Enantioselective Total Synthesis of (+)-Amphirionin-4

Article abstract of DOI:10.1021/acs.orglett.6b00942

An enantioselective total synthesis of (+)-amphirionin-4 has been accomplished in a convergent manner. The synthesis features an efficient enzymatic lipase resolution to access the tetrahydrofuranol core in optically active form. The functionalized tetrah

Full text of DOI:10.1021/acs.orglett.6b00942

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (+)-Amphirionin‑4
Arun K. Ghosh* and Prasanth R. Nyalapatla
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana
47907, United States
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* Supporting Information
ABSTRACT: An enantioselective total synthesis of (+)-amphirionin-4 has been
accomplished in a convergent manner. The synthesis features an efficient enzymatic
lipase resolution to access the tetrahydrofuranol core in optically active form. The
functionalized tetrahydrofuran derivative was synthesized via an oxocarbenium ion-
mediated highly diastereoselective syn-allylation reaction. The polyene side chain was
synthesized using Stille coupling reactions. Nozaki−Hiyama−Kishi coupling was utilized
to construct the C-8 stereocenter and complete the synthesis of (+)-amphirionin-4.
arine dinoflagellates of the genus Amphidiuium species are
rich sources of bioactive polyketide-like natural products
proliferation promotion when administered to MC3T3-E1 and
NIH3TC cells.4
M
with intriguing biological properties.1,2 Recently, Tsuda and co-
workers isolated a number of polyketides, amphirionins-2, -4,
and -5 from the dinoflagellate Amphidiuium species.3−5 Among
these, the linear polyketide (+)-amphirionin-4 (1, Figure 1) was
isolated from the Amphidiuium KCA09051 strain in the benthic
sea sand collected off the Iriomote Island. This compound
exhibited exceptionally potent proliferation-promoting activity
(95% promotion) on murine bone marrow stomal ST-2 cells at
0.1 ng/mL concentration. Interestingly, it did not show
The structure of (+)-amphirionin-4 was elucidated by Tsuda
and co-workers using extensive NMR analysis and the absolute
configuration of the C4 and C8 hydroxyl groups was determined
by Mosher ester analysis.4 Recently, Britton and co-workers have
reported the first synthesis of amphirionin-4.6 However, the
specific rotation of the synthetic compound was opposite to that
reported for natural amphirionin-4.4,6 Considering the extreme
proliferation-promoting activity of (+)-amphirionin-4 in ST-2
cells, its structural features, and its potential medicinal
application, we sought to develop a convergent and concise
enantioselective synthesis of (+)-amphirionin-4. Herein, we now
report a route that proceeds in nine linear steps, starting from a
readily available racemic butyrolactone.
Our retrosynthesis of (+)-amphirionin-4 is shown in Figure 1.
We planned to utilize a Nozaki−Hiyama−Kishi (NHK)7,8
reaction similar to that reported by Britton and co-workers6 to
assemble amphirionin-4 from vinyl iodide 2 and polyene
aldehyde 3 at a late stage in the synthesis. The functionalized
tetrahydrofuran ring 2 would be constructed from optically active
γ-lactone 4 via a cis-selective allylation of the corresponding
oxocarbenium ion derived from lactone 4. Optically active
lactone 4 would be readily synthesized via acid-catalyzed
condensation of pyruvic acid and acetaldehyde, followed by
hydrogenation and lipase-catalyzed optical resolution of racemic
lactone. This will provide rapid access to both enantiomers for
structure−activity relationship studies of amphirionin-4. The
polyene side chain 3 would be constructed by Julia−Kocienski
olefination of the aldehyde derived from allylic alcohol 5.9 The
requisite aldehyde precursor would be synthesized by iterative
Stille cross-coupling reactions with appropriately protected vinyl
iodide 6 and tributylstannanes 7 and 8.
