Syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C

Article abstract of DOI:10.1021/ol303515h

Divergent syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C have been achieved. The synthesis of the C15-C25 fragment featured cobalt-catalyzed modified Mukaiyama aerobic alkenol cyclization and sulfur-directed regiocontrolled Wacker oxidation of an internal alkene. The C1-C14 fragment was established by alkenyllithium addition to an aldehyde followed by a challenging olefination of a highly inert C9 ketone.

Full text of DOI:10.1021/ol303515h

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1178–1181
Syntheses of the C1ÀC14 and C15ÀC25
Fragments of Amphidinolide C
Dimao Wu and Craig J. Forsyth*
Department of Chemistry and Biochemistry, The Ohio State University, Columbus,
Ohio 43210, United States
forsyth@chemistry.ohio-state.edu
Received December 21, 2012
ABSTRACT
Divergent syntheses of the C1ÀC14 and C15ÀC25 fragments of amphidinolide C have been achieved. The synthesis of the C15ÀC25 fragment
featured cobalt-catalyzed modified Mukaiyama aerobic alkenol cyclization and sulfur-directed regiocontrolled Wacker oxidation of an internal
alkene. The C1ÀC14 fragment was established by alkenyllithium addition to an aldehyde followed by a challenging olefination of a highly inert
C9 ketone.
The amphidinolides represent a large family of marine
natural products with 34 structurally varied members.
They have been isolated from symbiotic dinoflagellates
Amphidinium sp. associated with the Okinawan aceol flat-
worm Amphiscolops sp.1 Among them, the amphidinolide
C subgroup including amphidinolide C (1, from Y-5, Y-56
and Y71 strain), C2 (2, from Y71 strain), C3 (3, from Y56
strain), and F (4, from Y56 strain) share an identical
25-membered macrolide moiety with different aliphatic poly-
ene substructures attached (Figure 1).2 Intriguingly, their
antitumor activities were highly related to the tail polyene
domain, especially the C29 oxidation state. Bearing a free
C29ÀOH, amphidinolide C (1) was the only subgroup
member displaying remarkable in vivo cytotoxicity with
IC50’s below 10 ng/mL. Since the stereochemistry of 1 was
fully elucidated in 2001À2003,3 significant synthetic efforts
have been made toward amphidinolide C and related
macrolides, including a recently reported total synthesis
of amphidinolide F.4 Herein we report synthetic progress
toward 1, focusing on the syntheses of the C1ÀC14 and
C15ÀC25 fragments.
To facilitate the generation of analogues to support
structureÀactivity relationship studies, a late-stage instal-
lation of the C26ÀC34 polyene domain after establishing
the C1ÀC25 macrolide was planned (Figure 1). Retro-
synthetically, the macrolide was disconnected at the C1
(3) (a) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363.
(b) Kubota, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59, 1613.
(4) (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 12, 3865. (b)
Bates, R. H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 9, 4343. (c)
Mahapatra, S.; Carter, R. G. Org. Biomol. Chem. 2009, 7, 4582. (d)
Mahapatra, S.; Carter, R. G. Angew. Chem., Int. Ed. 2012, 51, 7948. (e)
(1) For recent reviews, see: (a) Kobayashi, J.; Ishibashi, M. Chem.
Rev. 1993, 93, 1753. (b) Chakraborty, T. K.; Das, S. Curr. Med. Chem.
2001, 1, 131. (c) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451. (d)
Kobayashi, J. J. Antibiot. 2008, 61, 271.
(2) (a) Amphidinolide, C.; Kobayashi, J.; Ishibashi, M.; Walchli,
M. R.; Nakamura, H.; Hirata, Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem.
Soc. 1988, 110, 490. (b) Amphidinolide C2: Kubota, T.; Sakuma, Y.;
Tsuda, M.; Kobayashi, J. Mar. Drugs 2004, 2, 83. (c) Amphidnolide C3:
Kubota, T.; Suzuki, A.; Yamada, M.; Baba, S.; Kobayashi, J. Hetero-
cycles 2010, 82, 333. (d) Amphidinolide, F.; Kobayashi, J.; Tsuda, M.;
Ishibashi, M.; Shigemori, H.; Yamasu, T.; Hirota, H.; Sasaki, T.
J. Antibiot. 1991, 44, 1259.
ꢀ
ꢁ
Ferrie, L.; Figadere, B. Org. Lett. 2010, 12, 4976. (f) Paudyal, M. P.;
Rath, N. P.; Spilling, C. D. Org. Lett. 2010, 12, 2954. (g) Roy, S.;
Spilling, C. D. Org. Lett. 2010, 12, 5326. (h) Morra, N. A.; Pagenkopf,
B. L. Org. Lett. 2011, 13, 572. (i) Mohapatra, D. K.; Rahaman, H.;
Chorghade, M. S.; Gurjar, M. K. Synlett 2007, 567. (j) Mohapatra,
D. K.; Dasari, P.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50,
6276. (k) Fultz, M. W. Progress Towards the Total Synthesis of
Amphidinolide C. Ph.D. Dissertation, Indiana University, Bloomington,
IN, 2009.
r
10.1021/ol303515h
Published on Web 02/26/2013
2013 American Chemical Society

