Synthesis of enamides related to the salicylate antitumor macrolides using copper-mediated vinylic substitution

Article abstract of DOI:10.1021/ol005800t

(equation presented) A new approach to the assembly of enamides is described using copper(I) carboxylate-catalyzed substitution of vinyl iodides and amides. Modified reaction conditions have been developed to synthesize the O-methyloxime enamide side chai

Full text of DOI:10.1021/ol005800t

ORGANIC
LETTERS
2
000
Vol. 2, No. 9
333-1336
Synthesis of Enamides Related to the
Salicylate Antitumor Macrolides Using
Copper-Mediated Vinylic Substitution
1
Ruichao Shen and John A. Porco, Jr.*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue,
Boston Massachusetts 02215
porco@chem.bu.edu
Received March 13, 2000
ABSTRACT
A new approach to the assembly of enamides is described using copper(I) carboxylate-catalyzed substitution of vinyl iodides and amides.
Modified reaction conditions have been developed to synthesize the O-methyloxime enamide side chains related to the natural products
lobatamides A−F, oximidine I and II, and CJ-12 950.
7
The salicylate enamide macrolides represent a novel class
of antitumor natural products with a potentially novel and
thus far undetermined mechanism of action. Members of the
enamides suitable for late-stage introduction. In this Letter,
we disclose our initial studies related to the development of
copper-catalyzed vinylic substitution of alkenyl iodides and
amides which results in the assembly of stereochemically
well-defined enamides.
1
2
class include lobatamides A-F, oximidines I and II,
3
4
salicylihalamide B, CJ-12,950 and CJ-13,357, and apicu-
5
,6
larens A and B. As part of a program to synthesize the
O-methyloxime enamide containing compounds lobatamides
and oximidines, we required a general method to synthesize
(1) (a) Galinis, D. L.; McKee, T. C.; Pannell, L. K.; Cardellina, J. H.,
II; Boyd, M. R. J. Org. Chem. 1997, 62, 8968. (b) McKee, T. C.; Galinis,
D. L.; Pannell, L. K.; Cardellina, J. H., II; Laasko, J.; Ireland, C. M.; Murray,
L.; Capon, R. J.; Boyd, M. R. J. Org. Chem. 1998, 63, 7805. (c) Suzumura
et al. have independently isolated YM-75518 which is identical to lobatamide
A, see: Suzumura, K.-i.; Takahashi, I.; Matsumoto, H.; Nagai, K.; Setiawan,
B.; Rantiamodjo, R. M.; Suzuki, K.-i.; Nagano, N. Tetrahedron Lett. 1997,
3
8, 7573.
2) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y. Seto, H. J. Org.
Chem. 1999, 64, 153.
3) Erickson, K. L.; Beutler, J.; Cardellina, J. H., II; Boyd, M. R. J.
Org. Chem. 1997, 62, 8188.
4) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara, T.;
Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J. Antibiot. 1998,
1, 14.
5) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075.
6) For the synthesis of an enamide-truncated analogue of salicylihala-
mide A, see: Furstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55,
215.
(
(
(
5
(
(
Enamides have been previously synthesized using a
number of methods, including the Curtius rearrangement of
8
1
0.1021/ol005800t CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/05/2000

