Studies toward the Synthesis of Amphidinolide C1: Stereoselective Construction of the C(1)-C(15) Segment

Article abstract of DOI:10.1021/acs.orglett.0c03134

An enantioselective synthesis of the C(1)-C(15) segment of the marine natural product amphidinolide C has been accomplished by a route that includes a stereoselective boron-Wittig reaction to furnish a trisubstituted alkenylboronate. In addition, the rout

Full text of DOI:10.1021/acs.orglett.0c03134

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Studies toward the Synthesis of Amphidinolide C1: Stereoselective
Construction of the C(1)−C(15) Segment
Sheila Namirembe, Lu Yan, and James P. Morken*
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ABSTRACT: An enantioselective synthesis of the C(1)−C(15) segment of the marine natural product amphidinolide C has been
accomplished by a route that includes a stereoselective boron−Wittig reaction to furnish a trisubstituted alkenylboronate. In
addition, the route employs enantioselective alkene diboration to install the C(6) hydroxyl group which undergoes intramolecular
conjugate addition to establish a tetrahydrofuran ring. Lastly, a catalytic Suzuki−Miyaura cross-coupling is accomplished to construct
the C(9)−C(10) bond.
(amphidinolide C2, 2) or removal of the C(8) hydroxyl
(amphidinolide C4, 3) leads to a 100-fold loss in potency as
does alteration of the macrolide side chain (amphidinolide F,
4).3 Many other amphidinolides possess nanomolar potency
against cancer cell lines, and nearly all of the cytotoxic
examples bear alkenyl epoxide functional groups such as that
present in amphidinolide H (5).4 Amphidinolide H has been
shown to covalently modify actin, an activity that is thought to
originate from the electrophilicity of the alkenyl epoxide
group.5 That amphidinolide C1 can retain potency while not
enjoying the added binding ability proffered by a highly
electrophilic functional group has made this compound a target
of interest. Subsequent to Kobayashi’s reports on the isolation,
structural elucidation2 and absolute stereochemistry6 of
amphidinolide C1, several groups have worked toward its
efficient chemical synthesis. In addition to a number of
fragment studies,7 completed total synthesis have been
mphidinolides are a large family of macrolide natural
1
Aproducts isolated from dinoflagellates Amphidinium sp.
As of this writing, more that 40 compounds have been isolated
from this organism by the Kobayashi group with amphidino-
lide C1 (1, Figure 1) being a unique structure.2 As shown in
Figure 1, the bioactivity of the C1 macrolactone is very high
with an IC50 of 8 nM versus L1210 cells. Interestingly, very
subtle changes to the C1 structure lead to significant erosion of
cytotoxicity: protection of the C(29) hydroxyl group
recorded by teams from the Fu
̈
rstner8 and Carter9 laboratories.
In this report, we describe our approach to the C(1)−C(15)
segment of amphidinolide C1 via a combination of catalytic
synthetic methods.
Received: September 17, 2020
Figure 1. Structure and bioactivity of several members of the
amphidinolide family of marine natural products.
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Our interest in amphidinolide C stems from its biological
activity and the challenges posed by its efficient and practical
synthesis. To address the target, we planned to employ a
Yamaguchi esterification10 to complete the lactone and to join
fragments A and B (Figure 2) by a nitroalkane conjugate
Scheme 1. Synthesis of the C(10)−C(16) (10) Segment of
Amphidinolide C1
Figure 2. Synthetic approach to the construction of amphidinolide C1
from smaller fragments.
Scheme 2. Synthetic Approach to the Construction of
Amphidinolide C1 from Smaller Fragments
addition11/Nef reaction.12 Fragment A represents the C(1) to
C(15) segment of amphidinolide C and might be accessible by
transition metal-catalyzed cross-coupling of fragments C and D
to connect C(9) with C(10). Of note, a cross-coupling
approach was employed by the Furstner team to connect C(9)
̈
and C(10), albeit a Stille reaction was employed whereas we
wished to examine the utility of the Suzuki−Miyaura reaction
to establish this linkage. Lastly, the synthesis of the individual
C and D fragments, as delineated below, was accomplished
using boron-based methodology as described by our
laboratories.
