Gephyronic acid, a missing link between polyketide inhibitors of eukaryotic protein synthesis (Part II): Total synthesis of gephyronic acid

Article abstract of DOI:10.1002/anie.201005605

19 steps in the longest linear sequence are required in the 27 step total synthesis of gephyronic acid. A key step is a diastereodifferentiating Mukaiyama aldol reaction of an aldehyde and an enolsilane (see picture, PG: protecting group). The strongly cy

Full text of DOI:10.1002/anie.201005605

Communications
DOI: 10.1002/anie.201005605
Natural Product Synthesis
Gephyronic Acid, a Missing Link between Polyketide Inhibitors of
Eukaryotic Protein Synthesis (Part II): Total Synthesis of
Gephyronic Acid**
Timo Anderl, Lionel Nicolas, Johanna Mꢀnkemer, Angelika Baro, Florenz Sasse,
Heinrich Steinmetz, Rolf Jansen, Gerhard Hꢁfle, Richard E. Taylor,* and Sabine Laschat*
Dedicated to Professor Horst Kunz on the occasion of his 70th birthday
Marine invertebrates and microorganisms of marine and
terrestrial origin are rich sources of biologically active
secondary metabolites, which may be potent pharmaceutical
lead compounds.[1] Among them are the structurally related
polyketide natural products tedanolide (1), isolated from the
Caribbean sponge Tedania ignis,[2] its truncated congeners
myriaporone 3 and 4 (2) obtained from the Mediterranean
false coral Myriapora truncata,[3] and gephyronic acid (3)[4]
isolated from the myxobacterium Archangium gephyra strain
Ar 3895; the latter is also a possible pharmacophoric link
between structurally distinct classes of polyketides
(Scheme 1).
Compounds 1–3 were found to be potent inhibitors of
eukaryotic protein synthesis. On account of their pronounced
cytotoxicities, synthetic approaches were elaborated,[5,6] cul-
minating in the total synthesis of tedanolide (1)[7] and
myriaporones (2).[8] The presence of a trisubstituted epoxide
Scheme 1. Polyketide natural products tedanolide (1), myriaporones 3
and 4 (2), and gephyronic acid (3; structure from NMR studies[9,10]).
unit in gephyronic acid (3) was originally proposed in an
article detailing the structural similarities between com-
pounds 1–3 and pederin.[9] The lack of structural information
regarding C8 and C3–C5 severely hampered further biolog-
ical and synthetic studies, and thus, a detailed NMR study was
initiated.[10] As the possible diastereomers of 3 were not
unambiguously distinguishable from NMR data alone, anal-
ysis of synthetic fragments and ultimately total synthesis
proved essential. Our retrosynthetic strategy was based on
disconnection of gephyronic acid (3) into the fragments C9–
C17 (4) and C1–C8 (5), which can be traced back to methyl
(R)-3-hydroxy-2-methylpropionate ((R)-8) and 1,3-propane-
diol (9), respectively (Scheme 2).
[*] T. Anderl, J. Mꢀnkemer, Dr. A. Baro, Prof. S. Laschat
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-64285
E-mail: sabine.laschat@oc.uni-stuttgart.de
L. Nicolas, Prof. R. E. Taylor
Department of Chemistry & Biochemistry
University of Notre Dame, IN 46556-5670 (USA)
Dr. F. Sasse, H. Steinmetz, Dr. R. Jansen, Prof. G. Hꢂfle
Abteilung Chemische Biologie und
Arbeitsgruppe Mikrobielle Wirkstoffe
Helmholtz-Zentrum fꢀr Infektionsforschung (Germany)
[**] This work was supported by the National Science Foundation, the
Deutsche Forschungsgemeinschaft (CHE-0924351 for R.E.T. and
F.S.), the Deutsche Akademische Austauschdienst (fellowship for
T.A.), the Ministerium fꢀr Wissenschaft, Forschung und Kunst des
Landes Baden-Wꢀrttemberg (Landesgraduierten fellowship for
T.A.), and the Fonds der Chemischen Industrie.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005605.
Scheme 2. Retrosynthesis of gephyronic acid (3). PMB=para-methoxy-
benzyl.
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Angew. Chem. Int. Ed. 2011, 50, 942 –945

