Total synthesis and configurational assignment of chondramide A

Article abstract of DOI:10.1002/chem.200903500

The first total synthesis of the cyclodepsipeptide chondramide A (2b) is described. This depsipeptide is composed of four subunits, namely Lalanine, N-Me-D-tryptophan, 3-amino-2-methoxy-propionic acid (β-tyrosine derivative), and a 7-hydroxy-alkenoic acid. While the configuration of the stereogenic centers in the 7-hydroxy-alkenoic acid were known, the configuration of the tyrosine derivative required clarification and turned out to be (2S,3R) or (2L,3L), respectively. The synthesis of the 3-amino-2-methoxy-3-arylpropanoic ester 20 b relied on an asymmetric dihydroxylation yielding diol ent-15a followed by a regioselective Mitsunobu substitution leading to 3-azido-2-hydroxypropanoate 18 b. We could also show that the ester bond in the seco compound 26b can be fashioned by a Mitsunobu esterification by using hydroxy ester (7S)-7 and the tripeptide acid 25 b. This synthesis should allow for the preparation of various analogues.

Full text of DOI:10.1002/chem.200903500

DOI: 10.1002/chem.200903500
Total Synthesis and Configurational Assignment of Chondramide A
Anke Schmauder,[a] L. David Sibley,[b] and Martin E. Maier*[a]
Abstract: The first total synthesis of
the cyclodepsipeptide chondramide A
(2b) is described. This depsipeptide is
composed of four subunits, namely l-
alanine, N-Me-d-tryptophan, 3-amino-
2-methoxy-propionic acid (b-tyrosine
derivative), and a 7-hydroxy-alkenoic
acid. While the configuration of the
stereogenic centers in the 7-hydroxy-al-
kenoic acid were known, the configura-
tion of the tyrosine derivative required
clarification and turned out to be
(2S,3R) or (2l,3l), respectively. The
synthesis of the 3-amino-2-methoxy-3-
arylpropanoic ester 20b relied on an
asymmetric dihydroxylation yielding
diol ent-15a followed by a regioselec-
tive Mitsunobu substitution leading to
3-azido-2-hydroxypropanoate 18b. We
could also show that the ester bond in
the seco compound 26b can be fash-
ioned by a Mitsunobu esterification by
using hydroxy ester (7S)-7 and the tri-
peptide acid 25b. This synthesis should
allow for the preparation of various an-
alogues.
Keywords: amino acids · asymmet-
ric synthesis · cyclodepsipeptides ·
natural products · peptides
Introduction
since cell division relies on actin turnover for cytokynesis
and rapidly dividing cells should, therefore, be more suscep-
tible to inhibition.
The actin system comprises a major part of the cytoskeleton
of eukaryotic cells.[1] In nonmuscle cells there is a roughly
equal proportion of polymeric F-actin and monomeric G-
actin (globular). The polymerization of globular actin re-
quires ATP. Among known natural products that disturb the
actin system is cytochalasin, which blocks the polymeri-
zation of G-actin by binding to the end of the growing F-
actin filaments.[2] On the other hand, the cyclic peptide phal-
loidin[3] prevents depolymerization of F-actin by binding be-
tween actin monomers.[4] Another key component of the cy-
toskeleton is the tubulin system. In this case, the monomer
tubulin forms a dynamic equilibrium with the polymer
called microtubules. Compounds like taxol or the epothi-
lones that disturb the tubulin system have gained clinical
relevance as anticancer drugs.[5] Although not yet realized,
small-molecule inhibitors of actin might have similar utility
In addition to phalloidin, the jaspamide/chondramide
family of cyclic depsipeptides[6] also stabilizes F-actin. Previ-
ous studies have shown that jasplakinolide binds competi-
tively with phalloidin, which indicates that it interacts with a
common binding site, despite being structurally dissimilar.[7]
Jaspamide (Jasplakinolide, jas) (1; atom numbering follows
the suggestions from the isolation papers) features a 19-
membered macrocyclic ring. It was isolated from the marine
sponge[8] Jaspis splendens. Related compounds were later
[a] Dipl.-Chem. A. Schmauder, Prof. Dr. M. E. Maier
Institut fꢀr Organische Chemie, Universitꢁt Tꢀbingen
Auf der Morgenstelle 18, 72076 Tꢀbingen (Germany)
Fax : (+49)7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
[b] Prof. L. D. Sibley
Department of Molecular Microbiology
Washington University School of Medicine
660 S. Euclid Ave., St. Louis, MO 63110-1093 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903500.
4328
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FULL PAPER
found in several other sponges.[9] While showing promising
activity against cancer cell lines,[10] this activity is accompa-
nied by significant toxicity. The major difference between
the chondramides, which were isolated from the myxobacte-
rium Chondromyces crocatus,[11] and jaspamide is a different
polyketide moiety, resulting in an 18-membered ring in the
chondramides. Quite recently the configurational assign-
ment for chrondramide C (chon C) was achieved by inde-
pendent total synthesis by the Waldmann[12] and Kalesse[13]
groups. Not surprisingly, the configurations of the three
amino acids l-alanine, d-N-methyltryptophan, and l-b-tyro-
sine turned out to be the same as in jaspamide. However,
the proposal[14] for the configuration of the w-hydroxy acid
required revision. We became interested in the synthesis of
chondramide A (chon A), which is a closely related com-
pound. Whereas the l-configuration for the amine-bearing
stereocenters in the a-methoxy-b-tyrosine could be assumed,
the configuration at the a-carbon atom (C2’) remained to be
solved. In this paper we describe the syntheses of diastereo-
mers of the methoxy-b-tyrosine subunit and their incorpora-
tion into the chrondramide scaffold leading to the total syn-
thesis and configurational assignment of chon A.
Scheme 2. Summary of the synthesis of hydroxy ester 7. DEAD=diethyl-
AHCTUNGTERGaNNUN zodicarboxylate; TBDPS=tert-butyldiphenylsilyl; TBS=tert-butyldime-
thylsilyl.
ple, asymmetric nitroaldol reactions,[19] the Staudinger reac-
tion leading to b-lactam intermediates,[20] the Sharpless
asymmetric aminohydroxylation,[21] or asymmetric aldol re-
actions of glycolates to imines are known to produce these
types of structures.[22] And finally, chemoselective substitu-
tion reactions on 2,3-dihydroxy-3-arylpropanoates would
provide the syn diastereomer of 8.[23] We opted for the latter
due to its operational simplicity (Scheme 3). Thus, by start-
Results and Discussion
It was planned to close the macrocyclic ring by intramolecu-
lar amide formation (Scheme 1). The corresponding acyclic
ester would originate from the known dipeptide acid 6, a b-
tyrosine isomer 8, and the hydroxy ester 7. The dipeptide
acid 6 is available in six steps from N-Boc-d-tryptophan.[15]
For the more challenging hydroxy ester 7, we recently re-
ported a concise route that relies on a Kobayashi vinylogous
aldol reaction with acetaldehyde, a Mitsunobu inversion at
C7, and an asymmetric alkylation to incorporate the last
propionate unit (Scheme 2).[16] Overall this 12-step sequence
allows for the preparation of ester 7 in gram amounts.
ing from 4-(triisopropylsilyloxy)benzaldehyde[24] (13)
a
Wittig reaction with (methoxycarbonylmethylene)triphenyl-
phosphorane[25] provided cinnamate (E)-14 in good yield. A
subsequent asymmetric dihydroxylation[26] in the presence of
the ligand (DHQ)2PHAL (AD-mix-a) and potassium osma-
te(VI) dihydrate, furnished an excellent yield of diol 15a.
