Ring Expansion of Thiolactams via Imide Intermediates: An Amino Acid Insertion Strategy

Article abstract of DOI:10.1002/chem.202005035

The Ag^I-promoted reaction of thiolactams with N-Boc amino acids yields an N-(α-aminoacyl) lactam that can rearrange through an acyl transfer process. Boc-deprotection results in convergence to the ring-expanded adduct, thereby facilitating an overall insertion of an amino acid into the thioamide bond to generate medium-sized heterocycles. Application to the site-specific insertion of amino acids into cyclic peptides is demonstrated.

Full text of DOI:10.1002/chem.202005035

Accepted Article
Accepted Article
Title: Ring expansion of thiolactams via imide intermediates: an amino
acid insertion strategy
Authors: Jing Shang, Varsha J Thombare, Carlie L Charron, Uta Wille,
and Craig Anthony Hutton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202005035
Link to VoR: https://doi.org/10.1002/chem.202005035
01/2020

10.1002/chem.202005035
Chemistry - A European Journal
COMMUNICATION
Ring expansion of thiolactams via imide intermediates: an amino
acid insertion strategy
Jing Shang,[a,b] Varsha J. Thombare,[a,b] Carlie L. Charron,[a] Uta Wille[a] and Craig A. Hutton*[a]
Abstract: The Ag(I)-promoted reaction of thiolactams with N-Boc
amino acids yields an N-(a-aminoacyl) lactam that can rearrange
through an acyl transfer process. Boc-deprotection results in
convergence to the ring-expanded adduct, thereby facilitating an
overall insertion of an amino acid into the thioamide bond to generate
medium-sized heterocycles. Application to the site-specific insertion
of amino acids into cyclic peptides is demonstrated.
One limitation of most current methods for ring expansion,
particularly as applied to cyclic peptides, is site selectivity. The
imide formation–acyl transfer process requires N-acylation of a
single amide group within a cyclic peptide, which necessitates
protection of all other secondary amides. In the original SuRE
process the b-ketoester moiety confers chemoselectivity but
introduces a non-peptide component into the macrocycle. Thus,
the site-specific ring expansion of cyclic peptides remains a
significant challenge.
Macrocycles such as cyclic peptides are typically constructed
by head-to-tail cyclization, coupling the terminal amine and
carboxylic acid groups.1 However, medium-sized macrocycles are
often not accessed efficiently via head-to-tail macrocyclization
due to conformational constraints inherent in medium sized
rings.2-10 Macrocyclization can frequently lead to the formation of
cyclodimers and higher oligomers and is therefore typically
conducted under high dilution conditions.
Macrocyclization:
O
H
O
CO2H
N
O
+
NH
H
N
NH2
n
Ring expansion strategies:
β-ketoesters (Unsworth):
BocHN
In order to overcome conformational constraints and reduce
the entropic barrier to macrocyclization inherent in medium-sized
rings, ring expansion and ring contraction strategies have been
developed.11-13 An example of ring a contraction strategy reported
by Smythe and co-workers incorporates an auxiliary which
facilitates large ring formation, followed by contraction and
ultimately extrusion of the auxiliary, to generate cyclic
tetrapeptides.14,15 Ring expansions of small rings have also been
employed for the generation of medium-sized rings.16 Notable
examples include Unsworth’s ‘SuRE’ method,17,18 which appends
an amino acid onto a cyclic b-ketoester: nucleophilic attack by the
tethered N-nucleophile and ring opening results in overall
insertion of an a- or b-amino acid into enlarged macrocycle
(Scheme 1). Unsworth has applied this methodology to the ring
expansion of lactams via imides, 19-21 and Yudin has incorporated
b-amino acids into lactams and diketopiperazines via a similar
process.22 Yudin has also reported a site-selective formal ring
expansion of aziridine-containing cyclic peptides,23 whereas
Clayden24,25 and Clark-Still26 have employed Smiles
rearrangements to insert amino acid residues or urea derivatives
into small N-aryl heterocycles.
O
HN
O
O
CO2Et
O
CO2Et
O
CO2Et
Imides (Yudin, Unsworth):
R2
BocN
2N
O
O
R
O
O
NH
O
O
HN
N
N
R1
N
N
R1
O
R1
n
n
O
n
Smiles rearrangement (Clayden, Clark-Still):
R
R
R
NuH
Nu
NH
N
N
O
R
H
O
This work:
R
BocHN
O
S
H
O
O
HN
N
N
O
NH
Scheme 1. Ring expansion strategies for macrocycle synthesis.
