Total synthesis of marinomycins A-C

Article abstract of DOI:10.1002/anie.200601867

(Chemical Equation Presented) Ocean's three: Unearthed from the bottom of the ocean off the coast of La Jolla (California, USA), marinomycins A-C, which differ in geometry about the C8-C9 and C8′-C9′ double bonds, have been prepared by total synthesis through a strategy that features a Suzuki coupling reaction to forge their remarkable polyunsaturated 44-membered-ring systems (see picture).

Full text of DOI:10.1002/anie.200601867

Angewandte
Chemie
Natural Product Synthesis
Scheme 1. Structures of marinomycins A–C (1–3).
DOI: 10.1002/anie.200601867
Total Synthesis of Marinomycins A–C**
turated structures coupled with their potentially useful
biological activities prompted our interest in these molecules.
Herein, we report the total synthesis of marinomycins A–C
(1–3) and of two of their hitherto unknown monomeric
homologues, mono-marinomycin A (m-1) and iso-mono-mar-
inomycin A (m-2, Scheme 7).
K. C. Nicolaou,* Andrea L. Nold, Robert R. Milburn,
and Corinna S. Schindler
Marinomycins A–C (1–3, Scheme 1) are recently discovered
natural products with imposing molecular architectures and
impressive biological properties.[1] Isolated from actinomy-
cete Marinispora strain CNQ-140 cultured from a sediment
collected from the bottom of the ocean offshore of La Jolla,
California (USA), by Fenical and co-workers,[1] these novel
compounds exhibit significant antibiotic activities (minimum
inhibitory concentration, MIC = 0.1–0.6 mm) against methicil-
lin-resistant Staphylococcus aureus (MRSA) and vancomy-
cin-resistant Enterococcus faecium (VREF), and inhibit
cancer cell proliferation against the National Cancer Insti-
tuteꢀs 60 cancer cell line panel (LC50 = 0.2–2.7 mm). In
particular, these marinomycins 1–3 showed potent and
selective cytotoxicities against six of the eight melanoma
cell lines of that panel.[1] Their novel and sensitive polyunsa-
Given that 1, the most abundant of the marinomycins, is
photolytically convertible to a mixture of all three (i.e. 1, 2,
and 3),[1] a total synthesis of marinomycin A (1) would
constitute syntheses of 2 and 3 as well. Scheme 2 depicts our
[*] Prof. Dr. K. C. Nicolaou, A. L. Nold, Dr. R. R. Milburn, C. S. Schindler
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 Professor William Fenical for helpful discussions and Dr.
Hak Cheol Kwon for assistance in the HPLC purification of synthetic
marinomycins A–C. The assistance of Dr. D. H. Huang and Dr. R.
Chadha with spectroscopic and X-ray crystallographic analyses,
respectively, is also acknowledged. Financial support for this work
was provided by a grant from the National Institutes of Health
(USA) and the Skaggs Institute of Chemical Biology, the Pfeiffer
Foundation (predoctoral fellowship to A.L.N.), and the Kurt Fordan
Foundation (Germany) (fellowship to C.S.S.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Retrosynthetic analysis of marinomycin A (1). HWE=Horner–
Wadsworth–Emmons, TBS=tert-butyldimethylsilyl, TES=triethylsilyl.
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original retrosynthetic analysis of marinomycin A (1). The
gave, upon basic (K2CO3, MeOH) workup, the corresponding
primary allylic alcohol (81% yield). Benzylation of the latter
compound (88% yield) followed by desilylation (HF·py, 77%
yield) and oxidation with PCC afforded aldehyde 13 (73%
yield). Reaction of aldehyde 13 with the lithium species
derived from dimethyl methyl phosphonate and nBuLi
followed by oxidation (PDC) of the resulting epimeric
mixture of alcohols led to ketophosphonate 14 in 64%
overall yield (two steps). Finally, fluoride-induced (aq HF/
MeCN) desilylation of 14 gave the desired hydroxy keto-
phosphonate 5 in 92% yield.
