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Asymmetric Synthesis of -Substituted Ketones by Metalation and Alkylation of Chiral Hydrazones.

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Microbiological Synthesis of ( + )-cis-1,ZDihydroxy1,2-dihydronaphthalene-2~arboxylicAcid
By Hans-Joachim Knackmuss, Wilhelm Beckmann, and Walter
0tting PI
We recently reported the partial degradation of methylarenes by a haloarene-utilizing Pseudomonas strain"]. Methylsubstituted metabolites accumulated in preparative amounts
at the catabolic step corresponding to elimination of halide
since the analogous elimination of the methyl anion is impossible. We can now demonstrate by another example the general
applicability of this approach to the preparation of compounds
which are not easily accessible by chemical synthesis.
Pseudomonas testosteroni strain A3 (DSM 676) was isolated
from sewage samples by continuous enrichment on naphthalene (I a ) and subsequently on naphthalene-2-sulfonic acid
(1 c ) . The bacterium utilizes (I a ) , (I c ) , or 2-naphthol ( 1 b)
as sole source of carbon. Induction experiments and inhibition
kinetics show the organism to possess an exceptionally nonspecific naphthalene dioxygenase which hydroxylates the above
substrates and channels them into the catabolic pathway of
naphthalene.
&C02H
= H;
( b ) , X = OH;
( c ) , X = S03H;
Id).
x=
cO2H
Dr. W. Beckmann
lnstitut f i r Mikrobiologie der Gesellschaft f i r Strahlen- und Umweltforschung mbH, Munchen and
lnstitut fur Mikrobiologie der Universitat
Grisebachstrasse 8. 3400 Gottingen (Germany)
Dr. W. Otting
Max-Planck-Institut f i r medizinische Forschung
Abteilung Naturstoffchemie
Jahnstrasse 29, 6900 Heidelberg (Germany)
Anyew. Chem. Int. Ed. Engl. f Vol. 15 (1976) No. 9
l2d)
-
B
COzCH,
H
(6)
Under acidic conditions, compound (2d) rearomatizes with
elimination of water to give I-hydroxynaphthalene-2-carboxylic acid ( 5 ) (> 95 %). Treatment with diazomethane in ethanol/
ether leads to the methyl ester (6) [m.p. 124°C (from cyclohexane); MS (high resolution): M + = 220.0740, calc.
220.0736][41,which is more stable than the acid ( 2 d ) .
On treatment with 2,2-dimethoxypropane/HCl the methyl
ester (6) readily affords the 1,2-isopropylidene derivative
[yield 89 %, m. p. 94°C (from hexane), [a];' = 244" & 2" (c= 1,
methanol), MS (high resolution): M + =260.1051, calc.
260.1 049][41.
cis-1,2-Dihydrodiolshave always been identified as the initial
products in the metabolism of naphthalend2]and other arenescs1by bacteria. Only the cis isomer of ( 2 a ) reacts with 2,2dimethoxypropane[21.Since ( 2 d ) can be derivatized in corresponding manner and cell-free extracts of P. testosteroni only
react with (+)-cis-(2a) the cis configuration can be deduced
for ( 2 d ) .
Received: June 4, 1976 [Z 489 IE]
German version: Angew. Chem. 88,581 (1976)
During the degradation of naphthalene the intermediate
( 2 a ) undergoes enzymatic dehydrogenation to 1,2-naphthalenediol'']. Analogous oxygenation of (I b) and ( I c ) leads
to labile intermediates ( 2 b ) and ( 2 c ) , respectively, which
spontaneously eliminate hydroxide and hydrogen sulfite yielding ( 4 ) without dehydrogenation.
As a structural analog of the sulfonic acid ( 1 c ) , naphthalene2-carboxylic acid (1 d) is likewise readily hydroxylated. However, formate cannot be spontaneously eliminated from the
reaction product (2d), which consequently accumulates. Since
the double hydroxylation requires two reduction equivalents
(NAD(P)H)['', the amount of carboxylic acid ( I d ) which
can be cooxidized by resting cells is limited. Constitutively
utilizable substrates providing NAD(P)H, such as succinate
or malate, raise the yield of the cooxidation product.
