Modification of C-terminal peptides to form peptide enamides: Synthesis of chondriamides A and C

Full text of DOI:10.1021/jo0158027

J . Org. Chem. 2001, 66, 8215-8221
8215
Chondriamide A (5) shows cytotoxicity against KB and
LOVO cells and antiviral activity against HSV II.10
Chondriamide C (6) is a bis-indole-containing marine
natural product that shows both cytotoxicity and anthel-
mintic activity.11 Terpeptin (7) is a novel peptide recently
isolated from Aspergillus terreus that inhibits the cell
cycle at the G2/M phase.12 Due to the presence of numer-
ous amide functional groups in these molecules, we
considered alternatives to vinyl halide amidation7 devel-
oped in our laboratories to access natural and unnatural
compounds in this class. Since all of the compounds
contain unsaturated enamides derived from aromatic
amino acid residues, we reasoned that modification of
C-terminal peptides by an oxidative decarboxylation-
elimination process could be implemented to produce
natural and unnatural peptide enamides from readily
available peptide precursors (Figure 2). The overall (and
possibly biomimetic) process is analogous to known
enzymatic posttranslational, oxidative decarboxylation
reactions such as the EpiD flavoprotein-catalyzed oxida-
tive decarboxylation of peptidyl cysteines.13 Although
decarboxylation of dehydroamino acids has been utilized
to prepare enamides14 and â-elimination reactions have
been used to produce enamides and related compounds,15
synthesis of peptide enamides from tandem oxidative
decarboxylation-elimination of C-terminal amino acids
is underdeveloped.16 Herein, we report general protocols
for the synthesis of peptide enamides from C-terminal
peptides and application of this methodology to the syn-
thesis of the cytotoxic indole-enamide natural products
chondriamides A and C.
Mod ifica tion of C-Ter m in a l P ep tid es to
F or m P ep tid e En a m id es: Syn th esis of
Ch on d r ia m id es A a n d C
Xiang Wang and J ohn A. Porco, J r.*
Department of Chemistry and Center for Streamlined
Synthesis, Boston University, 590 Commonwealth Avenue,
Boston, Massachusetts 02215
porco@chem.bu.edu
Received May 29, 2001
In tr od u ction
Enamides have been studied extensively as synthons
in organic synthesis and have been used prominently in
the preparation of heterocycles1 and in asymmetric
synthesis.2 These functional groups are stable under
neutral or basic conditions, but with Brønsted acids, they
undergo protonation to form N-acyliminium ions that
may react with oxygen, sulfur, or π-based nucleophiles.3
Recently, there has been renewed interest in the syn-
thesis of enamides due to the isolation and potent
antitumor activity of the salicylate antitumor macrolides
(cf. oximidine II4 (1) and salicylihalamides A5 (2) and B
(3), Figure 1), which contain highly unsaturated enamide
side chains. As part of a general program toward the
synthesis of enamide-containing natural products, we
recently reported the synthesis of enamides related to
the salicylate antitumor macrolides lobatamides6 and
oximidines4 using copper(I)-carboxylate-catalyzed sub-
stitution of vinyl iodides and amides.7 An additional class
of bioactive enamide natural products that has attracted
our attention are the linear and cyclic peptide enamides,
representative members of which are shown in Figure
1. Frangufoline (4) is a cyclopeptide alkaloid8 with
sedative and antiinflammatory properties that has
been reported to bind to multiple sites on calmodulin.9
Resu lts a n d Discu ssion
Our first plan was to examine the elimination chem-
istry of O-acetyl-N-acyl-N,O-acetals, which are readily
available from oxidative decarboxylation of N-acyl-R-
(9) Han, Y. N.; Kim, G.-Y.; Hwang, K. H.; Han, B. H. Arch. Pharm.
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1992, 33, 3097.
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1998, 61, 1560.
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(14) (a) Schmidt, U.; Lieberknecht, A. Angew. Chem., Int. Ed. Engl.
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H. Liebigs Ann. Chem. 1985, 785.
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Kapur, N.; Parsons, A. F. Tetrahedron 2000, 56, 3941. (c) Baker, S.
R.; Burton, K. I.; Parsons, A. F.; Pons, J .; Wilson, M. J . Chem. Soc.,
Perkin Trans. 1 1999, 427. (d) Brodney, M. A.; Padwa, A. J . Org. Chem.
1999, 64, 556. (e) Okano, T.; Sakaida, T.; Eguchi, S. J . Org. Chem.
1996, 61, 8826. (f) Schultz, A. G.; Guzzo, P. R.; Nowak, D. M. J . Org.
Chem. 1995, 60, 8044.
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(b) Becker, Y.; Eisenstadt, A.; Stille, J . K. J . Org. Chem. 1980, 45, 2145.
(c) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J . Am.
Chem. Soc. 1993, 115, 10125. (d) Gilbertson, S. R.; Chang, C. T. J .
Org. Chem. 1995, 60, 6226. (e) Zhu, G.; Zhang, X. J . Org. Chem. 1998,
63, 9590.
(3) For reviews on N-acyliminium ion chemistry, see: (a) Zaugg, H.
E. Synthesis 1984, 85 and 181. (b) Speckamp, W. N.; Hiemstra, H.
Tetrahedron 1985, 41, 4367. (c) Speckamp, W. N.; Moolenaar, M. J .
Tetrahedron 2000, 56, 3817.
(4) (a) Kim, J . W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto,
H. J . Org. Chem. 1999, 64, 153. (b) For recent synthetic studies
regarding the enamide side chain, see: Kuramochi, K.; Kouji, W.;
Watanabe, H.; Kitahara, T. Synlett 2000, 397. (c) Raw, S. A.; Taylor,
R. J . K. Tetrahedron Lett. 2000, 41, 10357.
(5) (a) Erickson, K. L.; Beutler, J . A.; Cardellina, J . H., II; Boyd, M.
R. J . Org. Chem. 1997, 62, 8188. (b) For revision of the absolute
configuration of salicylihalamide, see: Wu, Y.; Esser, L.; De Brabander,
J . K. Angew. Chem., Int. Ed. 2000, 39, 4308.
(6) McKee, T. C.; Galinis, D. L.; Pannell, L. K.; Cardellina, J . H., II;
Laakso, J .; Ireland, C. M.; Murray, L.; Capon, R. J .; Boyd, M. R. J .
