Enantioselective total synthesis of (+)-gigantecin: Exploiting the asymmetric glycolate aldol reaction

Article abstract of DOI:10.1021/ja0455852

The enantioselective synthesis of the potent, selective, cytotoxic, annonaceous acetogenin, (+)-gigantecin, has been completed. An asymmetric glycolate aldol serves to establish the stereocenters at C13,14 and at C21,22. A Carreira asymmetric acetylide ad

Full text of DOI:10.1021/ja0455852

Published on Web 09/18/2004
Enantioselective Total Synthesis of (+)-Gigantecin: Exploiting the
Asymmetric Glycolate Aldol Reaction
Michael T. Crimmins* and Jin She
Department of Chemistry, Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received July 22, 2004; E-mail: crimmins@email.unc.edu
Plants of the family Annonaceae produce an abundant collection
of highly bioactive C35-C37 fatty acid metabolites.1 These aceto-
genins have been found to effect potent depletion of ATP levels
via inhibition of complex I (NADH, ubiquinone oxidoreductase)
of mammalian and insect mitochondrial transport systems and in-
hibition of the NADH oxidase of plasma membranes of tumor cells.2
Consequently, they disrupt ATP-driven resistance mechanisms and
have shown activity against multidrug-resistant tumor types.3 The
three main classes of annonaceous acetogenins are monotetrahy-
drofuran, adjacent bis-THF, and nonadjacent bis-THF subclasses.
The significant biological activity of the acetogenins, as well as
their interesting and diverse structures, has stimulated substantial
interest in their chemical synthesis.4 Gigantecin (1), a representative
nonadjacent bis-THF acetogenin, was isolated from the bark of
Goniothalamus giganteus in Southeast Asia5 and the seed of the
Brazilian plant Annona coriacea.6 The relative and absolute con-
figurations of gigantecin were assigned after extensive spectroscopic
and Mosher ester analysis, and the assignment was confirmed by
single-crystal X-ray analysis.5,6 Gigantecin displayed potent cyto-
toxicity against A-549 (lung carcinoma), HT-29 (colon adenocar-
cinoma), MCF-7 (breast adenocarcinoma), and U251MG (glioblas-
toma multiforme) human tumor cell lines at ED50s of 0.4, 0.001,
4.3, and 0.003 µg/mL, respectively.5
Figure 1. Retrosynthesis of (+)-gigantecin.
Scheme 1. Synthesis of Butenolide 2a
Herein we disclose the first total synthesis of (+)-gigantecin.7
The synthesis exploits a modified asymmetric aldol protocol using
chlorotitanium enolates of oxazolidinone glycolates. Strategically,
gigantecin was envisioned to derive from a convergent assembly
of three key subunits (Figure 1). The confluence of acetylene 4
and aldehyde 5 according to Carreira’s8 method would join the two
tetrahydrofuran rings and establish the C17 stereocenter. Conversion
of the acetylide adduct to acetylene 3 would set the stage for its
coupling9 to butenolide 2 leading to completion of the synthesis.
Both acetylene 4 and aldehyde 5 would be accessible by applying
an asymmetric glycolate aldol-ring-closing metathesis sequence.
The C1-C6 butenolide 2 was constructed as shown in Scheme 1.
Alkylation of the sodium enolate of oxazolidinone glycolate 6 with
allylic iodide 7 proceeded in good yield (71%) and excellent
diastereoselectivity (>98:2).10 The chiral auxiliary was reductively
cleaved, and the ensuing primary alcohol was protected as its
TBDPS ether to deliver vinyl bromide 9. Lithium-halogen
exchange of bromide 9 and reaction with CO2 produced the acrylic
acid derivative, which cleanly gave ester 11 upon inversion of
alcohol 10 under Mitsunobu conditions.11 Diene 11 was exposed
to the Grubbs second-generation catalyst12 to produce butenolide
12 in 95% yield. Removal of the silyl ether of 12 furnished primary
alcohol 13. Alcohol 13 was oxidized to aldehyde, which underwent
Takai olefination13 to give the required vinyl iodide 2.