5 and diene 6, containing trans-tetrahydrofuran moieties,
would be assembled from the corresponding building
blocks (7/8 and 9/10, respectively).
The synthesis began with recognizing that the stereo-
chemistry at C23ÀC24 of 5 could be derived from
the known lactone 11 (Scheme 1). Lactone 11 could be
prepared via either a vinylogous Mukaiyama aldol
process7 or from carbohydrate precursors.8 Lactone 11
was subjected to a DIBALH reduction/Wittig reaction
sequence4b to afford R,β-conjugated ester 12. A variety of
heteroconjugate addition conditions were initially sur-
veyed to close the THF ring via intramolecular alkoxide
additions upon the acrylate moiety. These included the use
of bases KHMDS, NaH, MeONa, t-BuOK, DBU, and
TBAF, among others. However, the diastereoselectivity of
trans- vs cis-THF ring formation was no more than 2:1,
respectively, and the separation of diastereomers was
tedious. In contrast, a Mukaiyama aerobic alkenol cycliza-
tion catalyzed by Hartung’s cobalt complex 139 was
Figure 1. Amphidinolide C subgroup and retrosynthesis.
Figure 2. Sulfur-directed regioselective Wacker oxidation.
Scheme 1. Synthesis of Ester 7
applied to 12 to establish the C20ÀC23 trans-THF moiety
of ester 14 in good yield and excellent diastereoselectivity.
An inherent trans-selectivity in thistype of cobaltcatalyzed
Mukaiyama THF ring formation is well established9 and
has been applied in similar contexts, most notably by
Pagenkopf.4h Although Hartung and co-workers observed
complete suppression of overoxidation side products
in the presence of γ-terpinene at high concentration,9a
an epimeric mixture of R-hydroxyester side products was
unavoidably generated in the reaction mixture here. A few
transformations converted the 1,2-acetonide into PMB
ether 7 (Scheme 1).
We envisioned that the C18 ketone within the challen-
ging 1,4-diketone moiety of amphidinolide C might be
installed via Raghavan’s sulfur-directed regioselective
Wacker oxidation of an internal alkene (Figure 2).10
Presumably, the sulfide moiety would direct palladium to
(7) Rassu, G.; Pinna, L.; Spanu, P.; Zanardi, F.; Battistini, L.;
Casiraghi, G. J. Org. Chem. 1997, 62, 4513.
(8) (a) Lyga, J. W. Org. Prep. Proced. Int. 1992, 24, 73. (b) Brimacombe,
J. S.; Tucker, L. C. N. Carbohydr. Res. 1966, 2, 341.
ester and the C14ÀC15 alkene, with a Yamaguchi macro-
lactonization5 and sulfone alkylation6 envisioned to
accomplish these junctions. A similar strategy was used
in Carter’stotal synthesisofamphidinolide F (4).4d Ketone
€
ꢀ
(9) (a) Schuch, D.; Fries, P.; Donges, M.; Perez, B. M.; Hartung, J.
J. Am. Chem. Soc. 2009, 131, 12918. (b) Inoki, S.; Mukaiyama, T. Chem.
ꢀ
Lett. 1990, 67. (c) Perez, B. M.; Schuch, D.; Hartung, J. Org. Biomol.
Chem. 2008, 6, 3532. (d) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem.,
Int. Ed. 2007, 46, 279.
(10) Raghavan, S.; Krishnaiah, V.; Rathore, K. Tetrahedron Lett.
(5) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(6) Roberts, D. W.; Williams, D. L. Tetrahedron 1987, 43, 1027.
2008, 49, 4999.
Org. Lett., Vol. 15, No. 6, 2013
1179

