Synthesis of the C-1-C-17 fragment of amphidinolides C, C2, C3, and F

Article abstract of DOI:10.1021/ol4004838

The C-1-C-17 fragment of amphidinolides C, C2, C3, and F has been constructed from a trans-2,5-disubstituted dihydrofuranone prepared by diastereoselective rearrangement of a free or metal-bound oxonium ylide generated from a metal carbenoid. The dihydrofuranone was converted into an aldehyde corresponding to the C-1-C-8 framework, and this was coupled to the C-9-C-17 unit by nucleophilic addition of a vinylic anion.

Full text of DOI:10.1021/ol4004838

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of the C‑1ÀC-17 Fragment
of Amphidinolides C, C2, C3, and F
J. Stephen Clark,* Guang Yang, and Andrew P. Osnowski
WestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow,
University Avenue, Glasgow G12 8QQ, United Kingdom
stephen.clark@glasgow.ac.uk
Received February 21, 2013
ABSTRACT
The C-1ÀC-17 fragment of amphidinolides C, C2, C3, and F has been constructed from a trans-2,5-disubstituted dihydrofuranone prepared by
diastereoselective rearrangement of a free or metal-bound oxonium ylide generated from a metal carbenoid. The dihydrofuranone was converted
into an aldehyde corresponding to the C-1ÀC-8 framework, and this was coupled to the C-9ÀC-17 unit by nucleophilic addition of a vinylic anion.
AmphidinolidesC, C2, C3, and Farestructurallyrelated
members of a large family of marine natural products
isolated from microalgae of amphidinium sp. (Figure 1).
Amphidinolide C possesses substantial anticancer activity
(IC50 values <0.01 μg mLÀ1 against certain cell lines).1
(1) (a) Kobayashi, J. J. Antibiot. 2008, 61, 271. (b) Kobayashi, J.;
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Figure 1. Amphidinolides C, C2, C3, and F.
The unique structures and bioactivities of amphidinolides
C,2 C2,3 C3,4 and F5 have aroused significant interest in
their syntheses, and several groups have reported syntheses
of fragments of the compounds.6 Very recently, Carter and
Mahapatra completed a synthesis of amphidinolide F in
which a common intermediate was used to prepare both
tetrahydrofurans.7
ꢀ
ꢁ
2010, 12, 2954. (g) Ferrie, L.; Figadere, B. Org. Lett. 2010, 12, 4976.
(h) Roy, S.; Spilling, C. D. Org. Lett. 2010, 12, 5326. (i) Morra, N. A.;
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r
10.1021/ol4004838
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The macrolactone common to amphidinolides C, C2,
C3, and F (1À4, Figure 1) contains two trans-2,5-disub-
stituted tetrahydrofurans. The similarity of the rings in-
spired us to design a synthesis in which a readily accessible
dihydrofuranone bearing suitable functionality would
serve as a common intermediate for the construction of
two acyclic fragments of similar size and complexity, thus
laying the foundations for convergent and efficient total
syntheses of all four natural products. This approach has
been validated recently by Mahapatra and Carter who
completed their total synthesis of amphidinolide F from a
common tetrahydrofuranyl intermediate.7
fragment.8 Consequently, the intermediate prepared by
diastereoselective rearrangement of a free or metal-bound
oxonium ylide, generated by intramolecular cyclization of
a copper carbenoid,9 will be used for the preparation of
both the ‘northern’ and ‘southern’ fragments ii and i.
Scheme 2. Construction of the C-1ÀC-8 Fragment
Scheme 1. Retrosynthetic Analysis of Amphidinolide C
The retrosynthetic analysis of amphidinolide C is shown
in Scheme 1. As described in the preceding paper,8 initial
disconnection of the lactone CÀO bond and the C-17ÀC-
18 bond gives the ‘northern’ and ‘southern’ fragments ii
and i. Disconnection of the ‘southern’ fragment i through
the C-8ÀC-9 bond leads to the vinylic organometallic
compound iii and the aldehyde iv. The vinylic organome-
tallic compound iii can be converted into the enyne v,
implying regioselective hydrometalation of the alkyne
in the forward direction. Disconnection through the
C-10ÀC-11 alkene and oxidation at C-13 then reveals the
β-hydroxy ketone vi. Subsequent aldol disconnection be-
tween C-14 and C-15 leads to the aldehyde vii and the
ketone viii, both of which can be prepared from chiral pool
materials. The aldehyde iv can undergo two one-carbon
disconnections to give the ketone ix which corresponds to
the intermediate used in our synthesis of the ‘northern’
The dihydrofuranone 5 corresponding to the C-1ÀC-7
fragment was prepared from dimethyl D-malate in six steps
as described in the preceding paper.8 Wittig methylenation
of the ketone 5 proceeded to afford diene 6 in quantita-
tive yield (Scheme 2). Selective dihydroxylation of the
(9) (a) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. (b) Clark, J. S.;
Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385. (c) Clark,
