Total Synthesis of Archazolid F

Article abstract of DOI:10.1021/acs.orglett.8b03715

A partial bioinspired as well as the total synthesis of archazolid F, a highly potent V-ATPase inhibitory, antiproliferative polyketide macrolide, is described. Key features of the synthetic routes include a highly stereoselective aldol condensation of tw

Full text of DOI:10.1021/acs.orglett.8b03715

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Archazolid F
Stephan Scheeff and Dirk Menche*
́
Kekule-Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A partial bioinspired as well as the total synthesis
of archazolid F, a highly potent V-ATPase inhibitory,
antiproliferative polyketide macrolide, is described. Key features
of the synthetic routes include a highly stereoselective aldol
condensation of two elaborate fragments and macrocyclizations
either by a Shiina macrolactonization or by a challenging RCM
reaction of an octaene substrate. The syntheses unequivocally
confirm the full architecture of this very scarce archazolid.
EPR studies in combination with limited SAR data and a
modeling study.2,3 More recently, archazolid V-ATPase
inhibition has emerged as a novel strategy in anticancer
therapy.4 The archazolids abrogate tumor metastasis,5a lead to
impaired cathepsin B activation,5b modulate anoikis resistan-
ce,5c overcome trastuzumab resistance of breast cancers,5d
augment cancer therapy by blocking iron metabolism,5e and
sensitize tumors in the context of the MDM2 antagonist
nutlin-3a.5f However, their further advancement is severely
hampered by their low natural supply, rendering total synthesis
of high importance to resolve the supply issue and enable
further SAR exploration. Thus far, one total synthesis of
archazolid A6a and two syntheses of archazolid B6b,c as well as
several fragment syntheses of 2,3-dihydroarchazolid B6d,e have
been reported.6f In all previous total syntheses of archazolids,
the ring closure of the macrocycle was critical. In the total
synthesis of archazolid A (1) in our group, the macrocyle was
closed by a somewhat unreliable HWE reaction along the C2−
C3 bond.6a In alternative strategies for total syntheses of
archazolid B (2), a very innovative but only moderately
yielding relay-RCM reaction along the C20−C21 was
accomplished by the Trauner group,6b while an alternative
Heck macrocyclization along the C19−C20 bond gave a
mixture of isomers in our approach.6c Despite these impressive
advances, the development of an alternative strategy remains
an important research goal, particularly with respect to a more
efficient macrocyclization and direct applicability to useful
analogue synthesis.
he myxobacterial polyketide macrolides archazolids A (1)
Tand B (2, Figure 1) demonstrate extremely potent
antiproliferative activities based on selective inhibition of
functional subunit c vacuolar-type ATPases (V-ATPases).1,2
On a molecular level, this selective noncovalent interaction is
increasingly well understood by cross-linking, mutagenesis, and
More recently, archazolid F (3), has been discovered as an
extremely scarce but more potent natural derivative that bears
a 3,4- instead of the 2,3-olefin substructure present in
archazolid B (Figure 1).7
Figure 1. Archazolids, an emerging class of potent V-ATPase
inhibitory anticancer drugs: retrosynthesis of archazolid F.
Received: November 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03715
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
Herein, we report the first total synthesis of archazolid F (3)
that unequivocally confirms the full 3D architecture of this
most potent and least abundant archazolid based on a novel,
improved strategy that will be directly applicable for useful
analog synthesis.
Scheme 1. Synthesis of Archazolid F by a Shiina
Macrolactonization of a Protective Group Free Precursor
(8)
On the basis of existing SAR data available so far in
combination with the in silico model for the target−inhibitor
interactions,3a−c it was rationalized that the C4−C18 part
would be critical for target interaction, while more flexibility
was suggested for the southern region. Consequently, our
synthetic strategy was based on a separate formation of this
northern pharmacophore 6 and its connection to the southern
building block 7 (Figure 1). For fragment union, an
adventurous stereoselective propionate aldol condensation
was envisioned that would also enable a direct modulation of
the hydroxylation and oxidation pattern in the northwestern
region.3a Given the existing limitations of the reported
archazolid macrocyclization, two alternative strategies were
planned, either by a more conventional macrolactonization
involving a compound of type 4 or a more challenging RCM
reaction of an octane substrate (5).