Our synthesis of functionalized tetrahydrofuran derivatives is
shown in Scheme 1. Racemic lactone 4 was synthesized on gram
scale by acid-catalyzed condensation of pyruvic acid 9 and
Received: April 1, 2016
Figure 1. Retrosynthetic analysis of (+)-amphirionin-4.
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00942
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diastereoselectivity. The observed stereochemical outcome can
be rationalized using similar steric and electronic arguments to
those proposed by Woerpel and co-workers.17 Presumably, the
oxocarbenium ion intermediate 17 is preferred over 18 due to
pseudoequatorial orientation of the C-2 alkoxy group (Figure 2).
Scheme 1. Synthesis of Substituted Tetrahydrofurans
Figure 2. Stereochemical analysis for cis-allylation.
The σC−H orbital at C2 maximizes electron donation to the
adjacent vacant orbital of the oxocarbenium ion. The bulky C2
siloxy group further enhances the pseudoequatorial orientation,
and therefore the overall cis-selectivity.
The desired allyl derivative 15 was converted to the
corresponding vinyl iodide as shown in Scheme 2. Oxidative
acetaldehyde, followed by hydrogenation of the resulting
unsaturated lactone over 10% Pd−C in EtOAc.10,11 Racemic
lactone 4 was then subjected to enzymatic resolution utilizing PS-
30 in vinyl acetate at 23 °C for 5 h.12,13 While the racemic lactone
was obtained in low yield, it can be readily prepared in gram
quantity and the current resolution protocol provided optically
active alcohol (+)-4 and acetate derivative 10 in 47% and 50%
yields, respectively, with high optical purity. Acetate 10 was
saponified with aqueous sodium hydroxide in methanol to
provide optically active alcohol (−)-4 in 82% yield.14 The
depicted absolute stereochemistry of lactones (+)-4 and (−)-4
was assigned based upon Kazlauskas’ model15 and comparison
with the reported specific rotations.16 Optically active lactone
(−)-4 was protected as the benzyl ether (>90% ee by chiral
HPLC analysis of this benzyl derivative). Dibal-H reduction of
the protected lactone provided the corresponding lactol, which
was treated with acetic anhydride and pyridine in the presence of
DMAP to provide acetate 11 in excellent yield. The hydroxyl
group of lactone (−)-4 was also protected as the TBS ether.
Dibal-H reduction of that lactone provided a mixture of lactols,
which were converted to the acetate 12. The reaction of acetate
11, bearing a C2 benzyl ether, with allyltrimethylsilane in the
presence of SnBr4 in CH2Cl2 at −78 to 23 °C provided the allyl
Scheme 2. Synthesis of Vinyl Iodide 2
cleavage of alkene 15 using PhI(OAc)2, NMO, and catalytic
OsO4 provided the corresponding aldehyde in 80% yield.18
Alkynylation of the resulting aldehyde with the Ohira−Bestmann
reagent19,20 and MeONa in a mixture of MeOH and THF gave
alkyne 19 in 70% yield. Hydrosilylation of the resulting alkyne 19
using Trost’s procedure21 with ([Cp*Ru(MeCN)3]PF6) and
triethylsilane followed by iododesilylation22 with NIS and 2,6-
lutidine in hexafluoroisopropanol (HFIP) furnished vinyl iodide
2 in 80% yield.
1
derivatives 13 and 14 as a 3:1 mixture of diastereomers by H
NMR analysis. The corresponding reaction of acetate 12
containing a C2 silyl ether with allyltrimethylsilane under similar
conditions furnished allylation products 15 and 16 in 80% yield.
However, the diastereomeric ratio of 15 and 16 improved to 10:1
(by 1H NMR analysis). The relative stereochemistry of alkenes
13, 14, and 15 was assigned by 1H NMR NOESY analysis.
