Enantioselective synthesis of apoptolidinone: Exploiting the versatility of thiazolidinethione chiral auxiliaries

Article abstract of DOI:10.1021/ja0549289

An efficient, enantioselective synthesis of apoptolidinone has been completed, demonstrating the versatility of thiazolidinethione auxiliaries. Three propionate aldol additions and two asymmetric glycolate alkylations function to establish 8 of the 12 ste

Full text of DOI:10.1021/ja0549289

Published on Web 09/20/2005
Enantioselective Synthesis of Apoptolidinone: Exploiting the Versatility of
Thiazolidinethione Chiral Auxiliaries
Michael T. Crimmins,* Hamish S. Christie, Kleem Chaudhary, and Alan Long
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, 2005; E-mail: crimmins@email.unc.edu
Apoptolidin A (1) (Figure 1) is a potent, selective mediator of
apoptosis in E1A transformed rat glia cells.1 Khosla has shown
that apoptolidin induces cell death by inhibiting the mitochondrial
F0F1-ATPase.1 As a result of its remarkably selective effects on
cancer cells, apoptolidin A shows great potential for the treatment
of cancer.1 The interesting chemical structure, combined with its
appealing biological properties, has made apoptolidin A an attractive
target for synthesis. Since the isolation1 and structure elucidation2
of apoptolidin A, two total syntheses,3 two syntheses of apoptoli-
dinone,4 several partial syntheses,5 as well as a number of synthetic
modifications6 have been reported. Wender recently identified two
Figure 1. Structure of apoptolidin A.
additional metabolites, apoptolidins B and C, which exhibit slightly
improved antitumor activity.7
Scheme 1. Retrosynthetic Analysis of Apoptolidinone
This report describes a synthesis of apoptolidinone (2), the
aglycone of apoptolidin A. Apoptolidinone contains the carbon
backbone of apoptolidin A, but lacks the 6-deoxy-4-O-methyl-L-
glucose and D-oleandrose/L-olivomycose sugars appended to the
C9 and C27 oxygens, respectively. Apoptolidinone was targeted
for synthesis as a check-point en route to a total synthesis of
apoptolidin A. The approach involves the construction and coupling
of components 3, 4, and 5 (Scheme 1), wherein a regio- and
stereoselective cross-metathesis reaction was chosen for the key
C10-C11 bond-forming reaction to assemble the C1-C10 and
C11-C28 subunits. Three thiazolidinethione propionate aldol
reactions and two glycolate alkylation reactions formed the basis
for controlling the configuration of 8 of 12 stereogenic centers in
apoptolidinone.
The synthesis of ketophosphonate 5 provided an opportunity to
demonstrate the utility and versatility of thiazolidinethione chiral
auxiliaries8 (Scheme 2). Alkylation of O-benzylglycolyloxazolidi-
The previous sequence demonstrates the capability to selectively
access either syn aldol product, from the same N-propionylthiazo-
none 69 followed by reductive removal of the auxiliary, methylation
of the intermediate primary hydroxyl, and finally oxidative cleavage
lidinethione, simply by altering reaction conditions (equivalent to
of the terminal alkene delivered aldehyde 7. The enolate of
thiazolidinethione 8 was formed by treatment with 1 equiv each of
TiCl4, (-)-sparteine, and N-methylpyrrolidinone.8 Addition of
conducting the same reaction using different enantiomers of chiral
auxiliary), to convert the N-acylthioimide to the aldehyde in one
rather than two synthetic steps, and to directly displace the auxiliary
with a carbon nucleophile to form a â-ketophosphonate.11
aldehyde 7 to the enolate solution produced aldol product 9 with
excellent selectivity (>98:2) for the Evans syn isomer. Aldol adduct
Preparation of aldehyde 4 began by alkylation of glycolyl imide
9 was transformed into aldehyde 10 by protection of the alcohol
12 with prenyl iodide12 (Scheme 3). The auxiliary was reductively
as its triethylsilyl ether and subsequent reduction of the N-acyl
removed using LiBH4, whereupon Swern oxidation13 of the resultant
thioimide with i-Bu2AlH. A second aldol reaction was then
alcohol provided aldehyde 13 in excellent yield. Titanium tetra-
performed with aldehyde 10. In this case, the enolate was prepared
chloride mediated allylation of aldehyde 13 with allyltrimethylsilane
from thioimide 8 using 1 equiv of TiCl4 and excess i-Pr2NEt.8 Use
provided the alcohol 14 resulting from chelation-controlled14
of these conditions led to the non-Evans syn isomer 11 with
nucleophile addition (>98:2 dr). The alcohol was protected to give
the TBS ether 15. Selective hydroboration of the less substituted
alkene using catecholborane and Wilkinson’s catalyst15 afforded,
after oxidative workup, a C13 primary alcohol. Conversion of the
alcohol to the corresponding acetate and subsequent ozonolysis of
the trisubstituted alkene afforded the requisite C13-C19 aldehyde
4 in good overall yield.