Org. Chem. 1998, 63, 7805.
(15) (a) Schmidt, U.; Lieberknecht, A.; Bokens, H.; Griesser, H.
Angew. Chem., Int. Ed. Engl. 1981, 20, 1026. (b) Schmidt, U.;
Lieberknecht, A.; Griesser, H.; Boekens, H. Tetrahedron Lett. 1982,
23, 4911. (c) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.; Kanazawa, T.; Aoki, T. J . Am. Chem. Soc. 1982, 104, 6697.
(d) Schmidt, U.; Lieberknecht, A.; Boekens, H.; Griesser, H. J . Org.
Chem. 1983, 48, 2680. (e) Schmidt, U.; Schanbacher, U. Liebigs Ann.
Chem. 1984, 1205. (f) Schmidt, U.; Schanbacher, U. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 152. (g) Berthon, L.; Uguen, D. Tetrahedron
Lett. 1985, 26, 3975. (h) Schmidt, U.; Zaeh, M.; Lieberknecht, A. J .
Chem. Soc., Chem. Commun. 1991, 1002. (i) Katritzky, A. R.; Ignatch-
enko, A. V.; Lang, H. Synth. Commun. 1995, 25, 1197. (j) J ohnson, A.
P.; Luke, R. W. A.; Boa, A. N. J . Chem. Soc., Perkin Trans. 1 1996,
895. (k) Xiao, D.; Stephen, P.; J oullie, M. M. Tetrahedron Lett. 1998,
39, 9631. (l) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J .
Org. Chem. 1999, 64, 6646. (m) Laib, T.; Bois-Choussy, M.; Zhu, J .
Tetrahedron Lett. 2000, 41, 7645. (n) Labrecque, D.; Charron, S.; Rej,
R.; Blais, C.; Lamothe, S. Tetrahedron Lett. 2001, 42, 2645.
(16) For an example, see: Harding, K. E.; Liu, L. T.; Farrar, D. G.;
Coleman, M. T.; Tansey, S. K. Synth. Commun. 1991, 21, 1409.
(7) Shen, R.; Porco, J . A., J r. Org. Lett. 2000, 2, 1333.
(8) “Cyclopeptide Alkaloids” in Progress in the Chemistry of Organic
Natural Products; Gournelis, D. C., Laskaris, G. G., Verpoorte, R., Eds.;
Springer: New York, 1998; p 1.
10.1021/jo0158027 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

8216 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
F igu r e 1. Representative enamide natural products.
F igu r e 2. Chemical modification of C-terminal peptides to form peptide enamides.
Ta ble 1. P a r a llel Eva lu a tion of Ad d itives in Elim in a tion
amino acids.17 In preliminary experiments, dipeptide
substrates related to natural products 4-7 containing
C-terminal tyrosine and tryptophan moieties were evalu-
ated. Treatment of C-terminal dipeptide 8 with lead
tetraacetate led to efficient formation of 9 as a 1:1
mixture of acetal diastereomers (Scheme in Table 1).16
Using the Argonaut FirstMate synthesizer,18 we evalu-
ated the effect of Lewis acid additives on the elimination
of 9 using diisopropylethylamine (DIEA) as a base (Table
1). Using La(OTf)3, ZnBr2, and LiClO4 as additives, we
identified LiClO4 (1.2 equiv, entry 4) as a useful additive
for high conversion to enamide 10.19 Using this general
condition, we found that a number of crude N,O-acetals
12 may be cleanly eliminated to form enamides 13 by
sequential addition of lithium perchlorate (LiClO4) and
DIEA (THF, 0-25 °C). In the case of C-terminal tryp-
tophan derivatives, protection of the indole with the
of N,O-Aceta l 9
entry
additive
ratio (Z:E)a
yield (%)b
1
2
3
4
5
none
1.1:1
1:3
1:11
1:1.1
1:-
24
23
14
87
45
ZnBr2 (1.2 equiv)
La(OTf)3 (1.2 equiv)
LiClO4 (1.2 equiv)
LiClO4 (10 equiv)
a
b
Determined by 1H NMR integration. Isolated yield.
(17) (a) Gledhill, A. P.; McCall, C. J .; Threadgill, M. D. J . Org. Chem.
1986, 51, 3196. (b) Seebach, D.; Charczuk, R.; Gerber, C.; Renaud, P.;
Berner, H.; Schneider, H. Helv. Chim. Acta 1989, 72, 401. (c) Corcoran,
R. C.; Green, J . M. Tetrahedron Lett. 1990, 31, 6827. (d) Apitz, G.;
Steglich, W. Tetrahedron Lett. 1991, 32, 3163. (e) Apitz, G.; J a¨ger, M.;
J aroch, S.; Kratzel, M.; Scha¨effeler, L.; Steglich, W. Tetrahedron 1993,
49, 8223. (f) Steglich, W.; J a¨ger, M.; J aroch, S.; Zistler, P. Pure Appl.
Chem. 1994, 66, 2167. (g) Osada, S.; Fumoto, T.; Kodama, H.; Kondo,
M. Chem. Lett. 1998, 675. (h) Boto, A.; Hernandez, R.; Suarez, E. J .
Org. Chem. 2000, 65, 4930.
(18) Argonaut Technologies FirstMate. http://www.argotech.com/
firstmate (accessed Oct 18, 2001).
(19) For the use of DBU/LiClO4 to prepare dehydroalanine-contain-
ing peptides by elimination of acetic acid from O-acetylserine residues,
see: Sommerfeld, T. L.; Seebach, D. Helv. Chim. Acta. 1993, 76, 1702.
p-toluenesulfonamide protecting group20 (entries 3 and
4, Table 2) was found to be optimal for protection against
oxidative degradation21 relative to Nin-Boc protection
(entry 2, Table 2).22 Interestingly, protected tryptophan
(20) For a review of sulfonamide protection of indoles, see: Ottoni,
O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
(21) For related use of the Nin-diphenylphosphinothioyl protecting
group to prevent oxidative destruction of the indole nucleus, see: Kiso,
Y.; Kimura, T.; Shimokura, M.; Narukami, T. J . Chem. Soc., Chem.
Commun. 1988, 287.

