Peptidomimetic synthesis by way of diastereoselective iodoacetoxylation and transannular amidation of 7-9-membered lactams

Article abstract of DOI:10.1021/acs.orglett.7b02275

Azacyclo-and azabicycloalkanone peptidomimetics were synthesized regio-and diastereoselectively by iodoacetoxylation and transannular amidation reactions on unsaturated lactam precursors contingent on ring size olefin position solvent and hypervalent iodi

Full text of DOI:10.1021/acs.orglett.7b02275

Letter
pubs.acs.org/OrgLett
Peptidomimetic Synthesis by Way of Diastereoselective
Iodoacetoxylation and Transannular Amidation of 7−9-Membered
Lactams
N. D. Prasad Atmuri, David J. Reilley, and William D. Lubell*
́ ́ ́ ́ ́
Departement de Chimie, Universite de Montreal, P.O. Box 6128, Station Centre-ville, Montreal, Quebec H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: Azacyclo- and azabicycloalkanone peptidomimetics were synthesized regio- and diastereoselectively by
iodoacetoxylation and transannular amidation reactions on unsaturated lactam precursors contingent on ring size, olefin
position, solvent, and hypervalent iodine(III) reagent. 4-Iodopyrrolizidinone 1, 7-iodoindolizidinone 2, and 4-iodo-5-
acetoxylactams (e.g., 6 and 7) were made stereospecifically from 7−9-membered olefins 16, iodine, and hypervalent iodine(III)
in acetonitrile or toluene, respectively. X-ray crystallography demonstrated potential for mimicry of natural peptide turn side
chain and backbone conformations.
tereoselective synthesis and functionalization of ring systems
1
Sarefundamentalgoalsinorganicandmedicinalchemistry. In
peptide mimicry, stereocontrolled ring synthesis is desired to
replicate precisely the side chain and backbone orientations
responsible for biological activity.2 Constrained dipeptide lactam
and azabicyclo[X.Y.0]alkanone rings have shown great utility for
the mimicry of biologically active peptide secondary structures.3,4
Although the stereoselective synthesis and functionalization of
small ring lactams have been effectively accomplished, their
introduction into bicyclic motifs and the construction and
modification of their larger 7−9-member ring counterparts
remain two relatively unmet challenges.5 Employing unsaturated
7−9-membered lactams, stereocontrolled means have now been
conceived for their conversion to fused bicycles composed of
small ring systems (fused 5,5-, 5,6-, and 6,4-bicycles 1−5) as well
as their functionalization (e.g., 6−8, Figure 1). Exploring the
scope and limitations of this method, a set of turn mimics bearing
ring substituents has been made for replicating peptide geometry.
Figure 1. Novel bicycles (2−5) and lactams (6−8) and previously
Recently,6,7 a ring-closure metathesis (RCM)−transannular
synthesized bicycles (1 and 9−11) from transannular lactamization and
lactam cyclization strategy was disclosed for the synthesis of iodo
substituted azabicyclo[X.Y.0]alkanone amino acid derivatives,
e.g. fused 5,5-, 6,5-, 6,6-, and 7,5-bicycles (1, 9−11, Scheme 1,
Figure 1). Iodolactamization using iodine gave effectively 6,5-,
6,6-, and 7,5-bicycles respectively from 9- and 10-membered
lactams; yet, similar conditions (i.e., I2, THF, 80 °C or I2,
NaHCO3, rt) failed to induce cyclization of 7- and 8-membered
lactams 15 and 16, as well as 9-membered lactam isomers 15c and
16c.
iodoacetoxylation reactions.
Previously, DIB had been used in oxidative cyclization of o-
hydroxystyrenes to benzofurans,8 and in situ generation of
hypervalent iodine species from DIB and I2 has been employed in
aromatic ring,9 olefin,10 and alkyne11 functionalization using
halogen, oxygen, and carbon nucleophiles. The nature of the
hypervalent iodine reagent has, to our knowledge, yet to be
Abreakthroughinthetransannulariodolactamization occurred
on addition of diacetoxy iodobenzene (DIB) to the I2 mixture,
which converted 16b diastereoselectively to pyrrolizidinone 1.6
Received: July 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Strategy to Azacyclo- and
Azabicycloalkanones of Different Ring Sizes
Table1.InfluenceofHypervalentIodine(III)onTransannular
Iodolactamization
entry
X
R
% yield 1 (m = 1)
% yield 2 (m = 2)
1
H
Me
626
51
52
62
61
59
71
61
65
78
52
52
60
68
62
61
70
57
62
75
2
F
Me
3
Me
OMe
H
Me
4
Me
5
t-Bu
t-Bu
t-Bu
6
Me
OMe
CF3
H
examined in such chemistry, particularly with nitrogen
nucleophiles. By studying the influence of sterically hindered
carboxylate and aromatic ligands with varying electron densities,
effective transannular iodolactamization as well as iodoacetox-
ylation of unsaturated lactams has now been achieved to provide
stereoselectively novel 5,5-, 5,6-, and 6,4-fused and 7- and 8-
membered ring systems 2−8 (Figure 1).