The syn isomer (2d,3l) of 3-amino-2-methoxyester 8 is
similar to the taxol side chain.[17] Accordingly, strategies that
came to use in the synthesis of this side chain, a 3-phenyliso-
serine, or related compounds were considered.[18] For exam-
Scheme 3. Synthesis of the (2d,3l)-diastereomer 20a via the anti-acetoxy
bromo ester 16a. TIPS=triisopropylsilyl. a) Ph3PCHCO2Me, CH2Cl2, RT,
3 d, 88%; b) (DHQ)2PHAL=hydroquinine 1,4-phthalazinediyl diether,
K2ACHTUNGTRENNUG
3 h, 92%; c) 1) MeCAHCTUNGTRENNUNG
CH2Cl2, RT, 90 min; 2) AcBr, CH2Cl2, RT, 90 min, 67%; d) NaN3,
DMSO, RT, 4 h, 70%; e) NaOMe, MeOH, 08C, 30 min, 84%;
f) Me3OBF4, proton sponge, CH2Cl2, RT, 24 h, 82%; g) Pd/C, H2, MeOH,
20 h, 99%.
Scheme 1. Key fragments for the synthesis of chondramide A diastereo-
mers. Boc=tert-butoxycarbonyl.
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M. E. Maier et al.
As has been described by Sharpless et al.[23] the benzylic al-
cohol can be substituted by bromide through the reaction of
the diol with trimethyl orthoacetate, and treatment of the
intermediate mixed orthoester with acetyl bromide. This
way, a 67% yield of acetoxy bromo ester 16a could be se-
cured after chromatographic separation of the wrong regio-
isomer. Substitution of the bromide on 16a with sodium
azide in DMSO at room temperature resulted in azide 17a
(70% yield). After saponification of the acetate, the 2-hy-
droxy group of 18a was methylated by using Meerweinꢃs
salt (Me3OBF4)[27] and proton sponge in dichloromethane.
At this stage, proof of the regiochemistry of the bromination
and, therefore, also the azide introduction came from a
HMBC spectrum of 18a. Thus, 3’-H (d=4.75 ppm (d, J=
3.3 Hz), chon A numbering) showed cross-peaks to C-4’ and
C-5’. A final hydrogenation of azide 19a in the presence of
Pd/C in methanol led to the desired syn-configured amino
ester 20a. The enantiomeric excess (ee) value of 15a and
the propanoate derivatives derived from it could be estimat-
ed at the stage of the tripeptide ester 24a to be 62% by in-
tegration of the corresponding 2’-H protons. This ee value
could be confirmed by chiral HPLC (Eurocel 03).
An alternative route to the
Scheme 4. Synthesis of the (2d,3l)-3-amino-2-methoxy acid 20a by an
aminohydroxylation reaction. Cbz=carbobenzyloxy. a) BnOC(O)NH2,
NaOH, (DHQ)2PHAL, 21, K2ACTHNUTRGEN[UGN OsO2(OH)4], nPrOH/H2O, 0 8C to RT,
22 h, 56%; b) Ag2O, MeI, acetone, RT, 80%; c) Pd/C, H2, MeOH, 24 h,
98%.
lective trimethylstannol, which produced tripeptide acid 25a
within 5 h at 808C.[32] The crude carboxylic acid could then
be esterified with hydroxyester 7 under Yamaguchi condi-
tions.[33] This way the chon A precursor 26a could be se-
cured in 64% yield. At this stage it was possible to remove
the diastereomer resulting from the minor enantiomer of
20a by chromatography. The macrocyclization required
(2d,3l)-b-tyrosine 20a was
based on an aminohydroxyla-
tion reaction[28,29,30] of cinna-
mate (E)-14 by using benzylcar-
bamate, 1,3-dichloro-5,5-dime-
thylhydantoin,[31]
and
(DHQ)2PHAL in a propanol/
water mixture (Scheme 4). This
produced the Cbz-protected 2-
hydroxy-3-amino acid ester 22.
Reductive cleavage of the Cbz-
protecting group (H2, Pd/C,
MeOH) gave b-tyrosine 20a as
well. In this case, the etherifica-
tion was performed with MeI
and Ag2O in acetone. The ee
value of 20a was estimated to
be 90% by chiral HPLC (Euro-
cel 01).
Construction of the corre-
sponding
cyclodepsipeptide
started with dipeptide acid 6
(Scheme 5). This acid was con-
densed with b-tyrosine deriva-
tive 20a by using TBTU in the
presence of additional HOBt
yielding tripeptide ester 24a.
The subsequent saponification
of the ester group turned out to
be crucial since cleavage of the
TIPS ether or epimerization
alpha to the carboxyl group had
to be avoided. We therefore
Scheme 5. Synthesis of diastereomer 2a, which does not correspond to chondramide A, from the three building
blocks 6, 20a, and 7. a) diisoproylethylamine (DIEA), hydroxybenzotriazole (HOBt), 2-(1H-benzotriazole-1-
yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), DMF, 08C, 2 h, 68%; b) Me3SnOH, 1,2-dichloro-
ethane (1,2-DCE); c) Cl3C6H2COCl, Et3N, 4-dimethylaminopyridine (DMAP), 7, toluene, 08C to RT, 2 h, 64%
(2 steps); d) 1) trifluoroacetic acid (TFA), CH2Cl2, 08C, 22 h; 2) HOBt, TBTU, DIEA, DMF, RT, 20 h; 3) tet-
turned to the highly chemose- rabutylammonium fluoride (TBAF), THF, 08C, 1 h, 29% (3 steps).
