Total synthesis of kinamycins C, F, and J

Article abstract of DOI:10.1021/ja074297d

The kinamycins are a series of naturally occurring compounds endowed with intriguing molecular architectures and potent biological properties, including antibiotic and antitumor activities. These novel diazofluorene-containing compounds defied chemical sy

Full text of DOI:10.1021/ja074297d

Published on Web 08/04/2007
Total Synthesis of Kinamycins C, F, and J
K. C. Nicolaou,* Hongming Li, Andrea L. Nold, Doron Pappo, and Achim Lenzen
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037, and the Department of Chemistry and Biochemistry,
UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093
Received June 27, 2007; E-mail: kcn@scripps.edu
Scheme 1. Construction of Bromo-aldehyde 2a
The kinamycins (e.g., A-D, F and J, 1a-1f, Figure 1) are a
series of naturally occurring compounds endowed with intriguing
molecular architectures and potent biological properties, including
1
antibiotic and antitumor activities. These novel diazofluorene-
2
containing compounds defied chemical synthesis since their initial
1
disclosure by Omura et al. in 1970 until the first total synthesis of
3
kinamycin C by Porco et al. in late 2006, and of methyl-kinamycin
4
C by the Kumamoto-Ishihawa group in 2007. We now report
our enantioselective total synthesis of kinamycins C, F, and J
through a convergent strategy that is both enantioselective and
expedient.
a
Reagents and conditions: (a) vinylacetic acid (1.3 equiv), AgNO3 (0.3
equiv), (NH4)2S2O8 (2.0 equiv), MeCN/H2O, 2:1, 65 °C, 3 h, 75%; (b) BnBr
(2.0 equiv), Ag2O (1.0 equiv), CH2Cl2, 25 °C, 18 h, 92%; (c) Na2S2O4 (5.0
equiv), Et2O/EtOAc/H2O, 10:1:10, , 25 °C, 30 min; NaH (2.1 equiv), MeI
(
2
1
)
2.2 equiv), DMF, -15 °C, 1 h, 82%; (d) t-BuOK (2.0 equiv), THF, 0 °C,
h, 98%; (e) OsO4 (0.01 equiv), NaIO4 (2.4 equiv), THF/H2O, 2:1, 70 °C,
8 h, 84%. Abbreviations: DMF ) dimethylformamide, Bn ) benzyl, THF
tetrahydrofuran.
Scheme 2. Construction of Iodo-enone 3a
Figure 1. Structures of kinamycins A-D, F, and J (1a-1f) and of key
building blocks 2 and 3.
The unique carbocyclic skeleton of the kinamycin molecule is
boldly defined by its fluorenone structural motif that could, in
principle, be forged through the union of key building blocks 2
and 3 (Figure 1) by a strategy featuring an Ullmann-type coupling
followed by an intramolecular benzoin-like condensation and further
elaboration. Cognizant of the sensitivity of the diazo group, we
left its installation toward the end of the designed synthetic
sequence, although we harbor aspirations to reach as many
kinamycin congeners as possible from a common intermediate
through the deployment of suitable conditions.
The construction of the building block 2 (see Scheme 1) began
5
with 4, whose allylation with vinyl acetic acid in the presence of
6
(NH ) S O
4 2 2 8
and cat. AgNO
3
proceeded smoothly to afford naptho-
a
Reagents and conditions: (a) MeMgBr (3.0 M in Et2O, 2.0 equiv),
quinone 5 in 75% yield, an intermediate that was suitably protected
as its dimethoxy benzyl form 6 [(i) BnBr, Ag O, 92% yield; (ii)
Na ; NaH, MeI, 82% yield]. The latter compound was then
converted to the desired fragment, bromo-aldehyde 2, by first
conjugating its olefinic bond (t-BuOK, 98% yield) and then
CuBr‚Me2S (0.1 equiv), THF/HMPA, 10:1, -78 °C, 30 min; enone 8 (1.0
equiv), TMSCl (2.5 equiv), -78 °C, 30 min; -78 f 25 °C, 30 min; then,
Pd(OAc)2 (0.1 equiv), DMSO, O2 (1 atm), 18 h, 25 °C, 90%; (b) OsO4
(0.02 equiv), NMO (1.5 equiv), Me2CO/H2O, 10:1, 25 °C, 45 min, 76%
after 3 recrytallizations, >98% ee; (c) 2-MeO-propene (10.0 equiv), CSA
2
2 2 4
S O
(
0.02 equiv), THF, 25 °C, 18 h, 95%; d) LiHMDS (1.0 M in THF, 3.0
4 4
oxidatively cleaving it (OsO , NaIO , 84% yield).
The construction of the other required fragment, iodo-enone 3,
equiv), TMSCl (3.0 equiv), THF, 0 °C, 30 min; then, Pd(OAc)2 (0.1 equiv),
DMSO, O2 (1 atm), 25 °C, 18 h, 84%; (e) I2 (3.0 equiv), CH2Cl2:py, 1:2,
25 °C, 30 min, 92%. Abbreviations: TBS ) tert-butyldimethylsilyl, HMPA
) hexamethyl phosphoramide, TMS ) trimethylsilyl, DMSO ) dimeth-
ylsulfoxide, NMO ) N-methylmorpholine-N-oxide, CSA ) camphorsulfonic
acid, HMDS ) 1,1,1,3,3,3-hexamethyldisilazane, py ) pyridine.
in its enantiomerically pure form was carried out as summarized
7
in Scheme 2. Thus, the readily available enone 7 (g80% ee) was
elaborated into its methylated derivative 8 through a two-step
sequence involving conjugate addition of a methyl group and
trapping (MeMgBr, CuBr‚Me
oxidation of the resulting silyl enol ether [Pd(OAc) cat., O , 90%