The synthesis of fragment 6 began with the readily
available aldehyde 15[5] and involved two iterations of
Brown allylation[6] [(+)-(ipc)2B-allyl]/ozonolysis (PPh3)
sequences with appropriate protections of the resulting
secondary alcohols (Scheme 4). Proceeding through inter-
symmetrical structure of the molecule renders it suitable for
several retrosynthetic disconnections; the one shown in
Scheme 2 was chosen to highlight and test the Suzuki reaction
as a means to construct large and complex macrocycles.[2] The
appropriately functionalized vinyl boronic acid vinyl bromide
4 needed for the originally intended dimerization was traced
to the three key building blocks ketophosphonate 5, aldehyde
6, and carboxylic acid 7, through the indicated Horner–
Wadworth–Emmons (HWE) olefination and Mitsunobu
reactions. It was expected that dimer versus monomer
formation in the cyclization process would be subject to
concentration conditions.
The required building blocks 5–7 were synthesized in their
enantiomerically pure forms as summarized in Schemes 3–5.
Starting with the construction of ketophosphonate
5
(Scheme 3), the enantiomerically pure epoxide 8[3] was
regioselectively opened in the presence of BF3·OEt2 with
the lithium reagent derived from propargylic ether 9[4] and
nBuLi at ꢀ788C, leading to the corresponding secondary
alcohol (89% yield), whose silylation (TBSCl, 96% yield)
and de-p-methoxybenzylation (DDQ, 79% yield) afforded
the chain-extended propargylic alcohol 10. Exposure of the
latter compound to Red-Al, followed by addition of NIS,
furnished the corresponding hydroxy vinyl iodide (66%
yield), whose temporary silylation (TMSCl) and subsequent
coupling with ZnMe2 in the presence of [Pd(dppf)Cl2](cat.)
Scheme 4. Preparation of aldehyde 6. Reagents and conditions:
a) (ꢀ)-B(Ipc)2OMe (1.7 equiv), allylMgBr (1.0m in Et2O, 1.7 equiv),
Et2O, ꢀ78!258C, 2 h; then 15 in Et2O, ꢀ788C, 4 h, ꢀ78!258C, 1 h,
95% (>40:1 d.r.); b) TESCl (1.8 equiv), imid. (4.0 equiv), DMF, 258C,
4 h; c) O3, CH2Cl2, ꢀ788C, 4 h; then PPh3 (1.3 equiv), ꢀ788C, 2 h,
ꢀ78!258C, 1 h, 64% over two steps; d) (ꢀ)-B(Ipc)2OMe (1.7 equiv),
allylMgBr (1.0m in Et2O, 1.7 equiv), Et2O, ꢀ78!258C, 2 h; then 17 in
Et2O, ꢀ788C, 4 h, ꢀ78!258C, 1 h, 85% (>40:1 d.r.); e) TBSCl
(2.0 equiv), imid. (5.0 equiv), DMF, 258C, 4 h; f) O3, CH2Cl2, ꢀ788C,
4 h; then PPh3 (1.3 equiv), ꢀ788C, 2 h, ꢀ78!258C, 1 h, 91% over two
steps. Ipc=isopinocampheyl.
mediates 16–18, this sequence afforded the desired compound
6 in good overall yield (47% from 15, six steps) and with high
diastereoselectivity (> 40:1 d.r.).
The dienyl bromide carboxylic acid 7 was synthesized
from known acetonide acetylene 19[7] (Scheme 5). Thus, 19
was reacted with the adduct of BH3·THF with 2,5-dimethyl-
hexa-2,4-diene,[8] and the resulting borane (87% yield) was
coupled with commercially available TMS vinyl bromide 20 in
the presence of [Pd(PPh3)4](cat.) and Cs 2CO3 to afford TMS
diene 21 (89% yield). Exposure of the latter compound, 21, to
NBS gave bromide 22 (88% yield), which was converted into
acetoxy carboxylic acid 7 through saponification (KOH, 87%
yield) and acetylation (Ac2O, Mg(ClO4)2;[9] 96% yield).
