Asymmetric total syntheses of marine cyclic depsipeptide halipeptins A-D

Article abstract of DOI:10.1002/chem.200600383

Halipeptins A-D (1a-d) are a family of natural cyclic depsipeptides isolated from marine sponges. Total syntheses of these four compounds are detailed in this report. The key elements in this synthesis include the elaboration of the polysubstituted decanoic acid parts by two asymmetric aldol reactions, assembly of the N-methyl-δ-hydroxyisoleucine residue by using either aza-Claisen rearrangement or methylation of aspartates as the key steps, and macrocyclization at the polysubstituted decanoic acid alanine site.

Full text of DOI:10.1002/chem.200600383

DOI: 10.1002/chem.200600383
Asymmetric Total Syntheses of Marine Cyclic Depsipeptide Halipeptins A–D
Shouyun Yu,[a] Xianhua Pan,[b] and Dawei Ma*[a]
Abstract: Halipeptins A–D (1a–d) are a family of natural cyclic depsipeptides iso-
lated from marine sponges. Total syntheses of these four compounds are detailed
Keywords: cyclic depsipeptides
·
in this report. The key elements in this synthesis include the elaboration of the
polysubstituted decanoic acid parts by two asymmetric aldol reactions, assembly of
the N-methyl-d-hydroxyisoleucine residue by using either aza-Claisen rearrange-
ment or methylation of aspartates as the key steps, and macrocyclization at the
polysubstituted decanoic acid alanine site.
macrocyclization · natural products ·
total synthesis · unnatural amino
acids
Introduction
by 3-hydroxy-2,2,4-trimethyl-7-methoxy decanoic acid
(HTMMD) in halipeptins A and D, and 3-hydroxy-2,2,4-tri-
methyl-7-hydroxy decanoic acid (HTMHD) in halipeptins B
and C. Another difference in these structures is in their N-
methyl amino acid fragments as N-methyl-d-hydroxyisoleu-
Halipeptins A–D (1a–d, Scheme 1) are a family of natural
cyclic depsipeptides recently isolated from marine sponges.[1]
The structures of 1a and b were initially assigned as the 17-
membered cyclic depsipeptides containing an unusual 1,2-
oxazetidine based on MS and NMR spectroscopic analysis
by Gomez-Paloma and co-workers.[1a] One year later anoth-
er member of this family, namely halipeptin C (1c), was iso-
lated by the same group and was accurately assigned as a
thiazoline-containing structure, which led to the revision of
the structures for halipeptins A and B from the oxazetidine
structures to the thiazoline structures, respectively.[1b]
During the same period, Manam and Faulkner discovered
halipeptin D from the marine sponge Leiosella cf. arenifi-
brosa collected in the northwestern waters off Boracay
Island (Philippines).[1c] Structurally, these four compounds
all bear two l-alanine residues, one of which is connected to
an a-methylcysteine unit through a methylthiazoline ring.
One difference in the structure of these compounds comes
from their polysubstituted decanoic acid parts as evidenced
[a] S. Yu, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu
Shanghai 200032 (China)
Fax : (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
[b] Dr. X. Pan
Department of Chemistry, Fudan University
Shanghai 200433 (China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1. Strategic bond disconnections of halipeptins A–D. PG=pro-
tecting group.
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FULL PAPER
cine (NMeOHIle) was found in halipeptins A and B, N-
methyl valine (NMeVal) in halipeptin C, and N-methyl iso-
leucine (NMeIle) in halipeptin D. A noteworthy point is
that HTMMD, HTMHD, and NMeOHIle residues had
never been discovered from other natural resources. Pre-
liminary pharmacological tests revealed that halipeptin A
has potent anti-inflammatory activity (60% reduction of car-
rageenan-induced edema at an intraperitoneal dose of
0.3 mgkgꢀ1 in mice),[1a] while the natural halipeptin D exhib-
ited a strong in vitro inhibitory activity against a human
colon cancer (HCT-116) cell line (IC50 =7 nm) and a BMS
ODCA (oncology diverse cell panel) of tumor cell lines
(IC50 =420 nm).[1c] The unique structures and important bio-
logical characteristics displayed by halipeptins have attract-
ed considerable synthetic attention.[2] The first total synthe-
sis and structural confirmation of halipeptin A was disclosed
by our group in early 2005.[2e] Later, Nicolaou and co-work-
ers reported their story for the construction of halipeptins A
and D. Interestingly, the synthetic halipeptin D exhibited
only weak cytotoxicity against the human colon cancer
(HCT-116) cell line (IC50 =32.5 mm).[2f] The reason behind
these controversial results is as yet unclear. Recently, the
third total synthesis for halipeptin A was described by the
Hamada group.[2g] In this report, we wish to detail our ef-
forts on the assembly of all the members of the halipeptin
family.
Scheme 2. Synthesis of the HTMMD and the HTMHD unit. a) NaOMe,
MeOH, 08C!RT, 82%; b) TBSCl, imidazole, DMF, 98%; c) DIBAL-H,
ether, ꢀ908C; d) [D]B-allyldiisopinocampheylborane, then H2O2, NaOH,
90% yield for 2 steps; e) NaH, MeI, DMF, RT; f) Ac2O, TEA, DMAP,
CH2Cl2, RT; g) TBAF, THF; h) Pt/C, H2, EtOAc; i) Swern oxidation; j) 1-
(trimethylsiloxy)-1-methoxy-2-methyl-1-propene, borane 9, CH2Cl2,
ꢀ788C; k) aq. LiOH, THF, MeOH, then allyl bromide, K2CO3, DMSO,
RT. TBS=tert-butyldimethylsilyl; DIBAL=diisobutylaluminun hydride;
TBAF=tetrabutylammonium fluoride; DMAP=4-dimethylaminopyri-
dine.
Retrosynthetic analysis: The strategic bond disconnections
of the halipeptins are outlined in Scheme 1. As these mole-
cules are highly methylated, the most critical problem in
their assembly is the connection of the sterically hindered
units with other amino acid residues. We envisaged that two
less hindered positions could be reserved for late-stage con-
nections, namely Ala1-NMeAA and HTMMD/HTMHD-
Ala2 sites. Our plan therefore required the elaboration of
ester parts A and amide units B, and hence the stereoselec-
tive synthesis of the building blocks polysubstituted decano-
ic acids 2, a-methylthiazoline 3, and N-methyl amino acids
4. Furthermore, ready racemization at C14 directed by the
a-methylthiazoline group would be another critical prob-
lem,[3,4] and therefore the protecting groups for all these
units should be removable under mild conditions.
lowed by cleavage of the silyl ether with TBAF yielded an
alcohol. Hydrogenation of the terminal C=C double bond
and subsequent Swern oxidation of the primary alcohol pro-
duced aldehyde 8a in 69% yield. Meanwhile, protection of
alcohol 7 with an acyl group, removal of TBS group, and
Swern oxidation gave aldehyde 8b in a yield of 73% for
three steps. At this stage we planned to build the requisite
b-hydroxy-a,a-dimethylester part by an enantioselective
chiral-borane-mediated Mukaiyama-aldol reaction.[8] Ac-
cordingly, treatment of the aldehydes 8a and b with 1-(tri-
methylsiloxy)-1-methoxy-2-methyl-1-propene in the pres-
ence of borane 9 at ꢀ788C produced methyl esters 10a
and b, respectively, as single isomers. Assembly of the
HTMMD unit 2a from 10a was accomplished by hydrolysis
with LiOH and subsequent esterification with allyl bromide.
In a parallel procedure, hydrogenation of 10b followed by
switching of the methyl ester to an allyl ester produced the
HTMHD fragment 2b, which was protected with TBSCl to
give silyl ether 2c.
Results and Discussion
Synthesis of the HTMMD and HTMHD units: Our cam-
paign towards halipeptins began from the assembly of poly-
substituted decanoic acids units. As depicted in Scheme 2,
(R)-4-methyl-5-valerolactone 5, an oxidative degradation
product of diosgenin,[5] was chosen as the starting material.
Ring opening of 5 with methanolic sodium methoxide fol-
lowed protection of the hydroxy group as the silyl ether af-
forded 6. Reduction of ester 6 with DIBAL-H gave an alde-
hyde,[6] which was subjected to asymmetric allylboration
based on the procedure by Brown and Racherla[7] to deliver
homoallyl alcohol 7. Methylation of 7 with NaH/MeI fol-
Syntheses of N-methyl amino acid units: NMeOHIle residue
is the most complex unit of the three N-methyl amino acids
in the halipeptins. Our initial approach to this residue is out-
lined in Scheme 3. The route was based on an asymmetric
aza-Claisen rearrangement developed by Tsunoda et al.[9]
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D. Ma et al.
Scheme 4.
HMPA by using LiHMDS as the base. Unfortunately, poor
diastereoselectivity was obtained as a 3:2 diastereomeric
mixture was detected by 1H NMR spectroscopy (Table 1,
Scheme 3. First-generation synthesis of the NMeOHIle unit. a) MsCl,
Et3N, ꢀ208C!RT; b) (R)-a-methylbenzylamine, 65% (2 steps); c) N-
Boc-Gly, EDCI, HOBT, iPr2NEt, 08C!RT, 96%; d) Lindlar catalyst, H2,
ether, RT 91%; e) TFA, CH2Cl2, 96%; f) LiHMDS, THF, ꢀ788C!RT;
g) CbzCl, Et3N, DMAP, CH2Cl2, RT, 52% yield for 2 steps; h) HCl (5n),
MeOH, reflux, then CH2N2, ether, 76%; i) BH3·THF; then H2O2, pH 7
buffer, 72%; EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride; HOBT=1-hydroxy-1H-benzotriazole; TFA=trifluoroacetic
acid; HMDS=hexamethyldisilazide.
Table 1. Methylation of aspartates.
Entry Substrate
R
R’
R’’
Product Yield [%][a] anti/syn[b]
1
2
3
4
5
15a
15b
15c
15d
15e
Me Bn TMSE
Me tBu Bn
tBu Bn TMSE
tBu Bn Me
tBu Bn allyl
1
16a
16b
16c
16d
16e
81
74
77
94
91
1.5:1
2.3:1
3.5:1
>20:1
>20:1
[a] Isolated yield. [b] Determined by H NMR spectroscopy.
Although in their report only diastereoselective rearrange-
ment of N-substituted N-(E)-2-butenylpropanamides to syn
products was mentioned,[9] according to the related stud-
ies[10] we envisaged that if (Z)-olefin 12 was used, the de-
sired anti product would be the major product. To this end,
mesylation of 2-butyn-1-ol followed by introduction of the
chiral auxiliary (R)-a-methylbenzylamine and subsequent
condensation with N-Boc-Gly yielded amide 11. Partial hy-
drogenation of 11 with Lindlar catalyst and subsequent de-
protection with trifluoroacetic acid delivered the (Z)-olefin
12. Exposure of 12 to LiHMDS afforded the aza-Claisen re-
arrangement products,[9] which were masked with Cbz to
give a mixture of diastereomers. 1H NMR spectroscopic
analysis revealed that the ratio of major isomer 13 to other
isomers was about 3:1, and pure 13 was isolated in 52%
overall yield by recrystallization. Next, removal of the chiral
auxiliary from 13 followed by treatment with CH2N2 provid-
ed a methyl ester, which was then elaborated to alcohol 14
through a hydroboration/oxidation operation.
entry 1). This ratio was much lower than that observed in
Hanessianꢁs allylation reaction, which showed the impor-
tance of steric hindrance in the alkylation agents. Consider-
ing that in Chamberlinꢁs studies bulkier N-protecting groups
were favored for anti selectivity,[12d] we next checked N-Boc
protected aspartate 15b, but surprisingly found that the se-
lectivity was still poor (entry 2). However, when a-tert-butyl
ester 15c was employed, the ratio for anti and syn isomers
reached 3.5:1 (entry 3). Encouraged by this result, further
optimization was undertaken by tuning the other protecting
groups in aspartates. We were pleased to find that excellent
diastereoselectivity could be achieved by reducing the size
of the b-ester moiety (entries 4 and 5). Taken together, we
concluded that in the methylation reaction larger a- and
smaller b-esters in aspartates are favored for anti selectivity.
This rule might be extended to the other alkylation reac-
tions of aspartates. The model proposed by Chamberlin and
co-workers could not rationalize the present selectivity be-
cause, as indicated in model C for our substrates, there is
Although the above protocol could provide the desired in-
termediate 14, the moderate diastereoselectivity in the
asymmetric aza-Claisen rearrangement step prompted us to
develop an alternative synthetic route. Consequently meth-
ylation of aspartates was considered because its product
could be easily converted into 14 through a carbon chain
elongation.