In order to evaluate the first macrocyclization strategy, we
turned our attention to a bioinspired partial synthesis of
archazolid F. In contrast to common polyketide biosynthesis,
the olefins in the northern and eastern part of the archazolids
are not situated between the acetate building blocks but within
these units,1a suggesting an isomerization during biosynthesis.
This is further corroborated by the co-occurrence of isomers B
(2) and F (3), which may suggest that an isomerization may
occur during the biosynthesis of archazolid F. Inspired by this
observation, in combination with a related double-bond shift
previously observed in our group,8 we turned our attention to a
direct conversion of archazolid B to F. Consequently, as shown
in Scheme 1, we first opened archazolid B (2) to ring-opened
seco-acid 8. Gratifyingly, a complete double-bond migration
was observed by use of LiOH (Scheme 1), thus confirming our
bioinspired design. After some experimentation, the desired
macrolactonization could also be accomplished under Shiina
conditions, giving archazolid F in a direct process and without
a need to protect the two additional hydroxyl groups.
However, the obtained yields remained low (17%). In contrast,
a direct esterification to 9 with TMSCHN2 (81%) proceeded
in good yields.
derived aldehyde 19 (96%, two steps) set the required (Z,Z,E)-
triene moiety with high stereocontrol and again with excellent
degrees of conversion. The corresponding aldehyde 20 was
then homologated by an Ipc-boron aldol reaction11 giving syn-
aldol product 21 in a reliable fashion which was protected as a
TBS ether to give the desired northern fragment (6). This
route proved reliable, rapid, and well scalable, enabling a
multigram access in 27% overall yield.
In contrast to previous routes,6 a shorter and more concise
entry into the southern fragment 7 was realized. As shown in
Scheme 3, this was based on a Grignard addition of
commercial thiazole 22 to isovaleraldehyde.12 After conversion
of the resulting alcohol 23 into the dicarbonyl derivative 24, a
selective Brown crotylation6a−c of the aldehyde functionality
set the required two vicinal stereogenic centers. After
protection of the derived hydroxyl group, ketone 25 was
reduced stereoselectively with the CBS reagent, and the
resulting alcohol was protected as an acetate (26). Finally, an
efficient cross-metathesis with acrolein completed the synthesis
of southern building block 7.
Therefore, we turned our attention to an apparently more
challenging RCM approach.9 As shown in Scheme 2, synthesis
of the required northern fragment 6 was based on reliable aldol
methodology and olefination reactions, previously established
for related systems in our group.6a,c
An initial Wittig reaction of commercial aldehyde 10 gave
diene 11,10 and the corresponding highly volatile aldehyde 12,
obtained by DIBALH reduction of the ester and allylic
oxidation (MnO2), was elongated by a boron mediated anti-
aldol reaction with lactate derived ethyl ketone to give the
aldol product 13 with excellent selectivity following a
procedure originally reported by Paterson.6a,c,11 After protec-
tion as a TBS ether (14) and removal of the chiral auxiliary
involving LiBH4 reduction and periodate cleavage, the derived
aldehyde 15 was homologated by a Still−Gennari olefination
with 16 to give ester 17 in high yield and selectivity (90%, dr >
20:1). In an analogous fashion, aldehyde 18, readily obtained
by DIBALH reduction and allylic oxidation, was homologated
with 16 installing the (Z,Z)-diene 19, likewise in excellent yield
and selectivity (98%, dr > 20:1). Finally, an HWE reaction of
While only a few stereoselective propionate aldol con-
densations have been reported in complex target synthesi-
s,13a−e this limited precedence with less elaborate substrates
suggested that a base-mediated elimination may lead
preferentially to the required E-isomer, independent of the
initial relative configuration.13 As shown in Scheme 4 judicious
choice of the base for the initial coupling were critical for
useful degrees of conversion. Finally, good yields were
obtained with uncommon Ph2NLi,14 while more conventional
bases (LiHMDS or LDA) led to side reactions or lower
conversion on a representative test system. Inspired by a
B
DOI: 10.1021/acs.orglett.8b03715
