Cross coupling of alkyl cobaloximes with maleic anhydrides. Basic studies and applications to the synthesis of chaetomellic acid A anhydride and C-glycosyl maleic anhydrides

Article abstract of DOI:10.1021/jo971852t

Photochemical cross coupling of alkyl cobaloximes with maleic anhydrides and PhSSPh led to addition of an alkyl moiety and an SPh moiety across the alkene. Oxidation of the sulfide to a sulfoxide followed by elimination of phenyl sulfenic acid provided substituted maleic anhydrides. Alkyl cobaloximes could also be coupled with maleic anhydrides in the absence of PhSSPh to provide substituted maleic anhydrides directly. These methods are applied to a short and efficient synthesis of the anhydride of the Ras farnesyl protein transferase inhibitor chaetomellic acid A and in preparations of C-glycosyl maleic anhydrides, in which the carbohydrate anomeric carbon is directly attached to a maleic anhydride alkene carbon, in modest yields (19-46%).

Full text of DOI:10.1021/jo971852t

3
544
J . Org. Chem. 1998, 63, 3544-3549
Cr oss Cou p lin g of Alk yl Coba loxim es w ith Ma leic An h yd r id es.
Ba sic Stu d ies a n d Ap p lica tion s to th e Syn th esis of Ch a etom ellic
Acid A An h yd r id e a n d C-Glycosyl Ma leic An h yd r id es
Rachel M. Slade and Bruce P. Branchaud*
Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253
Received October 7, 1997
Abstr a ct: Photochemical cross coupling of alkyl cobaloximes with maleic anhydrides and PhSSPh
led to addition of an alkyl moiety and an SPh moiety across the alkene. Oxidation of the sulfide
to a sulfoxide followed by elimination of phenyl sulfenic acid provided substituted maleic anhydrides.
Alkyl cobaloximes could also be coupled with maleic anhydrides in the absence of PhSSPh to provide
substituted maleic anhydrides directly. These methods are applied to a short and efficient synthesis
of the anhydride of the Ras farnesyl protein transferase inhibitor chaetomellic acid A and in
preparations of C-glycosyl maleic anhydrides, in which the carbohydrate anomeric carbon is directly
attached to a maleic anhydride alkene carbon, in modest yields (19-46%).
Substituted maleic anhydrides, maleimides, γ-hydroxy-
butenolides, and butenolides are widespread in Nature
and are in biologically active molecules such as the
1
anticancer antibiotic showdomycin (1), the cardiotonic
2
drug digitoxin (2), the antiinflammatory phospholipase
A
2
inhibitor manoalide (3),3 the Ras farnesyl protein
4
transferase inhibitor chaetomellic acid A (4), and the
serine/threonine phosphatase inhibitor tautomycin (5).5
Previous communications from our group have reported
the development of methods for radical cross coupling of
6
alkyl cobaloximes with maleic anhydrides and an ap-
plication of that method to the synthesis of chaetomellic
acid A anhydride.7 In this paper, experimental details
are reported on that work. Applications of the method
to the preparation of C-glycosyl maleic anhydrides of
glucose and mannose in which the carbohydrate anomeric
carbon is directly attached to a maleic anhydride alkene
carbon are reported. Finally, a new and direct method
for cross coupling alkyl cobaloximes with maleic anyhy-
drides is reported.
Resu lts a n d Discu ssion
Alk yl Coba loxim e Syn th esis, Ra d ica l Tr a p p in g,
a n d Oxid a tion /Elim in a tion Stu d ies. Primary and
secondary alkyl cobaloximes can be prepared by oxidative
F igu r e 1.
bromides, iodides, or sulfonate esters. The py(dmgH) -
2
-
+
-
+
addition (alkylation) of py(dmgH)
2
Co Na with alkyl
Co Na can be formed by NaBH4 reduction of ClCo-
8
(dmgH)
2
py or in situ from CoCl
2
9
, dimethylglyoxime,
. The reaction of
2
Co Na (formed in situ) with n-decyl bromide
*
Corresponding author. Email ) bbranch@oregon.uoregon.edu,
phone ) (541)346-4627, FAX ) (541)346-4645.
1) ) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck and Co.:
New J ersey, 1996, entry 8627 and references therein.
2) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck and Co.:
New J ersey, 1996, entry 3206 and references therein.
3) De Rosa, S.; Crispino, A.; De Guilio, A.; Iodice, C.; Tommonaro,
G. J . Nat. Prod. 1997, 60, 844 and references therein.
4) (a) Desai, S. B.; Argade, N. P. J . Org. Chem. 1997 62, 4862 and
NaOH, pyridine, and NaBH
4
-
+
py(dmgH)
under anaerobic conditions at 0 °C to room temp in CH
OH produced decyl cobaloxime 6 in 81% isolated yield
eq 1). The R-acetoxy cobaloxime 7 was prepared from
(
3
-
(
(
(
1
0
1-bromo-1-acetoxy-3-methylbutane in 37% isolated yield
(
-
+
using py(dmgH)
and NaBH
temp in CH
2 2
Co Na formed from ClCo(dmgH) py
under anaerobic conditions at 0 °C to room
CN (eq 2). The preparation of 2,3,4,6-tetra-
references therein. (b) Poigny, S.; Guyot, M.; Samadi, M. J . Chem. Soc.,
Perkin Trans. 1 1997, 2175. (c) Ratemi, E. S., Dolence, J . M., Poulter,
C. D.; Vederas, J . C. J . Org. Chem. 1996, 61, 6296. (c) Gibbs, J . B.;
Pompliano, D. L.; Mosser, S. D.; Rands, E.; Lingham, R. B.; Singh, S.