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Chondramide A
FULL PAPER
cleavage of the N-Boc group and the tert-butylester. This
was done with TFA in dichloromethane. It seemed that the
N-Boc group cleaved quite easy, whereas the ester cleavage
necessitated longer reaction times. After concentration of
the reaction mixture, macrolactam formation on the residue
was carried out in DMF (0.001m) in the presence of TBTU,
HOBt, and Hꢀnigꢃs base.[34,35] After workup, the crude cyclic
depsipeptide was treated with TBAF in THF to cleave the
phenolic triisopropylsilyl ether. Careful inspection of the
NMR spectroscopic data showed that macrocycle 2a did not
correspond to natural chondramide A. The macrocycles
show characteristic NMR spectroscopic signatures for the
four methyl doublets. In 2a (CD3OD) they appear at d=
0.81, 0.91, 0.92, 1.09 ppm (2-CH3).
Therefore, we surmised the (2l,3l)-3-amino-2-methoxy-
propionic acid to be the isomer present in chondramide A.
Based on the experience with the asymmetric dihydroxyla-
tion, we hoped to reach diastereomer 20b from a Z-config-
ured cinnamate. Accordingly, a Horner–Wittig reaction of
aldehyde 13 with the Ando phosphonate[36] (NaH, THF)
was performed that resulted in a 73:27 Z/E mixture of
enoates 14 from which (Z)-14 could be separated by flash
chromatography (Scheme 6). By using (Z)-14, a sequence of
dihydroxylation (with (DHQ)2PHAL as the ligand), or-
thoester formation ((MeO)3CMe), and reaction of the inter-
mediate orthoester with acetyl bromide was expected to
give acetoxy bromoester 16b. The obtained material was
converted in four steps to the presumed amino ester 20b.
This building block was then utilized for the synthesis of
presumed cyclodepsipeptide 2b (for details see the Support-
ing Information). In this sequence, the diastereomer result-
ing from the minor enantiomer of 20a could be separated
by chromatography at the stage of ester 26c. Again, the
spectral data of the macrocycle 2b (expected) did not match
with those of chondramide A.
The conclusion from this rather unexpected finding was
that either chondramide A contains a b-d-tyrosine deriva-
tive or that the substitution reaction on the benzylic position
took a different course. The latter turned out to be the case.
Thus, it seems that reaction of the presumed orthoester A
with acetyl bromide led to isomerization of the cyclic oxoni-
um ion B to the corresponding trans-isomer D before reac-
tion with the bromide (Scheme 7). Thus, instead of the syn
isomer, the corresponding trans-acetoxy bromo ester ent-16a
was formed. Accordingly, this sequence led to 3-amino-2-
methoxy-propionic ester ent-20a and ultimately to chondra-
mide A analogue 2c.
The structure of ent-20a could be proven by performing
an
aminohydroxylation
on
enoate
(E)-14
with
(DHQD)2PHAL as the ligand (Scheme 8). In fact, the two
compounds showed identical NMR spectra and signs for the
optical rotation. The measured values for ent-20a were
[a]2D0 =À1.1 (c=1.00 in CH2Cl2,
from enoate (Z)-14 through di-
hydroxylation (cf. Scheme 6))
and À8.2 (c=1.00 in CH2Cl2,
prepared through aminohydrox-
ylation from enoate (E)-14 (cf.
Scheme 8)), respectively. The
enantiomeric excess of ent-20a
from the aminohydroxylation
amounted to 94%, whereas the
material from the dihydroxyla-
tion route (Scheme 6) turned
out to be 36% according to
1H NMR spectroscopic analysis
of the derived tripeptide.
Therefore, access to the
2l,3l-diastereomer 20b of 3-
amino-2-methoxy-propionic
acid was sought from a diol pre-
cursor by substituting the ben-
zylic hydroxyl function with an
ammonia equivalent. Dihydrox-
ylation of E-enoate 14 in pres-
ence of (DHQD)2PHAL pro-
vided ent-15 in excellent yield
(Scheme 9). Initially, we tried
substitution of the 3-OH with
diphenylphosphoryl azide and
DEAD. However, under these
conditions no product was
formed. On the other hand, the
Scheme 6. Attempted synthesis of amino ester 20b and its incorporation in the cyclodepsipeptide. The ob-
tained product 2c did not correspond to chondramide A. a) (PhO)2P(O)CH2CO2Me, NaH, THF, À898C to
RT, 90 min; b) (DHQ)2PHAL, K2ACHTUNGTRENNUG[OsO2(OH)4], NMO, tBuOH/H2O, RT, 20 h, 90%; c) 1) MeCACHTUNTGRENN(UGN OMe)3, PPTS,
CH2Cl2, RT, 90 min; 2) AcBr, CH2Cl2, RT, 90 min, 65%; d) 1) NaN3, DMSO, 67%; 2) NaOMe, MeOH, 78%;
3) Me3OBF4, CH2Cl2, 73%; 4) H2, Pd/C, 98%.
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M. E. Maier et al.
cursors is 72%. This value was confirmed by chiral HPLC
(Eurocel 03).
As shown in Scheme 10 condensation of 20b with dipep-
tide acid 6 and the hydroxy ester 7 (three steps) led via tri-
peptide ester 24b to acyclic chondramide A precursor 26b
1
in good overall yield. Analysis of the H NMR spectrum of
24b indicated an ee of 72% for the dihydroxylation reaction
(14 to ent-15a). The ee values of 15a and its derivatives
depend very much on the used oxidant. Thus, instead of
using NMO[23] (72% ee), K3[Fe(CN)6] led to an ee of 99%.
The proven sequence consisting of cleavage of the tert-butyl
groups from the carbamate and ester function followed by
macrolactam formation and fluoride-induced silyl ether
cleavage gave a reasonable yield of cyclodepsipeptide 2b. If
b-tyrosine derivative 20b with an ee of 72% (NMO as oxi-
dant) was used for the synthesis of 2b the minor diastereo-
mer could be separated by chromatography on the final
stage. The spectral data of this synthetic compound proved
to be identical to the ones from chondramide A. In 2b
(CD3OD), the methyl doublets appear at d=0.80, 0.86, 0.92,
1.08 ppm (2-CH3). The optical rotation of synthetic 2b was
[a]2D0 =+7.9 (c=0.80 in MeOH), the literature reports
[a]D20 =+2.1 (c=2.0 in MeOH).[11] Furthermore, LCMS stud-
ies at the HZI in Braunschweig confirmed this assignment.
In the context of this synthesis, we also explored a more
direct access to the depsipeptide 26b (Scheme 10). Since the
7-epimer of hydroxy ester 7, compound (7S)-7 is more easily
available by the vinylogous aldol approach relative to 7 we
investigated the esterification under Mitsunobu condi-
tions.[39] In fact, reaction of acid 25b with alcohol (7S)-7 in
presence of Ph3P and DEAD gave rise to ester 26b in rea-
sonable yield.
