Synthesis of the C(26)-C(42) and C(43)-C(67) pyran-containing fragments of amphidinol 3 via a common pyran intermediate

Article abstract of DOI:10.1021/ol703042q

The pyran-containing fragments 1 and 2 of AM3 have been synthesized from the common pyran intermediate 3. Careful orchestration of the alcohol protecting groups was necessary to facilitate deprotection of alcohol functionality in the presence of the chemi

Full text of DOI:10.1021/ol703042q

ORGANIC
LETTERS
2008
Vol. 10, No. 4
681-684
Synthesis of the C(26)
−C(42) and
C(43) C(67) Pyran-Containing Fragments
−
of Amphidinol 3 via a Common Pyran
Intermediate
Jacqueline D. Hicks and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received December 18, 2007
ABSTRACT
The pyran-containing fragments 1 and 2 of AM3 have been synthesized from the common pyran intermediate 3. Careful orchestration of the
alcohol protecting groups was necessary to facilitate deprotection of alcohol functionality in the presence of the chemically sensitive polyene
chain.
Amphidinol 3 (AM3, Figure 1) is a biologically active poly-
ketide natural product isolated from the marine dinoflagellate
Amphidinium klebsii.1 The amphidinols display antifungal
activity against Aspergillus niger and hemolytic activity of
human erythrocytes.1,2 These biological properties are thought
to arise from disruption of cell membranes by the hydropho-
bic C(52)-C(67) polyene chain of AM3.1b,2d,3 Other intrigu-
ing structural features of the amphidinols include the acyclic
polyol region typically containing a series of 1,5-diols and
two highly substituted tetrahydropyran ring systems.
The biological activity and structural complexity of AM3
has ignited the interest of several synthetic laboratories,4 and
the Rychnovsky5 and Paquette6 groups have assembled large
portions of the natural product. We report herein syntheses
of the fully functionalized C(26)-C(42) and C(43)-C(67)
pyran-containing fragments of AM3.
(1) (a) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J.
Am. Chem. Soc. 1991, 113, 9859. (b) Paul, G. K.; Matsumori, N.; Konoki,
K.; Sasaki, M.; Murata, M.; Tachibana, K. Harmful and Toxic Algal Blooms.
Proceeding of the SeVenth International Conference on Toxic Phytoplankton;
Yasumoto, T., Oshima, Y., Fukuyo, Y., Eds.; UNESCO: Sendai, Japan,
1996; p 503.
Our retrosynthetic disconnection of AM3 provides three
major fragments (Figure 1): the C(43)-C(67) fragment 1,
(2) (a) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K. Tetra-
hedron Lett. 1995, 36, 6279. (b) Paul, G. K.; Matsumori, N.; Konoki, K.;
Murata, M.; Tachibana, K. J. Marine Biotech. 1997, 5, 124. (c) Morsy, N.;
Matsuoka, S.; Houdai, T.; Matsumori, N.; Adachi, S.; Murata, M.; Iwashita,
T.; Fujita, T. Tetrahedron 2005, 61, 8606. (d) Morsy, N.; Houdai, T.;
Matsuoka, S.; Matsumori, N.; Adachi, S.; Oishi, T.; Murata, M.; Iwashita,
T.; Fujita, T. Bioorg. Med. Chem. 2006, 14, 6548. (e) Echigoya, R.; Rhodes,
L.; Oshima, Y.; Satake, M. Harmful Algae 2005, 4, 383.
(3) (a) Houdai, T.; Matsuoka, S.; Matsumori, N.; Murata, M. Biochim.
Biophys. Acta Biomembranes 2004, 1667, 91. (b) Houdai, T.; Matsuoka,
S.; Morsy, N.; Matsumori, N.; Satake, M.; Murata, M. Tetrahedron 2005,
61, 2795.
(4) (a) Colobert, F.; Kreuzer, T.; Cossy, J.; Reymond, S.; Tsuchiya, T.;
Ferrie, L.; Marko, I. E.; Jourdain, P. Synlett 2007, 2351. (b) BouzBouz, S.;
Cossy, J. Org. Lett. 2001, 3, 1451. (c) Dubost, C.; Marko, I. E.; Bryans, J.
Tetrahedron Lett. 2005, 46, 4005.
10.1021/ol703042q CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/19/2008

