Total synthesis of the salicylate enamide macrolide oximidine II

Article abstract of DOI:10.1021/ja034030o

The asymmetric synthesis of the salicylate enamide macrolide oximidine II is reported. The synthesis involves a highly regio- and stereoselective ring-closing metathesis of a bis-diene substrate to construct the macrocyclic triene core. Copper(I)-mediated

Full text of DOI:10.1021/ja034030o

Published on Web 04/29/2003
Total Synthesis of the Salicylate Enamide Macrolide Oximidine II1
Xiang Wang and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
Received January 3, 2003; E-mail: porco@chem.bu.edu
Oximidines I (1)1 and II (2) (Figure 1) are closely related
metabolites isolated from Pseudomonas sp. Q52002 which display
potent antitumor activity. Relative and absolute stereochemistry
assignments were based on extensive NMR studies, including
modified Mosher ester analysis.2 Recently, 1, 2, and other salicylate
enamide macrolides such as the lobatamides3 and salicylihalamides4
Figure 1. Structures of oximidines I (1) and II (2).
have been shown to selectively inhibit mammalian vacuolar-type
proton ATPase.5 Both 1 and 2 contain a highly unsaturated 12-
membered macrolactone and (Z)-enamide side chain, differing only
in epoxidation at C12-C13. Oximidine II possesses an (E,Z,Z)-
conjugated triene within the macrolactone, which is very uncommon
in natural products.6 Recent reports have documented approaches
to the enamide side chain7 and core structures8 of the oximidines.
Herein, we report the first total synthesis of (-)-oximidine II (2),
employing an uncommon ring-closing metathesis of a bis-diene to
construct the macrocyclic triene core.9
Our retrosynthetic analysis of oximidine II is shown in Figure
2. We planned to utilize copper-mediated amidation10 of (Z)-vinyl
iodide 3 and amide 410a for the late-stage introduction of the (Z)-
Figure 2. Retrosynthetic analysis of oximidine II.
Scheme 1 a
enamide side chain. To construct the macrocyclic triene core, we
first considered ring-closing metathesis (RCM)11 of bis-diene
substrate 5. We anticipated that the strained, macrocyclic triene
would be prone to ring-opening metathesis and therefore hoped to
form the ring using kinetic control12 by alteration of the protective
groups (P1-P3) and diene substitution pattern of 5.
We initiated our studies to prepare terminal diene fragments 6
and 7.13 The synthesis commenced with asymmetric allylboration14
of aldehyde 815 to afford 9 as a single diastereomer in 80% yield
(90% ee) (Scheme 1). The secondary alcohol was silylated, and
the terminal olefin was oxidized to aldehyde 10 by a two-step
procedure. Using Yamamoto’s protocol,16 we converted aldehyde
10 to the desired cis-diene 6 after desilylation. Treatment of 6 with
NaHMDS, followed by addition of acetonide 7 (prepared by Stille
coupling17 of triflate 1110b and dienyl stannane 1218), afforded bis-
diene 13, which was silylated to provide compound 14. Attempted
MOM deprotection of 14 with BBr3 unexpectedly afforded the 1,3-
dioxepan 15, which was desilylated to phenol 16.
a Conditions: (a) allyl methoxymethyl ether, sBuLi, (+)-Ipc2BOMe,
BF3‚OEt2, -78 to 0 °C, 80%; (b) TBSCl, imidazole, DMF, 94%; (c) cat.
t
OsO4, NMO, THF/H2O; (d) K2CO3, Pb(OAc)4, MeOH, 0 °C; (e) BuLi,
allyldiphenylphosphine, Ti(OiPr)4, THF, -78 to 0 °C; then MeI; (f) TBAF,
THF, 71% (four steps); (g) Pd2dba3, P(2-furyl)3, LiCl, DMF, 60 °C, 89%;
(h) 6, NaHMDS, then 7, THF, 0-25 °C, 95%; (i) TBSCl, imidazole,
CH2Cl2, 95%; (j) BBr3, CH2Cl2, -78°C, 35%; (k) TBAF, THF, 0 °C, 60%.
With substrates 13-16 in hand, we examined their reactivity in
RCM reactions.19 Treatment of all substrates with Ru catalyst 17
afforded products resulting from reaction of the trans-diene and
gave no observable further conversion.20 When treated with catalyst
18, substrates 13 and 14 reacted with the trans-diene and gave no
further conversion (CH2Cl2, reflux, 3 h). These results suggested
that the trans-diene of substrates 13 and 14 was the initiation site
for RCM, but that macrocyclization was nonproductive. Constrained
substrates 15 and 16 afforded oligomeric products (20 min). In ad-
dition, HPLC-MS analysis indicated trace formation of 10-mem-
bered ring product(s) for substrate 16, but no desired macrocyclic
triene.
generation substrate 19 (Scheme 2) was initiated by homologation21
of (E)-crotonaldehyde to afford a dienyl stannane which coupled
with 11 to furnish the desired (E,E)-diene 21. Treatment of 6 with
NaHMDS, followed by addition of 21 and silylation, provided bis-
diene 19 in a one-pot procedure. After considerable experimentation,
we found that treatment of 19 with 5 mol % 18 in CH2Cl2 (2 mM,
reflux, 70 min) afforded the oximidine II core 22 in 48% yield
(one recycle) accompanied by oligomeric products. Extended
reaction time resulted in decomposition of both starting material
and product. It should be noted that under the same condition,
