A formal synthesis of the auriside aglycon

Article abstract of DOI:10.1021/ol8005908

(Chemical Equation Presented) A highly convergent formal synthesis of the auriside aglycon was achieved. An indene-based thiazolidinethione chiral auxiliary was used for the construction of both the C1-C9 and C10-C17 fragments via acetate aldol reactions. A Meinwald reaction was utilized to install the stereocenter at C2, and a conjugated addition to an ynone was used to construct the C9-C11 enone.

Full text of DOI:10.1021/ol8005908

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2191-2194
A Formal Synthesis of the Auriside
Aglycon
Rodolfo Tello-Aburto and Horacio F. Olivo*
DiVision of Medicinal and Natural Products Chemistry, The UniVersity of Iowa, Iowa
City, Iowa 52242
horacio-oliVo@uiowa.edu
Received March 13, 2008
ABSTRACT
A highly convergent formal synthesis of the auriside aglycon was achieved. An indene-based thiazolidinethione chiral auxiliary was used for
the construction of both the C1-C9 and C10-C17 fragments via acetate aldol reactions. A Meinwald reaction was utilized to install the
stereocenter at C2, and a conjugated addition to an ynone was used to construct the C9-C11 enone.
Aurisides A and B are two glycosidated macrolactones
isolated in minute amounts from Dolabella auricularia,1 a
sea hare that has proved to be a rich source of biologically
active and structurally unique natural products (Figure 1).2
The structure and absolute configuration of the aurisides was
established on the basis of spectroscopic data as well as
degradation experiments. Both aurisides A and B exhibit
cytotoxicity against human cervical cancer HeLa-S3 cells,
with IC50 values of 0.17 and 1.2 µg/mL, respectively. Both
natural products share a common aglycon attached to
different rhamnose-derived sugars; the aglycon contains five
stereogenic centers, a brominated conjugated diene side
chain, a 14-membered macrolactone, and a hemiketal moiety.
Due to their important activity, unique structure, and scarce
availability from the natural source, the aurisides have been
Figure 1. Structure of aurisides A and B.
(1) Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1996, 61, 8956–
8960.
(2) (a) For representative examples, see: Pettit, G. R.; Kamano, Y.;
Herald, C. L.; Fujii, Y.; Kizu, H.; Boyd, M. R.; Boettner, F. E.; Doubek,
D. L.; Schmidt, J. M.; Chapuis, J.-C.; Michel, C. Tetrahedron 1993, 49,
9151–9170. (b) Ojika, M.; Nagoya, T.; Yamada, K. Tetrahedron Lett. 1995,
36, 7491–7494. (c) Sone, H.; Shibata, T.; Fujita, T.; Ojika, M.; Yamada,
K. J. Am. Chem. Soc 1996, 118, 1874–1880. (d) Pettit, G. R.; Xu, J.-P.;
Doubek, D. L.; Chapuis, J.-C.; Schmidt, J. M. J. Nat. Prod. 2004, 67, 1252–
1255. Structure revision: Paterson, I.; Findlay, A. D.; Florence, G. J. Org.
Lett. 2006, 8, 2131-2134; Tetrahedron 2007, 63, 5806-5819.
attractive synthetic targets. Paterson’s group accomplished
the first enantioselective synthesis of both natural products3
using asymmetric Mukaiyama and vinylogous Mukaiyama
(3) Paterson, I.; Florence, G. J.; Heimann, A. C.; Mackay, A. C. Angew.
Chem., Int. Ed. 2005, 44, 1130–1133.
10.1021/ol8005908 CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

aldol reactions as key steps. On the basis of the synthesis of
the aglycon previously reported by Yamada,4 Kigoshi’s
group published a total synthesis5 using (R)-pantolactone as
chiral starting material, featuring a Nozaki-Hiyama-Kishi
reaction and a late-stage installation of the vinyl bromide
moiety. On continuation of our research program aimed at
the synthesis of biologically important natural products, we
became interested in the synthesis of the aurisides and the
structurally related callipeltosides.6,7 Our synthetic approach
had to be highly convergent, efficient, and provide flexibility
for the development of analogues. Recently, we developed
an indene-based thiazolidinethione chiral auxiliary which
allows efficient control of asymmetric aldol reactions, a key
transformation for the construction of polyketide-derived
natural products.8,9 Herein, we present the application of this
methodology to the synthesis of macrolide 21, a valuable
advanced intermediate in Paterson’s synthesis of the auri-
sides.
