Stereocomplementary synthesis of a natural product-derived compound collection on a solid phase

Article abstract of DOI:10.1039/b607816h

Enantiocomplementary allylation of solid phase-bound aldehydes gives rise to a natural product-derived compound collection, including all stereoisomers of cryptocarya diacetate. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607816h

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Stereocomplementary synthesis of a natural product-derived compound
collection on a solid phase{
Ana B. Garcia,{ Torben Leßmann,{ Jayant D. Umarye,{ Victor Mamane,§ Stefan Sommer and
Herbert Waldmann*
Received (in Cambridge, UK) 1st June 2006, Accepted 7th July 2006
First published as an Advance Article on the web 31st July 2006
DOI: 10.1039/b607816h
In order to identify the reaction conditions that would give rise
to allylation products with high enantioselectivity and in high
yield, immobilized aldehyde 3 was synthesized as a model
compound on a polystyrene resin and subjected to allylation with
B-allyl(diisopinocampheyl)borane (Ipc2BAll, 2)12 (Scheme 2) under
different conditions. After oxidative work-up, homoallyl alcohol 4
was released from the resin by treatment with sodium methoxide
and isolated by simple filtration of the crude reaction mixture
through a plug of silica gel. For results of the enantioselective
allylation reactions, see ESI Table 1.{
If four equivalents of 2 are employed at 278 uC in THF/ether
8 : 1.5 (v/v), the homoallylic alcohol 4 is obtained in 79% yield, in
.95% purity and with an enantiomer ratio of 95.5 : 4.5.13
Encouraged by this finding, we sought to synthesize a natural
product and a collection of stereoisomers derived from it by means
of multiple stereocomplementary allylation reactions on the
polymeric carrier. The target cryptocarya diacetate (11)14
(Scheme 3) was chosen as it is an a,b-unsaturated lactone isolated
from Cryptocarya latifolia that is representative of a large group of
biologically-active secondary metabolites.15
Enantiocomplementary allylation of solid phase-bound alde-
hydes gives rise to a natural product-derived compound
collection, including all stereoisomers of cryptocarya diacetate.
The development of synthetic methodologies giving access to
complex molecule architectures of high skeletal diversity1 for
diversity-oriented synthesis (DOS)2 and biology-oriented synthesis
(BIOS)3 is of major importance to chemical biology and medicinal
chemistry research. For such synthetic endeavours, which give
access to stereoisomer libraries (i.e. all diastereomers, see
Scheme 1), e.g., of a given natural product and analogues
thereof, powerful enantiocomplementary transformations are
indispensable. However, solutions to this demanding problem
have so far only been scarcely provided.4–6
For the synthesis of natural product-inspired and -derived
compound collections, solid phase organic synthesis is a viable
technology, enabling the efficient removal of all surplus reagents
required in multi-step sequences.1,2,3,7 However, to date, very few
enantioselective synthetic methods have been developed for solid
phase synthesis in general,8 and their application to the stereo-
complementary synthesis of compound libraries has remained
virtually unexplored.9
For the synthesis of cryptocarya diacetate, (S)-3-hydroxybutyric
acid ester (6) was immobilized on Wang resin 5, activated as the
trichloroacetimidate and converted into polymer-bound aldehyde
7 in two steps (loading 0.5 mmol g21, determined with 4-(9-
fluorenylmethoxycarbonyl)-phenylhydrazine16). Allylation with
l-Ipc2BAll, as described above, and protection of the secondary
alcohol as a silyl ether yielded resin 8, which was formed in a
syn : anti ratio of 85 : 15 (determined after release from the resin by
Here we disclose the development of stereocomplementary,
enantioselective, reagent-controlled carbonyl allylation10 on a solid
phase employing chiral allylboranes,11 and its application to the
synthesis of a natural product-derived compound collection,
including the combinatorial synthesis of all eight isomers of the
natural product cryptocarya diacetate.
Scheme 1 Synthetic pathway to stereoisomer libraries.