Scheme 7. Postulated formation of ent-16a from diol 15b by isomeriza-
tion of cyclic oxonium ion B to D.
Scheme 8. Independent synthesis of 3-amino-2-methoxy-propionic acid
derivative ent-20b by aminhydroxylation. a) BnOC(O)NH2, NaOH,
(DHQD)2PHAL, 21, K2ACHTUNRGTNEUNG[OsO2(OH)4], nPrOH/H2O, 0 8C to RT, 22 h,
52%; b) Ag2O, MeI, acetone, RT, 74%; c) Pd/C, H2, MeOH, 24 h, 91%.
Conclusion
We have developed a concise route to the cyclodepsipeptide
chondramide A (2b). The synthesis established the configu-
ration of the 3-amino-2-methoxypropanoic acid to be
(2S,3R) or (2l,3l). For the synthesis of the 3-amino-2-me-
thoxy-3-arylpropanoic ester 20b, the diol ent-15 was convert-
ed to the corresponding 3-azido-2-hydroxypropanoate 18b
by a regioselective Mitsunobu reaction. Extension of the
aminoester 20b on the amino function with dipeptide acid 6
and the carboxyl function with the hydroxy ester 7 secured
the open-chain precursor 26b of chondramide A. Macrolac-
tam formation could be achieved with TBTU in DMF. This
strategy should now allow for the preparation of chon A an-
alogues with modifications in all four subunits.
Scheme 9. Synthesis of the anti-diastereomer (2l,3l) 20b by dihydroxyla-
tion and substitution of the benzylic hydroxyl group by azide.
a) (DHQD)2PHAL, K2ACHTUNGTRENNUNG[OsO2(OH)4], NMO, tBuOH/H2, RT, 5 h, 95%;
b) PPh3, HN3, DEAD, THF, 08C to RT, 18 h, 47%; c) Me3OBF4, proton
sponge, CH2Cl2, 79%; d) Pd/C, H2, MeOH, 18 h, 98%.
Mitsunobu reaction on ester diol ent-15 with hydrazoic
acid[37] (HN3) in presence of DEAD/Ph3P gave the desired
azide 18b (47% yield) together with the corresponding syn
isomer (8% yield).[38] The two isomers could be separated
by chromatography at this stage. The pure anti-2-hydroxy-3-
azido ester 18b was carried on to the methylation step
(Me3OBF4, proton sponge).[27] Hydrogenation of diastereo-
mer anti-19b led to 3-amino-2-methoxy-propionic acid de-
rivative 20b. According to the integration of the 2’-H atoms
Experimental Section
Determination of the ee values for the products of aminohydroxylation
and dihydroxylation reactions
Materials and methods: The derivatized cellulose-based silica chiral sta-
tionary phases (CSP) Eurocel 01 and Eurocel 03 had a particle size of
1
in the H NMR spectrum of 24b, the ee of 20b and its pre-
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Chondramide A
FULL PAPER
J=7.4 Hz, 18H; Si(CH
ACHTNUGTNERN(UGN CH3)2)3), 1.22–
1.34 (m, 3H; Si(CH(CH3)2)3), 6.97 (d,
AHCTUNGTRENNUNG
J=8.4 Hz, 2H; Har), 7.77 (d, J=
8.7 Hz, 2H; Har), 9.87 ppm (s, 1H;
CHO); 13C NMR (100 MHz, CDCl3):
d=12.7 (Si(CH
ACHTNUGTRNEN(NUG CH3)2)3), 17.8 (Si(CH-
AHCNUTRTGEGNN(UN CH3)2)3), 120.3 (Car), 130.2 (Car),
131.9 (Car), 161.9 (Car), 190.8 ppm
(CO).
Compound (E)-14: (Carbomethoxy-
methylene)triphenylphosphorane
(3.16 g, 9.44 mmol) was added in one
portion to a stirred solution of alde-
hyde 13 (2.19 g, 7.87 mmol) in CH2Cl2
(30 mL). After 3 d the reaction mix-
ture was concentrated in vacuo and
the crude product was purified by
flash chromatography
(petroleum
ether/EtOAc 20:1) to give enoate
((E)-14) (2.32 g, 88%) as a colorless
oil. TLC (petroleum ether/EtOAc
20:1): Rf =0.33; 1H NMR (400 MHz,
CDCl3): d=1.09 (d, J=7.4 Hz, 18H;
Si(CHACHTNUGTRENNUNG
Si(CHACHTNUGTRENNUNG
6.29 (d, J=16.0 Hz, 1H; 2-H) 6.86 (d,
J=8.7 Hz, 2H; Har), 7.40 (d, J=
8.7 Hz, 2H; Har), 7.63 ppm (d, J=
16.0 Hz,
(100 MHz, CDCl3): d=12.6 (Si(CH-
(CH3)2)3), 17.8 (Si(CH(CH3)2)3), 51.5
(OCH3), 115.2 (C-2), 120.3 (Car), 127.4
(Car), 129.7 (Car), 144.6 (C-3), 158.3
(Car), 167.8 ppm (CO); HMRS (ESI):
m/z: calcd for C19H30O3Si: 357.18564
[M+Na]+; found: 357.18555.
1H;
3-H);
13C NMR
G
ACHTUNGTRENNUNG
Scheme 10. Synthesis of chondramide A (2b). a) DIEA, HOBt, TBTU, DMF, 08C, 2 h, 73%; b) Me3SnOH,
1,2-DCE, 808C, 5 h; c) Cl3C6H2COCl, Et3N, DMAP, 7, toluene, 08C to RT, 2 h, 69% (2 steps); d) 1) TFA,
CH2Cl2, 08C, 22 h; 2) HOBt, TBTU, DIEA, DMF, RT, 20 h; 3) TBAF, THF, 08C, 1 h, 24% (3 steps); e) PPh3,
DEAD, THF, 08C to RT, 5 h, 63% (from 24b).
Compound ent-15: By using NMO as
5 mm and a pore diameter of 1000 ꢄ with an approximate surface area of
25 m2 gÀ1 donated by Knauer GmbH, Berlin (Germany). The chiral selec-
tor of Eurocel 01 is the 3,5-dimethyl phenyl carbamate group and 4-
methyl benzoate for the Eurocel 03 stationary phase. The HPLC separa-
tions of 15a, ent-15a, 22, and ent-22 on the Eurocel columns were carried
out with a Knauer Smartline System equipped with a Smartline Manager
5000 with degasser and LPG unit, a pump 1000, PDA detector 2800, and
a Smartline column oven. The samples were introduced by use of an au-
tosampler 3950. The chromatograms obtained were analyzed with the
help of ChromGate software.
the oxidant: (DHQD)2PHAL (10.0 mg, 0.013 mmol) and NMO (400 mg,
2.96 mmol, 60% in water (270 mL)) were added to a stirred solution of
enoate (E)-14 (899 mg, 2.69 mmol) in tBuOH (2 mL). The solution was
cooled to 08C and K2ACHTNUGTRNE[UNG Os2O2(OH)4] (2.00 mg, 0.005 mmol) was added.