The assembly of fragments 5–7 and elaboration of the
growing molecule to the targeted enyne bromide 28 is shown
in Scheme 6. Thus, coupling of ketophosphonate 5 and
aldehyde 6 proceeded smoothly under the influence of
Scheme 3. Preparation of ketophosphonate 5. Reagents and conditions: a) 9
(2.0 equiv), nBuLi (2.5m in hexanes, 2.0 equiv), THF, ꢀ788C, 45 min; then
BF3·OEt2 (1.2 equiv), 8 in THF, ꢀ788C, 4 h, 89%; b) TBSCl (1.2 equiv), imid.
(3.0 equiv), DMF, 258C, 6 h, 96%; c) DDQ (1.5 equiv), CH2Cl2, pH 7 phosphate
buffer, 258C, 3 h, 79%; d) Red-Al (3.33m in toluene, 1.7 equiv), THF, 258C,
45 min; then NIS (1.8 equiv), THF, ꢀ788C, 30 min, 66%; e) TMSCl (2.0 equiv),
Et3N (5.0 equiv), 258C, 2 h; then [Pd(dppf)Cl2] (0.05 equiv), Me2Zn (2.0 equiv),
THF, 658C, 12 h; then K2CO3 (0.1 equiv), MeOH, 258C, 4 h, 81%; f) NaH
(1.6 equiv), BnBr (1.7 equiv), nBu4NI (0.1 equiv), THF, 258C, 6 h, 88%;
g) HF·py, THF, 08C, 3 h, 77%; h) PCC (2.0 equiv), NaHCO3 (0.5 equiv), 258C,
3 h, 73%; i) CH3P(O)(OMe)2 (4.0 equiv), nBuLi (2.5m in hexanes, 4.0 equiv),
THF, ꢀ788C, 2 h; then 13 in THF, ꢀ788C, 2 h; j) PDC (2.1 equiv), 4-Š M.S.,
DMF, 258C, 12 h, 64% over two steps; k) HF (48% aq), MeCN, 258C, 3 h,
92%. Bn=benzyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dppf=
bis(diphenylphosphino)ferrocene, DMF=N,N-dimethylformamide,
imid.=imidazole, PMB=p-methoxybenzyl, M.S.=molecular sieves, NIS=
N-iodosuccinimide, PCC=pyridinium chlorochromate, PDC=pyridinium
dichromate, py=pyridine, THF=tetrahydrofuran, TMS=trimethylsilyl.
Ba(OH)2 to afford the enone in 95% yield. Hydroxy-directed
[10]
reduction of this enone with Et2BOMe and NaBH4
at
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ized in pure form by preparative plate chromatog-
raphy (silica, CH2Cl2/MeOH 93:7, two elutions) in
the dark, followed by HPLC (C18-Dynamax
column, 60 Š, 10 mm ” 250 mm, 45% MeCN in
H2O). iso-Mono-marinomycin A (m-2) yielded
crystals (mp: 2138C (dec.), CDCl3-D3COD) that
were suitable for X-ray crystallographic analysis
(see ORTEP representation, Figure 1),[13] which
confirmed its assigned structure as well as that of
its sibling, mono-marinomycin A (m-1) and their
precursors. The NOESY, ROESY, and COSY
NMR data were also consistent with the assigned
structures of m-1 (Table 1) and m-2.
