Chemical variation of natural-product-like scaffolds: Design, synthesis, and biological activity of fused bicyclic acetal derivatives

Article abstract of DOI:10.1002/anie.200604688

(Chemical Equation Presented) A clue from nature: Can the bicyclic acetal framework, which is present in many structurally diverse biologically active natural products, be considered a privileged scaffold? Scaffolds with this framework were synthesized an

Full text of DOI:10.1002/anie.200604688

Angewandte
Chemie
DOI: 10.1002/anie.200604688
Drug Design
Chemical Variation of Natural-Product-Like Scaffolds: Design,
Synthesis, and Biological Activity of Fused Bicyclic Acetal
Derivatives**
Lech-Gustav Milroy, Giovanna Zinzalla, Giuseppe Prencipe, Patrick Michel, Steven V. Ley,*
Mekala Gunaratnam, Monica Beltran, and Stephen Neidle
Fused bicyclic acetals exist in many biologically active and
structurally diverse natural products.[1] The knowledge that
simple derivatives (1–3; Scheme 1)) function as important
semio- and allelochemicals in insects and mammals,[2] coupled
with the breadth of biological effects observed in more
complex examples 4–11,[3–10] suggests that the fused bicyclic
acetal may act as a privileged scaffold.[11] Along with
biological relevance,[12] molecular diversity has become an
important criteria in the selection of new frameworks for
drug-discovery programs. Recently, studies into the design
and synthesis of natural-product-like spiroketal derivatives as
potential orally bioavailable lead compounds and probes in
phenotopic screens have been reported.[13]
rearrangement at the carbon atom of the ketal as convenient
means of accessing both the 2,8- and 6,8-dioxabicyclo-
To extend the scope of our studies in this area, we have
focused our interest on other structures such as fused bicyclic
acetals. In view of the broad biological relevance of this unit,
we investigated the fused bicyclic acetal as a core component
by preparing a scaffold that possessed three points of
appendage variation (Scheme 2). Hydroxy and acetylene
groups would allow for considerable functional-group inter-
change, such as oxidation, followed by reductive amination or
Baeyer–Villiger oxidation in the former case, and Sonoga-
shira coupling as well as cycloaddition reactions in the latter.
Furthermore, we envisaged both the cyclization step and
[*] L.-G. Milroy, Dr. G. Zinzalla, G. Prencipe, Dr. P. Michel,
Prof. Dr. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB21EW (UK)
Fax: (+44)122-333-6442
E-mail: svl1000@cam.ac.uk
Homepage: http://leygroup.ch.cam.ac.uk
Dr. M. Gunaratnam, M. Beltran, Prof. Dr. S. Neidle
CRUK Biomolecular Structure Group
The School of Pharmacy, University of London
29–39 Brunswick Square, London, WC1N1AX (UK)
[**] The authors thank Novartis for a Novartis Research Fellowship
(S.V.L.), the EPSRC for a studentship (L.-G.M.), the Marie Curie
Fellowship for a research fellowship (G.Z.), and Cancer Research UK
for funding (M.G., M.B., and S.N.). We also thank Dr. John Davies at
the Cambridge University Chemistry Laboratory for X-ray crystal-
lography.
Scheme 1. Natural products that contain the fused bicyclic acetal ring
system.
Full experimental data for the preparation of all compounds except
28 may be found in the supporting information, which is available
on the WWW under http://www.angewandte.org or fromthe author.
CCDC-627561–627564 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Scheme 2. An example of stereochemical and skeletal variation.
Angew. Chem. Int. Ed. 2007, 46, 2493 –2496
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2493