The reaction mixture was allowed to warm to room temperature and
after stirring for 5 h, solid Na2SO3 (400 mg), water (2 mL), and EtOAc
(5 mL) were added. The layers were separated and the aqueous layer
was extracted with EtOAc (2ꢅ10 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum ether/EtOAc
2:1) to give diol (ent-15) (939 mg, 95%) as a colorless oil. [a]2D0 =+1.0
(c=1.00 in CH2Cl2).
Dihydroxyester 15a: Column: Eurocel 03, 5 mm, 250ꢅ4.6 mm, isocratic,
hexane/2-propanol (98.3:1.7 v/v), 1 mLminÀ1, 208C, UV: 210 nm; dihy-
droxylation carried out with NMO as the oxidant, 62% ee; tr (minor)
33.0, tr (major) 39.9 min; dihydroxyester ent-15a: dihydroxylation carried
out with NMO as the oxidant, 72% ee; dihydroxylation carried out with
K3[Fe(CN)6] as the oxidant, 99% ee.
By using K3[Fe(CN)6] as the oxidant:
K2ACTHNGUTERNNU[G Os2O2(OH)4] (4.00 mg,
0.012 mmol) and methanesulfonamide (0.274 g, 2.89 mmol) were added
to a stirred mixture of K3[Fe(CN)6] (2.85 g, 8.66 mmol), (DHQD)2PHAL
(23 mg, 0.029 mmol), and K2CO3 (1.20 g, 8.66 mmol) in tBuOH/H2O 1:1
(28 mL). The mixture was stirred for 15 min and then enoate (E)-14
(0.965 g, 2.89 mmol) in tBuOH (2 mL) was added in one portion. The re-
action mixture was cooled to 08C, slowly allowed to warm to room tem-
perature and stirred for 20 h. Then solid Na2SO3 (5.00 g) and EtOAc
(20 mL) were added and the aqueous layer was extracted with EtOAc
(2ꢅ20 mL). The combined organic layers were washed with 1n NaOH
solution (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography (petroleum
ether/EtOAc 2:1) to give diol (ent-15) (0.885 g, 83%) as a colorless oil.
[a]2D0 =+1.8 (c=1.00 in CH2Cl2); TLC (petroleum ether/EtOAc 2:1): Rf =
0.25; 1H NMR (400 MHz, CDCl3): d=1.08 (d, J=7.1 Hz, 18H; Si(CH-
Carbamate 22: Column: Eurocel 01, 5 mm, 250ꢅ4.6 mm, isocratic, metha-
nol/water (95:5 v/v), 1 mLminÀ1, 208C, UV: 220 nm, 90% ee; tr (minor)
6.2, tr (major) 7.3 min; carbamate ent-22: 94% ee.
Aldehyde 13: Et3N (4.96 mL, 3.62 mmol) and DMAP (0.364 g,
2.98 mmol) were added to a stirred solution of 4-hydroxybenzaldehyde
(3.64 g, 29.8 mmol) in CH2Cl2 (60 mL) at 08C. The mixture was stirred
for 10 min before TIPSCl (7.00 mL, 32.8 mmol) was added. The mixture
was allowed to warm to room temperature. After stirring for 18 h, the re-
action mixture was treated with water (20 mL) and the aqueous layer
was extracted with CH2Cl2 (2ꢅ30 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/EtOAc 20:1) to
afford aldehyde 13 (7.95 g, 96%) as a colorless oil. TLC (petroleum
ether/EtOAc 20:1): Rf =0.33; 1H NMR (400 MHz, CDCl3): d=1.10 (d,
ACHUTNGRENUN(G CH3)2)3), 1.15–1.32 (m, 3H; Si(CHACHTUGNTREN(NUNG CH3)2)3), 2.66 (d, J=6.4 Hz, 1H;
OH), 3.06 (d, J=6.1 Hz, 1H; OH), 3.76 (s, 3H; OCH3), 4.32 (dd, J=6.1,
3.3 Hz, 1H; 2-H), 4.90 (dd, J=6.4, 3.3 Hz, 1H; 3-H), 6.86 (d, J=8.7 Hz,
2H; Har), 7.24 ppm (d, J=7.9 Hz, 2H; Har); 13C NMR (100 MHz,
Chem. Eur. J. 2010, 16, 4328 – 4336
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4333

M. E. Maier et al.
CDCl3): d=12.6 (Si(CH
G
E
0.388 mmol) in DMF (7 mL) at 08C. After stirring for 2 h at 08C, water
(4 mL) was added and the mixture extracted with EtOAc (2ꢅ10 mL).
The combined organic extracts were washed with 1n HCl solution
(5 mL), saturated NaHCO3 solution (5 mL), water (5 mL), and saturated
NaCl solution (5 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (petroleum
ether/EtOAc 1:1) to give tripeptide 24b (212 mg, 73%) as a colorless
foam. TLC (petroleum ether/EtOAc 1:1): Rf =0.29; [a]2D0 =+26.4 (c=
74.4 (C-2), 74.8 (C-3), 119.8 (Car), 127.5 (Car), 132.2 (Car), 156.0 (Car),
173.3 ppm (CO); HMRS (ESI): m/z: calcd for C19H32O5Si: 391.19112
[M+Na]+; found: 391.190803.
Generation of a hydrazoic acid (HN3) solution: Toluene (8 mL) was
added to a stirred paste of NaN3 (1.56 g, 24 mmol) and water (1.56 mL).
The mixture was cooled to 08C before concentrated sulfuric acid
(0.581 mL, 12 mmol) was added dropwise. The organic layer was deca-
nted and dried over Na2SO4. To estimate the concentration, an aliquot
(3 mL) of the hydazoic acid solution in toluene was mixed with water
(30 mL) and titrated with 0.3n NaOH solution against phenolphthalein.
Typically, concentrations of around 1.6m were obtained.
