Total synthesis of halipeptins: Isolation of halipeptin D and synthesis of oxazoline halipeptin analogues

Article abstract of DOI:10.1002/chem.200500624

The isolation from the marine sponge Leiosella cf. arenifibrosa and structural elucidation of halipeptin D (5). a relative of the previously isolated halipeptins A-C (1-3), is described along with the total synthesis of a number of oxazoline analogues (7a

Full text of DOI:10.1002/chem.200500624

FULL PAPER
DOI: 10.1002/chem.200500624
Total Synthesis of Halipeptins: Isolation of Halipeptin D and Synthesis of
Oxazoline Halipeptin Analogues
K. C. Nicolaou,*[a, b] Daniel Schlawe,[a] David W. Kim,[b] Deborah A. Longbottom,[a]
[c]
Rita G. de Noronha,[a] Dimitrios E. Lizos,[a] Rama Rao Manam,[c] and D. John Faulkner†
Abstract: The isolation from the marine sponge Leiosella cf. arenifibrosa and
structural elucidation of halipeptin D (5), a relative of the previously isolated hali-
peptins A–C (1–3), is described along with the total synthesis of a number of oxa-
zoline analogues (7a–d and epi-7c–d).The developed synthetic strategy provides a
flexible entry into the various isomers of the polyketide domain of the halipeptins
and improvises for a late stage construction of the oxazoline ring after a macrolac-
tamization process which secures the required macrocycle.
Keywords: halipeptins
products · oxazolines · peptides ·
total synthesis
·
natural
Introduction
Figure 1) to one of them (A), and the impressive antiinflam-
matory properties of halipeptin A (60% reduction of carra-
geenan-induced paw edema in mice at the intraperitoneal
The halipeptins (A–C, 1–3, Figure 1) are a group of marine
derived natural products whose
structural identity and biological
properties were shrouded with
mystique until very recently.
Their story began in 2001 when
the Gomez-Paloma group re-
ported the isolation of halipep-
tins A and B from the sponge
Haliclona sp., the assignment of
a striking, 1,2-oxazetidine-con- Figure 1.Structures of halipeptins A-C ( 1–3)[2] and the original structural assignment for halipeptin A (4).[1]
taining
structure
(i.e.,
4,
dose of 0.3 mgkgꢀ1 body weight).[1] Soon thereafter in 2002,
the isolation and more accurate structural assignment of hal-
ipeptin C[2] as a thiazoline-containing structure 3 forced the
Gomez-Paloma group to revise their structures for halipep-
tins A and B from the oxazetidine structures[1,3] to the thia-
zoline structures 1 and 2, respectively.Yet another halipep-
tin (halipeptin D, 5, Figure 2) was later isolated (by Manam
and Faulkner, see below) from a different marine species.It
is important to note that neither we nor the Gomez-Paloma
group[1] could assign absolute stereochemistries at C-3 and
C-4 of the decanoic acid residue (e.g. 10a, Figure 3), al-
though the former group determined the stereochemical
identity at C-7 as being (S) in halipeptin B (2).[1] Based on
biosynthetic considerations, the assumption that all four hal-
ipeptins possess 7S configuration is reasonable but not con-
clusive.In addition, both we and the Gomez-Paloma group
did recognize the syn relationship of the substituents at this
[a] Prof.Dr.K.C.Nicolaou, Dr.D.Schlawe, Dr.D.A.Longbottom,
R.G.de Noronha, Dr.D.E.Lizos
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037 (USA)
Fax : (+1)858-784-2469
E-mail: kcn@scripps.edu
[b] Prof.Dr.K.C.Nicolaou, D.W.Kim
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[c] Dr.R.R.Manam, Prof.Dr.D.J.Faulkner
Scripps Institution of Oceanography
University of California, San Diego
La Jolla, CA 92093 (USA)
[†] Deceased November 23, 2002
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Results and Discussion
Isolation and structural elucidation of halipeptin D: The iso-
lation of halipeptin D (5, Figure 2) began with the collection
of the sponge Leiosella cf. arenifibrosa from the northwest-
ern waters off Boracay Island (Philippines) and was aided
by chromatographic techniques and biological assays.Thus,
the ethyl acetate soluble material from a methanol extract
of the sponge was purified by chromatography on sephadex
LH-20 by using methanol as eluent.The active fractions
were combined and re-chromatographed, first on silica gel
and then by normal-phase HPLC applying a hexane/ethyl
acetate gradient.Halipeptin D was isolated along with sev-
eral other highly active compounds; their structures and bio-
logical activities will be reported elsewhere in due course.
The new halipeptin was obtained as a colorless viscous oil
([a]2D5 =ꢀ26.0, c=0.2, CHCl3) and exhibited an [M+H]+ ion
at m/z 611.3932 and an [M+Na]+ ion at m/z 633.3745 in its
HRMS (MALDI FTMS), from which a molecular formula
of C31H54O6N4S was deduced.Preliminary 1H and 13C NMR
studies suggested a peptide-type structure, a conclusion that
was supported by IR bands at nmax = 3412, 3366, 1731, 1672
and 1637 cmꢀ1.The combined analysis of the 13C and DEPT-
1358 NMR spectra indicated eleven methyl, six methylene,
seven methine and two quater-
Figure 2.Proposed structure and HMBC correlations (curved arrows) of
halipeptin D (5).
nary carbon atoms, one double
bond (C=N), and four carbonyl
groups from which three were
associated with amides (d=
169.2, 172.3 and 173.4 ppm) and
one with an ester (d=
169.5 ppm), based on the ob-
served
connectivities
(see
Figure 2).On the basis of 2D
NMR analysis (Table 1), spin
systems for two alanines [dH =
7.01 (d, NH), 4.79 (quintet,
Ha), 1.42 (d, CH3) and 7.22 (d,
NH), 4.84 (quintet, Ha), 1.52
(d, CH3)] were easily identified.
The isoleucine spin system [dH =
5.01 (d, Ha), 2.22 (m, Hb), 1.34
(m, Hg), 0.98 (t, CH3g), 0.96 (d,
CH3b)] was also characterized
through well defined 2D NMR
connectivities.The N-Me group
Figure 3.Retrosynthetic analysis of halipeptins (eg. .of one likely structure, 5a, of halipeptin D) and their oxa-
zoline counterparts (e.g. 7a).
site (C-3/C-4), leaving open the precise structure as being
either 3S,4R,7S or 3R,4S,7S.It was not until recently that
the absolute configuration of halipeptin A[4,5] and halipeptin
D[4] could be revealed by total synthesis and that further de-
tails about their biological activity were obtained.[4] In this
article, we describe the isolation and structural elucidation
of halipeptin D (5) and the total synthesis of a number of its
oxazoline analogues.
was assigned to isoleucine, based on the strong HMBC cor-
relation between its signal and that of Ca[dH=2.81 (NMe)/
dC =65.4 (Ca)].The COSY, TOCSY and HMBC data con-
nected the other long chain fragment as 3-hydroxy-7-me-
thoxy-2,2,4-trimethyl decanoic acid (e.g. 10a, Figure 3).Da-
tabase searches (MarinLit, SciFinder) for the defined sub-
structures and the molecular formulae found only three
near matches, halipeptins A-C (1–3, Figure 1), among which
halipeptin A (1)[1,2] was the closest.Most significantly, the
NMR spectroscopic data, including coupling constants, for
halipeptin D were almost identical to those of halipeptin A
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Natural Products
FULL PAPER
Table 1. 1H, 13C and HMBC data of halipeptin D (5) as isolated from L. cf. arenifibrosa (CDCl3).
Total synthesis of oxazoline hal-
ipeptin analogues: In contem-
plating a synthetic pathway to
Residue
dC (100MHz)
dH, mult, J in Hz (300MHz)
HMBC
Ala 1
CO
a
169.5
49.9
18.6
the
halipeptins
(e.g.
5,
4.79, quintet, 7.0
1.42, d, 7.0
Me-b, CO
Ca
Figure 2), flexibility for the con-
struction of all plausible iso-
mers as well as their oxazoline
counterparts (e.g. 7a, Figure 3)
was deemed important.In fact,
the oxazoline analogues (e.g.
7a) were defined as the first
targets to be synthesized, for it
was anticipated that they could
serve as precursors to the natu-
rally occurring thiazolines via a
two-step thiolytic ring opening–
cyclization sequence[8] (see
Figure 3).The late-stage casting
of the five-membered heterocy-
cle within the halipeptin struc-
ture was preferred since the
stereocenter adjacent to that
structural motif was expected
to readily isomerize;[8b,9] fur-
thermore, the larger macrocycle
involved in this approach was
expected to form with greater
ease than its oxazoline-contain-
ing counterpart due to less
strain.The most suitable site
for the macrocyclization was,
however, not obvious at the
outset, and it was only after
considerable experimentation
that successful entries into the
macrocycle were found, the
original of which will be report-
ed here.Rupturing of all five
b
NH
NMeIle
CO
a
7.01, d, 7.0
CO-NMeIle
169.2
65.4
34.1
18.3
25.6
13.1
31.2
5.01, d, 11.0
2.22, m
0.96, d, 6.5
1.34, m
0.98, t, 7.0
2.81, s
CO, Cb, Me-b, NMe, CO-a-MeCys
Ca, Cb, Cg
b
Me-b
g
d
Cg
NMe
a-MeCys
CO
a
Ca, CO-a-MeCys
172.3
84.2
23.7
44.8
Me-a
b1
b2
N
Ala 2
SC=N
1.47, s
3.31, d, 12.0
4.16, d, 12.0
Ca, Cb, CO
Ca, SC=N-Ala2, Me-a
Ca, CO, Me-a
177.0
49.0
22.6
a
4.84, quintet, 7.0
1.52, d, 7.0
7.22, d, 7.0
SC=N, Cb
SC=N, Ca
CO-HTMMD
b
NH
HTMMD
1
2
Me-2
Me’-2
3
4
Me-4
5
6
7
7-OMe
8
9
10
173.4
46.2
26.7
22.9
82.8
34.7
15.0
32.4
31.8
80.8
56.8
36.2
19.1
14.9
1.15, s
1.22, s
C1, C2, C3, Me’-2
C1, C2, C3, Me-2
C1
4.71, d. 2.0
1.92, m
0.82, d, 7.0
1.37, m
1.46, m
3.10, m
3.31, s
1.34, m
1.30, m
0.92, t, 6.5
C3, C4, C5
C-7
C-8, C-9
[2]
(1).Hence, based on comparison with literature data,
the
strategic bonds as shown in Figure 3 revealed fragments 9–
13 as the required building blocks for the projected con-
structions.Significantly, the routes chosen to synthesize
some of these key intermediates could deliver any of the de-
sired stereoisomers, thus satisfying our flexibility criteria.
The construction of the most likely required decanoic
acid[10] fragments proceeded as exemplified for the two
3S,4R isomers 10a and 10b in Scheme 1.Thus, the readily
available hydroxy methyl ester 14 was converted by a modi-
fication of a known sequence[11] and in high yield into alco-
hol 18 which, after Swern oxidation to the corresponding al-
dehyde,[12] was subjected to a Mukaiyama-type aldol reac-
tion with methyl trimethylsilyl dimethylketene acetal in the
presence of BF3·Et2O to afford a 7:3 mixture of the insepa-
rable diastereomeric alcohols 19 and 20 in a combined 79%
yield from alcohol 18.Elaboration of the latter mixture by
TBS protection (for abbreviations of reagents and protect-
ing groups, see legends in schemes) and debenzylation af-
forded major isomer 21 in 88% (49% from alcohol 18)
remaining residue was identified as a-methyl cysteine and
structure 5 (Figure 2) was assigned to halipeptin D.The dif-
ference between halipeptins A (1) and D (5) is only an
extra oxygen atom residing at the terminus of the hydroxyi-
soleucine side chain within the structure of the former natu-
ral product 1.
In sharp contrast to the biological properties described
for halipeptin A,[1] halipeptin D (5) obtained as described
above exhibited a strong in vitro inhibitory activity against a
human colon cancer (HCT-116) cell line (IC50 =7 nm)[6] and
an average IC50 =420 nm against a BMS ODCA (oncology
diverse cell panel) of tumor cell lines.[7] In light of its struc-
tural similarity to halipeptins A–C (1–3) for which no such
activity was reported, the cytotoxicity of halipeptin D (5)
was rather puzzling and compounded the intrigue surround-
ing these natural products.Because of the scarcity of the
naturally occurring substances, and in order to demystify
these ambiguities, we undertook their total synthesis.[4]
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K.C.Nicolaou et al.
yield after chromatographic removal of its diastereomeric
counterpart.Swern oxidation to the aldehyde, and Brown al-
lylation employing (ꢀ)-(Ipc)2 allylborane (>90% dr) fol-
lowed by methylation of the resulting alcohol furnished
compound 22b in excellent overall yield (75%).Subsequent
hydrogenation of the olefin, desilylation and saponification
led to the targeted hydroxy acid 10b in 92% overall yield
from 22b.The application of ( +)-(Ipc)2 allylborane in the
allylation step led to hydroxy decanoic acid 10a, and the re-
maining stereoisomers possessing 3,4-syn configuration (10c
and 10d) were obtained starting from ent-14 by application
of each of the enantiomeric allylboranes.
The synthesis of the highly congested fragment 28 featur-
ing a carboxylic acid group and an azide moiety was carried
out following the sequence shown in Scheme 2.Thus, the a-
methyl serine methyl ester derivative 24[13] was silylated and
thence hydrolyzed under basic conditions to afford carboxyl-
ic acid 12 (96% yield).A stepwise coupling of 12 with iso-
leucine methyl ester followed by methylation of the nitrogen
atom within the resulting amide 26 proved much superior to
coupling of 12 with N-methyl isoleucine derivatives, and
yielded compound 27 in 87% yield from acid 12.Since
azide reduction of 27 led to instantaneous cyclization to the
corresponding diketopiperazine, chain elongation from the
N-terminus of 27 was abandoned in favor of coupling the C-
terminus to building block 31 (see Scheme 3).The required
methyl ester hydrolysis within 27 proved troublesome and
was best accomplished with aqueous nBu4NOH[14] at 08C in
THF, furnishing the desired carboxylic acid 28 in a 70%
crude yield.