The observed cis-diastereoselectivity is consistent with a C2-
benzyloxy substituted tetrahydrofuranyl substrate examined by
Woerpel and co-workers.17 It appears that substituents at the C4-
position, as in acetate 11, did not influence overall cis-
Synthesis of the amphirionin-4 side chain is shown in Scheme
3. A zirconium-catalyzed carboalumination of 4-pentyne-1-ol 20
followed by reaction with iodine provided the corresponding
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DOI: 10.1021/acs.orglett.6b00942
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Our synthesis of the polyene derivative 3 is shown in Scheme
4. Sulfone 26 was prepared in good yield by the reaction of 4-
Scheme 3. Synthesis of Aldehyde 23
Scheme 4. Synthesis of Aldehyde 3
vinyl iodide. TBS protection of the alcohol provided the vinyl
iodide 21 in 91% yield.23 We then investigated the Stille coupling
of vinyl iodide 21 with the known24 tributylstannane 7 under a
variety of conditions. The results are summarized in Table 1.
Table 1. Stille-Coupling Conditions to Access Diene 22
penten-1-ol 24 with 1-phenyl-1H-tetrazole-5-thiol 25, followed
by oxidation using catalytic ammonium molybdate and hydrogen
peroxide. Julia−Kocienski olefination9 between aldehyde 23 and
sulfone 26 gave the polyene 27 in 89% yield and only the E-
isomer was formed (by 1H NMR analysis). Removal of the TBS
group followed by DMP oxidation of the resulting alcohol
provided aldehyde 3 in good yield.
The final synthesis of (+)-amphirionin-4 is outlined in Scheme
5. NHK coupling6 between aldehyde 3 and vinyl iodide 2 was
carried out in DMF at 0° to 23 °C for 24 h. This provided TBS-
protected amphirionin-4 28 as the major diastereomer (4:1) in
65% yield. The diastereomers were separated by silica gel
chromatography. Deprotection of the TBS group using 70% HF,
entry catalyst and additive mol (%)
solvent
DMF
time (h) yield (%)
1
2
3
4
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd2(dba)3
10
20
30
30
24
24
96
24
30
30
28
25
DMF
DMF
DIPEA,
NMP
5
Pd(PPh3)4 CuCl,
LiCl
10
DMSO
2
90
Reactions with Pd(MeCN)2Cl2 (10 or 20 mol %) in DMF at 23
°C resulted in 30% yield (entries 1 and 2). Catalyst loading was
then increased to 30 mol % and reaction temperature was
increased to 50 °C for 96 h. This also resulted in low yield of
coupling product 22 (entry 3). Coupling with Pd2(dba)3 (30 mol
%) at 23 °C in a mixture of DIPEA/NMP again resulted in low
yield of product (25%, entry 4). We believe that these low yields
can be attributed to the disubstituted vinylstannane due to a slow
transmetalation step and a competing cine substitution.25 In an
attempt to enhance the transmetalation step, we decided to use
cuprous chloride as a promoter in the Stille-coupling reactions as
described by Corey and co-workers.25 Modified Stille-coupling
of vinyl iodide 21 and tributylstannane 7 in the presence of CuCl
and LiCl at 23 °C for 2 h furnished the desired diene 22 in
excellent (90%) yield. Acetylation of diene 22 furnished the
corresponding allyl acetate in 95% yield. Stille-coupling26 of the
resulting allyl acetate with the known27 hydroxystannane 8 using
Pd(dba)2 and LiCl in DMF at 50 °C afforded the coupling
product in 96% yield. MnO2 oxidation of the resulting allylic
alcohol furnished the aldehyde 23 in 80% yield.
30% pyridine in the presence of excess pyridine furnished
1
synthetic (+)-amphirionin-4 (1) in 98% yield. The H and 13
C
23
NMR of our synthetic amphirionin-4 {[α]D + 6.4 (c 0.08,
CHCl3)} are identical to the reported spectra for the natural
(+)-amphirionin-4 {lit4 [α]D + 6 (c 0.29, CHCl3)}, thus
20
confirming the absolute configuration of our synthetic material.