Literature survey indicated that diastereoselectivity for
the alkylation of aspartates relies highly on the bulkiness of
the alkylation agents. When allyl halides, benzyl bromide,
and tert-butyl bromoacetate were employed, moderate to
excellent diastereoselectivity was observed.[11] However,
only 3:1 to 1:1 diastereoselectivity has been recorded for
methylation except, for Chamberlinꢁs report.[12] As Cham-
berlinꢁs products were not satisfactory for our synthetic pur-
pose,[12d] we decided to study the methylation with protected
aspartates by using Hanessianꢁs reaction conditions (Sche-
me 4).[11b] Accordingly, methylation of N-Cbz-Asp-
not a big difference in steric hindrance between either side
of the enolate.[12d] However, transition-state D based on an
ordered Zimmerman–Traxler-type model could be used to
explain our results.[13,11c] The stereochemical outcome of the
alkylation reaction is due to 1,2-asymmetric induction of di-
anionic aspartates. Obviously, this transition state benefited
from increased hindrance of R and decreased hindrance of
R’ and R’’.
(OTMSE)-OMe 15a was conducted in mixed THF and
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Depsipeptide Halipeptins A–D
FULL PAPER
After our success in the highly diastereoselective methyla-
tion of aspartates, we next attempted to convert the alkyla-
tion products into the desired NMeOHIle unit 4a
(Scheme 5). Initially, methyl ester 16d was chosen for this
and the resultant acid was reacted with allyl bromide to fur-
nish the desired NMeOHIle unit 4a.
The preparation of the other two N-methyl amino acid
residues is outlined in Scheme 6. Boc-protected l-valine and
Scheme 6. Syntheses of NMeVal and NMeIle units. a) Boc2O, Na2CO3,
H2O, RT; b) NaH, MeI, THF, 08C!RT; c) allyl bromide, K2CO3, DMSO,
RT.
l-isoleucine were exposed to iodomethane and NaH,[16] fol-
lowed by esterification with allyl bromide to provide 4c
and d, respectively.
Synthesis of the a-methylthiazoline unit: As depicted in
Scheme 7, (S)-N-Boc-a-methylserine allyl ester 22 was pre-
Scheme 5. Second-generation synthesis of the NMeOHIle unit. a) aq.
LiOH, MeOH, THF; b) TFA, CH2Cl2, then CH2N2, Et2O, RT, 95 %;
c) [Pd
A
then CH2N2, Et2O, ꢀ208C!RT; e) AgNO3, H2O, THF; f) ClCO2Et,
NMM, THF, 08C then NaBH4, MeOH, 08C!RT 35% yield for 4 steps;
g) TsOH·H2O, PhH, reflux, 75%; h) TIPSCl, imidazole, DMAP, CH2Cl2,
RT, 89%; i) Pd/C, Boc2O, H2, MeOH, RT; j) Ag2O, MeI, DMF, 508C,
94% yield for 2 steps; k) aq. LiOH, THF, MeOH, then allyl bromide,
K2CO3, DMSO, RT, 92%. NMA=N-methylaniline; NMM=N-methyl-
morpholine; TIPS=triisopropylsilyl.
Scheme 7. Synthesis of a-methylthiazoline unit. a) AcCl, MeOH, reflux;
b) Boc2O, Na2CO3, THF, H2O, RT, 80% yield for 2 steps; c) aq. LiOH,
THF, MeOH, then allyl bromide, K2CO3, DMSO, RT, 94%; d) TFA,
CH2Cl2; e) 23, Et3N, CH2Cl2, 08C !RT, 50% yield for 2 steps; f) Fmo-
cOSu, Na2CO3, dioxane, H2O, 80%; g) DAST, CH2Cl2, ꢀ788C, 89%.
Fmoc=9-fluorenylmethoxycarbonyl; DAST=(diethylamino)sulphur tri-
fluoride.
purpose. Unfortunately, hydrolysis of 16d with aqueous
LiOH in methanol gave a mixture of the acid 17 and its 3-
epimer in a ratio of 5:1, indicating that partial racemization
had occurred at the C3 position of 16d. This observation
prompted us to employ compound 16e which contains an
easily removable allyl ester for further transformations. As a
result, treatment of 16e with TFA followed by esterification
of the resulting acid with diazomethane afforded methyl
ester 18. After removing the allyl-protecting group with [Pd-
pared from known compound 21[17] in three steps. After
cleavage of the Boc-protecting group in 22, the liberated
amine was condensed with known thioacylating agent 23[18]
to produce the thioamide 24 in 50% yield. Ring closure of
24 was accomplished with DAST at ꢀ788C to produce tri-
substituted thiazoline 3,[19] after switching the protecting
group of the amine from Boc to Fmoc.
A
carbon by the Arndt–Eistert reaction.[14] Reacting this prod-
uct with ethyl chloroformate and subsequent NaBH4 reduc-
tion produced the alcohol 14.[15] The stereochemistry of the
methyl group in 14 was further confirmed by NOE effects
observed in its cyclization product 19. Next, protection of 14
with TIPSCl yielded silyl ether, which was subjected to hy-
drogenolysis in the presence of di-tert-butyl carbonate, and
then methylation with iodomethane, to deliver ester 20 in
84% yield. Finally, the methyl ester of 20 was saponified
Connection of the alcohol 2 with l-alanine derivatives: Fol-
lowing our synthetic plan, the next task was esterification of
2 with suitable l-alanine derivatives (Scheme 8). The esteri-
fication was found to be very sluggish, mainly because of
the steric hindrance resulting from high methylation near
the secondary hydroxy group. This fact resulted in racemiza-
tion of l-alanine-derived activated esters. For example, the
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D. Ma et al.
Scheme 9. Synthesis of the ester 26. a) N-Fmoc-Ala-Cl (5.0 equiv),
DMAP (0.5 equiv), iPr2NEt (5.5 equiv), CH2Cl2, ꢀ158C, 37% yield, 62%
starting material was recovered.
Scheme 8.
coupling reaction of 2a with N-Boc-Ala in the presence of
DMAP (5 equiv) and EDCI (5 equiv) was completed in
24 h; however, a 1:1 mixture of 25b and its epimer were de-
tected (Table 2, entry 1). Attempts to minimize racemization
tional steric hindrance contributed by the silyl ether moiety
in 2c.
Assembly of halipeptins A–D: With all required fragments
3, 4, 25a, and 26 in hand, we started to elaborate the target
molecules by connecting them with each other. The synthe-
ses of halipeptins A (1a) and D (1d) are outlined in
Scheme 10. Removal of the allyl-protecting group from 3 by
palladium chemistry[26] gave an acid, which was coupled with
the amines liberated from 4a and d by using BEP[27] as an
Table 2. Esterification of alcohol 2a.
Entry Conditions
Product Yield
[%]
1
2
3
4
5
N-Boc-Ala (3 equiv), EDCI (5 equiv),
DMAP (5 equiv), CH2Cl2, RT
N-Boc-Ala (3 equiv), EDCI (3 equiv),
DMAP (1 equiv), CH2Cl2, RT
N-Tr-Ala (3 equiv), EDCI (5 equiv),
DMAP (5 equiv), CH2Cl2, RT
25b
95[a]
–
–
N-Boc-Ala-ONp (1.5 equiv),
–
HOBt (1.5 equiv), NMM, DMF, RT
N-Boc-Ala (2 equiv), 2,4,6-trichlorobenzoyl
chloride (2 equiv), DMAP (2 equiv),
iPr2NEt (2.5 equiv), PhH, reflux
N-Fmoc-Ala-Cl (5 equiv), DMAP (0.5 equiv),
iPr2NEt (5.5 equiv), CH2Cl2, ꢀ158C
–
6
25a
86[b]
[a] Racemization occurred at C7. [b] 10% of 2a was recovered. Tr=
trityl; Np=p-nitrophenol.
by reducing the amounts of DMAP and EDCI and by using
trityl-protected l-alanine[20] failed to give any coupling prod-
ucts (entries 2 and 3). Similar results were observed when
Yamaguchiꢁs mixed anhydride method[21] and the p-nitro-
phenol[22] activated ester procedure were employed (en-
tries 4 and 5). Other activated esters, such as succinimide[23]
and imidazolyl[24] ester, did not work either (data not
shown). At this stage we moved our attention to more reac-
tive acyl chlorides. After some experimentation, we were
gratified to find that the coupling reaction of 2a with N-
Fmoc-Ala-Cl[25] in the presence of DMAP (0.5 equiv) at
ꢀ158C worked well to afford 25a without racemization in
85% yield (entry 6). However, the reaction conditions were
quite critical, as racemization at C7 was still observed when
this reaction was conducted at 08C or when one equivalent
of DMAP was used, and poor conversion was noticed when
the amount of DMAP was reduced to 0.05 equivalents (data
not shown).
Scheme 10. Completion of syntheses of halipeptins A and D. a) [Pd-
A
By using the above optimized conditions, esterification of
HTMHD unit 2c was explored next (Scheme 9). It was
found that in this case the desired product 26 was isolated in
only 37% yield, while the starting material was recovered in
62% yield. The poor conversion might result from the addi-
CH2Cl2; d) BEP, iPr2NEt, CH2Cl2, 08C!RT; e) CH3CN, Et2NH;
f) HATU, iPr2NEt, DMF, CH2Cl2, 08C!RT; g) TBAF, THF, 70%.
BEP=2-bromo-1-ethyl-pyridinium tetrafluoroborate; HATU=N-[(dime-
thylamino)-1H-1,2,3-triazolo
thanaminium hexafluorophosphate N-oxide.
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Depsipeptide Halipeptins A–D
FULL PAPER
activating agent to deliver the amide parts 27a and d, re-
cleavage of the allyl ester in 27a or c, condensation with a li-
berated amine from 26 was carried out to afford 28b or c.
spectively. Surprisingly, two isomers in a ratio of 3:1 were
1
determined by H NMR in each coupling product, indicating
Treatment of 28b or c with [Pd(PPh3)4]/NMA and diethyla-
A
that partial racemization at C14 still occurred even under
the above mild conditions.
Deprotection of 27a and d gave free acids, which were re-
spectively coupled with the amine liberated from 25a assist-
ed by BEP to afford the precedents of macrocyclization 28a
mine subsequently provided the corresponding cyclization
precursor, which was exposed on HATU/iPr2NEt in a dilut-
ed mixture of CH2Cl2 and DMF to yield halipeptins B or C
protected as the silyl ethers. Removal of the silyl-protecting
group in these two products with aqueous HF delivered hali-
peptins B (1b) and halipeptin C (1c) and their C14 epimers,
respectively. The ratio for two isomers in these two products
was about 1:1. Interestingly, halipeptin C (1c) and its
epimer could be separated by preparative TLC, while hali-
peptin B (1b) and its epimer were inseparable. Fortunately,
the ratio for halipeptin B could be enriched to 6:1 after
treatment of the diastereomer mixture with TBAF in THF.
As expected, all analytical data of each synthetic halipep-
tin were identical with those of the corresponding natural
source compounds. Thus, the total syntheses of all the mem-
bers of the halipeptin family were achieved. The present
protocols would permit assembling halipeptin analogues in
great diversity, which will be of benefit for their structure-
activity relationship studies, as well as for exploring their
possible anti-inflammatory mechanism.
and d. Sequential deprotection of 28d ([Pd(PPh3)4]; then
A
Et2NH) followed by HATU-mediated[28] macrocyclization
furnished halipeptin D (1d) and its C14 epimer which could
be separated by preparative TLC. Similarly, a mixture of
TIPS-protected halipeptin A 29a and its C14 epimer were
obtained from 28a. Upon treatment with TBAF, we were
pleased to find that 1a was isolated as a single product. In
this case the undesired isomer might be transformed into
more thermodynamically stable halipeptin A. A similar phe-
nomenon has been observed by the groups of Wipf[3b] and
Pattenden[3c] during the syntheses of thiazoline-containing
cyclopeptides.
The elaborations of halipeptins B and C are illustrated in
Scheme 11. Deallylation of 3 with Pd0 followed by coupling
with a liberated amine from 4c produced amide 27c. After
Experimental Section
General procedure: All the reactions were carried out under an argon at-
mosphere with dry solvents under anhydrous conditions, unless otherwise
indicated. Optical rotations were measured by using a Perkin–Elmer
241MC polarimeter in the solvent indicated. IR spectra were recorded on
an AVATAR-360 spectrophotometer. 1H and 13C NMR spectra were re-
corded on a MERCURY300, Bruker DRX-400, and Bruker AV-500 spec-
trometers with TMS as the internal standard. HRMS were recorded by
using either FTMS-7 or IonSpec 4.7 spectrometers. Flash-column chro-
matography was carried out on silica gel (300–400 mesh). Yields refer to
chromatographically and spectroscopically pure compounds, unless other-
wise indicated.