excellent selectivity. While a very similar derivative to 11 has
previously been prepared by Sulikowski,5h the use of the glycolate
alkylation and thiazolidinethione aldol technologies led to a more
efficient preparation of 11. Aldol 11 was converted to the C20-
C28 phosphonate 5 by first protecting the hydroxyl group as the
trimethylsilyl ether followed by direct displacement of the auxiliary
with lithiodimethyl methylphosphonate.10
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C O M M U N I C A T I O N S
Scheme 4. Completion of the C13-C28 Fragment 20a
Scheme 2. Synthesis of the C20-C28 Fragment 5a
a Conditions: (a) NaN(SiMe3)2, PhMe, THF, H2CdCHCH2I, -78 to -45
°C, 75%; (b) NaBH4, THF, H2O, 1 h, 85%; (c) NaH, MeI, THF, 0 °C to 25
°C, 88%; (d) OsO4, NMO, THF, H2O, 15 h; (e) NaIO4, H2O, THF, 60%
(two steps); (f) 8, TiCl4, (-)-sparteine, NMP, CH2Cl2, then 7, -30 °C, 14
h, 90%; (g) Et3SiOTf, 2,6-lutidine, CH2Cl2, 97%; (h) i-Bu2AlH, heptane,
CH2Cl2, 86%; (i) 8, TiCl4, i-Pr2NEt, CH2Cl2, then 10, -13 °C, 13 h, 62%;
(j) Me3SiCl, Et3N, DMAP, CH2Cl2, 0 °C, 2 h, 79%; (k) (MeO)2P(O)Me,
n-BuLi, THF, -78 °C, 2 h, 96%.
a Conditions: (a) Ba(OH)2, THF, H2O, 88%; (b) PPTS, MeOH, 0 °C,
94%; (c) t-BuSiMe2OTf, lutidine, CH2Cl2, -78 °C, 95%; (d) OsO4, NMO,
pyr., acetone, H2O, 3 days, 57% + 14% isomer; (e) (Cl3CO)2CO, pyr.,
CH2Cl2, -78 °C, 40 min, 98%; (f) H2, Pd/C, EtOAc, 100%; (g)
t-BuSiMe2OTf, lutidine, CH2Cl2, -78 °C, 96%.
Scheme 3. Preparation of the C13-C19 Fragment 4a
Scheme 5. Synthesis of Trieneoate 3a
a Conditions: (a) LiN(i-Pr)2, THF, -78 °C, then Me2CdCHCH2I, THF,
-78 °C, 2 h, 70%; (b) LiBH4, MeOH, Et2O, 0 °C, 80%; (c) (COCl)2,
Me2SO, CH2Cl2, then Et3N, -78 °C to 25 °C, 99%; (d) TiCl4,
H2CdCHCH2SiMe3, CH2Cl2, -78 °C, 30 min, 79%; (e) t-BuSiMe2OTf,
2,6-lutidine, CH2Cl2, -78 °C, 97%; (f) catecholborane, ClRh(PPh3)3, THF,
then H2O2, NaOH; (g) Ac2O, Et3N, DMAP, CH2Cl2, 77% (two steps); (h)
O3, CH2Cl2, -78 °C, then Me2S, 80%.