Scheme 5. Preparation of aryl diene fragment 7. Reagents and conditions: a) 2,5-
dimethylhexa-2,4-diene (5.5 equiv), BH3·THF (2.5 equiv), THF, 08C, 3 h; then 19,
08C, 1.5 h; then H2O, 0!258C, 1 h; then (CH2O)n, 258C, 1 h; then pinacol
(2.0 equiv), 258C, 24 h, 87%; b) [Pd(PPh3)4] (0.1 equiv), Cs2CO3 (10 equiv), 20
(1.3 equiv), THF/H2O (2:1), 558C, 1 h, 89%; c) NBS (1.2 equiv), MeCN, 258C,
15 min, 88%; d) KOH (5.0 equiv), THF/H2O (1:1), 558C, 18 h, 87%; e) Mg(ClO4)2
(0.03 equiv), Ac2O (1.1 equiv), 258C, 48 h, 96%. NBS=N-bromosuccinimide.
Having realized the propensity of dienyl bro-
mide boronic acid 4 to cyclize before dimerization,
ꢀ788C resulted in the exclusive formation of the correspond-
ing allylic alcohol (89% yield), whose silylation (TBSCl) led
to the fully protected hexaol 23 (89% yield). The benzyl
group was then cleaved from the terminal oxygen atom of this
compound, 23, with Ca in liquid NH3 (75% yield), and the
resulting primary alcohol was oxidized with DMP to furnish
aldehyde 25 (87% yield). Enyne 26 was then generated from
aldehyde 25 upon acetylene installment (TMSCHN2-LDA;[11]
85% yield) and selective desilylation (TES) with PPTS in
ethanol (77% yield). Accompanied by inversion of config-
uration at C25 (marinomycin numbering scheme), the Mitsu-
nobu reaction between hydroxy compound 26 and carboxylic
acid 7 (DEAD, PPh3) proceeded in 93% yield to afford ester
27. Exchanging the Ac groups for a TIPS group (K2CO3,
MeOH; TIPSOTf, 2,6-lut.) then furnished the targeted bromo
enyne 28 in excellent yield (92% overall). This latter switch of
protecting groups was necessary because of difficulties
encountered in the subsequent hydroboration and Suzuki
coupling steps using the Ac-protected and free phenol
carboxylic acid variants of 28.
The stage was now set for the anticipated Suzuki
dimerization/cyclization in the hope of reaching marinomy-
cins A–C (see Scheme 7). Thus, the required boronic acid 4
was generated from enyne 28 by reaction with catecholborane
and catalytic amounts of dicyclohexylborane (THF, 258C;
then H2O) and exposed to the action of TlOEt (4.0 equiv) and
[Pd(PPh3)4](cat.) in THF/H 2O (4:1) at ambient temper-
ature[12] and 0.01m concentration, to afford, much to our
surprise, only the monomeric product 29 (72% yield over the
two steps). Increasing the concentration (up to 1.0m) did not
have much effect on the outcome of this reaction, suggesting
that the precursor had a well-preorganized disposition
towards cyclization once the palladium species was inserted.
However, the use of 300 equivalents of TlOEt produced, in
addition to 29, the dimeric product 1 in approximately 2%
yield (see Scheme 6), after global desilylation. Fluoride-
induced global desilylation (TBAF) of 29 (see Scheme 7) gave
the all-trans 22-membered ring m-1 (mono-marinomycin A)
and the all-trans 24-membered ring m-2 (iso-mono-marino-
mycin A), where the lactone had shifted during desilylation,
in 85% yield as a separable 1:1 mixture. The mono-
marinomycins A (m-1 and m-2) were isolated and character-
Figure 1. ORTEP representation of iso-mono-marinomycin A (m-2) with
thermal ellipsoids shown at the 30% probability level. Hydrogen
atoms are shown as white spheres.
we resorted to a stepwise approach to marinomycins A–C.