phenol 20 did not undergo RCM but afforded only oligomeric
products. Monte Carlo conformational searches on model com-
pounds A and B (Figure 3) show a potential rationale for control
of the C10-C11 olefin geometry by protection of the phenol.10b,13
On the basis of these results, we next incorporated a trans-methyl
group on the more reactive trans-diene in an effort to initiate the
RCM at the terminus of the cis-diene. Synthesis of second
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J. AM. CHEM. SOC. 2003, 125, 6040-6041
10.1021/ja034030o CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
macrocyclic triene core, and stereoselective copper-mediated ami-
dation of a (Z)-vinyl iodide to construct the enamide side chain.
Further synthetic studies on the oximidines and their biological
evaluation will be reported in due course.
Acknowledgment. We thank Mr. Ruichao Shen for helpful
discussions, Ms. Li-Ting Huang for experimental assistance, Dr.
Aaron Beeler for HPLC-MS, and Prof. Y. Hayakawa (University
of Tokyo) for providing an authentic sample of oximidine II. This
research was supported by the NIH (GM-62842).
Supporting Information Available: Experimental procedures,
theoretical calculation results, and characterization data for all new
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
a Conditions: (a) CrCl2, DMF, Bu3SnCHBr2, THF; (b) 11, Pd2dba3, P(2-
furyl)3, LiCl, DMF, 80 °C, 61% (two steps); (c) 6, NaHMDS, THF, 0-25
°C; then TBSCl, imidazole, 100%; (d) 18 (5 mol %), CH2Cl2, reflux, 48%
(one recycle); (e) DDQ, CH2Cl2/H2O (10/1), 0-25 °C, 93%; (f) PDC, 4 Å
mol. sieves, CH2Cl2; (g) (Ph3P+CH2I)I-, NaHMDS, THF, -78 to 25 °C,
References
i
60% (two steps); (h) CBr4, PrOH, 75 °C, 83%; (i) TBSOTf, 2,6-lutidine,
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Am. Chem. Soc. 2002, 124, 3245.
Figure 3. Representative reactive conformers of ring-closing metathesis
substrates A and B (dashed lines indicate newly formed C10-C11 bonds).
For phenol substrate (A), the salicylate carbonyl maintains near
planarity with the aromatic ring, leading to the predicted formation
of a high energy and potentially reactive (E,E,Z)-triene.22 In contrast,
silylation of the phenol forces the carbonyl out-of-plane from the
benzene ring;23 subsequent rotation of the C8-C9 bond affords
the desired (E,Z,Z)-macrocyclic triene.
To advance 22 to a substrate for copper-mediated vinylic
amidation, the PMB ether was removed (DDQ), and the resulting
alcohol 23 was oxidized with PDC. Wittig olefination using the
Stork/Zhao protocol24 led to 24 as a single olefin isomer. The MOM
protecting group was cleanly removed under mild, acidic conditions
(CBr4, iPrOH),25 and the resulting alcohol was reprotected to afford
(Z)-vinyl iodide 3.
(13) For base-mediated transesterification of 4H-1,3-benzodioxin-4-ones, see:
Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem.
Soc. 2002, 124, 3245.
(14) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110,
1535.
(15) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am.
Chem. Soc. 1990, 112, 7001.
Amidation of 3 with oxime amide 4 using conditions reported
earlier for (E)-vinyl iodides10a led to low yield due to competitive
elimination under basic conditions. After a model study involving
evaluation of various ligands and bases,22 we found that 3 coupled
smoothly with 4, employing stoichiometric amounts of CuTC26-
N,N′-dimethyl-ethylenediamine (25)27 and K2CO3 as base (50 °C).
Oximidine II (2) was obtained after desilylation (HF-pyridine/
pyridine) with retention of olefin geometry. Synthetic 2 was
(16) Ukai, J.; Yamamoto, H. Tetrahedron Lett. 1983, 24, 4029.
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(18) Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron
1981, 37, 3967.
(19) Conditions for RCM: the substrate was dissolved in CH2Cl2 (2.0 mM),
and then treated with the Ru catalyst (10 mol %). The mixture was then
heated to reflux.
(20) For example, a relatively stable Ru-alkylidene complex was isolated from
14. See Supporting Information.
(21) Hodgson, D. M.; Boulton, L. T.; Maw, G. N. Tetrahedron 1995, 51, 3713.
(22) See Supporting Information.
(23) Cf.: Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr.
Org. Lett. 2002, 4, 3103.
confirmed to be identical to natural oximidine II by the 1H and 13
C
(24) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(25) Lee, A. S. Y.; Hu, Y. J.; Chu, S. F. Tetrahedron 2001, 57, 2121.
(26) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(27) For use of diamine ligands in C-N bond formation, see: Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
NMR spectra, mass spectrum, [R]D, HPLC, and TLC Rf values in
three solvent systems.
In summary, the first enantioselective synthesis of the salicylate
enamide macrolide oximidine II has been accomplished using the
RCM of a well-defined bis-diene substrate to construct the unusual
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