The assembly of the synthesized fragments 10a–d
(Scheme 1), 28 (Scheme 2), and 11[15] into the macrocycliza-
tion precursor 34 are shown in Scheme 3.Thus, coupling of,
for example, decanoic acid segment 10a with alanine methyl
ester, followed by ester formation at the free hydroxyl
group of the resulting product (29a) with a 19-fold excess of
alanine-derived acid chloride 11[15] in the presence of 4-
DMAP at 508C in DMF afforded the amide ester 30a in
88% overall yield.Gratifyingly, no epimerization was ob-
served under these rather harsh conditions.The configura-
tion of the presumably stereochemically labile acid chloride
14 was shown to be intact by comparing the spectroscopic
data of 30a with those of a sample derived from 29a and
ent-11.Subsequent reduction of the azide group within 30a
was accomplished by catalytic hydrogenation (10% Pd/C),
furnishing the desired amine 31a.Coupling of the crude
amine 31a with a slight excess carboxylic acid fragment 28
in the presence of PyAOP, HOAt and iPr2NEt afforded
azide methyl ester 32a in 71% overall yield from azide 30a.
Selective hydrolysis of the methyl ester within compound
32a, under the mild conditions of Me3SnOH,[16] gave carbox-
ylic acid 33a in 95% yield; the azide moiety was hydrogeno-
lyzed, generating the required amino acid 34a.Direct mac-
rocyclization of 34a could be carried out with a number of
coupling agents (e.g. EDC/HOAt/iPr2NEt/CH2Cl2: 33%,
pentafluorophenyl diphenylphosphinate (FDPP)/iPr2NEt/
CH2Cl2: 25%), but was best achieved with HATU/HOAt/
Scheme 1.Synthesis of hydroxy decanoic acids 10a–d.a) TBDPSCl
(1.0 equiv), imidazole (3.0 equiv), CH2Cl2, 258C, 76 h, 99%; b) DIBAL-
H
(1.1 equiv), toluene, ꢀ788C, 1.5 h; c) (EtO)2P(O)CH2CO2Et
(1.2 equiv), LiCl (1.2 equiv), DBU (1.2 equiv), CH3CN, 258C, 19 h; d) H2
(1 atm), 5% Pd/C (33% by weight), EtOAc, 258C, 20 h, 82% (three
steps); e) DIBAL-H (2.5 equiv), toluene, ꢀ78 ! 258C, 2 h, 93%; f)
BnTCAI (1.5 equiv), TESOTf (2%), CH2Cl2, 258C, 8 h; g) TBAF
(3.0 equiv), THF, 258C, 3 h, 69% (two steps); h) DMSO (2.8 equiv),
(COCl)2 (1.9 equiv), CH2Cl2, ꢀ788C; then Et3N (5.0 equiv), ꢀ78
!
258C, 3 h, product not isolated; i) BF3·Et2O (1.1 equiv), Me2C=C-
(OMe)OTMS (1.2 equiv), CH2Cl2, ꢀ788C, 1.5 h, 79% (two steps, 19/20
7:3); j) TBSOTf (1.3 equiv), 2,6-lut. (1.5 equiv), CH2Cl2, 08C, 1 h, 99 %;
k) H2 (1 atm), 10% Pd/C (20% by weight), EtOH, 258C, 24 h, separation
of diastereoisomers, 88% (two steps, major isomer 21); l) (+)-(Ipc)2B-
allyl (2.0 equiv), Et2O, ꢀ100 ! ꢀ468C; then H2O2, aq NaOH; m)
Me3OBF4 (10.0 equiv based on 21), proton sponge (16 equiv), CH2Cl2,
258C, 75% (three steps); n) H2 (1 atm), 10% Pd/C (50% by weight),
EtOH, 258C, 2 h; o) TFA:H2O (9:1), ꢀ108C, 5 min, 93% (two steps); p)
LiOH·H2O (6.0 equiv), MeOH:H2O (4:1), 258C, 24 h, 99%.2,6-lut. =2,6-
lutidine; BnTCAI=benzyl 2,2,2-trichloroacetimidate; DBU=1,8-diazabi-
cyclo-[5.4.0]-undec-7-ene;
DIBAL-H=diisobutylalmuninumhydride;
Ipc=isopinocampheyl;
TBAF=tetra-n-butylammonium
fluoride;
TBDPSCl=tert-butyldiphenylsilyl
chloride;
TBS=tert-butylsilyl;
TESOTf=triethylsilyl trifluoromethanesulfonate; TFA=trifluoroacetic
acid; TMS=trimethylsilyl.
iPr2NEt in CH2Cl2 at a 1 mm concentration yielding macro-
cycle 35a in 68–74% overall yield in several experiments.
Removal of the TBS group from compound 35a led to its
hydroxy counterpart 8a, paving the way for the final step.
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Natural Products
FULL PAPER
The synthetic sequence to 7a/b was also employed to con-
struct the oxazoline analogues 7c and 7d (Scheme 4).Start-
ing from the 3R,4S decanoic acids 10c and 10d (Scheme 1),
the macrocyclization substrates 34c and 34d were construct-
ed as described for 34a/b in Scheme 3.The further transfor-
mation of these compounds into oxazolines 7c and 7d was
accompanied by a number of interesting observations.Thus,
out of all coupling conditions applied to achieve macrocycli-
zation of 34c and 34d (EDC/HOAt/iPr2NEt/CH2Cl2, FDPP/
iPr2NEt/CH2Cl2, DPPA/NaHCO3/DMF), only those em-
ployed previously (HATU/HOAt/iPr2NEt/CH2Cl2) furnished
the desired cyclic depsipeptides, although the reaction was
much slower and the yields of the macrocyclic products
were considerably lower (36/44%) than in the case of mac-
rocyclization of the 3S,4R-isomers 34a and 34b.Additional-
ly, the generated macrocycles 35c and 35d were accompa-
nied by their alanine epimers, epi-35c and epi-35d (ca.1:1
ratio, easily separable by silica gel flash column chromatog-
raphy).After TBAF-induced desilylation, the resulting hy-
droxy amides 8c,d and epi-8c,d (compare Figure 3) were
subjected to DAST[8c] in order to generate the correspond-
ing oxazolines.Presumably due to an unfavorable build-up
of further ring strain, the yields
Scheme 2.Synthesis of Ser( aMe)-MeIle-OH dipeptide 28.a) TBSOTf
(2.0 equiv), 2,6-lut. (4.0 equiv), CH2Cl2, 08C, 2 h, 98%; b) LiOH·H2O
(3.0 equiv), MeOH/H2O (4:1), 258C, 3 h, 96%, c) H-Ile-OMe (1.3 equiv),
EDC (1.1 equiv), HOAt (1.1 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C,
24 h, 91%; d) NaH (3.0 equiv), MeI (4.0 equiv), DMF, 08C, 1 h, 96%; e)
nBu4NOH (2.0 equiv), 08C, 6 h, approx.70%.EDC =1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide hydrochloride; HOAt=1-hydroxy-7-aza-
benzotriazole.
Indeed, exposure of crude 8a to DAST[8c] at ꢀ788C generat-
ed oxazoline halipeptin D 7a in 74% yield.Starting from
the other 3S,4R-decanoic acid (10b), differing in stereo-
chemistry from 10a only at the remote position C-7; the epi-
meric oxazoline 7b was also obtained in almost identical
overall yield (Scheme 3).
in this step were again low.
Starting from epi-35c/d, the ox-
azolines epi-7c/d were formed
in 31/36% yields.The reaction
between the alcohols derived
from 35c/d by TBAF deprotec-
tion and DAST also furnished
the corresponding cyclodehy-
dration products, oxazolines 7c/
d (in 43/40% yields), however,
they were accompanied by
major by-products, presumed to
be the fluorinated compounds
36c/d (45/51%).[17]
Attempts towards thiolysis
(H2S under various conditions)
of oxazoline halipeptin
D
(i.e.,7a) to the corresponding
hydroxy thioamide (i.e., 6a,
Figure 3) as a prelude to the
synthesis of halipeptin D (5),
however, failed.Prolonged re-
action times at elevated temper-
atures (MeOH/Et3N 2:1, satura-
tion with H2S, 60 8C, one week)
only led to methanolic cleavage
of the alanine ester bond with-
out any incorporation of H2S as
suggested by MS fragmentation
experiments.Apparently, the
constraints imposed upon 7a by
its own molecular architecture
did not allow it to undergo the
intended rupture, demanding,
Scheme 3.Assembly of key building blocks 31a and 8a and synthesis of halipeptin D analogues 7a and 7b
starting from 3(S),4(R) decanoic acids 10a and 10b. a) EDC (5.0 equiv), HOAt (4.0 equiv), H-Ala-OMe·HCl
(4.0 equiv), iPr2NEt (10.0 equiv), DMF, 258C, 3 h, 94%; b) 11 (19 equiv), 4-DMAP (0.5 equiv), Et3N
(25 equiv), DMF, 508C, 24 h, 94%; c) H2 (1 atm), 10% Pd/C (60% by weight), 258C, 2 h; d) 28 (1.4 equiv),
PyAOP (4.1 equiv), HOAt (3.7 equiv), iPr2NEt (4.8 equiv), DMF, 258C, 15 h, 71% (two steps); e) Me3SnOH
(20 equiv), 1,2-dichloroethane, 508C, 18 h, 95%; f) H2 (1 atm), 20% Pd(OH)2/C (300% by weight), EtOH,
08C, 0.5 h; g) HATU (1.5 equiv), HOAt (3.0 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 21 h, 74% (two steps);
h) TBAF (1.1 equiv), THF, ꢀ108C, 1.5 h; i) DAST (2.3 equiv), CH2Cl2, ꢀ78 ! ꢀ128C, 1 h, 74%.DAS T=(di-
ethylamino)sulfurtrifluoride; HATU=O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-
phosphate; PyAOP=(7-azabenzotriazole-1-yloxy) tripyrrolidinophosphonium hexaflurophosphate.
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K.C.Nicolaou et al.
Scheme 4.Macrocyclization and oxazoline synthesis starting from linear depsipeptides 34c and 34d incorporating 3(R),4(S) decanoic acids 10c and 10d.
a) as described for 34a in Scheme 3; b) HATU (1.5 equiv), HOAt (3.0 equiv), iPr2NEt (3.0 equiv), CH2Cl2, 258C, 24 h, 35c: 14%, epi-35c: 22%, 35d:
25%, epi-35d: 19%; c) TBAF (1.1 equiv), THF, 08C, 1 h (not isolated); d) DAST (3.0 equiv), CH2Cl2, ꢀ78 ! ꢀ128C, 1 h, 7c: 43%, 36c: 45%, 7d:
40%, 36d: 51%, epi-7c: 31%, epi-7d: 36% (yields over two steps).
instead, a new strategy[4] for the total synthesis of halipeptin
D and its siblings.
tin D by total synthesis are described in a separate commu-
nication.[4]
Biological evaluation of synthesized oxazoline halipeptin an-
alogues: The synthesized halipeptin analogues 7a–d and epi-
7c–d were tested against HCT-116 human colon carcinoma
cells and were found to be only weakly active (IC50 values:
7a: 74.7 mm, 7b: inactive, 7c: 58.0 mm, 7d: inactive, epi-7c:
8.2 mm, epi-7d: 4. 6mm).[18] These results were somewhat sur-
prising in light of the previously attributed activity of hali-
peptin D (5) against a human colon cancer (HCT-116) cell
line[6] and a BMS ODCA (oncology diverse cell panel) of
tumor cell lines,[7] thereby inviting further investigations
with the chemical synthesis of halipeptin D (5) became the
most urgent.The accomplishment of this goal and a specula-
tion regarding the above curiosity are reported elsewhere.[4]
Experimental Section
General procedures: All reactions were carried out under an argon at-
mosphere with dry solvents under anhydrous conditions.Dry tetrahydro-
furan (THF), toluene, diethyl ether (Et2O) and methylene chloride
(CH2Cl2) were obtained by passing commercially available pre-dried,
oxygen-free formulations through activated alumina columns.Reagents
and dry N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO)
and 1,2-dichloroethane were purchased at the highest commercial quality
and used without further purification.Yields refer to chromatographical-
ly and spectroscopically (1H NMR) homogeneous materials, unless other-
wise stated.Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) by
using UV light as visualizing agent and an aqueous (aq) solution of
cerium ammonium nitrate, ammonium molybdate and sulfuric acid, and
heat as developing agents.E.Merck silica gel (60, particle size 00.40–
0.063 mm) was used for flash column chromatography. NMR spectra
were recorded on Bruker DRX-600, DRX-500 and AMX-400 or Varian
Inova-400 and Mercury-300 instruments and calibrated by using residual
undeuterated solvent as an internal reference.The following abbrevia-
tions were used to explain the multiplicities: s=singlet, d=doublet, t=
triplet, q=quartet, m=multiplet, br=broad.IR spectra were recorded
on a Perkin–Elmer 1600 series FT-IR spectrometer.Electrospray ioniza-
tion (ESI) mass spectrometry (MS) experiments were performed on an
API 100 Perkin–Elmer SCIEX single quadrupole mass spectrometer at
4000 V emitter voltage.High resolution mass spectra (HRMS) were re-
corded on a VG ZAB-ZSE mass spectrometer using MALDI (matrix-as-
sisted laser-desorption ionization) or an Agilent ESI TOF (time of flight)
mass spectrometer at 4000 V emitter voltage.
Conclusion
The isolation of halipeptin D (5) adds a new member to the
growing class of halipeptins isolated from marine sponges.
The potent cytotoxicity originally attributed to this new sub-
stance coupled with its scarcity and structural similarity to
the previously isolated halipeptins A–C prompted us to un-
dertake its total synthesis.The developed synthesis, howev-
er, failed to deliver the thiazoline-containing natural prod-
uct, leading instead to a series of oxazoline analogues.The
insignificant cytotoxicity of the synthesized analogues creat-
ed a suspicion with regard to the initially obtained biological
results from the naturally derived material, making the total
synthesis of halipeptin D itself an even more urgent task.