The same key building blocks, 7 (Scheme 5), 26 (Scheme 6),
and 28 (Scheme 6) were required, and the revised strategy is
continued in Scheme 6. Thus, regioselective hydroboration of
hydroxy enyne 26 with catecholborane catalyzed by dicyclo-
hexylborane gave the corresponding boronic acid, whose
Suzuki coupling (KOH (10 equiv), [Pd(PPh3)4](cat.), THF/
H2O (4:1)) with dienyl bromide 28 (0.67 equiv) led to hydroxy
polyene 30 (63% yield based on 28). Mitsunobu reaction of
the latter compound, 30, with carboxylic acid 7 proceeded
with inversion of configuration at C25’ to afford, after
exchange of the Ac group for a TIPS group, enyne ester 31
(78% overall yield for the three steps; Table 1).
Reaction of enyne 31 with catecholborane under the
catalytic influence of dicyclohexylborane (THF, 258C) fur-
nished, after H2O quench, the corresponding boronic acid,
which was, without isolation, treated with [Pd(PPh3)4](stoi-
chiometric) and TlOEt (300 equiv) at ambient temperature to
afford the fully protected macrocycle 32. The product was
used without purification in the next step, which involved
global deprotection of 32 to give marinomycin A (1) in 23%
overall yield for the three steps from 31. Synthetic marino-
mycin A (1) was purified by HPLC (C8-Luna 5m column,
100 Š, 250 mm ” 10 mm, 60% MeCN in H2O) and exhibited
identical physical properties (Rf, Rt, UV spectral, a2D5, mass
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Scheme 6. Preparation of Suzuki coupling precursor 28 and completion of the total synthesis of marinomycins A–C (1–3). Reagents and
conditions: a) 5 (1.0 equiv), 6 (1.1 equiv), Ba(OH)2·H2O (0.75 equiv), THF/H2O (20:1), 258C, 1 h, 95%; b) Et2BOMe (1.0m in THF, 1.1 equiv),
NaBH4 (1.1 equiv), THF/MeOH (4:1), ꢀ788C, 3 h, 89%; c) TBSCl (4.0 equiv), imid. (8.0 equiv), DMF, 258C, 8 h, 89%; d) 23 in THF/iPrOH (3:1);
then liq. NH3; then Ca (30 equiv), ꢀ788C, 1 h, 75%; e) DMP (1.6 equiv), NaHCO3 (10 equiv), CH2Cl2, 258C, 30 min, 87%; f) iPr2NH (1.8 equiv),
nBuLi (2.5m in hexanes, 1.5 equiv), THF, ꢀ78!08C, 30 min, TMSCH2N2 (1.5 equiv), THF, ꢀ788C, 30 min; then 25, ꢀ788C , 1 h, ꢀ78!258C,
2 h, 85%; g) PPTS (0.1 equiv), EtOH, 258C, 3 h, 77%; h) DEAD (6.0 equiv), PPh3 (6.0 equiv), 7 (6.0 equiv), THF, 258C , 1 h, 93%; i) K2CO3
(0.05 equiv), THF/MeOH (1:1), 258C, 15 min; j) TIPSOTf (30 equiv), 2,6-lut. (60 equiv), CH2Cl2, 258C, 18 h, 92% over two steps; k) catecholbor-
ane (3.0 equiv), Cy2BH (0.1 m in THF, 0.2 equiv), THF, 258C, 1 h; then H2O (5.0 equiv); l) KOH (10 equiv), [Pd(PPh3)4] (0.1 equiv), THF/H2O
(4:1), 258C, 1 h, 63% based on 28; m) DEAD (6.0 equiv), PPh3 (6.0 equiv), 7 (6.0 equiv), THF, 258C, 1 h; n) K2CO3 (0.05 equiv), THF/MeOH
(1:1), 258C, 15 min; o) TIPSOTf (30 equiv), 2,6-lut. (60 equiv), CH2Cl2, 258C, 18 h, 78% over three steps; p) catecholborane (3.0 equiv), Cy2BH
(0.1 m in THF, 0.2 equiv), THF, 258C, 1 h; then H2O (5.0 equiv); q) TlOEt (300 equiv), [Pd(PPh3)4] (1.0 equiv), THF/H2O (10:1), 258C, 4 h;
r) TBAF (50 equiv), THF, 258C, 18 h, 23% over three steps. Cy=cyclohexyl, DMP=Dess–Martin periodinane, DEAD=diethyl azodicarboxylate,
LDA=lithium diisopropylamide, lut.=lutidine, PPTS=pyridinium p-toluenesulfonate, TBAF=tetra-n-butylammonium fluoride, Tf=trifluorometha-
nesulfonyl, TIPS=triisopropylsilyl.
