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Highly Stereoselective Synthesis of Racemic Nonactic Acid and Synthesis of Dextrorotatory (2S 3S 6R 8R)-Nonactic Acid.

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Proof of reaction (a)comes from the finding that ( I ) reacts
practically quantitatively with sodium phenoxide to form 5phenoxymethyl-I ,3,5-triphenylformazan; m. p. 97 "C (dec.), UV
(dioxane): h=236nm ( ~ = 2 9 3 0 0 )and 343 (19400); 60 MHz
'H-NMR (CC12=CC12): 6 ~ 2 . 9 (d,
5 2H, N-CH2-0).
a stream of 02.Formate formation can also be explained
by scheme (d).
Received: March 24. 1975 [Z 21 I IE]
German version: Angew. Chem. 87. 453 (1975)
CAS Registry numbers:
( I ) . 51940-1 1-5: 131, 17135-56-7; 14). 22459-51-0;
(51. ) I 54-65-6: /6). 531-52-2: 5-phenoxymethyl-1,3.5-~r1phenylformazan.
F. A. Neugebauer, Angew. Chem. 85.485 (1973); Angew. f h e m . Internat.
Edit. 12, 455 (1973).
[2] R . Kohn, F . A. Neugebauur. and H. Eischrnann. Monatsh. Chem. 98.
126 (1967).
[3] 0. M. Polumbrik. G. F . Drorko. and 0.M . Griwhin. Ukr. Khim. Zh.
3 5 , 1046 (1969).
+ 2 SaRr
Highly Stereoselective Synthesis of Racemic Nonactic
Acid and Synthesis of Dextrorotatory (2S,3S,6R,8R)Nonactic Acid
. \
Confirmation of the proposed reaction (b) is considered
to be provided by the finding that alkoxides-dissolved in
the corresponding alcohols or alternatively in DMF-quantitatively convert ( I ) into ( 5 ) in air or in a stream of N2.
The reaction apparently proceeds via 5-alkoxymethyl-1,3,5-triphenylformazan which then rapidly decomposes to leucoverdazyl ( 4 ) and a carbonyl compound.
Reaction (c) is the reversal of the disproportionation of
( 5 ) in the presence of acid"]. Kinetic studies in 75 % aqueous
CH3CN have shown that the salt ( I ) undergoes an S Nreac~
tion with NaOH. Since reaction (a) is the rate-determining
step, the leucoverdazyl ( 4 ) formed in reaction (b) is able
to react quantitatively with ( I ) , thus permitting formation
of (5) and ( 3 ) in the ratio 2 : 1.
O n the basis of these results it is now possible to explain
the quantitative formation of ( 5 ) in the reaction of (6) or
( I ) with CHzO and NaOH. An essential feature is the cyclic
reaction of 5-formylforrnazan (3). With an excess of NaOH
and C H 2 0 , (3) finally yields the radical (5) via the intermediates (6), (2), and ( 4 ) .
The leuco compound (41 is dehydrogenated to (5) by
atmospheric oxygen"': this reaction is fast in alkaline solut i ~ n [ ~The
] . validity of the proposed scheme (d) is confirmed
by the fact that (3) and (6) give ( 4 ) in a stream of N2,
but ( 5 ) in a stream of 02.
O n mixing with C H 2 0 and NaOH,
compound ( 1 ) cannot be reduced directly to ( 4 ) by formaldehyde, as has previously been assumed"], since in this case
the radical ( 5 ) is formed, both in a stream of N2 and in
By Hans Zak and Wlrich Schmidt[']
The macrotetrolides nonactin, monactin, dinactin, and
trinactin, specific complexing agents for potassium ions, contain nonactic acid ( I ) ; the principal metabolite nonactin is
composed of two molecules of dextrorotatory (2S,3S,6R,8R)and two molecules of levorotatory (2R.3R,6S.8S)-nonactic
acid[']. A synthesis of a mixture of the diastereoisomeric
pairs['', two syntheses of racemic nonactic a ~ i d [ ~and
. ~ ]a
synthesis of levorotatory nonactic acid['] have recently been
reported. All these syntheses display little stereoselectivity
and afford nbnactic acid and 2-epi-nonactic acid in approximately equal concentration, as well as 8-epi-nonactic acid and
2,8-di-epi-nonactic acid.