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8217
Ta ble 2. Syn th esis of P ep tid e En a m id es fr om C-Ter m in a l Tyr osin e a n d Tr yp top h a n Su bstr a tes
entry
substrate
base/additive
ratio (Z:E)
product
yield (%)a
1
2
3
4
Boc-L-Leu-L-Tyr(OBn)-OH
Boc-L-Leu-L-Trp(Nin-Boc)-OH
Boc-L-Leu-L-Trp(Nin-Ts)-OH
Boc-L-Leu-L-Trp(Nin-Ts)-OH
DIEA/LiClO4
DIEA/LiClO4
DIEA/LiClO4
DBU/---
0.9:1
7:1
12:1
8:1
14
15
16
16
80
33
64
55
a
Isolated yield, average of two runs.
Sch em e 1. Red u ctive Detosyla tion of In d ole
En a m id e 16Z
substrates (entries 2-4, Table 2) afforded high Z-enamide
selectivity (7-12:1 Z:E). Similar selectivity was found
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base
(entry 4, Table 2) indicating that the enamide stereo-
selectivity was not related to the use of lithium salt
additives. Treatment of 16Z with excess Mg in methanol23
(25 °C, 0.5 h) led to efficient formation of 17 (100% yield)
(Scheme 1) verifying the chemical and configurational
stabilities of the enamide product to reductive detosyla-
tion conditions that are required for syntheses of linear
peptide enamide natural products such as 5-7.
To further define the scope of the method, a number
of other peptide and non-peptide substrates were evalu-
ated (Table 3). In addition to C-terminal tyrosine- and
tryptophan-containing peptides, and C-terminal phenyl-
alanine-containing peptides, both dipeptide (entry 1) and
tripeptide substrates (entry 2), undergo oxidative decar-
boxylation-elimination to form the corresponding enam-
ides 18 and 19 (approximately 1:1 E:Z mixtures) in good
yield. Entry 4 demonstrates efficient syntheses of the
unsaturated Z-enamide natural product lansiumamide
A (21Z) and its E-enamide stereoisomer (21E), which are
fully separable by silica gel chromatography.24 Enamides
derived from C-terminal leucine (entry 5) were found to
require both a stronger base and a higher reaction
temperature (45 °C) to produce enamides 22 and were
shown to favor the Z isomer (2.2:1 Z:E) under these
conditions. To check for epimerization of the stereogenic
center using this procedure, we prepared the enantiomers
of both 22Z and 22E from Boc-D-phenylalanine. Chiral
HPLC analysis indicated that all enamides are greater
than 99% optically pure.25 Finally, we prepared model
compounds (entries 6 and 7) to illustrate potential
F igu r e 3. Spectra of an O-acetyl-N-acyl-N,O-acetal (Spectrum
I) and an N-acyl imine intermediate (Spectrum II).
application of this method to prepare the enamide side
chains of the salicylate antitumor macrolides. It is also
noteworthy that the Z-O-methyloxime enamide of prod-
ucts 24Z/24E were found to be configurationally stable
under the reaction conditions. In the latter two cases,
copper(II) acetate (30 mol %) was a required additive for
oxidative decarboxylation reactions for optimal yield and
reproducibility.26
To determine the mechanism for elimination of O-
acetyl-N-acyl-N,O-acetals and clarify the Z-enamide se-
lectivity observed for C-terminal tryptophan substrates,
1
we conducted mechanistic studies using H NMR spec-
troscopy. Our initial mechanistic hypothesis was that
treatment of O-acetyl-N-acyl-N,O-acetal substrates with
LiClO4 would lead to the generation of N-acyliminium
ion intermediates. However, addition of LiClO4 (1 equiv)
to representative N,O-acetals in [D8]THF showed little
change in the 1H NMR and no evidence for characteristic
absorptions for these reactive intermediates.27 However,
treatment of substrate 25 (Spectrum I, Figure 3) with
(22) For preparation of Nin-Boc tryptophan derivatives, see: Moody,
C. J .; Doyle, K. J .; Elliott, M. C.; Mowlem, T. J . J . Chem. Soc., Perkin
Trans. 1 1997, 16, 2413.
(23) For example, see: Hikawa, H.; Yokoyama, Y.; Murakami, Y.
Synthesis 2000, 2, 214.
(24) (a) Lin, J . Phytochemistry 1989, 28, 621. (b) For recent synthetic
studies, see: Stefanuti, I.; Smith, S. A.; Taylor, R. J . K. Tetrahedron
Lett. 2000, 41, 3735.
(25) HPLC analyses of 22Z, 22E, ent-22Z, and ent-22E: CHIRACEL
OD, 95/5 hexane/2-propanol, tR ) 16.1, 12.8, 8.8, and 8.8 min,
respectively.
(26) Kochi, J . K.; Bacha, J . D. J . Org. Chem. 1968, 33, 2746.

8218 J . Org. Chem., Vol. 66, No. 24, 2001
Ta ble 3. Ap p lica tion to Oth er P ep tid e a n d Non p ep tid e En a m id es
Notes
a
b
Isolated yield, average of two runs. Reaction temperature ) 45 °C. c Reaction temperature ) 60 °C.
F igu r e 4. Possible involvement of spiroindolenine intermediates for trytophan substrates.
DIEA (2.0 equiv) in the presence of lithium perchlorate
(1.2 equiv) in [D3]acetonitrile led to a loss of signals for
the NH (H1 ) δ 6.96) and N,O-acetal methine (H2 ) δ
6.37) protons and the appearance of a characteristic
proton (H3 ) δ 7.66, J ) 5.2 Hz) for N-acylimine 26
(Spectrum II, Figure 3).28 Further isomerization to ena-
mide products does not occur in this instance due to the
aliphatic substitution where we have found DBU to be
required (cf. entries 5-7, Table 3). For indole-containing
substrates (cf. entries 3-5, Table 2), the high Z-selectivi-
ties are clearly distinct from other C-terminal peptides.