To synthesize fragment C in a catalytic enantioselective
fashion, we considered the Krische anti crotylation13 as a
scalable and reliable method for efficient construction of the
two stereogenic centers. Thus, aldehyde 6 was employed as
substrate under reducing conditions with 2-propanol as
reductant and iridium complex (R)-I as the catalyst (Scheme
1). This process furnished alcohol 7 in good yield and with
excellent stereoselectivity (98% ee). While synthesis of
trisubstituted alkenyl boronates such as that which appears
in compound 10 can be effected by alkyne carbometalation/
borylation,14 this process employs potently pyrophoric
trimethylaluminum as a requisite reagent. As an alternative,
we considered the boron−Wittig reaction of ketones that was
recently established in our laboratory.15 Thus, after hydroxyl
protection, compound 8 was subjected to Wacker oxidation16
of the terminal alkene, which delivered ketone 9 in good yield.
Using the recently reported modified boron−Wittig reaction,15
we converted ketone 9 into the desired alkenyl boronic ester
access the trans tetrahydrofuran ring, we considered base-
promoted cyclization according to a stereoselectivity model
proposed by Roush.7c After investigating a number of bases
and reaction conditions, it was found that reaction in the
presence of DBU at 60 °C promoted the intramolecular
cyclization of 13 to give trans-disubstituted tetrahydrofuran 14
in good yield and diastereoselectivity. Completion of the
synthesis of fragment 16 employed Parikh−Doering oxida-
tion22 to transform alcohol 14 into the derived aldehyde
which, given its instability, was immediately subjected to
proline-catalyzed aldol reaction with α-siloxyacetone to give
1
10 in high yield and excellent diastereoselectivity. H NMR
NOESY analysis was used to establish the E configuration of
the olefin (see the Supporting Information for details).
15. This procedure was employed by Fu
̈
rstner8 and, with slight
To access fragment D (compound 16, Scheme 2), we started
with readily accessible known alcohol 11.17 Alcohol 11
underwent a Swern oxidation18 to afford an aldehyde which
was directly subjected to stabilized-Wittig olefination19 to
furnish known unsaturated ester 12.20 At this juncture, we
applied the recently developed carbohydrate and DBU co-
catalyzed diboration21 to terminal alkene 12 which enabled
formation of diol 13 in good yield and diasteroselectivity. To
modification was found to be effective for the production of
15. After silyl protection of 15 the ketone was deprotonated
with KHMDS and then treated with Comins’ reagent23 to
furnish the alkenyl triflate 16 in moderate yield.
Previous syntheses of amphidinolide C and F have relied on
the Stille cross-coupling to construct the diene motif. While
this methodology is feasible, it utilizes toxic organotin reagents
and might pose a safety concern on large scale. To the best of
B
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our knowledge, the Suzuki−Miyaura cross-coupling with
appropriate alkenyl derivatives has not been employed in the
construction of amphidinolide targets. Moreover, through the
use of the boron−Wittig reaction, ample material was available
to explore this strategy. During these studies, a number of
conditions were investigated to execute the Suzuki−Miyaura
cross-coupling. During the course of the optimization studies,
it was found that the amount of protodeboronation product
(19, Scheme 3) was affected by the amount of base. In
AUTHOR INFORMATION
Corresponding Author
■
James P. Morken − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0002-9123-9791; Email: morken@bc.edu
Authors
Sheila Namirembe − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
Lu Yan − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Scheme 3. Suzuki Coupling Reaction to Assemble the
C(1)−C(15) Fragment of Amphidinolide C
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03134
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the NIH for funding (NIGMS GM-
R35-127140). We also acknowledge Chenlong Zhang and Alex
Vendola for helpful experimental assistance.
