Total Synthesis of Amphirionin-4

Article abstract of DOI:10.1021/acs.orglett.5b01844

The first total synthesis of amphirionin-4 has been achieved using a combination of cross-coupling strategies to access the polyene side chain and a chlorohydrin-based approach to construct the tetrahydrofuranol core. The remote C9-stereocenter was introd

Full text of DOI:10.1021/acs.orglett.5b01844

Letter
pubs.acs.org/OrgLett
Total Synthesis of Amphirionin‑4
Michael Holmes, Daniel Kwon, Matthew Taron, and Robert Britton*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
S
* Supporting Information
ABSTRACT: The first total synthesis of amphirionin-4 has been achieved using a
combination of cross-coupling strategies to access the polyene side chain and a
chlorohydrin-based approach to construct the tetrahydrofuranol core. The remote
C9-stereocenter was introduced through a Nozaki−Hiyama−Kishi coupling that
proceeded with remote stereoinduction.
Amphidinium species of marine dinoflagellates have proven to
be a rich source of structurally diverse polyketides,1 many of
which are characterized by cyclic ethers of various ring sizes and
potent cytotoxic activity (e.g., amphidinolide B2 and
amphidinin A3). Recently, Tsuda and co-workers isolated a
number of new cyclic ether-containing polyketides (e.g., 1−3,
Figure 1) from the KCA09051 strain of Amphidinium collected
off the coast of Iriomote Island in the Okinawa archipelago.4 Of
particular interest is amphirionin-4 (1),4a which demonstrates
selective and potent proliferation activity on murine bone
marrow stromal ST-2 cells (+950% growth rate at 0.1 ng/mL).
medicinal chemistry purposes, we envisioned three key
retrosynthetic disconnections (Scheme 1). Specifically, the
Scheme 1. Retrosynthetic Analysis for Amphirionin-4 (1)
remote allylic alcohol at C9 would be introduced through a
Nozaki−Hiyama−Kishi (NHK)8 reaction involving the vinyl
iodide 4 and the aldehyde 5, while assembling the polyene side
chain would rely on iterative Pd-catalyzed cross-coupling
reactions. Although we were apprehensive about the stereo-
chemical outcome of the proposed NHK reaction, ultimately
the undesired epimer could be inverted through a Mitsunobu
reaction9 or oxidation/reduction sequence if necessary. Syn-
thesis of the tetrahydrofuranol 4 would then involve method-
ology previously developed by us7 that exploits readily available
and enantiomerically enriched α-chloroaldehydes10 as building
blocks for the stereoselective synthesis of heterocyclic natural
products.7 Thus, we anticipated that a lithium aldol reaction
between a suitably functionalized α-chloroaldehyde (e.g., 9)
and acetone, followed by a diastereoselective ketone reduc-
Figure 1. Structures of amphirionin-2, -4, and -5, isolated from a strain
of Amphidinium KCA09051.
These cells promote the development of lymphocytes from
bone marrow cells,5 and consequently, amphirionin-4 (1) may
have utility in enhancing immune response to disease and bone
regeneration.4a,6 Structurally, amphirionin-4 comprises an all-
syn-tetrahydrofuranol core with both a remote allylic alcohol at
C9 and skipped tetraene motif on the heptadecyl side chain.
Considering its unique structure and potentially useful
biological activity, we were interested in extending our
chlorohydrin-based strategies for tetrahydrofuranol synthesis7
to the preparation of this unusual Amphidinium polyketide.