2
S, TMSCl), followed by Saegusa
overall yield]. The latter compound was then stereoselectively
dihydroxylated (OsO cat., NMO, 76% yield after three recrystal-
4
8
2
2
10356
9
J. AM. CHEM. SOC. 2007, 129, 10356-10357
10.1021/ja074297d CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of Kinamycin C (1c)a
into conjugation (81% yield over the two steps). Allylic oxidation
2
of the resulting fluorenone with SeO provided, stereoselectively,
alcohol 15 in 72% yield. The TBS and acetonide groups were then
removed from 15 through the action of aq HF in MeCN, and the
resulting tetraol was selectively tri-acetylated (Ac
8
1
2
O, Et
9% overall yield for the two steps), and then debenzylated (H
0% Pd/C) to afford advanced fluorenone 16 in 99% yield. Finally,
3
N, DMAP,
2
,
temporary protection of the phenolic group (TBSCl, imid., 94%
yield) followed by tosyl hydrazone formation [TsNHNH , aq HCl,
2
4
ca. 4:1 mixture of isomers (inconsequential), 95% yield] and
oxidation (CAN) led to TBS-protected kinamycin C (17) in 42%
yield. Exposure of the latter compound to aq HCl in MeCN
furnished kinamycin C (1c) in 95% yield. Acetylation of 17 (Ac
2
O,
Et N, DMAP), followed by TBS-ether cleavage (aq HCl, MeCN)
3
provided kinamycin J (1f) in 80% yield over the two steps, while
LiOH-mediated removal of all protecting groups from 17 led to
kinamycin F (1e) in 92% yield. The spectroscopic data of synthetic
kinamycins C, F, and J were consistent with those reported for the
natural compounds.1
The described chemistry provides an expedient and flexible entry
into the kinamycin family of antitumor antibiotics and promises to
be useful in the total synthesis of their more complex dimeric
cousins, the lomaiviticins.12
Acknowledgment. Dedicated to George A. Olah on the occasion
of his 80th birthday. We thank Dr. D. H. Huang and Dr. L.
Pasterneck for NMR spectroscopic assistance and Dr. G. Siuzak
for mass spectrometric assistance. Financial support for this work
was provided by a grant from the National Institutes of Health
(U.S.A.) and the Skaggs Institute for Chemical Biology, and
postdoctoral fellowships from the Alexander von Humboldt Foun-
dation (to A.L.) and ICES A*STAR, Singapore (to D.P.).
a
Reagents and conditions: (a) 2 (1.5 equiv), 3 (1.0 equiv), Pd2(dba)3
(
(
(
0.1 equiv), CuI (0.4 equiv), Cu (10.0 equiv), DMSO, 65 °C, 2.5 h, 83%;
b) 13 (0.2 equiv), Et3N (2.0 equiv), CH2Cl2, 45 °C, 4 h, 78%; (c) Ac2O
10.0 equiv), Et3N (10.0 equiv), DMAP (1.0 equiv), CH2Cl2, 25 °C, 20 h,
5%; (d) SmI2 (2.0 equiv), MeOH (5.0 equiv), THF, -78 °C, 10 min; (e)
Et3N (2.0 equiv), CH2Cl2, 25 °C, 1 h, 81% over two steps; (f) SeO2 (1.2
equiv), 1,4-dioxane, 110 °C, 9 h, 72%; (g) aq HF/MeCN, 3:10, 25 °C, 3 h;
h) Ac2O (10.0 equiv), Et3N (10.0 equiv), DMAP (1.0 equiv), CH2Cl2, 25
C, 20 min, 89% over two steps; (i) 10% Pd/C (10% w/w), EtOAc/AcOH,
00:1, H2 (1 atm), 25 °C, 3 h, 99%; (j) TBSCl (5.0 equiv), imid. (6.0 equiv),
DMF, 25 °C, 3 h, 94%; (k) TsNHNH2 (5.0 equiv), 1 M aq HCl/i-PrOH,
:40, 25 °C, 18 h, ca. 4:1 mixture of isomers, 95%; (l) CAN (3.0 equiv),
MeCN/pH 7 buffer, 10:1, 0 °C, 1 h, 42%; m) 1 M aq HCl/MeCN, 1:2,
5 °C, 3 h, 95%; n) Ac2O (10.0 equiv), Et3N (10.0 equiv), DMAP (1.0
equiv), CH2Cl2, 25 °C, 2 h; o) 1 M aq HCl/MeCN, 1:2, 25 °C, 3 h, 80%
over two steps; p) 0.2 M aq LiOH/THF, 1:2, 25 °C, 1 h, 92%.
Abbreviations: dba ) dibenzylideneacetone, DMAP ) 4-dimethylami-
nopyridine, imid. ) imidazole, Ts ) tosyl, CAN ) cerium ammonium
nitrate.
Note Added after ASAP Publication. A correction to ref 9 was
made in the version published on August 9, 2007.
9
Supporting Information Available: Experimental procedures and
compound characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
°
3
References
1
(
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iodination of 11 (I , py) furnished the desired iodo-enone 3 in 92%
2
yield.
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dba)
). The latter entered into a benzoin-type reaction in the presence
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and then Et
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(
(
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2
-
(
9
(
3
3
cat.) to afford coupling product 12 in 83% yield (Scheme
(
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(
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2
O, Et
in the presence of MeOH
N to cleave the acetate and migrate the double bond
3
N,
11
2
3
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J. AM. CHEM. SOC.
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VOL. 129, NO. 34, 2007 10357