Concise formal synthesis of (+)-neopeltolide

Article abstract of DOI:10.1021/ol2025718

A concise formal synthesis of (+)-neopeltolide (1) has been accomplished. The synthesis demonstrated high atom efficiency employing only one step of functional group protection. Key steps involved iridium-catalyzed double asymmetric carbonyl allylation, palladium-catalyzed intramolecular alkoxycarbonylation, ruthenium-catalyzed olefin isomerization, and ring-closing metathesis.

Full text of DOI:10.1021/ol2025718

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5916–5919
Concise Formal Synthesis of (þ)-
Neopeltolide
Zhen Yang,† Bingbin Zhang,† Gaoyuan Zhao,† Juan Yang,† Xingang Xie,*,† and
Xuegong She*,†,‡
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou University, Lanzhou 730000, People’s Republic of China, and State Key
Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China
xiexg@lzu.edu.cn; shexg@lzu.edu.cn
Received September 22, 2011
ABSTRACT
A concise formal synthesis of (þ)-neopeltolide (1) has been accomplished. The synthesis demonstrated high atom efficiency employing only one
step of functional group protection. Key steps involved iridium-catalyzed double asymmetric carbonyl allylation, palladium-catalyzed
intramolecular alkoxycarbonylation, ruthenium-catalyzed olefin isomerization, and ring-closing metathesis.
Marine sponges of the polyphyletic order “Lithistida”
have been the source of a wealth of natural products with
various biological activities.1 Neopeltolide (1) was isolated
from a deep-water sponge of the family Neopeltidae by
Wright and co-workers in 2007 (Figure 1).2 Bioactivity
studies by Wright’s group showed that neopeltolide (1)
exhibits significantly potent in vitro cytotoxicity toward
several different cancer cell lines, including A-549 human
lung adenocarcinoma, NCI-ADR-RES human ovarian
sarcoma, and P388 murine leukemia cell lines, with IC50s
of 1.2, 5.1, and 0.56 nM, respectively. Neopeltolide (1) also
inhibited the growth of the fungal pathogen Candida albi-
cans with a minimum inhibitory concentration of 0.62 μg/
mL. In the PANC-1 pancreatic cancer cell line and the
DLD-1 colorectal adenocarcinoma cell line, both with p53
mutations, neopeltolide (1) showed strong inhibition of cell
proliferation at nanomolar concentrations but did not give
the typical sigmoidal curve, and instead showed 50% cell kill
over an extended dose range. Accordingly, it may be cyto-
static to these cell lines rather than cytotoxic.2
The structural features of neopeltolide (1) include a 14-
membered macrolactone, embedding with a tetrahydro-
pyran ring, and six stereogenic centers. The relative stereo-
chemistry of neopeltolide (1) was determined by combined
(3) For the total synthesis of neopeltolide, see: (a) Youngsaye, W.;
Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew. Chem., Int. Ed.
2007, 46, 9211. (b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am.
Chem. Soc. 2008, 130, 804. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 3242. (d) Paterson, I.; Miller, N. A. Chem.
Commun. 2008, 4708. (e) Fuwa, H.; Naito, S.; Goto, T.; Sasaki, M.
Angew. Chem., Int. Ed. 2008, 47, 4737. (f) Vintonyak, V. V.; Kunze, B.;
Sasse, F.; Maier, M. E. Chem.;Eur. J. 2008, 14, 11132. (g) Custar,
D. W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am.
Chem. Soc. 2009, 131, 12406. (h) Fuwa, H.; Saito, A.; Naito, S.; Konoki,
K.; Yotsu-Yamashita, M.; Sasaki, M. Chem.;Eur. J. 2009, 15, 12807.
(i) Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041.
(j) Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.; Sabharwal, S. S.;
Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4, 418.
(4) For the formal synthesis of neopeltolide, see: (a) Vintonyak, V. V.;
Maier, M. E. Org. Lett. 2008, 10, 1239. (b) Kartika, R.; Gruffi, T. R.;
Taylor, R. E. Org. Lett. 2008, 10, 5047. (c) Tu, W.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2009, 48, 4567. (d) Kim, H.; Park, Y.; Hong, J.
Angew. Chem., Int. Ed. 2009, 48, 7577. (e) Guinchard, X.; Roulland, E.
Org. Lett. 2009, 11, 4700. (f) Yadav, J. S.; Kumar, G. G. K. S. N.
Tetrahedron 2010, 66, 480.
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. Engl. 1988,
37, 2163.
(2) Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley,
P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.
2007, 70, 412.
r
10.1021/ol2025718
Published on Web 10/13/2011
2011 American Chemical Society