Communications
[3.2.1]octane ring systems, thus providing examples of ste-
reochemical and further skeletal change in the core compo-
nent. With a small collection of suitably derivatized com-
pounds in hand, our aim was to test their potency against a
broad panel of biological targets. Herein, we report the
synthesis of a series of derivatives along with some encourag-
ing results from preliminary screening.
For the study, we used our knowledge from the synthesis
of 5 (Scheme 1),[14] which employed butane-2,3-diacetal
(BDA)-protected tartrate derivatives,[15] to prepare the key
intermediate 16 which we anticipated would lead to the
isomeric units 12–15 (Scheme 3). Retrosynthetically, we
envisaged that 16 could be derived from the versatile BDA-
derived nonracemic enantiopure building block 17.
Scheme 5. Synthesis of the bicyclic acetal units 12a,b.
position of 12–15. Reduction of the resulting enones[18] led to
the precursors 16a–c, which, on treatment with acid, cyclized
to afford 12a and 12b as single diastereomers.[21]
From the opposite diastereomers 20a,b, the same syn-
thetic steps were followed for the synthesis of 16d–f, which,
when treated with acid, cyclized to form predominantly the
fused bicyclic acetal units 14a,b (Scheme 6).[19,21] Interest-
Scheme 3. Retrosynthetic analysis. TBS=tert-butyldimethylsilyl.
The route began with the elaboration of the known
compound 17. Swern oxidation and acetylide addition to the
resultant aldehyde afforded 18 as a deliberate 1:1 mixture of
diastereomers (Scheme 4). Efficient protecting-group manip-
ulation subsequently led to separable diastereomeric alcohols
19a,b and 20a,b.
Scheme 6. Synthesis of the bicyclic acetal units 14a,b and 15a,b.
Scheme 4. Synthesis of the BDA-derived alcohols 19a,b and 20a,b.
CSA=10-camphorsulfonic acid, DME=1,2-dimethoxyethane,
DMSO=dimethyl sulfoxide, MOM=methoxymethyl, TBAF=tetra-n-
butylammonium fluoride, Tf=trifluoromethanesulfonyl, TMS=trime-
thylsilyl.
ingly, purification of 14a or 14b resulted in their rearrange-
ment into 15a and 15b, respectively. Precedent from the
literature suggests that 14a,b are the kinetic products and
15a,b are the thermodynamic products;[20] this proposition
was reinforced by our ability to interconvert between the
isomeric units 14a and 15a under strongly acidic conditions as
an example of skeletal variation (Scheme 7).[19] The structural
assignment and absolute stereochemistry of 12b and 14b
were confirmed by X-ray analysis.
To introduce medicinally relevant groups at the R1
position, we initially chose the (CH2)2C6H4-p-CF3 and
(CH2)2C6H4-p-Br groups.[16] Swern oxidation of 19a,b gave
the aldehydes, which were then reacted with the phosphonate
diesters 21a and 21b under Horner–Emmons conditions
(Scheme 5).[17] The use of diverse phosphonate reagents was a
convenient way to introduce chemical variation at the R1
With the six structurally diverse units 12a,b, 14a,b, and
15a,b having been synthesized, our next aim was to transform
these units into a small collection of potential biological lead
2494 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2493 –2496

Angewandte
Chemie
Scheme 7. Acid-catalyzed interconversion of the isomeric units 14a
and 15a.
Scheme 9. Chemical elaboration of the bicyclic acetal 22.
HFIP=1,1,1,3,3,3-hexafluoro-2-propanol, mCPBA=meta-chloroperoxy-
benzoic acid, MS=molecular sieves.
compounds. Oxidation of 12a to ketone 22 was achieved using
Dess–Martin periodinane (DMP), while conversion of 12a
into the corresponding triflate was followed by a base-
induced elimination to afford olefin 23 (Scheme 8). The
carbamates 24 and 25 were synthesized in quantitative yield
using a combination of N,N’-disuccimidyl carbonate (DSC)
and NEt3.
Scheme 10. Further chemical elaboration of the bicyclic acetal 12a.
Scheme 8. Chemical elaboration of the bicyclic acetal 12a. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, Py=pyridine.
Ketone 22 was treated with mCPBA to form exclusively
the lactone 26 (Scheme 9). Conversion of 22 into oxime 27
and amine 28 was also possible, as was the homologative
epoxidation to give the epoxide 29,[21] which could be used for
further ring-opening transformations. We also explored the
reactivity of the acetylene functionality of 12a, 14a,b, and
15a, and found that both Sonogashira coupling (to give 30)
and triazole formation (to give 31–35) was achievable under
standard conditions (Scheme 10 and 11).[21]
Given the prevalence of fused bicyclic acetals in a number
of significant natural products with anticancer properties, we
commenced the broad biological profiling of the compounds
by evaluating their activity in cancer cells. Compounds 12a,
24, and 25 were examined in a primary cytotoxicity screen
(72 h exposure), and IC50 values (concentration required to
produce 50% cell-growth inhibition) were calculated. While
12a showed no activity (> 25 mm for both cell lines),
Scheme 11. Chemical elaboration of the bicyclic acetals 14a,b and 15a.
compound 24 gave IC50 values of 9.3 and 15.2 mm respectively
with the MCF7 breast carcinoma and the A549 lung carci-
noma cell lines; compound 25 gave values of 9.0 and greater
than 25 mm. We conclude that both 24 and 25 show activity in
the MCF7 line, with 25 showing selectivity compared to its
relative inactivity in the A549 line. Both lines have the wild-
type p53 gene, and thus the selectivity is not directly linked to
p53 status.
In conclusion, a series of new fused bicyclic acetal
compounds, 12a,b, 14a,b, and 15a,b, have been synthesized.
Units 12a, 14a,b, and 15a have been elaborated into a small
collection of further derivatives as potential lead com-
Angew. Chem. Int. Ed. 2007, 46, 2493 –2496
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2495

