Traceless solid phase synthesis of natural product inspired cis-1,2-dehydrodecalins

Article abstract of DOI:10.1039/b901041f

A tetrazole-based traceless linker for Diels-Alder reactions on solid support which can be cleaved by Pd(0)-, Cu(i)- and Ag(i)-assisted nucleophilic displacements has been developed and applied to the solid-phase/traceless release synthesis of natural pro

Full text of DOI:10.1039/b901041f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Traceless solid phase synthesis of natural product inspired
cis-1,2-dehydrodecalinsw
Masahito Yoshida,a Christian Hedberg,a Markus Kaiserc and Herbert Waldmann*ab
Received (in Cambridge, UK) 16th January 2009, Accepted 16th March 2009
First published as an Advance Article on the web 1st April 2009
DOI: 10.1039/b901041f
A tetrazole-based traceless linker for Diels–Alder reactions on
solid support which can be cleaved by Pd(0)-, Cu(I)- and Ag(I)-
assisted nucleophilic displacements has been developed and
applied to the solid-phase/traceless release synthesis of natural
product inspired cis-decalins.
could be achieved through a Horner–Wadsworth–Emmons
reaction with polymer-supported diethylphosphonate 1 and
a subsequent Diels–Alder reaction. With carbocyclic dienophiles,
this reaction sequence would lead to cis-1,2-dehydrodecalin
systems which are for example found in the cis-clerodane
diterpenoids solidagoic acid,10 linaridial11 and linarienone.12
Importantly, a diverse substitution of the cis-1,2-dehydro-
decalin scaffold can be achieved during each step of the
reaction sequence, employing diverse aldehydes in the
Horner–Wadsworth–Emmons (HWE) olefination, differently
substituted dienophiles in the Diels–Alder reaction and
various nucleophiles during release from the solid support.
For the synthesis of 1, benzoate 2 was alkylated with the
commercially available bromide 3 to obtain the ether 4
Biologically relevant compound classes, for instance derived
from or inspired by natural products (NPs), have proven to be
powerful tools for chemical biology and medicinal chemistry
research.1 For the synthesis of compound libraries based on
biological relevance, ‘Biology oriented synthesis’ (BIOS)
provides guidance.2 In BIOS relevance to nature is employed
as the key criterion for the selection of the underlying scaffold
of focussed libraries. Thus, for instance, compound collections
based on the decalin-scaffold occurring in numerous natural
products have yielded potent modulators of biochemical and
biological activity.3 For the synthesis of such libraries, highly
efficient methods are in high demand.3–6 In particular, for solid
phase synthesis, traceless linkers that allow the release of
the desired molecules from the solid support without any
unwanted linker-derived functional groups remaining in the
products are advantageous.7a–f In addition, the introduction
of structural diversity in the release step is a desirable feature
in compound library development allowing for the coverage of
larger areas of chemical space in a given synthesis.
(Scheme 1). After deprotection and tosylation,
6 was
coupled with the known 1-(p-hydroxphenyl)-5-thiotetrazole
phosphonate13 9 to yield the desired HWE phosphonate 7.
Final deprotection of the allyl group with Pd(PPh3)4 and
N-methyl morpholine afforded the linker 8 in 79% yield over
5 steps. The linker 8 was immobilized on polymeric support by
amidation with HATU–DIEA, yielding resin-bound diethyl-
phosphonate 1 with a loading efficiency of ca. 0.5 mmol gꢀ1
based on gravimetric analysis after cleavage with 20%
TFA–CH2Cl2. In order to investigate the feasibility of the
traceless linker, cycloadduct 12 was synthesized on solid
support. Horner–Wadsworth–Emmons olefination with
methacrolein proceeded best (90% conversion into 10) with
Here we describe the development of a new traceless linker
system and its application in the diversity-generating release of
dehydrodecalins synthesized by means of Diels–Alder cyclo-
additions on the solid phase.7f–k
We designed a traceless linker featuring a 5-thiotetrazole
moiety as illustrated in Fig. 1. 5-Thiotetrazoles and derivatives
have been recognized as versatile leaving groups, e.g. in the
Julia–Kocienski olefination (after oxidation to sulfone) or during
allylic substitutions.8,9 We envisioned that a placement of this
leaving group in an allylic position could enable a traceless
cleavage by metal-catalyzed reactions. Linkage to the solid
support was envisioned through a 1-(p-hydroxyphenyl)-5-thio-
tetrazole moiety. Its introduction to the required allylic position
a Max-Planck-Institut fur Molekulare Physiologie, Abteilung
¨
Chemische Biologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
E-mail: herbert.waldmann@mpi-dortmund.mpg.de;
Fax: +49 231-133-2499; Tel: +49 231-133-2400
b Technische Universitat Dortmund, Fakultat Chemie, Chemische
¨
¨
Biologie, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
c Chemical Genomics Centre der Max-Planck-Gesellschaft,
Otto-Hahn-Str. 15, 44227 Dortmund, Germany
w Electronic supplementary information (ESI) available: Procedures
for traceless linker and solid-phase synthesis and analytical data for
compounds. See DOI: 10.1039/b901041f
Fig. 1 Retrosynthetic analysis of a solid-phase synthesis of cis-decalins,
using a 5-thiotetrazole based traceless linker.
