Total synthesis of the marine macrolide (+)-neopeltolide

Article abstract of DOI:10.1039/b812914b

A concise total synthesis of the antiproliferative macrolide (+)-neopeltolide has been completed, utilising a Jacobsen hetero Diels-Alder reaction to install the trisubstituted tetrahydropyran ring. The Royal Society of Chemistry.

Full text of DOI:10.1039/b812914b

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Total synthesis of the marine macrolide (+)-neopeltolidew
Ian Paterson* and Natalie A. Miller
Received (in Cambridge, UK) 28th July 2008, Accepted 21st August 2008
First published as an Advance Article on the web 4th September 2008
DOI: 10.1039/b812914b
A concise total synthesis of the antiproliferative macrolide
(+)-neopeltolide has been completed, utilising a Jacobsen hetero
Diels–Alder reaction to install the trisubstituted tetrahydropyran
ring.
hetero Diels–Alder reaction11 between the C7–C16 aldehyde 4
and the C1–C6 siloxydiene 5 to install the tetrahydropyran ring,
followed by a suitable macrolactonisation.
The synthesis of the required aldehyde 4 commenced with a
Noyori asymmetric hydrogenation12 of the b-keto ester 6 using
the (S)-BINAP–Ru(II) catalyst to give the desired (13S)-alcohol5,9
(Scheme 2). Subsequent TBS ether formation and DIBALH
reduction of the ester gave the enantiopure aldehyde 7 in 76%
overall yield.13 Next, a Brown methallylation14 of 7 with the
reagent derived from 2-methylpropene (nBuLi, TMEDA, Et2O)
and (À)-Ipc2BOMe installed the required C11 alcohol with high
diastereoselectivity (81%, 94 : 6 dr), which was transformed
(NaH, MeI) into the methyl ether 8. Ozonolysis of 8 gave the
methyl ketone, which was used in a HWE reaction with trimethyl
phosphonoacetate (NaH, THF) to give ester 9 as an inconse-
quential mixture of E/Z isomers (75 : 25).15 Reduction of ester 9
to the corresponding alcohol with DIBALH followed by
Dess–Martin oxidation then provided aldehyde 10.
Marine macrolides having potent cytotoxic properties repre-
sent promising anticancer agents, provided the supply issue
can be resolved.1 Neopeltolide (1, Scheme 1) is a bioactive
macrolide isolated from a deep-water Caribbean sponge of the
family Neopeltidae by Wright et al. in 2007.2 Initial testing
revealed potent antiproliferative activity against several cancer
cell lines (e.g. IC50 = 1.2 and 5.1 nM against A549 lung and
NCI/ADR-RES ovarian carcinoma, respectively), as well as
inhibition of the growth of the fungal pathogen Candida
albicans. The key structural features of neopeltolide include
a 14-membered macrolactone ring, containing a trisubstituted
tetrahydropyran ring, and an oxazole-bearing unsaturated
side chain appended at C5 through an ester linkage. This side
chain is identical to that found in the 18-membered macrolide
We planned to perform a diastereoselective organocatalytic
hydride reduction of enal 10, using chemistry developed by
MacMillan.16 Thus, exposure of the mixture of E/Z isomers of
10 to the imidazolidinone catalyst 11ÁTFA (20 mol%) and
leucascandrolide A, which displays
profile.1a,3
a similar biological
The complex macrolide structure and potent biological
activity of neopeltolide have stimulated a flurry of synthetic
interest, with five total syntheses4–8 and one formal synthesis9
reported. Notably, the initially completed total syntheses of
(+)-neopeltolide, as reported by the Panek4 and Scheidt5
groups, resulted in the stereochemical reassignment of the
originally proposed structure. Recently, the Kozmin group8
achieved a total synthesis of neopeltolide, as well as preparing
a simplified analogue of leucascandrolide, enabling more
extensive biological analysis and leading to the identification
of the cytochrome bc1 complex as the cellular target for both
these antiproliferative macrolides. Importantly, neopeltolide
compares favourably to the most potent cytochrome bc1
complex inhibitors, suggesting that it could be a useful tool
for the investigation of eukaryotic energy metabolism.
Herein, we report
a new, efficient total synthesis of
(+)-neopeltolide (1) following a strategy involving the use of
only achiral starting materials, with four of the six stereo-
centres being introduced using asymmetric catalysis. As outlined
in Scheme 1, a Mitsunobu esterification reaction of macrocycle 2
with the unsaturated heterocyclic side chain 310 was anticipated
to provide neopeltolide directly. Furthermore, we envisaged that
the macrolide core in 2 could be constructed using a Jacobsen
University Chemical Laboratory, Lensfield Road, Cambridge, UK
CB2 1EW. E-mail: ip100@cam.ac.uk; Fax: +44 (0) 1223 336362;
Tel: +44 (0) 1223 336407
w Electronic supplementary information (ESI) available: Character-
isation data and copies of NMR spectra. See DOI: 10.1039/b812914b
Scheme 1 Retrosynthesis of (+)-neopeltolide (1).
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Scheme 2 Synthesis of C7–C16 aldehyde 4.
1.2 equiv. of ethyl Hantzch ester (CHCl3, À30 1C) resulted in
complete conversion to the 1,4-reduction product 4 (80%),
obtained as a mixture (76 : 24) of epimers at the newly formed
C9 stereocentre. Attempts to improve the diastereoselectivity
by carrying out the reaction on the pure E isomer of 10,