Communications
pounds[22,23] (22–35) that are currently being extensively
[10] For the most recent review, see: R. Halim, M. A. Brimble, Org.
Biomol. Chem. 2006, 4, 4048.
[11] For an example, see: K. C. Nicolaou, J. A. Pfefferkorn, A. J.
Roecker, G.-Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem.
Soc. 2000, 122, 9939.
evaluated in several phenotopic screens. Preliminary screen-
ing of a small number of derivatives has already revealed
some significant cytotoxic properties. Further analogues are
now being prepared for screening, and the results will be
reported at a later date.
[12] R. Balamurugan, F. J. Dekker, H. Waldmann, Mol. BioSyst.
2005, 1, 36.
[13] a) G. Zinzalla, L.-G. Milroy, S. V. Ley, Org. Biomol. Chem. 2006,
4, 1977; see also: b) A. A. Birkbeck, S. V. Ley, J. C. Prodger,
Bioorg. Med. Chem. Lett. 1995, 5, 2637; c) R. Haag, A. G. Leach,
S. V. Ley, M. Nettekoven, J. Schnaubelt, Synth. Commun. 2001,
31, 2965; d) O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U.
Mayer, O. Muller, H. Waldmann, Eur. J. Org. Chem. 2005, 4773;
e) B. A. Kulkarni, G. P. Roth, E. Lobkovsky, J. A. Proco, Jr., J.
Comb. Chem. 2002, 4, 56.
Received: November 17, 2006
Revised: January 8, 2007
Published online: February 26, 2007
Keywords: antitumor agents · bicyclic acetals · drug design ·
.
molecular diversity · natural products
[14] H. Kiyota, D. J. Dixon, C. K. Luscombe, S. Hettstedt, S. V. Ley,
Org. Lett. 2002, 4, 3223.
[1] H. Kiyota, Marine Natural Products, Springer, Berlin, 2006, p. 65
(Topics in Heterocyclic Chemistry, No. 5).
[2] a) K. Mori, Eur. J. Org. Chem. 1998, 1479; b) W. Francke, W.
Schröder, Curr. Org. Chem. 1999, 3, 407.
[15] S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince,
H. W. M. Priepke, D. J. Reynolds, Chem. Rev. 2001, 101, 53.
[16] For an example, see: M. Schlosser, Angew. Chem. 2006, 118,
5558; Angew. Chem. Int. Ed. 2006, 45, 5432.
[3] S. S. Mitchell, D. Rhodes, F. D. Bushman, D. J. Faulkner, Org.
Lett. 2000, 2, 1605.
[4] T. Chou, O. Kamo, D. Uemura, Tetrahedron Lett. 1996, 37, 4023,
and references therein.
[17] P. A. Grieco, C. S. Pogonowski, J. Am. Chem. Soc. 1973, 95, 3071.
[18] R. S. Dhillon, R. P. Singh, D. Kaur, Tetrahedron Lett. 1995, 36,
1107.
1
[19] Ratios of products were determined by H NMR spectroscopic
[5] K. Araki, K. Suenaga, T. Sengoku, D. Uemura, Tetrahedron
2002, 58, 1983.
[6] E. M. Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205, and
references therein.
analysis of the crude material.
[20] S. G. Hegde, D. C. Myles, Tetrahedron 1997, 53, 11179.
[21] The structures of 12a,b, 14a,b, 15a,b, 29, 31, 34a, and 35 were
confirmed by NOE enhancements.
[7] C. Wagner, H. Anke, O. Sterner, J. Nat. Prod. 1998, 61, 501.
[8] K. C. Nicolaou, A. Nadin, Angew. Chem. 1996, 108, 1732;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1622.
[22] Predictive pharmacokinetic calculations were made using ACD/
Structure Design Suite software (Advanced Chemistry Develop-
ment, Inc., Toronto, Canada).
[9] G. Koren-Goldshlager, P. Klein, A. Rudi, Y. Benayahu, M.
Schleyer, Y. Kashman, J. Nat. Prod. 1996, 59, 262.
[23] C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv.
Drug Delivery Rev. 1997, 23, 3.
2496 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2493 –2496