spectroscopic analysis. Shortly afterward, the absolute
stereochemistry was revised via two total syntheses by
Panek3a and Scheidt,3b respectively.
Inspired by Fuwa’s work,3i our retrosynthetic analysis is
briefly illustrated in Scheme 1. We envisioned that the
central macrolactone core 2 might be constructed by the
fragmental assembly of alcohol 4 and acid 3 via intermo-
lecular esterification and a ring-closing metathesis reaction.
Alcohol 4 could be prepared with the absence of protecting
groups from the known Weinreb amide 5, exploiting the
SmI2-promoted EvansꢀTishchenko reaction. The tetrahy-
dropyran ring in acid 3 could be obtained by means of
palladium-catalyzed5 intramolecular alkoxycarbonylation
of the diol 6, which was derived from 1,3-propanediol via
iridium-catalyzed asymmetric carbonyl allylation.
Scheme 2. Synthesis of Alcohol 4
Figure 1. Structure of (þ)-neopeltolide (1).
Due to its highly potent anticancer activity, considerable
effects have proceeded in the synthetic community.3,4 The
first total synthesis and stereochemical reassignment of (þ)-
neopeltolide (1) was reported by Panek and co-workers3a
using a [4 þ 2]-allylsilane annulation to construct the pyran
system. The most recent synthetic study by Fuwa3i is so far
the shortest synthesis of neopeltolide (1) within 13 linear
steps. Our group also aimed to develop an efficient synthetic
route for neopeltolide (1), which might serve for further
biological study and medicinal purposes. Herein, we re-
ported a concise formal synthesis of (þ)-neopeltolide (1).
Scheme 1. Retrosynthetic Analysis of (þ)-Neopeltolide (1)
We began the efficient synthesis of alcohol 4 with the
known Weinreb amide 5, which was easily prepared accord-
ing to the literature6 (Scheme 2). Hydrogenation of 5 with
the freshly prepared Raney-Ni followed by treatment with
(2-methylallyl)magnesium bromide afforded the known
β-hydroxy ketone 8 in 73% yield for two steps.4e SmI2-
promoted EvansꢀTishchenko reduction7 was employed to
ketone 8 generating alcohol 9 with high stereoselectivity
(anti/syn > 95:5). Sequential O-methylation and ester
hydrolysis of 9 gave alcohol 4 in excellent yield.8 We were
pleased with the utilization of the protection group free
(5) For recent reviews of palladium(II)-catalyzed alkene functionali-
zation, see: (a) Sigman, M. S.; Schultz, M. J. Org. Biomol. Chem. 2004, 2,
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ꢀ
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Org. Lett., Vol. 13, No. 21, 2011
5917