Compound 6: Metal Na (1.23 g, 53.4 mmol) was added to dry MeOH
(150 mL) at 08C. After the sodium had disappeared, a solution of lactone
5 (5.67 g, 49.7 mmol) in MeOH (10 mL) was added and the mixture was
stirred at room temperature for 36 h. After this time, the reaction was
quenched with saturated NH4Cl solution (500 mL) and the product was
extracted with EtOAc (4”200 mL), washed with brine, and dried over
anhydrous Na2SO4. The extract was concentrated to give the crude alco-
hol (5.98 g, 82%) as a colorless oil.
TBSCl (9.55 g, 61.4 mmol) was added in portions to a solution of the
above alcohol and imidazole (5.55 g, 81.6 mmol) in DMF (60 mL). The
mixture was stirred at room temperature for 12 h before being diluted
with EtOAc (100 mL) and hexane (500 mL). The solution was washed
with water and brine, dried (Na2SO4), and filtered. The solvent was re-
moved in vacuo and the residue was chromatographed on silica gel (hex-
anes/EtOAc 50:1) to give silyl ether 6 (10.37 g, 98%) as a colorless oil.
[a]2D5 =+4.1 (c=1.05 in CHCl3); 1H NMR (300 MHz, CDCl3): d=3.66 (s,
1H), 3.42 (d, J=2.1 Hz, 1H), 3.41 (d, J=2.1 Hz, 1H), 2.43–2.25 (m, 2H),
1.81–1.70 (m, 1H), 1.66–1.52 (m, 1H), 1.50–1.37 (m, 1H), 0.88 (s, 9H),
0.87 (d, J=3.0 Hz, 3H), 0.01 ppm (s, 6H); EIMS: m/z: 245 [MꢀCH3]+,
203 [MꢀC4H9]+.
Scheme 11. Completion of syntheses of halipeptins B and C. a) [Pd-
Compound 7: To a stirred solution of the silyl ether 6 (4.67 g, 17.9 mmol)
in dry ether (45 mL) at ꢀ908C was added DIBAL-H (1.0m solution in
toluene, 19 mL, 19.0 mmol) over 1 h. Stirring of the reaction mixture was
continued at ꢀ908C for 30 min, and then the reaction mixture was
A
08C!RT; d) CH3CN, Et2NH; e) HATU, iPr2NEt, DMF, CH2Cl2, 08C!
RT; f) aq. HF, CH3CN, RT.
Chem. Eur. J. 2006, 12, 6572 – 6584
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6577

D. Ma et al.
quenched with MeOH (1 mL). This mixture was subsequently poured
into a saturated solution of Rochelle salts (150 mL). The resulting mix-
ture was stirred until the solution became clear and was then extracted
with ether (3”100 mL). The combined organic phase was washed with
brine, dried (Na2SO4), and concentrated to give the crude aldehyde
(4.08 g) as a colorless oil.
added. The reaction mixture was stirred at ꢀ788C for 15 min and at 08C
for 30 min, before being quenched with phosphate buffer (pH 7,
100 mL), extracted with CH2Cl2 (100 mL ” 2), washed with brine, and
dried over Na2SO4. Concentration to remove the solvent and flash chro-
matography (hexanes/EtOAc 10:1) gave aldehyde 8a (1.88 g, 85%) as a
1
colorless oil. [a]2D6 =ꢀ9.8 (c=1.2 in CHCl3); H NMR (300 MHz, CDCl3):
d=9.61 (d, J=1.8 Hz, 1H), 3.31 (s, 3H), 3.16–3.12 (m, 1H), 2.36–2.31
(m, 1H), 1.73–1.67 (m, 1H), 1.52–1.26 (m, 7H), 1.10 (d, J=6.9 Hz, 3H),
0.93–0.85 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=205.0, 80.4, 56.4,
46.3, 35.5, 30.7, 26.1, 18.4, 14.2, 13.4 ppm; IR (film): n˜ =2960, 2934, 2875,
1729, 1709, 1460, 1378, 1316, 1297, 1095 cmꢀ1; HRMS (ESI-TOF): m/z:
calcd for C10H20O2Na: 195.1355; found: 195.1371 [M+Na]+.
A solution of the crude aldehyde (4.08 g) in dry ether (10 mL) was added
dropwise to a freshly prepared solution of (+)-Ipc2BAll (18.5 mmol) in
dry ether (45 mL) at ꢀ788C. After the reaction mixture had been stirred
at ꢀ788C for 2 h and room temperature for 3 h, it was treated with
NaOH (3n, 12 mL) and H2O2 (30%, 5 mL), and was then refluxed for
2 h. The resulting mixture was extracted with ether (2”100 mL), dried
over Na2SO4, and concentrated. Flash chromatography (hexanes/EtOAc
25:1 to 15:1) gave homoallyl alcohol 7 (4.41 g, 90% for 2 steps) as a col-
orless oil. [a]2D5 =+6.3 (c=1.1 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=5.88–5.79 (m, 1H), 5.20–5.11 (m, 2H), 3.67–3.59 (m, 1H), 3.48–3.37
(m, 2H), 2.35–2.27 (m, 1H), 2.21–2.10 (m, 1H), 1.76 (s, 1H), 1.66–1.36
(m, 4H), 1.31–1.02 (m, 1H), 0.89–0.87 (m, 12H), 0.04 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=134.9, 118.0, 70.9, 68.3, 41.9, 35.7, 34.1,
29.1, 25.9, 18.3, 16.7, ꢀ5.4 ppm; IR (film): n˜ =3370, 2957, 2931, 2859,
1642, 1473, 1256, 1097, 914, 837, 776 cmꢀ1; ESIMS: m/z: 273.3 [M+H]+;
elemental analysis calcd for C15H32O2Si: C 66.11, H 11.84; found: C
65.93, H 11.82.
Compound 10a: BH3·THF (1.0m solution in THF, 11 mL) was added
dropwise to a stirred solution of N-Ts-(R)-Val (3.09 g, 11.0 mmol) in
CH2Cl2 (110 mL) at room temperature. The reaction mixture was stirred
for 30 min at this temperature and was then cooled to ꢀ788C and a solu-
tion of the aldehyde 8a (1.88 g, 10.9 mmol) in CH2Cl2 (5 mL) and 1-(tri-
methylsiloxy)-1-methoxy-2-methyl-1-propene (2.28 g, 13.2 mmol) in
CH2Cl2 (5 mL) were added subsequently. Stirring was continued for 3 h
at the same temperature and the reaction mixture was quenched with
phosphate buffer (pH 7, 100 mL), extracted with CH2Cl2 (2”100 mL),
washed with brine, and dried over Na2SO4. Concentration and flash chro-
matography (hexanes/EtOAc 15:1) gave methyl eater 10a (2.85 g, 95%)
as a colorless oil. [a]2D6 =ꢀ10.9 (c=2.2 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=3.65 (s, 3H), 3.42 (brs, 1H), 3.26 (s, 3H), 3.08–3.04 (m, 2H),
1.60–1.56 (m, 1H), 1.44–1.25 (m, 7H), 1.24 (s, 3H), 1.19–1.17 (m, 1H),
1.11 (s, 3H), 0.85 (t, J=7.0 Hz, 3H), 0.71 ppm (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=178.5, 80.9, 79.9, 56.3, 51.8, 45.8, 35.7,
34.6, 31.5, 31.2, 24.5, 21.9, 18.4, 14.2, 13.2 ppm; IR (film): n˜ =3477, 2959,
Compound 8a: NaH (60% in mineral oil, 882 mg, 22.1 mmol) was added
to
a stirred solution of alcohol 7 (1.48 g, 5.4 mmol) in dry DMF
(20 mmol). The suspension was stirred at room temperature for 1 h and
was then treated with MeI (2.0 mL, 32.0 mmol). The mixture was stirred
for 24 h before quenched with saturated NH4Cl solution (100 mL). The
product was extracted with a solution of EtOAc (30 mL) and hexane
(150 mL), washed with water and brine, dried over Na2SO4, and concen-
trated. Flash chromatography (hexanes/EtOAc 75:1) gave the methyl
ether (1.40 g, 91%) as a colorless oil. [a]2D7 =+5.1 (c=1.8 in CHCl3);
1H NMR (300 MHz, CDCl3): d=5.87–5.75 (m, 1H), 5.10–5.02 (m, 2H),
3.46–3.31 (m, 2H), 3.30 (s, 3H), 3.21–3.16 (m, 1H), 2.35–2.23 (m, 2H),
1.60–1.37 (m, 4H), 1.16–1.01 (m, 1H), 0.88–0.85 (m, 12H), 0.03 ppm (s,
6H); 13C NMR (75 MHz, CDCl3): d=134.9, 116.8, 80.7, 68.2, 56.5, 37.7,
35.9, 30.7, 28.6, 25.9, 18.3, 16.7, ꢀ5.4 ppm; IR (film): n˜ =2957, 2931, 2858,
1745, 1642, 1472, 1362, 1097, 913, 837, 776, 667 cmꢀ1; HRMS (ESI-TOF):
m/z: calcd for C16H34O2SiNa: 309.2220; found: 309.2227 [M+Na]+.
1731, 1461, 1263, 1193, 1141, 1096, 991 cmꢀ1
; ESIMS: m/z: 275.2
[M+Na]+.
Compound 2a: LiOH·H2O (189 mg, 4.50 mmol) was added to a stirred
solution of 10a (604 mg, 2.20 mmol) in THF/H2O/MeOH (10 mL, 3:1:1).
After the reaction mixture had been stirred at room temperature for
12 h, it was acidified with HCl (5%), extracted with EtOAc (3”30 mL),
washed with brine, and dried over Na2SO4. After concentration, the resi-
due was dissolved in DMSO (20 mL) and K2CO3 (920 mg, 6.66 mmol)
and allylic bromide (0.38 mL, 4.49 mmol) were successively added. The
resulting reaction mixture was stirred at room temperature for 12 h and
was then poured into water (100 mL), extracted with EtOAc (50 mL ”
3), washed with brine, and dried over Na2SO4. Concentration and flash
chromatography (hexanes/EtOAc 15:1) gave 2a (611 mg, 92% for
2 steps) as a colorless oil. [a]1D8 =ꢀ12.7 (c=1.14 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.97–5.86 (m, 1H), 5.36–5.22 (m, 2H), 4.59–4.56
(m, 2H), 3.45 (dd, J=2.3, 9.2 Hz, 1H), 3.34 (s, 3H), 3.12–3.06 (m, 2H),
1.65–1.62 (m, 1H), 1.51–1.27 (m, 8H), 1.30 (s, 3H), 1.17 (s, 3H), 0.94–
0.86 (m, 3H), 0.75 ppm (d, J=6.9 Hz, 3H); IR (film): n˜ =3477, 2960,
TBAF (1.0m solution in THF, 2.2 mL, 2.2 mmol) was added to a stirred
solution of the above methyl ether (0.58 g, 2.0 mmol) in dry THF
(10 mL). The reaction mixture was stirred at room temperature until the
substrate had been completely consumed. The solvent was removed and
the residue was directly loaded onto a silica-gel column (hexanes/EtOAc
5:1) to afford the product (0.304 g, 90%) as a colorless oil. [a]2D7 =+20.8
(c=2.2 in CHCl3); 1H NMR (300 MHz, CDCl3): d=5.83–5.69 (m, 1H),
5.07–5.00 (m, 2H), 3.46–3.35 (m, 2H), 3.33 (s, 3H), 3.21–3.13 (m, 1H),
2.40 (s, 1H), 2.29–2.20 (m, 2H), 1.60–1.34 (m, 4H), 1.26–1.17 (m, 1H),
0.87 ppm (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=134.7,
116.8, 80.6, 67.8, 56.4, 37.6, 35.7, 30.4, 28.4, 16.4 ppm; IR (film): n˜ =3402,
2934, 1642, 1459, 1195, 1095, 1044, 993, 914, 734 cmꢀ1; HRMS (EI): m/z:
calcd for C10H20O2: 172.1463; found: 172.1432 [M]+.
2935, 1730, 1650, 1460, 1390, 1257, 1137, 1097, 987, 932, 823, 770 cmꢀ1
;
ESIMS: m/z: 301.3 [M+H]+; elemental analysis calcd for C17H32O4: C
67.96, H 10.74; found: C 67.84, H 10.65.
Compound 8b: Ac2O (0.73 mL, 7.74 mmol) and Et3N (1.4 mL,
10.1 mmol) were added successively to a stirred solution of the alcohol 7
(1.06 g, 3.89 mmol) and DMAP (48 mg, 0.39 mmol) in CH2Cl2 (25 mL).
