Stereocontrolled synthesis of the macrolactone core of neopeltolide

Article abstract of DOI:10.1016/j.tetlet.2018.12.066

A stereoselective synthesis of the macrolactone core of neopeltolide is described. The tetrahydropyran moiety was constructed via the intramolecular allylation of an α-acetoxy ether. A late-stage macrolactonization provided a known synthetic intermediate

Full text of DOI:10.1016/j.tetlet.2018.12.066

Accepted Manuscript
Stereocontrolled synthesis of the macrolactone core of neopeltolide
Andreas Meissner, Nobuhiro Tanaka, Hiroyoshi Takamura, Isao Kadota
PII:
S0040-4039(18)31524-7
https://doi.org/10.1016/j.tetlet.2018.12.066
TETL 50529
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Tetrahedron Letters
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21 November 2018
21 December 2018
27 December 2018
Please cite this article as: Meissner, A., Tanaka, N., Takamura, H., Kadota, I., Stereocontrolled synthesis of the
macrolactone core of neopeltolide, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.066
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Stereocontrolled synthesis of the
macrolactone core of neopeltolide
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Andreas Meissner, Nobuhiro Tanaka, Hiroyoshi Takamura, and Isao Kadota*
Neopeltolide

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Stereocontrolled synthesis of the macrolactone core of neopeltolide
Andreas Meissner, Nobuhiro Tanaka, Hiroyoshi Takamura, and Isao Kadota*
Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kitaku, Okayama 700-8530, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A stereoselective synthesis of the macrolactone core of neopeltolide is described. The
tetrahydropyran moiety was constructed via the intramolecular allylation of an α-acetoxy
ether. A late-stage macrolactonization provided a known synthetic intermediate of
neopeltolide.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Neopeltolide
Convergent synthesis
Macrolide
Allylation
Reductive acetylation
molecule in this study.2b For the construction of the THP ring,
we recently reported a stereoselective and convergent synthesis
Introduction
In 2007, Wright and co-workers isolated the macrolide
neopeltolide (1) from the deep-water sponge Daedalopelta and
elucidated its structure.1 The first proposed structure was later
corrected as shown in Figure 1 based on the total syntheses by
Panek and Scheidt groups, independently.2a,b The structure of 1
consists of a 14-membered macrolactone including a THP ring,
bound to an oxazole-containing side-chain. Biologically, 1 was
reported to show high in vitro inhibition of different cancer cell
lines in the nanomolar range (0.56 nM for P388 murine leukemia
cell lines). Furthermore, the unique structural features have
attracted attention of synthetic organic chemists, and various
approach to the total synthesis of 1 have been reported over the
past decade.2 In this paper, we wish to describe a convergent
approach to the THP macrolactone structure of 1 as a part of
synthetic study of THP macrolide derivatives based on the
intramolecular allylation methodology.
via the intramolecular allylation of -acetxy ether and used this
strategy in the convergent total synthesis of dactylolide3 and
formal total synthesis of enigmazole A.4 According to this
strategy, the synthetic intermediate 2 would be synthesized from
an -acetoxy ether 3 followed by macrolactonization. The
cyclization precursor 3 could be prepared from alcohol fragment
4 and carboxylic acid fragment 5.
Prepapration of the alcohol fragment 4 is illustrated in Scheme
2. The asymmetric allylboration of aldehyde 65 with the chiral
allylborane 7 gave 4 in 90% yield.3
Figure 1. Revised structure of neopeltolide (1)
Our retrosynthetic analysis of 1 is illustrated in Scheme 1.
Scheidt and co-workers published the total synthesis of
neopeltolide (1) from macrolactone 2, which we set as our target
Scheme 2. Synthesis of the alcohol fragment 4.

2
Tetrahedron
The synthesis of the carboxylic acid fragment 5 was started
from hydroxy lactone 9, prepared by the reported procedure
(Scheme 3).7 Stereoselective installation of the propyl group was
performed by three step sequence. Thus, oxidation of 9 with
TEMPO/BAIB followed by Brown’s allylation with a chiral
allylic borane reagent gave homoallylic alcohol 10 in 79%,
stereoselectively.8 The diastereomeric purity was higher than
95% as determined by Mosher`s ester analysis.6 Hydrogenation
of the olefin 10 with H2/Wilkinson catalyst provided 11 in 97%
yield.9 The alcohol 11 was protected with TBDPSCl/imidazole
to give silyl ether 12 in 72% yield. Treatment of 12 with MeNH-
OMe/i-PrMgCl opened the lactone to give Weinreb amide 13 in
Figure 2. Chemical shift differences (S-R) of MTPA esters 8
derived from 4.
90%. Reaction of 13 with Meerwein reagent/proton sponge
delivered methyl ether 14 in 76%.10 Since the hydrolysis of
Weinreb amide tend to require harsh conditions such as strong
base or microwave irradiation,11 the Weinreb amide 14 was
converted to the carboxylic acid 5 via two-step sequence. Thus,
partial reduction of 14 with DIBAL-H giving aldehyde 15 (92%)
followed by the Pinnick oxidation to furnish the carboxylic acid
fragment 5.
The absolute configuration of the hydroxyl group of 4 was
confirmed by the modified Mosher’s analysis on the MTPA ester
derivatives 8 as shown in Figure 2.6
Esterification of the alcohol 4 and carboxylic acid 5 was
carried out under the Shiina conditions to give ester 16 in 76%
overall yield (Scheme 4).12 Partial reduction of the ester 15 with