In order to maximize the convergence of our approach,
we envisioned a synthesis of the auriside aglycon to arise
from the coupling of two fragments, the C1-C9 fragment,10
containing four stereocenters, a hemiacetal moiety, and a
propionate unit, and a C10-C17 fragment,11 containing one
stereocenter and a conjugated diene with a vinyl bromide
already in place, Figure 2. We have previously disclosed the
use of a biocatalytically generated bicyclic lactone as chiral
starting material for the synthesis of the C1-C9 frag-
ment.10,12 In this work, we describe a more efficient, scalable,
and economical second-generation synthesis for this frag-
ment, utilizing an indene-based thiazolidinethione chiral
auxiliary8 to control the stereochemistry at C7 by means of
a key acetate aldol reaction.
Figure 2
.
Retrosynthesis of the aglycon core.
Scheme 1
The synthesis of the C1-C9 fragment is depicted in
Schemes 1 and 2. Known aldehyde 213 was subjected to aldol
reaction8,9 with N-acetyl thiazolidinethione 1 to afford 3.
(4) Sone, H.; Suenaga, K.; Bessho, Y.; Kondo, T.; Kigoshi, H.; Yamada,
K. Chem. Lett. 1998, 8, 5–86.
(5) Suenaga, K.; Hoshino, H.; Yoshii, T.; Mori, K.; Sone, H.; Bessho,
Y.; Sakakura, A.; Hayakawa, I.; Yamada, K.; Kigoshi, H. Tetrahedron 2006,
62, 7687–7698.
(6) (a) Synthesis of callipeltoside A: Trost, B. M.; Dirat, O.; Gunzner,
J. L. Angew. Chem., Int. Ed. 2002, 41, 841–843. (b) Trost, B. M.; Gunzner,
J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396–10415.
(c) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc.
2002, 124, 5654–5655. (d) Paterson, I.; Davies, R. D. M.; Heimann, A. C.;
Marquez, R.; Meyer, A. Org. Lett. 2003, 5, 4477–4480. (e) Huang, H.;
Panek, J. S. Org. Lett. 2004, 6, 4383–4385. (f) Evans, D. A.; Burch, J. D.;
Optimized conditions developed by Crimmins delivered aldol
product 3 as a single diastereomer.14The configuration of
the created stereogenic center was confirmed later in the
sequence by correlation with our previously described
lactone 7.10
Hu, E.; Jaeschke, G. Tetrahedron 2008, 64, 4671–4699
.
(7) For our efforts towards calipeltoside see: (a) Vela´zquez, F.; Olivo,
H. F. Org. Lett. 2000, 2, 1931–1933. (b) Olivo, H. F.; Vela´zquez, F.;
Trevisan, H. C. Org. Lett. 2000, 2, 4055–4058
.
Direct displacement of the chiral auxiliary15 with potas-
sium ethyl malonate gave keto ester 4 which was subjected
to hydroxyl-directed reduction16 to give anti-diol 5 in good
(8) (a) Osorio-Lozada, A.; Olivo, H. F. Org. Lett. 2008, 10, 617–620.
For another indene-based chiral auxiliary, see: (b) Ghosh, A. K.; Duong,
T. T.; McKee, S. P. J. Chem. Soc., Chem. Commun. 1992, 1673–1674
(9) (a) Hodge, M.; Olivo, H. F. Tetrahedron 2004, 60, 9397–9403. (b)
Vela´zquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303–340
.
.
(10) Rios, M. Y.; Vela´zquez, F.; Olivo, H. F. Tetrahedron 2003, 59,
6531–6537.
(14) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883–7884. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894–902. (c) Crimmins, M. T.;
She, J. Synlett 2004, 1371–1374. (d) Crimmins, M. T.; Shamzad, M. Org.
Lett. 2007, 9, 149–152.