Max-Planck-Institut fu¨r Molekulare Physiologie, Abteilung Chemische
BiologieUniversita¨t Dortmund, Fachbereich Chemie, Chemische
Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund,
Germany.Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
E-mail: herbert.waldmann@mpi-dortmund.mpg.de;
Fax: +49 231-133-2499; Tel: +49 231-133-2499
{ Electronic supplementary information (ESI) available: Procedures for
enantioselective allylation, RCM and analytical data for compounds 3, 4,
11, 12a and 14b. See DOI: 10.1039/b607816h
Scheme 2 Development of the enantioselective allylation on a solid
support employing Ipc2BAll (2) as a chiral allylation reagent. (a) Hydroxy-
polystyrene resin (loading 0.98 mmol g21), DCC, cat. DMAP, CH2Cl2, rt,
16 h; (b) O3, CH2Cl2, 278 uC, then PPh3, 278 uC to rt; loading of
{ These authors contributed equally to this work.
the aldehyde resin 0.6 mmol g21 7a
, 60% yield (two steps); (c) (i) 4 equiv. 2,
§ Current address: Synthese` Organometallique et Reactivite´, UMR
CNRS-UHP 7565, Faculte´ des Sciences et Techniques, Universite´ Henri
Poincare´ Nancy 1, BP 239 Bd. Des Aiguillettes, 54506 Vandoeuvre-les-
Nancy, France.
THF, 278 uC, (ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1 : 1, rt,
2 h; (d) MeONa (2 equiv.), THF/MeOH 2 : 1, rt, 12 h. DCC:
dicyclohexylcarbodiimide.
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lactone 10.17 Release from the solid support, with consecutive
cleavage of the silyl group by treatment with trifluoroacetic acid
and subsequent acetylation, yielded a mixture of four stereo-
isomers, from which the all-syn isomer of cryptocarya diacetate
was isolated in 11% overall yield after 11 steps by means of simple
flash chromatography. Formation of the syn-isomer was ascer-
tained by formation of the acetonide, obtained after the second
allylation.18 The absolute configuration of 11 was determined
by comparison of the specific rotation measured for synthetic 11
([a]2D0 = 47.2 (c 0.5, CHCl3)) with literature data ([a]2D9 = 45.4 (c 0.33,
CHCl3),14b [a]D20 = 47.5 (c 0.6, CHCl3),14c and [a]2D5 = 55.8 (c 1.06,
CHCl3)14a).
Based on this reaction sequence, all eight stereoisomeric
configurations possible for the scaffold of the natural product
were generated in a reaction sequence by employing the allylation
reactions in a stereocomplementary fashion (Scheme 4). To this
end, aldehyde 7 was synthesized, as described above, and subjected
to allylation with d- or l-Ipc2BAll. After silylation of the secondary
alcohols and ozonolysis, the resulting aldehydes were subjected to
a second allylation with either enantiomer of the allylborane.
Formation of the acrylic acid ester, ring closing metathesis, as
described above, and final release from the polymeric carrier with
DDQ (CH2Cl2, pH 7 buffer, 0 uC to rt, 16 h) yielded TBS-
protected stereoisomers 12a–d. The yields and stereoisomeric ratios
are given in Scheme 4. By analogy, isomers ent-12a–d were
obtained from aldehyde ent-7. All isomers were obtained in fairly
high overall yields for a 7-step sequence, as shown in Scheme 4.
In order to explore whether the synthesis sequence delineated
above can be extended even further and used for the synthesis of
whole families of natural product-derived and -inspired compound
collections, we synthesized lactones 14a–c (Scheme 5), embodying
up to four stereocenters.
Scheme 3 Enantioselective synthesis of cryptocarya diacetate (11) on a
solid support. (a) 5 (1.2 mmol g21), trichloroacetonitrile, DBU, CH2Cl2,
then 6, BF3?OEt2, cyclohexane/CH2Cl2; (b) DIBAL–H, THF, 278 uC to
rt, 16 h, (c) IBX, DMSO/THF, rt, 16 h; (d) (i) 3 equiv. 2, THF, 278 uC, (ii)
pH 7 buffer, H2O2 30%, DMF/MeOH 1 : 1, 0 uC, 2 h; (e) TBS–Cl,
imidazole, cat. DMAP, CH2Cl2, rt, 16 h; (f) O3, CH2Cl2, 278 uC, then
PPh3, 278 uC to rt; (g) acryloyl chloride, NEt3, cat. DMAP, CH2Cl2, 0 uC
to rt, 16 h; (h) 2 6 20 mol% Grubbs II catalyst, CH2Cl2, reflux, 24 h;
(j) trifluoroacetic acid/CH2Cl2 1 : 2, 20 min, rt; (k) Ac2O, NEt3, cat.
