The Synthesis of Structurally Diverse Macrocycles by Successive Ring Expansion

Article abstract of DOI:10.1002/anie.201509153

Structurally diverse macrocycles and medium-sized rings (9-24 membered scaffolds, 22 examples) can be generated through a telescoped acylation/ring-expansion sequence, leading to the insertion of linear fragments into cyclic β-ketoesters without performin

Full text of DOI:10.1002/anie.201509153

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201509153
German Edition: DOI: 10.1002/ange.201509153
Macrocycles
The Synthesis of Structurally Diverse Macrocycles By Successive Ring
Expansion
Christiana Kitsiou, Jordan J. Hindes, Phillip I’Anson, Paula Jackson, Thomas C. Wilson,
Eleanor K. Daly, Hannah R. Felstead, Peter Hearnshaw, and William P. Unsworth*
Abstract: Structurally diverse macrocycles and medium-sized
rings (9–24 membered scaffolds, 22 examples) can be gener-
ated through a telescoped acylation/ring-expansion sequence,
leading to the insertion of linear fragments into cyclic b-
ketoesters without performing a discrete macrocyclization step.
The key b-ketoester motif is regenerated in the ring-expanded
product, meaning that the same sequence of steps can then be
repeated (in theory indefinitely) with other linear fragments,
allowing macrocycles with precise substitution patterns to be
“
grown” from smaller rings using the successive ring-expan-
sion (SuRE) method.
[
1]
[2]
I
mportant applications in medicinal chemistry, catalysis,
[
3]
[4]
materials science, chiral sensing, supramolecular chemis-
try, self-assembly, nanotechnology, and natural product
[5]
[6]
[7]
[8]
synthesis rely on the synthesis of functionalized macro-
cycles. At present, macrocycles are typically made by the end-
to-end cyclisation of a linear precursor, a difficult and
unpredictable transformation; in particular, achieving macro-
cyclization (1!2, Figure 1a) rather than dimerization (1!3)
[9]
Figure 1. End-to-end macrocyclization and successive ring-expansion
SuRE) methods.
is a major challenge. The most common strategy used to
combat this is to perform the reactions at high-dilution
(
[10]
(
typically about 1–5 mm), but although successful in many
cases, such procedures are generally highly substrate-depen-
dent and impractical for large-scale synthesis. Other methods
designed to offer “pseudo high-dilution” conditions include
end-to-end macrocyclization is avoided entirely. Successive
ring expansion (SuRE; Figure 1b) is based on the sequential
insertion of linear fragments into existing cyclic systems, by
coupling a cyclic compound (starter unit 4) to a linear
fragment 5 which can then rearrange (see 6), initiating ring
expansion and forming the product 7. A key design feature is
the replication of the functionality in the cyclic starter unit in
the ring-expanded product (dashed circle), as this means that
the same coupling/ring-expansion sequence can be repeated,
allowing further iterations to be performed in the same way
(7!9; 9!11). The SuRE method can incorporate a range of
linear fragments and can theoretically be repeated indef-
initely, meaning macrocycles of virtually any ring size and
composition are potentially accessible. As no discrete macro-
cyclization step is involved, the reactions should not require
specialized conditions, preorganization, or high dilution to
proceed effectively. Of course, ring expansion is not a new
[
11]
[12]
the use of solid supports, biphasic solvent systems, and
[13]
DNA-templated synthesis.
Alternatively, dilution can be
minimized if the linear precursor is preorganized into
a conformation biased towards macrocyclization; for exam-
[14]
ple, using a small molecule/ion template or by exploiting
[9b, 15]
internal structural elements.
Each of these macrocycliza-
tion methods have been applied successfully in the past, but
invariably they are optimized for specific substrate classes
and/or utilize specialized reaction setups. Thus, there is a need
for new macrocyclization strategies that are practical,
scalable, and applicable to a broad range of systems.
The methods described above are all designed to improve
the efficiency of the difficult end-to-end cyclisation step.
