Total synthesis and stereochemical reassignment of (+)-neopeltolide

Article abstract of DOI:10.1002/anie.200704122

(Chemical Equation Presented) Take a closer look! The first enantioselective total synthesis, stereochemical reassignment, and absolute configuration of the metabolite neopeltolide is described (see picture). Synthetic highlights of this route include a modified Evans-Tishchenko reduction to introduce the C11 stereocenter, [4+2] annulation to construct the pyran system, and a Still-Gennari olefination to install the oxazole side chain.

Full text of DOI:10.1002/anie.200704122

Angewandte
Chemie
DOI: 10.1002/anie.200704122
Natural Products Synthesis
Total Synthesis and Stereochemical Reassignment of
(+)-Neopeltolide**
Willmen Youngsaye, Jason T. Lowe, Frauke Pohlki, Paul Ralifo, and James S. Panek*
Neopeltolide (1b) is a complex macrolide recently isolated by
Wright and co-workers from a deep-water sponge of the
family Neopeltidae which was found off the northwest coast
of Jamaica (Figure 1).[1] The species was not identified but was
described as a member of the genus Daedalopelta and a close
relative of Callipelta, the latter of which have proven to be a
rich source of biologically active marine metabolites.[2]
Although neopeltolide is isolated from the sponge, the
participation of epibiotic heterotrophic cyanobacteria in its
biosynthesis cannot be ruled out.[1,3]
On the basis of careful spectroscopic studies, the structure
of neopeltolide was reported as a 14-membered macrolactone
incorporating an anti 1,3-oxygenated pattern, an embedded
trisubstituted tetrahydropyran, and an oxazole-bearing side
chain identical to that found on leucascandrolide A (2,
Figure 1). Although coupling constant analysis, NOESY,
and a series of double-pulsed field gradient spin echo
(DPFGSE) NOE experiments permitted determination of
the relative stereochemistry, the lack of available material
prevented assignment of the absolute stereochemistry.[1a]
Biological assays of neopeltolide revealed potent in vitro
cytotoxicity toward several different cancer cell lines includ-
ing P388 murine leukemia, A-549 human lung adenocarci-
noma, and NCI-ADR-RES human ovarian sarcoma (IC50
values of 0.56, 1.2, and 5.1 nm, respectively). Neopeltolide
also showed strong inhibitory effects in PANC-1 pancreatic
and DLD-1 colorectal cell lines; however, only 50% cell
death was observed over an extended dose range, suggesting a
cytostatic rather than cytotoxic effect. In addition, 1b inhibits
growth of the pathogenic yeast Candida albicans with an MIC
value of 0.62 mgmLÀ1 in liquid cultures.[1] In comparison,
leucascandrolide A has higher IC50 values towards KB and
P388 cancer cell lines (0.05 and 0.25 mgmLÀ1, respectively)
but exhibits similar activity against Candida albicans.[4]
We were attracted to neopeltolide as a synthetic target
because of its structural complexity and bioactivity similar to
that of leucascandrolide A[5]. Our initial efforts focused on
synthesis of the proposed natural product 1a and afforded a
Figure 1. Sponge metabolites: the original neopeltolide structure (1a),
the correct structure of (+)-neopeltolide (1b),and leucascandrolide A
(2).
[*] W. Youngsaye,J. T. Lowe,Dr. F. Pohlki,Dr. P. Ralifo,
Prof. Dr. J. S. Panek
Department of Chemistry and
Center for Chemical Methodology and Library Development
Metcalf Center for Science and Engineering
Boston University
590 Commonwealth Avenue,Boston,MA 02215 (USA)
Fax: (+1)617-358-2847
1
compound that exhibited several H and 13C NMR spectro-
scopic discrepancies with the corresponding data reported for
naturally derived neopeltolide, suggesting a possible stereo-
chemical misassignment.[6] Upon close inspection of the
available spectral data, we undertook the synthesis of a
select set of diastereoisomers that would permit identification
of the correct stereochemical configuration of neopeltolide.
Herein we report the first enantioselective synthesis of
(+)-neopeltolide that culminates in a reassignment of the
C11 and C13 stereogenic centers and establishes the absolute
stereochemistry of the natural product.
E-mail: panek@bu.edu
Homepage: http://people.bu.edu/panek/
[**] The authors are grateful to Dr. Amy E. Wright from the Harbor
Branch Oceanographic Institution for forthright discussions and for
sharing comparative spectral data,and Dr. Les Dakin and Dr. Qibin
Su for the preparation of intermediates leading to the synthesis of 4.