J. S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381. (d) Clark, J. S.;
Dosseter, A. G.; Blake, A. J.; Li, W.-S.; Whittingham, W. G. Chem.
Commun. 1999, 749. (e) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N.
Chem. Commun. 2003, 2578. (f) Clark, J. S.; Fessard, T. C.; Wilson, C.
Org. Lett. 2004, 6, 1773. (g) Clark, J. S.; Fessard, T. C.; Whitlock, G. A.
Tetrahedron 2006, 62, 73. (h) Clark, J. S.; Hayes, S. T.; Wilson, C.;
Gobbi, L. Angew. Chem., Int. Ed. 2007, 46, 437. (i) Clark, J. S.; Berger,
R.; Hayes, S. T.; Thomas, L. H.; Morrison, A. J.; Gobbi, L. Angew.
Chem., Int. Ed. 2010, 49, 9867. (j) Clark, J. S.; Vignard, D.; Parkin, A.
Org. Lett. 2011, 13, 3980. (k) Clark, J. S.; Berger, R.; Hayes, S. T.; Senn,
H. M.; Farrugia, L. J.; Thomas, L. H.; Morrison, A. J.; Gobbi, L. J. Org.
Chem. 2013, 78, 673.
(8) Clark, J. S.; Yang, G.; Osnowski, A. P. Org. Lett. 2013, 15, DOI:
10.1021/ol400482j.
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side-chain alkene was achieved in 64% yield, and the result-
ing diol was then subjected to oxidative cleavage. The
intermediatealdehydewasreduced with NaBH4 toprovide
the alcohol 7, which was to be subjected to hydrogenation
of the methylene group to install the C-4 methyl substitu-
ent. The use of homogeneous catalysts to control the
stereochemical outcome hydrogenation reactions through
reversible coordination to hydroxyl or carbonyl groups is
precedented,10 and gratifyingly this approach proved to be
successful in our case. Hydrogenation of the alkene 7 using
Crabtree’s catalyst (12 mol %) afforded the saturated
product as a single isomer, and this compound was then
converted into the alcohol 8 in good yield by silylation of
the hydroxyl group with tert-butyldiphenylsilyl chloride
and subsequent cleavage of the TBS ether.
The carboxylic acid 9 was preparedfrom the alcohol8 by
sequential Dess-Martin and Pinnick oxidation reactions.
Subsequent HBTU-mediated coupling of the carboxylic
acid 9 to N,O-dimethylhydroxylamine afforded the Wein-
reb amide 10. Treatment of this amide with vinylmagne-
sium bromide resulted in the formation of the correspond-
ing enone. An alternative synthesis of the enone by
sequential oxidation of alcohol 8 to the aldehyde, addition
of vinylmagnesium bromide, and oxidation of the resulting
diastereomeric mixture of alcohols afforded material that
was difficult to purify in 53% yield. A Luche reduction of
the enone resulted in the clean formation of the required
diastereomer (dr > 9:1) and was followed by PMB protec-
tionof the allylic alcohol bya Lewis acid catalyzed reaction
with a trichloroacetimidate.11 Construction of the alde-
hyde 12, which corresponds to the C-1ÀC-8 fragment, was
completed by dihydroxylation of the alkene followed by
oxidative cleavage of the 1,2-diol.
Synthesis of the C-9ÀC-17 fragment began with con-
struction of the fragments shown in Scheme 3. The com-
mercially available ester 13 was first R-methylated stereo-
selectively (dr > 10:1) and in high yield.12 The hydroxyl group
of the resulting β-hydroxy ester 14 was then protected, and the
ester was converted into the Weinreb amide 15.13 Transforma-
tion of the amide into the target methyl ketone 16 was
accomplished cleanly and in high yield by reaction of the
amide 15 with methylmagnesium bromide. Aldehyde 19, the
requisite aldol coupling partner, was prepared from the
Roche ester 17. Protection of the hydroxyl group as a TBS
ether was followed by conversion of the ester into the
Weinreb amide 18. Reduction of the Weinreb amide with
DIBAL-H at low temperature afforded the aldehyde 19.
Aldol condensation of the aldehyde 19 with the boron
enolate generated from the methyl ketone 16 proceeded in
excellent yield and afforded the β-hydroxy ketone 20 as a
single diastereoisomer (Scheme 4), presumably as a con-
sequence of reinforcing 1,4- and 1,5-stereoinduction.14
Stereoselective directed ketone reduction with tetramethy-
lammonium triacetoxyborohydride afforded the anti-1,3-diol
with a high level of diastereocontrol (dr > 25:1).15 Silyla-
tion of both hydroxyl groups was accomplished by treat-
ment of the diol with tert-butyldimethylsilyl triflate,
and the PMB ether was cleaved with DDQ under standard
conditions. Oxidation of the resulting secondary alcohol
21 afforded the corresponding methyl ketone, and this was
subjected to HornerÀWadsworthÀEmmons olefination
with phosphonate 22 (E/Z > 15:1).16 Removal of the
trimethylsilyl group with potassium carbonate in wet
methanol afforded the terminal alkyne 23, and subsequent
palladium-catalyzed hydrostanylation with tributyltin hy-
dride afforded the vinylic stannane 24 in good yield.17
Scheme 3. Synthesis of Ketone 16 and Aldehyde 19
Scheme 4. Construction of the C-9ÀC-17 Fragment
(10) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
Org. Lett., Vol. XX, No. XX, XXXX
C

