DEGRADATION OF RAPAMYCIN: RETRIEVAL OF MAJOR INTACT SUBUNITS.

Article abstract of DOI:10.1016/S0040-4039(00)60797-9

The degradation of rapamycin has made available key substructures which have defined the structures of advanced synthetic intermediates.

Full text of DOI:10.1016/S0040-4039(00)60797-9

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Vol. 3 3 . No. 4 9 , PP.
in Great Brit ain
RETRIEVAL OF MAJOR INTACT
DEGRADATION OF
Daniel
and Samuel J.
of
Yale University, New Haven, CT
8 USA
The degradation of rapamycin has made available key substructures which have defined the
structures of advanced synthetic intermediates.
Rapamycin (1 ) a metabolite of Streptomyces
first isolated from Easter Island
undergoing clinical trials as
soil samples.1 It bears a structural similarity to FK-506, which is
an immunomodulator.3 While operating at a different cellular signaling level from
rapamycin
research into the biology of rapamycin
is also of interest in immunoregulation.3 Not surprisingly, the
has brought with it renewed activity at the chemical level.4
Our efforts in probing the chemistry of rapamycin were focused on degradations3 which would
retrieve major fragments of the molecule. These products would be examined with respect to their
biological activity. They might also serve as subtargets in a total synthesis effort In this regard we
were, to some extent, guided by degradative programs which we had developed in the FK-506
Our initial successes am recorded herein.
Treatment of 1 wit h benzylamine and sodium cyanoborohydride (7 equiv.) resulted in reduction
of the Cg
gave rise to a modest yield of keto ester 2. A serious drawback of this protocol was its inability, in our
hands, to deliver the segment of rapamycin in identifiable form. Another degradation reaction
and provided a product which, after treatment with methanolic sodium hydroxide,
which we had demonstrated in the case of
was employed to our advantage in the rapamycin
in methanol provided derivative 4. Exposure of this
of LDA, THF, -78 to -20 effected the
series. Treatment of 1 with
compound to optimized retroaldol conditions (1.5
cleavage of the
and keto
bond as well as p-elimination of the pipecolinate, thereby affording aldehyde 5
6 (Scheme I).
Keto aldehyde 9 has been synthesized in our laboratory as a possible intermediate in various
projected total syntheses of 1.7 Transformation of degradation fragment 6 into the same
TLC) compound was accomplished by a four step procedure. Methanolysis of 6
NMR, IR,
methanol)
followed by silylation of the
alcohol
DMF) afforded keto ester 8. This
and the resultant product
compound was exhaustively reduced (diisobutylaluminum
was oxidized to provide 9, thereby confirming our synthetic assignments (Scheme II).
Analysis of the
spectrum of 5 obtained by the degradation described above revealed that the
may have been compromised.3 This problem was attributed to the
aldehyde substructure encompassing carbons 28-32. prior reduction
stereochemical integrity of
presence of the vinylogous
of the
ketone would alleviate this problem and would also prevent the p-elimination of the
oxygen under the basic conditions of the retroaldol cleavage. Initial efforts to these ends were

7470
to the
(same vessel) silylation of the
followed by the hydroxyl group
of the
keto function in the context of cyclic substrate 10 (Scheme III).
Sequential
hydroxyl group of rapamycin
-78
afforded 10. Even after extensive
variation of experimental conditions for
yield of 11. Treatment of 11 with
of the ketone of 10, we obtained at best a 30%
and removal of the TMS ether of 12
25
provided the retroaldol precursor, 13. A major improvement in reduction efficiency and
aluminumhydride was carried out on
selectivity was achieved when reaction with lithium
derivative 14
of 13 (1.5 equiv of
THF, -78
-20
15 with
retention of the
oxygen function thereby providing access to the
segment of
rapamycin (Scheme IV).
rapamycin
6

