Total synthesis of halipeptins A and D and analogues

Article abstract of DOI:10.1002/anie.200500702

(Chemical Equation Presented) Deceptive rings: Halipeptins A (1 a) and D (1 b) and analogues thereof were synthesized from fragments 2 and 3 a, b, respectively. Key steps included peptide-bond formation, DAST-induced thiazoline construction, and macrolact

Full text of DOI:10.1002/anie.200500702

Angewandte
Chemie
Natural Products Synthesis
after,[3] did not reveal further stereochemical details but
raised our interest in this class of natural products once
halipeptin D (1d) was reported to exhibit strong inhibitory
activity in vitro against different human cancer-cell lines.[4]
Determining their structural identity beyond any doubt[5]
and rendering them available for further biological inves-
tigations were two reasons we undertook their total synthesis.
There was a third motivation: their intriguing molecular
architectures and the (subtle) challenge they posed for
chemical synthesis. Indeed, these depsipeptides include in
their molecular frameworks a novel, highly substituted
peptide backbone connected to a hydroxylated carbon chain
wrapped into a 16-membered macrolide ring. The entire C31
structure contains eight stereocenters (three of which are, in
principle, epimerizable) and 11 methyl groups. The highly
congested and conformationally rigid macrocyclic ring con-
tains within its thread a Me-substituted thiazoline ring
adjacent to an N-methyl-substituted amide, an arrangement
that forces this linkage into a cisoid geometry, unlike the other
two amide bonds that reside in their usual transoid forms. This
highly substituted cisoid bond, postulated to persist even in
open chain intermediates, is rare and was expected to present
an unprecedented and adventurous challenge in the total
synthesis of these molecules.
Our retrosynthetic analysis of halipeptins A (1a) and D
(1d) (Scheme 2) relied on a retrolactamization to open the
macrocycle and a subsequent retro amide-bond formation to
dissect the generated chain into two key fragments, thio-
amides 3a and 3d as direct precursors for thiazoline
formation, and alanine ester 2 within which are embedded
both a 3-hydroxydecanoic acid domain and a masked l-
alanine residue. This approach allows a late-stage construc-
tion of the thiazoline moiety, thus avoiding likely epimeriza-
tion at its a position.[6] Further disconnection of these frag-
DOI: 10.1002/anie.200500702
Total Synthesis of Halipeptins A and D and
Analogues**
K. C. Nicolaou,* David W. Kim, Daniel Schlawe,
Dimitrios E. Lizos, Rita G. de Noronha, and
Deborah A. Longbottom
The halipeptins are a group of natural products whose
structural identity and biological properties are still shrouded
in mystery. In 2001 Gomez-Paloma et al. reported the
isolation of halipeptins A and Bfrom the marine sponge
Haliclona sp. and showed that halipeptin A exhibits impres-
sive antiinflammatory properties that exceed those of well-
established drugs.[1] Their later isolation of halipeptin C
prompted them to revise their structural assignment to that
of thiazoline containing macrocycles as shown for halipep-
tins A–C (1a–c) in Scheme 1 leaving open the absolute
configuration at the marked positions.[2] The isolation of a
fourth member of this family of marine natural products,
halipeptin D (1d, Scheme 1), by the group of Faulkner soon
Scheme 1. Structures of halipeptins A–D (1a–d). Positions of
uncertain stereochemical assignment are marked
.
*
[*] Prof. Dr. K. C. Nicolaou, D. W. Kim, Dr. D. Schlawe, Dr. D. E. Lizos,
R. G. de Noronha, Dr. D. A. Longbottom
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respec-
tively. Financial support for this work was provided by the
National Institutes of Health (USA), the CaPCURE Foun-
dation, the Skaggs Institute for Chemical Biology, a
predoctoral fellowship fromthe Foundation for Science and
Technology, Portugal (grant SFRH/BD/5371/2001 to
R.G.N.), and postdoctoral fellowships fromthe Ernst
Schering Research Foundation (to D.S.) and the Royal
Society Fulbright Commission (to D.A.L.).
Scheme 2. Retrosynthetic analysis of halipeptins A (1a) and D (1d).
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75% overall yield. d-Hydroxyisoleucine methyl ester 8a was
then obtained from 13 in quantitative yield by reduction of
the azide group.