Salicylic acid is highly suitable as a metabolizable substrate
for the conversion of naphthalene-2-carboxylic acid (I d) on
a preparative scale. Without inhibiting the turnover of ( 1 d)
this permits rapid bacterial growth as well as formation of
reduction equivalents, and also acts as inducer of all enzymes
of the naphthalene pathway, including naphthalene dioxygenaseL31.
Cells of P. testosteroni A 3 which grow on salicylate cooxidize
2 g ( I d)/liter without loss of activity (6.5 pmol/g protein.min).
[*I Prof. Dr. H.-J. Knackmuss and
+-
151
141
(31
la), X
(2d) is formed in quantitative yield (high-pressure liquid chromatography). Acid extraction of the culture fluid with ethyl
acetate gives almost pure (+)-cis-1,2-dihydroxy-1,2-dihydronaphthalene-2-carboxylic acid ( 2 d ) . Crystallization from
ethyl methyl ketone furnishes colorless crystals of m. p. 147°C
[yield 74 %, [u]8'=29.1 +2" ( c = 1, methanol), MS (high resolution): M + = 206.0589, calc. 206.0579][4!
CAS Registry numbers:
(/u),91-20-3; ( l b ) , 135-19-3; ( 1 c ) . 120-18-3; (Id),93-09-4; ( 2 u ) . 51268-883 ; ( Z h ) , 59953-71-8; ( Z c ) , 59953-72-9; ( 2 d ) , 59953-73-0; ( 4 ) , 574-00-5; ( 5 ) ,
86-48-6; (61, 59953-74-1 ; 1,2-isopropylidene derivative of (61, 59953-75-2;
2,2-dimethoxypropane/HCI. 59953-76-3
M . Hellwig, H . Lockner, and W Otting, Eur. J. Appl.
Microbiol. 2, 267 (1976).
A. M. Jefrey, H . J . C . Yeh, D. M . Jerina. 7: R . Patrl, J . F. Davey,
and D . 7: Gibson, Biochemistry 14, 575 (1975).
E. A. Barnsley, J. Gen. Microbiol. 88, 193 (1975).
UV, IR, CD, and 'H-NMR spectra are in accord with the structures
given.
D. 7: Gibson, Crit. Rev. Microbiol. 1971, 199.
[I] H . 4 . Knuckmuss,
[2]
[3]
[4]
[5]
Asymmetric Synthesis of a-Substituted Ketones by
Metalation and Alkylation of Chiral HydrazonesI**]
By Dieter Enders and Herbert Eichenauer"]
Effective asymmetric synthesis with C - C coupling and
simultaneous generation of a new chirality center are rare.
A versatile method for the regio- and enantioselective a-alkylation of ketones is still lacking. Asymmetric alkylations via
metal derivatives of chiral iminesc'] afford only unsatisfactory
chemical and optical yields of desired products.
We have now developed a method permitting the asymmetric synthesis of a-substituted ketones ( 5 ) in good chemical
yields and in part high enantiomeric purity. The method
involves conversion of the ketones ( 1 ) into the chiral hydra[*] Dr. D. Enders and H. Eichenauer
Institut f i r Organische Chemie der Universitat
Heinrich-BUN-Ring 58, D-6300 Giessen (Germany)
[**I This work was supported by a Liebig-Stipendium from the Verband
der Chemischen Industrie to D. E. The authors thank Herr E . Riicker and
Herr K . Schneider for the preparation of compound (12).
549
zones (2), metalation with lithium diisopropylamide to the
metal derivatives (3)[’], alkylation to ( 4 ) , and regeneration
of the now substituted ketones (5) by ozonolysis or hydrolysis.
