Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol

Article abstract of DOI:10.1021/jacs.6b01731

Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (-)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control.

Full text of DOI:10.1021/jacs.6b01731

Communication
pubs.acs.org/JACS
Total Synthesis of (−)-Mandelalide A Exploiting Anion Relay
Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling
Protocol
Minh H. Nguyen, Masashi Imanishi, Taichi Kurogi, and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
synthetic material against a small panel of cancer cell lines by
several investigators yielded contradictory cell toxicity data,8
ABSTRACT: Anion relay chemistry (ARC), an effective,
multicomponent union tactic, was successfully employed
for the total synthesis of the highly cytotoxic marine
macrolide (−)-mandelalide A (1). The northern hemi-
sphere was constructed via a new type II ARC/CuCN
cross-coupling tactic, while the southern hemisphere was
secured via a highly efficient four-component type I ARC
union. Importantly, the synthesis of 1 showcases ARC as a
rapid, scalable coupling strategy for the union of simple
readily available building blocks to access diverse complex
molecular fragments with excellent stereochemical control.
pressing the demand for a modular preparative synthesis of
(−)-1 for detailed evaluation and future analog development.
Anion relay chemistry (ARC), an effective, multicomponent
union protocol, introduced and developed in our laboratory for
the rapid elaboration of structurally complex scaffolds in a
“single-flask” entails the ability to control the migration of
negative charge.9 Over the past decade, we have reported
extensive studies in the area of through-space ARC employing
Brook rearrangements, which led to the evolution of types I and
II ARC union tactics (Scheme 1).10 The potential of each of the
Scheme 1. Through-Space Types I and II ARC Tactics
he mandelalides constitute a family of unusual, variously
Tglycosylated polyketide macrolides isolated by McPhail et
al.1 via bioassay guided fractionation of the cytotoxic extracts of a
rare species of Lissoclinum ascidian collected from Algoa Bay,
South Africa. Among this family, (−)-mandelalide A (1, Figure
1) was reported to exhibit the most potent biological activity,
ARC tactics has been demonstrated separately in a number of
completed or ongoing synthetic ventures, including those on
(+)-spongistatin 1 and 2,11 (+)-spirastrellolide A and B,12
(−)-secu’amamine A,13 and most recently (−)-enigmazole A.14
Herein, we illustrate the strategic value of both types I and II ARC
union tactics with a total synthesis of (−)-mandelalide A (1). In
addition we demonstrate for the first time the combination of
through-space negative charge migration, followed by a new
CuCN-mediated cross-coupling of significant value for complex
molecule synthesis.
Figure 1. Structure of (−)-mandelalide A (1) and originally assigned
structure (1a).
From the retrosynthetic perspective (Scheme 2), we
envisioned the macrocyclic aglycon of (−)-mandelalide A (1)
to arise from advanced fragments 2 and 3, which in turn would be
united via a Yamaguchi esterification, followed by a ring-closing
Heck reaction. Glycosylation with the known 2-O-methyl-α-L-
rhamnose-based fragment (+)-43 would then yield the natural
product 1. The tetrahydrofuran and tetrahydropyran structural
motifs embedded in the northern and southern hemispheres in
with nanomolar cytotoxicities against both human NCI-H460
lung cancer cells (IC50, 12 nM) and mouse Neuro-2A
neuroblastoma cells (IC50, 29 nM), thus rendering (−)-man-
delalide A (1) and analogs attractive as lead structures for cancer
chemotherapeutics. The inaccessibility of the source organism2
however precludes ready biological investigation.
Notsurprisingly, this architecturally interesting family of
natural products has become of considerable interest to the
synthetic community, leading recently to the revision via
synthesis3,4b of the stereochemical configuration of (−)-man-
delalide A (Figure 1).3−7 Interestingly, initial evaluations of the
Received: February 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b01731
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Journal of the American Chemical Society
Communication
Scheme 2. Retrosynthetic Analysis of (−)-Mandelalide A
turn would be constructed from advanced intermediates 5 and 6,
respectively.