In summary, we have achieved an enantioselective synthesis of
(+)-amphirionin-4 (1). The synthetic route is convergent and
readily scalable. The longest linear path is nine steps from readily
available racemic butyrolactone. The synthesis featured lipase
resolution of a racemic lactone to give highly optically pure
isomers. Other key reactions include a highly diastereoselective
syn-allylation reaction, an efficient Stille coupling to construct the
polyene side chain and a NHK coupling to establish the C8 allylic
alcohol diastereoselectively. Our synthesis has provided rapid
access to (+)-amphirionin-4 (1) and structural variants for
biological studies. Further investigations of structural and
biological studies are in progress.
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DOI: 10.1021/acs.orglett.6b00942
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Letter
(8) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986,
108, 5644−5646.
Scheme 5. Synthesis of (+)-Amphirionin-4 (1)
(9) Blakemore, P. R.; Cole, W. J.; Kocienski, P.; Morley, A. Synlett
1998, 1998, 26−28.
(10) MaGee, D.; Mallais, T. C.; Mayo, P. D. M.; Strunz, G. M.
Tetrahedron 2006, 62, 4153−4161.
(11) Kang, H. Y.; Ji, Y.; Yu, Y. K.; Yu, J. Y.; Lee, Y.; Lee, S. J. Bull. Korean
Chem. Soc. 2003, 24, 1819−1826.
(12) Bianchi, D.; Cesti, P.; Battistel, E. J. Org. Chem. 1988, 53, 5531−
34.
(13) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 505−508.
(14) Enders, D.; Sun, H.; Leusink, F. R. Tetrahedron 1999, 55, 6129−
6138.
(15) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 1999.
(16) Ahrens, H.; Paetow, M.; Hoppe, D. Tetrahedron Lett. 1992, 33,
5327−5330.
(17) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879−10884.
(18) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, 12,
1552−1555.
(19) Ohira, S. Synth. Commun. 1989, 19, 561−564.
(20) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
1996, 521−522.
(21) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644−
17655.
(22) Llardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10, 1727−
1730.
(23) Zheng, Y. F.; Oehlschlager, A. C.; Hartman, P. G. J. Org. Chem.
1994, 59, 5803−5809.
(24) Bellina, F.; Carpita, A.; Santis, M. D.; Rossi, R. Tetrahedron 1994,
50, 4853−4872.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00942.
■
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(25) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600−7605.
(26) Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990, 55,
3019−3023.
(27) Chellat, M. F.; Proust, N.; Lauer, M. G.; Stambuli, J. P. Org. Lett.
2011, 13, 3246−3249.
Experimental procedures and 1H- and 13C- NMR spectra
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
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*E-mail: akghosh@purdue.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this work was provided in part by the
National Institutes of Health and Purdue University.
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REFERENCES
■
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77−93.
(b) Kobayashi, J.; Kubota, T. J. J. Nat. Prod. 2007, 70, 451−460.
(2) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35−94.
(3) Kumagai, K.; Minamida, M.; Akakabe, M.; Tsuda, M.; Konishi, Y.;
Tominaga, A.; Tsuda, M.; Fukushi, E.; Kawabata, J. Bioorg. Med. Chem.
Lett. 2015, 25, 635−638.
(4) Minamida, M.; Kumagai, K.; Ulanova, D.; Akakabe, M.; Konishi, Y.;
Tominaga, A.; Tanaka, H.; Fukushi, E.; Kawabata, J.; Masuda, A.; Tsuda,
M. Org. Lett. 2014, 16, 4858−4861.
(5) Akakabe, M.; Kumagai, K.; Tsuda, M.; Konishi, Y.; Tominaga, A.;
Tsuda, M.; Fukushi, E.; Kawabata, J. Tetrahedron Lett. 2014, 55, 3491−
3494.
(6) Holmes, M.; Kwon, D.; Taron, M.; Britton, R. Org. Lett. 2015, 17,
3868−3871.
(7) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281−5284.
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DOI: 10.1021/acs.orglett.6b00942
Org. Lett. XXXX, XXX, XXX−XXX