Fragment coupling to complete the entire C-1ÀC-17
fragment was performed as shown in Scheme 5. Subjection
of the vinyl stannane 24 to tinÀlithium exchange and
addition of the lithiated intermediate to the aldehyde 12
afforded the alcohol 25 with high diastereoselectivity
(dr > 10:1). The configuration of the newly created stereo-
genic center at C-8 was assigned as S based on comparison
of NMR data with those of closely related compounds pre-
pared by Carter and Mahapatra during their recently
reported total synthesis of amphidinolide F.7,18 Thus, it
was clear that the diastereomer of the required alcohol had
been obtained and inversion of configuration at the C-8
stereogenic center was required. Oxidation of the alcohol
with the Dess-Martin periodinane afforded the corre-
sponding enone, and highly diastereoselective 1,2-reduction
of the carbonyl group under Luche conditions afforded
the alcohol 26 (dr > 15:1) with the required R configura-
tion at the C-8 stereogenic center. The stereochemical
outcome of the ketone reduction reaction was confirmed
by comparison of the 1H and 13C NMR data obtained for
the diastereomeric alcohols 25 and 26 with those of the
closely related compound (C-1ÀC-14 fragment) prepared
by Mahapatra and Carter.7,18
Scheme 5. Coupling to Complete the C-1ÀC-17 Fragment
dihydrofuranone 5, a starting material from which the
carbon frameworks of both ‘northern’ and ‘southern’
fragments of the natural products have been synthesized.
Other key transformations include stereoselective boron-
mediated aldol condensation between the chiral pool
derived fragments 16 and 19 to produce the C-1ÀC-9 unit,
regioselective hydrostannylation of the enyne 23, and tinÀ
lithium exchange of the stannane 24 followed by nucleo-
philic addition to aldehyde 12.
In summary, the C-1ÀC-17 fragment of amphidinolide
C has been prepared in an efficient and stereoselective
fashion. An important feature of this synthesis is the use of
(11) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267.
(12) (a) Rabinowitz, M. H.; Andrews, R. C.; Becherer, J. D.; Bickett,
D. M.; Bubacz, D. G.; Conway, J. G.; Cowan, D. J.; Gaul, M.; Glennon,
K.; Lambert, M. H.; Leesnitzer, M. A.; McDougald, D. L.; Moss, M. L.;
Musso, D. L.; Rizzolio, M. C. J. Med. Chem. 2001, 44, 4252. (b)
Szpilman, A. M.; Cereghetti, D. M.; Wurtz, N. R.; Manthorpe, J. M.;
Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4335.
(13) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(14) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett.
1996, 37, 8585.
Acknowledgment. The authors acknowledge the sup-
port of WestCHEM, CSC, EPSRC, and the University of
Glasgow for funding.
(15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(16) Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000,
122, 4915.
Supporting Information Available. Experimental pro-
cedures and data for 6À12, 14À16, 18À21, and 23À26,
plus intermediate compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.,
Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 962.
(18) For tabulated selected NMR data, see Supporting Information.
(19) Luche reduction of the enone prepared from the alcohol 25 was
very slow, and some decomposition occurred. The yield of 37% is
unoptimized.
The authors declare no competing financial interest.
D
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