7
a
8
Ad
b
9
Ad
c
10
11
OMe
H
Ad
d
d
CF3
51
35
a
b
8 equiv of hypervalent iodine and 16 equiv of I2 employed. 6 equiv
c
of hypervalent iodine and 12 equiv of I2 employed. 3 equiv of
hypervalent iodine and 6 equiv of I2 employed. Isolated as 2,7-diiodo-
d
Unsaturated lactams of 7- to 9-atoms were made by coupling
4−7-carbon chain length ω-olefin amino carboxylates12 12a,b
and 13a−c, followed by RCM on the resulting dipeptides 14a−d
(Scheme 1).6 N-(Fmoc)Vinylglycine 12a was coupled as its acid
chloride to 2-N-(Dmb)aminopent-4-enoate 13a, hex-5-enoate
13b, and hept-6-enoate 13c to afford dipeptides 14a−c in 55%,
46%, and 57% yields, respectively.6 Dipeptide 14d was prepared
in 71% yield by coupling of N-(Fmoc)allylglycine (12b) and 2-N-
(Dmb)aminohex-5-enoate (13b) using HATU and N-ethyl-
morpholineinDCM. ForRCM, less(10−12mol%vs30−35mol
%) second generation Grubbs’ catalyst in 1,2-dichloroethane at
reflux gave higher yields in shorter reaction times (24 h vs 72 h)
than first generation Grubbs’ catalyst in dichloromethane at
reflux, e.g., 80% vs 68% yield of lactam 15c. Lactams 15a−d were
converted to 16a−d in 70−80% yields by Dmb group removal
using 50% TFA in DCM. Attempts at transannular iodolactam-
ization of 7−9-membered lactams failed using iodine in THF,
MeCN, ortolueneatrttorefluxresultinginlossoftheDmbgroup
in the case of 15a−d and recovered starting material from 16a−d.
The cyclization of 15b was also unsuccessful using I2 and DIB.
In acetonitrile, pyrrolizidinone 1 was prepared from 8-
membered lactam 16b, DIB, and I2 at reflux in 62% yield.6 Also,
iodoindolizidin-9-one 2 was prepared diastereoselectively in 52%
yield using the same conditions on 9-membered lactam 16c
(entry 1, Table 1). The ligands on the hypervalent iodine were
examined in the cyclization of lactams 16b and 16c using a set of
iodonium reagents,13 possessing different aryl substituents and
carboxylates,14 in MeCN at 80 °C (Table 1). Notably higher
yields were typically obtained employing electron-rich aromatic
substituents and bulky carboxylates. The highest yields (78% and
75%)ofpyrrolizidinoneandindolizidinone1and2wereobtained
using 4-methoxy-iodosobenzene di(adamantane-1-carboxylate)
(MIDAd, entry 10, Table 1). Concurrent iodination of the Fmoc
group using bis(trifluoroacetoxy)iodobenzene gave the corre-
sponding bicycles as 2,7-diiodo-Fmoc derivatives 1a and 2a
(entry 11, Table 1), which were characterized by X-ray
crystallography and NMR spectroscopy.
Fmoc derivatives 1a and 2a. Ad = 1-Adamantane.
Table 2. Synthesis of Azabicyclo[3.3.0]- and [4.2.0]Alkanone
a
Amino Esters 3−5
isolated yield (%)
X
R
(5R,6R)-3 (5S,6S)-3 (5R,6S)-4 (5S,6R)-4
5
1
2
3
H
Me
Ad
20
21
15
18
19
16
5
−
−
4
4
OMe
H
−
−
8
Me
−
a
Solvent = MeCN (entries 1 and 2); toluene (entry 3).
lactam 16a failed to react. Application of the MIDAd conditions
on lactam 16d increased slightly the yields of iodopyrrolizidi-
nones 3 and azetidine 5 (entry 2, Table 2). On lactam 16a, the
MIDAd conditions caused dehydration yielding 35% of
azepinone 8 (Figure 1), as ascertained by X-ray crystallography.