B.; Scolnick, E. M.; Kohl, N. E.; Oliff, A. J . Biol. Chem. 1993, 268,
4
3
O-benzoyl-D-mannopyranosyl cobaloxime 8 from 2,3,4,6-
7
1
1
617.
(5) Sheppeck, J . E., II; Liu, W.; Chamberlin, A. R. J . Org. Chem.
(8) Schrauzer, G. N. Inorg. Synth. 1968, 11, 61.
997, 62, 387 and references therein.
(9) (a) Schrauzer, G. N.; Windgassen, R. J . J . Am. Chem. Soc. 1967,
89, 1999. (b) Branchaud, B. P.; Meier, M. S.; Malekzadeh, M. N. J .
Org. Chem. 1987, 52, 212.
(
6) Branchaud, B. P.; Slade, R. M.; J anisse, S. K. Tetrahedron Lett.
993, 34, 7885.
7) Branchaud, B. P.; Slade, R. M. Tetrahedron Lett. 1994, 35, 4071.
(
(10) Bigler, P.; Muhle, H.; Neuenschwander, M. Synthesis 1978, 593.
S0022-3263(97)01852-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/13/1998

Cross Coupling of Alkyl Cobaloximes with Maleic Anhydrides
J . Org. Chem., Vol. 63, No. 11, 1998 3545
tetra-O-benzoyl-R-D-mannopyranosyl bromide was ac-
Sch em e 1
-
+
complished in 77% isolated yield using py(dmgH)
2
Co Na
under anaerobic
OH (eq 3). Cobaloxime 8 was obtained
2 4
formed from ClCo(dmgH) py and NaBH
conditions in CH
3
as a single diastereomer at the anomeric center, pre-
sumed to be the R anomer. Analogously, 2,3,4,6-tetra-
O-benzoyl-D-glucopyranosyl cobaloxime 9 was prepared
as a 1:1 mixture of R,â anomers in 74% isolated yield from
2
3
,3,4,6-tetra-O-benzoyl-R-D-glucopyranosyl bromide (eq
).
Initial attempts to directly cross couple 6 with maleic
anhydride were unsuccessful. Cobaloxime 6 was slowly
consumed under anaerobic photolysis in EtOH with 10-
2
0 equiv of maleic anhydride, but none of the desired
cross coupling product 15 (Scheme 1) was detected. The
decyl radical formed from photolysis of 6 should have
added to maleic anhydride since the rate constants for
addition of nucleophilic alkyl radicals to maleic anhydride
7
-1 -1 11
(78%), 41 (77%). The thiophenyl cobaloxime 149b was also
are approximately 10 M
s
,
about 100 times faster
than for other activated alkenes which have successfully
undergone cobaloxime-mediated cross couplings. It was
postulated that the decyl radical did add to maleic
anhydride but â-H elimination was unfavorable due to
ring strain in the maleic anhydride moiety, allowing
oligomerization and other side reactions to become
dominant.
Assuming that the decyl radical formed from photolysis
of 6 did add to maleic anhydride, conditions were devised
to trap the intermediate substituted succinic anhydride
radical with PhSSPh (Scheme 1). The reaction solvent
obtained as a major product (yields not determined). Only
the trans diastereomer of 10 could be detected by H
NMR. More efficient coupling was achieved using two
light bulbs as described in the Experimental Section:
photolysis of 6 (20 mM), maleic anhydride (400 mM, 20
equiv), and PhSSPh (21 mM, 1.05 equiv) for only 10 h at
1
15 °C led to the production of 10 in 87% yield (determined
1
by H NMR using Ph
3
CH as an internal standard) and
in 64% isolated yield after purification. Reaction of 7
under the same conditions with maleic anhydride pro-
vided 11 in 81% yield as a 6:4 mixture of diastereomers
was changed to CH
set of studies was done with 6 (20 mM), maleic anhydride
200 mM, 10 equiv), and PhSSPh (21 mM, 1.05 equiv) in
0 mL CH CN using one 300 W light bulb for photolysis
instead of two as described in the Experimental Section).
3
CN for better solubility. An initial
at the CH(OAc)CH
chemistry on the anhydride.
2 3 2
CH(CH ) center, with trans stereo-
(
1
(
Oxidation of 10 with m-chloroperoxybenzoic acid in a
biphasic buffered solvent system,12 followed by syn
elimination at 0 °C (or during workup at ambient
temperature), produced 15 in 81% yield.13 Performing
the same procedure on 11 produced 16 in quantitative
yield. The high yields of these syn â-H eliminations
confirm that radical addition and subsequent trapping
by PhSSPh is a trans addition.
3
The yields versus reaction time were determined in
multiple runs of the reaction which were stopped and
worked up at various times with the following results:
1
time in h (yield of 10, as determined by H NMR using
Ph
3
CH as an internal standard), 1 (14%), 2 (27%), 3
(33%), 4 (37%), 7 (46%), 10 (56%), 20 (60%), 24 (64%), 30
Visible light photolyses of 8 and 9 under the conditions
optimized for the decylcobaloxime cross-couplings pro-
(
11) Lorand, H. Carbon-Centered Radicals: Radical-Molecule Ad-
dition Reactions. In Landolt-Bornstein Numerical Data and Functional
Relationships in Science and Technology; Hellwege, K.-H., Madelung,
O., Eds. in Chief, Radical Reaction Rates in Liquids, Vol. 13, Subvol-
ume a, Fischer, H., Ed.; Springer-Verlag: New York, 1984; pp 135-
(12) Imuta, M.; Ziffer, H. J . Org. Chem. 1979, 44, 1351.
(13) Sulfoxide elimination played a central role in a radical synthesis
of showdomycin utilizing aryl tellurium glycosides and Barton ester
chemistry: Barton, D. H. R.; Ramesh, M. J . Am. Chem. Soc. 1990,
112, 891.