The reaction mixture was stirred at room temperature for 5 h and was
then poured into Et2O (50 mL), washed with brine, and dried over
Na2SO4. Concentration and flash chromatography (hexanes/EtOAc 50:1)
gave the ester (1.09 g, 89%) as a colorless oil. [a]2D4 =+12.0 (c=1.2 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=5.82–5.68 (m, 1H), 5.11–5.04
(m, 2H), 4.93–4.85 (m, 1H), 3.44–3.35 (m, 2H), 2.33–2.25 (m, 2H), 2.03
(s, 3H), 1.62–1.38 (m, 4H), 1.08–0.98 (m, 1H), 0.88 (s, 9H), 0.85 (d, J=
6.9 Hz, 3H), 0.03 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=170.7,
133.8, 117.6, 73.6, 68.1, 38.6, 35.6, 31.0, 28.7, 25.9, 21.2, 18.3, 16.7,
ꢀ5.4 ppm; IR (film): n˜ =3081, 2957, 1742, 1644, 1473, 1373, 1241, 1097,
Pt/C (5%, 233 mg) was added to a solution of the above alcohol (2.25 g,
13.0 mmol) in EtOAc (25 mL) and the reaction mixture was stirred
under H2 (1 atm) for 3 h. After this time, the catalyst was filtered off and
the filtrate was concentrated to give the alcohol (2.26 g, 99%) as a color-
1
less oil. [a]2D9 =+5.2 (c=0.70 in CHCl3); H NMR (300 MHz, CDCl3): d=
3.53–3.40 (m, 2H), 3.31 (s, 3H), 3.15–3.10 (m, 1H), 1.71 (s, 1H), 1.66–
1.55 (m, 1H), 1.54–1.29 (m, 6H), 1.27–1.13 (m, 2H), 0.93–0.86 ppm (m,
6H); 13C NMR (75 MHz, CDCl3): d=81.0, 68.1, 56.4, 35.8, 35.6, 30.6,
28.5, 18.5, 16.5, 14.2 ppm; IR (film): n˜ =3398, 2959, 2874, 1730, 1459,
1378, 1194, 1096, 1041, 940, 818 cmꢀ1
; HRMS (EI): m/z: calcd for
C9H19O2: 159.1385; found: 159.1398 [MꢀCH3]+.
1025, 917, 837, 776, 667 cmꢀ1
;
ESIMS: m/z: 315.3 [M+H]+, 337.3
A solution of DMSO (3.7 mL, 52.1 mmol) in CH2Cl2 (5 mL) was added
dropwise to a stirred solution of (COCl)2 (2.2 mL, 25.6 mmol) in CH2Cl2
(60 mL) at ꢀ788C. After 20 min, a solution of the above alcohol (2.26 g,
12.9 mmol) in CH2Cl2 (5 mL) was added dropwise. The mixture was stir-
red for another 15 min at ꢀ788C, and then TEA (11 mL, 79 mmol) was
[M+Na]+; elemental analysis calcd for C17H34O3Si: C 64.92, H 10.90;
found: C 65.30, 10.92.
To a stirred solution of the above ester (1.04 g, 3.32 mmol) in THF
(25 mL) was added TABF (1.0m solution in THF, 5.0 mL). After stirring
6578
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6572 – 6584

Depsipeptide Halipeptins A–D
FULL PAPER
at room temperature for 3 h, the reaction mixture was concentrated and
purified by flash chromatography (hexanes/EtOAc 3:1) to give the alco-
hol (579 mg, 87%) as a colorless oil.
39.4, 35.0, 34.8, 31.7, 25.9, 25.0, 21.7, 18.5, 18.1, 14.3, 13.4, ꢀ4.4 ppm; IR
(film): nmax =3499, 2959, 2933, 1732, 1650, 1473, 1390, 1255, 1136, 1079,
1040, 987, 938, 836, 774, 663 cmꢀ1; elemental analysis calcd (%) for
C22H44O4Si: C 65.95, H 11.07; found: C 65.89, H 10.75; HRMS (MALDI-
TOF): m/z: calcd for C22H44SiO4Na: 423.2901; found: 423.2921 [M+Na]+.
A solution of DMSO (0.89 mL, 12.5 mmol) in CH2Cl2 (1 mL) was added
dropwise to a stirred solution of (COCl)2 (0.54 mL, 6.29 mmol) in CH2Cl2
(30 mL) at ꢀ788C. After 20 min, a solution of the above alcohol (624 mg,
3.12 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stir-
red for 15 min at ꢀ788C, and then TEA (2.6 mL, 18.7 mmol) was added.
After the resulting reaction mixture had been stirred at ꢀ788C for
15 min and at 08C for 30 min, the reaction mixture was quenched with
phosphate buffer (pH 7, 50 mL), extracted with CH2Cl2 (2”50 mL),
washed with brine, and dried over Na2SO4. Concentration and flash chro-
matography (hexanes/EtOAc 10:1) gave aldehyde 8b (587 mg, 95%) as a
Compound 11: TEA (8.3 mmol) and MsCl (4.2 mmol) were successively
added to a stirred solution of 2-butyn-1-ol (3.50 g, 50 mmol) in CH2Cl2
(50 mL) at ꢀ408C. The reaction mixture was stirred at room temperature
for 2 h, diluted with CH2Cl2 (50 mL), washed with saturated NH4Cl solu-
tion and brine, and dried over Na2SO4. After concentration, the residue
was dissolved in (R)-(+)-1-phenylethylamine (11.4 mL, 90 mmol) and
stirred at room temperature overnight. Concentration and flash chroma-
tography (hexanes/EtOAc 2:1) gave the alkyne (5.60 g, 65% for 2 steps)
as a colorless oil.
1
colorless oil. [a]2D7 =+9.6 (c=1.4 in CHCl3); H NMR (300 MHz, CDCl3):
d=9.60 (s, 1H), 5.80–5.66 (m, 1H), 5.10–5.05 (m, 2H), 4.91 (p, J=6.0 Hz,
1H), 2.37–2.29 (m, 3H), 2.02 (s, 3H), 1.77–1.65 (m, 1H), 1.65–1.54 (m,
2H), 1.44–1.33 (m, 1H), 1.09 ppm (d, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=204.5, 170.7, 133.3, 117.9, 72.9, 46.0, 38.5, 30.8, 26.0,
21.1, 13.3 ppm; IR (film): n˜ =3081, 2978, 1739, 1709, 1644, 1375, 1241,
DIPEA (2.9 mL, 16.6 mmol) was added to a stirred solution of the above
oil (1.31 g, 7.56 mmol), N-Boc-Gly (1.54 g, 8.80 mmol), HOBt (1.35 g,
9.97 mmol), and EDCI (1.84 g, 9.60 mmol) at 08C. After the reaction
mixture had been stirred at room temperature for 15 h, it was diluted
with CH2Cl2 (100 mL), washed with water and brine, and dried over
Na2SO4. Concentration and flash chromatography (hexanes/EtOAc 5:1)
gave 11 (2.39 g, 96%) as a colorless oil. [a]2D5 =+98.1 (c=1.20 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.37–7.25 (m, 5H), 5.99 (q, J=3.6 Hz,
1H), 5.60 (brs, 1H), 4.16–4.12 (m, 2H), 3.76–3.54 (m, 2H), 1.83 (s, 3H),
1.61 (d, J=6.9 Hz, 3H), 1.48 ppm (s, 9H); ESIMS: m/z: 331.2 [M+H]+,
353.2 [M+Na]+.
1025, 920 cmꢀ1
; HRMS (MALDI-TOF): m/z: calcd for C11H18O3Na:
221.1148; found: 221.1156 [M+Na]+.
Compound 10b: Prepared from 8b by the same method as that described
for the preparation of 10a (80%). [a]2D4 =+0.11 (c=0.65 in CHCl3);
1H NMR (300 MHz, CDCl3): d=5.82–5.58 (m, 1H), 5.10–5.03 (m, 2H),
4.93–4.85 (m, 1H), 3.68 (s, 3H), 3.43–3.40 (m, 1H), 3.14 (brs, 1H), 2.34–
2.25 (m, 2H), 2.02 (s, 3H), 1.70–1.60 (m, 1H), 1.60–1.50 (m, 2H), 1.50–
1.20 (m, 2H), 1.28 (s, 3H), 1.15 (s, 3H), 0.73 ppm (d, J=3.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=178.7, 170.7, 133.7, 117.6, 80.1, 73.4, 52.0,
45.7, 38.5, 34.4, 31.4, 31.2, 24.9, 22.0, 21.2, 13.1 ppm; IR (film): n˜ =3500,
Compound 12: Lindlar catalyst (120 mg) was added to a solution of 11
(2.40 g, 7.3 mmol) in Et2O (70 mL). The reaction mixture was stirred at
room temperature under H2 (1 atm) for 10 h. The catalyst was filtered
off, and the filtrate was concentrated to give the crude olefin (2.2 g,
91%) as a colorless oil.
2952, 1737, 1644, 1436, 1375, 1244, 1193, 1141, 1024, 993, 919 cmꢀ1
;
ESIMS: m/z: 301.2 [M+H]+, 323.4 [M+Na]+.
A solution of the above olefin (1.89 g, 5.68 mmol) in CH2Cl2 (40 mL) and
TFA (10 mL) was stirred for 1 h at 08C. After this time the solvent was
removed in vacuo and the residue was dissolved in water (100 mL) and
TEA (2 mL) and extracted with EtOAc (3”100 mL). The combined or-
ganic phase was washed with water and brine and dried over Na2SO4.
Concentration and flash chromatography (EtOAc/MeOH 5:1) gave 12
Compound 2b: Pt/C (10%, 71 mg) was added to a solution of methyl
ester 10b (725 mg, 2.41 mmol) in EtOAc (20 mL). The reaction mixture
was stirred under H2 (1 atm) for 2 h and then the catalyst was filtered off
and the resulting filtrate was concentrated to give the crude product as a
colorless oil.
(1.27 g, 96%) as
a
colorless oil. [a]D25 =+118.2 (c=0.96 in CHCl3);
LiOH·H2O (502 mg, 12.0 mmol) was added to a stirred solution of the
above crude product in THF (9 mL), H2O (3 mL) and MeOH (3 mL).
After the mixture had been stirred at room temperature for 12 h, it was
quenched with solid KHSO4 (3.38 g, 24.8 mmol). The residue produced
was filtered off, concentrated, and then dissolved in DMSO (20 mL).
K2CO3 (974 mg, 7.05 mmol) and allyl bromide (0.40 mL, 4.73 mmol) were
added successively to this residue and the resulting mixture was stirred at
room temperature for 12 h. After this time, the reaction mixture was
poured into water (100 mL), extracted with EtOAc (3”50 mL), washed
with brine, and dried over Na2SO4. Concentration and flash chromatogra-
1H NMR (300 MHz, CDCl3): d=7.37–7.26 (m, 5H), 6.08 (q, J=6.9 Hz,
1H), 5.50–5.42 (m, 1H), 5.08–4.98 (m, 1H), 3.72–3.38 (m, 4H), 1.56–
1.51 ppm (m, 6H).
Compound 13: LiHMDS (2.4 mL of 1m solution in THF, 2.4 mmol) was
added dropwise to a solution of 12 (0.46 g, 2 mmol) in THF (10 mL) at
ꢀ788C. After the reaction mixture had been stirred at ꢀ788C for 30 min
and then at room temperature for 15 h, it was quenched with saturated
NH4Cl solution (50 mL), extracted with EtOAc (3”30 mL), washed with
brine, and dried over Na2SO4. After concentration, the residue was dis-
solved in CH2Cl2 (5 mL) and TEA (0.28 mL, 2 mmol), DMAP (12 mg,
0.1 mmol), and CbzCl (0.17 mL, 1.2 mmol) were added. The resulting
mixture was stirred at room temperature for 10 h and was then diluted
with CH2Cl2 (20 mL), washed with brine, and dried over Na2SO4. Con-
centration and flash chromatography (hexanes/EtOAc) gave a pair of di-
astereomers of 13 (3:1, the majority is the desired product). Pure 13
(0.28 g, 52% for 2 steps) was obtained by recrystallization (hexanes/
EtOAc) as a white solid. 1H NMR (300 MHz, CDCl3): d=7.38–7.26 (m,
10H), 6.07 (d, J=6.9 Hz, 1H), 5.77–5.69 (m, 1H), 5.41 (d, J=7.8 Hz,
1H), 5.13–5.06 (m, 4H), 4.14–4.04 (m, 1H), 1.47–1.38 (m, 4H), 0.98 ppm
(d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=169.8, 156.4, 143.0,
138.6, 136.2, 128.5, 128.2, 127.9, 127.4, 126.2, 116.8, 67.1, 59.0, 48.9, 40.0,
21.7, 15.7 ppm; ESIMS: m/z: 367.2 [M+H]+, 389.2 [M+Na]+.
phy (hexane/EtOAc 5:1) gave 2b (552 mg, 80%) as a colorless oil. [a]D24
=
ꢀ10.7 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=5.99–5.86 (m,
1H), 5.38–5.24 (m, 2H), 4.61–4.58 (m, 2H), 3.62–3.58 (m, 1H), 3.58–3.45
(m, 1H), 3.12 (brs, 1H), 1.70–1.62 (m, 1H), 1.60–1.38 (m, 8H), 1.32 (s,
3H), 1.19 (s, 3H), 0.94–0.91 (m, 3H), 0.77 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=177.9, 131.7, 118.6, 79.9, 71.8, 65.4, 45.9,
39.6, 35.1, 34.6, 31.9, 24.7, 22.0, 18.8, 14.1, 13.4 ppm; IR (film): n˜ =3428,
2960, 2935, 1717, 1650, 1458, 1393, 1258, 1139, 987, 932, 846, 771 cmꢀ1
;
HRMS (MALDI-TOF): m/z: calcd for C16H30O4Na: 309.2036; found:
309.2044 [M+Na]+.