Initial attempts to obtain alanine–a-methylserine–N-
methylisoleucine tripeptides as 3 (Scheme 2) by sequential
peptide coupling failed as a result of cyclization of the
dipeptide precursors upon activation (e.g. diketopiperazine
formation upon reduction of azide 17d). Instead, we devised a
strategy to attach the N-terminal alanine unit that did not
involve a free amino group as shown in Scheme 4. The O-
silylated dipeptides 16a and 16d were obtained from a-
methyl serine derivative 14,[10] after suitable protection/
deprotection steps and coupling to isoleucines 8a and 8d,
Scheme 3. Construction of TBDPS-protected d-hydroxy-l-isoleucine
methyl ester (8a). a) TBDPSCl (1.1 equiv), imidazole (2.2 equiv),
CH2Cl2, 258C, 16 h, 99%; b) nBuLi (2.5m in hexanes, 1.05 equiv), p-
formaldehyde (1.1 equiv), Et2O, ꢀ78!258C, 14 h, 72%; c) H2 (1 atm),
5% Pd/BaSO4 (7% by weight), quinoline (5% by weight), MeOH,
258C, 20 min, 98%; d) [Ti(OiPr)4] (0.3 equiv),
l-DET (0.35 equiv), tBuOOH (2.0 equiv), M.S. (4 Š), CH2Cl2, ꢀ208C,
17 h, 99%; e) NaIO4 (4.1 equiv), RuCl3·H2O (2.2 mol%), CCl4/CH3CN/
H2O (1:1:1.5), 258C, 2 h, 80%; f) AlMe3 (3.0 equiv), hexanes, 258C,
30 h, 80%; g) MeI (1.3 equiv), K2CO3 (1.1 equiv), acetone, 258C, 18 h,
90%; h) Tf2O (1.5 equiv), pyridine (10.0 equiv), CH2Cl2, 08C, 20 min;
i) NaN3 (1.5 equiv), DMF, 258C, 40 min, 75% (two steps); j) H2
(1 atm), 10% Pd/C (30% by weight), EtOH, 258C, 2.5 h, 99%. DET=
diethyl tartrate; DMF=N,N-dimethylformamide; M.S.=molecular
sieves; TBDPS=tert-butyldiphenylsilyl; Tf=trifluoromethanesulfonyl.
ments led to the identification of building blocks 4–7
and 8a for halipeptin A (1a), and 4–7 and 8d for
halipeptin D (1d), as shown in Scheme 2.
After having established[3] a stereochemically
flexible route to hydroxydecanoic acid 4,[5,7] our
first objective towards the synthesis of halipeptin A
(1a) was the construction of suitably protected d-
hydroxyisoleucine derivative[8] 8a (Scheme 3). Sily-
lation of homopropargylic alcohol 9 and trapping of
the corresponding acetylide with formaldehyde gave
propargylic alcohol 10 in 71% overall yield. Partial
hydrogenation[9] of 10 with Lindlar catalyst gave the
corresponding Z allylic alcohol (98% yield), which
was subjected to Sharpless asymmetric epoxidation
conditions to yield epoxy alcohol 11 in almost
quantitative yield (99%). Compound 11 was then
oxidized to the corresponding epoxy acid (80%
yield), which was subsequently treated with
Scheme 4. Synthesis of thioamides 3a and 3d. a) TBSOTf (2.0 equiv), 2,6-lutidine
(4.0 equiv), CH2Cl2, 08C, 1.5 h, 98%; b) LiOH·H2O (3.0 equiv), MeOH/H2O (4:1), 0!
258C, 2 h, 100%; c) 8a (1.0 equiv), EDC (1.2 equiv), HOAt (1.2 equiv), iPr2NEt (3.0 equiv),
CH2Cl2, 258C, 17 h, 55% (15a); 8d (2.0 equiv), EDC (2.0 equiv), HOAt (2.0 equiv), iPr2NEt
(3.0 equiv), CH2Cl2, 258C, 17 h, 91% (16d); d) TESOTf (1.3 equiv), 2,6-lutidine (2.0 equiv),
CH2Cl2, 08C, 20 min, 85%; e) NaH (4.0 equiv), MeOTf (2.5 equiv), THF, 08C, 1 h, 83%
(17a); NaH (3.0 equiv), MeI (4.0 equiv), DMF, 08C, 1 h, 96% (17d); f) aqueous HCl (1n;
20 equiv), THF, 258C, 1 h, 100%; g) TBAF (3.0 equiv), THF, 258C, 2 h, 98%; h) CDI
(4.0 equiv), Cbz-Ala-OH (4.0 equiv), CH2Cl2, 258C, 0.5 h; then 18a or 18d, 18 h, 19a:
88%, 19d: 96%; i) PMe3 (1.0m in THF; 1.8 equiv), toluene, 258C, 2 h, 20a: 79%, 20d:
83%; j) H2 (1 atm), 20% Pd(OH)2/C (30% by weight), EtOH, 258C, 1 h, 100%; k) H2S
(excess), MeOH/Et3N (2:1), 258C, 48–72 h, complete conversion, product not isolated.