The completion of this task together with associated findings
and the assignment of the absolute configuration of halipep-
Compound 15: Hydroxy ester 14 (20.0 mL, 0.181 mol) and imidazole
(37.03 g, 0.544 mol) were dissolved in CH2Cl2 (200 mL) and cooled to
08C. After the addition of TBDPSCl (47.0 mL, 0.18 mol) the solution
was stirred for 76 h at ambient temper-
ature and then washed with 1m aq
HCl (500 mL).The organic layer was
washed with brine (500 mL), the aq
layers were re-extracted with CH2Cl2
6202
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6197 – 6211

Natural Products
FULL PAPER
(2”150 mL), and the combined organic extracts were dried (Na2SO4), fil-
tered through a plug of silica gel and evaporated to dryness yielding 15
(64.34 g, 0.180 mmol, 99%) as a colorless liquid. Rf =0.48 (silica gel, 10%
EtOAc in hexanes); [a]2D5 =+16.4 (c=1.4, CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.65 (d, J=6.9 Hz, 4H), 7.45–7.35 (m, 6H), 3.77 (ddd, J=
15.4, 9.8, 6.3 Hz, 2H), 3.68 (s, 3H), 2.72 (m, 1H), 1.16 (d, J=7.0 Hz, 3H),
1.03 ppm (s, 9H); 13C NMR (150 MHz, CDCl3): d=175.4, 135.5, 134.8,
129.6, 127.6, 65.9, 51.5, 42.4, 26.7, 19.2, 13.4 ppm; IR (film): nmax =3048,
2932, 2857, 1741, 1589, 1472, 1428, 1389, 1361, 1257, 1199, 1176, 1112,
1026, 823, 739, 702, 614, 505 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C21H28O3SiNa: 379.1705, found: 379.1700 [M+Na]+.
ature and after 3 h was washed with sat aq NH4Cl (400 mL) and with
brine (400 mL).The aq layers were re-extracted with Et 2O (2”150 mL)
and the combined organic layer was dried (MgSO4), filtered and concen-
trated.The residue was purified by flash column chromatography (silica
gel, 10 ! 30% ethyl acetate in hexanes) to afford alcohol 18 (1.89 g,
9.06 mmol, 69% over two steps) as a colorless liquid. Rf =0.25 (silica gel,
30% EtOAc in hexanes); [a]2D5 =+8.2 (c=6.8, CHCl3); 1H NMR
(600 MHz, CDCl3): d=7.30–7.15 (m, 5H), 4.23 (s, 2H), 3.39 (t, J=
6.6 Hz, 2H), 3.42–3.29 (m, 2H), 2.1 (s, 1H), 1.62 (m, 1H), 1.53 (m, 1H),
1.40 (m, 1H), 1.11 (m, 1H), 0.84 ppm (d, J=6.8 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=138.4, 128.3, 127.6, 127.4, 72.8, 70.6, 67.8, 35.4,
29.5, 27.0, 16.5 ppm; IR (film): nmax =3392, 3063, 2934, 2868, 1496, 1454,
1204, 1098, 1028, 736, 698, 619 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C13H20O2Na: 231.1355, found: 231.1350 [M+Na]+.
Compound 17: A 1.5m DIBAL-H solution in toluene (6.0 mL, 9.0 mmol)
was added at ꢀ788C to a solution of ester 15 (2.92 g, 8.19 mmol) in tolu-
ene (80 mL).After 15. h, MeOH (5 mL) was added, the mixture was al-
lowed to warm to 258C and was then
Compound 21: A solution of DMSO (1.90 mL, 26.8 mmol) in CH2Cl2
(10 mL) was slowly added at ꢀ788C to a solution of oxalyl chloride
(1.57 mL, 17.6 mmol) in CH2Cl2
(100 mL).After 10 min, a solution of
alcohol 18 (1.89 g, 9.06 mmol) in
partitioned between water (500 mL)
and Et2O (200 mL).The organic layer
was washed with brine (200 mL), the
aq layers were re-extracted with Et2O
(2”100 mL) and the combined organic
CH2Cl2 (10 mL) was added and the
layer was dried (Na2SO4), filtered and evaporated.The residue was puri-
fied by flash column chromatography (silica gel, 2.5% EtOAc in hex-
anes) yielding TBDPS-protected (S)-3-hydroxy-2-methyl-propanal
(2.58 g, 7.90 mmol, 96%) as a colorless liquid which was dissolved in ace-
tonitrile (80 mL) and treated with triethyl phosphonoacetate (1.90 mL,
9.48 mmol) and DBU (1.45 mL, 9.48 mmol) in the presence of LiCl
(400 mg, 9.48 mmol) at ambient temperature. After 19 h, the solution was
partitioned between Et2O (100 mL) and sat aq NH4Cl (200 mL).The or-
ganic layer was washed with brine (200 mL), and the aq layers were re-
extracted with Et2O (100 mL).The combined organic layer was dried
(MgSO4), filtered through a plug of silica gel and evaporated to dryness
yielding TBDPS-protected (R)-5-hydroxy-4-methyl-2-pentenoic acid
ethyl ester (2.71 g, 7.20 mmol, 91%) as a colorless liquid. The product
was dissolved in EtOAc (5 mL) and added to a suspension of Pd (5% on
activated charcoal, 0.90 g) in EtOAc (50 mL). The mixture was then stir-
red under an H2-atmosphere at ambient pressure for 20 h.Subsequent
saturation with Ar, filtration of the catalyst and evaporation to dryness
gave pentanoic ester 17 (2.71 g, 6.80 mmol, 82% from 15) as a colorless
liquid. Rf =0.47 (silica gel, 10% EtOAc in hexanes); [a]2D5 =+2.5 (c=4.5,
CHCl3); 1H NMR (500 MHz, CDCl3): d=7.66 (dd, J=7.9, 1.5 Hz, 4H),
7.45–7.35 (m, 6H), 4.11 (q, J=7.0 Hz, 2H), 3.48 (m, 2H), 2.29 (m, 2H),
1.81 (m, 1H), 1.68 (m, 1H), 1.48 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), 1.05 (s,
9H), 0.92 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
173.9, 135.6, 133.8, 129.6, 127.6, 68.4, 60.2, 35.2, 32.0, 28.4, 26.9, 19.3, 16.5,
14.2 ppm; IR (film): nmax =3070, 2958, 2931, 2857, 1737, 1589, 1472, 1428,
1178, 1112, 824, 740, 702, 614, 505 cmꢀ1; HRMS (ESI-TOF): m/z: calcd
for C24H34O3SiNa: 421.2169, found: 421.2167 [M+Na]+.
mixture was stirred for 0.5 h before
the addition of Et3N (6.25 mL,
47 mmol).After 3 h, the solution was
allowed to warm to ꢀ208C and was then poured into 1m aq HCl
(100 mL, pre-cooled to 08C).The organic layer was washed with sat aq
NaHCO3 (100 mL) and with brine (100 mL), the aq layers were re-ex-
tracted with CH2Cl2 (100 mL), and the combined organic layer was dried
(Na2SO4), filtered through a plug of silica gel and evaporated.The crude
product was dissolved in CH2Cl2 (90 mL) and cooled to ꢀ788C before
BF3·Et2O (48%, 1.28 mL, 10 mmol) and methyl trimethylsilyl dimethyl-
ketene acetal (2.20 mL, 10.9 mmol) were added. The solution was stirred
for 1.5 h at ꢀ788C and then partitioned between ice cold Et2O (300 mL)
and 1m aq HCl (100 mL).The organic layer was washed with brine
(200 mL), the aq layers were re-extracted with Et2O (200 mL), and the
combined organic layer was dried (Na2SO4), filtered, concentrated and
purified by flash column chromatography (silica gel, 25% EtOAc in hex-
anes) to yield an inseparable mixture of hydroxy esters 19 and 20
(2.205 g, 7.16 mmol, 79%, 7:3 according to 1H NMR) as a colorless oil.
This mixture was reacted with TBSOTf (2.2 mL, 9.3 mmol) and 2,6-luti-
dine (1.25 mL, 10.7 mmol) in CH2Cl2 (50 mL) at 08C.After 1 h, the solu-
tion was washed with 1m aq HCl (100 mL) and subsequently with brine
(100 mL), the aq layers were re-extracted with CH2Cl2 (100 mL) and the
combined organic layer was dried (MgSO4), filtered through a plug of
silica gel and evaporated to dryness.The residue was dissolved in EtOH
(10 mL) and added to a suspension of Pd (10% on activated charcoal,
600 mg) in EtOH (40 mL) under an Ar atmosphere.The mixture was stir-
red under H2 at ambient pressure and temperature for 18 h and then de-
gassed, filtered and evaporated.The residue was purified by flash column
chromatography (silica gel, 33 ! 50% Et2O in hexanes) to afford 21
(1.225 g, 3.68 mmol, 41% from 18), its C-3 epimer (472 mg, 1.42 mmol,
16% from 18) and a mixture of both (399 mg, 1.20 mmol, 13%, 21/epi-21
1.2:1) as colorless oils. Compound 21: Rf =0.26 (silica gel, 20% EtOAc in
hexanes); [a]2D5 =+9.0 (c=2.2, CHCl3); 1H NMR (500 MHz, CDCl3): d=
3.85 (d, J=1.5 Hz, 1H), 3.85 (s, 3H), 3.61 (t, J=6.6 Hz, 2H), 1.62–1.22
(m, 6H), 1.16 (s, 3H), 1.12 (s, 3H), 0.90 (s, 9H), 0.87 (d, J=6.8 Hz, 3H),
0.08 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=177.8,
79.2, 63.0, 51.6, 49.4, 35.5, 33.4, 30.9, 26.2, 23.5, 20.1, 18.6, 15.3, ꢀ3.0,
ꢀ4.5 ppm; IR (film): nmax =3356, 2953, 2885, 2857, 1728, 1472, 1257, 1142,
Compound 18:
A 1m solution of DIBAL-H in hexane (109 mL,
109 mmol) was added at ꢀ788C to a solution of ester 17 (17.42 g,
43.7 mmol) in toluene (300 mL). The
solution was allowed to warm to 258C
and stirred for 2 h before MeOH
(20 mL) was added.The mixture was
extracted with a sat aq K/Na tartrate
(800 mL), the organic layer was washed with brine (300 mL), the aq
layers were re-extracted with Et2O (2”200 mL) and the combined organ-
ic layer was dried (MgSO4).Filtration through a plug of silica gel, con-
centration and evaporation in vacuo afforded (R)-5-(tert-butyldiphenylsi-
lyloxy)-4-methyl-pentanol (14.50 g, 40.1 mmol, 93%, pure based on
1H NMR analysis).The product was dissolved in CH 2Cl2 (200 mL),
benzyl trichloroacetimidate (11.3 mL, 60.2 mmol) was added, the solution
was cooled to 08C and treated with TESOTf (180 mL, 0.80 mmol). After
stirring for 8 h at ambient temperature, the solution was washed with
brine (400 mL).The aq layer was re-extracted with CH 2Cl2 (200 mL),
and the combined organic layer was dried (MgSO4), filtered through a
plug of silica gel and evaporated, yielding a crude product (19.63 g) con-
taminated with major amounts of Bn2O and BnOH.To a solution of this
crude material (6.31 g) in THF (100 mL) was added TBAF (1m in THF,
5% water, 39 mL, 39 mmol).The mixture was stirred at ambient temper-
1110, 1065, 1004, 837, 774 cmꢀ1
; HRMS (ESI-TOF): m/z: calcd for
C17H36O4SiNa: 355.2275, found: 355.2278 [M+Na]+.
Compound 22a: Primary alcohol 21 (2.156 g, 6.48 mmol) was oxidized
with DMSO (1.33 mL, 19.4 mmol), oxalyl chloride (11.5 mL, 12.9 mmol)
and Et3N (3.40 mL, 25.6 mmol) in CH2Cl2 (60 mL) as described above for
the oxidation of primary alcohol 18.
After aq work-up and filtration
through a pad of silica gel, the crude
product was dissolved in Et2O (30 mL)
and the solution was cooled to
Chem. Eur. J. 2005, 11, 6197 – 6211
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
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6203

K.C.Nicolaou et al.
ꢀ1008C.A solution of ( +)-(Ipc)2BCH2CHCH2 (approximately 0.2m in
Et2O, 65 mL, 13 mmol) was added.After 4 h, the temperature was al-
lowed to reach ꢀ468C and stirring at this temperature was continued for
0.5 h. The reaction mixture was treated with a solution of H2O2 (35% in
H2O, 16 mL) and NaOH (980 mg) in water (36 mL).After 5 min, the
mixture was buffered by the addition of aq NaH2PO4 (4.43 g in 100 mL
water) and allowed to warm to 258C.The organic layer was washed with
brine (100 mL) and the aq layers were re-extracted with Et2O (2”
100 mL).The combined organic layer was dried (Na 2SO4), filtered
through a plug of silica gel and concentrated, yielding a crude product
that was contaminated with IpcOH.This mixture was dissolved in
CH2Cl2 (100 mL) and proton sponge (1,8-bis[dimethylamino]-naphtha-
lene, 25.72 g, 120 mmol) and Me3OBF4 (11.83 g, 80 mmol) were added.
After 20 h, the solvent was removed and the residue was partitioned be-
tween Et2O (300 mL) and sat aq citric acid (300 mL).The organic layer
was washed with brine (500 mL), the aq layers were re-extracted with
Et2O (2”200 mL) and the combined organic layer was dried (Na2SO4),
filtered through a plug of silica gel and evaporated.The residue was puri-
fied by flash column chromatography (silica gel, 30 ! 55% CH2Cl2 in
hexanes) to yield homoallylic ether 22a (1.896 g, 4.89 mmol, 75% from
alcohol 21) as a colorless oil. Rf =0.28 (silica gel, 5% EtOAc in hexanes);
[a]2D5 =+14.4 (c=2.7, CHCl3); 1H NMR (500 MHz, CDCl3): d=5.78 (m,
1H), 5.09–5.01 (m, 2H), 3.82 (d, J=1.5 Hz, 1H), 3.63 (s, 3H), 3.32 (s,
3H), 3.16 (d, J=5.8 Hz, 1H), 2.24 (m, 2H), 1.50–1.25 (m, 5H), 1.15 (s,
3H), 1.10 (s, 3H), 0.89 (s, 9H), 0.83 (d, J=6.7 Hz, 3H), 0.07 (s, 3H),
0.02 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=177.7, 134.8, 116.8,
80.3, 79.4, 56.5, 51.5, 49.3, 37.7, 35.8, 32.7, 31.4, 26.1, 23.2, 20.2, 18.5, 15.1,
ꢀ3.0, ꢀ4.6 ppm; IR (film): nmax =3072, 2931, 2849, 1740, 1461, 1255, 1190,
1108, 832, 773 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C21H42O4SiNa:
409.2744, found: 409.2738 [M+Na]+.