2
51.

3
546 J . Org. Chem., Vol. 63, No. 11, 1998
Slade and Branchaud
Sch em e 2
Dir ect Cr oss-Cou p lin g Stu d ies. After much of the
preceding work was completed, it was discovered that
direct cross couplings could be performed using CH
3
CN
as the solvent rather than EtOH (eq 4). Direct cross
3
coupling of 6 with maleic anhydride in CH CN (10 h
vided the trapped products in yields of 19% for 12 (along
with 40% of 19) and 46% for 13. Subsequent oxidation
of each sulfide and syn elimination of the sulfoxide led
to quantitative yields (based on 12 and 13) of mannopy-
ranosyl- or glucopyranosyl-substituted maleic anhydrides
photolysis, 20 equiv of maleic anhydride) produced 15 in
1
66% yield (determined by H NMR using Ph CH as an
3
internal standard). As noted earlier, no cross coupling
was seen under similar conditions in EtOH. In benzene
only 32% of 15 was formed. Anaerobic photolysis of
myristylcobaloxime 20 (20 mM) and methylmaleic an-
1
7 and 18. Compound 17 was obtained as a mixture of
anomers, with one anomer predominating, according to
H NMR, but it was not possible to determine which
hydride (20 equiv, 400 mM) in CH CN provided 22 in
89% yield. Direct cross coupling of 20 with maleic
3
1
anomer was the major one. Compound 18 was obtained
as single anomer, according to H NMR, presumed to be
anhydride in CH CN provide 23 in 48% yield when 10
equiv of maleic anhydride was used and in 66% yield
3
1
R.
when 20 equiv of maleic anhydride was used. On the
basis of these results, it is clear that solvent effects are
very important for successful cross couplings, but the
exact reason direct cross couplings do not work in EtOH
is still unknown.
Studies directed toward a synthesis of showdomycin 1
were undertaken. Significant difficulties in the genera-
tion of the desired ribofuranosyl cobaloxime were en-
countered and are fully discussed elsewhere.14
Syn th esis of Ch a etom ellic Acid A An h yd r id e.
Chaetomellic acid A (4) is a potent and selective inhibitor
of ras farnesyl protein transferase (Ras FPTase). Inhibi-
tion of farnesylation prevents Ras membrane localization
and blocks Ras-induced cell transformation. Ras FTPase
Con clu sion
The methods described here provide a facile way to
attach the maleic anhydride moiety to functionalized
molecules under mild conditions. These reactions could
be useful in bioorganic and medicinal chemistry. The
chaetomellic acid A synthesis could be adapted to the
synthesis of chaetomellic acid A analogues. C-Glycosyl
maleic anhydrides may be useful in glycoconjugate
chemistry. Maleic anhydride has been used to label free
amino groups of peptides and proteins rapidly and
specifically,18 and such reactions of C-glycosyl maleic
anhydrides could be used to attach mono- or oligosac-
charides onto protein or cell surfaces.
inhibitors have the potential to be effective in anticancer
therapy.15 Chaetomellic acid A is unstable in the acid
form and readily converts to the stable anhydride 22
which is the form in which it is typically isolated.16
Aqueous base hydrolysis (pH 7.5) of 22 readily forms the
biologically active dianion. Several syntheses of 4 have
been reported. Our previously communicated synthe-
sis, described in detail here, utilizes alkyl cobaloxime-
mediated radical chemistry to provide a simple and
efficient synthetic route.
4
7
Preparation of myristyl cobaloxime 20 from com-
mercially available myristyl bromide proceeded in 84%
isolated yield (Scheme 2). Anaerobic photolysis of co-
baloxime 20 (20 mM), methylmaleic anhydride (20 equiv,
Exp er im en ta l Section
Gen er a l. All solvents were reagent grade unless otherwise
noted and were used as received with the exception of CH
3
-
4
00 mM), and PhSSPh (1.05 equiv, 21 mM) in CH
3
CN
CN (fractionally distilled over CaH under nitrogen for co-
2
provided 3-methyl-3-(phenylthio)-4-myristylsuccinic an-
hydride (21) in 83% yield. Note that the regioselectivity
and stereoselectivity of this reaction are the same as in
baloxime preparations or purchased as spectroscopic grade and
kept under nitrogen for photolysis experiments), THF (distilled
over benzophenone/Na under nitrogen), and pyridine (fraction-
ally distilled over KOH under nitrogen then stored over 4 Å
molecular sieves). A standard procedure was used to prepare
4
organomercury/NaBH radical addition reactions to me-
thylmaleic anhydride.17 Oxidation to the sulfoxide was
followed by immediate syn elimination under the reaction
conditions, producing chaetomellic acid A anhydride 22
in 98% yield.
py.8 Maleic anhydride was recrystallized from
CH was recrystallized from EtOH.
ClCo(dmgH)
CCl and Ph
2
4
3
Silica gel chromatography was performed using 60-200
mesh, grade 62 silica gel. Analytical TLC was performed on
aluminum-backed silica gel plates with UV-indicator.
1
(
(
14) Slade, R. M.; Branchaud, B. P. Organometallics 1996, 15, 2585.
15) (a) Tamanoi, F. Trends Biochem. Sci. 1993, 18, 349. (b) Gibbs,
All H NMR spectra were recorded at 300 MHz in CDCl
3
.
1
For quantitative H integration to determine reaction yields,
the delay time was extended to at least 5 s. C NMR spectra
J . B. Cell 1991, 65, 1.
16) Singh, S. B.; Zink, D. L.; liesch, J . M.; Goetz, M. A.; J enkins,
R. G.; Nallin-Omstead, M.; Silverman, K. C.; Bills, G. F.; Mosley, R.
13
(
were measured at 75.48 MHz. Low resolution mass spectra
T.; Gibbs, J . B.; Albers-Schonberg, G.; Lingham, R. B. Tetrahedron
1
993, 49, 5917.