This research was financially supported by GM55740. J.S.P. is
grateful to Amgen,AstraZeneca,Johnson & Johnson,Merck Co.,
Novartis,Pfizer,and GSK for financial support. J.T.L. acknowledges
an ACS Graduate Fellowship sponsored by Bristol-Myers Squibb
Pharmaceuticals and a Merck Graduate Fellowship. F.P. is grateful
to the Deutsche Forschungsgemeinschaft for a postdoctoral
fellowship.
Our retrosynthetic strategy began with disconnection of
À
the C19 C20 double bond to reveal the macrolide 3 and the
oxazole side chain 4 (see Still–Gennari olefination in
Scheme 1). We reasoned that the absolute stereochemistry
of 1b, particularly of the tetrahydropyran moiety, would
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Scheme 2. Synthesis of the C7–C16 fragment 5. a) BH3·SMe2,THF,
08C to RT; b) TBDPSCl,imidazole,DMF,0 8C to RT,80% (over 2
steps); c) DIBAL-H,diethyl ether, À788C; d) 1,3-propanedithiol, I2,
CHCl3,RT,85% (over 2 steps); e) tert-butyllithium,HMPA,THF, 7,
À788C,68%; f) CaCO 3,MeI,MeCN/H 2O,RT,73%; g) Zr(O tBu)4,
iPrCHO,toluene, À788C; h) Me3OBF4,Proton Sponge,4 Š molecular
sieves,CH 2Cl2,RT,90% (over 2 steps); i) 49% HF in H 2O,MeCN,RT,
91%; j) (COCl)2,DMSO,CH 2Cl2,Et N, À788C to RT,89%.
3
DMF=N,N-dimethylformamide,DIBAL-H =diisobutylaluminum hy-
dride,HMPA =hexamethylphosphoramide,Proton Sponge =1,8-bis(di-
methylamino)naphthalene,DMSO =dimethyl sulfoxide.
with CaCO3/MeI unmasked the desired ketone 11
(Scheme 2).
A
modified Evans–Tishchenko reduction[10]
(d.r. 14:1) provided the anti stereochemical relationship[11]
required for the C11 and C13 centers, in addition to installing
an isobutyrate protecting group, thereby differentiating the
anti 1,3-diol. The remaining secondary alcohol was treated
with Meerweinꢀs reagent[12] to give the C11 methyl ether.
Deprotection of the silyl ether by using aqueous HF released
the primary alcohol, which was immediately oxidized using
Swern conditions[13] to provide aldehyde 5.
Scheme 1. Retrosynthetic analysis of (+)-neopeltolide (1b). Mes=
mesitylenesulfonate,TBDPS =tert-butyldiphenylsilyl,TMS =trimethyl-
Aldehyde 5 was combined with allylsilane 6 in a triflic acid
promoted [4+2] annulation to access dihydropyran 12 in good
yield and diastereoselectivity (75%, d.r. 10:1, Scheme 3).[5h]
The sulfonate group of 12 was replaced with a nitrile moiety
through an SN2 displacement upon exposure to DIBAL-H,
and the acyl protecting group was cleaved to restore the C13
alcohol. The nitrile functionality was converted to the
corresponding aldehyde using DIBAL-H and was subse-
quently transformed to the carboxylic acid through Pinnick
oxidation.[14] Macrocyclization was effected through Yama-
guchi esterification of the seco acid intermediate to form
macrolide 13 in 44% yield.
Selective oxymercuration of the pyran olefin yielded the
axial C5 alcohol 14 as a single stereoisomer.[5h] Based on our
previous studies of leucascandrolide A, direct coupling of 14
with the corresponding acid of intermediate 4 was not
attempted.[5f] Instead, Still–Gennari olefination was used to
establish the cis enoate of the side chain.[5a] Acylation of
alcohol 14 with bis(2,2,2-trifluoroethyl)phosphonoacetic
acid[15] gave phosphonoacetate 15, which was immediately
deprotonated with KHMDS at À788C in THF in the presence
of [18]crown-6 ether; further treatment of the resulting anion
with side-chain aldehyde 4 at À858C successfully provided a
7:1 mixture of neopeltolide 1b and the corresponding E olefin
silyl.
reflect its structural homology to leucascandrolide A. As
such, it was anticipated that installation of the tetrahydro-
pyran unit would be carried out using a [4+2] annulation
strategy with allylsilane 6 while macrocyclization would be
achieved through Yamaguchi esterification. Allylsilane 6 can
be readily prepared in multigram quantities using a six-step
sequence from commercially available 3-propyn-1-ol.[5h]
Intermediate 5 would be constructed from the enantio-
enriched epoxide 7[7] and dithiane 8. Oxazole 4 could be
assembled as previously reported by our group.[5q]
Preparation of the C7–C11 fragment of neopeltolide
began from commercially available methyl (R)-(+)-3-methyl-
glutarate (Scheme 2).[8] Chemoselective reduction of the
carboxylic acid using borane/dimethyl sulfide complex[9]
provided the primary alcohol, which was subsequently
protected as a TBDPS ether to give 10. Hydride reduction
was followed by an iodine-catalyzed dithioacetalization of the
resulting aldehyde to afford dithiane 8 in 68% overall yield.