One possible explanation for this distinction would be
the transformation of an N-acylimine 27 to a spirocyclo-
propylindolenine intermediate 28 (Figure 4) that subse-
quently opens to the Z-enamide by preferential elimina-
tion of the indicated hydrogen (Chem3D model, Figure
4). Spiroindolenines have been proposed as intermediates
in electrophilic substitution of indoles,29 including both
three-30 and four-membered31 intermediates. Support for
this mechanistic hypothesis awaits further experimenta-
tion involving evaluation of indole modifications or trap-
ping of the spiro-intermediate.32
Finally, we applied the oxidative decarboxylation-
elimination methodology to short syntheses of the indole-
enamide natural products chondriamides A and C.33 Both
(29) (a) J ackson, A. H.; Smith, P. J . Chem. Soc., Chem. Commun.
1967, 264. (b) J ackson, A. H.; Naidoo, B.; Smith, P. Tetrahedron 1968,
24, 6119. (c) J ackson, A. H.; Naidoo, B. J . Chem. Soc., Perkin Trans.
2 1973, 548. (d) J ackson, A. H.; Lynch, P. P. J . Chem. Soc., Perkin
Trans. 2 1987, 1215.
(30) Decodts, G.; Wakselman, M. Bull. Soc. Chim. Fr. 1972, 4586.
(31) Ganesan, A.; Heathcock, C. H. Tetrahedron Lett. 1993, 34, 439.
(32) For examples, see: (a) Nakagawa, M.; Liu, J .; Ogata, K.; Hino,
T. J . Chem. Soc., Chem. Commun. 1988, 463. (b) Biswas, K. M.;
J ackson, A. H.; Kobaisy, M. M.; Shannon, P. V. R. J . Chem. Soc., Perkin
Trans. 1 1992, 461.
(27) There have been a few literature reports where 1H and 13C NMR
spectroscopy have been employed to detect N-acyliminium ion inter-
mediates, see: (a) Yamamoto, Y.; Nakada, T.; Nemoto, H. J . Am. Chem.
Soc. 1992, 114, 121. (b) Heaney, H.; Taha, M. O. Tetrahedron Lett.
1998, 39, 3341.
(28) (a) J endrzejewski, S.; Steglich, W. Chem. Ber. 1981, 114, 1337.
(b) Steglich, W.; J ager, M.; J aroch, S.; Zistler, P. Pure Appl. Chem.
1994, 66, 2167. (c) Bretschneider, T.; Miltz, W.; Munster, P.; Steglich,
W. Tetrahedron 1988, 44, 5403.
(33) For efforts to produce Z-indole enamides, see: Brettle, R. A.;
Mosedale, J . J . Chem. Soc., Perkin Trans. 1 1988, 2185.

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8219
Sch em e 2. Syn th esis of Ch on d r ia m id es A a n d C
compounds were isolated from the red alga Chondria sp.
and are E- and Z-enamide stereoisomers, respectively.
Their highly unsaturated structures include two 3-sub-
stituted indoles that are unstable to acidic, oxidative, and
reductive conditions, thus requiring mild reaction condi-
tions for both enamide formation and final deprotection.
To prepare a substrate for oxidative decarboxylation-
elimination, tryptophan methyl ester hydrochloride was
acylated with trans-3-indoleacrylic acid (EDC/HOBT,
DIEA, DMF) to afford 3-indole-acryltryptophan methyl
ester 29 (Scheme 2). Interestingly, the ethyl ester of 29
was isolated as a minor compound during the isolation
of chondriamide A, indicating that the free acid, 3-in-
doleacryltryptophan, may be a biosynthetic precursor.10
Bis-tosylation of the indole nitrogens of 29 (NaOH/TsCl/
CH2Cl2)34 was followed by ester hydrolysis (LiOH) to
produce enamide precursor 30 (70% overall yield). Oxida-
tive decarboxylation of 30 followed by elimination fur-
nished bis-Nin-Ts-protected chondriamide C 31 with high
Z-enamide stereoselectivity (14:1 Z:E) and good yield
(63% for two steps). Unfortunately, attempted deprotec-
tion of 31 using the aforementioned reductive detosyla-
tion conditions (Mg, MeOH, 25 °C) was not suitable for
this substrate and led to overreduction of the 3-indole-
acrylamide functionality. We therefore focused on the use
of nucleophilic protocols for detosylation. After consider-
able experimentation and screening of reaction condi-
tions, we found that use of NaOMe35 and LiClO4 as
additive selectively removed the tosyl group associated
with the 3-indoleacrylamide moiety to furnish monotosyl
enamide 32 (92%). Further treatment of 32 with NaOMe
(MeOH/THF) (0.01 M) provided the natural product
chondriamide C (6) in 42% yield (70% based on recovered
starting material) whose spectral data matched those
reported for the natural product.11 Enamide isomeriza-
tion was effected by treatment of 6 with LiClO4 (20 mol
%, THF, 24 h) to produce chondriamide A (5) in 43% yield
(75% yield based on recovered starting material). At-
tempted isomerization of other Z-enamide substrates
containing either conjugated acrylamide (21Z) or tryp-
tophan-containing substrates (17) was unsuccessful in-
dicating the requirement of both functionalities for
isomerization using LiClO4.
Con clu sion
We have described protocols for the synthesis of peptide
enamides based on tandem oxidative decarboxylation-
elimination of C-terminal peptides. Substrates containing
C-terminal tryptophans have been found to form Z-
enamides with high selectivity, which has been exploited
in expeditious syntheses of the cytotoxic indole-enamide
natural products chondriamides A and C. In preliminary
studies, synthetic peptide enamides have also shown
useful levels of cytotoxicity in tumor cell lines. For
example, in an ATP-based cell viability assay, compounds
14E and 17 showed cytotoxicity in a human acute T-cell
leukemia (J urkat) cell line (IC50 ca. 7 and 20 µM,
respectively). Other related compounds (e.g., 18E) did not
show cytotoxicity indicating significant levels of specific-
ity. Further biological evaluation of peptide enamides,
mechanistic studies, and applications of this methodology
to the synthesis of additional natural product targets are
in progress and will be reported in due course.
(34) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
(35) (a) Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993, 49,
8139. (b) Lin, C.; Ennis, M. D.; Hoffman, R. L.; Phillips, G.; Haadsma-
Svensson, S. R.; Ghazal, N. B.; Chidester, C. G. J . Heterocycl. Chem.
1994, 31, 129.