Herein, a conceptually different approach is taken, in which
[9,16]
concept in itself,
but successive ring-expansion processes
are far less common. Existing approaches either rely on
multiple steps to effect each iteration, or give rise to less
[
*] C. Kitsiou, J. J. Hindes, P. I’Anson, P. Jackson, T. C. Wilson, E. K. Daly,
H. R. Felstead, P. Hearnshaw, Dr. W. P. Unsworth
University of York
York, YO24 4PP (UK)
E-mail: william.unsworth@york.ac.uk
[17]
well-defined mixtures of products through ring-expansion
[18]
polymerization.
In this paper, the SuRE concept is
validated using a telescoped two-step sequence to generate
macrocyclic lactams and lactones from cyclic b-keto esters
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201509153.
(Figure 1c).
1
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Figure 2. Substrates 12a–g and 13a–j. PG=protecting group;
Bn=benzyl; Cbz=carbobenzyloxy.
Scheme 1. Successive ring-expansion reactions (12a to 17a; 17a to
1
8a; 18a to 19a). Fmoc=9-fluorenylmethoxycarbonyl.
The ring-expansion procedure was established using 12-
[19]
membered-ring cyclic b-ketoester 12a
and acid chloride
1
3a (Scheme 1). First, a C-acylation reaction was performed
[20]
(
using MgCl and pyridine at room temperature in CH Cl )
2
2
2
to generate tricarbonyl species 14a. This intermediate was
then treated with piperidine in CH Cl2 to cleave the 9-
2
fluorenylmethoxycarbonyl (Fmoc) protecting group, which
also resulted in spontaneous ring expansion, presumably via
fused bicycle 16a, affording 16-membered ring product 17a in
8
0% yield over the telescoped two-step sequence
[
21]
(
Scheme 1). The ease of the ring-expansion step (which is
likely to be driven by the formation of a stabilized enolate and
an amide group) was encouraging, but in order to validate the
SuRE concept, it was necessary to demonstrate that the
macrocyclic product could undergo further ring expansion.
Thus, the same reaction conditions were then applied to b-
keto ester 17a and pleasingly, this resulted in the formation of
[
24]
Scheme 2. Scope of the ring-expansion sequence. i) Dicarbonyl 12
2
0-membered ring macrocycle 18a (70% yield). The same
(
3
1 equiv), MgCl (2 equiv), and pyridine (6 equiv) were premixed for
0 min in CH Cl (7 mLmmol of 12) before adding acid chloride 13
3 equiv) in CH Cl (3 mLmmol of 12) and stirring for 1–2 h at RT.
ii) Conditions A: piperidine (10 equiv), CH Cl (10 mLmmol ), RT,
–2 h; Conditions B: H , Pd/C, EtOAc (10 mLmmol ), RT, 24 h;
Conditions C: H , Pd(OH) /C, MeOH (10 mLmmol ), RT, 24 h.
2
sequence was then used for a third time, resulting in the
conversion of 18a into the 24-membered ring product 19a
À1
2
2
À1
(
2 2
(
62% yield). Importantly, these reactions do not use high-
À1
2
2
dilution conditions (the reactions are performed at 0.1m) and
À1
1
2
[
22]
À1
can be scaled up easily.
2
2
Next, attention turned to exploring the scope of the
synthetic method. Cyclic starter units (12a–g) and linear
fragments (13a–j; Figure 2), were synthesized using standard
[a] Presumably, 17a is formed by hydrogenolysis of the NBn group.
2
5
[
b] An optically active product was isolated, 17n: ½aŠ ¼À51.2 (c=1.0,
D
CHCl ).
3
[23]
methods (see the Supporting Information).