Figure 1. Retrosynthetic analysis of amphidinol 3.
the C(26)-C(42) fragment 2, and the acyclic polyol fragment
(previously synthesized in our laboratory, not shown).7 We
envisioned that the C(42)-C(43) bond between the two
pyran-containing fragments would be formed via the coupling
of aldehyde 1 and a vinyl metal species formed from iodide
2. Fragments 1 and 2 can be further simplifed to pyran 3, an
intermediate containing all of the stereocenters within each
fragment.
We have previously reported the synthesis of polyene 48
and had planned to elaborate this fragment to an aldehyde
similar to 1. However, attempted deprotection of the terminal
C(43,44) acetonide of 4 to progress toward the required C(43)
aldehyde could be accomplished only in e20% yield (Fig-
ure 2), despite examining a number of protic and Lewis
acidic conditions that had been effective on intermediates
that lack the polyene side chain. Significant decomposition
of the polyolefinic intermediates occurred under all the
conditions examined.9 These efforts alerted us to the sensitiv-
ity of the polyolefin-containing intermediates and foreshad-
owed potential problems later in the synthesis were we to
continue with acetonide protecting groups for the vicinal
diols. The results also prompted us to pilot the removal of
the PMB ethers in the presence of the skipped-polyene.
However, employing conditions that were effective on earlier
intermediates lacking the skipped-polyene unit,10 we were
unable to effect deprotection of 4slikely due to competing
DDQ oxidation of the triene.11
The unsuccessful deprotection reactions summarized in
Figure 2 prompted us to reexamine our protecting group
strategy. After considering several options, we concluded that
(5) (a) De Vicente, J.; Betzemeier, B.; Rychnovsky, S. D. Org. Lett.
2005, 7, 1853. (b) De Vicente, J.; Huckins, J.; Rychnovsky, S. D. Angew.
Chem., Int. Ed. 2006, 45, 7258. (c) Huckins, J. R.; De Vicente, J.;
Rychnovsky, S. D. Org. Lett. 2007, 9, 4757.
(6) (a) Chang, S.-K.; Paquette, L. A. Synlett 2005, 2915. (b) Paquette,
L. A.; Chang, S.-K. Org. Lett. 2005, 7, 3111. (c) Bedore, M. W.; Chang,
S.-K.; Paquette, L. A. Org. Lett. 2007, 9, 513.
(7) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411.
(8) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509.
(9) A table containing conditions examined can be found in the
Supporting Information.
Figure 2. Deprotection studies of polyene 4.
682
Org. Lett., Vol. 10, No. 4, 2008