2,5-cis-dihydrofuran 19 in a stereocontrolled fashion, possessing
the requisite hydroxyl group at C21. A series of catalytic systems
employing various metals (e.g., osmium,17 ruthenium18 and
chromium19) known to facilitate oxidative cyclization of vicinal
diols adjacent to alkenes to generate cis-tetrahydrofurans was
screened. All attempts toward this end however proved
unsuccessful, leading either to very sluggish reactions or to
decomposition. We reason that the major reason for this
difficulty could be attributed to the inherent planar conformation
of the conjugated diene system which inhibits formation of the
requisite transition state 18.
Anion Relay Chemistry (ARC) was envisioned to provide
access to both 5 and 6 with great stereochemical flexibility for
future analog development, employing commercially available
and/or readily prepared intermediates or building blocks 7−13
(Scheme 2).15 Importantly, the proposed construction of
advanced intermediate 5 would showcase a novel type II ARC
tactic featuring the migration of negative charge to a sp2-
hybridized carbon center capable of undergoing cross-coupling
with an electrophilic partner.16
The synthesis of (−)-mandelalide A (1) began with the
construction of the northern hemisphere (2; Scheme 3). Toward
Gratifyingly, a solution to this problem could be achieved
exploiting the flexibility of the ARC tactic (Scheme 5).
Scheme 3. Type II ARC/Pd Cross-Coupling
Scheme 5. Revision of the ARC Tactic and Construction of the
Northern Hemisphere
this end, nucleophilic attack of the vinyl epoxide linchpin (−)-815
with 2-lithio-1,3-dithiane (7), followed by a CuI-triggered Brook
rearrangement to what we envisioned to be a sp2-hybridized
carbon nucleophile 15, then readily underwent Pd-catalyzed
cross-coupling reaction with vinyl iodide (+)-9 to furnish
advanced intermediate 5 in a “single flask” in excellent yield
(81%).
Adduct 5 in turn was subjected to the reaction sequence of
alcohol deprotection, dithiane removal, and carbonyl reduction
to furnish diol (+)-16 (Scheme 4), setting the stage to explore
the key strategic construction of the required tetrahydrofuran
ring. Here we envisioned the 1,3-diol to chelate to a metal catalyst
to facilitate a selective, syn-specific oxidative cyclization on the
disubstituted alkene of the conjugated diene system to generate
Application of the type II ARC/cross-coupling strategy employ-
ing 1,3-dithiane, vinyl iodide (+)-9 with the redesigned vinyl
epoxide linchpin (−)-20,15,20 now possessing a terminal olefin,
furnished tricomponent adduct (+)-23 in excellent yield (89%)
on a gram scale. Dithiane removal revealed 1,3-diol (+)-24, now
possessing a skipped diene system which underwent an efficient,
albeit slow,21 stereocontrolled osmium-catalyzed oxidative
cyclization17 to provide the desired advanced intermediate
[(−)-25] in good yield with excellent stereoselectivity (88%
brsm, >15:1 dr). The great advantage of ARC to readily
customize coupling partners [e.g., (−)-8 and (−)-20] with
programmable, preloaded functionality and stereochemistry to
access a wide variety of scaffolds was thus demonstrated.
Particularly important, we identified during this study a copper
cyanide-mediated cross-coupling reaction between vinyl iodide
Scheme 4. Planar Conformation Inhibits Oxidative
Cyclization
B
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Communication
(+)-9 and allyl silane 21, activated via what we presume to be a
pentavalent silicon-ate (22) derive from an adjacent alkoxide
group.22 Interestingly, attempts to use palladium catalysis to carry
out the same ARC/cross-coupling protocol failed to provide the
desired adduct in more than 5% yield, demonstrating the unique
utility of this CuCN-mediated reaction in a multicomponent union
protocol (i.e., ARC). A preliminary study on the substrate scope of
this ARC/CuCN cross-coupling strategy is outlined in Scheme 6.