Compound 23b (prepared from 22b in
91% yield): Rf =0.44 (silica gel, 20%
EtOAc in hexanes); [a]2D5 =+1.35 (c=
1.4, CHCl3); 1H NMR (600 MHz,
CDCl3): d=3.69 (s, 3H), 3.46 (d, J=
2.0 Hz, 1H), 3.31 (s, 3H), 3.11 (m, 1H), 1.65 (m, 1H), 1.52–1.24 (m, 8H),
1.30 (s, 3H), 1.16 (s, 3H), 0.91 (t, J=7.2 Hz, 3H), 0.75 ppm (d, J=6.7 Hz,
3H); 13C NMR (150 MHz, CDCl3): d=178.7, 81.0, 80.3, 56.5, 53.4, 52.0,
35.7, 34.7, 31.5, 31.2, 25.0, 21.9, 18.4, 14.3, 13.0 ppm; IR (film): nmax
=
3482, 2934, 2874, 1729, 1459, 1380, 1262, 1192, 1140, 1096, 991 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C15H30O4Na: m/z: 297.2036, found:
297.2036 [M+Na]+.
Compound 10a: LiOH·H2O (184 mg, 4.38 mmol) was added at ambient
temperature to a solution of methyl ester 23a (200 mg, 0.730 mmol) in
MeOH/H2O 4:1 (7 mL).The reaction
mixture was stirred for 24 h and then
partitioned between EtOAc (50 mL)
and 1m aq HCl (50 mL).The organic
layer was washed with brine (50 mL),
the aq layers were re-extracted with
EtOAc (2”50 mL) and the combined organic layer was dried (Na2SO4),
filtered and evaporated.The residue was purified by column chromatog-
raphy (silica gel, 25% EtOAc in hexanes with 5% AcOH) to afford dec-
anoic acid 10a (187.3 mg, 0.720 mmol, 99%) as a colorless viscous oil.
Rf =0.23 (silica gel, 20% EtOAc in hexanes with 10% AcOH); [a]D25
=
ꢀ28.9 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d=3.50 (d, J=
2.3 Hz, 1H), 3.29 (s, 3H), 3.13 (m, 1H), 1.67 (m, 1H), 1.49–1.22 (m, 8H),
1.33 (s, 3H), 1.13 (s, 3H), 0.87 (t, J=7.2 Hz, 3H), 0.80 ppm (d, J=6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=181.9, 81.1, 79.8, 56.3, 45.1, 35.4,
34.6, 30.9, 30.8, 25.5, 21.6, 18.4, 14.2, 12.9 ppm; IR (film): nmax =3426,
2927, 2871, 1698, 1460, 1255, 1150, 1088, 977 cmꢀ1; HRMS (ESI-TOF):
m/z: calcd for C14H28O4Na: 283.1880, found: 283.1880 [M+Na]+.
Compound 22b (prepared from 21 in 71% yield using (ꢀ)-
(Ipc)2BCH2CHCH2): Rf =0.53 (silica gel, 30% Et2O in hexanes); [a]D25
=
+6.5 (c=0.4, CHCl3); 1H NMR
(500 MHz, CDCl3): d=5.81 (m, 1H),
Compound 10b (prepared from ester 23b in 81% yield): Rf =0.15 (silica
gel, 20% EtOAc in hexanes with 5% AcOH); [a]2D5 =ꢀ36.7 (c=0.7,
CHCl3); 1H NMR (400 MHz, CDCl3):
d=3.54 (d, J=1.9 Hz, 1H), 3.32 (s,
3H), 3.14 (m, 1H), 1.68 (m, 1H),
5.11–5.03 (m, 2H), 3.83 (d, J=1.3 Hz,
1H), 3.64 (s, 3H), 3.32 (s, 3H), 3.17
(m, 1H), 2.25 (dd, J=7.0, 5.8 Hz, 2H),
1.51–1.18 (m, 5H), 1.16 (s, 3H), 1.11
1.54–1.24 (m, 8H), 1.32 (s, 3H), 1.15
(s, 3H), 0.90 (t, J=7.2 Hz, 3H),
(s, 3H), 0.90 (s, 9H), 0.85 (d, J=6.6 Hz, 3H), 0.09 (s, 3H), 0.04 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=177.7, 134.8, 116.9, 80.6, 70.3, 56.6,
51.6, 49.3, 37.7, 35.8, 33.0, 31.5, 26.2, 23.2, 20.3, 18.6, 15.2, ꢀ2.9,
ꢀ4.5 ppm; IR (film): nmax =2931, 2857, 2822, 1738, 1641, 1472, 1463, 1256,
1111, 835, 774 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C21H42O4SiNa:
409.2744, found: 409.2718 [M+Na]+.
0.83 ppm
(d,
J=6.8 Hz,
3H);
13C NMR (100 MHz, CDCl3): d=181.7, 81.4, 79.4, 56.4, 45.2, 35.5, 34.6,
31.1, 31.0, 25.6, 21.6, 18.4, 14.2, 13.1 ppm; IR (film): nmax =3380, 2935,
2873, 1698, 1462, 1152, 1094, 980 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C14H28O4Na: 283.1880, found: 283.1874 [M+Na]+.
Compound 23a: Compound 22a (1.896 g, 4.89 mmol) was dissolved in
EtOH (10 mL) and added to a suspension of Pd (10% on activated char-
coal, 1.05 g) in EtOH (30 mL). The mixture was stirred under an atmos-
phere of H2 at ambient temperature
Compound 25: A solution of compound 24 (327 mg, 2.06 mmol) in
CH2Cl2 (20 mL) was cooled to 08C and 2,6-lutidine (0.96 mL, 8.24 mmol)
and TBSOTf (0.94 mL, 4.09 mmol)
were added.The solution was stirred
for 2 h at 258C and then treated with
MeOH (5 mL).Stirring was continued
for 15 min, the solution was evaporat-
ed and the residue was purified by
column chromatography (silica gel,
for 2 h.After saturation with Ar, fil-
tration of the catalyst and evaporation
of the solvent, the crude saturated in-
termediate (1.833 g) was obtained. A
portion of this intermediate (893 mg)
was cooled to ꢀ108C and treated with a TFA/H2O mixture (9:1, 20 mL).
After 5 min, to the mixture was carefully added sat aq NaHCO3 enough
to neutralize all TFA, and the mixture was extracted with EtOAc
(100 mL).The organic was washed with brine (100 mL), the aq layers
were re-extracted with EtOAc (2”100 mL), and the combined organic
layer was dried (Na2SO4), filtered through a plug of silica gel and evapo-
rated to dryness to afford hydroxy ester 23a (590 mg, 2.16 mmol, 93%)
as a colorless viscous oil. Rf =0.44 (silica gel, 20% EtOAc in hexanes);
[a]2D5 =ꢀ9.8 (c=2.3, CHCl3); 1H NMR (600 MHz, CDCl3): d=3.64 (s,
3H), 3.42 (brs, 1H), 3.26 (s, 3H), 3.06 (m, 1H), 2.92 (brs, 1H), 1.59 (m,
1H), 1.56–1.22 (m, 8H), 1.24 (s, 3H), 1.12 (s, 3H), 0.86 (t, J=7.1 Hz,
3H), 0.71 ppm (d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=
178.6, 80.8, 79.9, 56.4, 51.9, 45.7, 35.6, 34.6, 31.4, 31.2, 24.6, 21.9, 18.4,
14.2, 13.2 ppm; IR (film): nmax =3476, 2933, 2877, 1730, 1458, 1266, 1192,
1141, 1096, 988 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C15H30O4Na:
297.2036, found: 297.2036 [M+Na]+.
5% EtOAc in hexanes) to furnish azido ester 25 (550.1 mg, 2.02 mmol,
98%) as a colorless oil. 25: Rf =0.72 (silica gel, 10% EtOAc in hexanes);
[a]2D5 =+28.5 (c=0.9, CHCl3); 1H NMR (500 MHz, CDCl3): d=3.95 (d,
J=9.8 Hz, 1H), 3.79 (s, 3H), 3.75 (d, J=9.8 Hz, 1H), 1.31 (s, 3H), 0.88
(s, 9H), 0.07 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d =
171.8, 69.5, 67.6, 52.6, 25.6, 19.7, 18.1, ꢀ5.7, ꢀ5.8 ppm; IR (film): nmax
=
2955, 2931, 2142, 2104, 1745, 1462, 1389, 1362, 1258, 1106, 840, 779 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C11H23N3O3NaSi: 296.1401, found:
296.1387 [M+Na]+.
Compound 12: LiOH·H2O (200 mg,
4.77 mmol) was added at ambient tem-
perature to a solution of TBS-protect-
ed alcohol 25 (417 mg, 1.52 mmol) in
MeOH/H2O 4:1 (30 mL) and the reac-
tion mixture was stirred for 3 h.The
6204
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6197 – 6211

Natural Products
FULL PAPER
solution was partitioned between 1m aq HCl (50 mL) and Et2O (50 mL)
and the organic layer was washed with brine (50 mL).The aq layers were
re-extracted with Et2O (3”50 mL) and the combined organic layer was
dried (Na2SO4).Filtration followed by evaporation and flash column
chromatography (silica gel, 5% MeOH in EtOAc) yielded carboxylic
acid 12 (379 mg, 96%) as a colorless oil. Rf =0.61 (silica gel, 10% MeOH
in EtOAc); [a]2D5 =+12.4 (c=0.3, CHCl3); 1H NMR (500 MHz, CDCl3):
d = 3.97 (d, J=10.5 Hz, 1H), 3.80 (d, J=10.5 Hz, 1H), 1.39 (s, 3H), 0.90
(s, 9H), 0.10 (s, 3H), 0.09 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d =
175.8, 69.1, 67.1, 25.6, 19.6, 18.1, ꢀ5.6, ꢀ5.8 ppm; IR (film): nmax =3420,
2925, 2855, 2104, 1719, 1460, 1258, 1108, 834, 778 cmꢀ1; HRMS (negative
ESI-TOF): m/z: calcd for C10H20N3O3Si: 258.1279, found: 258.1269
[MꢀH]ꢀ.
gel, 45% EtOAc in hexanes) yielding amide 29a (640 mg, 1.85 mmol,
94%) as a slightly yellowish viscous oil. Rf =0.43 (silica gel, 50% EtOAc
in hexanes); [a]2D5 =ꢀ11.9 (c=1.6, CHCl3); 1H NMR (400 MHz, CDCl3):
d=6.81 (d, J=7.0 Hz, 1H), 4.52 (dt, J=7.2 Hz, 1H), 3.80 (d, J=6.8 Hz,
1H), 3.72 (s, 3H), 3.42 (dd, J=6.8, 2.0 Hz, 1H), 3.29 (s, 3H), 3.10 (m,
1H), 1.64 (m, 1H), 1.48–1.27 (m, 8H), 1.37 (d, J=7.2 Hz, 3H), 1.31 (s,
3H), 1.13 (s, 3H), 0.88 (t, J=7.1 Hz, 3H), 0.76 ppm (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=178.0, 173.6, 80.9, 80.8, 56.5, 52.4, 47.9,
44.4, 35.6, 34.7, 31.2, 31.1, 26.9, 21.5, 18.5, 17.9, 14.3, 13.0 ppm; IR (film):
nmax =3324, 2938, 2864, 1742, 1636, 1531, 1452, 1374, 1213, 1177, 1149,
1094, 983 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C18H36NO5: 346.2593,
found: 346.2583 [M+H]+.
Compound 29b (prepared from 10b in 84% yield): Rf =0.39 (silica gel,
50% EtOAc in hexanes); [a]2D5 =ꢀ9.2 (c=1.4, CHCl3); 1H NMR
(400 MHz, CDCl3): d=6.83 (d, J=
7.0 Hz, 1H), 4.52 (dt, J=7.0 Hz, 1H),
3.80 (d, J=6.6 Hz, 1H), 3.73 (s, 3H),
Compound 26: H-Ile-OMe (385 mg, 2.12 mmol), EDC·HCl (343 mg,
1.79 mmol), HOAt (244 mg, 1.79 mmol) and iPr2NEt (0.85 mL,
4.88 mmol) were added to a solution of carboxylic acid 12 (422 mg,
1.63 mmol) in CH2Cl2 (25 mL).The re-
3.43 (dd, J=6.6, 2.0 Hz, 1H), 3.30 (s,
action mixture was stirred at ambient
3H), 3.08 (m, 1H), 1.64 (m, 1H),
temperature for 24 h and then concen-
1.62–1.25 (m, 9H), 1.38 (d, J=7.1 Hz,
trated.The residue was purified by
3H), 1.31 (s, 3H), 1.13 (s, 1H), 0.89 (t,
flash column chromatography (silica
J=7.0 Hz, 3H), 0.76 ppm (d, J=
gel, 10 ! 20% EtOAc in hexanes) af-
6.6 Hz, 3H); 13C NMR (100 MHz,
fording compound 26 as a colorless oil
CDCl3): d=178.0, 173.6, 81.1, 80.7, 56.5, 52.4, 47.8, 44.3, 35.6, 34.7, 31.4,
31.1, 27.0, 21.5, 18.4, 17.9, 14.2, 13.0 ppm; IR (film): nmax =3316, 2960,
(573 mg, 1.48 mmol, 91%). Rf =0.43 (silica gel, 20% EtOAc in hexanes);
[a]2D5 =+38.6 (c=0.9, CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.10 (d,
J=8.5 Hz, 1H), 4.51 (dd, J=8.5, 5.0 Hz, 1H), 3.87 (d, J=10.3 Hz, 1H),
3.82 (d, J=10.3 Hz, 1H), 3.74 (s, 3H), 1.91–1.87 (m, 1H), 1.50 (s, 3H),
1.46–1.41 (m, 1H), 1.21–1.15 (m, 1H), 0.93–0.86 (m, 15H), 0.09 (s, 3H),
0.08 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d = 171.9, 170.4, 68.4,
67.8, 56.5, 52.1, 37.8, 25.7, 25.1, 19.1, 18.2, 15.5, 11.5, ꢀ5.6, ꢀ5.7 ppm; IR
(film): nmax =3416, 2959, 2932, 2858, 2119, 1746, 1688, 1682, 1514, 1463,
1384, 1362, 1258, 1208, 1108, 1006, 840, 779 cmꢀ1; HRMS (ESI-TOF):
m/z: calcd for C17H35N4O4Si: 387.2422, found: 387.2423 [M+H]+.
2936, 2865, 1739, 1638, 1530, 1447, 1376, 1210, 1175, 1145, 1091, 985 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C18H36NO5: 346.2593, found: 346.2582
[M+H]+.