8220 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
concentrated in vacuo to provide 17 (75 mg, 100% yield) as a
yellow solid. Mp: 68-72 °C. [R]D ) +38° (c ) 0.62, CHCl3). IR
Exp er im en ta l Section
22
1
(neat) ν˜max: 1695, 1655, 1539, 1499, 1163 cm-1. 1H NMR δ: 8.43
(s, 1H), 8.35 (d, J ) 8.4 Hz, 1H), 7.56 (d, J ) 7.6 Hz, 1H), 7.35
(d, J ) 8.0 Hz, 2H), 7.20 (t, J ) 8.0 Hz, 1H), 7.12 (t, J ) 7.6 Hz,
1H), 6.87 (t, J ) 9.6 Hz, 1H), 5.95 (d, J ) 9.2 Hz, 1H), 4.89 (bs,
1H), 4.20 (bs, 1H), 1.67 (m, 2H), 1.49 (m, 1H), 1.31 (s, 9H), 0.89
(d, J ) 6.4 Hz, 3H), 0.87 (d, J ) 6.4 Hz, 3H). 13C NMR δ: 171.2,
157.0, 137.0, 127.7, 123.8, 123.2, 121.2, 121.0, 120.1, 112.3, 112.2,
81.5, 54.2, 41.6, 30.8, 29.3, 25.8, 24.0, 22.9. HR-MS (EI): calcd
for C21H29N3O3 [M+], 371.2209; found, 371.2235.
Gen er a l Meth od s. H NMR spectra were recorded on a 400
MHz spectrometer at ambient temperature with CDCl3 as the
solvent unless otherwise stated. 13C NMR spectra were recorded
on a 75.0 MHz spectrometer at ambient temperature. Chemical
shifts are reported in parts per million relative to chloroform
(1H, δ 7.24; 13C, δ 77.0). Data for 1H NMR are reported as
follows: chemical shift, integration, multiplicity (s ) singlet, d
) doublet, t ) triplet, q ) quartet, m ) multiplet, b ) broad),
and coupling constants. All 13C NMR spectra were recorded with
complete proton decoupling. Infrared spectra were recorded on
a Nicolet Nexus 670 FT-IR instrument. Chiral HPLC analysis
was performed on an Agilent 1100 series HPLC (CHIRALCEL
OD, Column No. OD00CE-AI015). Optical rotations were re-
corded on an AUTOPOL III digital polarimeter at 589 nm and
are reported as [R]D22 (concentration in grams/100 mL of solvent).
High-resolution mass spectra were obtained in the Boston
University Mass Spectrometry Laboratory using a Finnegan
MAT-90 spectrometer. Methylene chloride (CH2Cl2) and toluene
were distilled from calcium hydride. Tetrahydrofuran was
distilled from sodium and benzophenone. Analytical thin-layer
chromatography was performed on 0.25 mm silica gel 60-F
plates. Flash chromatography was performed using 200-400
mesh silica gel (Natland International Corporation). All other
reagents were used as supplied by Sigma-Aldrich, Fluka, Lan-
caster, and Strem Chemicals unless otherwise noted.
Gen er a l P r oced u r e for Oxid a tive Deca r boxyla tion of
Alip h a tic N-Acyl Am in o Acid s: En a m id e (24). To a flask
containing N-((2Z)-4-(methoxyimino)-2-butenamido)-leucine36 (223
mg, 0.92 mmol), Cu(OAc)2 (50 mg, 0.28 mmol), and pyridine (149
µL, 1.84 mmol) in distilled THF (4.0 mL) at 0 °C under N2 was
added Pb(OAc)4 (449 mg, 1.012 mmol). The resulting solution
was allowed to warm to room temperature and stirred for 2 h
and then diluted with 3% Et3N/EtOAc (10 mL). The mixture was
eluted through a cartridge containing silica gel (6 mL), washed
with 3% Et3N/EtOAc (20 mL), and concentrated in vacuo. The
crude acetate was used directly without further purification in
the next step. The crude product was dissolved in distilled THF
(10.0 mL) and then treated with DBU (203.6 µL, 1.38 mmol).
The mixture was heated to 45 °C for 2.5 h and cooled to room
temperature. The reaction was quenched with saturated NaH-
CO3, and the solution was extracted with EtOAc. The organic
extracts were combined, dried over Na2SO4, filtered, and con-
centrated in vacuo. Purification on silica gel (20% EtOAc, 3%
Et3N/hexanes) provided of 24Z (70 mg, 39% yield) as a white
solid and 24E (34 mg 19% yield) as a white solid. 24Z. Mp: 109-
111 °C. IR (neat) ν˜max: 1645, 1618, 1518, 1045 cm-1. 1H NMR δ:
8.99 (d, J ) 10.4 Hz, 1H), 7.39 (bd, J ) 10.4 Hz, 1H), 6.60 (t, J
) 10.8 Hz, 1H), 6.48 (dd, J ) 11.6, 10.0 Hz, 1H), 5.97 (d, J )
11.6 Hz, 1H), 4.66 (t, J ) 9.6 Hz, 1H), 2.44 (m, 1H), 0.97 (d, J )
7.2 Hz, 6H). 13C NMR δ: 163.0, 148.7, 136.3, 125.6, 121.6, 119.4,
Rep r esen ta tive P r oced u r e for Oxid a tive Deca r boxyla -
tion -Elim in a tion of Ar om a tic N-Acyl Am in o Acid s: P ep -
tid e En a m id e (18). To a flask containing Boc-L-Leu-L-Phe-OH
(227 mg, 0.60 mmol), Cu(OAc)2 (32.7 mg, 0.18 mmol), and
pyridine (97.2 µL, 1.20 mmol) in distilled THF (2.4 mL) at 0 °C
under N2 was added Pb(OAc)4 (292.6 mg, 0.66 mmol). The
resulting solution was allowed to warm to room temperature
and stirred for 2 h. The reaction was then quenched by saturated
NaHCO3, and the solution was extracted with EtOAc. The
organic extracts were dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude N,O-acetal was used directly without
further purification in the next step. The crude product was
dissolved in distilled THF (2.4 mL) and treated with LiClO4 (76.5
mg, 0.72 mmol). The reaction mixture was cooled to 0 °C, treated
with DIEA (208.8 µL, 1.20 mmol), and stirred for 10 min before
it was warmed to room temperature. After the starting material
was no longer detected by TLC, the reaction was quenched with
saturated NaHCO3 and the solution was extracted with EtOAc.