17) Giese, B.; Kretzschmar, G. Chem. Ber. 1984, 117, 3175.
(18) Butler, P. J . G.; Harris, J . I.; Hartley, B. S.; Leberman, R.
Biochem. J . 1969, 112, 679.
(

Cross Coupling of Alkyl Cobaloximes with Maleic Anhydrides
J . Org. Chem., Vol. 63, No. 11, 1998 3547
were generated using electron impact at 70 eV. FAB MS was
used in some cases with Xe bombardment at 8 kV from a
155, 117, 43. HRMS: calcd for C20
498.1763, obsd 498.1741.
33 5 6
H N O Co (M + 1)
3
-nitrobenzyl alcohol or magic bullet matrix. High-resolution
2,3,4,6-Tetr a -O-ben zoyl-r-D-m a n n op yr a n osyl Br om id e.
This known compound19 was synthesized from 1,2,3,4,6-penta-
O-benzoyl-D-mannopyranose following a literature procedure
for the preparation of 2,3,4,6-tetra-O-benzoyl-R-D-glucopyra-
nosyl bromide from 1,2,3,4,6-penta-O-benzoyl-D-glucopyra-
nose.20 The crude product was used immediately for the next
step.
mass spectra (HRMS) were performed using the peak match
method. Melting points are uncorrected.
Gen er a l P r oced u r es for th e Syn th esis of Alk yl Co-
ba loxim es. Reactions were conducted under anaerobic ni-
trogen. Solvents were deoxygenated by saturation with ni-
trogen bubbling for approximately 1 min/mL unless noted
otherwise. Reactions for formation of light-sensitive alkyl
cobaloximes (especially 7) were performed with fume hood
lights turned off and flasks wrapped in aluminum foil. Column
chromatography was performed anaerobically, using deoxy-
genated solvents, foil-wrapped columns, and bubbling of
column fractions with nitrogen as they were being collected.
Bis(dim eth ylglyoxim ato)(pyr idin e)(1-n -decyl)cobalt (6).
Bis(dim eth ylglyoxim ato)(pyr idin e)(2,3,4,6-tetr a-O-ben -
zoyl-D-m a n n op yr a n osyl)(coba lt) (8). Following the general
procedure for the synthesis and purification of 6 but using
-
+
ClCo(dmgH) py as the source of py(dmgH) Co
2
2
Na , 8 was
synthesized from 2,3,4,6-tetra-O-benzoyl-R-D-mannopyranosyl
bromide (2.711 g, 2.86 mmol), ClCo(dmgH) py (1.730 g, 4.29
2
mmol), dry MeOH (150 mL), dry THF (10.0 mL), and NaBH4
(approximately 0.52 g, 13.6 mmol) to provide 8 as an orange
foam in 77% yield after silica gel chromatography with
anaerobic EtOAc. Characterization data are for the single
A 500 mL round-bottom flask containing CoCl
2
hexahydrate
(2.408 g, 10.1 mmol), dimethylglyoxime (2.344 g, 20.2 mmol),
and MeOH (200 mL) was deoxygenated with nitrogen and then
cooled to 0 °C. Pyridine (2.5 mL, 30.9 mmol) and NaOH (1.62
g, 20.2 mmol of 50% aq solution) were added. After 10 min
NaBH
the deep green/black Co(dmgH)
bromide (1.05 mL, 5.06 mmol) in freshly distilled THF (10 mL)
was deoxygenated and then added to the Co(dmgH) py anion
1
anomer obtained, believed to be the R anomer. H NMR: δ
2.21 (s, 6H), 2.30 (s, 6H), 3.97 (br d, 1H; J ) 9.9 Hz), 4.25 (br
dd, 1H; J ) 1.5, 12.0 Hz), 4.42 (br dd, 1H; J ) 2.1, 12.0 Hz),
5.36 (d, 1H; J ) 3.0 Hz), 5.55 (s, 1H), 5.69 (dd, 1H; J ) 3.0,
10.2 Hz), 6.21 (t, 1H; J ) 10.0 Hz), 7.18-7.56 (m, 13H), 7.77
(m, 4H), 7.96 (d, 4H; J ) 7.5 Hz), 8.12 (d, 2H; J ) 7.5 Hz),
4
(0.785 g, 20.6 mmol) was added in portions, producing
2
py anion. A solution of decyl
2
1
3
solution by cannula. The solution was monitored by TLC for
disappearance of decyl bromide. After stirring for 3 h at 0
8.62 (d, 2H: J ) 5.1 Hz), 18.55 (br s). C NMR: δ (contains
some overlapping peaks) 12.45, 12.81, 62.75, 66.95, 71.64,
72.35, 73.10, 125.19, 127.99, 128.19, 128.21, 128.26, 129.50,
129.57, 129.63, 129.74, 129.80, 129.83, 130.24, 132.61, 132.71,
132.98, 137.61, 149.60, 151.15, 152.52, 162.22, 165.38, 165.45,
166.20. LRMS: (FAB) m/z (rel intensity); 948 (5%, M + 1),
868, 579, 289 (100%), 231, 154, 136, 77. HRMS: calcd for
C H N O Co (M - Pyr + H) 869.2080, obsd 869.2097.
°
C, the solution was warmed to room temperature and the
reaction was stirred for an additional 30 min. Excess NaBH
4
was quenched by the addition of 2 mL of deoxygenated acetone.
