Total synthesis of (-)-archazolid B

Article abstract of DOI:10.1021/ja0733033

A highly convergent synthesis of archazolid B, a potent and highly selective V-ATPase inhibitor, is described. A relay ring-closing metathesis reaction was used to form the 24-membered macrocyclic lactone, whereas the sensitive cis-triene moiety of the ar

Full text of DOI:10.1021/ja0733033

Published on Web 06/27/2007
Total Synthesis of (-)-Archazolid B
Paul A. Roethle, Ingrid T. Chen, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, Berkeley, California 94720-1460
Received May 9, 2007; E-mail: trauner@cchem.berkeley.edu
Scheme 1. Retrosynthetic Analysis of the Archazolids.
The archazolids are a family of unsaturated polyketides with low
nanomolar inhibitory activity and excellent selectivity against
mammalian V-ATPases (Scheme 1).1 The isolation of archazolids
A (1) and B (2) from the myxobacterium Archangium gephyra and
the constitutions of these natural products were reported by Ho¨fle
et al. several years ago.2 In 2006, Menche and co-workers disclosed
the relative and absolute configurations of 1 and 2, which were
obtained through careful analysis of 13C-1H coupling constants
combined with degradation studies.1b Shortly thereafter, this impres-
sive exercise in structure elucidation was matched by a total
synthesis of archazolid A.3 The structure of archazolid C (3), the
â-glucoside of archazolid A isolated from the myxobacterium
Cystobacter Violaceus, was also disclosed in 2007.4 We now report
an efficient total synthesis of archazolid B, the least stable and least
abundant member of the family.
The archazolids attracted our interest because of their exceptional
bioactivity and unusual structural features. Their 24-membered
macrolactone ring includes a rare (Z,Z,E)-triene moiety, whose
chemistry we were familiar with from our previous work on highly
unsaturated pyrone polyketides.5 From the outset, our synthetic plan
was governed by a desire to install the (Z,Z,E)-triene unit as late
as possible to avoid potentially troublesome (cyclo)isomerizations.
As our plan for archazolid B unfolded, however, we found it more
appealing to close the 24-membered macrolactone through ring-
closing metathesis (RCM), rather than intramolecular cross-coupling
reactions (Scheme 1).6,7 This strategy would confine protecting
group operations and oxidation state adjustments to a minimum.
We had doubts however, whether a “simple” RCM involving diene
4a (R ) H) would initiate at the more electron-rich diene moiety
rather than at the other terminal alkene, which would presumably
result in an unproductive excision of an unsaturated δ-lactone.
Therefore, we decided to promote the desired initiation through
relay-ring closing metathesis (RRCM) using 4b as a precursor [R
) (CH2)3CHCH2].8 Once the corresponding, relatively stable Ru
vinyl alkylidene would form, it would be expected to react with
the remaining terminal double bond faster than with any of the
more substituted double bonds present.
with inferior yield and stereoselectivity. Compound 12 underwent
a highly selective Trost Alder-ene reaction with 3-butenol to afford
triene 13 in good yield.11 To proceed with high regioselectivity,
this reaction required the presence of a coordinating carbonate (or
MOM) protecting group. Two-step oxidation of allylic alcohol 13
then gave carboxylic acid 6 in nearly quantitative yield.
The southern thiazole building block 7 was elaborated from the
known hydroxyalkyl thiazolecarboxylate 14 (available from leucine
in six steps)12 via carbamoylation, followed by chemoselective
reduction and Brown crotylation13 to efficiently yield multigram
quantities of this fragment.3
Further retrosynthetic disconnection of 4b, as shown in Scheme
1, yielded three building blocks: stannane 5, iodide 6, and thiazole
7, corresponding to the northwestern, northeastern, and southern
regions of archazolid B, respectively. These could be assembled
using the reactions shown in Scheme 2.
Our northeastern building block 6 was prepared from the known
ynone 9, easily available in three steps from (S)-Roche ester (8)
(Scheme 2).9 A highly diastereoselective reduction of 9 with (S)-
alpine borane gave a propargylic alcohol, which was protected as
the triisoproylsilyl ether and selectively desilylated to give primary
alcohol 10. Subsequent oxidation and olefination yielded dibro-
moalkene 11. Installation of a (Z)-vinyl iodide using the method
of Tanino and Miyashita,10 followed by exchange of the secondary
silyl protecting group for a tert-butylcarbonate, furnished compound
12. By comparison, attempted Stork-Zhao olefination proceeded
The synthesis of the remaining northwestern building block 5
started from iododienoate 15, which can be obtained in three steps
from propargyl alcohol.14 Reduction followed by oxidation gave
an aldehyde that underwent an efficient Evans syn-aldol addition
with the boron enolate of benzyl oxazolidinone 16 to afford 17.15
Conversion into the corresponding Weinreb amide followed by silyl
protection of the secondary alcohol and a phosphonate Claisen
reaction gave â-keto phosphonate 18, which underwent a Horner-
Wadsworth-Emmons reaction with enal 19 to afford dienone 20.
A highly diastereoselective reduction with NaBH4 followed by
etherification and iodine-tin exchange gave our building block 5.16
Esterification of 7 with 6 required Ru-catalyzed activation of 6
as the acyl ketene acetal according to Kita,17 since all base-mediated
methods led to the migration of the C2-C3-double bond. Subse-
quent thermal deprotection of the Boc group gave iodide 22, which
9
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10.1021/ja0733033 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Completion of the Synthesisa
Scheme 2. Preparation of the Building Blocksa
a Reagents and conditions: (a) [RuCl2(cymene)]2, ethoxyacetylene; then
7, TsOH (54%); (b) SiO2, 125 °C (66%); (c) 5, Pd(PPh3)4, CuTC, DMF
(32%; 92% based on recovered 6); (d) Grubbs’ II, PhCH3 (27%); (e) 3:6:1
formic acid/THF/H2O (84%).
transition-metal-catalyzed reactions operating on halogenated sub-
strates. The final Ru-catalyzed ring-closing metathesis, by contrast,
underscores the usefulness of relay tactics for the synthesis of highly
unsaturated macrolactones where several potential initiation sites
exist. Further elaboration of our general strategy should give rise
to archazolids A and C as well as a multitude of structurally
simplified and biologically interesting analogues.
Acknowledgment. This work was supported by National
Institutes of Health Grant R01 GM067636. We thank Dr. Steven
Diver (University of Buffalo) for helpful discussions.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a Reagents and conditions: (a) (S)-alpine borane, THF, 40 °C (89%,
>20:1 dr); (b) TIPSCl, imidazole, DMAP, CH2Cl2 (93%); (c) HOAc, THF/
H2O (97%); (d) Dess-Martin periodinane, NaHCO3, CH2Cl2; (e) PPh3,
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underwent a modified Liebeskind coupling with vinyl stannane 5
to yield the acyclic metathesis precursor 4b.18 It is interesting to
note that both palladium and copper were required to promote this
cross-coupling. The relay ring-closing metathesis using Grubbs’
second generation catalyst proceeded as planned to afford the
macrocycle in 27% yield. Finally, careful deprotection of the base-
sensitive macrolactone using aqueous formic acid gave archazolid
B (Scheme 3).
In summary, we have reported a highly convergent and stereo-
selective synthesis of archazolid B, which proceeds in only 19 steps
(longest linear sequence) starting from (S)-Roche ester and in less
than 40 total steps. Our synthesis of archazolid B includes several
transition-metal-catalyzed operations, including three very different
reactions promoted by Ru catalysts. The first two of these
demonstrate how well Ru-catalyzed reactions interface with other
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