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
Scheme 2. Synthesis of Northern Fragment 6
Scheme 4. Completion of the Total Synthesis of Archazolid
F
Scheme 3. Concise Synthesis of the Southern Fragment 7
for the pivotal RCM reaction. Notably, this polyene containing
eight olefinic double bonds presents a highly challenging
substrate for this key RCM reaction,6b,9,15 due to molecular
reversibility of the process enabling several competitive side
reactions including ring contraction15a,b,e or formation of
undesired isomers.15b After considerable experimentation with
suitable test systems, it was found that the cyclization could
indeed be realized with very unusual catalyst 3016 to give the
macrocyclic core in useful yields (49%) that compare favorably
to the results of reported procedures.6 Lower degrees of
selectivity and conversion were obtained with all other catalysts
studied (i.e., Grubbs II, nitro-Grela catalyst). Finally,
completion of the total synthesis of archazolid F was achieved
by global deprotection using HF/pyr. The analytical data of
synthetic archazolid F, obtained either by semi- or total
synthesis, were identical and in agreement with the data of an
authentic sample,7,17 thus confirming its full architecture.
In summary, we have reported a bioinspired partial synthesis
and the total synthesis of archazolid F (3). These syntheses
unequivocally confirm the full architecture of this most potent
and least abundant archazolid. The partial synthesis pursued a
bioinspired approach. It involved a remarkable double-bond
isomerization, which should be further analyzed and may be
effectively utilized in other ventures. The total synthesis, in
turn, was inspired by a pharmacophore analysis and relies on
two main fragments, a northern and a southern building block.
Key features include a scalable synthesis of the northern region
involving reliable olefination and aldol methodology and an
improved preparation of the southern fragment as well as the
methyl ketone aldol condensation,6a an acetate derivative was
then submitted to the elimination. Gratifyingly, after careful
balancing of the terminal protective group, this conversion
proceeded with excellent stereoselectivity to give the desired
(E)-isomer exclusively, independent of the initial configuration,
in a stereoconvergent manner. Following this procedure,
desired enone 27 was obtained with complete diastereose-
lectivity. This enone was then reduced stereoselectively with
NaBH4 (dr 7:1),6b and methylation of the alcohol set the
required C15−C17 region 28 in good yields. After acetate
saponification and carbamate installment, the butenoic acid 29
was attached after TES cleavage to access key intermediate 5
C
DOI: 10.1021/acs.orglett.8b03715
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
́
́
(4) (a) Perez-Sayans, M.; Somoza-Martín, J. M.; Barros-Angueira, F.;
Rey, J. M.; García-García, A. Cancer Treat. Rev. 2009, 35, 707.
(b) Hernandez, A.; Serrano-Bueno, G.; Perez-Castineira, J. R.;
Serrano, A. Curr. Pharm. Des. 2012, 18, 1383. (c) Cotter, K.;
Capecci, J.; Sennoune, S.; Huss, M.; Maier, M.; Martinez-Zaguilan, R.;
Forgac, M. J. Biol. Chem. 2015, 290, 3680. (d) von Schwarzenberg, K.;
Wiedmann, R. M.; Oak, P.; Schulz, S.; Zischka, H.; Wanner, G.;
Efferth, T.; Trauner, D.; Vollmar, A. M. J. Biol. Chem. 2013, 288,
1385.
connection of these elaborate fragments by an adventurous
highly stereoselective propionate aldol condensation. Finally,
macrocyclization was accomplished by an RCM reaction of a
challenging octaene precursor. Best results were obtained with
a very uncommon and underutilized catalyst (30), which may
find further applications in complex target synthesis. These
results demonstrate that RCM approaches may be effectively
used also for cyclizations of very elaborate polyenes. In
addition, the reported protocol for stereoselective propionate
aldol condensation may find further applications for con-
nection of complex fragments. This synthesis enhances the
supply of archazolid F for further biological evaluation. Finally,
the novel synthetic strategy will be directly applicable for useful
and simplified analogues by enabling a facile replacement of
the biologically presumably less important southern fragment
with retention of the northern, synthetically easily available
pharmacophore.