The reaction solution was transferred by cannula into a
nitrogen-purged 500 mL round-bottom flask containing 3 g of
silica gel. The solvent was evaporated (rotary evaporator)
leaving a dry powder which was loaded onto a column packed
with 20 g of silica gel and deoxygenated EtOAc. The orange
band was eluted with deoxygenated EtOAc and was collected
in a nitrogen-purged round-bottom flask. The solvent was
evaporated (rotary evaporator), and then the residue was
placed on a vacuum line for complete removal of residual
solvent. Decyl cobaloxime 6 was obtained as an orange solid
4
2
42
4
13
Bis(dim eth ylglyoxim ato)(pyr idin e)(2,3,4,6-tetr a-O-ben -
zoyl-D-glu cop yr a n osyl)(coba lt) (9). Following the proce-
dure for the synthesis and purification of 8, 9 was synthesized
from commercially available 2,3,4,6-tetra-O-benzoyl-R-D-glu-
copyranosyl bromide (0.796 g, 1.21 mmol), ClCo(dmgH)
2
py
(0.733 g, 1.82 mmol), dry MeOH (90 mL), dry THF (15 mL),
4
and NaBH (approximately 0.164 g, 4.32 mmol) to produce 9
1
in 81% yield. H NMR: δ 0.85 (m, 5H), 1.20 (br m, 14H), 1.61
as an orange foam in 74% yield after silica gel chromatography
(
8
t, 2H; J ) 8.3 Hz), 2.10 (s, 12H), 7.29 (t, 2H), 7.69 (t, 1H),
1
with anaerobic EtOAc. The anomeric ratio is R:â ∼ 1:1.
NMR (CDCl ) δ 2.05-2.15 (singlets, 24H; 12H for each
anomer), 3.78 (m, 1H), 3.95 (m, 1H), 4.30 (m, 3H), 4.55 (m,
H
1
3
.57 (d, 2H), 18.10 (br s).
C NMR: δ (contains some
3
overlapping peaks) 11.92, 14.06, 22.63, 29.30, 29.41, 29.54,
2
1
9.65, 30.64, 30.70, 31.87, 32.37 (br, v. short), 125.05, 137.26,
48.96, 149.97. LRMS: (FAB) m/z (rel intensity); 509 (10%,
2
2
H), 5.01-5.22 (m, 3H), 5.45-5.69 (m, 4H), 7.10-8.90 (m, 50H;
13
5H for each anomer), 18.20 (ss, 4H, O-H-O protons);
C
M), 430, 290 (100%), 205, 155, 117. HRMS: calcd for
Co 509.2412, obsd 509.2422.
Bis(d im eth ylglyoxim a to)(p yr id in e)(1-a cetoxy-3-m eth -
ylbu tyl)coba lt (7). A solution of ClCo(dmgH) py (5.789 g,
4.3 mmol) in freshly distilled CH CN (70.0 mL) was deoxy-
genated by bubbling with nitrogen for 25 min while cooling to
°C. In portions, NaBH (0.713 g, 18.8 mmol) was added; the
solution turned dark green-black. A deoxygenated solution of
NMR (CDCl
3
) δ 12.09, 12.18, 12.24, 63.26, 63.84, 70.11, 70.17,
23 40 5 4
C H N O
7
1
1
1
1
0.51, 72.63, 73.70, 73.83, 75.39, 77.72, 125.00, 125.07, 127.98,
28.21, 128.33, 128.49, 129.72, 129.92 129.98, 130.51, 132.26,
32.62, 132.73, 132.84, 133.01, 133.25, 137.56, 137.61, 149.67,
49.74, 150.21, 150.29, 151.11, 164.82, 164.95, 165.27, 165.36,
65.60, 166.08, 166.21, 166.27 (some carbon peaks were
2
1
3
0
4
superimposed). LRMS: (FAB) m/z (rel intensity); 948 (15%,
M + 1), 870, 757, 579, 290 (100%), 231, 205, 155, 137, 117,
1
0
1
-bromo-1-acetoxy-3-methylbutane (1.003 g, 4.80 mmol) in
CH CN (10 mL) was added via cannula to the cold green
solution, the cannula was rinsed through with approximately
mL more of dry CH CN, and then the solution was stirred
1
05, 77. HRMS: calcd for C47
47 5
H N O13Co (M + 1) 948.2502,
3
obsd 948.2479.
Gen er a l P r oced u r e for P h otolyses. Anaerobic nitrogen
was further deoxygenated by passage through warm BASF R3-
3
3
at 0 °C for another 2.5 h. The reaction solution was warmed
to room temp over 50 min and then was cannula-transferred
into a nitrogen-purged 250 mL round-bottom flask equipped
with a stir bar, and the alkyl cobaloxime was extracted with
1
1 catalyst. Reaction solutions were made anaerobic by
bubbling nitrogen through solutions for at least 1 min/mL.
Reactions were performed in magnetically stirred septum-
sealed Pyrex test tubes under positive nitrogen pressure.
Tubes were placed in a 1000 mL beaker containing a stir bar
2 2
deoxygenated EtOAc and H O until the H O layer was only
faintly yellow in color. The residue from evaporation of the
organic layer was adsorbed onto 5 g of silica gel as described
for 6. Chromatography on 25 g of silica gel using deoxygenated
EtOAc was performed as described for 6, providing solid
orange-red R-acetoxycobaloxime 7 in 37% yield (0.89 g, 1.79
mmol). H NMR: δ 0.77 (t, 6H; J ) 5.5 Hz), 1.25 (br t, 2H; J
)
5
1
1
1
2
and a copper coil through which a 15 °C H O/ethylene glycol
cooling solution was pumped. Two 300 W light bulbs were
clamped on each side of the beaker, roughly 4 in. away from
the beaker sides. The test tubes were allowed to come to
thermal equilibrium while stirring (∼5 min) before the lights
were turned on. It is important to monitor the rate of stirring
1
6.4 Hz), 1.44 (m, 1H), 1.98 (s, 3H), 2.10 (s, 6H), 2.18 (s, 6H),
.36 (t, 1H; J ) 6.6 Hz), 7.28 (t, 2H), 7.69 (t, 1H), 8.52 (d, 2H),
13
(19) Ness, R. K.; Fletcher, H. G., J r.; Hudson, C. S. J . Am. Chem.