ꢁc
This journal is The Royal Society of Chemistry 2009
2926 | Chem. Commun., 2009, 2926–2928

View Article Online
Scheme 2 Diversity generating cleavage of the 5-thiotetrazole linker
by metal catalysis. (a) PhMgBr (0.1 M), CuBr (0.06 M), THF, 50 1C,
5 h, 29%; (b) 1-Me indole (0.1 M), AgOTf (0.1 M), CH2Cl2, rt, 3 h,
23%; (c) PhSO2Na (0.1 M), Pd(PPh3)4, THF–MeOH (2 : 1), 70 1C, 8 h,
38%; (yields were calculated after gravimetric analysis and are based
on the initial loading of 1).
side (Scheme 2).9a Interestingly, the use of Pd(0) led to
replacement with stereochemical net retention (double inversion)
of the 5-thiotetrazole moiety if phenylsulfinates were
employed,9b,c,16 resulting in the synthesis of cis-2,3-dehydro-
decalins. This metal-dependent type of resin release signifi-
cantly extends the scope of the linker system since it allows a
diversity-generating cleavage of the polymer-supported
decalin derivatives. All release reactions could be carried out
under mild reaction conditions and gave the desired release
products 13–15 in good to moderate overall yields of 23–38%
for three steps, i.e. 61–67% average yield per step.
In order to further extend the scope of the reaction
sequence, we attempted to carry out the Diels–Alder reaction
in an enantioselective fashion and several chiral ligand–metal
Lewis acid combinations and 2-methoxycarbonylquinone15 as
a dienophile were employed (Scheme 3). The highest enantio-
selectivity (75% ee) and purity (490%) for 16 was obtained if
Gd(OTf)3 and (R,R)-iPrPybox as a chiral ligand were used.17
Due to the presence of the a,b-unsaturated carbonyl system,
the subsequent release of the 5-thiotetrazole system
represented a formidable challenge. The use of Ag(I) salts in
the absence of a nucleophile yielded olefin 17.18 Alternatively,
a cleavage with PhMgBr–CuBr in a two step process
which consisted of a controlled Michael addition to the
a,b-unsaturated Michael system to yield 18 followed by a
traceless release with C5H11MgBr–CuBr in THF at 50 1C
yielded the multi-substituted 1,2-dehydrodecalin derivative
19 in a 9% overall yield for five steps (i.e. 63% average yield
per step) and 75% ee.
Scheme 1 Synthesis of cis-decalins on solid support. (a) 3 (1.1 eq.),
K2CO3 (1 eq.), DMF, 80 1C, 20 h, 97%; (b) 20% TFA–CH2Cl2, rt, 16 h,
93%; (c) TsCl (1.3 eq.), NEt3 (2 eq.), DMAP (0.3 eq.), CH2Cl2, 0 1C,
4 h, 98%; (d) 9 (0.9 eq.), K2CO3 (1 eq.), KI (0.3 eq.), DMF, 80 1C, 6 h,
93% (based on 9); (e) Pd(PPh3)4 (0.2 eq.), N-methyl morpholine
(3 eq.), THF, rt, 1.5 h, 96%; (f) Rink amide or aminomethylated
resin, 8 (0.1 M), HATU (0.1 M), DIEA (0.15 M), DMF, rt, 12 h;
(g) methacrolein (0.3 M), LiHMDS (0.5 M), THF, rt, 16 h;
(h) 2-methoxycarbonyl cyclohexenone 11 (0.1 M), Sc(OTf)3 (0.02 M),
CH2Cl2, 0 1C, 5 h.
LiHMDS as a base.14 The subsequent Diels–Alder reaction
with 2-methoxycarbonyl cyclohexenone 1115 as the dienophile
in the presence of Sc(OTf)3 afforded the desired polymer-
supported cis-1,2-dehydrodecalin derivative 12 with full
conversion estimated by NMR spectroscopy after TFA release
from resin.
