Studies toward the Synthesis of Iriomoteolide-2a: Construction of the C(6)-C(28) Fragment

Article abstract of DOI:10.1021/acs.orglett.8b00542

The synthesis of an appropriately functionalized advanced C(6-28) fragment (3) of the marine macrolide iriomoteolide-2a (1) has been achieved in a highly efficient manner. The C(6)-C(18) fragment of 1 is prepared via a radical cyclization of a vinyl ether intermediate and palladium-promoted hydrostannylation/iodination. Paterson aldol reaction and Peterson olefination are used to construct the C(19)-C(28) fragment. The union of the C(6)-C(18) and C(19)-C(28) fragments is accomplished via a Suzuki-Miyaura coupling reaction.

Full text of DOI:10.1021/acs.orglett.8b00542

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Studies toward the Synthesis of Iriomoteolide-2a: Construction of
the C(6)−C(28) Fragment
Lushun Wang, Fusong Wu, Xuelei Jia, Zhengshuang Xu, Yian Guo,* and Tao Ye*
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Xili, Nanshan District, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: The synthesis of an appropriately functionalized advanced C(6−28)
fragment (3) of the marine macrolide iriomoteolide-2a (1) has been achieved in a
highly efficient manner. The C(6)−C(18) fragment of 1 is prepared via a radical
cyclization of a vinyl ether intermediate and palladium-promoted hydrostannylation/
iodination. Paterson aldol reaction and Peterson olefination are used to construct the
C(19)−C(28) fragment. The union of the C(6)−C(18) and C(19)−C(28) fragments
is accomplished via a Suzuki−Miyaura coupling reaction.
any of the natural products derived from marine
dinoflagellates are challenging synthetic targets and
stereochemistry assignments were based on extensive NMR
studies, including modified Mosher ester7 and J-based
configuration analysis.8 The unique biological profile and
structural complexity of iriomoteolide-2a (1) render it an
attractive target for synthesis and subsequent drug development
research.
As outlined in our retrosynthetic analysis, iriomoteolide-2a
(1) should be readily available from the advanced precursor (2)
by ruthenium-catalyzed ring-closing metathesis (RCM) and
subsequent global deprotection. It was envisaged that precursor
(2) would arise from the key intermediate 3 via a Yamaguchi
esterification. In turn, 3 was planned to be synthesized by
Suzuki−Miyaura coupling of vinyl iodide 4 with an alkyl
boronate derived from alkene 5 (Scheme 1).
M
could serve as lead compounds in drug development.1 A large
number of macrolides with ring sizes from 12 to 29, as well as
members of linear polyketides that possess unique molecular
structures and impressive biological activities, were isolated
from the dinoflagellate Amphidinium species.2 We have been
engaged in a program devoted to the total synthesis of bioactive
marine natural products and their synthetic derivatives/
analogues.3 In 2010, we disclosed our original approach that
resulted in completion of the synthesis of the fully function-
alized macrocyclic core of iriomoteolide-1a.4 We recently also
achieved the convergent total synthesis of amphidinins E and F
and epi-amphidinin F.5 Herein, we describe a concise and
efficient route for the stereocontrolled synthesis of the fully
elaborated C(6−28) fragment of iriomoteolide-2a (1) (Figure
1) as a prelude to ring-closure studies.
Scheme 1. Retrosynthetic Analysis
Figure 1. Structure of iriomoteolide-2a.