four-component adduct could be generated in a single flask in 87%
yield on half-gram scale, with an average yield for each of the three
carbon−carbon bond-forming steps over 95%. Mesylation of the
free hydroxyl group (Scheme 8) then set the stage for ring
Scheme 8. Construction of the Southern Hemisphere
Scheme 6. Multicomponent Union Featuring a Type II ARC/
CuCN Cross-Coupling Protocol
formation upon TBS group removal, to yield tetrahydropyran
(−)-32. Removal of dithiane, followed by reduction with NaBH4
next led with high stereocontrol to alcohol (+)-33 in 82% yield.
Further protecting group manipulations and cross-metathesis
with methyl acrylate furnished advanced intermediate (+)-34 in
76% yield for the three steps. Alcohol (+)-34 was then subjected
to Dess-Martin periodinane oxidation, Julia-Kocienski olefina-
tion with known sulfone 35,26 and ester saponification to
complete the construction of the southern hemisphere (−)-3 in
84% yield for the three steps.
Also of significance in the construction of (−)-25 is the
transition-metal-mediated oxidative cyclization of an allylic 1,3-
diol, known to be a difficult substrate, due both to the
unfavorable chelate ring size and to a variety of possible side
reactions (e.g., allylic alcohol oxidation, racemization of allylic
alcohol, and product instability).
Having the northern and southern fragments (−)-2 and (−)-3
in hand, final elaboration to (−)-mandelalide A (1) is outlined in
Scheme 9. To this end, (−)-2 and (−)-3 were smoothly united
Advanced intermediate (−)-25 (Scheme 5) was next subjected
to bis-hydroxy protection (TBSCl), followed by hydrogenation
with Wilkinson catalyst to install the desired stereocenter at C18.
Selective desilylation of primary alcohol, Dess-Martin period-
inane oxidation, and Stork-Zhao olefination23 then provided
advanced intermediate (−)-27 in 74% yield. Further protecting
group manipulations (two steps) completed the construction of
the mandelalide A northern hemisphere (−)-2.
Scheme 9. Fragments Union
We next turned attention to the construction of the
mandelalide A southern hemisphere aglycon (3), which as
outlined earlier would rely on a type I ARC tactic24 (Scheme 7).
Scheme 7. Four-Component Type I ARC
via Yamaguchi esterification, to furnish (−)-36 in 85% yield,
without isomerization of the enoate double bond, an issue
previously observed both by Furstner4 and Altmann.6 Removal
of PMB protecting group, followed by Kahne glycosylation27
with sulfoxide (+)-43 then furnished (−)-37 in 83% yield.
Macrocyclization employing Heck reaction28 on (−)-37 then
proceeded with remarkable ease. Global desilylation with HF/
pyridine completed the synthesis of (−)-mandelalide A (1),
which displayed spectral properties identical in all respects to
those reported for the natural product.15
Nucleophilic attack of known epoxide (+)-1115,25 with 2-lithio-2-
TBS-1,3-dithiane (10), followed by a solvent-triggered Brook
rearrangement generated what we envision to be a carbon
nucleophile at the 2-position of the dithiane (29). In the same
flask, (S)-epichlorohydrin was added as the second electrophile,
to generate chlorohydrin anion 30, which in turn formed a new
electrophilic terminal epoxide upon warming the reaction
mixture to room temperature. Addition of vinylmagnesium
bromide and copper iodide completed the construction of the
requisite advanced homoallylic alcohol (−)-6. Pleasingly, this
In summary, a highly convergent, modular synthesis of
(−)-mandelalide A (1) has been achieved exploiting ARC. The
C
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Communication
product, has recently confirmed synthetic 1 as a fully efficacious
cytotoxin against H460 lung cancer cells (ref 7).
(9) For reviews, see: (a) Smith, A. B., III; Adams, C. M. Acc. Chem. Res.