7471
Scheme
Scheme IV

7472
of 15 with fully synthetic material was undertaken. In this way it was hoped to
the configuration of the
which started with silylation of the
alcohol. The former issue was addressed in a three step sequence
alcohol. Compound 16 was subjected to reductive deacylation
of the pipecolinate. Oxidation of the resulting product with
substance proved to be similar to, but not identical with the
unambiguously, the stereochemistry at
afforded compound 17. This
synthetic aldehyde
we have assigned the
possessing,
stereocenter
of 17 to be of the configuration (Scheme IV).
Further investigations to explore various strategies for
the reconstruction of rapamycin and analogs thereof using these degradation fragments are in progress.
Acknowledgment. This work was supported by NIH Grant HL 25848. NMR spectra were
obtained through the auspices of the Northeast Regional
Facility at Yale University which
was supported by NSF Chemistry Division Grant CHE7916210. NIH (CA09059) and Merck
Postdoctoral Fellowships to D. Y. are gratefully acknowledged. In addition we would like to thank Dr.
Craig
of Wyeth Ayerst Pharmaceutical for providing us with a sample of rapamycin for these
References.
1.
a) Rapamycin isolation: Sehgal, S. N.; Baker, H.;
C
Antibiot.
C.; A.; Sehgal, S. N. Antibiot.
determination: J. A.; L. Can. Chem.
White, P. S.; Fiidlay, J. A. Chem.
Rapamycin structure
Swindells. D. C. N.;
2.
For a thorough recent review of immunophilin (FK-506. rapamycin and cyclosporin)
based immunoregulatory activity: Rosen, M. K.
S.
Chem
3.
4.
Mattel, R.
J.;
S.
Morris, R. E.;
S-H;.
B. M. Med Sci. Res.
Synthetic studies on rapamycin: Fisher, M. J.; Myers, C. D.; Joglar, J.
Danishefsky, S. J. Org. Chem.
5826. Chen, S.-H.; Horvath, R. F. Joglar, J.;
Fisher. M. J.; Danishefsky, S. J. Org. Chem. 1991.56. 5834. Hale, M. R.; Hoveyda, A. H.
Org. Chem.
5.
6.
7.
Previous degradation studies on rapamycin: Goulet, M. T.; Boger, J. Tetrahedron
4845. Goulet. M. T.;
D. W. Tetrahedron
a) Fisher, M. J.; Chow, K.; Villalobos, A; Danishefsky, S. J. Org. Chem.
b) Coleman, R. S.; Danishefsky. S. J. 1989.28, 157.
2900.
Horvath, R. F.; Linde, R. G.; Yohannes, D.; Myers, C. D.; Danishefsky. S. J. manuscript in
preparation.
8.
9.
Resonances assigned to
and its attached methyl group appeared as doubled signals in the
spectrum of 5. The remaining signals were not doubled.
Myers, C. D.; Fisher, M. J.; Danishefsky, S. J. manuscript in preparation.
(Received in USA 11 August 1992; accepted 9 September 1992)

vol. 33. No. 49. pp.
Printed in Groat Britain
00404039~2
+
Synthesis of
Acid Dichlorides
using
General
Chloride and
Catalysis
Roland S. Rogers
Chemical Sciences Department, Monsanto
Research
Monsanto Company, 800 N. Lindbergh Blvd. St Louis. MO. 63167
A
of
(1) using oxalyl
and catalytic DMF is described.
There are scattered reports in the literature of the synthesis of phosphorous acid chlorides. Those which
thionyl chloride2 as the
and ethyl or methylchloride are troublesome side products generated
under these conditions, and these reactions suffer from variable yields. Other first converted
phosphorous diesters into diesters before reaction with phosphorous pentachloride or oxalyl chloride.
In addition to the extra chemical transformation required. one now has a volatile silyl chloride as a side product,
which is problematic on large scale. A third approach has been the direct of phosphonic acids to
phosphonic dichlorides. Again, phosphorous has been widely used, but again, the yields are
start from alkylphosphonic diesters use phosphorous pentachloride
agent. However, phosphorous
mixed. Also, in all cases, one must distill the phosphonic dichloride product. Herein is reported an efficient and
broadly applicable method for generating phosphonic acid dichlorides (1) on large scale without distillation.
Scheme
0
0
oxalyl chloride; DMF
F - O H
-
R
While them are few good methods of monitoring the transformation of carboxylic acids to
acid chlorides apart from derivitization and analysis. one can accurately follow the conversion of phosphonic
acids to phosphonic acid dichlorides by
Table), simplifying analysis.
nmr. Typically, the
signal is shifted 14 to 20 ppm
(see
The phosphonic acid starting materials
either obtained from commercial
or prepared via
Arbuzov chemistry6 followed by acid hydrolysis. The DMF-catalyzed reaction of a phosphonic diacid with
oxalyl chloride is strongly
+ 2
and liberates large quantities of gas, as described by the equation:
+ 2HCl + 2C0 +
Distillation of the crude acid chlorides was not required, but is possible via vacuum distillation. For
acid dichlorides, yields were generally while distilled when performed for comparison to reported
were in the range of 92%. All reagents obtained from commercial sources and used without
7473