R,â unsaturated acyl azides,7,8 palladium(II)-catalyzed ami-
optimization using this catalyst. Using benzamide and (E)-
1-iodoheptene as model substrates, we performed parallel
syntheses on the Quest 210 Organic Synthesizer (Argonaut
9
10
dation of alkenes, direct addition of amides to alkynes,
acylation of imines,1 acid-catalyzed condensation of alde-
1
hydes and amides,12 amide Peterson olefination, and
13
Technologies) as shown in Table 1. These studies estab-
19
14
Horner-Wittig and Wadsworth-Emmons reactions. How-
ever, most of these methods are either unable to control E-Z
olefin stereoselectivity or often suffer from low yields, and
thus may not be suitable for use at a late stage in a synthesis.
In considering potential methods for the formation of
enamides, we have focused our initial efforts on transition
metal-catalyzed vinylic substitution reactions of vinyl iodides
and amides. Ogawa et al. have reported the copper iodide-
promoted substitution of vinyl bromides and potassium
amides (1 equiv of CuI, HMPA, 130 °C) to afford enamides
in low to moderate (38-45%) yields.15 On the basis of this
precedent, and reports of related copper-catalyzed substitution
Table 1. Parallel Evaluation of Bases and Solvents
16
reactions, our initial goal was to develop a copper-catalyzed
method that would occur at milder temperatures and be
suitable for the installation of potentially labile enamides.
Initial screening of catalyst systems compared phosphine
17
copper(I) and copper(I) carboxylate catalysts using cesium
16
2 3
carbonate (Cs CO ) as base (Scheme 1). Enhanced conver-
Scheme 1. Comparison of Copper Catalystsa
b
lished the requirement for polar aprotic solvents in the
reaction (NMP or DMSO) and a slight enhancement when
sions were obtained using Liebeskind’s copper(I) thiophen-
ecarboxylate (CuTC) which led us to pursue further reaction
18
using Cs
2 3 2 3
CO vs K CO as base. Further improvement to
>
95% conversion was found using 30 mol % of CuTC and
(
7) For a recent synthesis of the heptadienamide side chain of salicyli-
halamide A and apicularens A and B, see: Snider, B. B.; Song, F. Org.
Lett. 2000, 2, 407.
rigorous vacuum purge degassing of the reaction mixture
prior to heating (90 °C, 12 h). Using these conditions, a
number of enamides were synthesized as shown in Table
(
8) Brettle, R.; Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1. 1988,
185.
9) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I. Tetrahedron
Lett. 1992, 33, 6643.
10) (a) Mohre, H.; Kilian, R. Tetrahedron 1969, 25, 5745. (b) Kondo,
T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc., Chem. Commun.
995, 413.
11) (a) Boeckmann, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am.
Chem. Soc. 1988, 110, 8250.
12) (a) Zeeza, C. A.; Smith, M. B. Synth. Comm. 1987, 17, 729-40.
b) Kiefel, M. J.; Maddock, J.; Pattenden, G. Tetrahedron Lett. 1992, 33,
2
2
0
(
2. Both styrenyl and alkenyl iodides are workable in the
reaction and generally afford isolated yields of enamides in
(
1
(19) http://www.argotech.com/quest (March 27, 2000).
(
(20) Typical experimental procedure (Table 2, entry 2): Sorbamide
(83 mg, 0.75 mmol), CuTC (28.6 mg 0.15 mmol), and Cs2CO3 (245 mg,
0.75 mmol) were placed in an oven-dried 10 mL Schlenk flask equipped
with a stir bar. Anhydrous NMP (2 mL) was added using a dry syringe.
The suspension was degassed with high vacuum until gas evolution ceased.
(E)-1-Iodoheptene (112 mg, 0.5 mmol, 79 µL) was added using a microliter
syringe. The mixture was degassed again using high vacuum until no further
gas evolution was observed. The suspension was stirred at 90 °C for 12 h
under argon. The red slurry was cooled to room temperature and diluted
with ether, and the ether extracts were washed with pH 7 buffer. The aqueous
layer was extracted 2x further with ether. The organic layers were combined,
dried with anhydrous sodium sulfate, and concentrated. The pure enamide
3b was obtained as a white solid (71 mg, 69% yield) after flash
chromatography on silica gel (hexane:ethyl acetate ) 4:1, 1% Et3N): mp
(
(
3
227.
(13) (a) Cuevas, J.-C.; Patil, P.; Snieckus, V. Tetrahedron Lett. 1989,
3
0, 5841. (b) Palomo, C.; Aizpurua, J. M.; Legido, M.; Picard, J. P.;
Dunogues, J.; Constantieux, T. Tetrahedron Lett. 1992, 33, 3903.
14) (a) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett.
(
1
2
993, 34, 1479. (b) Paterson, I.; Cowden, C.; Watson, C. Synlett 1995,
09.
(15) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991, 1443.
16) (a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc.
(
1
997, 119, 10539. (b) Kiyomori, A.; Marcoux, J.-F.; Doye, S.; Buchwald,
S. L. Tetrahedron Lett. 1999, 40, 2657. (c) Kalanin, A. V.; Bower, J. F.;
Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986.
1
116-117 °C; H NMR (CDCl3, 400 MHz) δ 7.23 (1H, dd, J ) 14.8, 10
Hz), 7.16 (1H, d, J ) 9.6 Hz), 6.82 (1H, dd, J ) 14, 10.8 Hz), 6.12 (2H,
m), 5.71 (1H, d, J ) 14.8 Hz), 5.16 (1H, dt, J ) 14, 7.2 Hz), 1.82 (3H, d,
(
17) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org.
Chem. 1993, 58, 4716.
18) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
1
3
J ) 5.6 Hz), 1.30 (6H, m), 2.01 (2H, m), 0.86 (3H, t, J ) 6 Hz) ppm;
C
(
NMR (CDCl3, 67.5 MHz) δ 163.1, 142.4, 138.6, 129.7, 122.6, 120.7, 113.6,
2
2
748. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
312.
31.3, 29.7, 29.5, 22.5, 18.6, 14.0 ppm; HRMS (EI) calcd 207.1623, found
-
1
207.1588; IR (neat) 3247, 2921, 1654, 1629, 1534, 1350 cm
.
1334
Org. Lett., Vol. 2, No. 9, 2000