(5) (a) Wiedmann, R. M.; von Schwarzenberg, K.; Palamidessi, A.;
Schreiner, L.; Kubisch, R.; Liebl, J.; Schempp, C.; Trauner, D.; Vereb,
G.; Zahler, S.; Wagner, E.; Muller, R.; Scita, G.; Vollmar, A. M. Cancer
̈
̈
Res. 2012, 72, 5976. (b) Kubisch, R.; Frohlich, T.; Arnold, G. J.;
Schreiner, L.; von Schwarzenberg, K.; Roidl, A.; Vollmar, A. M.;
Wagner, E. Int. J. Cancer 2014, 134, 2478. (c) Schempp, C. M.; von
Schwarzenberg, K.; Schreiner, L.; Kubisch, R.; Mu
Vollmar, A. M. Mol. Cancer Ther. 2014, 13, 926. (d) von
Schwarzenberg, K.; Lajtos, T.; Simon, L.; Muller, R.; Vereb, G.;
Vollmar, A. M. Mol. Oncol. 2014, 8, 9. (e) Schneider, L. S.; von
Schwarzenberg, K.; Lehr, T.; Ulrich, M.; Kubisch-Dohmen, R.; Liebl,
J.; Trauner, D.; Menche, D.; Vollmar, A. M. Cancer Res. 2015, 75,
̈
ller, R.; Wagner, E.;
̈
ASSOCIATED CONTENT
* Supporting Information
■
2863. (f) Schneider, L. S.; Ulrich, M.; Lehr, T.; Menche, D.; Mu
R.; von Schwarzenberg, K. Mol. Oncol. 2016, 10, 1054.
̈
ller,
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03715.
(6) (a) Menche, D.; Hassfeld, J.; Li, J.; Rudolph, S. J. Am. Chem. Soc.
2007, 129, 6100. (b) Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am.
Chem. Soc. 2007, 129, 8960. (c) Menche, D.; Hassfeld, J.; Li, J.;
Mayer, K.; Rudolph, S. J. Org. Chem. 2009, 74, 7220. (d) O’Neil, G.;
Craig, A.; Williams, J.; Young, J.; Spiegel, P. Synlett 2017, 28, 1101.
(e) King, B.; Swick, S.; Schaefer, S.; Welch, J.; Hunter, E.; O’Neil, G.
Synthesis 2014, 46, 2927. For a review, see: (f) Scheeff, S.; Menche,
D.; Beilstein, J. Beilstein J. Org. Chem. 2017, 13, 1085.
Detailed experimental procedures, characterization, and
1
copies of H and 13C NMR spectra of new compounds
(PDF)
(7) Horstmann, N.; Essig, S.; Bockelmann, S.; Wieczorek, H.; Huss,
M.; Sasse, F.; Menche, D. J. Nat. Prod. 2011, 74, 1100.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dirk.menche@uni-bonn.de.
ORCID
̀
(8) Hassfeld, J.; Fares, C.; Steinmetz, H.; Carlomagno, T.; Menche,
D. Org. Lett. 2006, 8, 4751.
(9) While previous archazolid RCM approaches across the C13−
C146e or the C20-C21 bond had failed or required a relay approach,6b
it was anticipated that a coupling along the only remaining
disubstituted C3−C4 olefin may be possible.
(10) Yildizhan, S.; Schulz, S. Synlett 2011, 2011, 2831.
(11) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
Dirk Menche: 0000-0002-4724-8383
Notes
The authors declare no competing financial interest.
(12) Pop, L.; Lassalas, P.; Bencze, L. C.; Tosa
Irimie, F. D.; Hoarau, C. Tetrahedron: Asymmetry 2012, 23, 474.
̧ , M. I.; Nagy, B.;
ACKNOWLEDGMENTS
■
́
(13) (a) Dinh, M.-T.; Bouzbouz, S.; Peglion, J.-L.; Cossy, J.