Compound 2c: The alcohol 2b (528 mg, 1.84 mmol), TBSCl (431 mg,
2.86 mmol), and imidazole (250 mg, 3.67 mmol) were dissolved in DMF
(6 mL). After the reaction mixture had been stirred at room temperature
for 1.5 h, it was poured into a solution of EtOAc (10 mL) and hexane
(50 mL), washed with water and brine, and dried over Na2SO4. Concen-
tration and flash chromatography (hexanes/EtOAc 10:1) gave silyl ether
2c (700 mg, 95%) as a colorless oil. [a]2D4 =ꢀ6.6 (c=1.5 in CHCl3);
1H NMR (300 MHz, CDCl3): d=5.96–5.85 (m, 1H), 5.36–5.23 (m, 2H),
4.58 (d, J=4.8 Hz, 2H), 3.65–3.55 (m, 1H), 3.52–3.40 (m, 1H), 3.00 (d,
J=9.9 Hz, 1H), 1.68–1.60 (m, 1H), 1.48–1.25 (m, 8H), 1.30 (s, 3H), 1.17
(m, 3H), 0.90–0.80 (m, 12H), 0.75 (d, J=6.3 Hz, 3H), 0.02 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=177.8, 131.8, 118.5, 80.2, 72.3, 65.4, 46.1,
Compound 14: HCl (6m, 8 mL) was added to a stirred solution of 13
(0.37 g, 1 mmol) in MeOH (2 mL). After refluxing for 10 h, the reaction
mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic
phase was separated and the aqueous phase was extracted with EtOAc
(20 mL). The combined organic phase was washed with brine and dried
over Na2SO4. After concentration, the residue was dissolved in ether
(10 mL) and a solution of CH2N2 in ether was added dropwise until the
solution turned yellow. After the reaction mixture had been stirred for a
further 2 h, it was concentrated and flash chromatographed (hexanes/
Chem. Eur. J. 2006, 12, 6572 – 6584
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6579

D. Ma et al.
EtOAc 9:1) to give the methyl ester (0.2 g, 76% for 2 steps) as a color-
less oil.
47.6 mmol) was added, followed by the slow addition of MeOH
(150 mL). This mixture was stirred for 1 h, and then the reaction was
quenched by using HCl (10%, 100 mL). The organic solvent was re-
moved and the residue was partitioned between H2O and EtOAc. The
aqueous phase was extracted with EtOAc (2”100 mL). The combined or-
ganic phase was washed with brine and dried over Na2SO4. Concentra-
tion and flash chromatography (hexanes/EtOAc 4:1 to 2:1) gave alcohol
14.
BH3·THF was added dropwise (9.0 mL of
a 1m solution in THF,
9.0 mmol) to a stirred solution of 2-methyl-2-butene (0.95 mL, 9 mmol)
in dry THF (9 mL) at 08C. An hour later, a solution of the above methyl
ester (2.27 g, 8.2 mmol) in THF (4 mL) was added. After the reaction
mixture had been stirred at room temperature for 1 h, it was quenched
with MeOH (1 mL) at 08C and then buffer (pH 7, 10 mL) and H2O2
(30%, 10 mL) were added. This mixture was stirred at room temperature
for 14 h and was then poured into brine (150 mL) and extracted with
ether (3”100 mL). The combined organic phase was washed with saturat-
ed Na2S2O3 solution, water and brine, dried over Na2SO4, and concentrat-
ed. Flash chromatography (hexanes/EtOAc 2:1) gave 14 (1.91 g, 72%) as
TsOH·H2O (58 mg) and 4 Š MS (582 mg) were added to a solution of 14
(588 mg, 1.99 mmol) in PhH (10 mL). After refluxing for 12 h, the mix-
ture was filtered off. Concentration and flash chromatography (hexanes/
EtOAc 4:1) gave 19 (401 mg, 77%) as a white solid. [a]1D9 =+0.47 (c=
1
0.82 in MeOH); H NMR (300 MHz, CDCl3): d=7.38–7.27 (m, 5H), 5.71
a
colorless oil. [a]2D5 =+6.9 (c=1.5 in CHCl3); 1H NMR (300 MHz,
(d, J=5.7 Hz, 1H), 5.12 (s, 2H), 4.62 (t, J=6.5 Hz, 1H), 4.38–4.33 (m,
2H), 2.84–2.79 (m, 1H), 2.33–2.25 (m, 1H), 1.78–1.65 (m, 1H), 0.93 ppm
(d, J=7.1 Hz, 3H); IR (film): n˜ =3291, 3068, 2960, 1735, 1685, 1547,
1488, 1455, 1418, 1375, 1340, 1305, 1289, 1248, 1157, 1086, 1044, 987, 943,
905, 861, 759, 708, 593 cmꢀ1; elemental analysis calcd (%) for C17H17NO4:
C 63.87, H 6.51, N 5.32; found: C 63.87, H 6.51, N 5.29; ESIMS: m/z:
264.1 [M+H]+, 286.1 [M+Na]+.
CDCl3): d=7.34 (s, 5H), 5.69 (d, J=7.5 Hz, 1H), 5.11 (s, 2H), 4.38 (dd,
J=8.7, 4.5 Hz, 1H), 3.74 (s, 3H), 3.69–3.66 (m, 2H), 2.23–2.15 (m, 1H),
1.70–1.63 (m, 1H), 1.50–1.43 (m, 1H), 0.95 ppm (d, J=6.6 Hz, 3H);
ESIMS: m/z: 296.1 [M+H]+, 318.2 [M+Na]+.
Compound 16e: A solution of 15e (prepared according to ref. [29],
6.72 g, 18.6 mmol) in dry THF (80 mL) was added dropwise to a stirring
solution of LiHMDS (39.0 mL of a 1m solution in THF 39.0 mmol) and
HMPA (20 mL). After about 45 min, freshly distilled MeI (3.5 mL,
56.2 mmol, neat) was added and the reaction mixture was stirred at
ꢀ788C for 3 h. After this time, the mixture was quenched with HCl
(10%) at ꢀ788C, extracted with EtOAc (150 mL ”3), and dried over
Na2SO4. Concentration and flash chromatography (hexanes/EtOAc 15:1)
provided compound 16e (6.64 g, 95%). [a]2D1 =ꢀ6.2 (c=1.2 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.38–7.30 (m, 5H), 5.96–5.83 (m, 1H),
5.66 (d, J=8.7 Hz, 1H), 5.36–5.17 (m, 2H), 5.14 (s, 2H), 4.64–4.50 (m,
3H), 3.27–3.20 (m, 1H), 1.33 (s, 9H), 1.23 ppm (d, J=7.5 Hz, 3H); IR
(film): n˜ =3433, 2981, 1736, 1650, 1502, 1456, 1370, 1219, 1157, 1089,
1060, 985, 931, 846, 750, 698 cmꢀ1; ESIMS: m/z: 378.2 [M+H]+, 400.2
[M+Na]+.
Compound 20: Alcohol 14 (447 mg, 1.51 mmol), DMAP (19 mg,
0.16 mmol), imidazole (159 mg, 2.34 mmol), and TIPSCl (0.40 mL,
1.87 mmol) were dissolved in CH2Cl2 (5 mL). The resulting mixture was
stirred at room temperature for 12 h and was then partitioned between
water (100 mL) and EtOAc (100 mL). The organic phase was washed
with brine, dried over Na2SO4, and concentrated. Flash chromatography
(hexanes/EtOAc 100:1 to 20:1) gave the silyl ether (605 mg, 89%) as a
colorless oil. [a]1D8 =+0.43 (c=0.99 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.35–7.26 (m, 5H), 5.64 (d, J=6.0 Hz, 1H), 5.10 (s, 2H), 4.30
(dd, J=4.7, 8.9 Hz, 1H), 3.78–3.64 (m, 2H), 3.69 (s, 3H), 2.30–2.27 (m,
1H), 1.67–1.59 (m, 1H), 1.41–1.30 (m, 1H), 1.04 (s, 18H), 1.03 (s, 3H),
0.99 ppm (d, J=6.9 Hz, 3H); IR (film): n˜ =3354, 2945, 2867, 1729, 1523,
1463, 1385, 1340, 1209, 1104, 1072, 1013, 884, 738, 682, 659 cmꢀ1; ESIMS:
m/z: 452.4 [M+H]+, 474.4 [M+Na]+, 490.4 [M+K]+; elemental analysis
calcd (%) for C24H41NO5Si: C 63.82, H 9.15, N 3.10; found: C 63.94, H
8.92, N 3.18.
Compound 18: TFA (20 mL) was added to a solution of 16e (3.14 g,
8.36 mmol) in CH2Cl2 (60 mL). After the reaction mixture had been stir-
red for 3 h at room temperature, the solvent was removed. A solution of
CH2N2 in Et2O was added to a stirring solution of the residue in Et2O
(100 mL) until the solution turned yellow. When the yellow color had dis-
appeared, the solvent was removed and the residue was purified by
silica-gel column chromatography (hexanes/EtOAc 15:1) to give com-
pound 18 (2.68 g, 95%). [a]2D1 =+2.1 (c=1.1 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.38–7.30 (m, 5H), 5.94–5.83 (m, 1H), 5.70 (d, J=
9.3 Hz, 1H), 5.34–5.22 (m, 2H), 5.14 (s, 2H), 4.61–4.55 (m, 3H), 3.71 (s,
3H), 3.36–3.29 (m, 1H), 1.25 ppm (d, J=7.8 Hz, 3H); IR (film): n˜ =3359,
2954, 1734, 1649, 1508, 1457, 1438, 1388, 1214, 1089, 1062, 1002, 930, 775,
738, 699 cmꢀ1; HRMS: (MALDI-TOF): m/z: calcd for C17H21NO6Na:
358.1261; found: 358.1276 [M+Na]+.
Boc2O (180 mg, 0.82 mmol) and Pd/C (10%, 28 mg) were successively
added to a stirred solution of the above silyl ether (245 mg, 0.54 mmol)
in MeOH (5 mL). The reaction mixture was stirred at room temperature
under H2 (1 atm) for 2 h. After filtration and concentration, the residue
was dissolved in DMF (2.5 mL) and Ag2O (346 mg, 1.99 mmol) and MeI
(125 mL, 2.01 mmol) were added. This mixture was stirred at 508C over-
night and was then poured into a solution of hexane (50 mL) and EtOAc
(50 mL), washed with water and brine, and dried over Na2SO4. Concen-
tration and flash chromatography (hexanes/EtOAc 50:1) gave 20
(218 mg, 94% for 2 steps) as a colorless oil. [a]1D8 =+1.13 (c=0.95 in
1
CHCl3); H NMR (300 MHz, CDCl3): d=4.54, 4.22 (due to the rotamers,
each a d, J=10.7 Hz, 1H), 3.78–3.69 (m, 5H), 2.85, 2.83 (due to the ro-
tamers, each a s, 3H), 2.23–2.25 (m, 1H), 1.71–1.62 (m, 1H), 1.45 (s, 9H),
1.26–1.14 (m, 1H), 1.13–1.05 (m, 21H), 0.93 ppm (d, J=6.3 Hz, 3H); IR
(film): n˜ =2945, 2868, 1745, 1701, 1463, 1392, 1367, 1315, 1254, 1152,
1104, 997, 883, 738, 682, 659 cmꢀ1; ESIMS: m/z: 454.3 [M+Na]+, 470.4
[M+K]+; elemental analysis calcd (%) for C22H45NO5Si: C 61.21, H
10.51, N 3.24; found: C 61.20, H 10.32, N 3.34.
Compound 19: [Pd(PPh3)4] (537 mg, 0.46 mmol) and NMA (6.1 mL,
A
56.2 mmol) were added successively to a solution of 18 (9.53, 28.4 mmol)
in CH2Cl2 (200 mL). After the mixture had been stirred for 1 h, it was
concentrated and chromatographed (hexanes/EtOAc 5:1 to EtOAc/
MeOH 10:1) to give the crude acid.