In summary, we have developed a traceless linker based on a
5-thiotetrazole moiety placed in an allylic position that can be
easily cleaved with metal-assisted nucleophilic reactions
employing Pd(0), Cu(I) and Ag(I) salts. The methodology proved
suitable to perform even an enantioselective construction of the
decalin scaffold on polymeric support.
Next, we tested several metals for catalyzing the nucleo-
philic release of the cis-1,2-dehydrodecalin derivative 12 from
the resin. Release of the 5-thiotetrazole moiety as originally
anticipated could be achieved with Ag(I) and Cu(I) salts by
direct SN20 displacement by exo-attack from the least hindered
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2926–2928 | 2927

View Article Online
Commun., 2006, 3868–3870; (c) M. A. Koch, L.-O. Wittenberg,
S. Basu, D. A. Jeyaraj, E. Gourzoulidou, K. Reinecke,
A. Odermatt and H. Waldmann, Proc. Natl. Acad. Sci. U. S. A.,
2004, 101, 16721–16726; (d) O. Barun, S. Sommer and
H. Waldmann, Angew. Chem., Int. Ed., 2004, 43, 3195–3199;
(e) B. Meseguer, D. Alonso-Dıaz, N. Griebenow, T. Herget and
H. Waldmann, Angew. Chem., Int. Ed., 1999, 38, 2902–2906;
(f) B. Sauerbrei, V. Jungmann and H. Waldmann, Angew. Chem.,
Int. Ed., 1998, 37, 1143–1146; (g) H. Waldmann, V. Khedkar,
H. Duckert, M. Schurmann, I. M. Oppel and K. Kumar,
Angew. Chem., Int. Ed., 2008, 47, 6869–6872; (h) review:
K. Kumar and H. Waldmann, Angew. Chem., Int. Ed., 2009, 48,
DOI: 10.1002/anie.200803437.
6 (a) T. Leßmann and H. Waldmann, Chem. Commun., 2006,
3380–3389; (b) I. Paterson and T. Temal-Laieb, Org. Lett., 2002,
4, 2473–2476.
7 For examples of traceless release from solid phase see: (a) C. Gil
and S. Brase, Curr. Opin. Chem. Biol., 2004, 8, 230–237;
(b) F. Stieber, U. Grether and H. Waldmann, Angew. Chem., Int.
Ed., 1999, 38, 1073–1077; (c) T. Takahashi, S. Tomida, H. Inoue
and T. Doi, Synlett, 1998, 1261–1263; (d) K. C. Nicolaou,
J. A. Pfefferkorn and G.-Q. Cao, Angew. Chem., Int. Ed., 2000,
39, 734–739; (e) W.-X. Gu, S.-X. Liu and R. B. Silverman, Org.
Lett., 2002, 4, 4171–4174; (f) S. Brase, Acc. Chem. Res., 2004, 37,
805–816; (g) review: F. Guillier, D. Orain and M. Bradley, Chem.
Rev., 2000, 100, 2091–2157; (h) Diels–Alder reactions on solid
support: W. C. Cheng, M. M. Olmstead and M. J. Kurt, J. Org.
Chem., 2001, 66, 5528–5533; (i) L. Blanco, R. Bloch, E. Bugnet and
S. Deloisy, Tetrahedron Lett., 2000, 41, 7875–7878; (j) D. Craig,
M. J. Robson and S. J. Shaw, Synlett, 1998, 1381–1383.
8 P. R. Blakemore, W. J. Cole, P. J. Kocienski and A. Morley,
Synlett, 1998, 26–28.
Scheme
3
Enantioselective Diels–Alder reaction and traceless
cleavage from solid support. (a) 2-methoxycarbonylquinone,
Gd(OTf)3, (R,R)-iPrPybox, CH2Cl2, ꢀ78 1C, 3.5 h; (b) Ag(OTf),
CH2Cl2, rt, 5 h, 15%; (c) PhMgBr (0.15 M), CuBr (0.09 M), THF,
rt, 5 h; (d) C5H11MgBr (0.1 M), CuBr (0.06 M), THF, 50 1C, 3 h, 9%
(75% ee); (yields were calculated after gravimetric analysis and are
based on the initial loading of 1).