17) H
(S)-I-Amino-2-methoxymethylpyrrolidine(12), which can
be prepared in large amounts from the commercially available
amino acid (S)-proline (6), is used as chiral reagent. The
total yield of (12) is 53% for route A, 55% for route B.
In both cases purification of the (S)-prolinol (7) and the
end product (12) by distillation
The chiral hydrazine ( 1 2 ) [colorless oil, b. p. 56-57”C/3 torr, ‘H-NMR
(CCI4): 6=3.32 (s, OCH3), IR (film): 3340cm-’ (NHI),
[cx]~’=
-50” ( c = 1, benzene)] can be stored over a period
of months in the refrigerator.
while
The hydrazones (2) and ( 4 ) are distillable
the lithium compounds form colorless precipitates. Two
methods are available for the step ( 4 ) --t (5). Ozonolysis at
NO
/
f11)
the alternative method reaction with excess methyl iodide
generates salts of ( 4 ) which are hydrolyzed to ( 5 ) in a twophase system (n-pentane/i N HCI). The results are listed in
Table 1.
The enantiomeric purity varies greatly, depending on the
structure ofthe ketones (1) and R3X.The ketones (5a)-(5f),
which are remarkably stable towards racemization, are configurationally related, since the chelates (3) are preferably alkylated from the “underside” of the molecule.
, 0
3 R 3
-78°C gives rise to a mixture of (5) and (11 ), which after
separation of the ketones (5) can be isolated in SO-90%
yield and permits recovery of the chiral reagent (12). In
e3
0
0
f5e)
f-rfl
C6H5&R3
CsH5
(5~)-(5d)
(5s)
Table I . Optically active ketones ( 5 ) prepared by asymmetric synthesis. The newly coupled C-C bonds are shown
in bold print. Compounds ( 4 ) were generally converted into (5) by ozonolysis; ( 5 d ) and ( S j ) , however, were
obtained by hydrolysis of the salts of (4).
[NIL(c,
R3X
~~
~
_
_
~
_
solvent) [a]
Yield
optical
~
[%I [b]
chemical
-~
- I i.923 (2.5,
MeOH)
14 (0.23, MeOH) [S]
- 9.7” (neat)
- 15.22”(neat) [la]
- 30” (0.5, MeOH)
+
[CI
24.320 (4.2, MeOH)
27.9” (MeOH) [6]
- I 1.222(2.05, MeOH)
- 13.72’ ’(2.04, MeOH) [ I b, 61
- SO23 (1.0, MeOH)
-110.525 (1.19, MeOH) [7]
+ 19.220(2.5, ether)
32.1” (2.5, ether) [8]
+ 8X20 ( I .O, benzene)
~
~
+
~.
[a] First value: rotation of the distilled, spectroscopically and gas-chromatographically pure ketones. Second value:
rotation quoted in the literature (values in degrees).
[b] Chemical yields based o n chiral hydrazone (2). In brackets: total yields.
[c] Values by R . K K ~ H,. E. Drimen, and H . J . Haus, Justus Liebigs Ann. Cheni. 718, 98 (1968): ORD (c=O.S,
MeOH), [N]’”
(nm)= +992” (268). -878” (307). Under the same conditions we found the values: +492” (268),
-430 (307)= 5 0 % enantiomeric purity; since this value deviates greatly from those of the other 2-alkylcyclohexanones
we believe that our product has a greater optical purity than 50 %.
[d] Deterinined NMR spectroscopically with the shift reagent tris[3-(heptafluoro-l -hydroxybutylidene)-(d)-campherato]europium(lll) (Aldrich).
