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Five-Membered Cyclic Acyl Phosphates a New Class of Extremely Reactive Phosphorylating Agents.

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Five-Membered Cyclic Acyl Phosphates, a
New Class of Extremely Reactive Phosphorylating
By Fausto Ramirez, Stephen Glaser, Peter Stern,
Paul D. Gillespie, and Ivar Ugi"
In the synthesis of phosphate esters, including the polynucleotides, only phosphoryl halides and acyclic mixed
anhydrides["] of phosphoric acid, such as the mixed anhydrides with aryl sulfonic acids"], have been used. We
wish to introduce. a new class of versatile, extremely reactive, phosphorylating agents, namely the live-membered
cyclic acyl phosphates ( 5 ) . Frequently, they permit preparation of phosphoric acid esters in fewer steps than with
the common reagents used previously.
9 ocH3
( I ) * R = H, CH,, CsH5
t &H3 OCH,
The reaction of trimethyl phosphite with u-dicarbonyl
compounds yields the derivatives of 1,3,2h5-dioxaphosphole (I)[21. ( 1 ) R=H, undergoes 0-acylation by phosgene to form (2) or ( 3 ) , re~pectively'~~,
depending upon
the relative amounts ofthe reactants, whereas (1),R=CH3,
is C-acylated by phosgene (in hexane at 0°C) to give ( 4 )
(h31P= +3.0 ppm,H3P04)[41.
The diastereomers ( 5 b ) and ( 5 a ) interconvert in the presence of nucleophiles and form an equilibrium mixture of
70 : 30. At 150°C (5) loses CO, to form the enediol phosphate (6). In dioxane or CDCl, solution[***'(5) is hydrolyzed rapidly (in <15s) by one equivalent of water,
mainly via the intermediate (7), to the acetoin derivative
(8) ;traces of the cyclic hydrogen phosphate (9) and methanol are also produced. The intermediate (7) is decarboxylated relatively slowly, and its presence can be demonstrated
by esterification with diazomethane.
c PH
H,C - CO/ ' 0 - P - OCH,
H3C - CO/ \O- P- OCH,
+ CH30H
Upon heating for two hours at 120°C (4) is transformed
into a mixture of the diastereomeric cyclic acyl phosphates
(5a) and (5b), and the known enediol phosphate (6)[51
(h3'P= -11.6 ppm, H,PO,). The separation of ( 5 ) and
(6) can be achieved by short-path distillation in uacuo.
The prevalent diastereomer (5 b) (S3' P= - 2.42 ppm,
H,P04; r=7.62, 8.23, and 6.02 ppm; J,,=12.0 Hz, m.p.
82-84°C) can be obtained in crystalline form, but not
the other diastereomer ( 5 a ) (h3'P= -2.66 ppm (H3P04);
z = 7.66, 8.13, and 6.02 ppm; J,, = 12.0 Hz).
Prof. Dr. F. Ramirez, Dr. S. Glaser, and Dr. P. Stern
State University of New York at Stony Brook, New York 11790
Dr. P. D. Gillespie and Prof. Dr. I. Ugi
Laboratorium fur Organische Chemie der Technischen Universitat
8 Miinchen 2, Arcisstrasse 21 (Germany)
and University of Southern California, Los Angeles (USA)
F.R. gratefully acknowledges the extended support of these investigations by the Cancer Institute of the National Institutes of Health
(USA), as Grant CA-04769, and by the National Science Foundation
(USA), as Grant GB-6690. I.U. wishes to acknowledge the support of
the National Science Foundation (USA) as Grant GP-28927X. and
also the support of the Biomedical Sciences Support Grant of the
National Institutes of Health, as Grant RR 07012-05.
[**I l.e., the P-atom does not belong to a ring.
With primary and secondary alcohols, e.g., methanol,
ethanol, benzyl alcohol, and isopropanol, ( 5 ) reacts very
rapidly, with ring-opening and decarboxylation to yield
the acetoin derivatives of type (12) [alkyl methyl (l-methyl2-oxopropyl) phosphates]. In CDCl,r"'l the reaction with
one equivalent of each of the above alcohols is complete
in < 15 s, whereas under the same conditions the reaction
with tert-butanol proceeds with t , / , -135 s.
The reactivity of ( 5 ) toward hydroxyl compounds is higher
than that of any previously known organophosphorus
compound, including the most reactive, enediol phosphate
(6)[51( t , , , x 8 days for the reaction with one equivalent
of tert-butanol in CDCl,[*"l; t , / , ~ l 5 0s for the reaction
with one equivalent of water in dioxane. This pronounced
reactivity is due to the fact that ( 5 ) contains a strongly
apicophilic leaving group as part of a five-membered
0.1 M solution at 24°C.
Angew. Chem. internat. Edit. Vol. 12 (1973) 1 No. I
The cyclic acyl phosphate ( 5 ) N-methylates pyridine to
yield the salt (10). The structure of (10) was demonstrated
by the formation of the original cyclic acyl phosphate ( 5 )
upon treatment with trimethyloxonium tetrafluoroborate.
The nucleophilic attack of the pyridine at the methyl
carbon of (5)-and not at the electrophilic phosphorus
atom-can be attributed to the fact that the incipient formation of the C-N bond and the simultaneous rupture of the
bond are energetically favored over the initial
formation of a P-N bond and cleavage of a P-0 bond.