acid 4 (92%).23 The (Z)-O-methyloxime amide 5 was
prepared in 88% yield by formation of the mixed anhydride
of 1 and subsequent reaction with aqueous ammonia. Use
of the acid chloride of 4 in this transformation led to the
formation of the isomerized (E)-O-methyloxime amide 6 in
low yield. (Z)-Amide 5 could be fully isomerized to 6 in
Table 2. Copper-Catalyzed Enamide Formation
8
1% yield using concentrated HCl/MeOH (1:2). Treatment
of 6 (1.5 equiv) with (E)-1-iodoheptene or (E)-1-iodostyrene
1.0 equiv) under the previously described conditions (30
mol % of CuTC, 1.5 equiv of Cs CO , DMA, 90 °C, 12 h)
led to the formation of model enamide compounds 7 and 8
Scheme 2) in isolated yields of 52 and 57%, respectively.
(
2
3
(
However, use of amide 5 under the same conditions led to
1
consumption of vinyl iodide (as determined by H NMR)
but did not afford an enamide product. In an effort to improve
reactions employing (Z)-amide 5, it was found that use of
24
Rb
(36%). It was determined by control experiments that (Z)-
O-methyloxime enamide 9 was decomposed by Cs CO at
2 3
CO as base led to the formation of the desired enamide
9
2
3
2
5
high temperature.
Although a detailed mechanistic investigation of the copper
carboxylate-mediated vinylic substitution awaits further
experimentation, tentative proposals are outlined in Figure
1
. In the first scenario (A), a cesium carboxamide may react
the 57-75% range. Entries 2 and 5 demonstrate the use of
2
,4-hexadienamide21 as a coupling partner to afford conju-
gated enamides. Entries 3 and 6 represent efficient syntheses
of the N-alkenyl-N-methylformamide functionality present
in the cytotoxic marine macrolides ulapualides and mycalo-
lides.1
4b,22
To prepare enamides related to the salicylate antitumor
macrolides, we required (E)- and (Z)-O-methyloxime amides
which were prepared as shown in Scheme 2. Treatment of
malealdehydic acid with aqueous O-methylhydroxylamine
hydrochloride led to the formation of (Z)-O-methyloxime
Scheme 2. Synthesis of O-Methyloxime Enamides
Figure 1. Mechanistic scenarios for copper-catalyzed enamide
formation.
with CuTC to afford a cuprate-like intermediate which forms
the enamide after four-centered ipso-substitution of the vinyl
iodide. A related mechanism was recently proposed by
Buchwald and co-workers to explain the role of cesium in
(21) Pellegata, R.; Italia, A.; Villa, M. Synthesis 1985, 517.
(22) Liu, P.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 1235.
(23) For the synthesis of the oxime of malealdehydic acid, see: Schroeter,
S. H.; Appel, R.; Brammer, R.; Schenck, G. O. Justus Liebigs Ann. Chem.
966, 697, 42.
24) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 2000, 41, 481.
25) Further studies are in progress to determine the mode of decomposi-
tion of enamide 9 under basic conditions.
1
(
(
Org. Lett., Vol. 2, No. 9, 2000
1335

copper-catalyzed substitution of aryl halides with phenols.16a
It is also conceivable that electron-transfer mechanisms are
involved in the substitution process.26 In a second scenario
substrates and application of transition-metal catalyzed
vinylic substitution reactions to the synthesis of the lobata-
mides, oximidines, and unnatural analogues is in progress
and will be reported in due course.
(B), oxidative addition of the vinyl iodide to CuTC occurs
which, as proposed by Liebeskind and co-workers, may be
18
Acknowledgment. We thank Professor James Panek and
Jennifer Schaus (Boston University) for helpful suggestions.
Work at the Boston University Center for Streamlined
Synthesis (CSS) is supported by Argonaut Technologies,
Boehringer-Ingelheim, Glaxo-Wellcome, and Monsanto-
Searle.
favored by use of the carboxylate ligand. Displacement of
a copper iodide intermediate by the cesium carboxamide
would be followed by reductive elimination to afford the
enamide product.
In summary, enamides related to the side chains of the
salicylate antitumor natural products have been synthesized
using copper(I) carboxylate-catalyzed substitution of vinyl
iodides and amides. Extension of these methods to other
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 3a-f and 5-9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
26) (a) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
b) Matyjaszewski, K.; Wei, M.; Xia, J.; Gaynor, S. G. Macromol. Chem.
Phys. 1998, 199, 2289.
(
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