lowering the temperature and changing the solvent proved
unrewarding, with the same ratio of C9 epimers being ob-
tained. These findings suggest that the E/Z isomers converge
to the same product, as expected from the results obtained for
the 1,4-reduction of achiral enals,16 and that the lower level of
selectivity obtained with enal 10 may be due to the influence of
the existing stereocentres.
Scheme 3 Completion of the total synthesis of (+)-neopeltolide.
With the aldehyde 4 in hand, we turned our attention to the
formation of the tetrahydropyran ring of neopeltolide
(Scheme 3). Thus, a Jacobsen asymmetric hetero Diels–Alder
reaction between 4 and the readily available 2-siloxydiene 5,10
promoted by the chiral tridentate chromium(III) catalyst 1211
(10 mol%), was carried out. This key reaction led to the
corresponding [4+2] cycloadducts, which, upon workup with
mild acid, gave the expected cis-tetrahydropyranones with
complete control over the introduction of the C3 and C7
stereocentres. At this stage, the major isomer 13 (60%) could
be separated from its C9 epimer.
With the correctly configured tetrahydropyran installed, our
attention was directed towards the formation of the macro-
cyclic ring. Thus, oxidative removal of the PMB group of 13
with DDQ provided the primary alcohol. Dess–Martin oxida-
tion then gave the corresponding aldehyde, which was oxidised
to the acid, followed by cleavage of the TBS ether to give the
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seco-acid 14. Cyclisation of 14 under Yamaguchi conditions17
provided the 14-membered macrolactone 15 cleanly (80%). At
this stage, we had completed a formal synthesis of neopelto-
lide, with all spectroscopic data for lactone 15 being in good
agreement with that reported by Scheidt and co-workers (see
the ESIw).5 All that remained for the endgame was reduction
of the ketone 15 to the equatorial alcohol 2 (NaBH4, MeOH),
followed by a Mitsunobu esterification reaction with the side
chain acid 3,10 as employed by other groups,5–8 providing
(+)-neopeltolide (1) in 52% yield. The spectroscopic data and
5 D. W. Custar, T. P. Zabawa and K. A. Scheidt, J. Am. Chem. Soc.,
2008, 130, 804.
6 S. K. Woo, M. S. Kwon and E. Lee, Angew. Chem., Int. Ed., 2008,
47, 3242.
7 H. Fuwa, S. Naito, T. Goto and M. Sasaki, Angew. Chem., Int.
Ed., 2008, 47, 4737.
8 O. A. Ulanovskaya, J. Janjic, M. Suzuki, S. S. Sabharwal, P. T.
Schumacker, S. J. Kron and S. A. Kozmin, Nat. Chem. Biol., 2008,
4, 418.
9 V. V. Vintonyak and M. E. Maier, Org. Lett., 2008, 10, 1239.
10 The acid 3 was prepared in three steps: (i) H2, Lindlar catalyst,
quinoline, EtOAc; (ii) DMP, NaHCO3, CH2Cl2; (iii) NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH, H2O; 94% overall) from
the oxazole intermediate shown below, as used in our leucascan-
drolide A total synthesis. I. Paterson and M. Tudge, Angew.
Chem., Int. Ed., 2003, 42, 343; I. Paterson and M. Tudge, Tetra-
hedron, 2003, 59, 6833
20
specific rotation, [a]D +22.1 (c 0.06, MeOH), obtained for
synthetic 1 were in full accord with those reported for the
natural product (see the ESIw).2
In summary, a concise and efficient total synthesis of the
potent antiproliferative macrolide (+)-neopeltolide (1) has
been achieved in 18 steps (longest linear sequence) and 5.8%
overall yield, involving a Jacobsen hetero Diels–Alder reaction
as the key step. Notably, our strategy involves the use of only
achiral starting materials, with four of the six stereocentres
(C3, C7, C9 and C13) being introduced using asymmetric
catalysis, a tactic which should be readily adaptable to the
synthesis of a variety of structural analogues.
11 A. G. Dossetter, T. F. Jamison and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 1999, 38, 2398.
12 M. Kitamura, M. Tokunaga, T. Ohkuma and R. Noyori, Org.
Synth., 1992, 71, 1; R. Noyori, Angew. Chem., Int. Ed., 2002, 41,
2108.
13 For a similar sequence performed in the enantiomeric series, see:
L.-S. Deng, X.-P. Huang and G. Zhao, J. Org. Chem., 2006, 71,
4625.
14 H. C. Brown, P. K. Jadhav and P. T. Perumal, Tetrahedron Lett.,
1984, 25, 5111.
15 We also examined an olefin cross-metathesis reaction between 8 and
methyl crotonate to give 9 directly; however, this proved to be slow
and low yielding. While the two geometric isomers of 9 could be
separated chromatographically, this turned out to be unnecessary.
16 S. G. Ouellet, J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem.
Soc., 2005, 127, 32.
Financial support was provided by the EPSRC (EP/
F025734/1) and Merck Research Laboratories.
Notes and references
1 (a) K.-S. Yeung and I. Paterson, Chem. Rev., 2005, 105, 4237; (b) I.
Paterson and E. A. Anderson, Science, 2005, 310, 451.
2 A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody, P. Linley,
P. J. McCarthy, T. P. Pitts, S. A. Pomponi and J. K Reed, J. Nat.
Prod., 2007, 70, 412.
3 M. D’Ambrosio, A. Guerriero, C. Debitus and F. Pietra, Helv.
Chim. Acta, 1996, 79, 51.
4 W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo and J. S. Panek,
Angew. Chem., Int. Ed., 2007, 46, 9211.
17 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi,
Bull. Chem. Soc. Jpn., 1979, 52, 1989.
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4710 | Chem. Commun., 2008, 4708–4710