Compound 29c (prepared from decanoic acid 10c in 88% yield): Rf =
0.20 (silica gel, 33% EtOAc in hexanes); [a]2D5 =+6.5 (c=0.6, CHCl3);
1H NMR (500 MHz, CDCl3): d=6.85
(d, J=7.0 Hz, 1H), 4.53 (d, J=7.0 Hz,
1H), 3.97 (d, J=7.4 Hz, 1H), 3.73 (s,
3H), 3.40 (dd, J=7.0, 1.8 Hz, 1H), 3.29
(s, 3H), 3.10–3.06 (m, 1H), 1.65–1.62
(m, 1H), 1.38 (d, J=7.4 Hz, 3H), 1.31
(s, 3H), 1.49–1.24 (m, 8H), 1.12 (s,
Compound 27: A solution of TBS-protected dipeptide 26 (572.8 mg,
1.48 mmol) in DMF (50 mL) was cooled to 08C.NaH (60% in mineral
oil, 179 mg, 4.48 mmol) was added followed by iodomethane (0.370 mL,
5.93 mmol) after 20 min. The reaction
3H), 0.88 (d, J=7.2 Hz, 3H), 0.75 ppm
mixture was stirred at 08C for 45 min
before it was partitioned between
(d,
J=7.0 Hz,
3H);
13C NMR
(125 MHz, CDCl3): d = 178.1, 173.6, 81.2, 81.1, 56.5, 52.5, 47.8, 44.0,
35.6, 34.9, 31.3, 31.3, 27.3, 21.8, 18.4, 18.2, 14.3, 12.8 ppm; IR (film):
nmax =3323, 2960, 2924, 2875, 1747, 1644, 1529, 1457, 1208, 1178, 1093,
984 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C18H36NO5: 346.2588, found:
346.2582 [M+H]+.
Et2O (50 mL) and sat aq NH4Cl
(50 mL).The organic layer was
washed with brine (50 mL), the aq
layers were re-extracted with Et2O
(2”50 mL), and the combined organic layer was dried (MgSO4).Filtra-
tion, followed by evaporation and flash column chromatography (silica
gel, 9% EtOAc in hexanes) gave pure compound 27 (572.5 mg, 96%) as
a colorless oil. Rf =0.59 (silica gel, 20% EtOAc in hexanes); [a]2D5 =ꢀ67.1
(c=0.8, CHCl3); 1H NMR (600 MHz, CDCl3): d = 4.82 (d, J=10.8 Hz,
1H), 4.10 (brd, J=9.6 Hz, 1H), 3.83 (d, J=10.2 Hz, 1H), 3.72 (brs, 3H),
3.26 (brs, 3H), 2.05 (m, 1H), 1.46 (brm, 4H), 1.10–1.07 (m, 1H), 0.97 (d,
J=6.6 Hz, 3H), 0.91–0.88 (m, 13H), 0.10 (s, 3H), 0.09 ppm (s, 3H);
13C NMR (150 MHz, CDCl3): d = 172.0, 171.2, 69.5, 67.3, 61.9, 51.8, 32.7,
31.9, 30.3, 25.7, 25.1, 19.2, 18.2, 15.9, 10.6, ꢀ5.6, ꢀ5.7 ppm; IR (film):
nmax =2958, 2932, 2858, 2112, 1742, 1650, 1462, 1393, 1257, 1200, 1106,
Compound 29d (prepared from decanoic acid 10d in 84% yield): Rf =
0.20 (silica gel, 33% EtOAc in hexanes); [a]2D5 =+13.3 (c=1.2, CHCl3);
1H NMR (600 MHz, CDCl3): d = 6.83
(d, J=7.0 Hz, 1H), 4.52–4.49 (m, 1H),
3.99 (d, J=7.0 Hz, 1H), 3.72 (s, 3H),
3.39 (d, J=5.3 Hz, 1H), 3.27 (s, 3H),
3.10–3.06 (m, 1H), 1.65–1.61 (m, 1H),
1.37 (d, J=7.0 Hz, 3H), 1.30 (s, 3H),
1.46–1.25 (m, 8H), 1.11 (s, 3H), 0.97
(t, J=7.0 Hz, 3H), 0.74 ppm (d, J=
1068, 1006, 838, 778 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for
6.5 Hz, 3H); 13C NMR (150 MHz,
C18H37N4O4Si: 401.2578, found: 401.2581 [M+H]+.
CDCl3): d = 178.1, 173.5, 81.2, 80.9, 56.5, 52.4, 47.8, 44.0, 35.6, 34.8, 31.2,
31.2, 27.2, 21.7, 18.4, 18.1, 14.3, 12.8 ppm; IR (film): nmax =3320, 2957,
Compound 29a: Decanoic acid 10a (514 mg, 1.98 mmol), H-Ala-
OMe·HCl (1.122 g, 8.00 mmol), HOAt (1.081 g, 8.00 mmol) and
EDC·HCl (1.926 g, 10.0 mmol) were dissolved in DMF (20 mL) and
iPr2NEt (2.7 mL, 20 mmol) was added. The solution was stirred at ambi-
ent temperature for 16 h and then partitioned between Et2O (50 mL) and
1m aq HCl (100 mL).The organic
2933, 2872, 1746, 1643, 1522, 1455, 1376, 1310, 1213, 1176, 1092, 983 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C18H36NO5: 346.2588, found: 346.2584
[M+H]+.
Compound 30a:
A
solution of (S)-2-azido propionic acid[15] (4.28 g,
37.2 mmol) in DMF (19 mL) was cooled (NaCl ice bath) and oxalyl chlo-
ride (2.85 mL, 32.8 mmol) was added
layer was washed with brine (100 mL),
the aq layers were re-extracted with
cautiously.The solution was allowed
Et2O (2”50 mL), and the combined or-
to reach ambient temperature and was
ganic layer was dried (Na2SO4), filtered
stirred for 0.5 h. The resulting mixture
and evaporated.The residue was puri-
was then slowly added to a cooled
fied by column chromatography (silica
(NaCl ice bath) solution of hydroxy
Chem. Eur. J. 2005, 11, 6197 – 6211
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
6205

K.C.Nicolaou et al.
amide 29a (592 mg, 1.71 mmol), 4-DMAP (115 mg, 0.943 mmol) and
Et3N (6.50 mL, 46.7 mmol) in DMF (10 mL). The reaction mixture was
stirred at 508C for 24 h.After cooling to 25 8C, the mixture was parti-
tioned between EtOAc (100 mL) and sat aq NaHCO3 (200 mL).The or-
ganic layer was washed with 1m aq HCl (200 mL) and with brine
(200 mL), the aq layers were re-extracted with EtOAc (2”100 mL), and
the combined organic layer was dried (Na2SO4).After filtration and
evaporation, the residue was purified by flash column chromatography
(silica gel, 25% EtOAc in hexanes) to yield ester 30a (712 mg,
Compound 32a: An aq nBu4NOH solution (40%, 2.0 mL, 3.1 mmol) at
08C was added to a solution of methyl ester 27 (620 mg, 1.55 mmol) in
THF (30 mL).The solution was stirred for 6 h at this temperature and
then partitioned between a pre-cooled (08C) mixture of Et2O (100 mL)
and 1m aq HCl (100 mL).The organic layer was washed with brine
(100 mL) and the aq layers were re-extracted with Et2O (2”50 mL).The
combined organic layer was dried (Na2SO4), filtered and evaporated
(during the work-up the temperature was kept at approximately 08C),
yielding crude acid 28 (430 mg, ca.11. mmol, 70%) which was subse-
quently coupled to amine 31a without further purification.
1.609 mmol, 94%) as a reddish oil. Rf =0.63 (silica gel, Et2O); [a]D25
=
+1.0 (c=0.95, CHCl3); 1H NMR (600 MHz, CDCl3): d=6.59 (d, J=
6.9 Hz, 1H), 5.07 (d, J=1.9 Hz, 1H), 4.51 (m, 1H), 4.08 (m, 1H), 3.71 (s,
3H), 3.25 (s, 3H), 3.05 (m, 1H), 1.82 (m, 1H), 1.51 (d, J=7.1 Hz, 3H),
1.52–1.38 (m, 3H), 1.36 (d, J=7.2 Hz, 3H), 1.35–1.23 (m, 5H), 1.19 (s,
3H), 1.18 (s, 3H), 0.88–0.83 ppm (m, 6H); 13C NMR (150 MHz, CDCl3):
d=174.5, 173.5, 170.1, 82.1, 80.5, 57.9, 56.3, 52.3, 48.1, 45.9, 35.6, 34.1,
31.4, 31.0, 23.7, 22.5, 18.4, 17.9, 16.9, 14.6, 14.1 ppm; IR (film): nmax
=
3397, 2948, 2869, 2820, 2102, 1742, 1657, 1518, 1448, 1379, 1339, 1304,
1259, 1194, 1095, 935 cmꢀ1
; HRMS (ESI-TOF): m/z: calcd for
C21H39N4O6: 443.2864, found: 443.2859 [M+H]+.
Compound 30b (prepared from 29b in 65% yield): Rf =0.35 (silica gel,
33% EtOAc in hexanes); [a]2D5 =+2.7 (c=0.2, CHCl3); 1H NMR
(500 MHz, CDCl3): d=6.59 (d, J=
Under an Ar atmosphere, Pd (10% on activated charcoal, 190 mg) was
suspended in EtOH (20 mL).Azide 30a (340 mg, 0.768 mmol) was added
as a solution in EtOH (total volume 4 mL) and the mixture was saturated
6.9 Hz, 1H), 5.07 (d, J=2.8 Hz, 1H),
4.53 (dt, J=7.1 Hz, 1H), 4.09 (q, J=
7.1 Hz, 1H), 3.72 (s, 3H), 3.27 (s, 3H),
1.84 (m, 1H), 1.53 (d, J=7.0 Hz, 3H),
with H2 at ambient temperature.After 2 h, the H was exchanged with
2
Ar, the catalyst was filtered off and the filtrate was concentrated to
afford the crude amine 31a.The residue was dried by azeotropic distilla-
tion with toluene (3”10 mL).
1.47–1.40 (m, 3H), 1.39 (d, J=7.1 Hz,
Amine 31a and acid 28 obtained above were dissolved in DMF (10 mL)
and at 08C, HOAt (384 mg, 2.82 mmol), PyOAP (1.669 mg, 3.19 mmol)
and iPr2NEt (0.64 mL, 3.70 mmol) were added. The resulting solution
was stirred for 20 h at ambient temperature and then partitioned between
Et2O (50 mL) and sat aq NH4Cl (100 mL).The organic layer was washed
with brine (100 mL) and the aq layers were re-extracted with Et2O (2”
50 mL).The combined organic layer was dried (Na 2SO4), filtered, evapo-
rated and purified by flash column chromatography (silica gel, 30%
EtOAc in hexanes) yielding depsipeptide 32a (430 mg, 0.548 mmol, 71%
from azide 30a) as a yellowish oil. Rf =0.31 (silica gel, 25% EtOAc in
3H), 1.30–1.20 (m, 5H), 1.19 (s, 3H),
1.19 (s, 3H), 1.19–1.13 (m, 1H), 0.89–
0.86 ppm
(m,
6H);
13C NMR
(125 MHz, CDCl3): d=174.6, 173.6, 170.1, 82.2, 80.6, 58.0, 56.3, 52.4, 48.2,
45.9, 35.5, 34.2, 31.3, 30.8, 23.9, 22.6, 18.5, 18.0, 17.0, 14.7, 14.2 ppm; IR
(film): nmax =3402, 2929, 2864, 2100, 1743, 1636, 1517, 1452, 1253, 1195,
1092 cmꢀ1
; HRMS (ESI-TOF): m/z: calcd for C21H39N4O6: 443.2864,
found: 443.2862 [M+H]+.
Compound 30c (prepared from 29c in 95% yield): Rf =0.39 (silica gel,
33% EtOAc in hexanes); [a]2D5 =+23.7 (c=0.8, CHCl3); 1H NMR
(500 MHz, CDCl3): d = 6.67 (d, J=
1
hexanes); [a]2D5 =ꢀ69.7 (c=1.2, CHCl3); H NMR (400 MHz, CDCl3): d=
6.77 (d, J=7.4 Hz, 1H), 6.60 (d, J=6.7 Hz, 1H), 5.07 (d, J=2.8 Hz, 1H),
4.58–4.52 (m, 3H), 4.15 (d, J=9.9 Hz, 1H), 3.81 (d, J=9.9 Hz, 1H), 3.45
(s, 3H), 3.29 (s, 3H), 3.20 (s, 3H), 3.07 (m, 1H), 2.16 (m, 1H), 1.79 (m,
1H), 1.61–1.43 (m, 2H), 1.42 (d, J=7.1 Hz, 3H), 1.41 (d, J=7.1 Hz, 3H),
1.41–1.36 Hz (m, 2H), 1.36 (s, 3H), 1.36–1.20 (m, 6H), 1.20 (s, 3H), 1.19
(s, 3H), 1.03 (m, 1H), 0.93–0.84 (m, 20H), 0.10 (s, 3H), 0.09 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=174.6, 173.5, 172.0, 171.7, 169.3,
81.5, 80.5, 69.8, 67.3, 61.9, 56.3, 52.3, 48.1, 48.0, 45.9, 35.6, 34.3, 31.3, 31.1,
31.1, 30.6, 30.2, 25.6, 24.3, 23.4, 22.8, 19.1, 18.4, 18.1, 18.0, 17.9, 15.5, 14.8,
14.2, 10.1, ꢀ5.6, ꢀ5.8 ppm; IR (film): nmax =3342, 2955, 2941, 2865, 2097,
6.5 Hz, 1H), 5.06 (d, J=2.6 Hz, 1H),
4.51 (dq, J=7.0, 6.5 Hz, 1H), 4.12 (q,
J=7.0 Hz, 1H), 3.73 (s, 3H), 3.26 (s,
3H), 3.08–3.03 (m, 1H), 1.86–1.80 (m,
1H), 1.53 (d, J=7.0 Hz, 3H), 1.37 (d,
J=7.4 Hz, 3H), 1.61–1.22 (m, 8H),
1.18 (s, 6H), 0.87 (t, J=7.0 Hz, 3H),
0.83 ppm
(d,
J=6.8 Hz,
3H);
13C NMR (125 MHz, CDCl3): d = 174.7, 173.5, 170.3, 82.3, 80.6, 57.6,
56.3, 52.4, 48.2, 46.0, 35.5, 34.1, 31.4, 30.7, 23.8, 22.7, 18.5, 18.4, 16.8, 14.4,
14.2 ppm; IR (film): nmax =3396, 2960, 2935, 2875, 2100, 1747, 1669, 1517,
1457, 1378, 1196, 1093, 936 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C21H39N4O6: 443.2864, found: 443.2864 [M+H]+.