The ring expansion can be achieved using carbobenzyloxy
(
Cbz) derivative 13b as the linear fragment in place of
ditions to form 9–12-membered medium ring products 17d–
17g in good yields. N-Alkyl and branched linear fragments
are also compatible, forming ring-expanded products 17h–
17l, with the structure of 11-membered ring 17h confirmed by
Fmoc derivative 13a; in this case, following C-acylation in the
usual way, the Cbz group was cleaved by hydrogenolysis,
[24]
initiating spontaneous ring expansion (Scheme 2). Methyl
and benzyl esters in the starter unit are also tolerated,
furnishing macrocycles 17b and 17c. The reaction also
tolerates other ring sizes; 5–8-membered starter units each
reacted with linear fragment 13a under the standard con-
[25]
X-ray crystallography (see the Supporting Information).
Linear fragments derived from a-amino acids (forming
products 17m and 17n) have also been applied successfully,
which is likely to be useful in the synthesis of macrocyclic
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[
1,26,27]
peptidomimetics.
7o from b-ketoester 12 f and benzyl-protected alcohol
derivative 13j indicates that SuRE is not limited to amino
Finally, the synthesis of cyclic lactone
Thus, 20- and 14-membered macrocycles 18a and 18b
were formed in good yield using the standard procedure, by
insertion of linear fragment 13a for a second time. The
insertion of different linear fragments is also possible, as
demonstrated by the formation of mixed lactam/lactone
product 18c and mixed bis-lactam 18d. Furthermore, there
is no need to stop after two ring-expansion reactions, with 24-
membered macrocycles 19a and 19b, and 18-membered
product 19c, also being synthesized using the standard
procedure. Macrocyclic products 19b and 19c are especially
noteworthy, as they were prepared through the controlled
insertion of three different linear fragments (Scheme 3). The
practicality and versatility of the SuRE procedure means that
it is a genuine alternative to current macrocyclization
1
[28]
acid derived linear fragments. As with the Cbz-protected
variant, hydrogenolysis was used to promote benzyl group
cleavage and ring expansion in situ.
The reactions described in Scheme 2 represent a conven-
ient way to generate ring-enlarged products, and notably
include 9–11-membered ring products (17d–f, 17h, 17l–o),
compounds that are difficult to synthesize by conventional
[29]
methods.
Indeed, their formation from 5–7-membered
starting materials (ring sizes which are typically far more
thermodynamically stable than their respective products)
highlights the strength of the driving force for ring expansion.
However, the real value of this method is the fact the products
themselves are suitable substrates for further ring expansion,
as this allows more complex scaffolds to be assembled, as
[30]
methods (for example macrocycle “stapling” approaches)
and is expected to be adopted in various research fields that
rely on controlled macrocycle synthesis, especially those
[24]
[26e,31,32]
shown in Scheme 3.
focused on the generation of diversity.
In summary, a simple but effective strategy for the
formation of functionalized medium-sized rings (17d–f, 17h,
and 17l–o) and macrocycles (17a–c, 17g, 17i–k, 18a–d, and
1
9a–c) is described. The regeneration of the reactive func-
tionality in the starter unit is needed for the ring-expansion
procedure to be applied successively, and although in this case
the cyclic b-ketoester motif was chosen, a range of other ring-
expansion systems can easily be imagined, in which a similar
strategy may be applied. Using the SuRE synthetic method,
diverse families of macrocycles should be accessible more
easily than is possible using existing methods, and because
there is no discrete macrocyclization step, their syntheses
should be viable on a large scale. The freedom to install
precise sequences of functional groups into macrocycles is
likely to be of value in the design and development of many
such applications in the various research fields highlighted
[1–8,26–28]
above.
Future work will explore these possibilities, as
well as further expanding the substrate scope and challenging
the methodology to create even larger, more complex
macrocycles.
Acknowledgements
The authors wish to thank the University of York (all authors)
for funding, Dr. Adrian C. Whitwood (University of York) for
X-ray crystallography, and Profs. Richard J. K. Taylor and
Peter OꢀBrien for helpful advice.
Keywords: macrocycles · medium-sized rings · rearrangement ·
ring expansion · structural diversity
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15794–15798
Angew. Chem. 2015, 127, 16020–16024
[
1] For information and perspective on macrocycles in medicinal
chemistry, see: a) R. H. Kohli, C. T. Walsh, M. D. Burkart,
Nature 2002, 418, 658; b) E. M. Driggers, S. P. Hale, J. Lee, N. K.
