alanine according to the phosphite method[51in moderately
ring molecules are obviously always formed-besides the
simplest small rings-during the formation of polymers.
Heteroatoms”] as well as increasing temperature and concen[*I Prof. Dr. M. Rothe, Dr. D. Miihlhausen
tration favor the formation of large rings.
Lehrstuhl Organische Chemie I1 der Universitat
Oberer Eselsberg, D-7900 Ulm
The chromatographic separation of the rings could be
sowie Organisch-chemisches Institut der Universitat Mainz (Germany)
achieved quantitatively (baseline separation) up to the hept[**I Linear and Cyclic Oligomers, Part 25. This work was supported by
amide or octamide (after repeated GPC). Complete separation
the Fonds der Chemischen 1ndustrie.-Part 24: M . Rorke in J . Brandrup,
of the tri- and tetramide can be carried out by GPC on
E. J . Iinrnergut: Polymer Handbook. 2nd Edit. Wiley-Interscience, New York
Biogel P2. Thus, cycloamides with up to eight amide groups
1975, VI-1.
Angew. Chem. Int. Ed. Enql. 18 ( 1 9 7 9 ) No. I
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neutral, acylation, virtually, conditions
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