1743, 1666, 1619, 1519, 1455, 1378, 1255, 1190, 1091, 838, 779 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C38H73N6O9Si: 785.5203, found:
785.5189 [M+H]+.
Compound 32b (prepared from 30b in 64% yield): Rf =0.29 (silica gel,
25% EtOAc in hexanes): [a]2D5 =ꢀ66.2 (c=0.6, CHCl3); 1H NMR
(500 MHz, CDCl3): d= 6.74 (d, J=7.4 Hz, 1H), 6.57 (d, J=6.9 Hz, 1H),
5.04 (d, J=2.7 Hz, 1H), 4.54–4.49 (m, 3H), 4.11 (d, J=9.9 Hz, 1H), 3.78
(d, J=9.9 Hz, 1H), 3.71 (s, 3H), 3.25 (s, 3H), 3.16 (s, 3H), 3.04 (m, 1H),
2.10 (m, 1H), 1.78 (m, 1H), 1.57–1.13 (m, 25H), 1.01 (m, 1H), 0.96–0.82
(m, 20H), 0.07 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (125 MHz, CDCl3):
d=174.5, 173.6, 172.1, 171.8, 169.3, 81.7, 80.7, 69.8, 67.4, 62.0, 56.3, 52.4,
Compound 30d (prepared from 29d in 98% yield): Rf =0.39 (silica gel,
33% EtOAc in hexanes); [a]2D5 =+26.6 (c=0.9, CHCl3); 1H NMR
(600 MHz, CDCl3): d = 6.65 (d, J=
6.1 Hz, 1H), 5.06 (d, J=2.6 Hz, 1H),
4.53–4.48 (m, 1H), 4.11 (q, J=7.0 Hz,
1H), 3.72 (s, 3H), 3.26 (s, 3H), 3.07–
3.03 (m, 1H), 1.84–1.80 (m, 1H), 1.54
(d, J=8.8 Hz, 3H), 1.37 (d, J=7.0 Hz,
3H), 1.45–1.26 (m, 8H), 1.18 (s, 6H),
0.87 (t, J=7.0 Hz, 3H), 0.83 ppm (d,
J=6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d = 174.7, 173.5, 170.3, 82.3, 80.6, 57.6, 56.3, 52.4, 48.2, 46.0,
35.5, 34.1, 31.4, 30.8, 23.8, 22.7, 18.5, 18.4, 16.8, 14.,4, 14.2 ppm; IR (film):
nmax =3393, 2956, 2932, 2885, 2097, 1746, 1649, 1515, 1455, 1376, 1303,
1195, 1092, 934 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C21H39N4O6:
443.2864, found: 443.2868 [M+H]+.
6206
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Chem. Eur. J. 2005, 11, 6197 – 6211

Natural Products
FULL PAPER
48.2, 48.1, 46.0, 35.5, 34.4, 31.3, 30.9, 30.6, 25.7, 24.4, 23.5, 22.9, 19.2, 18.4,
18.2, 18.1, 17.9, 15.6, 15.4, 14.7, 14.2, 10.2, ꢀ5.6, ꢀ5.7 ppm; IR (film):
nmax =3342, 2931, 2860, 2108, 1743, 1666, 1631, 1519, 1455, 1373, 1255,
1096, 832, 779 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C38H73N6O9Si:
785.5203, found: 785.5198 [M+H]+.
quently with brine (50 mL).The aq layers were re-extracted with Et 2O
(3”20 mL) and the combined organic layers dried (Na2SO4), filtered and
evaporated.The crude product was purified by flash column chromatog-
raphy (silica gel, 40% EtOAc in hexanes with 2% AcOH) to give acid
33a (57.8 mg, 0.075 mmol, 95%) as a colorless viscous oil. Rf =0.20
(silica gel, 40% EtOAc in hexanes with 2% AcOH); [a]2D5 =ꢀ36.8 (c=
0.6, CHCl3); 1H NMR (600 MHz, CDCl3): d = 6.93 (d, J=7.9 Hz, 1H),
6.63 (d, J=7.0 Hz, 1H), 5.06 (d, J=2.6 Hz, 1H), 4.58–4.50 (m, 3H), 4.09
(d, J=10.1 Hz, 1H), 3.79 (d, J=10.1 Hz, 1H), 3.26 (s, 3H), 3.20 (s, 3H),
3.06 (m, 1H), 2.09 (m, 1H), 1.78 (m, 1H), 1.45–1.21 (m, 13H), 1.41 (d,
J=7.2 Hz, 3H), 1.38 (d, J=7.1 Hz, 3H), 1.18 (s, 3H), 1.17 (s, 3H), 1.00
(m, 1H), 0.91–0.81 (m, 12H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 ppm (s,
3H); 13C NMR (150 MHz, CDCl3): d = 175.4, 175.4, 172.2, 171.5, 169.3,
81.3, 80.7, 69.7, 67.4, 62.1, 56.2, 48.2, 48.1, 46.1, 35.5, 34.2, 31.3, 31.3, 31.0,
30.7, 30.2, 29.6, 25.6, 24.3, 23.5, 22.0, 18.4, 18.4, 18.1, 17.9, 17.5, 15.5, 14.9,
14.2, 10.1, ꢀ5.6, ꢀ5.8 ppm; IR (film): nmax =3331, 2931, 2861, 2108, 1737,
1684, 1625, 1461, 1373, 1255, 1196, 1108, 1061, 844 cmꢀ1; HRMS (ESI-
TOF): m/z: calcd for C37H71N6O9Si: 771.5029, found: 771.5029 [M+H]+.
Compound 32c (prepared from 30c in 40% yield): Rf =0.32 (silica gel,
33% EtOAc in hexanes): [a]2D5 =ꢀ51.9 (c=0.5, CHCl3); 1H NMR
(500 MHz, CDCl3): d = 6.96 (d, J=6.8 Hz, 1H), 6.71 (d, J=6.5 Hz, 1H),
4.97 (d, J=2.0 Hz, 1H), 4.58–4.51 (m, 3H), 4.12 (d, J=10.0 Hz, 1H), 3.79
(d, J=10.0 Hz, 1H), 3.72 (s, 3H), 3.26 (s, 3H), 3.18 (s, 3H), 3.10–3.00 (m,
1H), 2.15–2.01 (m, 1H), 1.85–1.81 (m, 1H), 1.46–1.26 (m, 16H), 1.18 (s,
3H), 1.17 (s, 3H), 1.13–0.99 (m, 2H), 0.88 (s, 9H), 0.88–0.72 (m, 12H),
0.08 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d = 174.9,
173.7, 172.4, 172.1, 169.7, 81.7, 80.6, 69.8, 67.5, 61.9, 56.3, 52.3, 48.5, 48.1,
45.7, 35.6, 34.1, 31.3, 31.1, 30.8, 30.7, 25.7, 24.6, 24.4, 23.0, 19.3, 18.5, 18.3,
18.2, 17.8, 15.5, 14.3, 14.0, 10.2, ꢀ5.6, ꢀ5.7 ppm; IR (film): nmax =3372,
3311, 2960, 2924, 2875, 2112, 1747, 1668, 1620, 1505, 1462, 1359, 1251,
1196, 1160, 1099, 1069, 845 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C38H73N6O9Si: 785.5203, found: 785.5202 [M+H]+.
Compound 33b (prepared from methyl ester 32b in 92% yield): Rf =0.20
(silica gel, 40% EtOAc in hexanes with 2% AcOH); [a]2D5 =ꢀ31.2 (c=
0.7, EtOH); 1H NMR (500 MHz, CDCl3): d= 6.91 (d, J=7.6 Hz, 1H),
6.54 (d, J=6.9 Hz, 1H), 5.05 (d, J=2.2 Hz, 1H), 4.56 (m, 2H), 4.52 (m,
1H), 4.08 (d, J=10.0 Hz, 1H), 3.77 (d, J=10.0 Hz, 1H), 3.26 (s, 3H),
3.19 (s, 3H), 3.06 (m, 1H), 2.10 (m, 1H), 1.79 (m, 1H), 1.45–1.18 (m,
19H), 1.18 (s, 3H), 1.16 (s, 3H), 0.98 (m, 1H), 0.91–0.81 (m, 12H), 0.87
(s, 9H), 0.06 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
175.5, 175.5, 172.2, 171.4, 169.2, 81.4, 80.8, 69.7, 67.4, 62.1, 56.3, 48.2, 48.1,
46.2, 35.5, 34.2, 31.4, 31.3, 30.9, 30.8, 29.7, 25.7, 24.3, 23.5, 21.8, 19.1, 18.4,
18.2, 17.8, 17.5, 15.6, 14.8, 14.2, 10.2, ꢀ5.6, ꢀ5.8 ppm; IR (film): nmax
=
Compound 32d (prepared from 30d in 46% yield): Rf =0.32 (33%
EtOAc in hexanes); [a]2D5 =ꢀ53.0 (c=0.6, CHCl3); 1H NMR (600 MHz,
CDCl3): d=6.95 (d, J=6.6 Hz, 1H), 6.70 (d, J=6.5 Hz, 1H), 4.97 (d, J=
1.7 Hz, 1H), 4.57–4.53 (m, 3H), 4.12 (d, J=9.9 Hz, 1H), 3.80 (d, J=
9.9 Hz, 1H), 3.72 (s, 3H), 3.26 (s, 3H), 3.18 (s, 3H), 3.06–3.02 (m, 1H),
2.12–2.08 (m, 1H), 1.84–1.81 (m, 1H), 1.59 (s, 3H), 1.46–1.20 (m, 15H),
1.18 (s, 3H), 1.17 (s, 3H), 1.06–0.99 (m, 1H), 0.92–0.87 (m, 15H), 0.84 (t,
J=7.4 Hz, 3H), 0.81 (d, J=7.0 Hz, 3H), 0.08 (s, 3H), 0.07 ppm (s, 3H);
13C NMR (150 MHz, CDCl3): d = 174.9, 173.6, 172.4, 172.1, 169.7, 81.7,
80.6, 69.8, 67.4, 61.9, 56.4, 52.3, 48.5, 48.1, 45.7, 35.7, 34.1, 31.3, 31.2, 31.1,
30.8, 25.7, 24.6, 24.4, 23.0, 19.3, 18.4, 18.3, 18.2, 17.8, 15.5, 14.3, 14.0, 10.2,
ꢀ5.6, ꢀ5.7 ppm; IR (film): nmax =3381, 3320, 2957, 2932, 2860, 2108, 1746,
3331, 2931, 2861, 2108, 1737, 1684, 1625, 1461, 1373, 1255, 1196, 1108,
844 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C37H71N6O9Si: 771.5029,
found: 771.5029 [M+H]+.
1655, 1618, 1522, 1461, 1382, 1255, 1195, 1158, 1098, 1067, 837 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C38H73N6O9Si: 785.5203, found:
785.5200 [M+H]+.
Compound 33c (prepared from methyl ester 32c in 90% yield): Rf =0.21
(silica gel, EtOAc); [a]D25 =ꢀ40.4 (c=0.7, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 7.13 (d, J=9.7 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 4.91 (d,
J=2.2 Hz, 1H), 4.69–4.63 (m, 1H), 4.53–4.47 (m, 2H), 4.02 (d, J=
12.3 Hz, 1H), 3.76 (d, J=12.3 Hz, 1H), 3.26 (s, 3H), 3.20 (s, 3H), 3.05–
3.02 (m, 1H), 2.11–2.05 (m, 1H), 1.89–1.83 (m, 1H), 1.44–1.40 (m, 10H),
1.38–1.22 (m, 8H), 1.18 (s, 3H), 1.17 (s, 3H), 1.10–0.93 (m, 2H), 0.89 (s,
9H), 0.88–0.81 (m, 10H), 0.72 (d, J=8.4 Hz, 3H), 0.07 (s, 3H), 0.06 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3): d
= 175.9, 175.3, 172.2, 171.8,
168.9, 82.0, 80.6, 69.4, 67.8, 62.9, 56.4, 48.6, 48.6, 45.4, 35.5, 33.8, 31.5,
31.3, 31.3, 30.9, 30.3, 25.7, 24.9, 24.1, 22.5, 19.5, 18.4, 18.2, 18.1, 15.8, 14.2,
13.6, 10.6, ꢀ5.6, ꢀ5.7 ppm; IR (film): nmax =3329, 2957, 2920, 2858, 2117,
Compound 33a: Methyl ester 32a (61.8 mg, 0.079 mmol) was dissolved in
1,2-dichloroethane (5 mL).The solution was degassed with Ar and
Me3SnOH (290 mg, 1.60 mmol) was added. The reaction vessel was
sealed and heated to 508C for 18 h.After cooling to 25 8C, the suspension
was diluted with CH2Cl2 (20 mL) and evaporated.The residue was dis-
solved in Et2O (20 mL) and washed with 1m aq HCl (50 mL) and subse-
1743, 1620, 1527, 1459, 1385, 1255, 1194, 1150, 1101, 1070, 835, 780 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C37H71N6O9Si: 771.5046, found:
771.5051 [M+H]+.
Chem. Eur. J. 2005, 11, 6197 – 6211
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
6207

K.C.Nicolaou et al.
Compound 33d (prepared from methyl ester 32d in 88% yield): Rf =0.36
(silica gel, 5% MeOH in EtOAc); [a]2D5 =ꢀ38.3 (c=3.2, CHCl3);
1518, 1459, 1380, 1252, 1212, 1094, 1065, 966, 838, 774 cmꢀ1; HRMS (ESI-
TOF): m/z: calcd for C37H71N4O8Si: 727.5035 found: 727.5030 [M+H]+.