[a]
[b]
Dr Jing Shang, Dr Varsha J. Thombare, Dr Carlie L. Charron, Prof.
Uta Wille, Prof. Craig A. Hutton,
School of Chemistry and Bio21 Molecular Science and
Biotechnology Institute
University of Melbourne
Parkville, Vic 3010, Australia
We have previously shown that thioamides can undergo a
Ag(I)-facilitated coupling reaction with amino acids to generate
imides,27,28 and that such N-(a-aminoacyl) amide adducts
undergo facile acyl transfer processes.10,27,29 We envisaged that
elaboration of this coupling reaction to cyclic systems – i.e.
thiolactams – would lead to an overall insertion process (Scheme
1). Herein we report the development of a ring expansion process
that enables the site-specific insertion of an amino acid residue
E-mail: chutton@unimelb.edu.au
equal first authorship
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202005035
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into a thiolactam, or cyclic peptide thioamide, via an imide
intermediate.
efficiency of the 1,3-acyl transfer has been shown to be intricately
controlled by competing steric and electronic factors.28,29,32,33 We
presumed that the failure of the 5- and 6-membered thiolactams
to generate the corresponding imides was a result of an
unfavourable 1,3-acyl transfer that must proceed through a
strained 4,5- (or 4,6-) bicyclic transition state. In such strained
systems where 1,3-acyl transfer is slow, the isoimide 10 could
undergo reaction with a nucleophile, such as acetate or water, to
generate the lactam 11 (Scheme 2).
To date, the Ag(I)-promoted conversion of thioamides to
imides has not been performed on cyclic systems:27,30,31
accordingly, we first investigated whether thiolactams are viable
starting materials in this transformation. The simple thiolactams
1–8 were first prepared from the corresponding lactams by
treatment with Lawesson’s reagent, and their conversion to N-
acetyl imides through reaction with AgOAc was investigated.
Surprisingly, 5- and 6-membered thiolactams 1–4 (including
thioketopiperazines) did not undergo transformation to the
corresponding imides, instead undergoing reversion back to the
lactam (Table 1, entries 1–4). Nevertheless, caprothiolactam 5 did
generate the corresponding imide in low yield (Table 1, entry 5).
Larger ring thiolactams 6–8 generated the corresponding imides
in moderate to good yields (Table 1, entries 6–8).
O
S
O
O
Nu
AgOAc
NH
NH
O
(AcO or H2O)
ring size <7
ring size >7
N
11
9
10
1,3 O→N
acyl shift
O
N
Table 1. Imide formation from thiolactams.[a]
S
O
O
12
AgOAc
NH
N
Scheme 2. Isoimide rearrangement to imide or hydrolysis to amide.
To provide support for this hypothesis, computational analysis
was performed for selected reaction systems at the M062X/6-
31+G* level of theory in dichloromethane (Figure 1).34-38} The 1,3-
acyl transfer of the isoimide derived from pyrrolidine-2-thione 1
requires an activation energy of 118.6 kJ mol-1, which is too high
to proceed under ambient conditions. The equivalent process in
the six-, seven-membered or eight-membered isoimide is
obviously facilitated by an increased conformational flexibility,
which leads to a gradual reduction of the barrier by up to 30 kJ
mol-1. This finding is reflected in the geometry of the transition
states, which shows for the smallest ring system a nearly
symmetrical arrangement of the migrating acyl moiety and the O-
and N-reaction centres (Figure 2a). In contrast, the transition state
structures for the larger substrates are not only more compact but
are also slightly unsymmetrical with the O-acyl distance being
shorter by ca. 0.2 Å compared with the N-acyl distance for the
seven- and eight-membered ring system, which is in-line with an
earlier transition state. The particularly high barrier for the
smallest ring system (n = 1) is likely due to a nearly planar and
therefore strained five-membered ring (Figure 2b). Increasing ring
size leads to a more flexible and less strained geometry, which
results in a lower barrier for the 1,3-acyl transfer.
Entry
1
Substrate
Yield of imide (%)
–
S
1
2
NH
–
2
S
N
H
S
–
–
3
4
3
4
NH
Ph
S
HN
NH
O
S
20
54
5
6
5
6
NH
S
NH
S
55
78
7
8
7
8
NH
Interestingly, although this rearrangement is exothermic in all
cases, it is thermodynamically most preferable for the smallest
ring system. This finding could be rationalized by a reduction of
ring strain in the 5-membered imide, compared with the isoimide,
that allows a more staggered arrangement of the methylene
groups in the ring. Overall, these data clearly indicate that the 1,3-
acyl migration is a kinetically driven process.