Soc. 1950, 72, 2200.
7.96 (br s). C NMR: δ (contains some overlapping peaks)
1.86, 12.09, 21.08, 21.51, 23.93, 25.15, 45.16, 63.27, 125.04,
37.33, 149.93, 149.96, 150.39, 169.90. LRMS: (FAB) m/z (rel
(20) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman
intensity); 498 (5%, M + 1), 419, 290 (100%), 234, 218, 205,
Scientific: Essex, 1989; p 648.

3
548 J . Org. Chem., Vol. 63, No. 11, 1998
Slade and Branchaud
to ensure that solid PhSCo(dmgH) py, which forms as a
2
internal standard). Without further isolation, crude 12 was
used directly for the next step. Following the procedure for
the synthesis and purification of 15, crude 12 (0.0510 g, 0.0648
product of the reaction, stays near the bottom of each tube as
a lightly stirred precipitate rather than as a vigorously stirred
cloudy suspension which will slow the rate of reaction.
2 2
mmol), m-CPBA (0.0139 g, 0.0805 mmol), dry CH Cl (5.0 mL),
2
-Decyl-3-(th iop h en yl)su ccin ic An h yd r id e (10). Fol-
and 0.2 M pH 7.4 phosphate buffer (5.0 mL) provided 17 in
1
lowing the general procedure for photolyses, a solution of decyl
cobaloxime 6 (0.1054 g, 0.207 mmol), PhSSPh (0.0476 g, 0.218
quantitative yield. H NMR: δ 4.47-4.72 (m, 4H), 5.91 (br s,
1H), 6.06 (dd, 1H, J ) 3.0, 10.1 Hz), 6.29 (t, 1H; J ) 10.1 Hz),
1
3
mmol), and maleic anhydride (0.4069 g, 4.15 mmol) in dry CH
CN (10.0 mL) in an 18 mL Pyrex test tube was photolyzed for
0 h. Removal of the volatiles (rotary evaporation) and silica
gel chromatography provided 10 as a yellowish waxy solid.
Further purification by sublimation of excess maleic anhydride
and PhSSPh in a coldfinger sublimation apparatus at room
temp under vacuum, providing pure 10 in 64% isolated yield.
3
-
6.63 (s, 1H), 7.29-8.22 (20H). C NMR: δ (contains some
overlapping peaks) 29.67, 62.40, 66.28, 69.47, 69.99, 71.21,
91.40, 128.37, 128.43, 128.47, 128.62, 128.69, 128.77, 129.75,
129.88, 129.93, 130.11, 132.97, 133.33, 133.47, 133.60, 133.79,
133.99, 163.77, 165.10, 165.27, 165.34, 165.99. LRMS: (EI)
m/z (rel intensity); 677 (5%, M + 1), 579, 307, 289, 219, 154
1
(100%), 137, 105, 77. HRMS: calcd for C38
677.1659, obsd 677.1640.
29
H O12 (M + 1)
1
H NMR: δ 0.88 (m, 3H), 1.27 (br s, 14H), 1.45 (m, 2H), 1.69-
1
(
.95 (m, 2H), 2.92-2.99 (m, 1H), 3.83 (d, 1H; J ) 6.0 Hz), 7.39
1-(Th iop h en yl)-2,3,4,6-tetr a -O-ben zoyl-D-m a n n op yr a -
n ose (19). The product mixture from a reaction to convert 8
to 12 (see preceding paragraph) was purified by silica gel
column chromatography using 1:1 hexanes:EtOAc to provide
19 in 40% isolated yield. 1H NMR: δ 4.53-4.69 (m, 2H), 4.99-
5.03 (br m, 1H), 5.79 (s, 1H), 5.87 (dd, 2H; J ) 3.1, 10.1 Hz),
5.98 (s, 1H), 6.15 (t, 1H; J ) 10.2 Hz), 7.11-7.58 (m, 16H),
1
3
m, 3H), 7.55 (m, 2H). C NMR: δ (contains some overlapping
peaks) 13.85, 14.24, 22.63, 25.84, 26.31, 29.06, 29.22, 29.48,
2
1
3
9.92, 30.20, 47.09, 50.22, 121.20, 129.40, 129.71, 130.02,
34.68, 135.32, 169.36, 170.97. HRMS: calcd for C20
48.1759, obsd 348.1764.
28 3
H O S
2
-(1-Acetoxy-3-m eth ylbu tyl)-3-(th ioph en yl)su ccin ic An -
1
3
h yd r id e (11). This compound was synthesized and purified
as described for 10; R-acetoxycobaloxime 7 (0.1053 g, 0.212
mmol), PhSSPh (0.0486 g, 0.226 mmol), and maleic anhydride
0.4179 g, 4.26 mmol) in CH
for 10 h at 15 °C to give 11 in 81% yield. After purification,
1 was obtained as a clear yellow liquid as a 6:4 mixture of
diastereomers. H NMR: δ (containing both isomers) 0.91-
.99 (m, 6H), 1.46 (m, 1H), 1.61 (m, 2H), 2.00 and 2.05 (2s,
H), 3.15 and 3.22 (2m, 1H), 3.97 and 4.18 (2d, 1H; J ) 4.5
and 5.1 Hz), 5.30 and 5.48 (2m, 1H), 7.43 (m, 3H), 7.55 (m,
7.86 (d, 2H; J ) 7.5 Hz), 8.01-8.06 (m, 6H).
