Total synthesis of the formamicin aglycon, formamicinone.

Article abstract of DOI:10.1021/ol027569k

[structure: see text] The total synthesis of formamicinone (2), the aglycone of formamicin (1), has been accomplished via the late-stage Suzuki cross-coupling of fragments 5 and 6, the macrolactonization of seco ester 14, and the Mukaiyama aldol reaction

Full text of DOI:10.1021/ol027569k

ORGANIC
LETTERS
2003
Vol. 5, No. 3
377-379
Total Synthesis of the Formamicin
Aglycon, Formamicinone
Brad M. Savall, Nicolas Blanchard, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
roush@umich.edu
Received December 30, 2002
ABSTRACT
The total synthesis of formamicinone (2), the aglycone of formamicin (1), has been accomplished via the late-stage Suzuki cross-coupling of
fragments 5 and 6, the macrolactonization of seco ester 14, and the Mukaiyama aldol reaction of aldehyde 3 and methyl ketone 4. An efficient
and highly stereoselective second generation synthesis of vinyl iodide 6 is also described.
Formamicin (1) was isolated by Igarashi and co-workers in
1997 from an actinomycete strain (MK27-91F2) obtained
from a soil sample.1,2 Formamicin possesses strong activity
against phytopathogenic fungi and moderate activity toward
Gram-positive bacteria. More interestingly, formamicin has
strong cytotoxicity against murine tumor cell lines. The
stereochemistry of formamicin was assigned by using two-
dimensional NMR techniques and confirmed by X-ray
structure analysis. Alkaline degradation liberated 2-deoxy-
D-rhamnose from C(21), thereby confirming the absolute
stereochemistry of 1.2
V112-17). We report herein the first total synthesis of the
formamicin aglycone, formamicinone (2).
Our synthetic strategy (Scheme 1) called for the C(19)-
C(24) tetrahydropyran unit of 2 to be assembled via an aldol
Scheme 1. Retrosynthetic Analysis
Formamicin is one of the more structurally complex
members of the plecomacrolide family,3,4 several of which
have been synthesized (e.g., elaiophylin (or its aglycone),5-8
hygrolidin,9 concanamycin F,10,11 and bafilomycins A1 and
(1) Igarashi, M.; Kinoshita, N.; Ikeda, T.; Nakagawa, E.; Hamada, M.;
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1997, 50, 932. Correction: J. Antibiot. 1998, 51, C1.
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Tetrahedron Lett. 1996, 37, 9077.
10.1021/ol027569k CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/14/2003

reaction of aldehyde 318 and methyl ketone 4, which in turn
would derive from fragments 5 and 6. The C(12-20)
fragment 5 is an intermediate in our total synthesis of
bafilomycin A1.14,17 A highly efficient and stereoselective
second generation synthesis of 5 has been developed17 by a
route utilizing an R-alkoxypropargylation reaction of a chiral
aldehyde.19 We have also previously reported a synthesis of
the C(1-11) fragment 6; however, this route suffered from
poor selectivity in the aldol reaction used to establish the
C(6-7) bond.20 Accordingly, we have developed an im-
proved second generation synthesis of 6 (Scheme 2) en route
to the total synthesis of 2.
Scheme 3. Synthesis of Formamicinone (2)a
Scheme 2. Synthesis of the C(1-11) Fragment 6a
a Key: (a) Pd(PPh3)4, TlOEt, THF (85%); (b) KOSi(Me)3, THF;
(c) 2,4,6-TCBC, pyridine, THF; (d) DMAP, toluene, 110 °C (62%,
from 14); (e) TFA, H2O, THF; (f) Dess-Martin, pyridine, CH2Cl2
(90%, from 15); (g) TMS-Cl, Et3N, LiHMDS, THF, -78 °C; (h)
3, BF3-Et2O, -78 °C, CH2Cl2 (65% from 16); (i) TAS-F, DMF-
H2O (80%).
a Key: (a) MOMCl, i-PrNEt2, CH2Cl2, 0 f 23 °C; (b) LiBH4,
Et2O-EtOH, 0 °C, 86% from 7; (c) (COCl)2, DMSO, CH2Cl2, -70
°C, then 8; (d) R-ethoxyvinyllithium, THF, -115 °C; (e) PMBBr,
KHMDS, Et3N, THF, 0 °C; (f) 1 N HCl, THF, H2O, 23 °C, (70%
from 8); (g) 1-propynylmagnesium bromide, THF, -45 f -30
°C, 94%; (h) Bu3SnH, Pd2dba3 (4 mol %), THF, 23 °C, 79%; (i)
Me2BBr, 2,6-DTBMP, CH2Cl2, -60 °C, 92%; (j) (E)-ethyl-â-
iodoacrylate, CuTC, Ph2P(O)OBu4N, NMP, 92%; (k) DDQ, CH2Cl2-
H2O, 0 f 23 °C; (l) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 77%
from 13; (m) NIS, CH3CN, 0 °C, 87%.
acyl oxazolidinone unit provided primary alcohol 8 (86%).
Oxidation of 8 using the standard Swern protocol22 followed
by treatment of the resulting aldehyde with R-ethoxyvinyl-
lithium23 in THF at -115 °C delivered allylic alcohol 9 with
g20:1 diastereoselectivity. Protection of the hydroxyl group
of this intermediate as a p-methoxybenzyl (PMB) ether
followed by acidic hydrolysis of the enol ether gave the
R-alkoxyketone 10 in 70% overall yield from 8.
Protection of the hydroxyl group of aldol 720 as a
methoxymethyl (MOM) ether followed by reduction21 of the
Installation of the C(6) quaternary center was accomplished
with >20:1 selectivity by chelate-controlled addition of
(10) Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T.
Angew. Chem., Int. Ed. 2000, 39, 1308.
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Matsumura, S. J. Org. Chem. 2001, 66, 1708.
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J. 1999, 5, 2984.
(12) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(13) Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida,
T.; Murase, H.; Nakata, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271.
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W. R. Angew. Chem., Int. Ed. 1999, 38, 1652.
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10200.
(19) Savall, B. M.; Powell, N. A.; Roush, W. R. Org. Lett. 2001, 3,
3057.
(20) Powell, N. A.; Roush, W. R. Org. Lett. 2001, 3, 453.
(21) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
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378
Org. Lett., Vol. 5, No. 3, 2003