S
NH
[a] Reaction Conditions: thiolactam (0.5 mmol), AgOAc (1.0 mmol) in CH2Cl2
(2 mL), rt 18 h.
The Ag(I)-promoted conversion of thioamides 9 to imides 12
in the presence of carboxylic acids proceeds via an isoimide
intermediate 10.28 The isoimide 10 then undergoes a pseudo-
pericyclic 1,3-acyl transfer to generate the imide 12. The
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Table 2. Reaction of thiolactams with Boc-Gly 13 + Ag2CO3.[a]
O
O
O
Boc
N
S
O
N
BocHN
13
CO2H
n = 1: 118.6
n = 2: 92.8
n = 3: 86.7
n = 4: 85.7
NHBoc
HO
+
N
NH
N
n H
O
N
( )n
O
Ag2CO3
n
n
O
Boc
N
a
b
O
N
O
O
n
( )n
n = 1: -67.4
O
cyclol
n = 2: -39.6
n = 3: -36.4
n = 4: -37.0
N
( )n
0.0
Entry[a]
thiolactam
n
1
2
3
time
Yield a (%)
Yield b (%)
1
2
1
3
5
18 h
18 h
18 h
48 h
18 h
48 h
18 h
48 h
18 h
48 h
0
0
0
Figure 1. Potential energy surface for the rearrangement of isoimides to imides
through 1,3-acyl transfer calculated with M062X/6-31+G* in dichloromethane.
0
3
14a, 16
14a, 39
15a, 38
15a, 36
16a, 37
14b,
0
(a) top view
4
14b, 30
15b, 17
15b, 18
16b, 19
16b, 88
17b, 25
17b, 31
1.619
1.599
1.582
1.788
1.792
1.785
5
6
7
8
4
5
9
1.733
1.809
6
7
n = 1
n = 2
n = 3
n = 4
8
16a,
1
(b) side view
9
17a, 69
17a, 65
10
n = 1
n = 2
n = 3
[a] Reaction conditions: thiolactam (0.2 mmol), Boc-Gly 13 (0.1 mmol),
Ag2CO3 (0.2 mmol) in CH2Cl2 (2 mL), rt 18–48 h.
Figure 2. Calculated transition state geometries for the 1,3-O–N acyl transfer
from isoimides generated from 5-, 6-, 7- and 8- membered thiolactams (with
selected geometrical data (in Å; M062X/6-31+G*; in dichloromethane)).
Reaction of the 9-membered caprylothiolactam 7 furnished
the imide 16a and ring-expanded product 16b in reasonable
combined yield after 18 h (Table 2, entry 7). After 48 h, in contrast
to the 7- and 8-membered systems, essentially all the initial imide
16a had rearranged to the ring-expanded system 16b, which was
isolated in excellent yield (Table 2, entry 8).
With the results of the model reactions of thiolactams with
AgOAc in hand, coupling reactions with Boc-glycine 13 as the acid
component were next undertaken (Table 2). Reactions of the 5-
and 6-membered pyrrolidine-2-thione 1 and piperidine-2-thione 3
with Boc-glycine 13 in the presence of silver carbonate did not
furnish any imide adducts (Table 2, entries 1,2), in accordance
with previous observations. Treatment of the 7-membered
caprothiolactam 5 generated the imide 14a in low yield after 18 h
(Table 2, entry 3). After 48 h, the yield of the imide 14a had
increased, and notably the ring expanded product 14b was also
formed, with a combined yield of 14a and 14b of 69% (Table 2,
entry 4). The structures of isomeric 14a and 14b were confirmed
by 1D and 2D 1H-NMR spectroscopy, which demonstrated
coupling between the carbamate NH and glycinyl CH2 group in
imide 14a and the lack of such coupling in 14b. Thus, the
formation of the initial imide product 14a is accompanied by a slow
rearrangement/ring expansion to generate the glycine-inserted
Reaction of the 13-membered laurothiolactam 8 furnished the
imide 17a in good yield after 18 h, with a moderate amount of
rearrangement to the ring-expanded product 17b at this time
(Table 2, entry 9). After 48 h, only a minor change was observed,
with the 17a and 17b formed in excellent overall yield in ~2:1 ratio
(Table 2, entry 10).