a Conditions: (a) t-BuSiMe2OTf, 2,6-lutidine, CH2Cl2, -78 °C, 84%;
(b) i-Bu2AlH, heptane, CH2Cl2, -78 °C, 75%; (c) 23, PhH, reflux, 12 h,
95%; (d) i-Bu2AlH, heptane, CH2Cl2, -78 °C, 83%; (e) MnO2, PhH, reflux,
20 min, (f) 23, PhH, reflux, 12 h; (g) i-Bu2AlH, heptane, CH2Cl2, -78 °C;
(h) MnO2, PhH, reflux, 20 min, (i) 23, PhH, reflux, 12 h, 85% (five steps);
(j) H2SiF6, CH3CN, H2O, 5 h, 96%.
Coupling of aldehyde 4 and ketophosphonate 5, in a Horner-
Wadsworth-Emmons reaction, was effected using Ba(OH)2 under
the mild conditions described by Sinisterra16 and Paterson17 (Scheme
4). Treatment of enone 16 with mildly acidic methanol at 0 °C
effected cleavage of the silyl ethers, which led to cyclization
forming mixed methyl ketal 17 in high yield.18 Importantly, when
the C23 hydroxyl protecting group was triethylsilyl or tert-
butyldimethylsilyl, the rate of formation of ketal 17 was substan-
tially slower, leading to significant decomposition, prior to ketal
formation. The C23 hydroxyl of ketal 17 was protected as the TBS
ether, and the alkene at C19-C20 was dihydroxylated with OsO4
to produce a mixture of diastereomers, favoring the desired diol.19
Importantly, pyridine-acetone-H2O was required as the solvent
for the reaction to proceed at a reasonable rate.20 The pure major
isomer, readily obtained by flash chromatography, was protected
as its cyclic carbonate 18 by treatment with triphosgene.21 The C27
benzyl ether was selectively removed by hydrogenolysis to provide
the C27 alcohol 19. Revealing the C27 hydroxyl at this stage opens
the opportunity for the selective attachment of the C27 D-olean-
drose-L-olivomycose disaccharide unit required for the synthesis
of apoptolidin A. In contrast, for the synthesis of apoptolidinone,
the C27 hydroxyl group was protected as the TBS ether 20.
The C1-C10 trieneoate 3, needed for the metathesis reaction,
was readily synthesized beginning with known aldol 21 (Scheme
5).8a Protection of the alcohol 21 followed by reduction with i-Bu2-
AlH delivered aldehyde 22. Wittig reaction with phosphorane 2322
provided unsaturated ester 24 with good selectivity for the E isomer.
Two iterations of a i-Bu2AlH reduction, MnO2 oxidation, and Wittig
olefination sequence, followed by removal of the silyl group
converted diene 24 to tetraene 3, in high overall yield.
Elaboration of the C13-C28 acetate 20, to form the C11-C28
diene coupling partner 26 for the key olefin metathesis reaction,
commenced with cleavage of the acetate group with basic methanol
followed by Swern oxidation13 (Scheme 6). Wittig reaction of the
aldehyde with phosphorane 2523 produced an unsaturated aldehyde,
with high E selectivity, which afforded diene 26 upon reaction with
methylenetriphenylphosphorane.
The trisubstituted, conjugated olefins of tetraene 3 and the
trisubstituted olefin of diene 26 were expected to be unreactive
under cross-metathesis conditions.24 A cross-metathesis reaction
between the terminal vinyl groups of these compounds was
anticipated to be facile and selective for the desired C10-C13 diene
27, based on the expected difference in reactivities24 of the two
alkenes. In the event, exposure of the alkenes 325 and 26 to the
Grubbs heterocyclic carbene catalyst [Cl2(Cy3P)(IMes)RudCHPh]26
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C O M M U N I C A T I O N S
Scheme 6. Apoptolidinone Endgame Strategya
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bright yellow color of the acylated thiazolidinethiones simplify the use
and purification of these compounds.