Cbz=benzyloxycarbonyl; CDI=carbonyldiimidazole; EDC=1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride; HOAt=1-hydroxy-7-azabenzotriazole; TBAF=tetra-n-
butylammonium fluoride; TBS=tert-butyldimethylsilyl; TES=triethylsilyl.
[9]
AlMe3 at ambient temperature to afford, upon
methylation with MeI, hydroxyester 12 as a single
isomer in 72% overall yield for the two steps.
Treatment of 12 with triflic anhydride, followed by
exposure of the resulting triflate to sodium azide
furnished, with inversion of configuration, the
orthogonally protected isoleucine derivative 13 in
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Chemie
respectively. Deprotonation of the amide with
NaH allowed selective methylation with MeOTf
(!17a) or MeI (!17d), and selective desilyla-
tion with HCl or TBAF furnished the desired
azide fragment 18a (HCl) or 18d (TBAF),
respectively, which were converted into their
alanine ester counterparts, 19a (88% yield) and
19d (96% yield), by CDI-mediated couplings
with Cbz-Ala-OH in preparation for the
impending tripeptide construction. It was postu-
lated[11] that reaction of the azide group of 19a
and 19d with a suitable phosphine reagent would
generate the corresponding azaylide (22a and
22d, respectively) which, upon intramolecular
collapse onto the closest ester grouping, could
furnish the desired oxazolines 20a and 20d,
respectively. Indeed, this much-anticipated cas-
cade proceeded smoothly upon exposure of 19a
and 19d to PMe3 in benzene or toluene at
ambient temperature to furnish oxazolines 20a
(79% yield) and 20d (83% yield) accompanied
by only small amounts of the undesired six-
membered rings (that is, dihydropyrazinones
21a (17%) and 21d (16%)). The chromato-
graphically purified 20a and 20d were then
converted into thioamides 3a and 3d, respec-
tively, by hydrogenolytic cleavage of their Cbz
group (100% yield) followed by thiolysis of the
oxazoline rings with H2S–Et3N.[12] After evapo-
ration of the solvents, the products 3a and 3d
were used directly in the next step without
further purification.
In our first attempt to synthesize halipep-
tin D (1d) from thioamide 5d we improvised for
a last-stage construction of the thiazoline moiety
due to fears of epimerization[6] of the adjacent
stereocenter (Scheme 5). The sterically con-
gested ester 2 was prepared in 94% yield from
hydroxydecanoic acid 4 and excess acid chloride
5 (10 equiv, prepared in situ from the corre-
sponding carboxylic acid[13] and oxalyl choride in
DMF) in the presence of Et3N and 4-DMAP at
508C. It is noteworthy that no epimerization at
the azide-bearing center was observed in this
step despite the basic conditions employed, as
confirmed by the synthesis and characterization
of the alanine epimer of 2 from 4 and ent-5.