In all cases, it is apparent that slow interconversion between
the initial imide and the ring-expanded adduct is established, with
differing ratios dependent on ring size.
We next sought to expand the scope of the appended/inserted
amino acid residue beyond the simple Boc-glycine 13.
Accordingly, coupling reactions of Boc-alanine 18 and Boc-
phenylalanine 19 were also investigated with 9-membered and
13-membered thiolactams 7 and 8. Treatment of the 9-membered
caprylothiolactam 7 with Boc-alanine 18 in the presence of
Ag2CO3 for 48 h generated the ring expansion product 20b in 90%
yield, with only a trace of the ring open form (Table 3, entry 4).
Treatment of 7 with Boc-phenylalanine 19 under the same
conditions furnished the ring-expanded product 22b in 87% yield,
along with 9% of imide 22a (Table 3, entry 5). Treatment of the
22
medium-sized cyclic product 14b via the ‘cyclol’ intermediate.
Extended reaction times beyond 48 h did not increase the
proportion of the ring expanded adduct 14b further.
Treatment of the 8-membered thiolactam 6 under the same
conditions afforded the imide 15a in 38% yield after 18 h, together
with 17% yield of ring-expanded imide 15b (Table 2, entry 5). After
48 h, the proportions of imide 15a and ring expanded imide 15b
were virtually unchanged (Table 2, entry 6).
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larger 13-membered laurothiolactam 8 with Boc-alanine 18
resulted in 58% yield of the imide 21a and 34% yield of the ring
expanded product 21b (Table 3, entry 7), whereas treatment of
with Boc-phenylalanine 19 generated mainly the imide 23a in 90%
yield and the ring expansion product 23b in 5% yield (Table 3,
entry 8).
These results are consistent with the related work of
Unsworth,20 with a minor caveat. Unsworth showed that for N-(N’-
methylglycinyl) lactams, a ‘switch on’ point is reached at 8-
membered rings at which point the ring expanded form is more
stable than the ring-open form, and the acyl migration–insertion
process occurs. Our results suggest that for N-glycinyl lactams,
possessing a primary amine, the ‘switch-on’ point is from the 7-
membered acylated lactam. These experimental findings are
supported by DFT calculations (Table S1).
Table 3. Amino acid insertion into thiolactams.[a]
O
O
N
We next sought to apply this ring expansion methodology to
cyclic peptide thioamides. Linear peptide thioamides were
prepared10 and cyclized according to previous protocols.39 With
the cyclic peptide thioamide 24 in hand, Ag(I)-promoted coupling
of Boc-glycine was performed at 40 °C in acetonitrile to generate
the amino-acid appended adduct. Analysis of this species by RP-
HPLC showed two peaks with identical mass, consistent with
generation of a mixture of the N-acylated cyclic peptide 27a and
the ring-expanded isomer 27b (Figure 3). Deprotection of the
mixture of 27a/b with TFA followed by evaporation then
dissolution in CH3CN/H2O/DIPEA furnished cyclic heptapeptide
28 (Scheme 3). Comparison of cyclic peptide 28 with an authentic
sample of c(GASPGYA) prepared by standard methods,
confirmed the structure of the ring-expanded cyclic peptide
(Figure 3).
NHBoc
n
R
R
O
S
H
N
a
i) TFA
BocHN
CO2H
R
NH
N
n H
ii) CH3CN,
DIPEA
O
Ag2CO3
Boc
N
n
O
R
c
N
n H
O
b
Entry
n
R
Product
Ratio a:b
Yield c (%)
over 2 steps
1
2
3
4
5
6
7
8
3
4
5
5
5
9
9
9
H
14
15
16
20
22
17
21
23
1.3:1
2.0:1
1:>20
1:>20
1:9.7
2.1:1
1.7:1
18:1
69
54
89
90
96
96
92
95
H
R
R
S
H
H
N
BocHN
CO2H
O
NH
Xaa
Ser
Gly Pro
24 Xaa =
Ala
Ala
Ser
i) Ag2CO3
Me
Bn
H
Ser
Tyr
Xaa
Ser
ii) TFA
iii) CH3CN,
DIPEA
Tyr
Gly Pro
–
25 Xaa = Phe
26 Xaa = Lys-Phe
28–33
Me
Bn
OH
O
OH
N
R
N
[a] Reaction conditions: thiolactam (0.2 mmol), Boc-amino acid 13, 18 or 19
(0.1 mmol), Ag2CO3 (0.2 mmol) in CH2Cl2 (2 mL), rt 48 h; then 1:1
CH2Cl2:TFA 1 h; then DIPEA (1.0 mmol) in CH3CN (2 mL), 50 °C, 2 h.