the proximal terminus of the tethered alkene, while water
would preferably attack the distal carbon, affording the
δ-keto-sulfide regioselectively after reductive elimination.
Raghavan’s Wacker process was reportedly most efficient
with (E)-olefins, so this was targeted first.
longest linear sequence from known lactone 11. Notably,
this involved application of Hartung’s cobalt-mediated
oxacyclization and a sulfur-directed Wacker oxidation.
The synthesis of the C1ÀC9 segment 9 evolved from
Roush’s route which featured acidic butenolide formation
followed by diastereoselective hydrogenation and intra-
molecular oxo-Michael cyclization (Scheme 3).4b Alterna-
tively, we relied upon the known aldehyde 1813 arising
Surprisingly, Julia-type olefination11 employing sulfone
derivatives of 7 were unreliable in providing the C17ÀC18
(E)-alkene. Alternatively, the anion of phosphonium
iodide 16, prepared from 7 via iodide 15, was coupled
with the known aldehyde 812 under standard (Z)-selective
Wittig olefination conditions to give alkene 17 in good
yield (Scheme 2). Thereafter, an optimized procedure for
Raghavan’s Wacker oxidation was applied to convert 17
into ketone 5 with moderate yield and excellent regioselec-
tivity, accompanied mostly by untransformed 17. The
(Z)-olefin geometry and the enhanced electron donation
of sulfides versus sulfoxides may contribute to the ob-
served low catalyst turnover. The C15ÀC25 fragment 5
was achieved in 12 steps and 13% overall yield in the
Scheme 4. Synthesis of Allylic Alcohol 27
Scheme 2. Synthesis of C15ÀC25 Fragment 5
from δ-gluconolactone as the origin of the C7ÀC8 stereo-
chemistry instead of Roush allylation to construct the
anti-stereochemistry at C7ÀC8. Also, a practical Ando
olefination14 involving diphenyl phosphonate 19 was em-
ployed to establish the C4ÀC5 (Z)-alkene. Acidic lactoni-
zation with a modified workup15 afforded triol 21. Facial
selective hydrogenation then established the C4 stereo-
genic center.4b Selective monosilylation and bis-MOM
installation provided lactone 23. Conversion into the
corresponding lactol with DIBALH allowed incorpora-
tion of the R,β-conjugated ester of 24.
Intermediate 24 was cyclized to the C3ÀC6 trans-THF
ring upon treatment with TBAF,3,4b with concomitant loss
of the C9 O-silyl group (Scheme 4). The C9 alcohol was
temporarily resilylated before the C1 ester was reduced,
and the resultant alcohol was protected with a robust
TBDPS group. Chemoselective cleavage of the C9
O-TES ether in the presence of MOM and TBDPS pro-
tecting groups was then achieved with PPTS in MeOH/
CH2Cl2 to give primary alcohol 26. ParikhÀDoering
oxidation16 converted 26 into aldehyde 9 as a prelude to
installation of the C10ÀC14 side chain. For this, we relied
upon lithiumÀhalogen exchange of Carter’s iodide 104c
Scheme 3. Preparation of Ester 24
(11) Aıssa, C. Eur. J. Org. Chem. 2009, 1831.
¨
(12) (a) Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.;
Somers, K.; Wallace, P. A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.;
Yang, Z. Chem.;Eur. J. 1999, 5, 599. (b) Larsson, M.; Andersson, J.;
€
Liu, R.; Hogberg, H.-E. Tetrahedron: Asymmetry 2004, 15, 2907.
(13) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777.
(14) Ando, K. J. Org. Chem. 1998, 63, 8411.
(15) See Supporting Information for details.
(16) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505.
1180
Org. Lett., Vol. 15, No. 6, 2013

and addition to 9 to provide allylic alcohol 27 as a 1:1
diastereomeric mixture.
Scheme 5. Completion of C1ÀC14 Fragment Diene 6
In the conversion of 27 into enone 28, the use of pyridine
with Dess-Martin periodinane17 was superior to sodium
bicarbonate powder for buffering acidic species and sup-
pressing decomposition (Scheme 5). As similarly observed
by Carter,4c methylenation of the C9 ketone was challen-
ging. Several common methylenation reagents failed to
convert ketone 28 into the desired diene 6, including
Petasis’ reagent,18 which was effective for Carter’s enone.
Encouragingly, TakaiÀUtimoto olefination involving
19
cyclization to close the C20ÀC23 trans-tetrahydrofuran
moiety and a sulfur-directed regiocontrolled Wacker oxi-
dation to install the C18 ketone. The complementary
C1ÀC14 fragment synthesis featured the assembly of
the C3ÀC6 trans-tetrahydrofuran ring by an established
intramolecular oxo-Michael cyclization, and an efficient
Peterson olefination of the recalcitrant C9 ketone. This
work establishes an avenue toward a projected total
synthesis of amphidinolide C and targeted analogs.
bis(iodozincio)methane and TiCl4 provided diene 6 in
40À60% yield. However, the modest and variable yields
associatedwithpartial lossofa MOM groupand otherside
products due to the strong Lewis acidity were overall
unsatisfactory. Alternatively, Peterson olefination in
a two-step protocol20 provided 6 in reproducibly high
efficiency. Specifically, the use of KHMDS rather than
t-BuOK or KH was the most effective and convenient
reagent to initiate the Peterson elimination under basic
conditions. The C1ÀC14 fragment 6 was synthesized from
known aldehyde 18 in 11% overall yield in 17 steps in the
longest linear sequence.
Acknowledgment. We thank OSU for financial support
and the Ohio BioProducts Innovation Center for support
of the OSU Chemistry Department Mass Spectrometry
Facility.
In summary, the C15ÀC25 fragment of amphidinolide
C was prepared using a Mukaiyama aerobic alkenol
(17) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(18) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(19) (a) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron
Lett. 1985, 26, 5579. (b) Matsubara, S.; Mizuno, T.; Otake, T.; Kobata,
M.; Utimoto, K.; Takai, K. Synlett 1998, 1369. (c) Matsubara, S.;
Oshima, K.; Utimoto, K. J. Organomet. Chem. 2001, 617À618, 39.
(20) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (b) Wiedner,
S. D.; Vedejs, E. Org. Lett. 2010, 12, 4030.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
for previously unreported compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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