NMM (3.5 mL, 31.8 mmol) and ClCO2iBu (4.1 mL, 31.2 mmol) were suc-
cessively added to a solution of the above acid in THF (170 mL) at
ꢀ208C. After the solution had been stirred for 15 min, CH2N2 (400 mL
of 0.4m in Et2O) was added. The mixture was warmed to room tempera-
ture over 10 h and was then quenched with H2O (400 mL). The mixture
was extracted with Et2O (3”150 mL), dried over Na2SO4, and concen-
trated. AgNO3 (5.43 g, 40.0 mmol) was added to a solution of the residue
in THF (100 mL) and H2O (10 mL). After the reaction mixture had been
stirred at room temperature for 10 h, it was concentrated and partitioned
between EtOAc and H2O. The aqueous phase was extracted with EtOAc
(2”100 mL). The combined organic phase was washed with brine and
dried over Na2SO4. Concentration and flash chromatography (hexanes/
EtOAc 5:1 to EtOAc) gave the crude acid.
Compound 4a: Prepared from 20 by the same method as for the prepara-
tion of 2a (92%). [a]1D8 =+0.50 (c=1.4 in MeOH); 1H NMR (300 MHz,
CDCl3): d=5.97–5.85 (m, 1H), 5.35–5.20 (m, 2H), 4.63–4.59 (m, 2H),
4.60, 4.26 (due to the rotamers, both a d, J=10.5 Hz, 1H), 3.78–3.68 (m,
2H), 2.84, 2.87 (due to the rotamers, each a s, 3H), 2.34–2.22 (m, 1H),
1.76–1.67 (m, 1H), 1.46 (s, 9H), 1.27–1.15 (m, 1H), 1.12–1.01 (m, 21H),
0.96 (d, J=6.6 Hz, 3H); ESIMS: m/z: 480.4 [M+Na]+, 496.3 ppm
[M+K]+; elemental analysis calcd (%) for C24H47NO5Si: C 62.98, H
10.35, N 3.06; found: C 62.75, H 10.25, N 3.17.
Compound 4c: Na2CO3 (5.17 g, 48.6 mmol) and Boc2O (7.95 g,
36.5 mmol) were added to a solution of l-valine (2.85 g, 24.3 mmol) in
H2O (40 mL) and THF (5 mL) at 08C. After the reaction mixture had
been stirred at room temperature for 12 h, it was neutralized with HCl
(10%) until pH 2 had been reached. The mixture was then extracted
NMM (2.0 mL, 18.1 mmol) and ClCO2Et (1.7 mL, 17.7 mmol) were suc-
cessively added to a solution of the above acid in THF (150 mL) at 08C.
After the solution had been stirred for 15 min, NaBH4 (1.81 g,
6580
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6572 – 6584

Depsipeptide Halipeptins A–D
FULL PAPER
with EtOAc (50 mL ”3), washed with brine, and dried over Na2SO4.
Concentration gave the crude N-Boc-valine (5.29 g, 100%).
vacuo. The residue was dissolved in CH2Cl2 (10 mL) at 08C and TEA
(0.63 mL, 4.5 mmol) was added. Ten minutes later, a solution of 23
(790 mg, 2.24 mmol) in CH2Cl2 was added. The reaction mixture was left
at room temperature for 12 h, and a further portion of 23 (393 mg,
1.12 mmol) was added. After another 12 h, concentration and flash chro-
matography (hexanes/EtOAc 6:1 to 3:1) gave 24 (391 mg, 50% for
2 steps) as light yellowfoam. [ a]2D7 =ꢀ41.0 (c=1.03 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.49 (s, 1H), 6.00–5.82 (m, 1H), 5.36–5.15 (m,
3H), 4.66 (d, J=4.2 Hz, 2H), 4.43 (d, J=11.4 Hz, 1H), 4.39–4.30 (m,
1H), 4.09 (d, J=10.8 Hz, 1H), 2.90 (brs, 1H), 1.71 (s, 3H), 1.42 ppm (m,
12H); IR (film): n˜ =3315, 2982, 2935, 1695, 1510, 1450, 1369, 1282, 1251,
1166, 1053, 987, 935, 859, 734 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C15H26N2O5SNa: 369.1455; found: 369.1454 [M+Na]+.
NaH (60% in mineral oil, 4.91 g, 122.7 mmol) was added in ortions to a
solution of N-Boc-valine (5.29 g, 24.3 mmol) and MeI (12.1 mL,
184 mmol) in THF (100 mL) at 08C. After the reaction mixture had been
stirred at room temperature for 36 h, it was poured into saturated NH4Cl
solution (500 mL), extracted with EtOAc (3”150 mL) and dried over
Na2SO4. Concentration gave N-methyl-N-Boc-valine (5.16 g, 92%).
K2CO3 (6.17 g, 44.7 mmol) and allyl bromide (2.8 mL, 33.1 mmol) were
added to a solution of N-methyl-N-Boc-valine (5.16 g, 22.3 mmol) in
DMSO (80 mL). After the mixture had been stirred at room temperature
for 12 h, it was partitioned between EtOAc (150 mL) and brine
(150 mL). The organic phase was separated and the aqueous phase was
extracted with EtOAc (2”100 mL). The combined organic phase was
dried over Na2SO4 and concentrated. Flash chromatography gave 4c
Compound 3: A solution of 24 (0.391 g, 1.13 mmol) in CH2Cl2 (6 mL)
was treated with TFA (2 mL) and the mixture was stirred at room tem-
perature for 2 h. After this time, the solvent was removed in vacuo and
the residue was dissolved in dioxane (5 mL) and water (5 mL). Na2CO3
(304 mg, 2.87 mmol) and FmocOSu (474 mg, 1.26 mmol) were added suc-
cessively to the mixture and it was then stirred at room temperature
overnight. The reaction mixture was diluted with water (50 mL), extract-
ed with EtOAc (3”30 mL), washed with brine, and dried over Na2SO4.
Concentration and flash chromatography (hexanes/EtOAc 4:1 to 2:1)
gave N-Fmoc thioamide (396 mg, 75% for 2 steps) as a colorless foam.
1
(5.52 g, 91%) as a colorless oil. [a]2D4 =ꢀ85.1 (c=1.1 in CHCl3); H NMR
(300 MHz, CDCl3): d=5.97–5.84 (m, 1H), 5.34–5.20 (m, 2H), 4.62–4.60
(m, 2H), 4.47, 4.12 (due to the rotamers, both a d, J=10.5 Hz, 1H), 2.85,
2.81 (due to the rotamers, both a s, 3H), 2.21–2.17 (m, 1H), 1.45 (s, 9H),
0.97 (d, J=6.3 Hz, 3H), 0.89 ppm (d, J=6.3 Hz, 3H); IR (film): n˜ =2971,
2935, 1741, 1700, 1473, 1392, 1368, 1330, 1313, 1147, 993, 879, 773 cmꢀ1
;
ESIMS: m/z: 294.2 [M+Na]+, 272.2 [M+H]+; elemental analysis calcd
(%) for C14H25NO4: C 61.97, H 9.29, N 5.16; found: C 62.24, H 9.45, N
5.14.
1
[a]2D7 =ꢀ19.4 (c=1.12 in CHCl3); H NMR (300 MHz, CDCl3): d=8.49 (s,
1H), 7.76 (d, J=7.2 Hz, 2H), 7.61–7.57 (m, 2H), 7.43–7.34 (m, 2H),
7.31–7.27 (m, 2H), 5.94–5.84 (m, 1H), 5.57 (d, J=6.6 Hz, 1H), 5.35–5.22
(m, 2H), 4.66 (d, J=5.7 Hz, 2H), 4.50–4.31 (m, 4H), 4.20 (t, J=7.1 Hz,
1H), 3.97 (d, J=10.8 Hz, 1H), 2.89 (brs, 1H), 1.72 (s, 3H), 1.47 ppm (m,
3H); IR (film): n˜ =3309, 2985, 2947, 1706, 1514, 1450, 1370, 1248, 1230,
1128, 1053, 987, 937, 760, 741, 621 cmꢀ1; HRMS (ESI-TOF): m/z: calcd
for C25H28N2O5SNa: 491.1611; found: 491.1622 [M+Na]+.
Compound 4d: Prepared from l-isoleucine by the same method as for
the preparation of 4c (76% for 3 steps). [a]2D1 =ꢀ74.7 (c=1.1 in CHCl3);
1H NMR (300 MHz, CDCl3): d=5.97–5.84 (m, 1H), 5.34–5.20 (m, 2H),
4.62–4.60 (m, 2H), 4.55, 4.26 (due to the rotamers, both a d, J=11.1 Hz,
1H), 2.81, 2.78 (due to the rotamers, both a s, 3H), 2.04–1.95 (m, 1H),
1.45 (m, 10H), 1.13–1.01 (m, 1H), 0.92 (d, J=6.0 Hz, 3H), 0.87 (d, J=
7.2 Hz, 3H); IR (film): n˜ =3089, 2971, 2936, 2880, 1741, 1701, 1650, 1480,
1456, 1393, 1367, 1313, 1255, 1183, 1145, 1047, 990, 931, 871, 773 cmꢀ1; el-
emental analysis calcd (%) for C15H27NO4: C 63.13, H 9.54, N 4.91;
found: C 63.15, H 9.72, N 4.97; ESIMS: m/z: 286.1 [M+H]+.
A
solution of the above thioamide (0.518 g, 1.11 mmol) in CH2Cl2
(10 mL) at ꢀ788C was treated with DAST (0.22 mL, 1.67 mmol). After
the mixture had been stirred at ꢀ788C for 30 min, it was quenched with
K2CO3 (307 mg), poured into brine, extracted with CH2Cl2 (3”50 mL)
and dried over Na2SO4. Concentration and flash chromatography (hex-
anes/EtOAc 4:1) gave 3 (0.447 g, 89%) as a colorless foam. [a]2D7 =ꢀ6.2
(c=0.53 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.82–7.76 (m, 2H),
7.64–7.59 (m, 2H), 7.43–7.38 (m, 2H), 7.34–7.29 (m, 2H), 6.01–5.88 (m,
1H), 5.61 (d, J=7.8 Hz, 1H), 5.38–5.25 (m, 2H), 4.70 (d, J=5.1 Hz, 2H),
4.69–4.60 (m, 1H), 4.46–4.33 (m, 2H), 4.24 (t, J=6.9 Hz, 1H), 3.81 (d,
J=11.1 Hz, 1H), 3.21 (d, J=11.4 Hz, 1H), 1.57 (s, 3H), 1.47 ppm (d, J=
6.9 Hz, 3H); IR (KBr): n˜ =3188, 3004, 2916, 1729, 1712, 1621, 1539, 1479,
1451, 1385, 1293, 1251, 1166, 1112, 1066, 1028, 980, 934, 749, 663,
574 cmꢀ1; ESIMS: m/z: 451.3 [M+H]+, 473.2 [M+Na]+, 489.3 [M+K]+;
elemental analysis calcd (%) for C25H26N2O4S: C 66.64, H 5.82, N 6.22;
found: C 66.47, H 5.42, N 6.20.
Compound 22: AcCl (20 mL) was added to a solution of 21 (prepared ac-
cording to the literature,[17] 1.05 g, 4.59 mmol) in MeOH (40 mL) at 08C.
After the mixture had been refluxed for 10 h, the solvent was removed.
The residue was dissolved in THF (25 mL) and H2O (5 mL). Na2CO3
(1.24 g, 1.17 mmol) and Boc2O (1.60 g, 7.34 mmol) were added and the
resulting mixture was stirred for 10 h and then another portion of Boc2O
(0.80 g, 3.67 mmol) was added. After another 10 h, the solvent was re-
moved. The residue was partitioned between EtOAc (50 mL) and H2O
(50 mL). The aqueous phase was extracted with EtOAc (2”50 mL). The
combined organic phase was washed with brine and dried over Na2SO4.
Concentration and flash chromatography gave the methyl ester (857 mg,
80%) as a colorless oil.
LiOH·H2O (409 mg, 9.75 mmol) was added to a stirred solution of the
above ester (1.12 g, 4.80 mmol) in THF/H2O/MeOH (20 mL, 3:1:1).
After the mixture had been stirred at 08C for 1 h, the reaction mixture
was quenched with KHSO4 (2.63 g). The solvent was removed in vacuo,
and the resulting residue was diluted with EtOAc (150 mL), filtered, and
dried over Na2SO4. The solvent was removed, the residue was dissolved
in DMSO (20 mL), and K2CO3 (1.99 g, 14.4 mmol) and allylic bromide
(0.82 mL, 9.70 mmol) were successively added. This mixture was stirred
at room temperature for 12 h, before being poured into water (100 mL),
extracted with EtOAc (100 mL ”3), washed with brine, and dried over
Na2SO4. Concentration and flash chromatography (hexanes/EtOAc 3:1)
gave 22 (1.09 g, 88% for 2 steps) as a colorless oil. [a]1D9 =ꢀ11.0 (c=1.04
Compound 25a: DIPEA (112 mL, 0.64 mmol) was added dropwise to a
stirred solution of 2a (35 mg, 0.12 mmol), N-Fmoc-Ala-Cl (193 mg,
0.59 mmol), and DMAP (7.5 mg, 61 mmol) in CH2Cl2 (2 mL) at ꢀ158C.