The synthesis of building block 4 started with a Wittig
olefination of aldehyde 6[11,12] and subsequent acidic depro-
tection[13] to give alcohol 10. Oxidation with Dess–Martin
periodinane followed by Wittig olefination with the stabilized
ylide 11 afforded ester 12 (Scheme 3). Aldehyde 13, which
Scheme 4. Synthesis of the C1–C8 fragment 5. LDA=lithium diisopro-
pylamide, TBAF=tert-butylammonium fluoride.
ketone 5. The syn stereochemistry in 20 was supported by
NMR analysis of lactone 22 derived from 20 (Scheme 4).[26]
As the key step for coupling of the fragments 4 and 5, a
stereodifferentiating BF3·OEt2 promoted Mukaiyama aldol
reaction[27] was chosen (Scheme 5). Based on the facial
selectivities of anti aldehyde 4 and the enolsilane of 5 we
expected an anti-selective aldol formation.[22a,28,29] Indeed,
enolsilane 23, derived from 5 and fragment 4, coupled to give
the Felkin diastereomer 24 as the major product. Comparison
of coupling constants (J8-H,9-H = 9.8 Hz, J9-H,10-H = 1.4 Hz) with
those of structurally related compounds[27] revealed an anti
configuration at C8–C9. Mild deoxygenation involving treat-
ment with NaHMDS in CS2 and MeI,[30] reduction of the
xanthogenate with Bu3SnH·Et3B,[31] and subsequent depro-
tection with DDQ[32] provided primary alcohol 25 in 78%
yield over three steps. Successive Swern and Pinnick oxida-
tion with NaClO2 in the presence of 2-methyl-2-butene,[33]
methylation of the resulting carboxylic acid with (trimethyl-
silyl) diazomethane,[34] and cleavage of the TBS protecting
groups at C3 and C11 with 3HF·NEt3[12] gave methyl ester 26.
The latter reaction required 7 days to yield 26 in 77% yield
together with the ester singly deprotected at C3 in 21% yield.
The coupling constants of the fully characterized spiro acetate
27 prepared from 26 confirmed the configuration at C8.
Unfortunately, with substrate 26, epoxidation with
mCPBA at ꢀ608C[8,12] after 2 days led to a mixture of
oxidation products, and thus diol 26 was submitted to a
Sharpless epoxidation.[35] However, with S configuration at
C11, 26 is a typical mismatched case for classical Sharpless
Scheme 3. Synthesis of the C9–C17 fragment 4. DMP=Dess–Martin
periodinane, DIBAL-H=diisobutylaluminum hydride, DMSO=di-
methyl sulfoxide, TFA=trifluoroacetic acid, TMS=trimethylsilyl,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
was obtained after reduction with DIBAL-H[14] and Swern
oxidation, was submitted to a MgBr2·OEt2 catalyzed anti-
aldol reaction[15,16] with oxazolidin-2-one 14 to provide the
aldol product 15. The major diastereomer could be separated
chromatographically only after TBS protection of the secon-
dary hydroxy substituent at C3. Removal of the Evans
auxiliary from 15 with LiBH4 in MeOH[17] and Swern
oxidation of 16 accomplished the synthesis of fragment 4.
We utilized Evansꢀ aldol methodology[18] and treated
(4R)-oxazolidinone 14 with propanal 7[19–21] to give the syn
aldol product 17 with high diastereoselectivity (d.r. > 95:5)
(Scheme 4). Aldehyde 18 was accessible from 17 by a
sequence of TBS protection, removal of the auxiliary, and
Dess–Martin oxidation.[20] The BF3·OEt2 mediated
Mukaiyama aldol reaction[22] of 18 with silylketene acetal
19[22b] occurred with excellent syn selectivity (Felkin–Anh
control), and after O-methylation with Meerweinꢀs salt and
proton sponge,[23] the syn,syn methyl ester 20 was isolated as a
single diastereomer (d.r. > 95:5). Treatment of 20 with
TMSCH2Li and quenching with MeOH[24,25] gave methyl
ketone 21, which was methylated[24] to provide the target ethyl
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Scheme 5. Completion of the synthesis of gephyronic acid (3). Reagents and conditions: a) 1. LDA
(1.3 equiv), THF, ꢀ788C!ꢀ508C, 30 min, 2. HMPA (2.0 equiv), ꢀ788C, 30 min, 3. TMSOTf (2.0 equiv),
ꢀ788C!RT, 5 h; b) 23 (3.0 equiv), BF3·OEt2 (3.3 equiv), CaH2 (1.0 equiv), +4 (1.0 equiv), ꢀ1008C!
ꢀ788C, 3 h; c) 1. NaHMDS (1.4 equiv), CS2, ꢀ788C, 1 h, then MeI (15.0 equiv), ꢀ788C!08C, 3 h, 99%,
2. Bu3SnH (7.0 equiv), Et3B (1.1 equiv), air, toluene, RT, 1 h, 86%; d) DDQ (1.3 equiv), CH2Cl2/pH 7 buffer
9:1, 08C!RT, 1 h, 93%; e) 1. (COCl)2 (2.0 equiv), DMSO (3.0 equiv), NEt3 (6.0 equiv), CH2Cl2, ꢀ788C!
RT, 2. NaClO2 (2.5 equiv), KH2PO4 (7.0 equiv), 2-methyl-2-butene (4.5 equiv), tBuOH/H2O 3:1, RT, 1 h,
3. TMSCHN2 (2.0 equiv), CH2Cl2/MeOH 4:1, RT, 1 h, 94%; f) 3HF·NEt3, NEt3, MeCN, RT, 7 d, 77%;
g) HOOtBu (1.5 equiv), Ti(OiPr)4 (0.2 equiv), CH2Cl2, ꢀ208C, 14 h; h) 0.1m KOH solution/MeOH 1:1, RT,
1.5 h; i) PPTS (20 mol%), MeOH, RT, 24 h. HMDS=bis(trimethylsilyl)amide, HMPA=hexamethylphos-
phoramide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, PPTS=pyridinium p-toluenesulfonate.
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reaction rate was so low that no conversion was observed.
Upon reaction with tBuOOH and Ti(OiPr)4 in CH2Cl2 at
ꢀ208C epoxides 28a,b were obtained in 88% yield
(d.r. 44:56). After chromatographic separation, 28a (40%
yield) was finally treated with KOH/MeOH (1:1)[36] to afford
gephyronic acid (3) in 99% yield.
In conclusion, a 27 step (longest linear sequence 19 steps)
convergent total synthesis of gephyronic acid 3 in 4.4% yield
was realized. Comparison of the optical rotation in MeOH
20
[natural product: ½aꢁD ¼ + 46.5 degcm3 gꢀ1 dmꢀ1 (c = 1.00 in
20
100 mL), synthetic product: ½aꢁD ¼ + 45.7 degcm3 gꢀ1 dmꢀ1
(c = 0.42 in 100 mL)] and spectroscopic data proved the
identity with the natural product. The total synthesis has
provided an alternative source of the natural product,
enabling further biological investigations which are currently
under way.
Received: September 7, 2010
Published online: December 29, 2010
Keywords: aldol reaction · natural products · polyketides ·
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