1
1.00 in CH2Cl2); H NMR (400 MHz, CDCl3): d=0.90 (d, J=6.4 Hz, 3H;
Ala CH3), 1.06 (d, J=7.1 Hz, 18H; Si(CH
ACHTNUGTRNEN(NUG CH3)2)3), 1.16–1.26 (m, 3H;
Si(CH(CH3)2)3), 1.40 (s, 9H; C(CH3)3), 2.94 (s, 3H; NCH3), 3.26 (dd, J=
A
ACHTUNGTRENNUNG
15.4, 5.2 Hz, 1H; CH2), 3.33–3.39 (m, 1H; CH2), 3.36 (s, 3H; OCH3),
3.53 (s, 3H; OCH3), 4.05 (d, J=4.8 Hz, 1H; CHOCH3), 4.47–4.55 (m,
1H; Ala CH), 5.37 (dd, J=8.7, 5.1 Hz, 1H; b-Tyr CH), 5.44 (d, J=
7.4 Hz, 1H; Ala NH), 5.55 (dd, J=9.7, 6.4 Hz, 1H; Trp CH), 6.75 (d, J=
8.7 Hz, 2H; b-Tyr Har), 6.91 (s, 1H; Trp Har), 7.04–7.11 (m, 4H; b-Tyr
NH, b-Tyr Har, Trp Har), 7.14 (t, J=7.5 Hz, 1H; Trp Har), 7.30 (d, J=
8.1 Hz, 1H; Trp Har), 7.58 (d, J=7.6 Hz, 1H; Trp Har), 8.33 ppm (brs,
Compound 18b: PPh3 (683 mg, 2.61 mmol) and HN3 (2.7 mL, 4.34 mmol,
~1.6m in toluene) were added to a stirred solution of diol ent-15 (800 mg,
2.17 mmol) in THF (5 mL) at 08C, followed by dropwise addition of
DEAD (1.29 mL, 2.82 mmol, 40% in toluene) within 4 h. The reaction
mixture was allowed to warm to room temperature and after stirring for
14 h, saturated NaHCO3 solution (4 mL) was added, followed by separa-
tion of the layers. The aqueous layer was extracted with EtOAc (2ꢅ
15 mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. Flash chromatography (petroleum ether/
EtOAc, 9:1) provided azide 18b (399 mg, 47%) as a colorless oil. The
syn diastereomer (66.0 mg, 8%, Rf =0.16) was also obtained as a color-
less oil. TLC (petroleum ether/EtOAc, 9:1): Rf =0.13; [a]2D0 =+50.5 (c=
1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.08 (d, J=7.1 Hz,
1H; Trp NH); 13C NMR (100 MHz, CDCl3): d=12.5 (Si(CH
17.8 (Si(CH(CH3)2)3), 18.0 (Ala CH3), 23.3 (CH2), 28.3 (C(CH3)3), 30.7
(NCH3), 46.7 (Ala CH), 51.7 (OCH3), 53.6 (b-Tyr CH), 56.7 (Trp CH),
59.1 (OCH3), 79.5 (C(CH3)3), 82.4 (CHOCH3), 110.6 (Trp Car), 111.1 (Trp
ACHTUNGTRENNUNG(CH3)2)3),
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Car), 118.4 (Trp Car), 119.4 (Trp Car), 119.8 (b-Tyr Car), 122.0 (Trp Car),
122.2 (Trp Car), 127.2 (Trp Car), 128.6 (b-Tyr Car), 129.1 (b-Tyr Car), 136.1
(Trp Car), 155.1 (CO), 155.7 (b-Tyr Car), 169.3 (CO), 170.2 (CO),
174.3 ppm (CO); HMRS (ESI): m/z: calcd for C40H60N4O8Si: 775.40726
[M+Na]+; found: 775.406789.
18H; Si(CHACHTUNGTRENNUNG(CH3)2)3), 1.17–1.30 (m, 3H; Si(CHCAHTUTGNERN(NUGN CH3)2)3), 2.92 (s, 1H;
OH), 3.68 (s, 3H; OCH3), 4.49 (d, J=4.1 Hz, 1H; 2-H), 4.80 (d, J=
4.1 Hz, 1H; 3-H), 6.86 (d, J=8.7 Hz, 2H; Har), 7.18 ppm (d, J=8.7 Hz,
Compound 26b: By Yamaguchi esterification: Me3SnOH (105 mg,
0.580 mmol) was added to a stirred solution of tripeptide fragment 24b
(87.0 mg, 0.116 mmol) in 1,2-dichloroethane (2 mL). After stirring for 5 h
at 808C, TLC showed complete conversion and the reaction mixture was
diluted with KHSO4 (5% in water, 4 mL). The aqueous layer was ex-
tracted with EtOAc (2ꢅ5 mL) and the combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo to afford the
crude acid 25b as a colorless foam. This crude product was dissolved in
toluene (2.5 mL) and cooled to 08C. Et3N (48.0 mL, 0.348 mmol) and
2,4,6-trichlorobenzoyl chloride (20.0 mL, 0.128) were added. After 30 min,
hydroxy ester 7 (33.0 mg, 0.128 mmol) in toluene (0.2 mL) and DMAP
(57.0 mg, 0.464 mmol) were added and the yellow reaction mixture was
stirred for 1 h at 08C, allowed to warm to room temperature, and stirred
again for 1 h. Then, saturated NaHCO3 solution (3 mL) was added and
the aqueous layer was extracted with EtOAc (2ꢅ5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (petroleum ether/EtOAc, 2:1) provided
ester 26b (78.0 mg, 69% over two steps) as a colorless foam.
2H; Har); 13C NMR (100 MHz, CDCl3): d=12.9 (Si(CH
ACHTUNGTRENNUNG
(Si(CHACHTUNGTRENNUNG
(Car), 129.3 (Car), 157.0 (Car), 172.1 ppm (CO); HMRS (ESI): m/z: calcd
for C19H31N3O4Si: 416.19760 [M+Na]+; found: 416.197583.