By means of almost complete Walden inversion at C-8
we have now succeeded in conducting our synthesis of racemic
nonactic acidL4]with a high degree of stere~selectivity~~!
same principle was also used for "inversion" of the 8-epi-nonacticacid, formed during the production of levorotatory nonactic
acid[41from ( - )-propylene oxide, to form ( +)-(2S,3S,6R,SR)nonactic acid.
The mixture of four diastereoisomeric pairs produced in
our synthesis of racemic nonactic acid['] was oxidized to
a mixture of the 8-keto acid and 2-epi-8-keto acid. Catalytic
hydrogenation of the keto group with Raney nickel afforded
almost exclusively a mixture of 8-epi-nonactic acid and 2,8-diepi-nonactic acid. Very good yields were obtained in the formation of the 8-tosyl esters and their reaction with potassium
acetate in dimethyl sulfoxide, which was accompanied by
Walden inversion. After complete hydrolysis and esterification
with diazomethane the reaction product consisted entirely
of a mixture of methyl nonactate and methyl 2-epi-nonactate
(1.5: l), which could readily be separated. Methyl 2-epi-nonactate can be equilibrated with sodium methoxide to a mixture
of methyl nonactate and methyl 2-epi-nonactate ( I .5 : 1); we
were unable to confirm the ratio of 4 : l reported in ref.'''.
Starting with (-)-propylene oxide (from (+)-lactic ester),
our ~ynthesis[~~furnisheda
mixture from which 25 of methyl
Dr. H. Zak and Prof. Dr. U. Sthintdt [ + ]
Organisch-Chemisches l n s l i t u t der Universirat
1090 Wien 9. WPhringer Slrssse 38 (Austria)
[ +] To whom correspondence should be addressed
(-)-(2R,3R,6S,8S)-nonactate could be isolated by column
chromatography. The mixture of the other three diastereoisomers~2S,3R,6S,8S),(2R,3S,6R,8S), and (2S,3S.6R.8S}-were converted by Walden inversion into a mixture from
which methyl ( + )-(2S,3S,6R,8R)-nonactate could be isolated
in approximately the same amount as the (-)-antipode by
chromatography over silica gel. Both the levo- and dextrorotatory nonactic acid present in the natural product are thus
accessible by asymmetric synthesis from a single optically
active starting compound.
Received: April I . 1975 [Z 212 IE]
G e r m a n version: Angew. Chem. 87. 454 (1975)
CAS Registry numbers:
) - f / i 55220-86-5 : ( + ) - / ).
I 16221-10-6
W K r l l r r - S h e r l e i n a n d H . Co.lach, Fortschr. Chem. Org Naturst. 26.
161 (1968).
C . Beck and E . Hensrlrit. Chem. Ber. 104. 21 (1971).
H . Cerluch a n d H. Wetrer. Helv. Chim. Acta 57, 250 (1974).
J . Combos, E. Huslingrr. H . Zak. a n d L'. Schmidt, Monatsh. Chem.
106. 219(1975).
In ref. [3] these compounds a r e reduced nonstereospecifically with
NaBH,and primarily to the 8-rpi-alcohols with lithium trisl I-methylpropy1)hydridoborate.
The mass spectrum of ( I ) contains the molecular ion at
m/e 536 (relative .to)%
Successive loss of ten CO groupsevidenced by corresponding mass peaks and metastable
transitions-leads to [Cr2AsC6Hs] +, which decomposes to
[CrAsC6Hs] with loss of a chromium atom.
The 'H-NMR spectrum of ( I ) contains no signals apart
from a multiplet due to the phenyl protons (6 = 7.5-8.0 ppm,
TMS as internal standard).
The IR spectrum of ( I ) displays absorptions in the vco
region at 2082 (w), 2032 (m), 1984 (vs), and 1953 (w) cm-'
(n-hexane), whose number indicates a distorted CqUsymmetry
of the Cr(C0)5 groups. By way of contrast, the vc0 bands
of (2) lie at lower frequencies: 2068 (s), 1950 (vs), and 1923
(w) cm- ' (n-hexane). The V A ~ Hand i j A F H absorptions appearing
in the spectrum of (2) at 2140 and 775 cm-' cannot of
course be observed in the case of ( I ) , while the vibrations
of the C,H,As group in the two compounds appear at about
the same wave numberslq1.