Iriomoteolide-2a (1), isolated from the cultured broth of the
benthic dinoflagellate Amphidinium sp. (HYA024 strain)
collected off the Iriomote Island, Okinawa, by the Tsuda
group, is a new anticancer macrolide.6 It possesses potent
cytotoxic activities against human B lymphoma DG75 cells and
human cervix adenocarcinoma HeLa cells with IC50 values of 6
and 30 ng/mL, respectively.6 The structure, comprising an
olefin-bearing three-stereogenic-center side chain, appended to
the 23-membered macrocyclic lactone ring, was elucidated via a
combination of NMR experiments. Relative and absolute
The synthesis of the key fragment 4 started from a
displacement of the readily available iodide 69 with cesium
trifluoroacetate, followed by cleavage of the trifluoroacetate
ester with diethylamine to give rise to the corresponding
alcohol 7 in 70% yield as a single diastereomer after flash
chromatography (Scheme 2).10 Treatment of alcohol 7 with the
Received: February 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00542
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
18 was obtained in 60% yield. Vinyl iodide 18 was then
transformed into the key intermediate 4 in a three-step
sequence involving (1) oxidation of the primary alcohol with
the Dess−Martin periodinane; (2) one-carbon homologation of
the resulting aldehyde with (methoxymethyl)triphenylphos-
phonium ylide, followed by an acidic hydrolysis of the enol
ether intermediately formed; and (3) Wittig olefination of the
homologated aldehyde with triphenylphosphonium methylide.
The synthesis of alkene 5 commenced with diazotization of
(R)-2-aminobutyric acid to afford 19 in 60% yield (Scheme 3).
Scheme 2. Synthesis of Intermediate 4
Scheme 3. Synthesis of Intermediate 5
This acid was first converted into the corresponding methyl
ester and then reacted with N,O-dimethylhydroxylamine
hydrochloride in the presence of i-PrMgBr to give the Weinreb
amide 20 in 70% yield.18 Reaction of the Weinreb amide 20
with ethylmagnesium bromide cleanly provided the corre-
sponding ethyl ketone, which underwent subsequent O-
benzoylation to give rise to ketone 21 in 60% yield over two
steps. A boron-mediated Paterson aldol reaction19 of ethyl
ketone 21 with readily available aldehyde 2220 furnished anti-
aldol product 23 as the sole detectable diastereomer, which was
immediately protected as its TBS ether 24 in 81% yield over
two steps. Mosher ester analysis7 confirmed that we had
correctly assigned the stereochemistry at the newly formed
hydroxyl position. Transesterification of the benzoate with
potassium carbonate in methanol, followed by protection of the
resulting alcohol, as its TBS ether 25 to set the stage for the
upcoming olefination step. Attempted conversion of ketone 25
into its corresponding alkene 5 with various reagents/
conditions, including those developed by Wittig,21 Nysted,22
and Petasis23 afforded either very poor yield or none of the
desired product. Eventually, we found that Peterson olefination
protocol24 was effective in this capacity, and the desired
product 5 was obtained in 60% yield.
Dess−Martin reagent11 provided aldehyde 8, which was
subjected to an auxiliary-controlled Evans aldol reaction12
using the standard boron enolate to provide the desired syn-
aldol adduct 10 in 60% yield. Reductive cleavage of the
oxazolidinone moiety from 10 with lithium borohydride and
subsequent selective tosylation of the primary alcohol, followed
by treatment with ethyl propiolate in the presence of N-
methylmorpholine,13a afforded vinyl ether 11 in 85% yield over
three steps. Displacement of the tosylate group of 11 with
sodium iodide in tetrahydrofuran furnished iodide 12 in 96%
yield. To our delight, treatment of 12 with tris(trimethylsilyl)-
silane in the presence of triethylborane gave rise to the cyclized
product 13 in 99% yield as the sole diastereomer.13 To
continue, 13 was converted into alcohol 14 in 89% yield by a
four-step sequence that included reduction of the ethyl ester
with DIBAL-H, cleavage of the PMB ether with DDQ,
protection of the resulting diol as the corresponding bis-TBS
ether, and reductive removal of the 2,5-dichlorobenzyl group by
hydrogenolysis. Oxidation of the primary alcohol of 14 with
Dess−Martin periodinane, followed by exposure of the
resulting aldehyde to the Ohira−Bestmann14 modification of
the Seyferth−Gilbert reagent,15 provided alkyne 16 in 72%
yield.