Compound 19b: Me3OBF4 (280 mg, 1.89 mmol) and proton sponge
(580 mg, 2.71 mmol) were added to a stirred solution of alcohol 18b
(213 mg, 0.541 mmol) in CH2Cl2 (7 mL). After stirring for 20 h at room
temperature in the dark, water (4 mL) was added and the mixture ex-
tracted with CH2Cl2 (2ꢅ10 mL). The combined organic extracts were
washed with 1n HCl (5 mL), saturated NaHCO3 solution (5 mL), and sa-
turated NaCl solution (5 mL). The extracts were then dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/EtOAc 9:1) to afford methyl ether
19b (175 mg, 79%) as a colorless oil. TLC (petroleum ether/EtOAc, 9:1):
Rf =0.40; [a]2D0 =+36.6 (c=1.00 in CH2Cl2); H NMR (400 MHz, CDCl3):
d=1.08 (d, J=7.1 Hz, 18H; Si(CH
ACHTUNGTRENNUNG(CH3)2)3), 3.34 (s, 3H; OCH3), 3.71 (s, 3H; OCH3), 3.95 (d, J=6.6 Hz,
By Mitsunobu esterification: Me3SnOH (30.0 mg, 0.165 mmol) was added
to a stirred solution of tripeptide fragment 24b (25.0 mg, 0.033 mmol) in
1,2-dichloroethane (1 mL). After stirring for 5 h at 808C, TLC showed
complete conversion and the reaction mixture was diluted with KHSO4
(5% in water, 2 mL). The aqueous layer was extracted with EtOAc (2ꢅ
3 mL) and the combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo to afford the crude acid 25b as a colorless
foam. This crude product and alcohol (7S)-7 (13.0 mg, 0.050 mmol) were
dissolved in THF (2 mL) and Ph3P (26.0 mg, 0.099 mmol) was added at
08C. This was followed by the dropwise addition of DEAD (0.045 mL,
0.099 mmol, 40% in toluene). The cooling bath was removed and the
mixture stirred for 4 h at room temperature. The reaction mixture was
concentrated in vacuo and the residue purified by flash chromatography
(petroleum ether/EtOAc, 2:1) to give ester 26b (20 mg, 63% over two
steps) as a colorless foam. TLC (petroleum ether/EtOAc 2:1): Rf =0.19;
[a]2D0 =+11.3 (c=1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.81
(d, J=7.1 Hz, 3H; 2’-CH3), 0.82 (d, J=6.4 Hz, 3H; 1’-CH3), 0.91 (d, J=
6.6 Hz, 3H; Ala CH3), 1.01 (d, J=6.9 Hz, 3H; 6’-CH3), 1.05 (d, J=
1H; 2-H) 4.68 (d, J=6.9 Hz, 1H; 3-H), 6.86 (d, J=8.7 Hz, 2H; Har),
7.22 ppm (d, J=8.4 Hz, 2H; Har); 13C NMR (100 MHz, CDCl3): d=12.6
(Si(CHACHTUNGTRENNUNG(CH3)2)3), 17.8 (Si(CHACHTUGNTNERN(UGN CH3)2)3), 52.2 (OCH3), 59.2 (OCH3), 65.5
(C-3), 83.5 (C-2), 120.1 (Car), 127.5 (Car), 129.3 (Car), 156.5 (Car),
170.3 ppm (CO); HMRS (ESI): m/z: calcd for C20H33N3O4Si: 430.21325
[M+Na]+; found: 430.21319.
Compound 20b: A catalytic amount of Pd/C was added to a stirred solu-
tion of azide 19b (218 mg, 0.535 mmol) in MeOH (5 mL). After stirring
for 18 h at room temperature, the Pd/C was filtered off and the filtrate
concentrated in vacuo. The residue (98 mg, 98%) was used for the next
step without further purification. TLC (petroleum ether/EtOAc 3:7):
Rf =0.23; [a]2D0 =À6.2 (c=1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=1.07 (d, J=7.12 Hz, 18H; Si(CHACTHNUTGRNE(UNG CH3)2)3), 1.16–1.30 (m, 3H; Si(CH-
ACHTUNGTRENNUNG(CH3)2)3), 2.20 (brs, 2H; NH2), 3.37 (s, 3H; OCH3), 3.59 (s, 3H; OCH3),
4.00 (d, J=5.3 Hz, 1H; 2-H), 4.26 (d, J=5.3 Hz, 1H; 3-H), 6.83 (d, J=
8.4 Hz, 2H; Har), 7.17 ppm (d, J=8.4 Hz, 2H; Har); 13C NMR (100 MHz,
CDCl3): d=12.6 (Si(CHACTHNURTGENNUG(CH3)2)3), 17.8 (Si(CHACHUTNGTREN(NUGN CH3)2)3), 51.6 (OCH3),
57.0 (C-3), 58.9 (OCH3), 85.2 (C-2), 119.7 (Car), 128.0 (Car), 133.7 (Car),
155.5 (Car), 171.2 ppm (CO); HMRS (ESI): m/z: calcd for C20H35NO4Si:
382.24081 [M+H]+; found: 382.24086.
7.1 Hz, 18H; Si(CH
N
ACHTNUGTNER(NUGN CH3)2)3), 1.40 (s,
9H; C(CH3)3), 1.41 (s, 9H; CACHTGNUTRENNUNG
T
13.7, 7.6 Hz, 1H; CH2), 2.34 (dd, J=13.6, 6.7 Hz, 1H; CH2), 2.40–2.49
(m, 2H; 6’-H, 2’-H), 2.95 (s, 3H; NCH3), 3.24 (dd, J=15.5, 9.9 Hz, 1H;
Trp CH2), 3.31–3.39 (m, 1H; Trp CH2), 3.40 (s, 3H; OCH3), 4.05 (d, J=
4.3 Hz, 1H; CHOCH3), 4.48–4.59 (m, 2H; Ala CH, 1’-H), 4.86 (d, J=
Compound 24b: DIEA (197 mL, 1.16 mmol), HOBt (79.0 mg,
0.582 mmol), and TBTU (182 mg, 0.582 mmol) were added to a stirred
solution of amine 20b (151 mg, 0.388 mmol) and acid
6 (148 mg,
4334
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4328 – 4336

Chondramide A
FULL PAPER
9.4 Hz, 1H; 3’-H), 5.36 (dd, J=8.7, 4.3 Hz, 1H; b-Tyr CH), 5.44 (d, J=
7.4 Hz, 1H; Ala NH), 5.52 (dd, J=9.4, 6.6 Hz, 1H; Trp CH), 6.73 (d, J=
8.7 Hz, 2H; b-Tyr Har), 6.90 (s, 1H; Trp Har), 7.04 (d, J=8.9 Hz, 1H; b-
Tyr NH), 7.07–7.12 (m, 1H; Trp Har), 7.13–7.18 (m, 1H; Trp Har), 7.14 (d,
J=7.9 Hz, 2H; b-Tyr Har), 7.30 (d, J=7.9 Hz, 1H; Trp Har), 7.58 (d, J=
7.6 Hz, 1H; Trp Har), 8.15 ppm (brs, 1H; Trp NH); 13C NMR (100 MHz,
columns and help with chiral separations from S. Marten, Head of Appli-
cations and Columns Department, Knauer GmbH, Berlin (Germany).
[1] A. Disanza, A. Steffen, M. Hertzog, E. Frittoli, K. Rottner, G. Scita,
Cell. Mol. Life Sci. 2005, 62, 955–970.
CDCl3): d=12.6 (Si(CH
CH3), 17.6 (2’-CH3), 17.9 (Si(CH
CH2), 28.1 (C(CH3)3), 28.3 (C(CH3)3), 30.8 (NCH3), 37.6 (C-2’), 38.6 (C-
6’), 43.4 (C-5’), 46.7 (Ala CH), 53.6 (b-Tyr CH), 56.7 (Trp CH), 59.2
(OCH3), 75.9 (C-1’), 79.5 (C(CH3)3), 79.9 (C(CH3)3), 81.9 (CHOCH3),
ACHTUNGTRENNUG
[2] a) G. Kustermans, J. Piette, S. Legrand-Poels, Biochem. Pharmacol.