5 50
A n g n v . Chrm. lnt. E d . E n g f . J Vof.15 ( 1 9 7 6 ) No. 9
(R)-2-n-Propylcyclohexanone( 5 c ) from cyclohexanone
Compound ( 1 2 ) (2.6g, 20mmol) is treated with cyclohexanone (2.19m1, 21 mmol) with stirring at room temperature
and then heated to 60°C for 8 h. The crude product is dissolved
in CH2C12and the resulting solution dried over sodium sulfate,
concentrated in a rotary evaporator, and finally distilled. ( 2 ) ,
R'/R2=-(CH2)4-,
is obtained in 90% yield (3.78g) as a
colorless oil, b. p. 72-73 "C/0.025 torr, [a];'=
290" (c = 0.5,
benzene). (2) (2.1 g, 10mmol) is added dropwise with stirring
at 0°C to a solution of lithium diisopropylamide (prepared
from 6.5 ml 1.6 N n-butyllithium solution and 1.7 ml diisopropylamine in 50ml tetrahydrofuran at 0°C). After 2 h the reaction mixture is cooled to - 100°C and 1.0ml (10.5 mmol)
of n-propyl iodide is added dropwise. The mixture is stirred
for a further 3h, allowed to warm to room temperature,
treated with ether, dried over magnesium sulfate and the
solvent removed. A solution of the crude product in CH2CI2
(50ml) is cooled to -78°C and treated with ozone until
the solution is colored blue. After removal of excess ozone
by introduction of argon, warming, and concentration, ( 5 c)
is separated from the nitrosamine ( I I ) by molecular distillation over glass wool (oil bath temperature 125"C/18 torr).
+
Received: June 8. 1976 [Z 494 I E ]
German version: Angew. Chem. 88. 579 (1976)
CAS Registry numbers:
( i f J ) ,I O ~ - Y ~( i-eI j;, 120.~2-3;( i / j , ~ 6 - 2 2 - 0(iy),
;
102-04-5;(2~).5~~83-345; ( 2 ~ 1 59983-35-6;
,
( 2 f J 59983-36-7; (291, 59983-37-8;( 5 0 ) . 22554-29-6;
( 5 h i . 22617-19-2; ( j C j .36302-45-1; (5d), 36302-35.9; ( 5 e ) , 39947-50.7;
(511, 20086-34-4; ( 5 y ) . 59983-38-9; (CH3j2SO4, 77-78-1; CH31, 74-88-4;
C2H51,75-03-6; ri-C3H7Ir107-08-4; CH2=CHCHZBr, 106-95-6; ( 1 2 j . 59983-
systems the chromophores are bound to proteins or lipoproteins which embed the highly reactive radicals in a hydrophobic
matrix and thus protect them from irreversible destruction
by external nucleophiles such as water. We have studied the
reactions of magnesium octaethylporphyrin ( I a ) (as the simplest chlorophyll model) in synthetic copolymers of styrene
and 1 -vinylimidazole (as a model for hydrophobic, possibly
electron-c~nducting[~~
protein components), the proportion
of imidazole being varied between 0.1 and 20mol%.
Irradiation of ( I a ) in a solid matrix of polystyrene containing 0.1 % or less of 1-vinylimidazole in the presence of oxygen
rapidly gives rise to the previously characterized compound
formylbiliverdin (3)I4Iin more than 80 % yield, i. e. the magnesium porphyrin added molecular oxygen at its periphery. Use
of a copolymer containing 20 % of imidazole under otherwise
identical conditions led to quantitative conversion of ( I a )
into its n radical cation ( 2 ) f 2 'within one hour. N o addition
of oxygen took place. Dissolution of the polymer-porphyrin
mixture in benzene and reduction with triethylamine regenerated the magnesium porphynn (I a ) in over 80 % yield. Both
the radical ( 2 ) and formylbiliverdin (3) were stable for months
in the solid polymer, while they quantitatively decomposed
within a few hours in solution.
( I U J , R = FI
f l b ) ,R
=
-NJ=$-Polyrner
39-0
-
111 a)
121
131
141
D. MPu-JucAerr and
A. Horrau, Bull. Soc. Chim. Fr. 196X. 4571;
b) M. Kitumoto, K . Miroi. S . Terusltinia, and S . Yurnudu, Chem. Pharm.