Coupling of dithiane 8 with epoxide 7 provided the
complete carbon framework of the C7–C16 fragment of
neopeltolide. Removal of the dithioketal protecting group
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Angewandte
Chemie
118, 6202 – 6209; c) A. Zampella, M. V.
DꢀAuria, L. Minale, C. Debitus, C. Rous-
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[3] L. T. Tan, B. L. Mµrquez, W. H. Gerwick,
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[4] M. DꢀAmbrosio, A. Guerriero, C. Deb-
itus, F. Pietra, Helv. Chim. Acta 1996, 79,
51 – 60.
[5] For total syntheses of leucascandroli-
de A, see a) K. R. Hornberger, C. L.
Hamblett, J. L. Leighton, J. Am. Chem.
Soc. 2000, 122, 12894 – 12895; b) Y.
Wang, J. Janjic, S. A. Kozmin, J. Am.
Chem. Soc. 2002, 124, 13670 – 13671;
c) A. Fettes, E. M. Carreira, Angew.
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Paterson, M. Tudge, Angew. Chem. 2003,
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dron 2003, 59, 6833 – 6849; g) Y. Wang, J.
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2005, 77, 1161 – 1169; h) Q. Su, L. A.
Dakin, J. S. Panek, J. Org. Chem. 2007,
72, 2 – 24; i) L. J. Van Orden, B. D. Pat-
terson, S. D. Rychnovsky, J. Org. Chem.
Scheme 3. Completion of (+)-neopeltolide (1b) synthesis. a) 5,TfOH,CH 2Cl2/benzene (3:1),
À788C,75% (d.r. 10:1); b) NaCN,DMF,60 8C,84%; c) DIBAL-H,diethyl ether, À788C,96%;
d) DIBAL-H,CH 2Cl2, À788C,60%; e) NaClO 2,2-methyl-2-butene,NaH 2PO4·H2O, tBuOH,H 2O,
85%; f) 2,4,6-trichlorobenzoyl chloride, toluene, DMAP, Et3N,44%; g) Hg(O CCF3)2 then
2
NaBH4,THF:H 2O (1:1),63% (d.r. >20:1); h) (CF3CH2O)2P(O)CH2CO2H,EDCI·HCl,
HOBT·H2O,CH 2Cl2,99%; i) 15,[18]crown-6,KHMDS, À788C,then 4, À858C,62%. TfOH =
triflic acid,DMAP =4-dimethylaminopyridine,EDCI =N-(3-dimethylaminopropyl)-N’-ethylcarbo-
diimide,HOBT =1-hydroxy-1H-benzotriazole,KHMDS = potassium bis(trimethylsilyl)amide.
in 62% overall yield. The spectroscopic data of our synthetic
2007, 72, 5784 – 5793. For syntheses of the leucascandrolide A
macrolide, see j) D. J. Kopecky, S. D. Rychnovsky, J. Am. Chem.
Soc. 2001, 123, 8420 – 8421; k) P. Wipf, J. T. Reeves, Chem.
Commun. 2002, 2066 – 2067; l) D. R. Williams, S. V. Plummer, S.
Patnaik, Angew. Chem. 2003, 115, 4064 – 4068; Angew. Chem.
Int. Ed. 2003, 42, 3934 – 3938; m) D. R. Williams, S. Patnaik, S. V.
Plummer, Org. Lett. 2003, 5, 5035 – 5038; n) M. T. Crimmins, P.
Siliphaivanh, Org. Lett. 2003, 5, 4641 – 4644; o) L. Ferriꢁ, S.
Reymond, P. Capdevielle, J. Cossy, Org. Lett. 2007, 9, 2461 –
2464. Other reports of leucascandrolide A fragments include:
p) M. T. Crimmins, C. A. Carroll, B. W. King, Org. Lett. 2000, 2,
597 – 599; q) S. A. Kozmin, Org. Lett. 2001, 3, 755 – 758; r) L. A.