The organic extracts were combined, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification on silica gel (20% EtOAc,
3% Et3N/hexanes) provided 65 mg (33%) of 18Z as a white solid
and 99 mg (50%) of 18E as a white solid. 18Z. Mp: 77-80 °C.
[R]D22 ) -7.1° (c ) 0.59, CHCl3). IR (neat) ν˜max: 1674, 1652, 1507,
63.4, 26.9, 23.9. HR-MS (EI): calcd for
C
10H16N2O2 [M+],
196.1212; found, 196.1221. 24E. Mp: 121-123 °C. IR (neat)
ν˜max: 1637, 1618, 1533, 1044 cm-1. 1H NMR δ: 9.00 (d, J ) 10.0
Hz, 1H), 7.29 (bd, J ) 9.6 Hz, 1H), 6.74 (dd, J ) 14.4, 10.4 Hz,
1H), 6.46 (dd, J ) 11.6, 10.8 Hz, 1H), 5.86 (d, J ) 11.6 Hz, 1H),
5.19 (dd, J ) 14.0, 6.8 Hz, 1H), 2.32 (m, 1H), 0.98 (d, J ) 6.4
Hz, 6H). 13C NMR δ: 161.8, 147.7, 135.0, 124.6, 122.1, 120.1,
62.3, 29.0, 22.7. HR-MS (EI): calcd for
196.1212; found, 196.1217.
C
10H16N2O2 [M+],
3-In d ole-a cr yltr yp top h a n Meth yl Ester (29). To a mixture
of trans-3-indole-acrylic acid (225 mg, 1.20 mmol), tryptophan
methyl ester hydrochloride (255 mg, 1.0 mmol), HOBt (149 mg,
1.1 mmol), EDC (211 mg, 1.1 mmol), and DMF (3 mL) at 0 °C
under N2 was added DIEA (627 µL, 3.6 mmol). The resulting
solution was allowed to warm to room temperature and stirred
for 20 h. The reaction mixture was diluted with EtOAc, washed
with 1 N NaHCO3, brine, dried, filtered, and concentrated to
provide 29 (373 mg, 96% yield) as a yellow solid. Mp: 70-73
1485, 1165 cm-1 1H NMR δ: 8.49 (d, J ) 9.6 Hz, 1H), 7.36 (t,
.
J ) 7.2 Hz, 2H), 7.21-7.28 (m, 4H), 6.91 (dd, J ) 11.2, 9.2 Hz,
1H), 5.76 (d, J ) 9.2 Hz, 1H), 4.73 (bs, 1H), 4.12 (m, 1H), 1.64-
1.78 (m, 2H), 1.43-1.50 (m, 1H), 1.40 (s, 9H), 0.92 (t, J ) 6.8
Hz, 6H). 13C NMR δ: 170.2, 155.8, 135.5, 129.0, 127.8, 126.9,
121.5, 110.7, 80.6, 53.2, 40.3, 28.2, 24.8, 22.9, 21.8. HR-MS
(EI): calcd for C19H28N2O3 [M+], 332.2100; found, 332.2094. Anal.
Calcd for C19H28N2O3: C, 68.65; H, 8.49; N, 8.43. Found: C,
1
°C. IR (neat) ν˜max: 3405, 1736, 1653, 1604, 1436, 1213 cm-1. H
NMR δ: 9.04 (s, 1H), 8.43 (s, 1H), 7.79 (d, J ) 16.0 Hz, 1H),
7.71 (d, J ) 7.6 Hz, 1H), 7.54 (d, J ) 8.0 Hz, 1H), 7.29 (t, J )
9.2 Hz, 2H), 7.05-7.18 (m, 5H), 6.95 (s, 1H), 6.26-6.30 (m, 2H),
5.11 (dd, J ) 9.2, 5.2 Hz, 1H), 3.64 (s, 3H), 3.37 (m, 2H). 13C
NMR δ: 173.9, 168.4, 138.3, 137.3, 136.6, 130.0, 128.7, 126.4,
124.2, 124.0, 123.2, 122.1, 121.2, 120.7, 119.6, 115.9, 114.1, 113.0,
112.5, 110.9, 61.5, 53.4, 28.9. HRMS (EI): calcd for C23H21N3O3
[M+], 387.1583; found, 387.1619.
22
68.87; H, 8.80; N, 8.29. 18E. Mp: 118-122 °C. [R]D ) -51° (c
) 0.56, CHCl3). IR (neat) ν˜max: 1669, 1650, 1532, 1167 cm-1. 1H
NMR δ: 8.75 (d, J ) 8.8 Hz, 1H), 7.40 (t, J ) 12.4 Hz, 1H),
7.12-7.21 (m, 5H), 6.08 (d, J ) 14.8 Hz, 1H), 5.13 (d, J ) 6.0
Hz, 1H), 4.24 (bs, 1H), 1.69 (m, 2H), 1.55 (m, 1H), 1.44 (s, 9H),
0.94 (d, J ) 6.4 Hz, 3H), 0.92 (d, J ) 6.4 Hz, 3H). 13C NMR δ:
170.4, 156.2, 136.1, 128.6, 126.6, 125.6, 122.6, 80.6, 53.2, 40.9,
28.4, 24.8, 23.0, 21.9. HR-MS (EI): calcd for C19H28N2O3 [M+],
332.2100; found, 332.2089. Anal. Calcd for C19H28N2O3: C, 68.65;
H, 8.49; N, 8.43. Found: C, 68.54; H, 8.70; N, 8.21.
In d ole En a m id e (17). A mixture of Mg turnings (184 mg,
7.6 mmol) and distilled MeOH (1 mL) was stirred at room
temperature for 5 min under argon. After this time, the mixture
was cooled to 0 °C and a solution of 16Z (105 mg, 0.2 mmol) in
MeOH (0.5 mL) was added. The resulting mixture was warmed
to room temperature and vigorously stirred for 30 min. The
reaction was quenched by saturated NH4Cl, and the solution
was extracted with CH2Cl2. The organic layer was washed with
saturated NaHCO3 and brine, dried over Na2SO4, filtered, and
(36) Prepared from (2Z)-4-methoxyimino-2-butenoic acid (ref 7)
using the following procedure: (1) L-leucine methyl ester hydrochloride,
EDC, HOBt, and DMF and (2) LiOH, aqueous THF, (85%, two steps).