7474
further purification, and all
standard in
were recorded at 80.99 MHz on a Varian VXR 200 without internal
nmr
59.6
ppm
40.9
yield,
crude distilled
R
found
178 (21)
94
95
94
92
92
NA
NA
85
127
50.8
52.6
33.1
32.2
32.0
19.2
NA
NA
___
127 (8)
107 (4)
NA
77
93
89
A
105
37.3
47.4
20.9
23.7
(4)
___
N
Typical is the synthesis of phenylphosphonic dichloride. A solution of phenylphosphonic acid
(2.0 G) and anhydrous DMF (10
was gently refluxed in dichloromethane (30
in anhydrous dichloromethane was added, via modified addition
temperature at
C. Upon complete addition of the oxalyl chloride solution, the reaction was held at reflux for
under dry nitrogen. To
this, a solution of oxalyl chloride (2.4
funnel.7 During the addition, copious gas was evolved, and heat was applied to keep the
or above
approximately one hour, then the reflux condenser was replaced
a still head, and the volatiles (distillation
temperature
C at 763 mm) were removed. Analysis of the residual oil (2.29 G; 93%) by nmr
revealed a single peak (see Table), consistent with clean formation of phenylphosphonic dichloride. The product
was distilled only for comparison to the literature value.* and could be used without distillation.
References
la.
lb.
2.
Frank, Arlen W. J. Org. Chem
Helmut; Heuschmann,
1521.
Abdel-Rahman, Mohamed 0. Synthesis, 1974,490.
Maier, Ludwig, Phosphorus,
Silicon,
465.
3a.
3b.
4.
Bhongle. N. N.;
R. H.; Turcotte, J. G. Syn Comm,
H. Chem 1980,435.
1071.
Morita, T.; Okmoto. Y.;
Doak, G. 0.; Freedman, Leon D. J. Am. Chem.
76, 1621.
5.
Freedman, L. D.;
U.S. Patent No.
A
H.; Doak, G. 0.; Magnuson, H. J. J. Am. Chem
1953, 75, 1379.
6.
7.
inventors Karanewsky, D. S., and Petrillo. Jr., E. W.
addition funnel’s
was extended with teflon tuhing such that it
below the surface of the reaction solution.
8.
Fild. M.;
R. and Peake, S. C. in
Phosphorus
G. M.
Kosolapoff
L. Maier, John Wiley Sons, 1972, Vo1.4, page 155.
(Received in USA 22 July 1992; accepted 2 September 1992)

Vol. 33. No. 49. PP.
Britain
+
in
THE CONVERSION OF CARBOXYLIC ACIDS INTO ACID BROMIDES ON
ALUMINA
Satinder
James Green, Lay Choo Tan, Richard M.
and George W. Kabalka*
Department of
University of
Knoxville,
379961600
with boron tribromide. A different reaction occurs
solution.
Acid chlorides are versatile reagents for the synthesis of esters,
containing
chlorides, relatively few preparative procedures are available and those that are require brominating
agents which are not readily We wish to report a new method to prepare acid bromides which
ketones, and other
Acid bromides are less commonly used for these reactions because, unlike acid
is simple to use, versatile, and employs readily available chemicals. The procedure
carboxylic acids with boron tribromide which has been chemisorbed onto
treating
RCOOH +
is prepared by treating alumina, which has been activated at
with a 1.0 M
is adjusted so
solution of
that 1
in hexane for 0.5 hours at
The ratio of the
solution to
of
is chemisorbed per gram of alumina. Copious quantities of gaseous
are
broad singlet
Based on the
liberated in the reaction. The reagent, which fumes in air, contains boron
at 7.1 ppm relative to at 6 0 ppm) and has considerable acidity
SS
weight increase of the solid and the (assumed) loss of bromide generated in the chemisorption reaction
as each chemisorbed boron contains one boron-bromine bond (eq. which is the active agent in
the formation of acid bromides.
Br
+
2HBr
The
which give moderate to excellent yields of products (Table
in a molar ratio of acid to
are run by treating the
bonds, at
correspondii carboxylic acids with
room temperature. The reactions can be run in the absence of solvent if the carboxylic acid is a liquid
and in solution the acid is a solid. No starting carboxylic acids were recovered from the reactions.
7475

7476
Table 1. Synthesis of Acid Bromides by the Reaction of Carboxylic Acids with
Acid
% Yield of
Temperature
RT
67%
None
Decanoic
RT
Benzene
Benzene
Benzene
64%
65%
70%
59%
84%
86%
Benzoic
l-Adamantaneacetic
p-Nitrophenylacetic
RT
RT
RT
RT
determinations.
reacts with
the absence of the
acid.
Interestingly, reaction of hexanoic acid with neat
Instead, the acid was, partially converted to the hexanoic boric anhydride (eq.
did not afford the corresponding acid bromide.
This result illustrates
again that chemistry on a solid may take a markedly different route than the seemingly identical reaction
in
solution
+
+ 3HBr
(3)
REFERENCES
1.
a) March, J. Advanced
ed.; Wiley: New York, 1985. b) Larock, RC.
Comprehensive
New York, 1989. c)
Halides;
Patai, S. ed.; Interscience: New York, 1972.
2.
a) Adams, R.;
1406. c) Homer, L;
LH. Am.
H.; Hoffmann, H. Ann
J.;
b)
E.A.
d)
Mott,
L Ann. 1966,693, 132. e)
Chem. Chem.
Gaetano, Pagni, R.M.; Kabalka, G.W.; Bridwell, P.;
A-M.; Colens, A; Ghoses
C.
L
J.M.;
3.
4.
5.
E.; True, J.; Underwood,
G.; Plesco, M.; Kurt, R.; Cox, D.; Green,
and Academic Press: New York,
Org.
G.W.; Pagni, R.M.;
J. Tetrahedron:
The indicator method described in Tanaba, K.
S.;
1283.
1970 was used to determine the acidity of the solid.
6.
7.
A
admixture of chemisorbed B and
can yield a weight increase identical to that of
This type of chemistry has been reported previously:
P.V.; Prokofev,
Y.K.; Belyakova, Z.V.; Kostetskii,
8.
This work was supported by the Research Corporation and the Department of Energy.
(Received in USA 22 July 1992; accepted 2 September 1992)