N
HN
H
NH
O
O
O
O
NH
HN
O
O
O
O
O
H
N
O
In all cases, coupling of the 9-membered thiolactam 7 with
Boc amino acids generates an imide which undergoes acyl
migration and ring expansion to afford predominantly the amino
acid-inserted macrocycles (i.e. product ‘b’) in relatively high yields.
In contrast, coupling of the 7-, 8- and 13-membered thiolactams
with Boc amino acids generates a mixture of the initial ring open
product (product ‘a’) and ring expanded product (product ‘b’), with
the ring open adduct predominating. In order to facilitate the acyl
transfer process and complete conversion to the ring expanded
product, deprotection of the Boc-protected adducts was
performed. Treatment of the mixture of imides 14–17a/b and 20–
23a/b with TFA, followed by neutralization with base, effected
conversion of the intermediate a-aminoacyl imide (a) to the ring-
expanded products (c). That is, the mixture of imides converge to
the desired ring expansion product after Boc-deprotection, in
excellent yields (Table 3). Accordingly, the most efficient
procedure involves a one-pot, Ag(I)-promoted coupling of Boc-
amino acids and thiolactams to generate a mixture of the imides,
which is then deprotected with TFA and neutralized with DIPEA
to generate the ring expansion products in high yield.
R
O
NH
NH
NH
N
H
HO
O
HO
HO
NH
HN
O
HN
O
30 R = H (63%)
31 R = Me (trace)
28 R = H (63%)
29 R = Me (59%)
OH
OH
N
HN
NH2
HN
HN
O
O
O
O
NH
NH
32 R = H (67%)
33 R = Me (55%)
O
O
R
HN
HN
O
O
O
N
H
HO
OH
Scheme 3. Ring expansion of cyclic peptide by silver carbonate.
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10.1002/chem.202005035
Chemistry - A European Journal
COMMUNICATION
Institute MSP and Peptide Technologies facilities. V.T.
acknowledges the award of a Norma Hilda Schuster Scholarship.
Keywords: ring expansion • thioamides • imides • acyl transfer •
ring insertion
(1)
(2)
(3)
White, C. J.; Yudin, A. K. Nat. Chem. 2011, 3, 509–524.
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Figure 3: Conversion of cyclic thiopeptide 24 to ring expanded product 28 via
intermediate 27.
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To explore the scope of this ring expansion methodology
variation of the ring size and inserted amino acid were varied.
Cyclic hexa-, hepta- and octa-peptides all underwent ring
expansion to the corresponding cyclic hepta-, octa- and nona-
peptides. Examples of insertion of both glycine and alanine
residues were demonstrated, and at different sequence insertion
points, typically in good yield (Scheme 3). No evidence for
epimerization was observed. In general, insertion of alanine
proceeded in slightly lower yield than for glycine, consistent with
observations by Unsworth.17-19 One example proceeded in low
yield, with the major product being the cyclic peptide oxoamide.
This single example was the insertion of an alanine residue into
an Ala–Phe thioamide in cyclic heptapeptide 25 to generate 31,
with a combination of sequence, steric and conformational effects
presumably contributing to the low yield in this case.
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In conclusion, we have demonstrated a novel Ag(I)-promoted
reaction of thiolactams to generate N-(a-aminoacyl)-lactams. A
subsequent acyl transfer process facilitates insertion of the a-
amino acid to generate a ring-expanded product. Application to
cyclic peptides facilitates a site-specific ring expansion process.
Ultimately, a single atom substitution (O–S) in a cyclic peptide
enables exploitation of the chemoselective reactivity of
thioamides to facilitate the site-selective insertion–ring expansion,
without necessitating protection of the remaining secondary
amide groups.
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Conflict of Interest
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COMMUNICATION
Jing Shang, Varsha J. Thombare, Carlie
L. Charron, Uta Wille and Craig A.
Hutton*
R
R
BocHN
O
S
H
O
O
HN
Boc-Xaa-OH
N
N
O
NH
Ag(I)
Page No. – Page No.
Ring expansion of thiolactams via
imide intermediates: an amino acid
insertion strategy
Ag(I)-promoted reaction of thiolactams and amino acids enables an insertion–ring
expansion process.
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