Financial support by the DFG (FOR 1406) is gratefully
acknowledged. We thank Andreas J. Schneider (University of
Bonn) for technical assistance and Simon Dedenbach
Tetrahedron 2008, 64, 5703. (b) Doundoulakis, T.; Xiang, A. X.; Lira,
R.; Agrios, K. A.; Webber, S. E.; Sisson, W.; Aust, R. M.; Shah, A. M.;
Showalter, R. E.; Appleman, J. R.; et al. Bioorg. Med. Chem. Lett. 2004,
14, 5667. (c) Hatakeyama, S.; Sakurai, K.; Numata, H.; Ochi, N.;
Takano, S. J. Am. Chem. Soc. 1988, 110, 5201. (d) Kuilya, T. K.;
Goswami, R. K. Org. Lett. 2017, 19, 2366. (e) Vedejs, E.; Buchanan,
R. A.; Conrad, P. C.; Meier, G. P.; Mullins, M. J.; Schaffhausen, J. G.;
Schwartz, C. E. J. Am. Chem. Soc. 1989, 111, 8421. (f) Lister, T.;
Perkins, M. V. Org. Lett. 2006, 8, 1827.
̀
(University of Bonn) and Solenne Riviere (University of
Bonn) for exploratory studies toward related thiazole frag-
ments. Finally, we thank our cooperation partners within the
CRC-TR initiative 261.
REFERENCES
■
(14) Osborne, N. F.; Atkins, R. J.; Broom, N. J. P.; Coulton, S.;
̈
(1) (a) Sasse, F.; Steinmetz, H.; Hofle, G.; Reichenbach, H. J.
Harbridge, J. B.; Harris, M. A.; Stirling-Franco
Chem. Soc., Perkin Trans. 1 1994, 102, 179.
(15) (a) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525.
(b) Gallenkamp, D.; Furstner, A. J. Am. Chem. Soc. 2011, 133, 9232.
(c) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z. Org. Lett.
2006, 8, 1193. (d) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde,
D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I. Angew. Chem., Int. Ed.
2000, 39, 1664. (e) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell,
M. D.; Chou, T.-C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9825.
̧ is, I.; Walker, G. J.
Antibiot. 2003, 56, 520. (b) Huss, M.; Sasse, F.; Kunze, B.; Jansen, R.;
Steinmetz, H.; Ingenhorst, G.; Zeeck, A.; Wieczorek, H. BMC Biochem
2005, 6, 13.
(2) Bockelmann, S.; Menche, D.; Rudolph, S.; Bender, T.; Grond, S.;
von Zezschwitz, P.; Muench, S. P.; Wieczorek, H.; Huss, M. J. Biol.
Chem. 2010, 285, 38304.
(3) (a) Menche, D.; Hassfeld, J.; Sasse, F.; Huss, M.; Wieczorek, H.
Bioorg. Med. Chem. Lett. 2007, 17, 1732. (b) Persch, E.; Basile, T.;
Bockelmann, S.; Huss, M.; Wieczorek, H.; Carlomagno, T.; Menche,
D. Bioorg. Med. Chem. Lett. 2012, 22, 7735. (c) Dreisigacker, S.; Latek,
D.; Bockelmann, S.; Huss, M.; Wieczorek, H.; Filipek, S.; Gohlke, H.;
Menche, D.; Carlomagno, T. J. Chem. Inf. Model. 2012, 52, 2265.
̈
(16) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R.
H.; Schrodi, Y. Org. Lett. 2007, 9, 1589.
(17) In some cases, the 13C NMR assignment had to be corrected
(see the SI). A full spectral data set in two different solvents is
provided.
̈
(d) Golz, J. P.; Bockelmann, S.; Mayer, K.; Steinhoff, H.-J.;
Wieczorek, H.; Huss, M.; Klare, J. P.; Menche, D. ChemMedChem
2016, 11, 420.
D
DOI: 10.1021/acs.orglett.8b03715
Org. Lett. XXXX, XXX, XXX−XXX