(11) (a) Romero-Ortega, M.; Colby, D. A.; Olivo, H. F. Tetrahedron
Lett. 2002, 43, 6439–6441. (b) Tello-Aburto, R.; Ochoa-Teran, A.; Olivo,
H. F. Tetrahedron Lett. 2006, 47, 5915–5917.
(12) (a) Grieco, P. A. J. Org. Chem. 1972, 37, 2363–2364. (b) Corey,
E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832–6833
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(15) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.; Carroll,
K. A.; van Alpen, S. Org. Lett. 2004, 6, 2317–2320.
(13) (a) Richter, F.; Bauer, M.; Perez, C.; Maichle-Mossmer, C.; Maier,
M. E. J. Org. Chem. 2002, 67, 2474–2480. (b) Trost, B. M.; Yang, H.;
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Org. Lett., Vol. 10, No. 11, 2008

yield and diastereoselectivity (87%, 14:1 dr). The relative
stereochemistry of 5 was confirmed by conversion to the
corresponding acetonide and applying Rychnovsky’s
method.17,18 Acid-catalyzed cyclization of anti-diol 5 pro-
vided hydroxyvalerolactone 6. At this stage, correlation with
known lactone 710 was carried out by protection of 6 as the
TIPS derivative, whose characterization data are identical
to our previously described intermediate 7, thus confirming
the stereochemical outcome of the key aldol reaction between
1 and 2.
Scheme 3
Scheme 2
the aldol product 13 as the TBS ether and reductive cleavage
of the chiral auxiliary afforded aldehyde 15. Direct homolo-
gation of aldehyde 15 to alkyne 1611b could be carried out
using the Ohira-Bestmann reagent24 at low temperature, but
we found this transformation easier to scale up when using
TMS-diazomethane25 to give gram quantities of 16 in good
yield.
The addition of Me2CuLi to an ynone system is a strategy
that has proved to be useful for the synthesis of trisubstituted
enones.26 The required ynone was thus synthesized by
coupling of the C9-C11 (11) and C10-C17 (16) fragments
with LHMDS at low temperature to give propargylic alcohol
17 as an inconsequential mixture of diastereomers in excel-
lent yield, Scheme 4. Attempts to hydrolyze ethyl ester 17
To continue the sequence of the C1-C9 fragment 11, we
found it to be more convenient the use of a PMB protecting
group at position C5 (auriside numbering), Scheme 2.
Lactone 8 could be obtained from 5 by cyclization and
protection of hydroxyvalerolactone 6; however, better results
were obtained when diol 5 was taken into a three-step
sequence of hydrolysis, cyclization, and protection19 to give
lactone 8 in excellent yield. Meinwald reaction of 8 with
the lithium enolate of ethyl propionate afforded a separable
∼2:1 mixture of C2 diastereomers, from which the major
product 9 was identified as the required (2S)-isomer.20 Upon
prolonged exposure to silica (∼72 h), the minor diastereomer
epimerized completely to give 9 in 89% overall yield.21
Protection of the hemiketal 9 as the methyl ketal occurred
under acidic conditions with concomitant cleavage of the
TBS group at C9 to give alcohol 10. Oxidation of 10 using
Ley’s protocol22 gave aldehyde 11.
Scheme 4
The synthesis of fragment C10-C17 16 started with the
aldol reaction between known aldehyde 1223,11a and N-acetyl
thiazolidinethione 1 again using Crimmins’ protocol,14
Scheme 3. The aldol product 13 was obtained in good yield
and good diastereoselectivity (74%, dr 9:1). Protection of
always resulted either in recovery of starting material,
elimination of the methyl ketal, and/or cleavage of the silyl
protectinggroup.Therefore,wefollowedareduction-oxidation
sequence to obtain the corresponding carboxylic acid.
(17) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945–948. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511–3515
.
(18) See the Supporting Information for details
.
(24) Ohira, S. Synth. Commun. 1989, 19, 561–564.
(19) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.
(20) The stereochemistry at C2 of the major diastereomer 15 was
assigned on the basis of the 1H NMR chemical shifts of H4; see ref 10.
(21) For related examples, see: (a) Loubinoux, B.; Sinnes, J.-L. J. Org.
Chem. 1995, 60, 953–959. (b) Loubinoux, B.; Sinnes, J.-L.; O’Sullivan,
A. C. J. Chem. Soc., Perkin Trans. 1 1995, 521–525.
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1992, 72, 1–722. (b) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107,
108.