cyclopentylidene ketals might be a good replacement for the
acetonide protecting groups of 4. Cyclopentlylidene ketals
are more acid labile than acetonides,12 and the use of cyclic
ketals would result in minimal changes to our previously
developed route.8 To test this proposal, we performed some
initial experiments with polyene 7 (eq 1).13 These studies
revealed that the terminal C(43,44) cyclopentylidene ketal
and the more acid stable C(50,51) trans-cyclopentylidene
ketal could be removed by brief treatment with acidic
methanol in modest yield (unoptimized). Encouraged by this
result, we chose to explore pyran 3 (Scheme 1) as our
common pyran intermediate in order to facilitate late-stage
deprotection.
Scheme 1. Synthesis of the C(43)-C(67) Fragment
Accordingly, by using appropriate modifications of our
previously reported sequence,8 we developed a synthesis of
the key common pyran intermediate 3 by replacing the
problematic acetonide protecting groups in 4 with more acid
labile cyclopentlylidene ketals. Moreover, the polyene-
incompatible PMB ethers of 4 were replaced with TBS ether
protecting groups in 3 (see the Supporting Information for
details).
The fully functionalized C(43)-C(67) fragment 1 was syn-
thesized from pyran 3 (Scheme 1). Removal of the primary
TBDPS ether of 3, in the presence of the two secondary TBS
ethers, by using TAS-F proceeded in 70-96% yield.14 Swern
oxidation of the primary alcohol, addition of vinyl-MgBr to
the resulting aldehyde, and then Johnson orthoester Claisen
rearrangement15 of the derived allylic alcohol provided ester
9 with excellent E:Z selectivity (43% overall yield). We opted
to remove the terminal C(43,44) cyclopentylidene ketal of
9 by using FeCl3 on silica gel.16 We found these conditions
to be the most efficent way to selectivity deprotect the
terminal acetonide in the presence of the two TBS ethers
and the internal trans-cyclopentylidene ketal; however, the
polyene was not stable to these conditions, therefore neces-
sitating deprotection prior to installation of the polyene. Thus,
the diol resulting from deprotection of 9 was protected as
the bis-silyl ether by using TESCl, and the C(56)-ethoxy-
carbonyl group was reduced with DIBAL at -78 °C to
provide aldehyde 10. Olefination of 10 with the ylide derived
from dimethylphosphonium salt 11 installed the polyene
chain in 75% yield and 92:8 E/Z selectivity. This olefination
represents an improvement over our previously published
Horner-Wadsworth-Emmons olenfination that we used for
the synthesis of 4 (86:14 E/Z).8 Swern oxidation of the
primary TES ether17 then provided aldehyde 1, the fully
elaborated C(43)-C(67) fragment of AM3.
Construction of the C(26)-C(42) pyran fragment began
by deprotection of the terminal cyclopentylidene ketal of 3
(FeCl3 on silica gel, 85%)16 to reveal diol 12, which was
converted to epoxide 13 by using Martinelli’s selective
tosylation protocol (Scheme 2).18 Treatment of 13 with
dilithiopropyne19 installed the propargyl unit of 14 (85%).
Use of the unusual dilithiopropyne reagent was necessary
because treatment of 13 with the corresponding Grignard
reagent20 resulted in significant bromohydrin formation.
(10) It is speculated that the two-step deprotection sequence was
necessary because after removal of the first PMB ether, oxidation of the
second PMB ether results in p-methoxybenzylidene acetal formation. The
acetal is further oxidized to the benzoate, which then undergoes hydrolysis
with basic methanol.
(11) For examples of low-yielding PMB deprotection on polyolefinic
substrates see: (a) Couladouros, E. A.; Bouzas, E. A.; Mangos, A. D.
Tetrahedron 2006, 62, 5272. (b) Evans, D. A.; Gage, J. R.; Leighton, J. L.
J. Org. Chem. 1992, 57, 1964. (c) Asato, A. E.; Kiefer, E. F. Chem.
Commun. 1968, 1684.
(12) (a) Van Heeswijk, W. A.; Goedhart, J. B.; Vliegenthart, J. F. G.
Carbohydr. Res 1977, 58, 337. (b) Hampton, A.; Fratantoni, J. C.; Carrol,
P. M.; Wang, S. J. Am. Chem. Soc. 1965, 87, 5481. (c) Evans, D. A.;
Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899.
(13) See the Supporting Information for the synthesis of 7.
(14) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(17) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161.
(18) Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.;
Dhokte, U. P.; Doecke, C. W.; Zollars, L. M.; Moher, E. D.; Van Khau,
V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578.
(15) Johnson, W. S.; Werthermann, L.; Bartlett, W. R.; Brocksom, T.
J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741.
(16) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem.
1986, 51, 404.
(19) Pereira, A. R.; Cabezas, J. A. J. Org. Chem. 2005, 70, 2594.
Org. Lett., Vol. 10, No. 4, 2008
683

Scheme 2. Synthesis of the C(26)-C(42) Fragment
Protection of the secondary hydroxyl group of the bisho-
rearrangement followed by conversion of the methoxycar-
bonyl to the methyl ketone unit in 2, 30% yield).
mopropargyl alcohol afforded TBS-ether 14 (83% overall
from 13). Stannylalumination21 of 14 followed by iodination
yielded 15 (94%). Deprotection of the primary TBDPS ether
using TAS-F14 provided alcohol 16 (76%), which underwent
Swern oxidation and propenyl Grignard addition to afford
allylic alcohol 17 as an inconsequential 2:1 diastereomeric
mixture (82%). Treatment of 17 with 2-methoxypropane and
PPTS generated an intermediate vinyl ether which was heated
at 170 °C in chlorobenzene to effect Claisen rearrangement.22
This provided the C(26)-C(42) pyran fragment 2 with 95:5
E/Z selectivity in 43% yield. While the efficency of this
Claisen sequence is moderate, the yield of 2 from 17 is higher
from this two-step sequence than from other Claisen
sequences that we explored (e.g., Johnson ortho ester Claisen
In summary, the fully functionalized pyran-containing
fragments 1 and 2 of AM3 have been synthesized from the
common pyran intermediate 3. A revised protecting group
strategy was employed to facilitate deprotection of alcohol
functionality in the presence of the sensitive polyene chain.
The silyl ether and cyclopentylidene ketal protected pyran 3
was elaborated to the C(43)-C(67) fragment in nine steps
(10% yield) and to the C(26)-C(42) fragment in 12 steps
(17% yield). Further progress toward completion of the total
synthesis of amphidinol 3 will be reported in due course.
Acknowledgment. This work was supported by the
National Institutes of Health (GM038436).
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Hopf, H.; Bohm, I.; Kleinschroth, J. Org. Synth. 1981, 60, 41.
(21) (a) Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1989, 54, 5064.
(b) Corminboef, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc.
2003, 125, 6650.
(22) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125,
8798.
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