a Conditions: (a) NaN(SiMe3)2, THF, -78 to -45 °C, iodide 7, 71%; (b) NaBH4,
THF, H2O, 92%; (c) TBDPSCl, imidazole, CH2Cl2, 72%; (d) t-BuLi, THF, -78 °C;
CO2, 82%; (e) DEAD, Ph3P, THF, alcohol 10, 87%; (f) Cl2(Cy3P)(IMes)RudCHPh,
CH2Cl2, 40 °C, 95%; (g) 3HF-Et3N, CH3CN, 94%; (h) (COCl)2, DMSO, Et3N, CH2Cl2,
97%; (i) CHI3, CrCl2, THF, 62% (two steps).
Scheme 2. Synthesis of C9-C16 Fragment 4a
a Conditions: (a) Me3SI, n-BuLi, THF, -10 to 25 °C, 99%;16 (b) NaH, BrCH2CO2H,
THF, 98%; (c) Me3CCOCl, Et3N, THF, -78 to 0 °C; (R)-lithio-4-benzyl-oxazolidin-
2-one, 78%; (d) TiCl4, i-Pr2NEt, N-methyl-2-pyrrolidinone, aldehyde 16, CH2Cl2, -78
to -40 °C, 93%; (e) MeOCH2Cl, i-Pr2NEt, CH2Cl2, DMAP, 91%; (f) LiBH4, MeOH,
Et2O, 0 °C, 92%; (g) (COCl)2, DMSO, Et3N, CH2Cl2; (h) Ph3PdCH2, THF, 91%, two
steps; (i) Cl2(Cy3P)(IMes)RudCHPh, CH2Cl2, 40 °C, 99%; (j) n-Bu4NF, THF, 98%.
prepared in three straightforward steps from (S)-benzyl glycidyl
ether 14 as shown in Scheme 2. Glycolate 15 was treated with TiCl4
(1.05 equiv) and i-Pr2NEt (2.5 equiv) for 1 h at -78 °C followed
by N-methyl-2-pyrrolidinone (1.0 equiv) at -78 °C for 10 min.
Aldehyde 16 was added to the enolate followed by warming to
-40 °C. This procedure resulted in a highly diastereoselective aldol
The syntheses of both the C9-C16 alkyne 4 and the C17-C34
aldehyde 5 were predicated on the implementation of a newly
developed protocol for asymmetric aldol reactions of complex
glycolyl oxazolidinone chlorotitanium enolates.14 Glycolate 15 was
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J. AM. CHEM. SOC. 2004, 126, 12790-12791
10.1021/ja0455852 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Synthesis of (+)-Gigantecina
Scheme 3. Synthesis of C17-C34 Fragment 5a
a Conditions: (a) TiCl4, i-Pr2NEt, N-methyl-2-pyrrolidinone, tridecanal, CH2Cl2,
-78 to -40 °C, 74%; (b) MeOCH2Cl, i-Pr2NEt, CH2Cl2, DMAP, 91%; (c) LiBH4,
MeOH, Et2O, 0 °C, 95%; (d) (COCl)2, DMSO, Et3N, CH2Cl2; (e) Ph3PdCH2,
THF, 90%, two steps; (f) Cl2(Cy3P)(IMes)RudCHPh, CH2Cl2, 40 °C, 99%; (g)
H2, Pd/C, EtOH, 83%; (h) (COCl)2, DMSO, Et3N, CH2Cl2.