1H NMR (400 MHz, CDCl3): d
= 6.95 (brs, 1H), 6.89 (d, J=6.2 Hz,
Compound 35b (obtained from 33b in 73% yield): Rf =0.24 (silica gel,
50% EtOAc in hexanes); [a]2D5 =ꢀ75.1 (c=0.4, CHCl3); 1H NMR
(500 MHz, CDCl3, spectrum contains at least three sets of poorly re-
solved signals due to hindered rotation): d= 7.77 (brs, 1H), 7.63 (brs,
1H), 7.55 (d, J=6.8 Hz, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.26 (brs, 1H),
6.99 (d, J=6.1 Hz, 1H), 4.98–4.87 (m, 1.5H), 4.93 (d, J=2.5 Hz, 1H),
4.78–4.66 (brs, 1.5H), 4.69 (d, J=8.0 Hz, 1H), 4.63 (dt, J=6.7 Hz, 1H),
4.43 (dt, J=7.1 Hz, 1H), 4.31 (brd, J=9.1 Hz, 1H), 4.21 (d, J=10.1 Hz,
1H), 3.91 (d, J=3.1 Hz, 0.5H), 3.88 (d, J=10.1 Hz, 1H), 3.80 Hz (d, J=
9.5 Hz, 0.5H), 3.69 (d, J=9.4 Hz, 0.5H), 3.60 (brd, J=9.2 Hz, 1H), 3.26
(s, 3H), 3.24 (s, 3H), 3.12–2.98 (brs, 3H), 3.02 (s, 3H), 2.19 (s, 1.5H),
2.04–1.75 (m, 5H), 1.68 (m, 1H), 1.62–0.74 (m, >120H), 0.14–
[ꢀ0.06 ppm] (m, 15H); IR (film): nmax =4338, 3307, 2931, 2861, 1743,
1678, 1637, 1519, 1455, 1378, 1255, 1096, 1067, 834, 779 cmꢀ1; HRMS
(ESI-TOF): m/z: calcd for C37H71N4O8Si: 727.5035 found: 727.5038
[M+H]+.
1H), 4.95 (brs, 1H), 4.66–4.59 (m, 1H), 4.53 (d, J=11.1 Hz, 1H), 4.47
(m, 1H), 4.06 (d, J=9.8 Hz, 1H), 3.77 (d, J=9.8 Hz, 1H), 3.26 (s, 3H),
3.19 (s, 3H), 3.07–3.01 (m, 1H), 2.14–2.05 (m, 1H), 1.86–1.81 (m, 1H),
1.56–1.19 (m, 19H), 1.17 (s, 6H), 1.08–0.95 (m, 1H), 0.88–0.81 (m, 18H),
0.73 (d, J=9.1 Hz, 3H), 0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d = 175.0, 172.1, 172.0, 169.1, 81.8, 80.7, 69.6, 67.7,
62.6, 56.4, 48.7, 48.5, 45.6, 35.7, 33.9, 31.6, 31.4, 31.1, 31.1, 25.7, 24.2, 22.8,
19.4, 18.5, 18.4, 18.2, 18.1, 15.8, 14.2, 14.0, 10.4, ꢀ5.6, ꢀ5.7 ppm; IR
(film): nmax =3342, 2955, 2919, 2861, 2108, 1743, 1619, 1537, 1455, 1384,
1255, 1190, 1155, 1096, 838, 779 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C37H71N6O9Si: 771.5046, found: 771.5039 [M+H]+.
Compound 35a: Pd(OH)2 (20% on activated charcoal, 200 mg) was sus-
pended in EtOH (8 mL).The mixture was stirred for 05. h under an at-
mosphere of H2 and subsequently degassed with Ar.Azide 33a (61.8 mg,
0.080 mmol), dissolved in EtOH (2 mL), was added and the mixture was
stirred for 0.5 h under an atmosphere of H2.After saturation with Ar, the
catalyst was filtered off, the filtrate was evaporated, and the residue was
taken up in toluene (3”5 mL) and evaporated to dryness.The resulting
Compound 35c/epi-35c (obtained from 33c; 35c: 14%, epi-35c: 22%).
35c: Rf =0.36 (silica gel, 5 0% EtOAc in hexanes); [a]3D2 =ꢀ55.3 (c=0.7,
CHCl3); 1H NMR (600 MHz, CDCl3): d = 7.50 (brd, J=5.2 Hz, 1H),
7.33 (d, J=6.3 Hz, 1H), 7.13 (brs, 1H), 6.96 (s, 1H), 6.83 (brs, 1H), 6.71
(d, J=5.9 Hz, 1H), 4.90 (s, 1H), 4.81 (s, 1H), 4.62 (d, J=7.7 Hz, 1H),
4.62–4.51 (m, 1H), 4.44–4.38 (m, 1H), 4.29–4.27 (m, 1H), 4.12 (d, J=
10.3 Hz, 1H), 3.84 (d, J=10.3 Hz, 1H), 3.63 (brd, J=9.2 Hz, 1H), 3.29
(s, 3H), 3.27 (s, 1H), 3.11 (s, 1H), 3.08–3.01 (m, 1H), 2.71 (s, 3H), 2.04–
2.00 (m, 1H), 1.87–1.80 (m, 1H), 1.60 (s, 3H), 1.53 (s, 1H), 1.41 (s, 3H),
1.35 (d, J=6.6 Hz, 3H), 1.16 (s, 3H), 1.13 (s, 1H), 1.06 (d, J=6.3 Hz,
3H), 1.46–1.19 (m, 9H), 0.87 (s, 9H), 0.94–0.85 (m, 13H), 0.05 (s, 6H),
0.02 ppm (s, 6H); IR (film): nmax =3305, 2962, 2928, 2873, 1744, 1683,
1638, 1516, 1455, 1256, 1095, 1067, 840, 773 cmꢀ1; HRMS (ESI-TOF):
m/z: calcd for C37H71N4O8Si: 727.5035, found: 727.5037 [M+H]+.
crude amino acid 34a was dissolved in CH2Cl2 (40 mL) and the resulting
solution was added to a solution of HATU (45.4 mg, 0.120 mmol), HOAt
(32.7 mg, 0.241 mmol) and iPr2NEt (40 mL, 0.24 mmol) in CH2Cl2
(40 mL) over a period of 4 h at ambient temperature.After 17 h of stir-
ring, the solution was concentrated to approximately 20 mL and washed
with sat aq NaHCO3 (50 mL) and then with brine (50 mL).The aq layers
were re-extracted with CH2Cl2 (2”20 mL) and the combined organic
layer was dried (Na2SO4), filtered and evaporated.The crude product
was purified by flash column chromatography (silica gel, 55% EtOAc in
hexanes) yielding macrocycle 35a (43.3 mg, 0.060 mmol, 74%) as a white
wax. 35a: Rf =0.28 (silica gel, 50% EtOAc in hexanes); [a]2D5 =ꢀ38.0 (c=
Compound epi-35c: Rf =0.28 (silica gel, 50% EtOAc in hexanes); [a]D25
=
1
0.6, CHCl3); H NMR (300 MHz, CDCl3, spectrum contains at least three
ꢀ7.3 (c=0.2, CHCl3); 1H NMR (500 MHz, CDCl3, spectrum contains at
least two sets of poorly resolved signals due to hindered rotation): d =
6.68 (brs, 1H), 6.64 (brd, J=7.0 Hz, 1H), 6.38 (s, 1H), 5.01 (d, J=
2.6 Hz, 1H), 4.98–4.95 (m, 1H), 4.50–4.45 (m, 1H), 3.90–3.88 (m, 2H),
3.56 (d, J=10.3 Hz, 1H), 3.27 (s, 3H), 3.07–3.02 (m, 1H), 2.92 (s, 3H),
2.04–1.97 (m, 1H), 1.88–1.84 (m, 1H), 1.70 (d, J=7.7 Hz, 3H), 1.55 (s,
3H), 1.29 (d, J=7.0 Hz, 3H), 1.24 (s, 3H), 1.16 (s, 3H), 1.52–1.06 (m,
sets of poorly resolved signals due to hindered rotation): d= 7.85 (brs,
1H), 7.76 (brs, 1H), 7.54 (d, J=6.9 Hz, 1H), 7.37 (d, J=6.4 Hz, 1H),
7.26 (brs, 1H), 7.00 (d, J=6.1 Hz, 1H), 4.92 (d, J=2.5 Hz, 1H), 4.90
(brs, 2H), 4.79–4.57 (m, 5H), 4.48 (m, 2H), 4.31 (brd, J=8 Hz, 1H), 4.21
(d, J=10.1 Hz, 2H), 4.12–3.99 (m, 1H), 3.91–3.67 (m, 2H), 3.84 (d, J=
10.1 Hz, 2H), 3.61 (brs, J=8 Hz, 1H), 3.26 (s, 3H), 3.25 (s, 3H), 3.08–
3.00 (brs, 3H), 3.02 (s, 3H), 2.75 (m, 1H), 2.69 (s, 3H), 2.04–1.93 (m,
1H), 1.93–1.77 (m, 3H), 1.59–0.73 (m), 0.07–0.00 ppm (m, 15H);
13C NMR (75 MHz, CDCl3, at least two sets of poorly resolved signals):
d= 175.9, 175.5, 174.5, 172.3, 171.9, 170.0, 170.3, 169.4, 167.7, 164.4, 81.3,
80.6, 80.5, 80.3, 77.2, 69.2, 65.7, 64.3, 64.1, 61.1, 59.8, 56.5, 50.2, 49.9, 48.8,
48.2, 48.1, 46.4, 45.7, 39.9, 39.9, 37.6, 36.2, 35.6, 34.6, 33.6, 33.3, 31.7, 31.6,
31.4, 31.3, 30.9, 30.6, 29.7, 26.9, 26.6, 25.9, 25.8, 23.2, 21.7, 20.6, 20.5, 18.4,
18.2, 18.1, 17.9, 17.3, 16.5, 16.4, 15.0, 14.8, 14.2, 12.6, 12.4, 11.9, 10.8, ꢀ5.4,
ꢀ5.5 ppm; IR (film): nmax =3370, 3301, 2956, 2927, 2858, 1744, 1675, 1636,
6208
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6197 – 6211

Natural Products
FULL PAPER
9H), 1.00 (d, J=6.3 Hz, 3H), 0.91 (s, 9H), 0.93–0.90 (m, 4H), 0.88 (t, J=
7.0 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H), 0.10 ppm (s, 6H); 13C NMR
(125 MHz, CDCl3, signals of most abundant rotomer): d = 175.8, 172.0,
170.9, 170.7, 170.6, 80.6, 79.8, 66.0, 61.7, 56.4, 51.3, 48.5, 46.1, 35.5, 34.2,
31.3, 30.9, 30.3, 25.8, 24.4, 24.3, 22.3, 20.3, 19.4, 18.4, 18.2, 16.9, 16.8, 14.8,
14.3, 10.9, ꢀ5.4, ꢀ5.6 ppm; IR (film): nmax =3370, 3304, 2956, 2917, 2858,
1749, 1641, 1518, 1459, 1360, 1252, 1193, 1119, 1099, 961, 838, 779 cmꢀ1
;
HRMS (ESI-TOF): m/z: calcd for C37H71N4O8Si: 727.5035, found:
727.5033 [M+H]+.
all starting material was consumed and the solution was partitioned be-
tween EtOAc (10 mL) and sat aq NH4Cl (30 mL).The organic layer was
washed with brine (30 mL), the aq layers were re-extracted with EtOAc
(2”10 mL) and the combined organic layers dried over Na2SO4.After fil-
tration through a plug of silica and evaporation of the solvents, the resi-
due was taken up in toluene (3”10 mL) and evaporated to dryness.The
crude hydroxy amide 8a thus obtained was dissolved in CH2Cl2 (10 mL),
cooled to ꢀ788C and reacted with DAST (9 mL, 0.07 mmol). After 0.5 h,
the temperature was raised to ꢀ128C and after an additional 0.5 h, sat aq
NaHCO3 (10 mL) was added.After washing of the organic layer with
brine (10 mL), the aq layers were re-extracted with CH2Cl2 (2”10 mL),
and the combined organic layer was dried (Na2SO4), filtered and evapo-
rated.The resulting residue was purified by flash column chromatogra-
phy (silica gel, 40 ! 50% EtOAc in hexanes) to afford oxazoline 7a
(12.9 mg, 0.022 mmol, 74%) as a colorless oil. Rf =0.38 (silica gel, 60%
EtOAc in hexanes); [a]2D5 =ꢀ68.8 (c=0.4, CHCl3); 1H NMR (600 MHz,
CDCl3): d=7.78 (d, J=10.1 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 5.01 (dq,
J=10.1, 7.0 Hz, 1H), 4.84 (d, J=2.6 Hz, 1H), 4.81 (d, J=9.2 Hz, 1H),
4.79–4.72 (m, 2H), 4.29 (d, J=9.2 Hz, 1H), 3.27 (s, 3H), 3.07–3.04 (m,
1H), 2.80 (s, 3H), 2.24–2.17 (m, 1H), 1.94–1.88 (m, 1H), 1.52–1.39 (m,
3H), 1.42–1.41 (m, 6H), 1.36 (d, J=7.0 Hz, 3H), 1.36–1.23 (m, 6H), 1.20
(s, 3H), 1.18 (s, 3H), 0.98–0.94 (m, 4H), 0.90–0.86 (m, 6H), 0.83 ppm (d,
J=7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3): d = 173.9, 171.8, 171.0,
169.0, 168.6, 82.5, 80.5, 79.2, 74.3, 64.1, 56.5, 48.8, 45.6, 43.7, 35.6, 34.5,
33.2, 31.5, 31.2, 29.7, 27.3, 26.5, 24.8, 22.3, 19.3, 19.1, 18.4, 16.8, 14.3, 14.3,
12.4 ppm; IR (film): nmax =3323, 2982, 1727, 1663, 1527, 1451, 1286, 1251,
1216, 1140, 1063, 981, 746, 699 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for
C31H55N4O7: 595.4065, found: 595.4067 [M+H]+.
Compound 35d/epi-35d (obtained from 33d; 35d: 25%, epi-35d: 19%).