Alkylation with methyl iodide, followed by acid-catalyzed
selective desilylation provided primary alcohol 17 in 78% yield.
To directly access vinyl iodide 18 from alkyne 17, we explored
Schwartz hydrozirconation/iodination.16 Unfortunately, under
various conditions, the reaction resulted in either recovery of
starting material or compound destruction. Fortunately, a two-
step palladium-promoted hydrostannylation/iodination17 pro-
tocol completed construction of the desired vinyl iodide 18.
Thus, slow addition of excess n-Bu3SnH to 17 in the presence
of catalytic PdCl2(PPh3)2 afforded vinyl stannane as a mixture
of geometrical isomers (E/Z = 4:1) which were readily
separated. Upon treatment with iodine, the desired vinyl iodide
With both key intermediates 4 and 5 in hand, the stage was
set for the crucial coupling reaction (see Scheme 4). Thus,
hydroboration of olefin 5 with 9-borabicyclo[3.3.1] nonane (9-
BBN), followed by in situ β-alkyl Suzuki coupling25 with vinyl
iodide 4 furnished fragment 3 in 90% yield. This key fragment
Scheme 4. Synthesis of Fragment 3
B
DOI: 10.1021/acs.orglett.8b00542
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) White, J. D.; Quaranta, L.; Wang, G. Q. Org. Lett. 2003, 5, 4109.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Zhang, W.; Carter, R. G. Org. Lett. 2005, 7, 4209.
possesses 10 stereogenic centers of iriomoteolide-2a and was
assembled using a highly effective synthetic strategy.
In summary, we have developed a novel stereoselective
approach to the key fragment of the marine macrolide
iriomoteolide-2a (1). Key features of the synthesis of the
building blocks include a radical cyclization of a vinylic ether
intermediate, palladium-promoted hydrostannylation/iodina-
tion, Paterson aldol reaction, Peterson olefination, and
Suzuki−Miyaura coupling reaction. Further work is currently
underway to achieve the total synthesis of iriomoteolide-2a.
́
(c) Furstner, A.; Bouchez, L. C.; Funel, J. − A.; Liepins, V.; Poree, F.
̈
H.; Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew. Chem.,
Int. Ed. 2007, 46, 9265. (d) Sohn, T.; Kim, M. J.; Kim, D. J. Am. Chem.
Soc. 2010, 132, 12226. (e) Sokolsky, A.; Cattoen, M.; Smith, A. B., III
Org. Lett. 2015, 17, 1898.
(13) (a) Lee, E.; Jin, S. T.; Lee, C.; Park, C. M. Tetrahedron Lett.
1993, 34, 4831. (b) Kwon, H. K.; Lee, Y. E.; Lee, E. Org. Lett. 2008,
10, 2995.
(14) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mueller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 1996, 521.
(15) (a) Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc.
1967, 89, 4811. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979,
44, 4997.
(16) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc.
1975, 97, 679. (b) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(c) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675. (d) An, C.; Jurica,
J. A.; Walsh, S. P.; Hoye, A. T.; Smith, A. B. J. Org. Chem. 2013, 78,
4278.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00542.
■
S
Experimental details and data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(17) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
(18) Williams, M. J.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
*E-mail: bryan_pku@qq.com.
*E-mail: yet@pkusz.edu.cn.
ORCID
́
(19) (a) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron
Lett. 1994, 35, 9083. (b) Paterson, I.; Wallace, D. J.; Cowden, C. J.
Synthesis 1998, 1998, 639. (c) Paterson, I.; Mackay, A. C. Tetrahedron
Lett. 2001, 42, 9269. (d) Paterson, I.; Doughty, V. A. S.; McLeod, M.
D.; Trieselmann, T. Tetrahedron 2011, 67, 10119. (e) Paterson, I.; Ng,
K. K. H.; Williams, S.; Millican, D. C.; Dalby, S. M. Angew. Chem., Int.
Ed. 2014, 53, 2692.