Terrett, Nat. Rev. Drug Discovery 2008, 7, 608; c) E. Marsault,
M. L. Peterson, J. Med. Chem. 2011, 54, 1961; d) J. Xie, N.
Bogliotti, Chem. Rev. 2014, 114, 7678; e) A. K. Yudin, Chem. Sci.
2015, 6, 30.
[
24]
Scheme 3. Examples of successive ring expansion. i) Dicarbonyl 17/
1
3
1
8 (1 equiv), MgCl (2 equiv), and pyridine (6 equiv) were premixed for
0 min in CH Cl (7 mLmmol of 17/18) before adding acid chloride
3 (3 equiv) in CH Cl (3 mLmmol of 17/18) and stirring for 2 h at
RT. ii) Conditions A: piperidine (10 equiv), CH Cl (10 mLmmol ), RT,
2
À1
2
2
À1
2
2
À1
2
2
À1
1
–2 h; Conditions C: H , Pd(OH) /C, MeOH (10 mLmmol ), RT, 24 h.
2 2
1
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[
2] For macrocycles in catalysis, see: a) S. Dawn, M. B. Dewal, D.
Sobransingh, M. C. Paderes, A. C. Wibowo, M. D. Smith, J. A.
Krause, P. J. Pellechia, L. S. Shimizu, J. Am. Chem. Soc. 2011,
Chem. Commun. 1981, 1123; c) R. Wälchli, A. Guggisberg, M.
Hesse, Tetrahedron Lett. 1984, 25, 2205; d) K. Oda, T. Ohnuma,
Y. Ban, J. Org. Chem. 1984, 49, 953; e) S. Kim, G. H. Joe, J. Y.
Do, J. Am. Chem. Soc. 1993, 115, 3328; f) K. Kostova, M. Hesse,
Helv. Chim. Acta 1995, 78, 440; g) J. E. Forsee, J. AubØ, J. Org.
Chem. 1999, 64, 4381; h) J. A. Heerklotz, C. Fu, A. Linden, M.
Hesse, Helv. Chim. Acta 2000, 83, 1809; i) B. Moon, S. Han, Y.
Yoon, H. Kwon, Org. Lett. 2005, 7, 1031; j) Y.-M. Jia, X.-M.
Liang, L. Chang, D.-Q. Wang, Synthesis 2007, 744.
1
33, 7032; b) Y. Demizu, N. Yamagata, S. Nagoya, Y. Sato, M.
Doi, M. Tanaka, K. Nagasawa, H. Okuda, M. Kurihara,
Tetrahedron 2011, 67, 6155.
[
[
[
[
3] For examples of macrocyclic advanced materials, see: a) H.
Richtzenhain, A. J. Blake, D. W. Bruce, I. A. Fallis, W.-S. Li, M.
Schrçder, Chem. Commun. 2001, 2580; b) K. Sato, Y. Itoh, T.
Aida, J. Am. Chem. Soc. 2011, 133, 13767.
4] For macrocyclic chiral sensing applications, see: a) T. Ema, D.
Tanida, T. Sakai, J. Am. Chem. Soc. 2007, 129, 10591; b) T. Ema,
D. Tanida, K. Sugita, T. Sakai, K.-I. Miyazawa, A. Ohnishi, Org.
Lett. 2008, 10, 2365.
[17] Y.-S. Lee, J.-W. Jung, S.-H. Kim, J.-K. Jung, S.-M. Park, N.-J. Kim,
D.-J. Chang, J. Lee, Y.-G. Suh, Org. Lett. 2010, 12, 2040.
[18] a) N. Hadjichristidis, M. Pitsikalis, S. Pispas, H. Iatrou, Chem.