9 (a) K. Takeda, K. Tsuboyama, K. Torii, M. Murata and H. Ogura,
Tetrahedron Lett., 1988, 29, 4105–4108; (b) K. Takeda, K. Torii
and H. Ogura, Tetrahedron Lett., 1990, 31, 265–266; (c) H.-J. Gais,
T. Jagusch, N. Spalthoff, F. Gerhards, M. Frank and G. Raabe,
Chem.–Eur. J., 2003, 9, 4202–4221.
This work was supported by the Alexander-von-Humboldt
Stiftung (postdoctoral fellowship to M.Y.).
10 (a) T. Anthonsen, M. S. Henderson, A. Martin, R. D. H.
Murray, R. McCrindle and D. McMaster, Can. J. Chem., 1973,
51, 1332–1345; (b) M. S. Henderson, R. McCrindle and
D. McMaster, Can. J. Chem., 1973, 51, 1346–1358;
(c) S. Manabe and C. Nishino, Tetrahedron, 1986, 42, 3461–3470.
11 I. Kitagawa, M. Yoshihara, T. Tani and I. Yosioka, Tetrahedron
Lett., 1975, 16, 23–26.
Notes and references
1 (a) D. R. Spring, Chem. Soc. Rev., 2005, 34, 472–482;
(b) K. Hinterding, D. Alonso-Diaz and H. Waldmann, Angew.
Chem., Int. Ed., 1998, 37, 688–749.
2 A. Noren-Muller, I. Reis-Correa, H. Prinz, C. Rosenbaum,
K. Saxena, H. J. Schwalbe, D. Vestweber, G. Cagna, S. Schunk,
O. Schwarz, H. Schiewe and H. Waldmann, Proc. Natl. Acad. Sci.
U. S. A., 2006, 103, 10606–10611.
12 I. Kitagawa, M. Yoshihara and T. Kamigauchi, Tetrahedron Lett.,
1977, 18, 1221–1224.
13 (a) H. Morita, S. Tashiro, M. Takeda, K. Fujimori, N. Yamada,
Md. C. Shiekh and H. Kawaguchi, Tetrahedron, 2008, 64,
3589–3595; (b) P. Mauleon, I. Alonso, M. R. Rodriguez and
J. C. Carretero, J. Org. Chem., 2007, 72, 9924–9935.
14 The use of NaHMDS or KHMDS resulted in E/Z mixtures and
incomplete conversion.
15 D. Liotta, C. Barnum, R. Puleo, G. Zima, C. Bayer and
H. S. Kezar III, J. Org. Chem., 1981, 46, 2920–2923.
16 For a previous example of traceless release from solid support
employing a Pd(0)-mediated allylic substitution, see: S. C. Schurer
and S. Blechert, Synlett, 1998, 166–168.
3 (a) P. Stahl, L. Kissau, R. Mazitschek, A. Giannis and H. Waldmann,
Angew. Chem., Int. Ed., 2002, 41, 1174–1178; (b) M. A. Koch,
A. Schuffenhauer, M. Scheck, S. Wetzel, M. Casaulta, A. Odermatt,
P. Ertl and H. Waldmann, Proc. Natl. Acad. Sci. U. S. A., 2005, 102,
17272–17277; (c) L. Kissau, P. Stahl, R. Mazitschek, A. Giannis and
H. Waldmann, J. Med. Chem., 2003, 46, 2917–2931; (d) P. Stahl,
L. Kissau, R. Mazitschek, A. Huwe, P. Furet, A. Giannis and
H. Waldmann, J. Am. Chem. Soc., 2001, 123, 11586–11593.
4 (a) A. Ganesan, Curr. Opin. Chem. Biol., 2008, 12, 306–317;
(b) R. Breinbauer, I. R. Vetter and H. Waldmann, Angew. Chem.,
Int. Ed., 2002, 41, 2879–2890.
17 D. A. Evans and J. Wu, J. Am. Chem. Soc., 2003, 125,
10162–10163.
18 The regiochemistry of 17 was assigned by NMR spectroscopy
by comparison with known compounds, see e. g.: B. Witte,
L. Meyer and P. Margaretha, Helv. Chim. Acta, 2000, 83, 554–561.
5 For examples of natural product-based compound collections from
our laboratories, see: (a) A. Noren-Muller, W. Wilk, K. Saxena,
H. Schwalbe, M. Kaiser and H. Waldmann, Angew. Chem., Int.
Ed., 2008, 47, 5973–5977; (b) A. B. Garcia, T. Lessmann,
J. D. Umarye, V. Mamane, S. Sommer and H. Waldmann, Chem.
ꢁc
This journal is The Royal Society of Chemistry 2009
2928 | Chem. Commun., 2009, 2926–2928