After the mixture had been stirred at ꢀ158C for 5 h, it was poured into
water (20 mL) and extracted with CH2Cl2 (2”20 mL). The combined or-
ganic phase was washed with HCl (5%) and brine, dried over Na2SO4,
and concentrated. Flash chromatography (hexanes/EtOAc 25:1 to 15:1)
gave 25a (60 mg, 86%) as a colorless oil and 2a (3.5 mg). [a]2D5 =+1.6
(c=0.98 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.76 (d, J=7.8 Hz,
2H), 7.60 (d, J=7.5 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.30 (t, J=7.2 Hz,
2H), 5.95–5.84 (m, 1H), 5.41–5.18 (m, 4H), 4.55 (d, J=5.4 Hz, 2H),
4.44–4.37 (m, 3H), 4.22 (t, J=6.8 Hz, 1H), 3.25 (s, 3H), 3.04- 3.08 (m,
1H). 1.78–1.66 (m, 1H), 1.45 (d, J=7.2 Hz, 3H), 1.42–1.25 (m, 8H), 1.21
(s, 6H), 0.91–0.82 ppm (m, 6H); IR (film): n˜ =3341, 2957, 2937, 1731,
1527, 1452, 1391, 1337, 1252, 1209, 1182, 1145, 1078, 964, 759, 741,
622 cmꢀ1; elemental analysis calcd (%) for C35H47NO7: C 70.80, H 7.98, N
2.36; found: C 70.77, H 8.00, N 2.17; HRMS (ESI-TOF): m/z: calcd for
C35H47NO7Na: 616.3244; found: 616.3224 [M+Na]+.
1
in MeOH); H NMR (300 MHz, CDCl3): d=5.97–5.86 (m, 1H), 5.38–5.22
(m, 3H), 4.68- 4.64 (m, 2H), 3.99 (d, J=10.1 Hz, 1H), 3.79 (d, J=
10.1 Hz, 1H), 3.31 (brs, 1H), 1.48 (s, 3H), 1.41 ppm (s, 9H); IR (film):
n˜ =3412, 2981, 2941, 1718, 1650, 1502, 1456, 1393, 1369, 1299, 1552, 1171,
1129, 1058, 987, 933, 783 cmꢀ1; EIMS: m/z: 228 [Mꢀ31]+, 204 [Mꢀ55]+;
elemental analysis calcd (%) for C12H21NO5: C 55.58, H 8.16, N 5.40;
found: C 55.45, H 8.32, N 5.35.
Compound 26: Prepared from 2c by the same method as that described
for the preparation of 25a (37%, 60%, 2c was recovered). [a]2D3 =+1.7
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.75 (d, J=7.2 Hz,
Compound 24: A solution of the allyl ester 22 (0.58 g, 2.24 mmol) in
CH2Cl2 (15 mL) was treated with TFA (5 mL). The resulting mixture was
stirred at room temperature for 2 h, and then the solvent was removed in
Chem. Eur. J. 2006, 12, 6572 – 6584
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6581

D. Ma et al.
2H), 7.58 (d, J=7.5 Hz, 2H), 7.38 (t, J=7.2 Hz, 2H), 7.29 (t, J=7.5 Hz,
2H), 5.93–5.83 (m, 1H), 5.40 (d, J=7.2 Hz, 1H), 5.34–5.16 (m, 3H), 4.54
(d, J=5.4 Hz, 2H), 4.42–4.35 (m, 3H), 4.21 (t, J=6.9 Hz, 1H), 3.60–3.50
(m, 1H), 1.78–1.65 (m, 1H), 1.43 (d, J=6.9 Hz, 3H), 1.43–1.30 (m, 8H),
1.19 (s, 6H), 0.92–0.78 (m, 15H), 0.00 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3): d=175.2, 143.8, 141.3, 132.0, 127.7, 127.1, 125.1, 120.0, 118.5,
80.9, 72.2, 67.0, 65.5, 49.8, 47.2, 46.9, 39.3, 34.9, 34.7, 31.7, 25.9, 22.6, 21.3,
18.9, 18.5, 18.1, 15.2, 14.3, ꢀ4.37, ꢀ4.45 ppm; IR (film): n˜ =3348, 2957,
2934, 2858, 1733, 1651, 1526, 1452, 1338, 1255, 1209, 1143, 1076, 1039,
1006, 964, 836, 775, 759, 740, 622 cmꢀ1; elemental analysis calcd (%) for
C40H59NO7Si: C 69.23, H 8.57, N 2.02; found: C 69.32, H 8.45, N 2.07;
HRMS (MALDI-TOF): m/z: calcd for C40H59NO7SiNa: 716.3950; found:
716.3938 [M+Na]+.
A solution of 29a (2.6 mg, 3.3 mmol) in THF (0.5 mL) was treated with
TBAF (6 mL of a 1m solution in THF, 6 mmol). The mixture was stirred
at room temperature for 48 h. Concentration and preparative TLC
(EtOAc) gave halipeptin A (1a) (1.4 mg, 70%). [a]2D7 =ꢀ13.6 (c=0.20 in
CHCl3), (lit.[1a] [a]D =ꢀ16.6 (c=2.9 in CHCl3)); 1H NMR (500 MHz,
CDCl3): d=7.21 (d, J=7.9 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 5.08 (d, J=
10.2 Hz, 1H), 4.82 (q, J=7.1 Hz, 1H), 4.78 (q, J=7.4 Hz, 1H), 4.71 (d,
J=2.4 Hz, 1H), 4.16 (d, J=12.1 Hz, 1H), 3.75–3.80 (m, 1H), 3.70–3.64
(m, 1H), 3.29 (d, J=11.9 Hz, 1H), 3.30 (s, 3H), 3.12–3.06 (m, 1H), 2.82
(s, 3H), 2.54–2.49 (m, 1H), 1.93–1.88 (m, 1H), 1.51 (d, J=6.9 Hz, 3H),
1.48 (s, 3H), 1.42 (d, J=7.2 Hz, 3H), 1.39–1.28 (m, 10H), 1.20 (s, 3H),
1.13 (s, 3H), 1.00 (d, J=6.9 Hz, 3H), 0.87–0.93 (m, 3H), 0.81 ppm (d, J=
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=174.4, 173.6, 172.5, 169.7,
169.2, 84.0, 82.6, 80.6, 64.7, 60.8, 56.5, 49.6, 48.6, 45.8, 44.3, 35.8, 35.3,
34.3, 32.0, 31.3, 30.7, 28.2, 26.2, 23.1, 22.4, 22.1, 18.5, 18.4, 18.1, 14.5,
14.3 ppm; HRMS (ESI-TOF): m/z: calcd for C31H54N4O7SNa: 649.3605;
found: 649.3620 [M+Na]+.
Compound 27a: AlCl3 (25 mg, 0.19 mmol) was added in portions to a
stirred solution of 4a (57 mg, 0.12 mmol) in dry CH2Cl2 (2 mL) at 08C.
The suspension was vigorously stirred at room temperature for 2 h and
was then neutralized with saturated NaHCO3 solution, extracted with
EtOAc (3”10 mL), and dried over Na2SO4. Concentration and flash
chromatography (hexane/EtOAc 4:1) gave the free amine.
Halipeptin D (1d) and epi-halipeptin D (epi-1d): Halipeptins 1d and
epi-1d were prepared from 3, 4d, and 25a by the same method as that
described for the preparation of 29a, and were separated by preparative
TLC (CH2Cl2/acetone 20:1).
[Pd(PPh3)4] (25 mg, 22 mmol) and NMA (55 mL, 0.51 mmol) were added
N
to a solution of 3 (76 mg, 0.17 mmol) in CH2Cl2 (2 mL). After the mix-
ture had been stirred at room temperature for 30 min, it was diluted with
CH2Cl2, washed with 5% HCl and brine, and dried over Na2SO4. Con-
centration gave the crude carboxyl acid.
Halipeptin
D
(1d): Yield: 8% for 7 steps; [a]2D3 =ꢀ29.1 (c=0.3 in
CHCl3), (lit.[1c] [a]D25 =ꢀ26.0 (c=2.9 in CHCl3)); 1H NMR (500 MHz,
CDCl3): d=7.22 (d, J=7.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.01 (d, J=
10.4 Hz, 1H), 4.84 (q, J=7.2 Hz, 1H), 4.79 (q, J=7.0 Hz, 1H), 4.71 (d,
J=2.4 Hz, 1H), 4.15 (d, J=12.0 Hz, 1H), 3.31 (d, J=12.0 Hz, 1H), 3.31
(s, 3H), 3.12–3.05 (m, 1H), 2.80 (s, 3H), 2.25–2.18 (m, 1H), 1.95–1.87 (m,
1H), 1.51 (d, J=7.0 Hz, 3H), 1.50–1.30 (m, 10H), 1.46 (s, 3H), 1.41 (d,
J=7.2, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 1.00–0.85 (m, 9H), 0.81 ppm (d,
J=6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=177.3, 173.6, 172.6,
169.6,169.4, 84.0, 82.7, 80.6, 65.1, 56.5, 49.5, 48.6, 45.8, 44.4, 35.7, 34.3,
33.6, 32.0, 31.3, 30.7, 26.2, 25.1, 23.2, 22.3, 22.0, 18.5, 18.1, 17.7, 14.4, 14.3,
12.6 ppm; HRMS (MALDI-TOF): m/z: calcd for C31H55N4O6S: 611.3867;
found: 611.3841 [M+H]+.
DIPEA (120 mL, 0.69 mmol) was added to a stirred solution of BEP
(103 mg, 0.38 mmol) and the above amine and acid in CH2Cl2 (2 mL) at
08C. The reaction mixture was stirred at room temperature overnight.
Flash chromatography (hexane/EtOAc 6:1) gave a pair of epimers of 27a
(67 mg, 71% for 2 steps) as
a
colorless foam. 1H NMR (300 MHz,
CDCl3): d=7.76 (d, J=7.5 Hz, 2H), 7.59 (d, J=6.9 Hz, 2H), 7.43–7.38
(m, 2H), 7.33–7.27 (m, 2H), 5.95–5.80 (m, 1H), 5.51–5.21 (m, 3H), 4.97–
4.897 (m, 1H), 4.65–4.50 (m, 3H), 4.48–4.37 (m, 2H), 4.25–4.05 (m, 2H),
3.81–3.63 (m, 2H), 3.37–2.89 (m, 4H), 2.46–2.34 (m, 1H), 1.80–1.73 (m,
1H), 1.57–1.52 (m, 3H), 1.47–1.39 (m, 3H), 1.27–1.22 (m, 1H), 1.11–
0.92 ppm (m, 24H); HRMS (ESI-TOF): m/z: calcd for C41H59N3O6SSiNa:
772.3786; found: 772.3755 [M+Na]+.
epi-Halipeptin D (epi-1d): Yield: 8% for 6 steps; [a]2D3 =ꢀ17.5 (c=0.45
in CHCl3) (lit.[2e] [a]D32 =ꢀ13.8 (c=0.45 in CHCl3)); 1H NMR (500 MHz,
CDCl3): d=6.80 (d, J=5.2 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 5.32 (d, J=
10.2 Hz, 1H), 4.86 (q, J=7.3 Hz, 1H), 4.77 (q, J=6.3 Hz, 1H), 4.74 (s,
1H), 4.03 (d, J=12.1 Hz, 1H), 3.34 (d, J=12.1 Hz, 1H), 3.29 (s, 3H),
3.10–3.08 (m, 1H), 2.81 (s, 3H), 2.23–2.10 (m, 1H), 2.15–2.00 (m, 1H),
1.47 (d, J=6.7 Hz, 3H), 1.45–1.25 (m, 10H), 1.45 (s, 3H), 1.35 (d, J=7.1,
3H), 1.25 (s, 3H), 1.13 (s, 3H), 1.02 (d, J=6.4 Hz, 3H), 1.00 (t, J=
7.2 Hz, 3H), 0.91 (t, J=7.1 Hz, 3H), 0.68 ppm (d, J=6.8 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=176.9, 173.6, 172.8, 170.4, 169.4, 84.9,
82.3, 80.6, 64.9, 56.5, 49.2, 49.1, 45.2, 43.4, 35.7, 33.5, 33.0, 32.4, 31.2, 30.7,
25.6, 24.4, 23.3, 22.9, 21.5, 19.6, 18.5, 17.5, 14.3, 14.1, 12.5 ppm; HRMS
(MALDI-TOF): m/z: calcd for C31H55N4O6S: 611.3867; found: 611.3841
[M+H]+.