Rev. 2001, 101, 3747; b) J. A. Castro-Osma, C. Alonso-Moreno,
J. C. García-Martinez, J. Fernµndez-Baeza, L. F. Sµnchez-Barba,
A. Lara-Sµnchez, A. Otero, Macromolecules 2013, 46, 6388.
[19] J. A. Marshall, V. H. Audia, J. Org. Chem. 1987, 52, 1106.
[20] The C-acylation procedure used was based on a known method,
see: M. W. Rathke, P. J. Cowan, J. Org. Chem. 1985, 50, 2622.
[21] The identity of macrocycle 17a is supported by full spectroscopic
data (see the Supporting Information). In particular, the
5] For recent reviews of catenanes and rotaxanes respectively, see:
a) N. H. Evans, P. D. Beer, Chem. Soc. Rev. 2014, 43, 4658; b) M.
Xue, Y. Yang, X. Chi, X. Yan, F. Huang, Chem. Rev. 2015, 115,
7
398.
6] For macrocycles which self-assemble into nanotubes for bio-
medical applications, see: a) D. Pasini, M. Ricci, Curr. Org.
Synth. 2007, 4, 59; b) J. Montenegro, M. R. Ghadiri, J. R. Granja,
Acc. Chem. Res. 2013, 46, 2955; c) I. Alfonso, R. Quesada, Chem.
Sci. 2013, 4, 3009.
1
3
C NMR and DEPT data were important to rule out isomeric
species 15a and 16a; the presence of a CH signal (d = 58.2 ppm),
two amide/ester C=O signals (169.4, 173.0 ppm), and one ketone
C=O signal (206.5 ppm) is consistent only with the ring-
expanded product 17a. Similar signals were clearly detectable
in all of the other ring-expanded products (17–19) reported
herein.
[
[
7] M. Iyoda, J. Yamakawa, M. J. Rahman, Angew. Chem. Int. Ed.
2
011, 50, 10522; Angew. Chem. 2011, 123, 10708.
8] For accounts of macrocyclisation in natural product synthesis,
see: a) M. Yu, C. Wang, A. F. Kyle, P. Jakubec, D. J. Dixon, R. R.
Schrock, A. H. Hoveyda, Nature 2011, 479, 88; b) A. Fürstner,
Chem. Commun. 2011, 47, 6505; c) P. Winter, W. Hiller, M.
Christmann, Angew. Chem. Int. Ed. 2012, 51, 3396; Angew.
Chem. 2012, 124, 3452; d) W. P. Unsworth, K. A. Gallagher, M.
Jean, J. P. Schmidt, L. J. Diorazio, R. J. K. Taylor, Org. Lett. 2013,
[22] The ring expansion of compound 12a to 17a has been performed
on 20 mmol scale (to produce circa 5 g of 17a) with no
appreciable drop in reaction yield.
[23] See the Supporting Information for preparations. For original
literature procedures, see Ref. [19] and the following: a) P.
Dowd, S.-C. Choi, Tetrahedron 1992, 48, 4773; b) M. Yoshida, C.
Sugimura, K. Shishido, Org. Lett. 2011, 13, 3482; c) R. W. A.
Luke, P. G. T. Boyce, E. K. Dorling, Tetrahedron Lett. 1996, 37,
263; d) R.-F. Yang, P.-Q. Huang, Chem. Eur. J. 2010, 16, 10319;
e) G. A. G. Sulyok, C. Gibson, S. L. Goodman, G. Hçlzemann,
M. Wiesner, H. Kessler, J. Med. Chem. 2001, 44, 1938; f) A.-H.
Li, S. Moro, N. Forsyth, N. Melman, X.-D. Ji, K. A. Jacobson, J.
Med. Chem. 1999, 42, 706.
1
5, 262; e) T. O. Ronson, R. J. K. Taylor, I. J. S. Fairlamb,
Tetrahedron 2015, 71, 989; f) S. M. Rummelt, J. Preindl, H.
Sommer, A. Fürstner, Angew. Chem. Int. Ed. 2015, 54, 6241;
Angew. Chem. 2015, 127, 6339.