REFERENCES
■
(1) Review: Kobayashi, J. J. Antibiot. 2008, 61, 271−284.
(2) Kobayashi, J.; Ishibashi, M.; Walchli, M. R.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490−
̈
494.
addition, the amount of isomerized product 18 was influenced
by the nature of the base and light. After optimization, we
found that Pd(dppf)Cl2, K3PO4, THF/H2O, and reaction at 60
°C in the dark provided the desired cross coupling product in
52−61% isolated yield. During the course of the reaction, the
silyl ether group at C(7) was cleaved to generate alcohol 17 as
the product. This outcome is expected to be inconsequential to
the ultimate synthesis strategy.
In conclusion, we have accomplished the synthesis of the
C(1)−C(15) segment of amphidinolide C. The key steps
included a catalytic and enantioselective anti Krische
crotylation and a modified boron-Wittig olefination. Also
critical were the carbohydrate/DBU co-catalyzed diboration
and an organocatalytic anti aldol reaction. This report also
describes the first time a Suzuki−Miyuara cross-coupling has
been demonstrated to assemble two advanced intermediates
for the synthesis amphidinolide C. An important aspect of the
cross-coupling is that it should be done in the absence of light;
otherwise, isomerization of the product diene occurs.
Collectively, the knowledge gained from the syntheses
described above will assist in completion of amphidinolide C.
(3) Amphidinolide F: Kobayashi, J.; Tsuda, M.; Ishibashi, M.;
Shigemori, H.; Yamasu, T.; Hirota, H.; Sasaki, T. J. Antibiot. 1991, 44,
1259−1251.
(4) Kobayashi, J.; Shigemori, H.; Ishibashi, M.; Yamasu, T.; Hirota,
H.; Sasaki, T. J. Org. Chem. 1991, 56, 5221−5224.
(5) Usui, T.; Kazami, S.; Dohmae, N.; Mashimo, Y.; Konda, H.;
Tsuda, M.; Terasaki, A. G.; Ohashi, K.; Kobayashi, J.; Osada, H.
Chem. Biol. 2004, 11, 1269−1277.
(6) (a) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3,
1363−1366. (b) Kubota, T.; Tsuda, M.; Kobayashi, J. Tetrahedron
2003, 59, 1613−1625.
(7) (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865−3868.
(b) Williams, D. R.; Fultz, M. W. J. Am. Chem. Soc. 2005, 127,
14550−14551. (c) Mohapatra, D. K.; Rahaman, M.; Chorghade, S.;
Gurjar, M. K. Synlett 2007, 18, 567−570. (d) Bates, R. H.; Shotwell, J.
B.; Roush, W. R. Org. Lett. 2008, 10, 4343−4346. (e) Armstrong, A.;
Pyrkotis, C. Tetrahedron Lett. 2009, 50, 3325−3328. (f) Mohapatra,
D. K.; Dasari, P.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50,
6276−6279. (g) Paudyal, M. P.; Rath, N. P.; Spilling, C. D. Org. Lett.
́
̀
2010, 12, 2954−2957. (h) Ferrie, L.; Figadere, B. Org. Lett. 2010, 12,
4976−4979. (i) Roy, S.; Spilling, C. D. Org. Lett. 2010, 12, 5326−
5329. (j) Morra, N. A.; Pagenkopf, B. L. Org. Lett. 2011, 13, 572−575.
(k) Wu, D.; Forsyth, C. J. Org. Lett. 2013, 15, 1178−1181. (l) Clark,
J. S.; Yang, G.; Osnowski, A. P. Org. Lett. 2013, 15, 1460−1463.
(m) Clark, J. S.; Yang, G.; Osnowski, A. P. Org. Lett. 2013, 15, 1464−
1467. (n) Morra, N. A.; Pagenkopf, B. L. Tetrahedron 2013, 69,
8632−8644. (o) Morra, N. A.; Pagenkopf, B. L. Eur. J. Org. Chem.