C NMR: δ
(contains some overlapping peaks) 63.08, 67.14, 69.92, 70.44,
71.95, 85.98, 126.27, 128.07, 128.33, 128.38, 128.60, 128.90,
129.23, 129.43, 129.76, 129.82, 129.84, 132.08, 132.71, 133.03,
133.27, 133.51, 165.30, 165.43, 165.48, 166.09. LRMS: (magic
bullet + NaI) m/z (rel intensity); 711 (80%, M + Na), 579, 481,
(
3
CN (10.0 mL) were photolyzed
1
1
323, 177, 105 (100%). HRMS: calcd for C40
obsd 711.1610.
32 9
H O SNa 711.1665,
0
3
(2,3,4,6-Tetr a -O-ben zoyl-D-glu cop yr a n osyl)m a leic An -
h yd r id e (18). Following the procedure for the synthesis of
10, 13 was synthesized from 9 (0.1945 g, 0.205 mmol), PhSSPh
(0.0506 g, 0.232 mmol), maleic anhydride (0.4023 g, 4.10
1
3
2
H). C NMR: δ (for both isomers; contains some overlapping
peaks) 20.57, 20.68, 21.98, 22.32, 22.41, 22.54, 24.64, 24.74,
2
1
1
9.66, 40.03, 41.08, 45.84, 47.91, 51.15, 70.47, 70.84, 129.23,
29.84, 129.88, 130.30, 135.05, 135.16, 167.48, 168.55, 168.94,
69.05, 169.14, 170.28. LRMS: (EI) m/z (rel intensity); 336
mmol), and 10.0 mL of dry CH
3
CN to produce 13 in 46% yield
CH as an internal stan-
(determined by 1H NMR using Ph
3
dard). Following the procedure for the synthesis and purifica-
(
C
15%, M), 294 (100%), 276, 249, 165, 95, 43. HRMS: calcd for
S 336.1031, obsd 336.1035.
Decylm a leic An h yd r id e (15). A two-phase system of 10
0.0850 g, 0.244 mmol) and m-CPBA (0.0509 g, 0.295 mmol)
in 5.0 mL of CH Cl and 5.0 mL of 0.2 M pH 7.4 phosphate
tion of 15, crude 13 (0.1133 g, 0.144 mmol), m-CPBA (0.0299
g, 0.173 mmol), dry CH Cl (5.0 mL), and 0.2 M pH 7.4
2 2
phosphate buffer (5.0 mL) provided 18 in quantitative yield.
17
H
20
O
5
(
Characterization data is given for the major isomer, presumed
1
2
2
to be the R isomer. H NMR: δ 4.46 (dd, 1H; J ) 3.8, 12.2
buffer was stirred under nitrogen at 0 °C for 2.5 h. The
reaction was poured into a 100 mL separatory funnel, 5.0 mL
of cold phosphate buffer was added, and the product was
extracted with cold CH
were combined, washed successively with dilute cold Na
and cold phosphate buffer (1 × 25 mL each), dried over Na
SO
removal of residual solvent on a vacuum line, clear liquid
product 15 was obtained in 81% yield. H NMR: δ 0.88 (t,
3
6
1
3
Hz), 4.63-4.69 (m, 1H), 5.15 (d quart, 1H; J ) 3.3, 9.0, 12.2
Hz), 5.42 (t, 1H; J ) 3.8 Hz), 5.68 (m, 2H), 5.88 (t, 1H; J ) 4.2
1
3
Hz), 7.01 (d, 1H; J ) 1.5 Hz), 7.2-8.3 (m, 20H). C NMR: δ
(contains some overlapping peaks) 60.94, 66.07, 66.92, 67.52,
67.86, 124.32, 128.39, 128.52, 128.69, 128.80, 129.26, 129.70,
129.92wd1, 133.42, 133.60, 133.94, 134.01, 135.36, 148.41,
162.71, 163.16, 164.52, 164.99, 165.25, 166.20. LRMS: (EI)
m/z (rel intensity); 676 (5%, M), 579, 335, 310, 231, 122, 105
2
Cl
2
(3 × 10 mL). The organic layers
2
S
2
O
3
2
-
4
, filtered, and evaporated (rotary evaporator). After
1
(100%), 77, 51. HRMS: calcd for C38
676.1602.
28
H O12 676.1581, obsd
H), 1.26 (br m, 14H), 1.63 (m, 2H), 2.51 (t, 2H; J ) 7.2 Hz),
13
.58 (s, 1H). C NMR: δ (contains some overlapping peaks)
4.04, 22.62, 25.91, 26.90, 29.04, 29.09, 29.22, 29.35, 29.46,
1.82, 128.39, 153.80, 163.98, 165.84. LRMS: (FAB) m/z (rel
Bis(d im e t h ylglyoxim a t o)(p yr id in e )(1-m yr ist yl)co-
ba lt (20). Following the procedure for the synthesis of 6, 20
was synthesized from bromotetradecane (myristyl bromide;
intensity); 239 (M, 45%), 186, 151, 141, 137, 125 (100%), 112,
1.73 mL, 5.8 mmol), CoCl
dimethylglyoxime (2.714 g, 23.4 mmol), pyridine (2.8 mL, 34.6
mmol), NaOH (50% aq solution; 1.63 g, 20.4 mmol), NaBH
(0.519 g, 13.7 mmol), CH OH (175 mL), and THF (5 mL). After
2
hexahydrate (2.757 g, 11.6 mmol),
1
2
09. HRMS: calcd for C14
39.1652.