[
9] For useful insight, see: a) M. Hesse in Ring Enlargement in
Organic Chemistry, Wiley-VCH, Weinheim, 1991; b) C. J. White,
A. K. Yudin, Nat. Chem. 2011, 3, 509.
[
[
10] Countless macrocyclisation reactions performed at high-dilution
have been reported (for example see Refs. [1–9]). For a theoret-
ical study and more recent perspective, see: a) J. Fastrez, J. Phys.
Chem. 1989, 93, 2635; b) J. C. Collins, K. James, MedChemCom-
mun 2012, 3, 1489.
[24] In solution in CDCl , some of the ring-expanded products exist
3
as equilibrating mixtures of keto/enol tautomers (17d–g, 17i–k,
17m, 17o, 18c, 19c), rotamers (17h–j, 19c) and diastereoisomers
(17k–l, 18d, 19b). See the Supporting Information for details.
[25] CCDC 1426909 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
11] For examples of the use of solid supports in macrocycle
synthesis, see: a) S. Mazur, P. Jayalekshmy, J. Am. Chem. Soc.
1
979, 101, 677; b) C. Rosenbaum, H. Waldmann, Tetrahedron
Lett. 2001, 42, 5677.
[26] a) T. Liu, S. H. Joo, J. L. Voorhees, C. L. Brooks, D. Pei, Bioorg.
Med. Chem. 2009, 17, 1026; b) K. Sasaki, D. Crich, Org. Lett.
2010, 12, 3254; c) M. Gongora-Benítez, J. Tulla-Puche, F.
Albericio, Chem. Rev. 2013, 113, 901; d) T. A. Hill, N. E.
Shepherd, F. Diness, D. P. Fairlie, Angew. Chem. Int. Ed. 2011,
50, 10522; Angew. Chem. 2011, 123, 10708; e) T. A. Hill, N. E.
Shepherd, F. Diness, D. P. Fairlie, Angew. Chem. Int. Ed. 2014,
53, 13020; Angew. Chem. 2014, 126, 13234; f) A. Isidro-Llobet,
K. H. Georgiou, W. R. J. D. Galloway, E. Giacomini, M. R.
Hansen, G. MØndez-Abt, Y. S. Tan, L. Carro, H. F. Sore, D. R.
Spring, Org. Biomol. Chem. 2015, 13, 4570.
[
[
12] A.-C. BØdard, S. K. Collins, J. Am. Chem. Soc. 2011, 133, 19976.
13] a) Z. J. Gartner, B. N. Tse, R. Grubina, J. B. Doyon, T. M.
Snyder, D. R. Liu, Science 2004, 305, 1601; b) B. N. Tse, T. M.
Snyder, Y. Shen, D. R. Liu, J. Am. Chem. Soc. 2008, 130, 15611.
14] a) K. Haas, W. Ponikwar, H. Nçth, W. Beck, Angew. Chem. Int.
Ed. 1998, 37, 1086; Angew. Chem. 1998, 110, 1200; b) N. V.
Gerbeleu, V. B. Arion, J. P. Burgess in Template Synthesis of
Macrocyclic Compounds, Wiley-VCH, Weinheim, 1999.
15] a) R. Hili, V. Rai, A. K. Yudin, J. Am. Chem. Soc. 2010, 132,
[
[
2
889; b) H. Fu, H. Chang, J. Shen, L. Yu, B. Qin, K, Zhang, H,
Zeng, Chem. Commun. 2014, 50, 3582; c) C. J. White, J. L.
Hickey, C. C. G. Scully, A. K. Yudin, J. Am. Chem. Soc. 2014,
[27] For macrocyclic peptidomimetics as inhibitors of protein–
protein interactions, see: a) A. J. Wilson, Chem. Soc. Rev. 2009,
38, 3289; b) J. Gavenonis, B. A. Sheneman, T. R. Siegert, M. R.
Eshelman, J. A. Kritzer, Nat. Chem. Biol. 2014, 10, 716; c) E. A.