Coupling of carboxylic acid 2 with amino frag-
ments 3a and 3d was best achieved by PyAOP
activation in the presence of iPr2NEt (92%
yield). Protection of 23d as a TBS ether (99%),
selective hydrolysis of the methyl ester with
Me3SnOH[14] (52%), followed by Staudinger
Scheme 5. Completion of the total synthesis of halipeptins A (1a) and D (1d) and their epimers
29a, 29d, 31a, and 31d. a) 5 (10.0 equiv), 4-DMAP (0.5 equiv), Et3N (12 equiv), DMF, 508C,
2 h, 94%; b) 3a (1.0 equiv), PyAOP (1.5 equiv), iPr2NEt (2.0 equiv), DMF, 258C, 17 h, 71%
(23a); 3d (2.0 equiv), PyAOP (2.5 equiv), iPr2NEt (2.5 equiv), DMF, 258C, 17 h, 92% (23d);
c) TBSOTf (1.2 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2, 08C, 0.5 h, 99%; d) Me3SnOH
(20 equiv), CH2ClCH2Cl, 808C, 48 h, 52% at 79% conversion; e) PMe3 (3.0 equiv), THF/H2O
(9:1), 258C, 48 h; f) HATU (2.0 equiv), HOAt (2.0 equiv), iPr2NEt (2.0 equiv), CH2Cl2 (0.5 mm),
258C, 18 h, 38% (two steps); g) DAST (1.5 equiv), CH2Cl2, ꢀ78!ꢀ208C, 1 h, 25a: 85%; 25d:
84%; h) Me3SnOH (20 equiv), CH2ClCH2Cl, 908C, 48–72 h, 82% from 25a; 85% from 25d;
i) PMe3 (2.5 equiv), THF/H2O (9:1), 258C, 2 h; j) HATU (2.0 equiv), HOAt (2.0 equiv), K2CO3
(10.0 equiv), CH2Cl2 (0.5 mm), 258C, 24 h, 27a: 31%, 28a: 10%, 30a: 14%; 1d: 25%, 29d:
5%, 31d: 18%; k) TAS-F (5.0 equiv), DMF, 258C, 24 h, 1a: 85%; 29a: 81%; 31a: 85%.
DAST=(diethylamino)sulfur trifluoride; 4-DMAP=4-(dimethylamino)pyridine; HATU=O-(7-
azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; PyAOP=(7-azaben-
zotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; TAS-F =tris(dimethylamino)-
sulfur (trimethylsilyl)difluoride.
reduction of the azide group within the resulting carboxylic
acid, and direct macrolactamization (HATU, HOAt, iPr2NEt)
yielded macrocycle 24d as the only product (38%) with
complete epimerization of the C-terminal isoleucine unit.
This problem was overcome by a detour, which adopted
thiazoline formation prior to macrocyclization as shown in
Scheme 5. Thus, exposure of thioamide intermediates 23a and
23d to DAST[15] in CH2Cl2 at ꢀ788C led to thiazolines 25a
(85% yield) and 25d (84% yield). Selective hydrolysis of the
methyl esters of 25a (82% yield) and 25d (85% yield) was
achieved by the mild action of Me3SnOH,[14] delivering, upon
Staudinger reduction with PMe3/H2O, amino acids 26a and
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Table 1: Selected physical properties of 1d, 29a, 29d, and 31d.
26d, respectively. The latter were utilized without isolation in
1d: colorless oil; Rf =0.36 (silica, hexanes/EtOAc 1:1); [a]3D2 =ꢀ19.1
(c=0.46, CHCl3); IR (thin film): n˜max =3435, 3331, 2966, 2931, 2782,
1749, 1671, 1637, 1514, 1455, 1401, 1373, 1261, 1155, 1091, 1038, 973,
808, 756, 585 cmꢀ1; 1H NMR (500 MHz, CDCl3): d=7.20 (d, J=7.7 Hz,
1H), 7.01 (d, J=8.5 Hz, 1H), 4.98 (d, J=10.3 Hz, 1H), 4.84–4.74 (m,
2H), 4.68 (d, J=3.0 Hz, 1H), 4.13 (d, J=12.1 Hz, 1H), 3.28 (s, 3H),
3.27 (d, J=12.1 Hz, 1H), 3.09–3.05 (m, 1H), 2.78 (s, 3H), 2.22–2.16 (m,
1H), 1.92–1.88 (m, 1H), 1.49 (d, J=7.4 Hz, 3H), 1.44 (s, 3H), 1.39 (d,
J=7.4 Hz, 3H), 1.49–1.27 (m, 9H), 1.18 (s, 3H), 1.12 (s, 3H), 1.04–0.99
(m, 1H), 0.96–0.88 (m, 9H), 0.79 ppm (d, J=7.0 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=177.2, 173.6, 172.5, 169.6, 169.3, 83.9, 82.5, 80.6,
65.0, 56.5, 49.5, 48.5, 45.8, 44.3, 35.7, 34.2, 33.5, 31.9, 31.2, 30.7, 26.2,
25.0, 23.1, 22.3, 22.0, 18.5, 18.0, 17.7, 14.4, 14.3, 12.5 ppm; HRMS
(ESI TOF): calcd for C31H54N4O6S [M+H+]: 611.3837; found: 611.3836
the macrocyclization experiments.