1-propynylmagnesium bromide to 10.24,25 Hydrostannylation
of the propargyl alcohol was best accomplished by using
Pd2dba3 and Bu3SnH, which provided vinylstannane 11 in
79% yield after two recycles of recovered starting material.
Treatment of 11 with Me2BBr in the presence of 2,6-di-t-
butyl-4-methylpyridine (2,6-DTBMP) at -60 °C delivered
cyclic acetal 12 in 92% yield.26 Stille-type cross-coupling
of 12 and ethyl (E)-â-iodoacrylate promoted by copper(I)
thiophene-2-carboxylate (CuTC) then gave enoate 13 in 92%
yield.27 The C(7)-PMB ether was removed and replaced by
a TES ether (77% from 13), and the vinylsilane was
converted into the vinyl iodide by treatment with N-
iodosuccinimide (NIS) in CH3CN. Vinyl iodide 6 thus
obtained (87%) was identical to material prepared via the
first generation sequence.20
treated with aldehyde 3 and BF3‚Et2O in CH2Cl2 at -78 °C.
This provided aldol 16 in 72% yield with g95:5 selectivity.
The stereochemistry of this intermediate was assigned by
using our NMR method.33 Finally, treatment of 16 with
TAS-F in wet DMF provided formamicinone 2 in 80%
yield.34
Formamicinone has not been described in the literature.
Our assignment of synthetic 2 as the aglycon of the natural
product follows from the known stereochemistry of fragments
1
517 and 620 and is strongly supported by comparison of H
and 13C NMR data for 2 with those of natural formamicin
(see Supporting Information). The only significant difference
between the two sets of data are for the 13C resonances for
C(20) and C(21), the site that is glycosylated in the natural
product.
The final stages of the synthesis of formamicinone (2)
commenced with the modified28 Suzuki coupling29 of 5 and
6, which provided 14 in 85% yield (Scheme 3). Deprotection
of the methyl ester was performed by treatment of 14 with
KOSiMe3 in THF.30 Application of the Yamaguchi macro-
lactonization protocol transformed the seco acid to macro-
lactone 15 in 62% yield from 14.31 Selective deprotection
of the C(19)-TES ether proceeded smoothly upon treatment
of 14 with TFA in wet THF. The C(19)-alcohol was then
oxidized by using the Dess-Martin periodinane,32 thereby
providing methyl ketone 4.
Efforts to complete a total synthesis of formamicin are in
progress35 and will be reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health (GM 38436), an Abbott
Graduate Fellowship to B.M.S., and a Lavoisier Fellowship
to N.B. from the Ministe`re Franc¸ais des Affaires Etrange`res
is gratefully acknowledged.
Supporting Information Available: Procedures and
tabulated spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The latter intermediate was converted to the silyl enol ether
(LiHDMS, TMS-Cl, Et3N, THF, -78 °C), which was then
OL027569K
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J., III. J. Org. Chem. 2002, 67, 4284.
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