With an ultimate goal of developing a modular synthesis of
amphirionin-4 (1) that would provide access to analogues for
Received: June 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01844
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion11 and cyclization, would secure the all-syn tetrahydrofur-
Scheme 3. 1,4-Stereoinduction in the NHK Reaction of
Vinyl Iodide 4
anol 4 in an expedient manner.7d
The synthesis of the tetrahydrofuranol 4 is described in
Scheme 2 and began with hydroiodination of the alkyne
Scheme 2. Synthesis of Tetrahydrofuranol 4
Having established a means to control the stereochemical
outcome of the key NHK coupling, we focused on preparing
the requisite pentadecatetraenal 5. Toward this goal, the vinyl
bromide 26 was accessed from 2,3-dibromopropene following a
copper(I) catalyzed reaction with the Grignard reagent derived
from TMS-acetylene (Scheme 4).18 A zirconium catalyzed
Scheme 4. Synthesis of the Vinyl Halides 23 and 26
function in 4-pentyn-1-ol (12)12 followed by a Swern
oxidation13 to give aldehyde 13. Notably, the modest yield
for the hydroiodination of 12 (46%) reflects the necessary
stoppage of this reaction at ∼60% conversion, which was
required to prevent the generation of an inseparable byproduct
produced after prolonged reaction times (yield >70% yield
based on unreacted 12). A subsequent asymmetric α-
chlorination of 13 using MacMillan’s catalyst 1810c and
NCS14 gave the α-chloroaldehyde 14 in good enantiomeric
excess (90% ee). We were pleased to find that reaction of this
later material with the lithium enolate generated from acetone
afforded the desired β-ketochlorohydrin (not shown) in good
yield and diastereoselectivity (dr = 7:1), and a subsequent 1,3-
anti selective reduction11 of the resulting β-ketochlorohydrin
provided diol 15. This later material cyclized smoothly to the
tetrahydrofuranol 4 when heated (120 °C) in MeOH in a
microwave reactor.7d The relative stereochemistry of 4 was
assigned by analysis of correlations in 1D NOESY spectra,
while synthesis of the corresponding (R)- and (S)-MTPA esters
and subsequent analysis using the modified Mosher’s method15
confirmed the absolute stereochemistry of 4 as shown.16
Having secured the correctly configured tetrahydrofuranol
core of amphirionin-4, it was of interest to explore the planned
NHK reaction. Toward this goal, we evaluated the reaction of
vinyl iodide 4 with 4-pentenal (19) and were disappointed to
find this reaction produced a 1:1 mixture of diastereomeric
alcohols 20 and 21 as did the reaction of the corresponding
acetate 17 (Scheme 3). Considering the competing coordina-
tion sites in 4 and 17 with the putative vinyl chromium
intermediate, the C4 alcohol in 4 was also protected as a TBS
ether to preclude coordination at this position and we were
delighted to find that the diastereoselectivity of the subsequent
NHK reaction improved to ∼4:1 in favor of the desired
stereoisomer 20. This unusual example of 1,4-stereoinduction
may involve coordination of the vinyl chromium intermediate
to the tetrahydrofuran oxygen,17 with subsequent addition
through the pro-S TS (see inset) to minimize steric interactions
(cf. pro-R TS).
carboalumination19 of the alkyne 22 followed by reaction with
I2 afforded the vinyl iodide 24 in excellent yield. As described
below, it was expected that the cross-coupling of the vinyl
halides 23 and 26 could be effected following conversion of one
of these compounds into the corresponding vinyl boronic acid
(e.g., 23 → 24).
Table 1 summarizes our efforts to effect a cross-coupling
reaction between derivatives of the vinyl halides 23 and 26,
Table 1. Cross-coupling Reactions to Access Diene 30
entry reactants
temp
catalyst
additive
yield
a
1
2
3
4
5
6
7
23+28
23+28
23+28
23+29
27+26
24+26
25+26
50 °C
50 °C
50 °C
50 °C
50 °C
55 °C
55 °C
Pd(PPh3)4
Pd(PPh3)4
Pd(dtbpf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
CsCO3
∼10%
<5%
<5%
<5%
<5%
<5%
68%
a
a
Ba(OH)2
Ba(OH)2
a
CsCO3
b
CuI, CsF
c
CsCO3
a
CsCO3
a
b
A 1:1 mixture of THF−H2O was used as solvent. DMF was used as
c
solvent. EtOH was used as solvent.
B
DOI: 10.1021/acs.orglett.5b01844
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
which proved challenging. As summarized in entries 1−4,
coupling of the vinyl iodide 23 with either the Bpin or BF3K
salts derived from 2620,21 using various combinations of
palladium catalyst, base, and solvent only afforded trace
amounts of the desired diene 30 accompanied by degradation
products derived from the vinyl boron species. Likewise, the
cross-coupling of vinyl stannane 27 (entry 5) or boronic acid
24 (entry 6) with the vinyl bromide 26 were equally
unsuccessful and only products of proteo-destannylation or
deborylation were observed. Considering these results, we
explored use of the corresponding vinyl trifluoroborate 25,
which reportedly offers improved stability in Suzuki−Miyaura
couplings.21 Gratifyingly, as indicated in entry 7, cross-coupling
of the vinyl trifluoroborate 25 with the vinyl bromide 26 using
Molander’s conditions21 afforded the desired diene 30 cleanly
and in good yield (68%) on multigram scale.
attempts to remove the TBS protecting group from this
material resulted in decomposition. Considering the instability
of the skipped tetraene function in 37, we elected to modify the
synthetic plan and thus incorporate the sensitive tetraene at the
final stage in the synthesis.