Villar, D. Beglov, S. Chennamadhavuni, J. A. Porco, Jr., D.
Kozakov, S. Vajda, A. Whitty, Nat. Chem. Biol. 2014, 10, 723.
[28] For biologically active medium-sized and macrocyclic lactones,
see: V. B. Riatto, R. A. Pilli, M. M. Victor, Tetrahedron 2008, 64,
2279.
1
36, 3728; d) S. Zaretsky, J. L. Hickey, J. Tan, D. Pichugin, M. A.
St. Denis, S. Ler, B. K. W. Chung, C. C. G. Scully, A. K. Yudin,
Chem. Sci. 2015, 6, 5446.
[
16] For examples of ring-expansion reactions which operate by
a similar mechanism, see: a) A. Guggisberg, B. Dabrowski, U.
Kramer, C. Heidelberger, M. Hesse, H. Schmid, Helv. Chim.
Acta 1978, 61, 1039; b) V. Bhat, R. C. Cookson, J. Chem. Soc.
Angew. Chem. Int. Ed. 2015, 54, 15794 –15798
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15797

.
Angewandte
Communications
[
29] a) F. Kopp, C. F. Stratton, L. B. Akella, D. S. Tan, Nat. Chem.
Biol. 2012, 8, 358; b) R. A. Bauer, T. A. Wenderski, D. S. Tan,
Nat. Chem. Biol. 2013, 9, 21.
30] a) Y. H. Lau, P. de Andrade, S.-T. Quah, M. Rossmann, L.
Laraia, N. Skçld, T. J. Sum, P. J. E. Rowling, T. L. Joseph, C.
Verma, M. Hyvçnen, L. S. Itzhaki, A. R. Venkitaraman, C. J.
Brown, D. P. Lane, D. R. Spring, Chem. Sci. 2014, 5, 1804;
b) Y. H. Lau, P. de Andrade, Y. Wu, D. R. Spring, Chem. Soc.
Rev. 2015, 44, 91.
31] For general aspects of diversity-oriented synthesis, see: a) S. L.
Schreiber, Science 2000, 287, 5460; b) D. R. Spring, Org. Biomol.
Chem. 2003, 1, 3867; c) D. Morton, S. Leach, C. Cordier, S.
Warriner, A. Nelson, Angew. Chem. Int. Ed. 2009, 48, 104;
Angew. Chem. 2009, 121, 110.
32] For examples of diversity-oriented synthesis applied to macro-
cyclic compounds, see: a) F. Leon, D. G. Rivera, L. A. Wessjo-
hann, J. Org. Chem. 2008, 73, 1762; b) A. R. Kelly, J. Wei, S.
Kesavan, J. C. MariØ, N. Windmon, D. W. Young, L. A. Mar-
caurelle, Org. Lett. 2009, 11, 2257; c) A. Isidro-Llobet, T. Murillo,
P. Bello, A. Cilibrizzi, J. T. Hodgkinson, W. R. J. D. Galloway, A.
Bender, M. Welch, D. R. Spring, Proc. Natl. Acad. Sci. USA
2011, 108, 6793; d) K. M. G. O’Connell, H. S. Beckmann, L.
Laraia, H. T. Horsley, A. Bender, A. R. Venkitaraman, D. R.
Spring, Org. Biomol. Chem. 2012, 10, 7545; e) H. S. G. Beck-
mann, F. Nie, C. E. Hagerman, H. Johansson, Y. S. Tan, D.
Wilcke, D. R. Spring, Nat. Chem. 2013, 5, 861; f) K. V. Lawson,
T. E. Rose, P. G. Harran, Tetrahedron 2013, 69, 7683; g) A.
Grossmann, S. Bartlett, M. Janecek, J. T. Hodgkinson, D. R.
Spring, Angew. Chem. Int. Ed. 2014, 53, 13093; Angew. Chem.
2014, 126, 13309.
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Received: September 30, 2015
Revised: October 28, 2015
Published online: November 13, 2015
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