a Conditions: (a) Zn(OTf)2, (-)-N-methylephedrine, PhCH3, 4 then 5, 70% for
two steps from 26; (b) MeOCH2Cl, i-Pr2NEt, CH2Cl2, DMAP, 97%; (c) H2, Pd/C,
EtOH, 97%; (d) Tf2O, Et3N, CH2Cl2 -78 °C; (e) Me3SiCtCH, n-BuLi, THF,
HMPA, -78 °C; MeOH, 25 °C, 95% for two steps; (f) iodide 2, Pd(PPh3)4, CuI,
i-Pr2NEt, THF, 64%; (g) H2, Rh(PPh3)3Cl, C6H6, EtOH, LiI 61%; (h) BF3‚OEt2,
Me2S, 0 °C, 71%.
reaction to deliver the alcohol 17 in 93% yield and >20:1 dr (major:
all other isomers). Protection of the secondary alcohol as its MOM
ether and reductive removal of the auxiliary afforded the alcohol
18. The primary alcohol 18 was oxidized under Swern conditions,15
and the aldehyde was immediately converted to the alkene 19.
Exposure of diene 19 to the Grubbs second-generation catalyst12
led to selective formation of the dihydrofuran 20 in high yield with
no indication of reaction of the acetylene. The terminal TIPS group
was readily removed leading to the desired alkyne 4.
The C17-C34 aldehyde 5 was similarly constructed as illustrated
in Scheme 3. Once again, the NMP-promoted asymmetric aldol
reaction was exploited, in this instance to establish the C21 and
C22 stereogenic centers. The alcohol 22 was obtained in 74% yield
(>15:1 dr) upon exposure of glycolate 21 (ent-15) to aldol con-
ditions identical to those described above with the exception of
utilizing tridecanal as the aldehyde component. Protection of the
secondary alcohol as its MOM ether followed by reduction of the
glycolate carbonyl gave the alcohol 23. Oxidation of the alcohol
and olefination of the derived aldehyde provided the diene 24. The
diene 24 was subjected to the Grubbs catalyst12 as before, resulting
in formation of the dihydrofuran 25. Exposure of dihydrofuran 25
to hydrogen in the presence of Pd/C effected concomitant reduction
of the alkene and hydrogenolysis of the C17 benzyl ether to give
26. The C17 alcohol 26 was then converted to the aldehyde 5 under
Swern conditions.15
With the three required fragments in hand, their assembly to (+)-
gigantecin was undertaken. The Carreira method for asymmetric
acetylide8 addition was chosen for the addition of acetylene 4 to
aldehyde 5 since others had noted low diastereoselectivity in similar
additions without chiral additives.17 In the event, addition of acetyl-
ene 4 to Zn(OTf)2 and (-)-N-methylephedrine in toluene followed
by addition of aldehyde 5 produced the propargylic alcohol 27 in
70% yield (two steps including Swern oxidation) as a single detec-
table stereoisomer (Scheme 4). The C17 hydroxyl was protected
as its MOM ether to deliver 28. Treatment of enyne 27 with hydro-
gen in the presence of Pd/C led to the concomitant reduction of
the double and triple bonds as well as removal of the C9 benzyl
ether to give alcohol 29. Formation of the C9 triflate with its ensuing
displacement by lithium trimethylsilylacetylide provided the acetyl-
ene 3 in high yield. The final C-C bond was fashioned by
palladium-mediated coupling9 of the acetylene 3 with vinyl iodide
2 to provide enyne 30. Selective hydrogenation4d of the C5-C8
enyne followed by removal4d of the protecting groups led to the
completion of the synthesis of (+)-gigantecin. Synthetic gigantecin
was identical (1H, 13C NMR, [R]24D) to the natural material.
The first total synthesis of the annonaceous acetogenin (+)-
gigantecin has been completed in an enantioselective manner in
19 linear steps from commercially available benzyl glycidyl ether.
Acknowledgment. This work was supported by a research grant
(GM60567) from the National Institutes of General Medical Scien-
ces. We also thank Daiso Chemicals for a generous gift of benzyl
glycidyl ether.
Supporting Information Available: Experimental procedures as
well as 1H and 13C NMR spectra for all new compounds and synthetic
(+)-gigantecin (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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