Dakin, N. F. Langille, J. S. Panek, J. Org. Chem. 2002, 67, 6812 –
6815; s) P. Wipf, T. H. Graham, J. Org. Chem. 2001, 66, 3242 –
3245.
material were in complete agreement with those reported for
naturally derived neopeltolide (1H, 13C NMR spectroscopy,
mass spectrometry, infrared spectroscopy, and [a]2D0 = + 29.5
(c = 0.47, MeOH)), thus allowing confident reassignment of
the relative and absolute configurations.[16]
In summary, the first enantioselective total synthesis, with
reassigned stereochemical and absolute configurations, for
the metabolite (+)-neopeltolide has been reported. The
longest linear sequence required 19 steps with an overall
yield of 1.3%.[17] Highlights of this route include a modified
Evans–Tishchenko reduction to introduce the C11 stereo-
center, [4+2]-allylsilane annulation to construct the pyran
system, and a Still–Gennari olefination to install the oxazole
side chain. Investigations into the preparation of structural
analogues of (+)-neopeltolide to help identify in vivo biolog-
ical targets and elucidate its mode of action are in progress
and will be reported in due course.
[6] For comparisons of the 1H and 13C NMR spectra of these
compounds, see the Supporting Information. These spectroscop-
ic differences, along with identical mass spectroscopy data and
fragmentation patterns for both samples, suggested a possible
misassignment (data were kindly provided by Dr A. E. Wright).
[7] Compound 7 was synthesized in the same way as its enantiomer,
see N. Holub, J. Neidhofer, S. Blechert, Org. Lett. 2005, 7, 1227 –
1229.
Received: September 6, 2007
Revised: October 8, 2007
Published online: November 16, 2007
[8] Methyl (R)-(+)-3-methylglutarate is available from Sigma–
Aldrich Co. (Catalog number 380466). Alternatively, it can be
prepared through enzymatic desymmetrization of racemic
dimethyl 3-methylglutarate with porcine liver esterase, see
L. K. P. Lam, R. A. H. F. Hui, J. B. Jones, J. Org. Chem. 1986,
51, 2047 – 2050.
[9] P. Herold, P. Mohr, C. Tamm, Helv. Chim. Acta 1983, 66, 744 –
754.
[10] a) D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112,
6447 – 6449; b) C. Schneider, K. Klapa, M. Hansch, Synlett 2005,
91 – 94; c) T. E. La Cruz, S. D. Rychnovsky, J. Org. Chem. 2007,
72, 2602 – 2611.
Keywords: annulation · antitumor agents · macrolides ·
.
natural products · total synthesis
[1] a) A. E. Wright, J. C. Botelho, E. Guzmµn, D. Harmody, P.
Linley, P. J. McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J.
Nat. Prod. 2007, 70, 412 – 416; b) A. E. Wright, S. A. Pomponi,
P. J. McCarthy, US Patent 7179828B2, 2007.
[2] a) M. V. DꢀAuria, A. Zampella, L. Gomez-Paloma, L. Minale, C.
Debitus, C. Roussakis, V. Le Bert, Tetrahedron 1996, 52, 9589 –
9596; b) A. Zampella, M. V. DꢀAuria, L. G. Paloma, A. Casa-
pullo, L. Minale, C. Debitus, Y. Henin, J. Am. Chem. Soc. 1996,
[11] The anti relationship of the C13 and C11 centers was determined
by 13C NMR spectroscopic analysis of the acetonide derived
from the diol product obtained after DIBAL-H reduction of the
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Communications
C13 acyl protecting group. S. D. Rychnovsky, B. Rogers, G. Yang,
J. Org. Chem. 1993, 58, 3511 – 3515.
[15] For preparation of the phosphonoacetic acid, see S. Sano, Y.
Takemoto, Y. Nagao, Tetrahedron Lett. 2003, 44, 8853 – 8855, and
references therein.
[12] H. Meerwein, Org. Synth. 1973, Coll. Vol. 5, 1080.
[13] a) K. Omura, D. Swern, Tetrahedron 1978, 34, 1651 – 1660;
b) S. L. Huang, K. Omura, D. Swern, D. Further, Synthesis 1978,
297 – 299.
[14] B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981,
37, 2091 – 2096.
[16] In comparison, the specific rotation reported for natural neo-
peltolide by Wright (Ref. [1a]) was [a]2D0 = + 24.0 (c = 0.24,
MeOH) while the observed specific rotation for 1a was [a]D20
=
+ 12.4 (c = 0.63, MeOH). For 1H and 13C NMR spectra of 1b and
1a, see the Supporting Information.
[17] Starting from commercially available methyl (R)-(+)-3-methyl-
glutarate 9.
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