Initial attempts to cyclize 26d to halipeptin D (1d) under
the influence of HATU in the presence of HOAt and iPr2NEt
resulted in the predominant formation of, again, the isoleu-
cine epimer 31d (epimeric at the indicated ( ) site, 17% yield
*
from the corresponding azido carboxylic acid) which, how-
ever, this time was accompanied by the natural product,
halipeptin D (1d, 13% from the corresponding azido carbox-
ylic acid) and traces of 29d, epimeric at the indicated (*) site
adjacent to the thiazoline moiety. Changing the base to
K2CO3 in the macrolactamization step increased both the
yield and selectivity for the natural product (1d: 25% yield;
29d: 5% yield; 31d: 18% yield; Table 1). Owing to the
profound differences in their Rf values, all isomers could be
separated easily by preparative TLC (silica gel) by using
hexane/EtOAc or CH2Cl2/acetone mixtures.
29a: colorless oil; Rf =0.20 (silica, EtOAc); [a]3D2 =ꢀ12.1 (c=0.2,
CHCl3); IR (thin film): n˜max =3430, 2961, 2917, 2855, 1733, 1710, 1662,
1
1644, 1507, 1485, 1374, 1255, 1095 cmꢀ1; H NMR (500 MHz, CDCl3):
d=6.79 (d, J=5.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 5.39 (d, J=10.0 Hz,
1H), 4.87–4.84 (m, 1H), 4.78–4.75 (m, 1H), 4.74 (d, J=1.9 Hz, 1H),
4.03 (d, J=12.0 Hz, 1H), 3.82–3.79 (m, 1H), 3.72–3.67 (m, 1H), 3.33 (d,
J=12.0 Hz, 1H), 3.27 (s, 3H), 3.09–3.07 (m, 1H), 2.78 (s, 3H), 2.55–
2.51 (m, 1H), 2.17–2.08 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.41 (s, 3H),
1.31 (d, J=7.1 Hz, 3H), 1.22 (s, 3H), 1.52–1.14 (m, 10H), 1.09 (s, 3H),
1.08–1.02 (m, 1H), 1.02–0.96 (m, 6H), 0.68 ppm (d, J=6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=176.9, 173.6, 172.8, 170.3, 169.2, 84.7,
82.2, 80.5, 64.4, 60.9, 56.4, 49.2, 49.1, 45.1, 43.3, 35.7, 32.9, 32.3, 31.1,
30.7, 29.7, 28.3, 24.3, 23.2, 22.9, 21.5, 19.5, 18.4, 18.2, 14.3, 14.2 ppm;
HRMS (ESI TOF): calcd for C31H54N4O7S [M+H+]: 627.3786; found:
627.3790
Under the HATU/HOAt/K2CO3 conditions for the mac-
rolactamization step, amino acid 26a was converted into
halipeptin A TBDPS derivatives 27a (31%; yield) and its
epimers 28a (10% yield) and 30a (14% yield; Scheme 5).
Exposure of these compounds to TAS-F liberated halipep-
tin A (1a, 86% yield) and its epimers 29a (81% yield;
Table 1) and 31a (85% yield). Synthetic halipeptins A (1a)
and D (1d) exhibited identical physical properties to those
reported (1a,[1] 1d[3]) for the natural products. Intriguingly,
however, and despite previous reports regarding naturally
derived halipeptin D,[4] synthetic halipeptin D (1d) and its
synthesized epimers exhibited only weak toxicity against
tumor cells (HCT-116 human colon carcinoma, IC50 values,
1d: 32.5 mm; 29d: 105.4 mm; 31d: 111.4 mm).[16] Since natural
halipeptin D (1d) was isolated from a marine species that
contained several potent cytotoxic agents,[3] we attribute this
discrepancy to contamination of the naturally derived mate-
rial by one or more such contaminants.