3
DIBAL-H followed by trapping of the acetal intermediate with
(CH2ClCO)2O/DMAP/pyridine gave α-acetoxy ether 3.13,14 The
cyclization precursor 3 obtained was then subjected to the
intramolecular allylation using MgBr2·OEt2 as a Lewis acid and
MS5A in CH3CN/CH2Cl2 (1:1) yielding the desired methylene
THP derivative 17 as a single stereoisomer in 84% overall yield.
The stereochemistry of the methylene THP ring moiety newly
Chem. Int. Ed. 2007, 46, 9211-9214; (b) Custar, D. W.;
Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008,
130, 804-805; (c) Woo, S. K.; Kwon, M. S.; Lee, E.
Angew. Chem. Int. Ed. 2008, 47, 3242-3244; (d) Fuwa,
H.; Naito, S.; Goto, T.; Sasaki, M. Angew. Chem. Int. Ed.
2008, 47, 4737-4739; (e) Paterson, I.; Miller, M. A.
Chem. Commun. 2008, 4704-4710; (f) Guinchard, X.;
Roulland, E.; Org. Lett. 2009, 11, 4700-4703; (g) Fuwa,
H.; Saito, A.; Sasaki, M. Angew. Chem. Int. Ed. 2010, 49,
3041-3044; (h) Yu, M.; Schrock, R. R.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2015, 54, 215-220.
1
generated was confirmed by the H NMR analysis and NOE
experiments as shown in Figure 3. Both of the TBDPS and TBS
groups were removed using TBAF at elevated temperature to
give diol 18 in 92% yield. Selective oxidation of the primary
hydroxyl group of 18 was performed with TEMPO/BAIB to
provide aldehyde 19 in 87% yield. According to a reported
procedure, the olefin of 19 was subjected to oxidative cleavage
with OsO4/NaIO4 to yield 20 in 87% yield.2f Pinnick oxidation of
the aldehyde 20 followed by macrolactonization under the
Yamaguchi conditions furnished the lactone 2 in 53% overall
yield.15 The spectroscopic data (1H and 13C NMR) and optical
3. Tanaka, T.; Murai, Y.; Kishi, T.; Takamura, H.; Kadota,
I. Tetrahedron Lett. 2018, 59, 763-766.
4. Meissner, A.; Kishi, T.; Fujisawa, Y.; Murai, Y.;
Takamura, H.; Kadota, I. Tetrahedron Lett. 2018, 59,
4492-4495.
5. Groth, T.; Meldal, M. J. Comb. Chem. 2001, 3, 34-44.
6. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092-4096.
7. For the synthesis of the enantiomer of 9, see: Trost, B.
M.; Seganish, W. M.; Chung, C. K.; Amans, D. Chem.
Eur. J. 2012, 18, 2948-2960.
21
25
rotation ([]D +18.0 (c 0.16, CHCl3), lit.2b []D +32.6 (c 0.1,
CHCl3), lit.2f []D +18.0 (c 0.4, CHCl3)) of the synthetic
material 2 were in good agreement with those reported previously.
21
8. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401-404.
9. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G.
J. Chem. Soc. A 1966, 1711-1732.
10. Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil,
E. J. Prakt. Chem. 1937, 147, 257-285.
11. For example, see: Jaipuri, F. A.; Jofre, M. F.; Schwarz,
K. A.; Poh, N. L. Tetrahedron Lett. 2004, 45, 4149-4152.
12. Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 31,
286-287.
Figure 3. Observed NOEs are shown by arrows.
13. Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46-47.
14. For the original conditions, see: (a) Dahanukar, V. H.;
Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317-8320;
(b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem.
2000, 65, 191-198; (c) Kopecky, D. J.; Rychnovsky, S.
D. Org. Synth. 2003, 80, 177-183.
15. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-
1993.
Conclusion
In conclusion, we have achieved the stereocontrolled synthesis
of the macrolactone core of neopeltolide via the intramolecular
allylation methodology. The current work demonstrates the
ability of our methodology for the synthesis of methylene THP
macrolide derivatives. Further application of the methodology to
the total syntheses of natural products is in progress.
Acknowledgments
Highlights
This work was financially supported by JSPS KAKENHI
(Grant Number 17K05863).
Reporting a stereocontolled synthesis of the
macrolide core of neopeltlide, a cytotoxic
macrolide.
Supplementary data
The 2,6-disubstituted THP ring moiety was
constructed by the intramolecular allylation of an
-acetoxy ether derivative.
Supplementary data associated with this article can be found,
in the online version, at http://
A stereocontrolled synthesis of the macrolide core
of neopeltlide was accomplished.
References and notes
* Corresponding author (E-mail: kadota-i@okayama-u.ac.jp)
1. Wright, A. E.; Botelho, J. C.; Guzmán, E.; Harmody, D.;
Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.;
Reed, J. K. J. Nat. Prod. 2007, 70, 412-416.
2. For the total synthesis of 1, see: (a) Youngsaye, W.;
Lowe, J. T.; Pohlke, F.; Ralifo, P.; Panek, J. S. Angew.

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Tetrahedron