Two alternative modes of bonding must be considered for
the four-electron ligand C6H5-AS: in ( 1 ) :
Arsinidene Complexes: Stabilization of Phenylarsanediyl, CsHsAs, in C6H~As[Cr(C0)5]2[**]
By Gottfried Huttner and Hans-Georg Schmid"]
In contrast to the chemistry of their lower homologs, the
nitrenes, R-N, little is known about phosphinidines, R-P,
and arsinidenes, R-As. The occurrence of phosphinidenes
nevertheless appears likely on the basis of several organic
trapping reactions['], while no such evidence has been obtained
for arsinidenes. They are suspected to act as intermediates
during the formation of cyclooligoarsanes (RAs),I2I. We have
now succeeded in the first stabilization of the "arsinidene",
phenylarsanediyl in a metal complex on synthesis of
C~H&[C~(CO)S]Zf I ).
The pale yellow complex ( O C ) ~ C ~ A S ( C ~ H(2)[31
S ) H ~can
be metalated with n-butyllithium to the orange
(OC)'CrAs(C6H5)Li2 which can be converted into ( 1 ) by
treatment with N,N-dichlorocyclohexylamine and chromatographic work-up:
The product ( I ) crystallizes as dark violet platelets with
a metallic sheen, which appear blue by transmitted light: it
is readily soluble in benzene. toluene, and methylene chloride
to give intensely blue-green solutions. At 45 "C/10-, torr the
new complex can be sublimed with partial decomposition ;
it melts at 104°C under N, in a sealed tube. Crystals of ( I )
can be kept for several hours in air. but solutions decompose
Doz. Dr. G. Huttner a n d H:G. Schmid
Anorganisch-chemisches Laboratorium
Fachbereich Chemie der Technischen Universitat
8 Munchen 2, Arcisstrasse 21 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft
and the F o n d s der Chemischen Industrie.
In ( I a ) the potential four-electron ligand would only contribute two electrons to the bond; the chromium atoms would
attain the noble gas configuration by one metal-metal and
one metal-arsene bond. In ( I b ) the arsenic atom completes
its octet of electrons by Crda-Aspa back bonding; the electron
vacancies on the chromium atoms of the Cr(CO), groups
are filled by the two electron pairs of the arsinidene ligand.
The short wavelength of the vco absorption in ( I ) evidences
strong metal-ligand back bonding, and thus, like the unusual
color of ( 1 ), points to the structural alternative ( 1 b), which
has meanwhile been established by structural analysis['!
We propose the name "arsinidene complexes" for the new
type of compound in which an arsanediyl group is stabilized
by metal-dn-arsene-pn double bonds.
All operations are carried out under N2. 'H-NMR: Jeol
C-60HL; mass spectra: Atlas CH4, ion source T04.
Compound (2) (2.75 g , 7.9 mmol) is dissolved in tetrahydrofuran (100ml). At -78°C a solution of n-butyllithium
(16mmol) in n-pentane (16ml) is added dropwise within 5 min
with vigorous stirring. The orange reaction solution is immediately treated with N,N-dichlorocyclohexylamine (2 ml,
14.2mmol) and stirred for 30min at -50"C, after which the
solvent is drawn off at -20°C. The orange residue (the calculated amount of LiCl can be detected as toluene-insoluble
component) is taken up in CH2CI2 (5ml) and chromatographed (silica gel, Merck,
0.063-0.200mm, 3
eluent CH2C12;column dimensions: length 10cm, diam. 4cm).
The greenish yellow first runnings contain azocyclohexane
and a mixture of cycloarsane-chromium complexes that has
not yet been precisely characterized. The greenish black zone
of ( 1 ) develops only slowly and is eluted with 250ml of
CH2CI2. After removal of the solvent at 18 "C, chromatography
is repeated at - 15 "C (silica gel, as above, 0 % H 2 0 ; eluent
CH2CI2;column dimensions: length 25cm, diam. 2cm). ( I )
migrates as a broad greenish black zone, which affords 0.23 g
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acid, stereoselective, racemic, synthesis, dextrorotatory, nonactic, highly
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