Notes
Bis-su lfon a m id e (33). A mixture of 29 (218 mg, 0.56 mmol),
NaOH (56.0 mg, 1.40 mmol), and distilled CH2Cl2 (3.0 mL) was
stirred for 15 min, and then toluenesulfonyl chloride (191 mg,
1.68 mmol) was added. The reaction mixture was heated to 35
°C and stirred for 30 min and then diluted with EtOAc. The
organic layer was washed exhaustively with water, dried with
Na2SO4, filtered, and concentrated in vacuo. Purification on silica
gel (45% EtOAc/hexanes) provided bis-sulfonamide 30 (317 mg,
J . Org. Chem., Vol. 66, No. 24, 2001 8221
in vacuo. Purification on silica gel (35% acetone/hexanes)
provided 32 (223 mg, 92% yield) as a yellow powder. Mp: 183-
185 °C. IR (neat) ν˜max: 3280, 1696, 1644, 1605, 1491, 1249, 1174
cm-1 1H NMR (400 MHz, [D6]acetone) δ: 10.83 (bs, 1H), 9.14
.
(d, J ) 11.2 Hz, 1H), 7.93-8.04 (m, 6H), 7.91(s, 1H), 7.80 (d, J
) 2.8 Hz, 1H), 7.64 (d, J ) 8.0 Hz, 1H), 7.52 (d, J ) 11.6 Hz,
1H), 7.18-7.41 (m, 7H), 7.94 (d, J ) 15.6 Hz, 1H), 5.76 (d, J )
9.6 Hz, 1H). 13C NMR (75 MHz, [D6]acetone) δ: 166.5, 147.4,
139.7, 138.1, 136.9, 136,5, 132.6, 132.4, 131.9, 128.8, 127.2, 126.8,
126.4, 125.3, 124.5, 122.6, 122.1, 121.7, 119.6, 116.6, 115.3, 115.1,
114.1, 99.0, 22.4. HR-MS (EI): calcd for C28H23N3O3S [M+],
481.1460; found, 481.1466.
81% yield) as a yellow solid. Mp: 114-117 °C. IR (neat) ν˜max
:
1742, 1624, 1447, 1368, 1174, 1126 cm-1. H NMR δ: 7.98 (d, J
) 8.4 Hz, 2H), 7.93 (d, J ) 8.0 Hz, 2H), 7.67-7.78 (m, 5H), 7.45
(d, J ) 8.0 Hz, 2H), 7.37 (s, 1H), 7.10-7.36 (m, 7H), 7.44 (d, J
) 15.6 Hz, 1H), 6.29 (s, 1H), 5.08 (d, J ) 5.6 Hz, 1H), 3.68 (s,
3H), 3.29 (m, 2H), 2.30 (s, 3H), 2.19 (s, 3H). 13C NMR δ: 173.0,
166.7, 146.5, 145.9, 136.6, 136.3, 136.2, 135.9, 133.8, 131.9, 131.1,
130.9, 129.3, 128.9, 128.0, 127.8, 126.4, 126.0, 125.6, 125.0, 124.3,
121.6, 121.2, 120.5, 119.4, 118.2, 114.9, 114.8, 61.4, 53.6, 28.7,
22.6, 22.4. HR-MS (EI): calcd for C37H33N3O7S2 [M+], 695.1760;
found, 695.1825.
1
Ch on d r ia m id e C (6). To a solution of 32 (60 mg, 0.125 mmol)
in freshly distilled THF (10 mL) at 0 °C under argon was added
NaOMe (1 M solution in MeOH, 1.12 mmol) dropwise. The
resulting solution was allowed to warm to room temperature
and stirred for 2 h. The reaction was quenched with 1 N NaHCO3
solution, and the solution was extracted with EtOAc. The organic
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification on silica gel (35%
acetone/hexanes) afforded recovered starting material (23.4 mg,
39%) and the desired product chondriamide C (6) (17.4 mg, 42%
yield; 75% yield based on recovered starting material) as a yellow
solid. Mp: 223-225 °C. IR (neat) ν˜max: 3396, 3262, 1704, 1644,
1606, 1484, 1272 cm-1. 1H NMR (400 MHz, [D6]acetone) δ: 10.76
(bs, 1H), 10.42 (bs, 1H), 8.75 (d, J ) 10.8 Hz, 1H), 7.97 (d, J )
7.6 Hz, 1H), 7.92 (d, J ) 15.6 Hz, 1H), 7.77 (d, J ) 2.4 Hz, 1H),
7.63-7.77 (m, 2H), 7.50 (d, J ) 8.0 Hz, 1H), 7.44 (d, J ) 8.0 Hz,
1H), 7.06-7.23 (m, 5H), 7.96 (d, J ) 15.2 Hz, 1H), 5.94 (d, J )
9.2 Hz, 1H). 13C NMR (75 MHz, [D6]acetone) δ: 166.2, 139.7,
138.1, 137.2, 132.2, 129.0, 127.2, 125.0, 124.4, 123.7, 122.4, 122.2,
121.1, 120.5, 117.3, 115.2, 113.9, 113.2, 112.8, 102.9. HR-MS
(EI): calcd for C21H17N3O [M+], 327.1372; found, 327.1361.
Ch on d r ia m id e A (5). To the solution of chondriamide C (44
mg, 0.134 mmol) in freshly distilled THF (3 mL) under argon
was added LiClO4 (2.9 mg, 0.027 mmol). The resulting solution
was stirred at room temperature for 20 h before it was diluted
with EtOAc, washed with brine, dried, and concentrated in
vacuo. Purification on silica gel (40% acetone/hexanes) afforded
recovered starting material (19 mg, 43%) and the desired product
chondriamide A (5) (19 mg, 43% yield; 75% yield based on
recovered starting material) as a yellow solid. Mp: 235-238 °C.
Ca r boxylic Acid (30). To a solution of 33 (317 mg, 0.456
mmol) in distilled THF (2 mL) and distilled water (1 mL) at room
temperature was added lithium hydroxide monohydrate (32.8
mg, 0.781 mmol). The resulting solution was stirred for 3 h at
25 °C. The pH of the aqueous layer was adjusted to 2 with 1 N
HCl solution. The mixture was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated in vacuo to afford acid 30
(282 mg, 90% yield) as a yellow solid. Mp: 125-128 °C. IR (neat)
ν˜max: 3379, 1734, 1654, 1447, 1372, 1125, 1077 cm-1 1H NMR
.