Yian Guo: 0000-0002-0341-6816
Tao Ye: 0000-0002-2780-9761
Notes
The authors declare no competing financial interest.
(20) Chiral aldehyde 22 was prepared from PMB glycolate as
reported by Crimmins. For detailed procedures, see the Supporting
Information of: Crimmins, M. T.; McDougall, P. J.; Ellis, J. M. Org.
Lett. 2006, 8, 4079.
ACKNOWLEDGMENTS
■
We acknowledge financial support from Shenzhen Peacock
Plan (KQTD2015071714043444), NSFC (21772009),
S Z S T I C ( J C Y J 2 0 1 6 0 5 2 7 1 0 0 4 2 4 9 0 9 ,
JCYJ20170818090017617, JCYJ20170818090238288), and
GDNSF (2014B030301003).
(21) (a) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318.
̈
(b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654.
(22) (a) Nysted, L. N. U.S. Patent 3,865,848, 1975; Chem. Abstr.
1975, 83, 10406q. (b) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett
1998, 1998, 313. (c) Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68,
8042.
REFERENCES
■
(1) (a) Kobayashi, J. Chem. Pharm. Bull. 2016, 64, 1079. (b) Van
Wagoner, R. M.; Satake, M.; Wright, J. L. C. Nat. Prod. Rep. 2014, 31,
1101. (c) Gallardo- Rodríguez, J.; San
(23) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
(24) Peterson, D. J. J. Org. Chem. 1968, 33, 780.
(25) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
20, 3437. (b) Miyaura, N.; Suzuki. J. Chem. Soc., Chem. Commun. 1979,
866.
́ ́
chez-Miron, A.; García-
Camacho, F.; Lopez-Rosales, L.; Chisti, Y.; Molina-Grima, E.
́
Biotechnol. Adv. 2012, 30, 1673.
(2) (a) Kobayashi, J. J. Antibiot. 2008, 61, 271. (b) Kobayashi, J.;
Kubota, T. J. Nat. Prod. 2007, 70, 451.
(3) (a) Liao, L.; Zhou, J.; Xu, Z.; Ye, T. Angew. Chem., Int. Ed. 2016,
55, 13263. (b) Zhou, J.; Gao, B.; Xu, Z.; Ye, T. J. Am. Chem. Soc. 2016,
138, 6948. (c) Gunasekera, S. P.; Li, Y.; Ratnayake, R.; Luo, D.; Lo, J.;
Reibenspies, J. H.; Xu, Z.; Clare-Salzler, M. J.; Ye, T.; Paul, V. J.;
Luesch, H. Chem. - Eur. J. 2016, 22, 8158. (d) Liu, J.; Wang, L.; Zhang,
J.; Xu, Z.; Ye, T. Chem. Commun. 2016, 52, 1002. (e) Qu, S.; Chen, Y.;
Wang, X.; Chen, S.; Xu, Z.; Ye, T. Chem. Commun. 2015, 51, 2510.
(f) Lei, H.; Yan, J.; Yu, J.; Liu, Y.; Wang, Z.; Xu, Z.; Ye, T. Angew.
Chem., Int. Ed. 2014, 53, 6533.
(4) Li, S.; Chen, Z.; Xu, Z. S.; Ye, T. Chem. Commun. 2010, 46, 4773.
(5) Chen, K.; Xu, Z.; Ye, T. Org. Chem. Front. 2018, 5, 629.
(6) Tsuda, M.; Kumagai, K.; Masuda, A.; Fukushi, E.; Kawabata, J.
Heterocycles 2015, 91, 265.
(7) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(8) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866.
(9) Compound 6 (cis/trans = 8:1) was prepared in seven steps from
TBDPS-protected α-hydroxy aldehyde in a manner similar to that
reported previously (see the Supporting Information).
C
DOI: 10.1021/acs.orglett.8b00542
Org. Lett. XXXX, XXX, XXX−XXX