Bull. 22, 459 ( I 974).
See E . J . Curry and D. Efidrr.\, Tetrahedron Lett. 1976, 3, I I : E.. J .
Carry, D . Enden, and M . C . Bock, h i d . 1976, 7.
Preparation of(/ 1 ) i:iu route A : H . Horfuturvt, Examensarbeit. Universitit
Giessen 1974; ( 1 1 1 has also been reported by 7: P d d s k i and K . Prujrr
(Tetrahedron 32. 847 (1976)).
The new compounds ( 2 ) and ( 4 ) and ( 8 ) - - ( 1 3 ) give correct elemental
analyses; IR, N M R , and mass spectra are in agreement with the given
structures.
[51 C. Brurd, C. Djrrussi, J . Sichrr, F . Sipoi, and M . Tichj., Tetrahedron
19, 919 (1963).
161 K . Hinir, K . Adtin.u, and S. Yumudu, Chem. Pharm. Bull. 20, 246 (1972).
[71 J . J . Puririrftgr. N . K . Cliudliu. and M . R . Uskokot ;I:. J. Am. Chem. Soc.
Y5, 532 ( I973).
P I F . Verdrl and E. Htwkc4, Chem. Ber. 86, 1002 (1953); M . E,,schlrr.
Diplomarbeit, Universitdt Giessen 1972.
J
A . I . Mcyrrs et ul. have reported the enantioselective
P I Norr udded ~ I proofalkylation of cyclohexanonc riu llthiated enamines, J. Am. Chem. Soc.
98, 3032 (1976).
Reaction of Magnesium Porphyrinates in Polymers
Containing Imidazole
By S. Besecke, B. Evans, G . H . Barnett, K . M . Smith, and
J.-H. Fuhrhop"I
The x radicals of magnesium porphyrinates, e. y. of protochlorophyll and chlorophyll a, play a central role in the biosynthesis of chlorophyllsli1and in photosynthesisfz1.In biological
~
.~
~
-~
~
[*] Dr. S. Besecke and Dr. .1.-11. Fuhrhop ['I
Gesellschaft fur Biotechnologische Forschung m b H
D-3300 Braunschweig-StBckheim und
lnstitut fur Organische Chemie A der Technischen Universitit
Schlcinitzstrasse, D-3300 Braunschweig (Germany)
Dr. B. Evans, G. H. Barnett. and D r . K. M . Smith
The Robert Robinson Laboratories
University of Liverpool, Ilepartment of Organic Chemistry
Liverpool L69 3BX (England)
[ I ] T o whom correspondence should b e addressed.
( l d ) , R = -N /"N
J
N
L
N
/
131
J
Chemical oxidation of ( I a ) with benzoyl peroxide in a
benzene solution containing the polymer with 20 % imidazole
took a different course. Although the radical cation ( 2 ) was
again generated initially, it immediately reacted with the
polymer to form new covalent bonds. Shaking of the resulting
solution with 10 % hydrochloric acid containing 50 % of ethanol did demetalate the polymer-bound magnesium porphyrin,
but the porphyrin dication could not be transferred to the
water/ethanol phase. Our explanation of this behavior assumes
that benzoyl peroxide oxidizes not only the magnesium porphyrin (I a} to the'radical (2) but also the imidazole to
the imidazole radical. The two radicals then react together
to form ( I b ) .
In order to confirm the formation of (f b ) we oxidized
a mixture of ( 1 a) and imidazole in chloroform with benzoyl
peroxide. Apart from 202, of 5-benzoyloxyporphyrin ( I c) we
obtained 60 % of the expected 5-imidazolyl derivative (I d).
O n the basis of these findings we suspect that in biological
systems chlorophyll is protected from irreversible autoxidation
not only by carotenes but also by surrounding proteins, and
that addition of imidazole and protein constituents of similar
551
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