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Table 1: Selected physical properties for compounds m-1 and 31.
m-1: Rf =0.54 (silica gel, CHCl3/MeOH/H2O 40:9:1); [a]3D7 =ꢀ276.6
(c=0.06, CDCl3); IR(film): n˜max =3352, 2926, 2851, 1709, 1656, 1595,
1449, 1376, 1259, 1218, 1118, 1065, 999 cmꢀ1; 1H NMR(600 MHz,
CDCl3): d=7.35 (t, J=7.8 Hz, 1H), 7.13 (d, J=14.4 Hz, 1H), 6.92 (d,
J=8.4 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.47 (dd, J=14.4, 11.4 Hz,
1H), 6.34 (t, J=11.4 Hz, 1H), 6.16–6.03 (m, 3H), 5.91 (d, J=10.8 Hz,
1H), 5.38–5.20 (m, 3H); 4.16 (br, 1H, OH), 4.06 (m, 1H), 3.95 (m, 1H),
3.71 (t, J=9.0 Hz, 1H), 3.65 (m, 1H), 3.58 (br, 1H, OH), 3.29 (br, 1H,
OH), 2.56 (d, J=10.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.14 (t,
J=10.8 Hz, 1H), 1.97–1.85 (m, 4H), 1.88 (s, 3H), 1.79–1.75 (m, 2H),
1.70–1.62 (m, 3H), 1.20 ppm (d, J=6.0 Hz, 3H); 13C NMR(150 MHz,
CDCl3): d=171.9, 162.4, 141.7, 135.8, 135.3, 134.6, 134.5, 133.3, 132.8,
131.9, 131.1, 130.3, 129.7, 128.2, 120.1, 117.0, 73.1, 72.5, 66.4, 65.8, 65.6,
50.4, 48.3, 45.5, 43.8, 42.5, 23.4, 17.8, 14.2 ppm; HRMS (ESI-TOF) calcd
for C29H38O7Na [M+Na+]: 521.2510; found: 521.2530.
31: Rf =0.57 (silica gel, hexanes/EtOAc, 8:1); [a]3D7 =ꢀ98.8 (c=0.09,
CH2Cl2); IR(film): n˜max =2952, 2828, 2856, 1729, 1570, 1465, 1255, 835,
775 cmꢀ1; 1H NMR(600 MHz, C 6D6, mixture of two rotamers around the
aryl–carbonyl bond, ca. 1:1 ratio): d=7.15 (J=8.4 Hz, 1H), 7.11 (d,
J=8.4 Hz, 1H), 7.03–6.96 (m, 2H), 6.94–6.89 (m, 3H), 6.85 (dd,
J=15.6, 10.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H),
6.61 (dd, J=13.2, 13.2 Hz, 1H), 6.55 (dd, J=13.8, 11.4 Hz, 1H), 6.49–
6.37 (m, 2H), 6.31 (dd, J=15.6, 10.8 Hz, 1H), 6.16 (d, J=11.4 Hz, 1H),
6.03 (d, J=13.8 Hz, 1H), 5.85 (dt, J=15.0, 7.2 Hz, 1H), 5.83 (dt,
J=15.0, 7.2 Hz, 1H), 5.66 (dd, J=15.6, 7.2 Hz, 1H), 5.59 (dd, J=15.6,
7.2 Hz, 1H), 5.51–5.45 (m, 2H), 5.46 (s, 1H), 4.38 (q, J=7.2 Hz, 1H),
4.28 (q, J=7.2 Hz, 1H), 4.16–4.05 (m, 6H), 2.83 (d, J=2.4 Hz, 1H),