2004, 37, 365. (b) Smith, A. B., III; Wuest, W. M. Chem. Commun. 2008,
5883.
central features of this synthetic venture entailed the develop-
ment of a novel three-component type II ARC/CuCN cross-
coupling protocol and a four-component type I ARC union, both
performed on preparative scale employing commercially
available and/or readily accessible building blocks. The
advantages of the ARC tactic are evident in the short synthetic
sequences29 and the excellent stereochemical control, holding
the promise for all possible stereogenicities in the macrocyclic
aglycon of mandelalide A (1). Also of significance, we have
identified an effective new CuCN-mediated cross-coupling
reaction of allyl silanes with vinyl and aryl iodides that is
compatible with the ARC multicomponent union protocol.
Application of the strategies presented here for the synthesis of
other members of mandelalide family and analogs thereof
continues in our laboratory.
(10) (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119,
6925. (b) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;
Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.
(c) Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc.
2006, 128, 12368. (d) Smith, A. B., III; Xian, M. J. Am. Chem. Soc. 2006,
128, 66.
(11) (a) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar,
M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.;
Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191. (b) Smith, A. B., III;
Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.; Brook,
C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int. Ed. 2001, 40, 196.
(12) Smith, A. B., III; Smits, H.; Kim, D.-S. Tetrahedron 2010, 66, 6597.
(13) Han, H.; Smith, A. B., III. Org. Lett. 2015, 17, 4232.
(14) Ai, Y.; Kozytska, M. V.; Zou, Y.; Khartulyari, A. S.; Smith, A. B., III.
J. Am. Chem. Soc. 2015, 137, 15426.
ASSOCIATED CONTENT
■
S
* Supporting Information
(15) See Supporting Information.
(16) For precedent to the ARC/Pd cross-coupling tactic, see: Smith, A.
B., III; Kim, W.-S.; Tong, R. Org. Lett. 2010, 12, 588.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b01731.
Experimental details and data (PDF)
(17) (a) Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed. 2005,
44, 4766. (b) Donohoe, T. J.; Wheelhouse, K. M. P.; Lindsay-Scott, P. J.;
Churchill, G. H.; Connolly, M. J.; Butterworth, S.; Glossop, P. A. Chem. -
Asian J. 2009, 4, 1237. (c) Pilgrim, B. S.; Donohoe, T. J. J. Org. Chem.
2013, 78, 2149 and refs cited therein.
(18) Cheng, H.; Stark, C. B. W. Angew. Chem., Int. Ed. 2010, 49, 1587.
(19) Walba, D. M.; Stoudt, G. S. Tetrahedron Lett. 1982, 23, 727.
(20) The chiral epoxide was accessed via Jacobsen HKR from the
racemic epoxide, which is a known compound, see: Hojo, M.; Ishibashi,
N.; Ohsumi, K.; Miura, K.; Hosomi, A. J. Organomet. Chem. 1994, 473,
C1.
AUTHOR INFORMATION
■
Corresponding Author
*smithab@sas.upenn.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(21) Reaction was performed on 800 mg scale at room temperature in
approximately 2 weeks.
Financial support was provided by the NIH through Grant CA-
19033 and in part by GM-29028. T.K. thanks JSPS for a
Fellowship for Young Japanese Scientist. We also thank Drs.
George Furst and Jun Gu and Dr. Rakesh K. Kohli for assistance
obtaining NMR and high-resolution mass spectra, respectively.
(22) To the best of our knowledge, there have been no reports of
transition-metal-mediated cross-coupling reactions between allyl silanes
and vinyl halides. The closest example is a Pd-catalyzed cross-coupling
between allyl silane and styryl bromide in 28% yield, see: Hatanaka, Y.;
Hiyama, T. J. Org. Chem. 1988, 53, 918.
(23) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b) Li, P.;
Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org.
Chem. 2010, 75, 2429.
(24) Melillo, B.; Smith, A. B., III. Org. Lett. 2013, 15, 2282.
(25) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem.
Soc. 1990, 112, 5276.
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(28) (a) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse,
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̈
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D
DOI: 10.1021/jacs.6b01731
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX