Iterative Assembly of Macrocyclic Lactones using Successive Ring Expansion Reactions

Article abstract of DOI:10.1002/chem.201803064

Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring expansion protocol. The products can also be expanded using amino acid-based linear fragments, meaning that macrocycles with precise

Full text of DOI:10.1002/chem.201803064

A Journal of
Accepted Article
Title: Iterative Assembly of Macrocyclic Lactones using Successive
Ring Expansion Reactions
Authors: Thomas C Stephens, Aggie Lawer, Thomas French, and
William Paul Unsworth
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To be cited as: Chem. Eur. J. 10.1002/chem.201803064
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Iterative Assembly of Macrocyclic Lactones using Successive
Ring Expansion Reactions
Thomas C. Stephens, Aggie Lawer, Thomas French and William P. Unsworth*
Abstract: Macrocyclic lactones can be prepared from lactams and
hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring
expansion protocol. The products can also be expanded using amino
acid-based linear fragments, meaning that macrocycles with precise
sequences of hydroxy- and amino acids can be assembled in high
yields by ‘growing’ them from smaller rings, using a simple procedure
in which high dilution is not required. The method should significantly
expedite the practical synthesis of diverse nitrogen containing
macrolide frameworks.
cyclisation precursors. This means that generalised, building
block approaches to prepare macrocyclic lactones are rare,
although a notable exception is the excellent work of Seiple,
Zhang, Myers and co-workers, in which a modular platform for the
efficient synthesis of >300 macrolide antibiotic candidates (c.f. 3,
Figure 1) is described.14f
Introduction
Nature routinely makes use of exquisitely selective assembly line-
type processes1 to construct molecules vital to life, such as DNA
and polyketide metabolites,2 and artificial synthetic methods
based on similar principles have long been known for the
synthesis of peptides3 and oligonucleotides,4 thus transforming
synthetic biology and its associated fields. Indeed, the value of
assembly line type approaches is increasingly being recognised
for the preparation of other compound classes: seminal methods
include those for the synthesis of sugars,5 polyketide derivatives,6
sp3-rich hydrocarbons,7 polyenes,8 cyclic ethers,9 polyaromatics10
and various others.11
This manuscript concerns our efforts to develop a practical,
iterative method for the assembly of macrocyclic lactones.
Medicinal interest in macrocycles has risen markedly in recent
years,12,13 with macrocyclic lactones (especially macrolide
antibiotics)14 featuring heavily in medicinally oriented research.
Naturally occurring macrolides such as erythromycin 114a have
long been used as antibiotics, while analogues prepared via semi-
synthesis (e.g. azithromycin 2)14b as well as fully synthetic
analogues (e.g. 3)14f,g have since been developed to address the
challenge of rising anti-microbial resistance (Figure 1).15
Macrocyclic lactones (and indeed most macrocycles) are usually
difficult to make, largely due to the energetic barriers that must be
overcome to promote the end-to-end cyclisation of a linear
precursor.16 Nonetheless, several powerful strategies have
emerged over the years to address this,17,18 with ring closure via
the lactone C–O bond (e.g. the Yamaguchi macrolactonisation
reaction) and ring closing metathesis amongst the most popular.18
However, such methods usually rely on high dilution conditions to
favour macrocyclisation over competing dimerisation or
oligomerisation pathways, and this impacts their practicality.16
Furthermore, macrocyclisation reactions are typically highly
sensitive to structural and conformational changes in the
Figure 1. Macrolide antibiotics 1–3.
In terms of developing a general, practical route to
macrocyclic lactones, ring expansion strategies have much
potential,19,20 as the end-to-end cyclisation step that hampers
conventional macrocyclisation methods is completely avoided.
Thus, in this manuscript, we describe the development of a high
yielding, iterative strategy for the synthesis of macrocyclic
lactones using Successive Ring Expansion (SuRE) reactions.21
The new synthetic protocols reported enable a broad array of
functionalised lactone- and lactam-containing macrocycles (10–
24-membered) to be prepared in high yields by the iterative
insertion of both hydroxy acid and amino acid-based linear
fragments into lactams (Figure 2).
Figure 2. Iterative Assembly of Macrocyclic Lactones using Successive Ring
[a]
T. C. Stephens, Dr. A. S. Lawer, T. French, Dr. W. P. Unsworth*
University of York
Expansion Reactions (SuRE).
York, YO10 5DD (UK)
E-mail: william.unsworth@york.ac.uk
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Results and Discussion
Previous research in our group has focused on the development
of ring expansion routes to macrocyclic lactams,21,22 although we
recently uncovered two examples of lactone-forming reactions
that operate via a similar strategy.21c Thus, following N-acylation
of lactam 4a, the resulting imides (6/7a) were shown to undergo
hydrogenolysis (to form alcohols 8/9a) and rearrange via cyclols
10/11a to furnish ring expanded lactones 12a and 13a (Scheme
1). Unlike in our previous lactam work, ring expansion did not take
place spontaneously following protecting group cleavage (an
equilibrating mixture of isomers 8/9a, 10/11a, and 12/13a was
formed in each case) but stirring this mixture in chloroform was
sufficient to drive the equilibrium towards ring expanded
macrocyclic lactones 12a and 13a, which were isolated in 88%
and 47% yields respectively.
Scheme 2. N-acylation of lactams 4a–j.
We then moved on to examine their ring expansion reactions,
starting with the α-hydroxyacid derivatives 6a–j. Although we had
already shown that ring-expanded lactone 12a could be made in
high yield from 6a, literature precedent suggested that other ring
sizes would not be so easy; for example, imides 6c–6e have been
described previously in separate studies by Shemayakin, Antonov
and co-workers24a and Griot and co-workers,24b but in their hands
were found to produce mixtures of alcohol (8) and cyclol (10)
products following hydrogenolysis, with no evidence for having
undergone ring expansion. However, when our hydrogenolysis
conditions were applied to novel imide 6f, N,O-acetal 15f was
unexpectedly formed in 87% yield, presumably via reduction of a
dehydrated intermediate of the form A (Scheme 3). The same
process also operates on other ring sizes, with N,O-acetals 15d–
h all being formed similarly, from their respective imides 6d–h
(Scheme 3 box).25
Scheme 1. Ring expansion sequence to macrocyclic lactones 12a and 13a.
To establish whether these proof-of-concept results could be
expanded into a general method, we began by evaluating the
effect of the ring size of the starting lactam on the reaction
outcome. Ring size was predicted to have a major impact on the
alcohol/cyclol/lactone equilibrium shown in Scheme 1; in
particular, the expansion of normal ring sizes (5–7-membered)
into medium-sized rings (8–11-membered) was expected to be
challenging, in view of the well-known difficulties associated of
making medium-sized rings.23 To facilitate this, a total of 20 N-
acylated derivatives 6a–j and 7a–j were prepared, using 4–13-
membered lactams 4a–j and α- and β-hydroxyacid derivatives 5a
and 5b, which were coupled using a high yielding, lactam N-
acylation procedure summarised in Scheme 2.
Scheme 3 Solvent dependent fates of intermediate 14.
While this discovery represents an interesting way to prepare
cyclic N,O-acetals,26 it was problematic in the context of
generating ring-expanded lactones. A solution was found by
changing the hydrogenolysis solvent; thus, if the hydrogenolysis
was carried out in methanol, intermediate A was trapped by the
solvent to form a methanol adduct (14f) that is stable with respect
to over-reduction and was isolated in 95% yield. We then
considered that by exchanging methanol for water, a water-
trapped adduct (i.e. cyclol 10f) would form similarly, and serve as
an intermediate towards the desired ring expansion lactone.
Pleasingly this idea worked well; thus, the hydrogenolysis was
performed in a mixed THF/water solvent system, and following
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filtration, the reaction mixture (which at this stage was largely
comprised of cyclol 10f) was stirred in chloroform/NEt3 at RT,
which promoted clean isomerisation to the desired ring expansion
product 12f in 89% yield (Scheme 3).
ring expansion following hydrogenolysis, with alcohols 9b and 9c
being isolated instead, but all cyclic imides from 6-membered 7d
to 13-membered 7a were successfully converted into the desired
ring expansion products 13d–j and 13a in high yields (85–96%,
Scheme 5).
Having established a viable hydrogenolysis method in which
over-reduction can be avoided, this procedure was applied to all
of the 4-13-membered cyclic imide precursors 6a–j (Scheme 4).
From these experiments, a clear trend emerged linking the size of
the cyclic starting material 6 to the reaction outcome. Thus, in the
cases of 4- and 5-membered cyclic imides 6a and 6b,
debenzylation proceeded smoothly, but isomerisation did not
occur following stirring in chloroform/NEt3, with imides 8b and 8c
being isolated in high yields. Conversely, under the same
conditions, 6- and 7-membered imides 8d and 8e only partially
rearranged; cyclol isomers 10d and 10e were formed as the major
products in CDCl3 solution, although the corresponding imide and
1
ring expanded isomeric forms were also visible in their H NMR
spectra. Finally, all the cyclic imides from 8-membered 6f to 13-
membered 6a underwent hydrogenolysis and ring expansion as
desired, to deliver ring expanded products 12f–j and 12a in high
yields (83–97%).
Scheme 5. Ring expansion of β-hydroxyacid derivatives 7a–j.
Thus, both the α- and β-hydroxyacid series have a clear point at
which the ring expansion reactions ‘switch on’, i.e ≥8-membered
rings expand effectively in the α-hydroxyacid series, and ≥6-
membered for their β-hydroxyacid analogues. Of course, there
will likely be some substrate specific variation, but these ring size
guidelines should be helpful in predicting the viability of ring
expansion processes on related systems. We believe that these
are thermodynamic outcomes, and that following hydrogenolysis,
the three isomeric forms 8, 10 and 12 (or 9, 11 and 13) equilibrate
upon stirring in chloroform/NEt3. The observed results are
consistent with what we know about the difficulties associated
with medium ring system,23 (which typically suffer from ring strain
and/or destabilizing transannular interactions) and are supported
by a relatively simple computational study, using Density
Functional Theory (DFT),27 which drew inspiration from a related
study on lactam-forming ring expansions by Yudin and co-
workers.22 Thus, the relative Gibbs free energies of isomeric imide
(8/9), cyclol (10/11) and ring expanded products (12/13) were
calculated for the four reaction systems which lie on the borderline
of undergoing ring expansion or remaining as the imide form (i.e.
those leading to the formation of 8c, 12f, 9c and 13d) with these
results summarised in Table 1. Pleasingly, the calculations agree
with the synthetic outcomes; thus, for the α-hydroxyacid series,
the 5-membered ring imide form 8c was calculated to be
significantly lower in energy than either the cyclol or ring
Scheme 4. Ring expansion of α-hydroxyacid derivatives 6a–j. a For simplicity,
the major isomeric form of 10d is drawn, but in CDCl3 solution, this compounds
exists as a 3:2 ratio of 10d:8d. b For simplicity, the major isomeric form of 10e
is drawn, but in CDCl3 solution, this compounds exists as a 69:13:1 ratio of
10e:8e:12e.
We then examined β-hydroxyacid derivatives 7a–j. Helpfully, in
this series over-reduction was not observed, hence
hydrogenolysis could be performed in ethyl acetate, and was
followed by stirring in chloroform/NEt3 as before. Again, clear ring
size trends emerged; as in the α-hydroxyacid series, the 4- and
5-membered ring starting materials 7b and 7c failed to undergo
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expanded isomers, whereas the ring expanded form 12f was
calculated to have the lowest Gibbs free energy for the 8-
membered starting material. A similar trend was also seen for the
β-hydroxyacid series, in which the switch in the reaction outcome
between the 5- and 6-membered starting materials observed
synthetically was predicted by the DFT calculations.27,28 Full
details of the computational methods can be found in the
Supplementary Information (SI). Also included in the SI are
calculations for the two reaction systems which produced
mixtures of products (8d/10d/12d and 8e/10e/12e). In these
cases, the three isomeric forms 8/10/12 were found to be much
closer in Gibbs free energy in comparison to those shown in Table
1, with no isomer being >3 kcal/mol lower in Gibbs free energy
than each of the other two, hence it is not surprising that a mixture
of products was obtained in the synthetic reactions; indeed, these
results further corroborate the notion that the reactions are under
thermodynamic control.
First, examples of the ring expansion were performed with
lactams containing an ether linkage (16a) and a benzannulated
system (16b), with both proceeding in good yield using the
standard protocol. The high yielding synthesis of 12-membered
ring 16c is an interesting case, as this shows that the ring
expansion can be performed using phenol nucleophiles, whilst
branched hydroxyacid derivatives are also well tolerated (16d and
16e). Also, whilst not a ring expansion reaction, the insertion of
acid chloride 5b into linear amide 4m to make 16f shows that the
rearrangement is not restricted to cyclic amides.
We then went on to examine successive ring expansion
reactions. In total, 12 macrocyclic lactones in a range of ring sizes
(14–21-membered rings) were prepared in consistently high
yields via the expansion of lactams for a second time (17a–l, 61–
98%), involving the installation of various combinations of α- and
β-hydroxyacid derived linear fragments. We were especially
pleased to discover that the new methods and products are
compatible with our published lactam SuRE method; macrocycles
were formed which involved the insertion of amino acid-based
linear fragments in lactams before (17f,h) and after (17d,k,l) ring
expansion using a hydroxy acid derivative. The ability to install
both lactone and lactam motifs into the ring expanded products
(in any order) is important, as this significantly increases the
freedom with which functional macrocycles can be designed and
prepared using the SuRE method; for example, this could have
important implications for its use in the preparation of azaketolide-
type antibiotics (e.g. 2 and 3, Figure 1).
n
m
Ring sizes
8/9
10/11
12/13
ΔG°rel (kcal/mol)
13.4 (10c)
8.9 (10f)
2
5
2
3
1
1
2
2
5 → 8
8 → 11
5 → 9
0.0 (8c)
6.3 (8f)
0.0 (9c)
2.4 (9d)
10.3 (12c)
0.0 (12f)
4.1 (13c)
0.0 (13d)
We also prepared
5 macrocyclic lactones (18–24-
membered rings) that demonstrate that the rings can be
expanded for a third time (18a–e). Triple ring-expanded product
18a was formed in a relatively modest 36% yield, with 35% of the
starting lactam 17c being recovered from the reaction due to
incomplete N-acylation in this case, even after adding additional
doses of acid chloride 5a. Whilst the yield in this example was
somewhat disappointing, it is perhaps inevitable that there will be
some variation in the efficiency of the N-acylation step, especially
in larger ring systems where the conformation of the starting
material may impact upon the ease with which the acid chloride
approaches the lactam. Nonetheless, we were pleased that once
formed, the N-acylated material underwent hydrogenolysis and
ring expansion as expected, enabling the isolation of the highly
oxygenated trilactone 18a. Furthermore, we were delighted to
discover that the reactions proceeded more smoothly for the
preparation of products 18b–e, which were formed in much higher
yields (68–84%) using both α- and β-hydroxyacid derived linear
fragments, and including examples which had previously been
expanded with amino acid derivatives to form mixed
lactam/lactone macrocycles 18c and 18e.
11.7 (11c)
8.1 (11d)
6 → 10
Table 1. DFT [B3LYP/6-31G*] calculated relative Gibbs free energy values (in
vacuum) for isomeric imides (8/9), cyclols (10/11) and lactones (12/13).27
We next went on to examine more complex reaction systems and
test whether the products could be further elaborated in
successive ring expansion reactions (Scheme 6). Additional
starting materials were required for this phase of work, all of which
were either commercially available, or easily prepared via
literature routes, with further details included in the SI (Scheme 6
box). The yields given in Scheme 6 refer to the overall
acylation/deprotection/ring expansion sequence and are all real
synthetic yields of purified products following column
chromatography. Some examples (indicated with a superscripted
‘a’ or ‘b’) required more than the standard 1.5 equivalents of acid
chloride for the N-acylation to proceed to completion, but
otherwise, all reactions were performed using the standard sets
of conditions.
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Scheme 6. Successive ring expansion reactions. For all Procedures A–C: i) Lactam (1 equiv.), Pyridine (6 equiv.), DMAP (0.1 equiv.), ROCl 5a–g (1.5 equiv.),
CH2Cl2 (0.1 M), 18 h, 45 °C, then: Procedure A: ii) H2, Pd/C in H2O/THF; iii) NEt3, CHCl3 18 h, RT (for XPG = OBn, m = 1) Procedure B: ii) H2, Pd/C in EtOAc; iii)
NEt3, CHCl3 18 h, RT (for XPG = OBn, m = 2) Procedure C: ii) DBU (10 equiv.), CH2Cl2 18 h, RT (for XPG = NRFmoc, m = 1 or 2). [a] An additional 1.5 equiv. of
ROCl 5 was used in the N-acylation (step i) to help ensure complete conversion; [b] An additional 4.5 equiv. of ROCl 5 was used in the N-acylation (step i) to help
ensure complete conversion.
Finally, to further demonstrate the ease and practicality of
the SuRE method, we performed the preparation of one of the
triple ring expanded products (18d) without chromatographic
purification at any of the intermediate stages. To help ensure
complete N-acylation in each iteration, three equivalents of acid
chloride 5b were used in this telescoped reaction sequence
(rather than the usual 1.5 equivalents), but otherwise, no changes
were made to the standard protocol other than not performing any
chromatography until after the final iteration. Thus, lactam 4f was
N-acylated with acid chloride 5b, and following a short aqueous
work up, taken on directly to hydrogenolysis with palladium on
carbon in ethyl acetate. Following this, filtration, a solvent switch
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(ethyl acetate to CHCl3), stirring overnight with triethylamine and
aqueous work completed the first iteration. This furnished crude
product 13f, which was simply reacted in the same way (to form
crude 17g) and then again, to form crude 18d, which was finally
purified by column chromatography and isolated in 48% overall
yield over the three complete iterations.
RT for 5 mins. Next, a solution of acid chloride 5 in DCM (3.5 mL)
was added and the resulting mixture was heated, at reflux, at 50
°C for 16 h. The solvent was concentrated in vacuo, loaded onto
a short silica plug and eluted with hexane:ethyl acetate, to remove
the majority of excess carboxylic acid and pyridine residues, and
concentrated in vacuo. This material was re-dissolved in THF (10
mL) and placed under an argon atmosphere. Palladium on carbon
(100 mg, Pd 10% on carbon) and water (2 mL) was then added
and the reaction vessel was backfilled with hydrogen (via balloon)
several times, then stirred at RT under a slight positive pressure
of hydrogen (balloon). The reaction was then purged with argon,
filtered through Celite, washed with methanol where the solvent
was removed in vacuo. The crude material was then re-dissolved
in chloroform (10 mL) and triethylamine (1.5 mmol) added, and
stirred at RT for 16 h, then reduced in vacuo and purified by flash
column chromatography.
Procedure B.
A mixture of lactam (1 mmol), DMAP (0.1 mmol) and pyridine (6
mmol) in DCM (7 mL) under an argon atmosphere was stirred at
RT for 5 mins. Next, a solution of acid chloride 5 in DCM (3.5 mL)
was added and the resulting mixture was heated, at reflux, at 50
°C for 16 h. The solvent was concentrated in vacuo, loaded onto
a short silica plug and eluted with hexane:ethyl acetate, to remove
the majority of excess carboxylic acid and pyridine residues, and
concentrated in vacuo. This material was re-dissolved in
ethylacetate (10 mL) and placed under an argon atmosphere.
Palladium on carbon (100 mg, Pd 10% on carbon) was then
added and the reaction vessel was backfilled with hydrogen (via
balloon) several times, then stirred at RT under a slight positive
pressure of hydrogen (balloon). The reaction was then purged
with argon, filtered through Celite, washed with methanol where
the solvent was removed in vacuo. The crude material was then
re-dissolved in chloroform (10 mL) and triethylamine (1.5 mmol)
added, and stirred at RT for 16 h, then reduced in vacuo and
purified by flash column chromatography.
Scheme 7. Telescoped triple ring expansion of lactam 4f into macrocycle 18d.
Conclusions
In summary, our new lactone-forming SuRE reaction system has
been demonstrated in a range of high yielding ring successive ring
expansion reactions. It has also been shown to be compatible with
our published lactam-forming SuRE method, enabling mixed
lactam and lactone-containing macrocycles using a versatile,
practical protocol. Crucially, none of the methods rely on
specialised reaction conditions or high dilution at any stage, with
all the reactions described in this manuscript having been
performed at 0.1 M concentration. Whilst all the steps in the
overall SuRE process are relatively simple when considered
individually (and indeed, conceptually related lactone forming ring
expansion processes have been described previously),20 we
know of no other study in which such an array of complex ring
expanded lactones can be assembled with the ease described in
this manuscript, and none in which the ring expansion reactions
can be performed iteratively. Thus, we view the relative simplicity
of our SuRE method to be a key strength. The freedom to install
precise sequences of lactone and lactam containing linear
fragments into macrocycles in this way, and the ability to scale up
the reactions if required,29 is expected to be of high value in the
myriad scientific fields that rely on the design and synthesis of
functionalised macrocycles.
Procedure C
A mixture of lactam (1 mmol), DMAP (0.1 mmol) and pyridine (6
mmol) in DCM (7 mL) under an argon atmosphere was stirred at
RT for 5 mins. Next, a solution of acid chloride 5 (1.5 mmol) in
DCM (3.5 mL) was added and the resulting mixture was heated,
at reflux, at 50 °C for 16 h. The solvent was then concentrated in
vacuo, loaded onto a short silica plug and eluted with 2:1
hexane:ethyl acetate, to remove the majority of excess carboxylic
acid and pyridine residues, and concentrated in vacuo. This
material was re-dissolved in DCM (10 mL) and placed under an
argon atmosphere. DBU (10 mmol) was then added and stirred at
RT for 16 h, then reduced in vacuo and purifiied by flash column
chromatography.
Experimental
Full synthetic detail and spectroscopic data for all compounds are
provided in the Supporting Information. General procedures A, B
and C (Scheme 6) are also included below:
Acknowledgements
Procedure A.
The authors wish to thank the Leverhulme Trust (for an Early
Career Fellowship, ECF-2015-013, W. P. U.), the University of
York (T. C. S., W. P. U.) and the EPSRC (EP/P029795/1, A. L.)
A mixture of lactam (1 mmol), DMAP (0.1 mmol) and pyridine (6
mmol) in DCM (7 mL) under an argon atmosphere was stirred at
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T. R. Siegert, M. R. Eshelman, J. A. Kritzer, Nat. Chem. Biol., 2014, 10,
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computational chemistry.
Keywords: Macrocycles • Medium-sized Rings • Ring
Expansion • Macrolides • Lactones
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relative ground state energies of isomeric imide (8/9), cyclol (10/11) and
ring expanded products (12/13) were optimised using DFT/B3LYP/6-
31G* (in a vacuum). Conformational searches of the optimised structures
were performed at Molecular Mechanics Force Field (MMFF) level, and
all the generated structures were retained and their energies were
calculated using DFT/B3LYP/6-31G*. The lowest energy geometry in
each system was selected, fully optimised and determined to be minima
by the absence of negative vibrational modes using DFT/B3LYP/6-31G*.
The final optimisation and frequency calculations were then done in a
solvated model system (non-polar solvent) using DFT/B3LYP/6-31G*.
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similar free energy difference) when the same systems were calculated
using Hartree-Fock calculations (HF/6-31G*), with full details of included
in the SI.
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[29] For example, expanded lactones (12f, 13a, 13f and 17g) were prepared
on
5 mmol scale using the standard synthetic protocol with no
appreciable reduction in yield.
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Macrocyclic lactones can be prepared
from lactams and hydroxyacid
derivatives via an efficient 3- or 4-
atom iterative ring expansion protocol.
The products can also be expanded
using amino acid-based linear
fragments, meaning that macrocycles
with precise sequences of hydroxy-
and amino acids can be assembled in
high yields by ‘growing’ them from
smaller rings.
Thomas C. Stephens, Aggie Lawer,
Thomas French and William P.
Unsworth*
Page No. – Page No.
Iterative Assembly of Macrocyclic
Lactones using Successive Ring
Expansion Reactions
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