35d: Rf =0.32 (silica gel, 50% EtOAc in hexanes); [a]2D5 =ꢀ46.7 (c=0.7,
CHCl3); 1H NMR (600 MHz, CDCl3, spectrum contains at least two sets
of poorly resolved signals due to hindered rotation): d=7.52 (d, J=
6.6 Hz, 1H), 7.34 (d, J=6.0 Hz, 1H), 7.02 (brs, 1H), 6.72 (d, J=6.0 Hz,
1H), 4.91 (brs, 1H), 4.81 (brs, 1H), 4.63 (d, J=8.4 Hz, 1H), 4.59–4.54
(m, 1H), 4.42–4.39 (m, 1H), 4.29 (brd, J=9.6 Hz, 1H), 4.12 (d, J=
9.6 Hz, 1H), 3.84 (d, J=9.6 Hz, 1H), 3.63 (brd, J=9.6 Hz, 1H), 3.30–
3.27 (m, 3H), 3.10 (s, 3H), 3.05 (m, 1H), 2.70 (s, 1H), 2.02 (m, 1H),
1.84–1.79 (m, 1H), 1.62–1.60 (m, 3H), 1.53 (s, 3H), 1.35 (d, J=6.6 Hz,
3H), 1.23 (s, 3H), 1.15 (s, 3H), 1.72–1.07 (m, 10H), 0.92–0.87 (m, 18H),
0.64 (d, J=5.4 Hz, 1H), 0.57 (d, J=6.6 Hz, 3H), 0.04 (s, 6H), 0.02 ppm
(s, 1H); 13C NMR (75 MHz, CDCl3, major signals): d = 175.3, 174.8,
174.7, 172.7, 172.5, 171.7, 171.5, 169.7, 169.3, 81.4, 81.3, 80.8, 80.7, 64.7,
64.7, 60.7, 60.3, 56.5, 50.3, 49.6, 49.4, 48.6, 45.1, 44.9, 36.4, 35.7, 33.9, 33.7,
33.5, 31.7, 31.6, 31.4, 31.2, 31.0, 29.7, 26.6, 25.9, 25.8, 25.6, 22.6, 22.2, 19.5,
19.4, 18.5, 18.3, 18.2, 18.1, 17.7, 14.3, 14.1, 13.3, 12.9, ꢀ5.3, ꢀ5.2 ppm; IR
(film): nmax =3303, 2944, 2920, 2585, 1743, 1638, 1515, 1459, 1373, 1249,
1095, 1064, 959, 835, 774 cmꢀ1
; HRMS (ESI-TOF): m/z: calcd for
C37H71N4O8Si: 727.5035, found: 727.5036 [M+H]+.
Compound 7b (obtained from 35b in 63% yield): Rf =0.38 (silica gel,
60% EtOAc in hexanes); [a]2D5 =ꢀ50.8 (c=0.6, CHCl3); 1H NMR
(600 MHz, CDCl3): d = 7.78 (d, J=10.1 Hz, 1H), 7.06 (d, J=7.9 Hz,
1H), 5.01 (dq, J=10.1, 7.1 Hz, 1H), 4.84 (d, J=2.6 Hz, 1H), 4.81 (d, J=
9.2 Hz, 1H), 4.77–4.74 (m, 1H), 4.73 (d, J=11.0 Hz, 1H), 4.29 (d, J=
9.2 Hz, 1H), 3.27 (s, 3H), 3.07 (m, 1H), 2.80 (s, 3H), 2.24–2.17 (m, 1H),
1.94–1.88 (m, 1H), 1.48–1.42 (m, 3H), 1.42 (s, 3H), 1.42 (d, J=6.2 Hz,
3H), 1.36 (d, J=7.0 Hz, 3H), 1.36–1.23 (m, 6H), 1.20 (s, 3H), 1.17 (s,
3H), 0.98–0.92 (m, 4H), 0.91–0.84 (m, 6H), 0.83 ppm (d, J=6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3): d = 173.9, 171.8, 171.1, 168.9, 168.6, 82.6,
80.5, 79.1, 74.3, 64.1, 56.4, 48.8, 45.6, 43.7, 35.5, 34.5, 33.2, 31.2, 30.8, 29.7,
27.3, 26.6, 24.8, 22.3, 19.3, 19.0, 18.4, 16.8, 14.3, 14.2, 12.4 ppm; IR (film):
nmax =3295, 2926, 2868, 1749, 1673, 1634, 1513, 1450, 1380, 1242, 1086,
1029, 965 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C31H55N4O7: 595.4065,
found: 595.4056 [M+H]+.
Compound epi-35d: Rf =0.24 (silica gel, 50% EtOAc in hexanes); [a]D25
=
ꢀ8.8 (c=0.5, CHCl3); 1H NMR (500 MHz, CDCl3, spectrum contains at
least two sets of poorly resolved signals due to hindered rotation): d =
6.74–6.65 (brs, 1H), 6.66 (d, J=7.4 Hz, 1H), 6.45 (brs, 1H), 6.03 (brs,
1H), 5.00 (d, J=2.3 Hz, 1H), 4.95 (m, 1H), 4.48 (dq, J=7.2 Hz, 1H),
4.12–4.03 (m, 1H), 3.92–3.84 (m, 1H), 4.92 (d, J=3.1 Hz, 1H), 3.87 (d,
J=10.2 Hz, 1H), 3.81 (d, J=9.5 Hz, 1H), 3.73–3.66 (m, 1H), 3.69 (d, J=
9.5 Hz, 1H), 3.57 (d, J=10.2 Hz, 1H), 3.26 (brs, 6H), 3.07–2.99 (m, 2H),
2.92 (s, 3H), 2.91 (brs, 3H), 2.05–1.96 (m, 1H), 1.96–1.88 (m, 2H), 1.88–
1.79 (m, 1H), 1.72–1.06 (m, > 60H), 0.94–0.79 (m, > 40H), 0.10 (s, 6H),
0.05–0.02 (m, 4H), 0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3, major signals): d = 175.8, 172.0, 170.6, 167.7, 164.4, 80.7, 79.7,
69.2, 66.0, 65.7, 61.7, 59.7, 56.6, 51.3, 48.5, 46.0, 37.6, 33.6, 31.6, 29.7, 26.6,
25.8, 24.4, 24.2, 22.3, 20.3, 19.4, 16.9, 16.8, 14.8, 14.3, 14.1, 12.4, 10.9, ꢀ5.5,
ꢀ5.6 ppm; IR (film): nmax =3367, 3296, 2956, 2932, 2860, 1746, 1655, 1643,
1509, 1455, 1393, 1362, 1257, 1195, 1101, 835, 780 cmꢀ1; HRMS (ESI-
TOF): m/z: calcd for C37H71N4O8Si: 727.5035, found: 727.5030 [M+H]+.
Compound 7c (obtained from 35c in 43% yield): Rf =0.35 (silica gel,
50% EtOAc in hexanes); [a]2D5 =ꢀ8.3 (c=0.1, CHCl3); 1H NMR
(600 MHz, CDCl3): d=8.16 (d, J=10.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H),
5.00 (d, J=2.0 Hz, 1H), 4.96–4.81 (m, 3H), 4.63 (d, J=10.8 Hz, 1H), 4.25
(d, J=9.1 Hz, 1H), 3.27 (s, 3H), 3.03–2.98 (m, 1H), 2.80 (s, 3H), 2.23–
2.14 (m, 1H), 1.94–1.89 (m, 1H), 1.45 (s, 3H), 1.42 (d, J=4.4 Hz, 3H),
1.35 (d, J=7.0 Hz, 3H), 1.47–1.22 (m, 9H), 1.19 (s, 3H), 1.14 (s, 3H),
Compound 7a: Macrocycle 35a (21.6 mg, 0.030 mmol) was dissolved in
THF (5 mL) and treated with a 1m TBAF solution in THF (water con-
tent ~5%, 34 mL, 0.034 mmol) at ꢀ108C.After 15. h at that temperature,
Chem. Eur. J. 2005, 11, 6197 – 6211
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6209

K.C.Nicolaou et al.
1.08–0.99 (m, 1H), 0.96–0.93 (m, 6H), 0.92–0.84 ppm (m, 6H); 13C NMR
(150 MHz, CDCl3): d = 174.8, 171.6, 170.4, 170.2, 168.7, 81.8, 80.6, 78.9,
74.8, 64.6, 56.5, 48.1, 45.2, 43.6, 35.6, 34.3, 33.2, 31.1, 30.0, 29.7, 27.8, 27.3,
1H), 4.86–4.74 (m, 2H), 4.33 (d, J=9.5 Hz, 1H), 3.29 (s, 3H), 3.30–3.18
(m, 1H), 2.82 (s, 3H), 2.20–2.15 (m, 1H), 1.79–1.72 (m, 1H), 1.49 (s, 3H),
1.39 (d, J=7.5 Hz, 3H), 1.28 (s, 3H), 1.49–1.22 (m, 9H), 1.19 (d, J=
7.5 Hz, 3H), 1.18 (s, 3H), 0.99–0.96 (m, 4H), 0.94 (d, J=6.5 Hz, 3H),
0.89 (t, J=7.0 Hz, 3H), 0.82 ppm (d, J=7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d = 174.8, 172.2, 170.6, 170.6, 168.3, 81.3, 80.7, 79.1,
75.1, 63.8, 56.5, 47.5, 46.7, 43.9, 35.7, 33.0, 32.7, 32.6, 31.6, 29.7, 28.2, 25.2,
24.6, 22.1, 20.2, 19.4, 18.5, 17.4, 14.2, 13.7, 12.4 ppm; IR (film): nmax
=
2919, 1729, 1680, 1636, 1554, 1516, 1453, 1385, 1259, 1240, 1095, 1041,
972, 798, 609 cmꢀ1
; HRMS (ESI-TOF): m/z: calcd for C31H55N4O7:
595.4065, found: 595.4057 [M+H]+.
23.8, 19.1, 19.1, 18.4, 18.4, 16.6, 15.7, 14.3, 12.2 ppm; IR (film): nmax
=
Compound epi-7c (obtained from epi-35c in 31% yield): Rf =0.21 (silica
gel, 50% EtOAc in hexanes); [a]2D5 =ꢀ46.2 (c=0.1, CHCl3); 1H NMR
(600 MHz, CDCl3): d=7.50 (d, J=10.0 Hz, 1H), 6.50 (d, J=7.4 Hz, 1H),
5.06 (d, J=11.2 Hz, 1H), 5.00 (d, J=2.3 Hz, 1H), 4.79 (d, J=9.7 Hz,
1H), 4.89–4.72 (m, 2H), 4.34 (d, J=9.7 Hz, 1H), 3.30 (s, 3H), 3.13–3.07
(m, 1H), 2.82 (s, 3H), 2.23–2.16 (m, 1H), 1.80–1.75 (m, 1H), 1.48 (s, 3H),
1.39 (d, J=7.0 Hz, 3H), 1.28 (s, 3H), 1.20–1.18 (m, 6H), 1.52–1.31 (m,
9H), 1.01–0.97 (m, 4H), 0.94 (d, J=6.5 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H),
0.81 ppm (d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d = 174.8,
172.2, 170.7, 170.6, 168.4, 81.6, 80.7, 79.1, 75.1, 63.8, 56.5, 47.5, 46.8, 43.9,
35.6, 33.0, 32.7, 32.5, 31.2, 29.7, 28.2, 25.2, 23.8, 19.1, 19.1, 18.4, 18.4, 16.6,
15.4, 14.3, 12.2 ppm; IR (film): nmax =3317, 2958, 2925, 2870, 1743, 1694,
1667, 1628, 1530, 1454, 1312, 1252, 1094, 1056, 974, 794 cmꢀ1; HRMS
(ESI-TOF): m/z: calcd for C31H55N4O7: 595.4065, found: 595.4071
[M+H]+.
3319, 2958, 2919, 2850, 1741, 1635, 1556, 1537, 1454, 1312, 1253, 1126,
1097, 965 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C31H55N4O7: 595.4065,
found: 595.4058 [M+H]+.
Acknowledgements
We thank Dr.D.H.Huang and Dr.G.Siuzdak for NMR spectroscopic
and mass spectrometric assistance, respectively, and M.Kay Harper and
Dr.J.Hooper for identifying the sponge halipeptin D was extracted
from.Financial support for this work was provided by the National Insti-
tutes of Health (USA), the CaPCURE Foundation, the Skaggs Institute
for Chemical Biology, American Bioscience, postdoctoral fellowships
from the Ernst Schering Research Foundation (to D.S.) and the Royal
Society-Fulbright Commission (to D.A.L.), and a graduate fellowship
from the Portuguese Foundation for Science & Technology (to R.G.N.).
R.G.N. is an exchange graduate student to TSRI from REQUIMTE-
CQFB, Chemistry Department, FCT, Universidade Nova de Lisboa, Ca-
parica, Portugal.
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(500 MHz, CDCl3): d=8.16 (d, J=10.0 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H),
5.00 (d, J=1.5 Hz, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.93–4.82 (m, 2H), 4.63
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1H), 2.80 (s, 3H), 2.18 (m, 1H), 1.90 (m, 1H), 1.45 (s, 3H), 1.43 (d, J=
7.5 Hz, 3H), 1.36 (d, J=7.0 Hz, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.45–1.14
(m, 10H), 0.96–0.95 (m, 6H), 0.91–0.88 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d = 174.8, 171.6, 170.4, 170.2, 168.7, 81.5, 80.7, 78.8,
74.8, 64.5, 56.6, 48.1, 45.2, 43.6, 35.6, 34.2, 33.2, 31.4, 30.9, 30.0, 27.8, 27.3,
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D.J.Faulkner, C.Sincich, R.M.Rao, E.J.Kantoroski, L.M.West,
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M.T. Davies-Coleman, R.A. Kramer, C.R. Fairchild, W.C. Rose,
24.6, 22.0, 20.2, 19.4, 18.3, 17.5, 14.3, 14.0, 12.4 ppm; IR (film): nmax
=
3421, 3296, 2958, 2935, 2868, 1746, 1633, 1509, 1458, 1374, 1233, 1092,
1041, 968 cmꢀ1; HRMS (ESI-TOF): m/z: calcd for C31H55N4O7: 595.4065,
found: 595.4061 [M+H]+.
R.C.Wild, G.D.Vite, R.W.Peterson,
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Bull. Chem. Soc. Jpn. 1970, 43,
Compound epi-7d (obtained from epi-35d in 36% yield): Rf =0.23 (silica
gel, 50% EtOAc in hexanes); [a]2D5 =ꢀ51.0 (c=0.1, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.48 (d, J=10.0 Hz, 1H), 6.49 (d, J=7.0 Hz, 1H),
5.06 (d, J=11.0 Hz, 1H), 5.01 (d, J=2.5 Hz, 1H), 4.80 (d, J=9.5 Hz,
[11] J.A.Marshall, M.M.Yanik, J. Org. Chem. 2001, 66, 1373–1379.
6210
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Chem. Eur. J. 2005, 11, 6197 – 6211

Natural Products
FULL PAPER
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637.3952 [M+Na]+) strongly suggested an OH ! F displacement.
[18] We are grateful to Professor William Fenical for these biological
studies.
Received: June 1, 2005
Published online: August 1, 2005
Chem. Eur. J. 2005, 11, 6197 – 6211
ꢀ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
6211