In toluene, 7- and 8-membered lactams 16a and 16b reacted
with DIBand I2 togive iodoacetoxylation products 6 and 7in59%
and 70% yields, respectively (Scheme 2). On the other hand,
lactam 16c gave a 45% yield of indolizidin-9-one 2 along with
Scheme 2. Synthesis of Iodoacetoxy Lactams
Using DIB and I2 in MeCN at 80 °C, 8-membered lactam 16d
gave a mixture of 6-iodo- and 6-acetoxy pyrrolizidinones 3 and 4
and azetidinylpiperidine 5 (entry 1, Table 2). Yet, 7-membered
B
DOI: 10.1021/acs.orglett.7b02275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Comparison of Dihedral Angles of Lactams with Ideal
Secondary Structures
Type of β-turn
ϕi+1
ψi+1
ϕi+2
ψi+2
Ideal type VIb β-turn
Ideal type VI2 β-turn
7-membered lactam 16a
7-membered lactam 8
8-membered lactam 7
8-membered lactam 16d
9-membered lactam 16c
−135°
−120°
−120°
−89°
−158°
−156°
−157°
135°
120°
178°
174°
155°
176°
160°
−75°
−60°
160°
0°
10°
0°
154°
168°
175°
−158°
−143°
−146°
−154°
−151°
Figure 2. Representative NOESY correlations used to assign the relative
configurations of ring systems 3−5 and 7.
acetyl hypoiodite, which serves as iodinating agent.10,17,18 On the
other hand, exchange of iodide for one acetoxy group has been
suggested to provide acetyl hypoiodite and an acetoxy
iodobenzene iodide salt, which reacts with the olefin.19 In our
NMR experiments, DIB and I2 reacted in CD3CN to give rapidly
iodobenzene and AcOI.10b Preparation of AcOI in situ from silver
acetate (500 mol %) and I2 (500 mol %) in MeCN and reaction
with lactam 16c gave indolizidinone 2 in 45% yield; moreover,
addition of 4-iodoanisole (300 mol %) to the reaction mixture
increased the yield of 2 to 54%. Analysis by LCMS demonstrated
thatlactam16breactedwithAcOAgandI2 togivepyrrolizidinone
1 and iodoacetate 7 in a 2:1 ratio, which reduced to 1.3:1 on
addition of AgI (500 mol %) to the DIB condition indicating that
the silver salt may interfere with lactamization, perhaps by amide
coordination. Mixing AgOAc with I2 in CD3CN gave AcOI, the
acetate carbonyl, and methyl group 13C NMR signals of which
were respectively up- and downfield shifted on addition of anisole
(50 mol %), which also caused an upfield shift of the methyl
singlet in the 1H NMR spectrum, indicating coordination
between AcOI and the electron-rich aromatic ring (SI).20,21
Iodination of the Fmoc group using ditrifluoroacetoxy-
iodobenzene and I2 may also be explained by in situ formation
of the iodinating reagent CF3CO2I.22,23
Figure 3. X-ray structures of lactams 7, 8, 16a,c,d and bicycle 1f
(fluorenylmethyl group removed and represented as Fm for clarity; C,
gray; H, off-white; N, blue; O, red; I, magenta).
trace amounts of iodoacetoxylation product. Lactam 16d gave
(S,S)- and (R,R)-6-iodopyrrolizidinones 3 (15% and 16%) along
with (S,R)-6-acetoxypyrrolizidinone 4 (4%) and trace amounts of
iodoacetoxylation product (Table 2).
The influences of hypoiodite, solvent, and ring size on the
products from iodoacetoxylation and transannular cyclization
maybeexplainedusingRCO2Iasanactivereagent. Theselectivity
of facial attack of olefins 16a−c by RCO2I is directed by the allylic
amine which may hydrogen bond with solvent or acyl hypoiodite
reagent respectively in MeCN and toluene (Figure 4). Iodonium
ion formation is likely reversible.24 In toluene, subsequent attack
of the iodonium ion by acetate occurs from the opposite face to
give 6 or 7. In MeCN, the iodonium ion is opened by
intramolecular attack of the amide to give bicycles 1 and 2. The
influences of the allylic amine and hydrogen bonding were further
demonstrated by the synthesis and reactivity of o-nitrobenzene-
sulfonamides (o-NBS, Supporting Information) 16e and 16f
(Figure 4). N-Methyl sulfonamide 16e cannot hydrogen bond
and gave predominantly bicycle 1e in both solvents; sulfonamide
16f behaved like carbamate 16b and gave mainly bicycle 1f and
iodoacetate 7f contingent on solvent. Stereochemical assign-
ments for 1e, 1f, and 7f were based on NMR spectroscopy, X-ray
analysis (1f) and analogy with their Fmoc counterparts. Favored
formation of iodoacetate inthe smallerringsystems may correlate
withdistancebetweentheallylicamineandolefin, becausealinear
relationshipbetweenringsizeandtheacutenessoftheallylicbond
dihedral angle about the α- and vinyl-carbon C−C bond (16a,
175°; 16b, −154°;6 16c, −134°) was observed in the X-ray
structures of 7−9-membered lactams.