2008, 76, 1310–1322; b) M. Binder, C. Tamm, Angew. Chem. 1973,
85, 369–381; Angew. Chem. Int. Ed. Engl. 1973, 12, 370–380.
[3] a) T. Wieland, Naturwissenschaften 1987, 74, 367–373; J. A. Cooper,
J. Cell Biol. 1987, 105, 1473–1478.
[4] T. Oda, K. Namba, Y. Maꢆda, Biophys. J. 2005, 88, 2727–2736.
[5] For recent reviews, see: a) D. C. Myles, Annu. Rep. Med. Chem.
2002, 37, 125–132; b) K.-H. Altmann, J. Gertsch, Nat. Prod. Rep.
2007, 24, 327–357; c) K.-H. Altmann, B. Pfeiffer, S. Arseniyadis,
B. A. Pratt, K. C. Nicolaou, ChemMedChem 2007, 2, 396–423;
d) K. C. Nicolaou, J. S. Chen, S. M. Dalby, Bioorg. Med. Chem. 2009,
17, 2290–2303.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
110.9 (Trp Car), 111.1 (Trp Car), 118.6 (Trp Car), 119.5 (Trp Car), 119.6 (b-
Tyr Car), 122.1 (Trp Car), 127.3 (Trp Car), 128.0 (C-3’), 129.1 (b-Tyr Car),
129.2 (Trp Car), 133.7 (C-4’), 136.1 (Trp Car), 155.1 (CO), 155.8 (b-Tyr
Car), 169.2 (CO), 169.3 (CO), 174.2 (CO), 175.8 ppm (CO); HMRS
(ESI): m/z: calcd for C54H84N4O10Si: 999.58489 [M+Na]+; found:
999.584938.
Chondramide A (2b): TFA (33.0 mL, 0.45 mmol) was added to a stirred
solution of compound 26b (44.0 mg, 0.045 mmol) in CH2Cl2 (1 mL) at
08C. The reaction mixture was allowed to warm to room temperature
and after stirring for 22 h, the solvent was removed in vacuo. For azeo-
tropic removal of TFA, the residue was taken up in toluene (3ꢅ0.5 mL)
and concentrated in vacuo each time. The crude product was dissolved in
DMF (45 mL) and DIEA (30.0 mL, 0.180 mmol), HOBt (21.0 mg,
0.158 mmol), and TBTU (49.0 mg, 0.158 mmol) were added. The solution
was stirred at room temperature for 20 h and then diluted with water
(20 mL) and EtOAc (20 mL). The aqueous layer was extracted with
EtOAc (3ꢅ20 mL) and the combined organic layers were washed with
5% aqueous KHSO4 solution (20 mL), water (20 mL), saturated
NaHCO3 solution (20 mL), water (2ꢅ20 mL), and saturated NaCl solu-
tion (20 mL). The combined organic extracts were dried over Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was dissolved in
THF (0.5 mL) and TBAF·3H2O (28.0 mg, 0.090 mmol) was added at 08C.
After stirring for 1 h, the solvent was removed in vacuo followed by flash
chromatography (petroleum ether/ethyl acetate 1:1; then petroleum
ether/acetone 3:2) of the residue to give depsipeptide 2b (9.00 mg, 31%
over three steps) as a colorless foam. TLC (petroleum ether/acetone 3:2):
Rf =0.13; [a]2D0 =+7.9 (c=0.80 in MeOH); 1H NMR (400 MHz, MeOD):
d=0.80 (d, J=7.1 Hz, 3H; Ala CH3), 0.86 (d, J=6.1 Hz, 3H; 7-CH3),
0.91 (d, J=6.6 Hz, 3H; 6-CH3), 1.08 (d, J=6.8 Hz, 3H; 2-CH3), 1.68 (s,
3H; 4-CH3), 2.03 (dd, J=13.0, 2.6 Hz, 1H; CH2), 2.23 (dd, J=12.6,
12.6 Hz, 1H; CH2), 2.45–2.57 (m, 1H; 6-H), 2.59–2.72 (m, 1H; 2-H), 3.02
(d, J=8.1 Hz, 2H; Trp CH2), 3.08 (s, 3H; NCH3), 3.14 (s, 3H; OCH3),
3.85 (d, J=10.1 Hz, 1H; CHOCH3), 4.47–4.56 (m, 1H; 7-H), 4.73–4.81
(m, 1H; Ala CH), 4.81–4.87 (m, 1H; 5-H), 5.03 (d, J=9.9 Hz, 1H; b-Tyr
CH), 5.52 (dd, J=8.1, 8.1 Hz, 1H; Trp CH), 6.67 (d, J=8.6 Hz, 2H; b-
Tyr Har), 6.83 (s, 1H; Trp Har), 6.95–7.02 (m, 1H; Trp Har), 6.99 (d, J=
8.6 Hz, 2H; b-Tyr Har), 7.02–7.09 (m, 1H; Trp Har), 7.26 (d, J=8.1 Hz,
1H; Trp Har), 7.57 ppm (d, J=7.8 Hz, 1H; Trp Har); 13C NMR (100 MHz,
MeOD): d=16.0 (4-CH3), 17.9 (6-CH3), 18.4 (Ala CH3), 18.9 (7-CH3),
19.1 (2-CH3), 26.4 (Trp CH2), 30.9 (NCH3), 38.7 (C-6), 40.2 (C-2), 45.9
(Ala CH), 46.0 (C-3), 55.7 (b-Tyr CH), 56.9 (Trp CH), 58.3 (OCH3), 79.2
(C-7), 83.4 (CHOCH3), 110.1 (Trp Car), 112.2 (Trp Car), 116.1 (b-Tyr Car),
119.4 (Trp Car), 119.6 (Trp Car), 122.3 (Trp Car), 124.4 (Trp Car), 128.5 (Trp
Car), 129.1 (C-5), 129.5 (b-Tyr Car), 131.3 (b-Tyr Car), 134.7 (C-4), 137.9
(Trp Car), 157.9 (b-Tyr Car), 171.3 (CO), 173.5 (CO), 174.9 (CO),
176.9 ppm (CO); HMRS (ESI): m/z: calcd for C36H46N4O7: 669.32587
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft, the NIH
(grant: AI073155), and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank G. Nicholson and Dr. D. Wistuba (Institute of
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Received: December 21, 2009
Published online: March 10, 2010
4336
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4328 – 4336