A modified and ultimately successful synthetic approach to
amphirionin-4 (1) is depicted in Scheme 6. Oxidation of the
Scheme 6. Completion of the Synthesis of Amphirionin-4
(1)
Completion of the synthesis of the pentadecatetraenal is
described in Scheme 5. Conversion of 4-pentenal into the trans-
Scheme 5. Synthesis of TBS-Protected Amphirionin-4 37
alcohol function in 34 followed by an NHK coupling and
deprotection afforded the tetrahydrofuranol 38 cleanly and in
excellent overall yield. The alkyne was subsequently converted
into the requisite vinyl iodide following the sequence of
reactions described above for the preparation of the related
vinyl iodide 35 (Scheme 5). Disappointingly, efforts to effect
the subsequent Stille cross-coupling with vinyl stannane 33
were unsuccessful using several standard reaction conditions
including those that had provided the diene 30 (Table 1, entry
7) and resulted only in intractable mixtures of products.
However, we were delighted to find that Furstner’s
̈
conditions,26 which are ideal for sensitive substrates, proved
effective and yielded access to amphirionin-4 (1) in excellent
1
yield over these final two steps. The H and 13C NMR spectra
recorded on synthetic amphirionin-4 were in agreement with
that reported for the natural product;4a however, the specific
rotation (−5.8, c 0.34, CHCl3) differed in sign from that of
natural amphirionin-4 (+6, c 0.29, CHCl3).4a Considering that
the absolute stereochemistry for 1 was originally assigned by
analysis of bis(R)- and bis(S)-MTPA esters using the modified
Mosher’s method,15 we also converted our synthetic amphir-
ionin-4 into the corresponding bis(R)-MTPA ester 39. The
spectral data recorded on this derivative were in complete
agreement with those reported by Tsuda4a for the bis(R)-
MTPA ester derived from natural amphirionin-4 and differed
significantly from the data reported for the corresponding
bis(S)-MTPA ester of 1.4a Considering these facts, the
difference in specific rotation of synthetic and natural
amphirionin-4 can then only result from its small absolute
value and the consequent difficulty in accurately measuring
specific rotation with small sample sizes.
vinyl trifluoroborate 32 or tributylstannane 33 involved a Takai
reaction22 followed by lithium−iodide exchange and treatment
with triisopropylborate followed by potassium hydrogenfluor-
ide21 or tributyl tin chloride. Sequential carboalumination of
23
alcohol 34 and reaction with I2 gave the vinyl iodide 35 in
good overall yield. Our initial efforts to couple this sensitive
vinyl iodide with vinyl trifluoroborate 32 were unsuccessful due
to isomerization of the diene system in the former material at
elevated temperatures in basic solution. However, a Stille
coupling24 between the vinyl stannane 33 and vinyl iodide 35
gave access to the polyene 36 in good yield. Subsequent
oxidation25 and NHK coupling with tetrahydrofuran 16
afforded the TBS-protected amphirionin-4 37 in good yield
and expected diastereoselectivity (vide supra). Unfortunately, all
In summary, we have completed the first total synthesis of
amphirionin-4 through a linear 11-step sequence and confirmed
both the relative and absolute stereochemistry of this unique
C
DOI: 10.1021/acs.orglett.5b01844
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1716−1719. (e) Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett.
2009, 11, 1717−1720. (f) Holmes, M. T.; Britton, R. Chem. - Eur. J.
2013, 19, 12649−12652.
(8) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281−5284. (b) Jin, H.; Uenishi, J.; Christ,
W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644−5646.
(9) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−
2382.
(10) (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790−4791. (b) Brochu,
M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
4108−4109. (c) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121−5124.
(11) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560−3578.
(12) Kim, G.; Jung, S.-d.; Kim, W.-j. Org. Lett. 2001, 3, 2985−2987.