29d: colorless oil; Rf =0.36 (silica, hexanes/EtOAc 1:1); [a]3D2 =ꢀ13.8
(c=0.45, CHCl3); IR (thin film): n˜max =2965, 2924, 2874, 1749, 1673,
1638, 1613, 1507, 1452, 1397, 1371, 1261, 1095, 1035, 970, 804,
668 cmꢀ1; 1H NMR (500 MHz, CDCl3): d=6.79 (d, J=5.5 Hz, 1H), 6.58
(d, J=9.2 Hz, 1H), 5.28 (d, J=10.3 Hz, 1H), 4.87–4.81 (m, 1H), 4.77–
4.72 (m, 1H), 4.71 (d, J=1.9 Hz, 1H), 4.01 (d, J=12.2 Hz, 1H), 3.32 (d,
J=12.2 Hz, 1H), 3.27 (s, 3H), 3.09–3.05 (m, 1H), 2.78 (s, 3H), 2.24–
2.18 (m, 1H), 2.10–2.02 (m, 1H), 1.45 (d, J=6.6 Hz, 3H), 1.43 (s, 3H),
1.32 (d, J=7.0 Hz, 3H), 1.22 (s, 3H), 1.51–1.15 (m, 9H), 1.10 (s, 3H),
1.06–1.02 (m, 1H), 1.02–0.96 (m, 6H), 0.88 (t, J=7.1 Hz, 3H),
0.66 ppm(d, J=6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=176.9,
173.6, 172.7, 170.4, 169.3, 87.8, 82.1, 80.5, 64.8, 56.4, 49.1 (2 peaks),
45.1, 43.4, 35.7, 33.4, 32.9, 32.3, 31.1, 30.6, 25.5, 24.3, 23.3, 22.8, 21.5,
19.5, 18.4, 17.5, 14.3, 14.1, 12.5 ppm; HRMS (ESI TOF): calcd for
C31H54N4O6S [M+H+]: 611.3837; found: 611.3833
The chemistry described herein confirmed the structures
of halipeptins A (1a) and D (1d), highlighted their interesting
chemical properties, and rendered them and their analogues
readily available for further biological investigations.
Received: February 24, 2005
Revised: May 13, 2005
Published online: July 12, 2005
31d: colorless oil; Rf =0.55 (silica, hexanes/EtOAc 1:2); [a]3D2 =+6.0
(c=0.15, CHCl3); IR (thin film): n˜max =3413, 3342, 2966, 2932, 2861,
1743, 1667, 1637, 1514, 1455, 1373, 1261, 1096, 1032, 961, 797, 750,
585 cmꢀ1; 1H NMR (500 MHz, CDCl3, 3:1 ratio of conformers): d=7.17
(d, J=5.3 Hz, 1H), 7.11 (d, J=7.0 Hz, 1H), 6.28 (minor d, J=6.5 Hz),
6.02 (minor d, J=6.1 Hz), 5.02 (d, J=1.7 Hz, 1H), 4.93 (minor d,
J=10.6 Hz), 4.89 (minor d, J=2.2 Hz), 4.84–4.83 (minor m), 4.74–4.70
(m, 1H), 4.62–4.56 (m, 1H), 4.53 (minor d, J=11.0 Hz), 4.48 (d,
J=10.9 Hz, 1H), 3.50 (d, J=11.6 Hz, 1H), 3.49 (d, J=11.6 Hz, 1H),
3.27 (s, 3H), 3.24 (minor s), 3.09 (minor d, J=11.0 Hz), 3.07–3.04 (m,
1H), 2.98 (s, 3H), 2.19–2.14 (m, 1H), 1.99–1.84 (m, 1H), 1.60 (d,
J=7.0 Hz, 3H), 1.50 (d, J=7.0 Hz, 3H), 1.45 (s, 3H), 1.22 (s, 3H),
1.48–1.20 (m, 9H), 1.13 (s, 3H), 0.90–0.86 (m, 10H), 0.81–0.79 ppm
(m, 3H); 13C NMR (150 MHz, CDCl3, 3:1 ratio of confomers, only major
peaks are shown): d=174.7, 174.3, 172.4, 169.6, 169.6, 84.8, 82.8, 80.6,
63.6, 56.5, 51.6, 47.9, 45.4, 44.5, 35.6, 34.4, 33.9, 31.5, 31.2, 30.8, 26.9,
26.4, 25.7, 22.3, 20.3, 19.5, 18.4, 15.5, 14.4, 14.3, 11.6 ppm; HRMS
(ESI TOF): calcd for C31H54N4O6S [M+H+]: 611.3837; found: 611.3844
Keywords: macrocycles · natural products · oxazolines ·
.
thiazolines · total synthesis
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Angewandte
Chemie
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[16] We thank Professor William Fenical for these biological data.
Angew. Chem. Int. Ed. 2005, 44, 4925 –4929
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