Scheme 3. Formal Synthesis of (þ)-Neopeltolide (1)
(Scheme 3). Iridium-catalyzed double asymmetric carbonyl
allylation of 1,3-propanediol furnished the C2-symmetric
diol 6 in 70% yield.9 Subjecting diol 6 to the palladium-
catalyzed intramolecular alkoxycarbonylation reaction10
smoothly provided tetrahydropyran 11 in 83% isolated
yield (d.r. > 20:1). The free secondary hydroxy group in
11 further underwent protection as the corresponding ben-
zyl ether 12 in 90% yield.11 Isomerization of the terminal
olefin in 12 using Grubbs’ second generation catalyst (G-II)
in methanol12 gave alkene 13 (E/Z = 8:1). Hydrolysis of the
methyl ester group in 13 under basic conditions afforded
carboxylic acid 3 in nearly quantitative yield.13
Table 1. Ring-Closing Metathesis of 14a
catalyst
yieldc
(%)
(8) (a) Smith, A. B.; Jurica, J. A.; Walsh, S. P. Org. Lett. 2008, 10,
5625. (b) Paterson, I.; Gibson, L. J.; Kan, S. B. J. Org. Lett. 2010, 12,
5530.
entry
(20 mol %)
conditions
1
G-II
CH2Cl2, rt, 24 h
N.R.
N.R.
N.R
trace
74
(9) (a) Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J.
Angew. Chem., Int. Ed. 2009, 48, 5018. (b) Han, S. B.; Hassan, A.; Kim,
I. S.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559.
(10) (a) Yang, Z.; Xie, X. G.; Jing, P.; Zhao, G. Y.; Zheng, J. Y.;
Zhao, C. G.; She, X. G. Org. Biomol. Chem. 2011, 9, 984. (b) White, J. D.;
Hong, J.; Robarge, L. A. TetrahedronLett. 1999, 40, 1463.(c)Hornberger,
K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122
12894.
2
G-II
toluene, 80 °C, 24 h
toluene, 80 °C, 24 h
toluene, rt, 8 h
3b
4
G-II
HG-II
HG-II
5
toluene, 80 °C, 4 h
a Reactions were run in the indicated solvent (0.005 M) under argon,
and the catalysts were added in one portion. b 1.0 equiv of 1,4-benzo-
quinone was used as the additive, and the catalyst was added over 6 h (see
ref 3i). c N.R. = no reaction.
(11) (a) White, J. D.; Reddy, G. N.; Spessard, G. O. J. Am. Chem.
Soc. 1988, 110, 1624. (b) Eckenberg, P.; Groth, U.; Huhn, T.; Richter,
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10, 1637.
strategy to prepare alcohol 4 from Weinreb amide 5 in 54%
yield over five steps.
With alcohol 4 in hand, we turned our attention to the
synthesis of the macrolactone core 2 of (þ)-neopeltolide (1)
5918
(13) (a) Smith, A. B.; Han, Q.; Breslin, P. A. S.; Beauchamp, G. K.
€
Org. Lett. 2005, 7, 5075. (b) Smith, A. B.; Davulcu, A. H.; Kurti, L. Org.
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Org. Lett., Vol. 13, No. 21, 2011

Intermolecular esterification between alcohol 4 and acid 3
was examined. To our delight, esterification under Shiina’s
(MNBA = 2-methyl-6- nitrobenzoic anhydride) conditions14
smoothly provided diene 14 in 91% yield. Ring-closing
metathesis15 of diene 14 was tested using various conditions,
and the results are summarized in Table 1. Hoveydaꢀ
Grubbs’ second generation catalyst (HG-II) was found as
the only effective one while G-II showed no activity. Finally, a
metathesis reaction of diene 14 in toluene at 80 °C provided
the macrolactone 15 as a (Z)-isomer in 74% yield.16 The
ensuing hydrogenation of the double bond in the presence of a
catalytic amount of Pd/C and at the same time removal of the
C5 benzyl ether, thus, completed our synthesis of (þ)-macro-
lactone 2, which would be easily transformed into (þ)-
neopeltolide (1) according to the previous reports.3bꢀi
In summary, a concise formal synthesis of (þ)-neopel-
tolide (1) has been achieved in 12 steps (longest linear
sequence) and 18% overall yield from commercially avail-
able L-valinol. Notable features include high atom econ-
omy with minimized protective group manipulation, iri-
dium-catalyzed double asymmetric carbonyl allylation,
palladium-catalyzed intramolecular alkoxycarbonylation,
ruthenium-catalyzed olefinisomerization, and ring-closing
metathesis. This efficient pathway would enable large scale
preparation of (þ)-neopeltolide (1) offering convenience
for further studies.
(14) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822.
Acknowledgment. We are grateful for the generous
financial support by the MOST (2010CB833200), the
NSFC (20872054, 20732002, 21072086), and program 111.
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2007, 450, 243. (b) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int.
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Chem. Soc. 2005, 127, 6948. (d) Deiters, A.; Martin, S. F. Chem. Rev.
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Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR spec-
tra. This material is available free of charge via the
Internet at http://pubs.acs.org.
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