δ: 7.86 (t, J ) 9.2 Hz, 2H), 7.77 (s, 1H), 7.43 (d, J ) 8.0 Hz,
2H), 7.62 (d, J ) 8.4 Hz, 2H), 7.52-7.56 (m, 2H), 7.46 (d, J )
8.0 Hz, 1H), 7.07-7.20 (m, 7H), 6.94 (m, 1H), 6.89 (d, J ) 8.0
Hz, 2H), 6.52 (d, J ) 15.6 Hz, 1H), 5.10 (dd, J ) 12.4, 6.4 Hz,
1H), 3.30 (m, 2H), 2.20 (s, 3H), 1.85 (s, 3H). 13C NMR δ: 175.3,
168.2, 146.5, 145.8, 136.4, 136.1, 135.9, 135.8, 131.8, 131.1, 130.8,
129.2, 128.0, 127.7, 126.3, 125.9, 125.8, 125.0, 124.4, 121.4, 120.8,
120.6, 119.2, 118.5, 114.6, 53.8, 28.3, 22.5, 22.2. HR-MS (EI):
calcd for C36H31N3O7S2 [M+], 681.1603; found, 681.1594.
Bis-Ts Ch on d r ia m id e C (31). To a flask containing acid (30)
(68.2 mg, 0.10 mmol), Cu(OAc)2 (5.4 mg, 0.03 mmol), and
pyridine (16.2 µL, 0.20 mmol) in 0.4 mL of distilled THF at 0 °C
under N2 was added Pb(OAc)4 (48.8 mg, 0.11 mmol). The
resulting solution was warmed to room temperature and stirred
for 1 h. The reaction was quenched with saturated NaHCO3,
and the solution was extracted with EtOAc. The organic extracts
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude N,O-acetal was used directly without further purification
in the next step. The crude product was dissolved in distilled
THF (2.0 mL), treated with LiClO4 (32 mg, 0.72 mmol), and
cooled to 0 °C. To this solution was added DIEA (209 µL, 0.30
mmol). After being stirred for 10 min, the reaction mixture was
warmed to room temperature. After the starting material was
no longer detected by TLC (ca. 15 min), the reaction was
quenched with saturated NaHCO3 and the solution was ex-
tracted with EtOAc. The organic extracts were combined, dried
over Na2SO4, filtered, and concentrated in vacuo to give 31 (40
IR (neat) ν˜max: 3421, 3193, 1666, 1636, 1589, 1420, 1249 cm-1
.
1H NMR (400 MHz, [D6]acetone) δ: 10.75 (bs, 1H), 10.25 (bs,
1H), 9.29 (d, J ) 10.4 Hz, 1H), 7.97 (d, J ) 8.0 Hz, 1H), 7.90 (d,
J ) 16.0 Hz, 1H), 7.77-7.80 (m, 2H), 7.72 (dd, J ) 14.8, 10.4
Hz, 1H), 7.51 (d, J ) 7.6 Hz, 1H), 7.40-7.43 (m, 2H), 7.10-7.25
(m, 4H), 6.79 (d, J ) 15.2 Hz, 1H), 6.46 (d, J ) 15.2 Hz, 1H). 13
C
NMR (75 MHz, [D6]acetone) δ: 165.3, 139.7, 139.2, 136.5, 131.8,
127.4, 124.4, 123.5, 122.9, 122.4, 122.0, 121.2, 117.5, 115.1, 114.9,
114.0, 113.4, 106.8. HR-MS (EI): calcd for C21H17N3O [M+],
327.1372; found, 327.1413. Synthetic and natural chondriamide
A gave the same Rf value in the following three solvent
systems: Rf ) 0.31 (silica gel, 1/1 acetone/hexanes), Rf ) 0.76
(3/2 EtOAc/acetone), Rf ) 0.50 (3/1 EtOAc/CH2Cl2).
1
mg, 63% yield, 14:1 Z:E as determined by H NMR integration)
as a yellow powder. Mp: 248-249 °C. IR (neat) ν˜max: 1642, 1612,
Ack n ow led gm en t. We thank Profs. J ohn Snyder
(Boston University) and Scott J . Miller (Boston College)
for helpful discussions, Prof. Eduardo Manta (Univer-
sidad de la Republica, Uruguay) for samples and
spectral data for the chondriamides, and Prof. J unying
Yuan and Dr. Alexei Degterev (Harvard Medical School)
for conducting preliminary cytotoxicity assays.
1445, 1366, 1267, 1171, 1138, 1088 cm-1 1H NMR (400 MHz,
.
[D6]acetone) δ: 9.19 (d, J ) 10.4 Hz, 1H), 8.19 (s, 1H), 8.08 (d,
J ) 8.4 Hz, 2H), 7.98 (d, J ) 8.4 Hz, 2H), 7.85-7.96 (m, 7H),
7.63 (d, J ) 8.0 Hz, 1H), 7.36-7.46 (m, 8H), 7.30 (t, J ) 8.4 Hz,
1H), 7.23 (d, J ) 10.0 Hz, 1H), 7.08 (d, J ) 16.0 Hz, 1H), 5.82
(d, J ) 9.6 Hz, 1H), 2.36 (s, 3H), 2.33 (s, 3H). HR-MS (EI): calcd
for C35H29N3O5S2 [M+], 635.1549; found, 635.1504.
Nin -Ts Ch on d r ia m id e C (32). To a flask containing 31 (320
mg, 0.503 mmol), LiClO4 (134 mg, 1.258 mmol), and freshly
distilled THF (60 mL) at 0 °C under N2 was added NaOMe (1 M
in MeOH, 4.02 mL) dropwise. The resulting solution was
warmed to room temperature and stirred for 40 min. The
reaction was quenched with 1 N NaHCO3, and the solution was
extracted with EtOAc. The organic extracts were washed with
saturated brine, dried over Na2SO4, filtered, and concentrated
Su p p or tin g In for m a tion Ava ila ble: Characterization for
E and Z isomers of enamides 10, 14-16, and 19-23, and NMR
data comparison of natural and synthetic chondriamides A and
C. This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0158027