Stereochemical assignments for the ring systems were made
based on a combination of NMR spectroscopy and X-ray
crystallography [Supporting Information (SI)]. The configu-
rations of iodo acetates 6 and 7 were assigned based on analysis of
dihedral angle coupling constants, which correlated with the X-
ray structure of the latter. After through-bond correlations were
madeusingCOSYexperimentstoassignallprotonsinthebicycle,
through-space nuclear Overhauser effects were measured to
correlate the stereochemistry of the amino acid derived α-carbons
with the newly generated ring fusion and iodide or acetate bearing
carbons (Figure 2). The trans relationship of the ring fusion and
iodide carbon bearing protons was in certain cases inferred based
on the reaction mechanism. In addition, in bicycles (5R, 6R)-3,
(5R, 6S)-4, and 5, upfield shifting of the β-proton was observed
due to anisotropy from the neighboring carboxylate.15
Type VI β-turn mimicry by 7−9-membered lactams was
established using X-ray crystallography of 16a, 16c, and 16d, as
well as 8-membered iodo acetate 7 (Figure 3, Table 3).16 The
dihedral angles of 8- and 9-membered lactams matched closely
those of the central residues of an ideal type VI β-turn (except for
ϕi+2); those of 7-membered lactam 16a reflected values of an ideal
type VI2 β-turn.
The literature offers two lines of thought on the reaction
mechanism using DIB and I2. Their combination has been
suggested to rapidly provide iodobenzene and two equivalents of
In conclusion, we have shown that diastereoselective trans-
annular iodolactamization and iodoacetoxylation of 7−9-
membered lactams can be effectively achieved using the
C
DOI: 10.1021/acs.orglett.7b02275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NSERC, Canada. We thank Dr. A.
■
Furtos, K. Venne, M.-C. Tang (mass spectrometry); S. Bilodeau,
̈
̈
A. Hamel, C. Malveau (NMR spectroscopy); and F. Belanger-
Gariepy (X-ray) from the U. de Montreal Laboratories for aid in
́
analyses. Shastri Indo-Canadian Institute, India is thanked for a
Quebec Tuition Fee Exemption grant to N.D.P.A.
REFERENCES
■
(1) Nicolaou, K. C. Proc. R. Soc. A 2014, 470, 2163.
(2) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241.
(3) St-Cyr, D. J.; García-Ramos, Y.; Doan, N.-D.; Lubell, W. D.
Peptidomimetics I; Topics in Heterocyclic Chemistry, Vol. 48; Lubell, W. D.,
Ed.; Springer-Berlin Heidelberg; Germany, 2017; pp 125−176.
(4) Khashper, A.; Lubell, W. D. Org. Biomol. Chem. 2014, 12, 5052−
5070.
(5) Ballet, S.; Guillemyn, K.; Van der Poorten, O.; Schurgers, B.;
Verniest, G.; Tourwe, D. Peptidomimetics I; Topics in Heterocyclic
́
Chemistry, Vol. 48; Lubell, W. D., Ed.; Springer-Berlin Heidelberg,
Germany, 2017; pp 177−209.
Figure 4. Proposed mechanisms for iodoacetoxylation and transannular
lactamization (NO = Not Observed).
(6) Atmuri, N. D. P.; Lubell, W. D. J. Org. Chem. 2015, 80, 4904.
(7) Surprenant, S.; Lubell, W. D. Org. Lett. 2006, 8, 2851.
(8) Singh, F. V.; Wirth, T. Synthesis 2012, 44, 1171.
(9)(a)Ogata, Y.;Aoki,K. J. Am. Chem. Soc. 1968,90, 6187. (b)Evans, P.