DMAP, CH2Cl2, 0 uC to rt, 3 h. DBU: 1,8-diazabicyclo[5.4.0]undec-7-
ene, DIBAL–H: di-iso-butylaluminiumhydride, IBX: ortho-iodoxybenzoic
acid, TBS: tert-butyldimethylsilyl, DDQ: 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone.
means of integration of the methyl signal intensities in the 500 MHz
1H NMR spectrum). After careful ozonolysis of the double bond
for 6 min, the resulting aldehyde was subjected to a second
allylation with l-Ipc2BAll and the formed secondary alcohol was
converted to acrylic ester 9. Ring closing metathesis employing the
Grubbs II catalyst induced formation of the a,b-unsaturated
Employment of phenylbutyl-substituted immobilized alcohol
1319 in the multiple allylation sequence delineated above allows us
to demonstrate that from one reaction sequence, several different
Scheme 4 Enantiocomplementary solid phase synthesis of eight stereoisomers based on the structure of cryptocarya diacetate. (a) (i) 3 equiv. ent-2, THF,
278 uC; (ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1 : 1, 0 uC, 2 h; (b) (i) 3 equiv. 2, THF, 278 uC; (ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1 : 1, 0 uC, 2 h;
(c) TBS–Cl, imidazole, cat. DMAP, CH2Cl2, rt, 16 h; (d) O3, CH2Cl2, 278 uC, then PPh3, 278 uC to rt; (e) acryloyl chloride, NEt3, cat. DMAP, CH2Cl2,
0 uC to rt, 16 h; (f) 2 6 20 mol% Grubbs II catalyst, CH2Cl2, reflux, 24 h; (g) 10 equiv. DDQ, CH2Cl2, pH 7 buffer, 0 uC to rt, 16 h.
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8 Review: T. Leßmann and H. Waldmann, Chem. Commun., 2006, DOI:
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9 For the stereocomplementary use of chiral catalysts for hetero Diels–
Alder reactions on a solid support, see: R. A. Stavenger and
S. L. Schreiber, Angew. Chem., Int. Ed., 2001, 40, 3417–3421.
10 Previous reports on asymmetric carbonyl allylation on solid supports:
(a) J. Panek and B. Zhu, J. Am. Chem. Soc., 1997, 119, 12022–12023; (b)
C. M. DiBlasi, D. E. Macks and D. S. Tan, Org. Lett., 2005, 7,
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Scheme 5 Enantioselective solid phase synthesis of natural product-
derived lactones 14a–c.
11 Review: P. V. Ramachandran, Aldrichimica Acta, 2002, 35, 23–35.
12 U. S. Racherla and H. C. Brown, J. Org. Chem., 1991, 56, 401–404.
13 In a corresponding solution phase experiment, the methyl ester
corresponding to aldehyde 3 yielded homoallylic alcohol 4 in 83% yield
and in an enantiomer ratio of 92.5 : 7.5 with the same sense of
stereoinduction.
14 Isolation: (a) S. E. Drewes, M. M. Horn and R. S. Shaw,
Phytochemistry, 1995, 40, 321–323; Syntheses: ; (b) K. B. Jørgensen,
T. Suenaga and T. Nakata, Tetrahedron Lett., 1999, 40, 8855–8858; (c)
T. J. Hunter and G. A. O’Doherty, Org. Lett., 2001, 3, 2777–2780; (d)
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16 K. S. Shannon and G. Barany, J. Org. Chem., 2004, 69, 4586–4594.
17 The combination of asymmetric allylation and ring closing metathesis
has been used before for the asymmetric synthesis of natural products
with a,b-unsaturated d-lactone structures. See, for example: (a)
P. V. Ramachandran, M. V. Ram Reddy and H. C. Brown,
Tetrahedron Lett., 2000, 41, 583–586; (b) M. V. Ram Reddy,
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natural products (and consequently also their stereoisomers, if the
sequence is carried out in a stereocomplimentary fashion) can be
obtained (Scheme 5). Thus, after the first allylation, ring closing
metathesis and release from the polymeric carrier by treatment
with DDQ, as described above, gave compound 14a in 31% overall
yield, which is the enantiomer of a natural product isolated from
Ravensara anisata.20 After a second allylation, compound 14b,
which represents the deacetylated version of a natural product
isolated from the same plant,21 was obtained in 6.3% overall yield.
After a third allylation, lactone 14c was obtained in an overall
yield of 4.3%. The synthesis of compound 14c required a total of
12 consecutive steps on the polymeric carrier, including three
stereoselective carbonyl allylation reactions.
These results convincingly demonstrate the applicability of the
allylation reaction on solid supports to the stereocomplementary
synthesis of natural product-derived and -inspired compound
collections.
This
work
was
supported
by
the
Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen Industrie,
the European Union (Postdoctoral fellowship to A. B. G.), the
Alexander-von-Humboldt Stiftung (Postdoctoral fellowship to
J. D. U.) and the Max-Planck-Gesellschaft.
Notes and references
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19 The alcohol for immobilization was obtained by enantioselective
solution-phase allylation of 5-phenylpentanal with l-Ipc2BAll.
20 G. E. Raoelison, C. Terreaux, E. F. Queiroz, F. Zsila, M. Simonyi,
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