2.49–2.40 (m, 4H), 2.33–2.25 (m, 2H), 2.23–2.10 (m, 6H), 2.05–1.92
(m, 5H), 2.04 (s, 3H), 1.86 (s, 3H), 1.85–1.79 (m, 2H), 1.70 (ddd,
J=13.2, 7.2, 4.8 Hz, 1H), 1.35–1.28 (m, 12H), 1.19–1.16 (m, 36H), 1.07
(s, 9H), 1.06 (s, 9H), 1.06 (s, 27H), 1.05 (s, 9H), 1.02 (s, 9H), 1.01 (s,
9H), 0.28 (s, 3H), 0.26 (s, 6H), 0.23 (s, 3H), 0.21 (s, 3H), 0.20 (s, 3H),
0.19 (s, 3H), 0.19 (s, 3H), 0.19 (s, 3H), 0.16 (s, 6H), 0.15 (s, 3H), 0.15
(s, 3H), 0.14 (s, 3H), 0.14 (s, 3H), 0.12 ppm (s, 3H); 13C NMR
(150 MHz, C6D6, mixture of rotamers around the aryl–carbonyl bond, ca.
1:1 ratio): d=167.4 (0.5 C), 167.4 (0.5 C) 167.1, 153.9, 153.8 (0.5C),
153.8 (0.5C), 150.8, 137.8 (3C), 137.7, 137.2, 137.1, 136.4, 136.2 (0.5C),
136.2 (0.5C), 135.7, 132.4 (0.5C), 132.3 (0.5C), 131.5 (0.5C), 130.9
(0.5C), 130.9, 130.1, 130.1 (0.5C), 130.0, 129.9 (0.5C), 129.1, 129.0,
126.5 (0.5C), 126.4 (0.5C), 126.3 (0.5C), 126.2 (0.5C), 118.1, 117.9,
117.9, 117.4, 110.6, 110.4 (0.5C), 110.3 (0.5C), 107.8, 81.9, 80.7, 72.0,
71.9 (0.5C), 71.8 (0.5C), 71.5, 71.4, 69.8 (0.5C), 69.7 (0.5C), 68.7, 68.2,
66.5, 66.4 (2C), 51.7, 48.6, 47.4, 47.2, 46.7, 45.6, 45.5, 42.6, 42.5, 41.0,
30.2, 26.3 (9C), 26.2 (9C), 26.2 (3C), 26.2 (3C), 24.5, 24.4, 20.3, 18.3
(8C), 17.9 (12C), 12.7 (6C), ꢀ3.4, ꢀ3.4, ꢀ3.8 (2C), ꢀ3.9 (3C), ꢀ3.9,
ꢀ4.0, ꢀ4.1 (4C), ꢀ4.2, ꢀ4.3, ꢀ4.4 ppm; HRMS (ESI-TOF) calcd for
Scheme 7. Formation of mono-marinomycins m-1 and m-2. Reagents and
conditions: a) catecholborane (3.0 equiv), Cy2BH (0.1m in THF, 0.2 equiv),
THF, 258C, 1 h; then H2O (5.0 equiv); b) TlOEt (4.0 equiv), [Pd(PPh3)4]
(0.1 equiv), THF/H2O (4:1), 258C, 30 min, 72% over two steps; c) TBAF
(30 equiv), THF, 18 h, 85% yield.
marinomycin A (m-2), and opens the way to the construction
of other members of the class of natural or designed origins.
Received: May 11, 2006
Revised: June 28, 2006
Published online: September 15, 2006
Keywords: antibiotics · antitumor agents · natural products ·
.
Suzuki coupling · total synthesis
[1]H. C. Kwon, C. A. Kauffman, P. R. Jensen, W. Fenical, J. Am.