This argument is based upon an estimate of activation
energies according to Szabo's method[''.
Synthesis of Deacetoxycephalosporin S-Oxides by
Oxidative Trapping of Sulfenic Acids from
Penicillin S-Oxides"]
By Stjepan Kukolja and S. R. Lammert"'
Previous studies have shown that sulfenic acids (2) can
be generated during the heating of penicillin S-oxides
( I ) [ ' ] . The high reactivity of sulfenic acids (2) has hitherto
precluded their isolation, and only intra- and intermolecular
trapping of this reactive group has thus far been accomplished. These reactions demonstrated that protonated
sulfenic acids exhibit electrophilic properties. However,
the sulfur atom in sulfenic acids should also possess some
nucleophilic character',] ; to examine this possibility we
have studied oxidative trapping of this transient functionality.
The salt (10) undergoes rapid hydrolysis at 25"C, and
yields, after decarboxylation, the compound ( I I ) , R = H,
while alcoholysis or phenolysis gives ( I l ) , R = alkyl or aryl
respectively; it reacts substantially faster with primary
alcohols than with secondary alcohols.
Since the phosphate esters of a-hydroxy carbonyl compounds are hydrolyzed with particular easef6],the 3-keto2-butyloxy groups of the phosphate esters (11) and (12)
can be selectively replaced by hydrogen. Trialkyl phosphates (12) are obtained from the compounds (11) by
known methods. The recyclization of compound (7), and
subsequent reaction with an alcohol is an attractive alternative.
To our knowledge, ( 5 ) is the first isolated example of a
five-membered cyclic acyl phosphate. Clark and Kirby'"
postulated the formation of the five-membered cyclic acyl
phosphate (13) derived from the en01 form of pyruvic
acid. Marecek and Griffiith['] reported the isolation of the
six-membered cyclic acyl phosphate (14), derived from
benzoyl acetic acid.
Received : August 14,1972 [Z 727 IE]
German version: Angew. Chem. 85,39 (1973)
[I] See e.g. K . L Agarwal, A. Yamazaki, P. J . Cashion, and H . G . Khorana, Angew. Chem. 84, 489 (1972); Angew. Chem. internat. Edit. I I ,
451 (1972).
[Z] F. Ramirez, Accounts Chem. Res. I , 168 (1968).
[3] F. Ramirez, S. L. Glaser, A . J . Bigler, and J . F . Pilot, J. Amer. Chem.
SOC.91, 496, 5696 (1969).
[4] F. Ramirez, S. B. Bhatia, A. J . Bigler, and C . P. Smith, J. Org. Chem.
33,1192 (1968).
[5] F. Ramirez, 0.P. Madan, and C. P. Smith, J. Amer. Chem. Soc. 87,
670 (1965); D. Swank, C . N . Caughlan, F. Ramirez, 0. P. Madan, and
C . P. Smith, ibid. 89, 6503 (1967).
[6] See e.g. P. D. Gillespie, F . Ramirez, I . Ugi, and D. Marquarding,
Angew. Chem., in press.
[7] Z. G. Szabo, Magy. Tud. Akad. Kem. Tud. Oszt. Kozlem. 19, 291,
303 (1963); Z. G. Szabo, Z . Phys. Chem. N F 5 5 , l (1967); Z. G. Szabo
and T Berces, ibid. 57, 3 , 8 (1968).
181 i! M . Clark and A . J . Kirby, J. Amer. Chem. SOC.85, 3705 (1963).
[9] J . F. Marecek and D. L Griflith, J. Amer. Chem. Soc. 92,917 (1970).
Angew. Chem. internat. Edit./ Vol. 12 (1973) / No. I
When methyl 7-phthalimidopenicillanate 1-oxide (1a) is
heated with I equiv. of sulfuryl chloride in boiling carbon
tetrachloride for 50 min, an inseparable mixture of two
isomeric compounds is obtained in a 2 : 1 ratio. The mixture has the composition C, 7H* ,ClN,O,. The IR spectrum exhibits absorptions at 1075 and 1086 cm-', indicating the presence of a sulfmyl group[41,and it shows the
characteristic azetidinone peak at 1800 cm-'. The NMR
spectrum of the mixture indicates that the isomers are
closely related. The major product gives signals at 117
(s, C-CH,), 231 (s, CO-OCH,),
306 (2 vinylic H, and
H-3, J=1.5 Hz), 348 and 356 (d, 2 cis-azetidinone H, J =
5.0 Hz), and 470 Hz (4 aromatic H). The minor component shows the following NMR data: 119 (s, 3 H), 228
(s, 3H), 313 (s, IH), 315 (d, 2H, J = 1.5 Hz), 343 (d, I H ,
J = 5.0 Hz), 356 (d, 1H, J = 5.0 Hz), and 470 Hz (m,
4 aromatic H).
These data, together with mechanistic considerations, suggest that the mixture consists of two diastereoisomers of
the compound methyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-
Dr. S. Kukolja and S. R. Lammert, M.S.
The Lilly Research Laboratories
Eli Lilly and Company
Indianapolis, Indiana 46206 (USA)
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