(26) See, for example: (a) Marshall, J. A.; Crooks, S. L.; DeHoff, B. S.
J. Org. Chem. 1988, 53, 1616–1623. (b) Marshall, J. A.; Andersen, M. A.
J. Org. Chem. 1992, 57, 2766–2768. (c) Dounay, A. B.; Urbanek, R. A.;
Frydrychowsky, V. A.; Forsyth, C. J. J. Org. Chem. 2001, 66, 925–938.
(d) Balnalves, A. S.; McGowan, G.; Shapland, P. D. P.; Thomas, E. J.
Tetrahedron lett. 2003, 44, 2713–2716. (e) Houghton, T. J.; Choi, S.; Rawal,
V. H. Org. Lett. 2001, 3, 3615–3617.
(22) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 162, 5–1627.
(23) Vicart, N.; Castet-Caillabet, D.; Ramondenc, Y.; Ple´, G.; Duhamel,
L. Synlett 1998, 41, 1–412
.
Org. Lett., Vol. 10, No. 11, 2008
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Reduction of 21 with Dibal-H gave diols 18 in excellent
yield. Oxidation of both the primary and propargylic alcohols
was then accomplished by using NaHCO3-buffered Dess-
Martin reagent.27 Lindgren-Pinnick oxidation28 of the keto-
aldehyde intermediate followed to afford the corresponding
ynone-acid, that was subjected to 1,4 addition of Me2CuLi
to produce 19 as a 1.6:1 mixture of E and Z enones in 50%
overall yield over three steps.29 Similar diatereomeric ratios
were observed in model systems.11b Better diastereomeric
ratios favoring the E-olefins have been observed in cyclic
systems when quenching the reaction with i-PrSH.26b
Isomerization of the Z-olefin can also be achieved by treating
the olefin with LiS-i-Pr in cyclic systems.26a Quenching our
Gilman reagent addition with other than NH4Cl solution
resulted in lower diastereoselectivities. At this stage, the
required 19-E could be isolated in 31% over three steps from
18 and then treated with TASF30 in wet DMF to promote
cleavage of the TBS group, giving hydroxy acid 20.
valuable advanced intermediate for the synthesis of the
aurisides; therefore, our efforts represent a formal synthesis
of these natural products. Our approach features the use of
a propionate Meinwald reaction to install the stereocenter at
C2 and makes use of a chemoselective addition of an
acetylide to aldehyde 11 and 1,4-addition of Me2CuLi to an
ynone system to construct the C9-C11 enone. Following
Paterson’s work, Yamaguchi’s macrolactonization gave the
14-membered macrolide 21. The synthesis of 21 proceeded
in 17 steps (longest linear sequence) and 8.04% overall yield
from known aldehyde 2. The synthesis is highly convergent
and highlights the versatility and efficiency of an indene-
based thiazolidinethione chiral auxiliary in the context of
polyketide-derived natural product synthesis.
Acknowledgment. We thank Prof. Ian Paterson (Univer-
sity of Cambridge) and Prof. Gordon. J. Florence (University
of St. Andrews) for kindly providing us with detailed
characterization data for compounds 20 and 21 as well as
for useful comments. We thank the Center for Biocatalysis
and Bioprocessing at The University of Iowa for a predoc-
toral fellowship (RTA). This work was supported by a
research grant from the National Science Foundation (CHE-
0111292).
As previously reported by Paterson,3 hydroxy acid 20
underwent macrolactonization using Yamaguchi’s protocol31
to afford macrolide 21. The spectral data for compounds 20
and 21 matched Paterson’s intermediates. Macrolide 21 is a
(27) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(28) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–
890. (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091–2096.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds (3-6
(29) NOE experiments were not conclusive due to overlapping of signals;
the dr was determined to be 1.6:1 based on the integration of the H14 protons
on the crude mixture, and the geometry of the major diastereomer 19-E
was later confirmed by conversion to 20 and 21.
1
and 8-21) and copies of H and 13C NMR spectra (3-21).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(30) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436–6437.
(31) Inanaga, J.; Hirata, K.; Saeki, T.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
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