23 3
H O (M + 1) 239.1647, obsd
4
(
1-Acetoxy-3-m eth ylbu tyl)m a leic An h yd r id e (16). Fol-
3
lowing the procedure for the synthesis of 15, 16 was synthe-
sized from 11 (0.1416 g, 0.421 mmol) and m-CPBA (0.0890 g,
addition of the alkyl bromide, the reaction was stirred for 1 h
at 0 °C and at room temp for 7.5 h, monitoring the disappear-
ance of the alkyl bromide by TLC. Following the general
procedure for the isolation and purification of 6 provided 20
as an orange solid in 84% isolated yield after chromatography.
0
.516 mmol) in CH
buffer (10.0 mL) in quantitative yield. H NMR: δ 0.96 (s,
H), 0.98 (s, 3H), 1.68-1.80 (m, 3H), 2.15 (s, 3H), 5.72-5.77
2 2
Cl (10.0 mL) and 0.2 M pH 7.4 phosphate
1
3
1
3
1
(
4
(
1
m, 1H), 6.68 (s, 1H). C NMR: δ 20.58, 21.52, 22.97, 24.76,
1.91, 66.71, 135.33, 152.07, 162.77, 163.36, 169.64. LRMS:
FAB, magic bullet) m/z (rel intensity); 227 (M, 20%), 185, 167,
49, 134, 124, 118, 84, 72, 54, 42 (100%). HRMS: calcd for
H NMR: δ 0.894 (m, 5H), 1.17-1.24 (m, 22H), 1.62 (t, 2H; J
) 8.7 Hz), 2.17 (s, 12H), 7.30 (t, 2H), 7.70 (t, 1H), 8.58 (d, 2H),
1
3
18.24 (br. s, dmgH-O-H).
C NMR: δ (contains some
overlapping peaks) 11.92, 14.06, 22.66, 29.32, 29.44, 29.63,
29.67, 30.66, 30.72, 31.89, 125.04, 137.23, 148.93, 149.98.
LRMS: (FAB) m/z (rel intensity); 565 (10%, M), 487, 463, 290
C
11
H
15
O
5
(M + 1) 227.0919, obsd 227.0930.
(
2,3,4,6-Tetr a-O-ben zoyl-D-m an n opyr an osyl)m aleic An -
h yd r id e (17). Following the procedure for the synthesis and
purification of 10, 12 was synthesized from 8 (0.1439 g, 0.152
mmol), PhSSPh (0.0348 g, 0.159 mmol), maleic anhydride
(100%), 205, 155, 117, 43. HRMS: calcd for C27
565.3037, obsd 565.3017.
2-Meth yl-2-(th iop h en yl)-3-m yr istylsu ccin ic An h yd r id e
(21). Following the procedure for the synthesis and purifica-
tion of 10, 21 was synthesized from myristyl cobaloxime (20;
48 5 4
H N O Co
(
0.2973 g, 3.03 mmol), and 7.6 mL of dry CH
3
CN to produce
1
1
2 in 19% yield (determined by H NMR using Ph CH as an
3

Cross Coupling of Alkyl Cobaloximes with Maleic Anhydrides
J . Org. Chem., Vol. 63, No. 11, 1998 3549
0
.1139 g, 0.201 mmol), PhSSPh (0.0469 g, 0.215 mmol), and
methylmaleic anhydride (citraconic anhydride; 0.35 mL, 3.89
mmol) in 10 mL of dry CH CN to produce 21 in 83% yield
determined by H NMR using Ph CH as an internal stan-
dard). H NMR: δ 0.878 (m, 3H), 1.26 (br s, 24H), 1.59 (m,
13C NMR: δ (contains some overlapping peaks) 9.45, 14.07,
22.65, 24.42, 27.56, 29.16, 29.32, 29.40, 29.53, 29.59, 29.61,
29.64, 31.89, 140.37, 144.75, 165.82, 166.22. LRMS: (EI) m/z
(rel intensity); 308 (15%, M), 280, 263, 207, 150, 126 (100%),
110. HRMS: calcd for C H O 308.2351, obsd 308.2354.
3
1
(
3
1
1
9
32
3
2
2
H), 2.16 (s, 3H), 2.89 (quart, 1H; J ) 2.7, 5.8 Hz), 7.30 (t,
13
H; J ) 6.9 Hz), 7.38-7.53 (m, 3H). C NMR: δ (contains
Ack n ow led gm en t. This research was supported by
NSF CHE 8806805, NSF CHE 9423782, and a fellow-
ship from the U.S. Department of Education GAANN
program (R.M.S.).
some overlapping peaks) 14.04, 18.21, 21.48, 22.64, 24.73,
2
1
6.87, 27.48, 29.62, 31.88, 50.08, 51.94, 55.46, 56.07, 128.50,
29.10, 129.42, 130.71, 130.80, 137.16, 170.67, 171.91.
LRMS: (EI) m/z (rel intensity); 418 (20%, M), 346, 290, 280,
2
4
63, 207, 150, 126 (100%), 110. HRMS: calcd for C25
18.2541, obsd 418.2549.
Ch a etom ellic Acid A An h yd r id e (22). Following the
38 3
H O S
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 6, 7, 8, 9, 15, 16, 17, 18, 19, 20, and 22 (11 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
procedure for the synthesis and purification of 15, 22 was
synthesized from 21 (0.1172 g, 0.280 mmol), m-CPBA (0.0578
g, 0.335 mmol), dry CH Cl (5.0 mL), and 0.2 M pH 7.4
2 2
phosphate buffer (5.0 mL) to provide 22 (0.0846 g, 0.274 mmol)
in 98% yield. H NMR: δ 0.877 (t, 3H; J ) 6.5 Hz), 1.25 (br
s, 22H), 1.59 (m, 2H), 2.07 (s, 3H), 2.45 (t, 2H; J ) 7.7 Hz).
1
J O971852T