Chem. Soc. 2006, 128, 1622. We thank Professor William Fenical
for a preprint of this article.
[2]For selected examples of Suzuki macrocyclizations, see: a) J. D.
White, R. Hanselmann, R. W. Jackson, W. J. Porter, Y. Ohba, T.
Tiller, S. Wang, J. Org. Chem. 2001, 66, 5217; b) J. T. Njardarson,
K. Biswas, S. Danishefsky, Chem. Commun. 2002, 23, 2759;
c) G. A. Molander, F. Dehmel, J. Am. Chem. Soc. 2004, 126,
10313; d) B. Wu, Q. Liu, G. A. Sulikowski, Angew. Chem. 2004,
116, 6841; Angew. Chem. Int. Ed. 2004, 43, 6673.
C
124H226BrO14Si10 [MꢀHꢀ]: 2298.3853; found: 2298.3852.
[3]D. R. Williams, S. V. Plummer, S. Patnaik, Angew. Chem. 2003,
115, 4064; Angew. Chem. Int. Ed. 2003, 42, 3934.
[4]J. A. Marshall, E. A. Van Devender, J. Org. Chem. 2001, 66,
8037.
[5]Prepared from commerically available ethyl-( R)-(ꢀ)-3-hydroxy-
butyrate (Aldrich, 99% ee) according to a published method: K.
Ohta, O. Miyagawa, H. Tsutsui, O. Mitsunobu, Bull. Chem. Soc.
Jpn. 1993, 66, 523.
[6]U. S. Racherla, H. C. Brown, J. Org. Chem. 1991, 56, 401.
[7]G. A. Molander, F. Dehmel, J. Am. Chem. Soc. 2004, 126, 10313.
[8]A. V. Kalinin, S. Scherer, V. Snieckus, Angew. Chem. 2003, 115,
3521; Angew. Chem. Int. Ed. 2003, 42, 3399.
1
spectrometric, and H and 13C NMR spectral data) to those
recorded for the naturally occurring substance.[1,14] When
allowed to isomerize in ambient light, marinomycin A (1)
formed mixtures with marinomycins B (2) and C (3) as
previously reported (1/2/3 ꢁ 16:2:9 after 30 min; ca. 1:1:1 after
2 h by HPLC).[1,15]
The success of the Suzuki reaction in these syntheses
underscores its usefulness in the construction of complex
molecules. Besides rendering the naturally occurring marino-
mycins A–C (1–3) readily available, the described synthetic
technology also provides access to their monomeric deriva-
tives, mono-marinomycin A (m-1) and its isomer iso-mono-
[9]A. K. Chakraborti, L. Sharma, R. Gulhane, Shivani, Tetrahe-
dron 2003, 59, 7661.
ˇ
[10]K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic , M. J.
Shapiro, Tetrahedron Lett. 1987, 28, 155; see also: K. Narasaka,
F.-C. Pai, Tetrahedron 1984, 40, 2233.
Angew. Chem. Int. Ed. 2006, 45, 6527 –6532
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6531

Communications
[11]S. Ohira, K. Okai, T. Moritani, J. Chem. Soc. Chem. Commun.
1992, 721; for a review of trimethylsilyldiazomethane, see: T.
Shiori, T. Aoyama, J. Synth. Org. Chem. Jpn. 1986, 44, 149.
[12]S. A. Frank, H. Chen, R. K. Kunz, M. J. Schnaderbeck, W. R.
Roush, Org. Lett. 2000, 2, 2691; see also: J.-i. Uenishi, J.-M.
Beau, R. W. Armstrong, Y. Kishi, J. Am. Chem. Soc. 1987, 109,
4756.
[13]CCDC-607141 ( m-2) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14]We thank Professor William Fenical and Dr. Hak Cheol Kwon
for an authentic sample and spectra of marinomycins A–C (1–3).
[15]Exact ratios of marinomycins A–C ( 1–3) varied from one
experiment to another.
6532
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6527 –6532