Compound 28a: A solution of 25a (46 mg, 77 mmol) in CH3CN (1 mL)
and Et2NH (0.5 mL) was stirred for 30 min. Concentration and flash
chromatography (hexane/EtOAc 10:1 to 1:1) gave the free amine.
[Pd(PPh3)4] (10 mg, 8.7 mmol) and NMA (19 mL, 0.17 mmol) were added
N
to a solution of 27a (43 mg, 0.057 mmol) in CH2Cl2 (1 mL). After the re-
action mixture had been stirred at room temperature for 30 min, flash
chromatography (hexane/EtOAc 5:1 to EtOAc/MeOH 50:1) gave the
crude carboxyl acid.
DIPEA (50 mL, 0.29 mmol) was added to a stirred solution of BEP
(42 mg, 0.15 mmol) and the above amine and acid in CH2Cl2 (1 mL) at
08C. The reaction mixture was stirred at room temperature overnight.
Flash chromatography (hexane/EtOAc 4:1) gave a pair of diastereomers
1
Compound 28b: Prepared from 26 and 27a by the same method as for
the preparation of 28a. 1H NMR (300 MHz, CDCl3): d=7.74 (d, J=
7.2 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=6.6 Hz, 2H), 7.40–7.36
(m, 2H), 7.30–7.24 (m, 2H), 6.70 (d, J=8.1 Hz, 1H), 5.91–5.80 (m, 1H),
5.37–5.15 (m, 3H), 4.62–4.52 (m, 4H), 4.45–3.99 (m, 4H), 3.69–3.48 (m,
3H), 3.34–2.85 (m, 4H), 2.69–2.37 (m, 1H), 2.10–1.95 (m, 1H), 1.56–1.17
(m, 23H), 1.10–0.60 (m, 39H), 0.04–0.00 ppm (m, 6H); HRMS (MALDI-
TOF): m/z: calcd for C63H102N4O10SSi2Na: 1185.6747; found: 1185.6763
[M+Na]+.
of 28a (43 mg, 71% for 2 steps) as a colorless foam. H NMR (300 MHz,
CDCl3): d=7.76 (d, J=6.6 Hz, 2H), 7.60 (d, J=6.6 Hz, 2H), 7.42–7.36
(m, 2H), 7.33–7.28 (m, 2H), 6.80–6.61 (m, 1H), 5.95–5.82 (m, 1H), 5.36–
5.09 (m, 3H), 4.74–4.42 (m, 5H), 4.40–3.94 (m, 3H), 3.74–3.62 (m, 3H),
3.37–2.87 (m, 3H), 2.51–2.41 (m, 1H), 2.07–1.59 (m, 14H), 1.54–1.38 (m,
13H), 1.04 (s, 21), 0.98–0.71 ppm (m, 9H); ESIMS: m/z: 1063.7 [M+H]+,
1085.8 [M+Na]+.
Halipeptin
A
(1a): [Pd(PPh3)4] (3.5 mg, 3.0 mmol) and NMA (8 mL,
A
74 mmol) were added to a solution of 28a (20 mg, 19 mmol) in CH2Cl2
(1 mL), and the reaction mixture was stirred at room temperature for
30 min. Flash chromatography (hexanes/EtOAc 5:1 to EtOAc/MeOH
100:1) gave the crude carboxyl acid. A solution of the acid in CH3CN
(0.35 mL) and Et2NH (0.35 mL) was stirred for 30 min. Concentration
gave the amino acid. DIPEA (21 mL, 0.12 mmol) was added to a stirred
solution of the amino acid and HATU (23 mg, 0.060 mmol) in CH2Cl2
(8 mL) and DMF (2 mL) at 08C. The reaction mixture was stirred at
room temperature for 3 d, after which time, the solvent was removed and
the residue was purified by flash chromatography (hexanes/EtOAc 6:1 to
3:1) to give a pair of diastereomers 29a (6.7 mg, 45% for 3 steps) as a
colorless foam.
Halipeptin B (1b) and epi-halipeptin B (epi-1b): The halipeptin B silyl
derivative was prepared from 28b by the same method as that described
for the preparation of 29a (33% for 4 steps).
HF (40%, 0.05 mL) was added to a solution of the above silyl ether
(25 mg, 0.028 mmol) in CH3CN (1 mL). After the mixture had been stir-
red for 2 h, it was partitioned between H2O (10 mL) and EtOAc
(10 mL). The organic phase was separated and the aqueous phase was ex-
tracted with EtOAc (10 mL). The combined organic phase was washed
with brine and dried over Na2SO4. Preparative TLC (EtOAc/MeOH
20:1) gave a pair of diastereomers 1b and epi-1b (13 mg, 76%) in a ratio
of about 1:1.
6582
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6572 – 6584

Depsipeptide Halipeptins A–D
FULL PAPER
TBAF (30 mL, 30 mmol) and hexylOTBS (3.3 mg, 15 mmol) were added to
a solution of 1b/epi-1b (9 mg, 15 mmol). After the mixture had been stir-
red at room temperature for 48 h, it was purified by preparative TLC to
give a pair of diastereomers, 1b and epi-1b (4.5 mg, 50%), in the ratio of
about 6:1. [a]2D3 =ꢀ22.7 (c=0.95 in CHCl3) (lit.[1a] [a]D =ꢀ22.7 (c=0.2 in
CHCl3)); 1H NMR (300 MHz, CDCl3): major: d=7.21 (d, J=7.2 Hz,
1H), 7.02 (d, J=8.4 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.87–4.80 (m,
1H), 4.78–4.73 (m, 1H), 4.72 (d, J=2.7 Hz, 1H), 4.16 (d, J=12.0 Hz,
1H), 3.85–3.75 (m, 1H), 3.75–3.62 (m, 1H), 3.62–3.50 (m, 1H), 3.30 (d,
J=11.4 Hz, 1H), 2.82 (s, 3H), 2.60–2.43 (m, 1H), 2.00–1.90 (m, 1H),
1.55–1.30 (m, 10H), 1.51 (d, J=7.5 Hz, 3H), 1.48 (s, 3H), 1.42 (d, J=
6.9 Hz, 3H), 1.21 (s, 3H), 1.13 (s, 3H), 0.98 (d, J=6.0 Hz, 3H), 0.92 (t,
J=6.9 Hz, 3H), 0.81 ppm (d, J=6.9 Hz, 3H); minor: d=6.82 (d, J=
5.7 Hz, 1H), 6.60 (d, J=9.3 Hz, 1H), 5.39 (d, J=9.9 Hz, 1H), 4.87–4.73
(m, 3H), 4.05 (d, J=12.0 Hz, 1H), 3.85–3.75 (m, 1H), 3.75–3.62 (m, 1H),
3.62–3.50 (m, 1H), 3.34 (d, J=11.7 Hz, 1H), 2.83 (s, 3H), 2.40–2.30 (m,
1H), 2.18–2.08 (m, 1H), 1.55–1.30 (m, 10H), 1.51 (d, J=7.5 Hz, 3H),
1.50 (s, 3H), 1.38 (d, J=5.4 Hz, 3H), 1.21 (s, 3H), 1.13 (s, 3H), 1.06 (d,
J=5.7 Hz, 3H), 0.92 (t, J=6.9 Hz, 3H), 0.68 ppm (d, J=6.9 Hz, 3H);
HRMS (MALDI-TOF): m/z: calcd for C30H52N4O7SNa: 635.3449; found:
635.3467 [M+Na]+.
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences, National
Natural Science Foundation of China (grant 20321202) and the Science
and Technology Commission of Shanghai Municipality (grants
02 JC14032 and 03XD14001) for their financial support.
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Compound 27c: Prepared from 3 and 4c by the same method as descri-
bed for the preparation of 27a (82%). 1H NMR (300 MHz, CDCl3): d=
7.76 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H),
7.41 (d, J=7.5 Hz, 2H), 7.31 (d, J=6.6 Hz, 2H), 5.90–5.84 (m, 1H), 5.43–
5.21 (m, 2H), 4.80–4.54 (m, 3H), 4.42–4.20 (m, 2H), 4.25–4.21 (m, 2H),
3.33–2.98 (m, 4H), 2.29–2.23 (m, 1H), 1.53 (d, J=7.5 Hz, 3H), 1.01–
0.78 ppm (m, 6H); ESIMS: m/z: 564.5 [M+H]+, 586.4 [M+Na]+.
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Compound 28c: Prepared from 27c and 26 by the same method as de-
scribed for the preparation of 28a (70%). 1H NMR (300 MHz, CDCl3):
d=7.71 (d, J=6.6 Hz, 2H), 7.70–7.65 (m, 1H), 7.56 (d, J=6.9 Hz, 2H),
7.40–7.30 (m, 2H), 7.28–7.18 (m, 2H), 6.70–6.64 (m, 1H), 5.92–5.78 (m,
1H), 5.36–5.14 (m, 3H), 4.81–4.45 (m, 4H), 4.43–3.96 (m, 4H), 3.56–3.50
(m, 2H), 3.26–2.81 (m, 3H), 2.50–2.23 (m, 1H), 1.75–1.60 (m, 2H), 1.50–
1.10 (m, 23H), 1.10–0.60 (m, 21H), 0.00 ppm (s, 6H); HRMS (MALDI-
TOF): m/z: calcd for C53H80N4O9SSiNa: 999.5308; found: 999.5313
[M+Na]+.
Halipeptin C (1c) and epi-halipeptin C (epi-1c): Halipeptins 1c and epi-
1c were prepared from 28a by the same method as that described for the
preparation of 1b/epi-1b, which were separated by preparative TLC
(CH2Cl2/MeOH 25:1).
Halipeptin C (1c): Yield: 23% for 4 steps; [a]2D3ꢀ33.4 (c=0.30 in CHCl3),
(lit.[1b] [a]D =ꢀ30 (c=0.3 in CHCl3)); 1H NMR (500 MHz, CDCl3): d=
7.23 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.99 (d, J=10.3 Hz,
1H), 4.83 (q, J=7.4 Hz, 1H), 4.74 (q, J=7.3 Hz, 1H), 4.71 (d, J=2.6 Hz,
1H), 4.16 (d, J=12.1 Hz, 1H), 3.60–3.50 (m, 1H), 3.31 (d, J=12.0 Hz,
1H), 2.81 (s, 3H), 2.60–2.51 (m, 1H), 1.98–1.93 (m, 1H), 1.51 (d, J=
6.8 Hz, 3H), 1.50 (s, 3H), 1.45–1.25 (m, 8H), 1.41 (d, J=7.2 Hz, 3H),
1.20 (s, 3H), 1.16 (s, 3H), 0.98 (d, J=6.4 Hz, 3H), 0.93 (d, J=7.1 Hz,
3H), 0.91 (t, J=7.0 Hz, 3H), 0.80 ppm (d, J=6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=177.2, 173.6, 172.6, 169.8, 169.5, 84.0, 82.6, 71.5,
65.2, 49.7, 48.6, 45.8, 44.4, 39.8, 34.9, 34.1, 32.2, 30.9, 26.5, 26.2, 23.3, 22.4,
22.0, 21.1, 18.8, 18.4, 17.9, 14.4, 14.1 ppm; HRMS (MALDI-TOF): m/z:
calcd for C29H51N4O6S: 583.3524; found: 583.3544 [M+H]+.
epi-Halipeptin C (epi-1c): Yield: 23% for 4 steps; [a]2D3 =ꢀ19.2 (c=0.5 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=6.82 (d, J=5.4 Hz, 1H), 6.55
(d, J=8.9 Hz, 1H), 5.28 (d, J=10.2 Hz, 1H), 4.82 (q, J=8.0 Hz, 1H),
4.77 (q, J=6.3 Hz, 1H), 4.73 (d, J=1.2 Hz, 1H), 4.04 (d, J=12.1 Hz,
1H), 3.55–3.50 (m, 1H), 3.35 (d, J=12.1 Hz, 1H), 2.82 (s, 3H), 2.61–2.52
(m, 1H), 2.15–2.08 (m, 1H), 1.49 (s, 3H), 1.48 (d, J=8.6 Hz, 3H), 1.37
(d, J=7.2 Hz, 3H), 1.50–1.25 (m, 8H), 1.24 (s, 3H), 1.12 (s, 3H), 1.07 (d,
J=6.4 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 0.92 (t, J=6.4 Hz, 3H),
0.69 ppm (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=176.8,
173.6, 172.9, 170.5, 169.5, 84.8, 82.3, 71.4, 65.1, 49.2, 49.1, 45.2, 43.5, 39.7,
35.0, 32.9, 32.5, 30.8, 26.5, 24.4, 23.5, 22.9, 21.5, 21.0, 19.4, 18.85, 18.83,
14.2, 14.1 ppm; HRMS (MALDI-TOF): m/z: calcd for C29H51N4O6S:
583.3524; found: 583.3544 [M+H]+.
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Received: March 17, 2006
Published online: July 18, 2006
6584
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6572 – 6584