2013, 2013, 756−760. (p) Williams, D. R.; De, R.; Fultz, M. W.;
ASSOCIATED CONTENT
■
sı
́
* Supporting Information
Fischer, D. A.; Morales-Ramos, A.; Rodríguez-Reyes, D. Org. Lett.
2020, 22, 4118−4122.
(8) Valot, G.; Mailhol, D.; Regens, S. C.; O’Malley, P. D.; Godineau,
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03134.
E.; Takikawa, H.; Philipps, P.; Fu
2398−2408.
̈
rstner, A. Chem. - Eur. J. 2015, 21,
Procedures, characterization, spectral and chromato-
graphic data (PDF)
(9) Mahapatra, S.; Carter, G. R. J. Am. Chem. Soc. 2013, 135,
10792−10803.
C
https://dx.doi.org/10.1021/acs.orglett.0c03134
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(10) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989−1993.
(11) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M.
Chem. Rev. 2005, 105, 933−971. (b) Ono, N.; Kamimura, A.; Kaji, A.
Synthesis 1984, 1984, 226−227. (c) Pollini, G. P.; Barco, A.; De Giuli,
G. Synthesis 1972, 1972, 44−45. (d) Chavan, S. P.; Pasupathy, K.;
Venkatraman, M. S.; Kale, R. R. Tetrahedron Lett. 2004, 45, 6879−
6882. (e) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D. Synthesis
2002, 18, 2725−2728.
(12) For recent examples: (a) Ballini, R.; Petrini, M. Adv. Synth.
Catal. 2015, 357, 2371−2402. (b) Aghahosseini, H.; Ramazani, A.;
́
Jalayer, N. S.; Ranjdoost, Z.; Souldozi, A.; Slepokura, K.; Lis, T. Org.
Lett. 2019, 21, 22−26.
(13) (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 6340−6341. (b) Kim, I. S.; Ngai, M. Y.; Krische, M. J. J.
Am. Chem. Soc. 2008, 130, 14891−14899. (c) Gao, X.; Townsend, I.
A.; Krische, M. J. J. Org. Chem. 2011, 76, 2350−2354. (d) Dechert-
Schmitt, A. M.; Schmitt, D. C.; Krische, M. J. Angew. Chem., Int. Ed.
2013, 52, 3195−3198.
(14) Zhurakovskyi, O.; Dias, R. M. P.; Noble, A.; Aggarwal, V. K.
Org. Lett. 2018, 20, 3136−3139.
(15) (a) Coombs, J. R.; Zhang, L.; Morken, J. P. Org. Lett. 2015, 17,
1708. (b) Namirembe, S.; Gao, C.; Wexler, P. R.; Morken, J. P. Org.
Lett. 2019, 21 (11), 4392−4394.
(16) Czuba, I. R.; Zammit, S.; Rizzacasa, M. A. Org. Biomol. Chem.
2003, 1, 2044−2056.
(17) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83−91.
(b) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77−82. (c) Meiries,
S.; Bartoli, A.; Decostanzi, M.; Parrain, J.-L.; Commeiras, L. Org.
Biomol. Chem. 2013, 11, 4882−4890.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651−1660.
(19) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198−
2200.
(20) Sakamoto, K.; Hakamata, A.; Iwasaki, A.; Suenaga, K.; Tsuda,
M.; Fuwa, H. Chem. - Eur. J. 2019, 25, 8528−8542.
(21) (a) Fang, L.; Yan, L.; Haeffner; Morken, J. P. J. Am. Chem. Soc.
2016, 138, 2508−2511. (b) Yan, L.; Meng, Y.; Haeffner, F.; Leon, R.
M.; Crockett, M. P.; Morken, J. P. J. Am. Chem. Soc. 2018, 140, 3663−
3673.
(22) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505−5507.
(23) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299−
6302.
D
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