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the best yields; see ref 9.
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(18) The yield of cyclization product was critically dependent on the choice
of hydroxyl protecting groups at C25 and C23; for example, the bis-TES
derivative gave only 50-60% of product 17.
(19) Koert has reported dihydroxylation reactions on similar alkenes in his
apoptolidin A synthetic studies; see refs 3a, 4b, and 5f.
a Conditions: (a) K2CO3, MeOH, 10-15 °C, 5 h, 93%; (b) (COCl)2,
Me2SO, CH2Cl2, then Et3N, -78 °C to 25 °C, 94%; (c) Ph3PdC(Me)CHO
(25), PhCl, 90 °C, 78%; (d) CH3PPh3Br, KOt-Bu, THF, 25 °C, 98%; (e) 3,
10% Cl2(PCy3)(Imes)RudCHPh, CH2Cl2, 25 °C, 3 h, 63% + 31% 26; (f)
t-BuSiMe2Cl, imidazole, DMF, 25 °C, 12 h, 75%; (g) LiOH-H2O, THF,
MeOH, H2O (6:2:1), 25 °C, 2.5 days, 77%; (h) 2,4,6-Cl3C6H2C(O)Cl, Et3N,
THF, 25 °C, 4 h, then PhMe, DMAP, 25 °C, 20 h, 68%; (i) H2SiF6, CH3CN,
H2O, -18 °C, 2 days, then 0 °C, 2 days, 61%.
provided the desired E isomer 27 in good yield (>95:5 E:Z by 1H
NMR analysis). While 2 equiv of the tetraene 3 was utilized in the
cross-metathesis, the homodimer of tetraene 3 could be recovered
and recycled. To complete the synthesis of apoptolidinone, the
alcohol 27 was protected as its TBS ether 28.27 Treatment of the
ester 28 with LiOH at room temperature rapidly cleaved the
carbonate group and eventually the ester to give a good yield of
the desired seco acid. Regioselective macrolactonization proceeded
smoothly under Yamaguchi’s conditions to deliver lactone 29.28
Cleavage of the silyl ethers and hydrolysis of the mixed methyl
3a,29
acetal were effected in one operation using H2SiF6
to furnish
apoptolidinone (2),30 the analytical data for which were consistent
with those reported previously.4a,b
An efficient, enantioselective synthesis of apoptolidinone has
been completed, demonstrating the versatility of thiazolidinethione
auxiliaries. This successful approach will be directly applicable to
the synthesis of apoptolidin A; progress toward this goal is
underway.
(20) DeCamp, A. E.; Mills, S. G.; Kawaguchi, A. T.; Desmond, R.; Reamer,
R. A.; DiMichele, L.; Volante, R. P. J. Org. Chem. 1991, 56, 3564.
(21) Over 5 g of carbonate 18 has been prepared by this sequence.
(22) Bestmann, H.-J.; Hartung, H. Chem. Ber. 1966, 99, 1198.
(23) Kiyooka, S.; Hena, M. A. J. Org. Chem. 1999, 64, 5511.
(24) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360.
Acknowledgment. Financial support from the National Cancer
Institute (CA63572) is gratefully acknowledged.
(25) Two equivalents of the trieneoate 3 was used.
(26) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(27) The cross-metathesis reaction proceeds in poor yield (∼20%) if the reaction
is performed with the TBS group present on the C9 oxygen. However,
the subsequent lactonization reaction fails if the reaction is attempted with
the free hydroxyl group at C9.
Supporting Information Available: Experimental procedures and
1
copies of H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) See ref 3c and Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(29) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.; DeShong,
P. J. Org. Chem. 1992, 57, 2492.
(30) HF-pyr used by both Koert (ref 4b) and Sulikowski (ref 4a) in their similar
deprotections was not useful in our hands.
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