(13) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651−1660.
(14) Winter, P.; Swatschek, J.; Willot, M.; Radtke, L.; Olbrisch, T.;
Amphidinium polyketide. The ultimately successful synthetic
route highlights the efficiency of our chlorohydrin-based
approach to access tetrahydrofuranols and relied on an unusual
example of 1,4-stereoinduction to establish the correctly
configured C9 allylic alcohol. Further investigation of remote
stereoinduction of this kind for the purpose of analogue
synthesis and potentially as a general method for the substrate-
controlled synthesis of other tetrahydrofuran-containing natural
products is currently being explored in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analysis data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01844.
Schafer, A.; Christmann, M. Chem. Commun. 2011, 47, 12200−12202.
̈
(15) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543−2549. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512−519.
AUTHOR INFORMATION
Corresponding Author
■
(16) See Supporting Information for full details.
(17) Mowat, J.; Kang, B.; Fonovic, B.; Dudding, T.; Britton, R. Org.
Lett. 2009, 11, 2057−2060.
*E-mail: rbritton@sfu.ca.
Notes
The authors declare no competing financial interest.
(18) Terrell, L. R.; Ward, J. S.; Maleczka, R. E. Tetrahedron Lett.
1999, 40, 3097−3100.
(19) Zheng, Y. F.; Oehlschlager, A. C.; Hartman, P. G. J. Org. Chem.
1994, 59, 5803−5809.
ACKNOWLEDGMENTS
■
This work was supported by an NSERC Discovery Grant to
R.B., an MSFHR Career Investigator Award to R.B., and SFU
Graduate Fellowships to M.H., D.K., and M.T. The authors
thank Dr. Jake Goodwin-Tindall (Simon Fraser University) and
Professor Masashi Tsuda (Kochi University) for helpful
discussions.
(20) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem.
Soc. 2002, 124, 8001−8006.
(21) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950−3956.
(22) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408−7410.
(23) Zhu, G.; Negishi, E. I. Chem. - Eur. J. 2008, 14, 311−318.
(24) (a) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed.
2004, 43, 1132−1136. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508−524.
REFERENCES
■
(1) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26−78. (b) 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. (c) Van Wagoner, R. M.;
Satake, M.; Wright, J. L. C. Nat. Prod. Rep. 2014, 31, 1101−1137.
(d) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009, 26, 170−244. (e) Kobayashi,
J.; Kubota, T. J. Nat. Prod. 2007, 70, 451−460. (f) Kobayashi, J. J.
Antibiot. 2008, 61, 271−284. (g) Kobayashi, J.; Tsuda, M. Nat. Prod.
Rep. 2004, 21, 77−93.
(25) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156.
(26) Furstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.;
̈
Nevado, C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun.
2008, 2873−2875.
(2) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1987,
1127−1129.
(3) Kobayashi, J.; Yamaguchi, N.; Ishibashi, M. Tetrahedron Lett.
1994, 35, 7049−7050.
(4) (a) 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. (b) Akakabe,
M.; Kumagai, K.; Tsuda, M.; Konishi, Y.; Tominaga, A.; Tsuda, M.;
Fukushi, E.; Kawabata, J. Tetrahedron Lett. 2014, 55, 3491−3494.
(c) 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.
(5) Tominaga, A.; Mita, S.; Kikuchi, Y.; Hitoshi, Y.; Takatsu, K.;
Nishikawa, S.; Ogawa, M. Growth Factors 1989, 1, 135−146.
(6) (a) Baddour, J. a.; Sousounis, K.; Tsonis, P. A. Birth Defects Res.,
Part C 2012, 96, 1−29. (b) Sassoli, C.; Zecchi-Orlandini, S.; Formigli,
L. Cells 2012, 1, 832−850.
(7) (a) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083−5086.
(b) Halperin, S. D.; Kang, B.; Britton, R. Synthesis 2011, 4, 1946−
1953. (c) Britton, R.; Kang, B. Nat. Prod. Rep. 2013, 30, 227−236.
(d) Kang, B.; Chang, S.; Decker, S.; Britton, R. Org. Lett. 2010, 12,
D
DOI: 10.1021/acs.orglett.5b01844
Org. Lett. XXXX, XXX, XXX−XXX