A.; Brandt, T. A. J. Org. Chem. 1997, 62, 5321. (c) Togo, H.; Muraki, T.;
Hoshina, Y.; Yamaguchi, K.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1
1997, 787.
combination of iodine and hypervalent iodine(III). Contingent
on solvent, an allylic carbamate appeared to serve as a key
directing group for iodonium ion formation. In acetonitrile,
subsequent intramolecular transannular cyclization provided
stereoselectivity 4-iodopyrrolizidinone 1 and 4-iodoindolizidi-
none 2. In toluene, intermolecular attack of acetate provided 7-
and 8-membered iodoacetates 6 and 7. Bulky carboxylates and
electron-rich aromatic ligands on the hypervalent iodine
improved yields in the formation of bicycles. X-ray crystallo-
graphic analysis has also shown the potential of 7−9-membered
lactams to serve as β-turn mimics with complementary structures
to those previously reported for azabicyclo[X.Y.0]alkanones. The
fundamental findings and novel peptidomimetics from this study
offer thus rich potential for the synthesis and functionalization of
lactam ring systems for exploring peptide conformation−activity
relationships.
(10)(a)Gottam,H.;Vinod,T. K.J. Org.Chem. 2011,76,974.(b)Achar,
T. K.; Maiti, S.; Mal, P. Org. Biomol. Chem. 2016, 14, 4654.
(11) Priebbenow, D. L.; Gable, R. W.; Baell, J. J. Org. Chem. 2015, 80,
4412.
(12) Atmuri, N. D. P.; Lubell, W. D. Org. Synth. 2015, 92, 103.
(13) (a) Chun, J.-H.; Pike, V. W. J. Org. Chem. 2012, 77, 1931. (b) Wu,
́
Y.; Izquierdo, S.; Vidossich, P.; Lledos, A.; Shafir, A. Angew. Chem. 2016,
128, 7268. (c) Wang, B.;Qin, L.;Neumann, K. D.;Uppaluri, S.;Cerny, R.
L.; DiMagno, S. G. Org. Lett. 2010, 12, 3352.
(14) Stang, P. J.; Boehshar, M.; Wingert, H.; Kitamura, T. J. Am. Chem.
Soc. 1988, 110, 3272.
(15) Mauger, A.; Irreverre, F.; Witkop, B. J. Am. Chem. Soc. 1966, 88,
2019.
(16) Creighton, C. J.; Leo, G. C.; Du, Y.; Reitz, A. B. Bioorg. Med. Chem.
2004, 12, 4375.
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b02275.
́
(17) (a) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett. 1994,
■
35, 1003. (b)Chen, E.;Keefer, R.;Andrews, L. J. Am. Chem. Soc. 1967, 89,
428.
S
(18) Radical intermediates may be possible. See: (a) Zard, S. Z. Chem.
Soc. Rev. 2008, 37, 1603. (b) Glover, S. A.;Goosen, A. J. Chem. Soc., Perkin
Trans. 1 1977, 1348.
Experimental procedures; characterization data (1H, 13C,
2D NMR, HRMS, IR, mp, and specific rotation) (PDF)
X-ray data for 1a (CIF)
X-ray data for 7 (CIF)
X-ray data for 8 (CIF)
X-ray data for 16a (CIF)
X-ray data for 16c (CIF)
X-ray data for 16d (CIF)
X-ray data for 1f (CIF)
(19) (a) Yuan, W.; Szabo,
(b) Geary, G. C.; Hope, E. G.; Stuart, A. M. Angew. Chem., Int. Ed. 2015,
54 (49), 14911. (c) Ilchenko, N. O.; Tasch, B. O.; Szabo, K. J. Angew.
Chem., Int. Ed. 2014, 53, 12897. (d) Ulmer, A.; Brunner, C.; Arnold, A.
́
K. J. Angew. Chem. 2015, 127, 8653.
́
M.; Pothig, A.; Gulder, T. Chem. - Eur. J. 2016, 22, 3660. (e) Boye, A. C.;
̈
Meyer, D.; Ingison, C. K.; French, A. N.; Wirth, T. Org. Lett. 2003, 5,
2157.
(20) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.;
Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684−3691.
(21) Heasley, V. L.; Holstein, L. S.; Moreland, R. J.; Rosbrugh, J. W.;
Shellhamer, D. F. J. Chem. Soc., Perkin Trans. 2 1991, 1271.
(22) Carruthers, W.; Coggins, P.; Weston, J. B. J. Chem. Soc., Perkin
Trans. 1 1991, 611.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: william.lubell@umontreal.ca.
ORCID
(23) Lipshutz, B. H.; Barton, J. C. J. Am. Chem. Soc. 1992, 114, 1084.
(24) Brown, R. Acc. Chem. Res. 1997, 30, 131.
N. D. Prasad Atmuri: 0000-0001-5359-5325
D
DOI: 10.1021/acs.orglett.7b02275
Org. Lett. XXXX, XXX, XXX−XXX