Insight into Transannular Cyclization Reactions to Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams

Article

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Insight into Transannular Cyclization Reactions To Synthesize

Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from

8‑, 9‑, and 10-Membered Macrocyclic Dipeptide Lactams

N. D. Prasad Atmuri 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: An eﬃcient method for synthesizing diﬀerent

functionalized azabicyclo[X.Y.0]alkanone amino acid deriva-

tives has been developed employing electrophilic transannular

cyclizations of 8-, 9-, and 10-membered unsaturated macro-

cycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino

acids, respectively. Macrocycles were obtained by a sequence

featuring peptide coupling of vinyl-, allyl-, homoallyl-, and

homohomoallylglycine building blocks followed by ring-

closing metathesis. X-ray crystallographic analyses of the

8-, 9-, and 10-membered macrocyclic lactam starting materials

as well as certain bicyclic amino acid products provided insight

into their conformational preferences as well as the mechanism

for the diastereoselective formation of speciﬁc azabicycloalkanone amino acids by way of transannular iodolactamization

reactions.

In the interest of developing a general strategy for synthesizing

azabicyclo[X.Y.0]alkanone amino acids of varying ring sizes, we

have pursued electrophilic transannular lactamizations of unsatu-

rated macrocyclic dipeptides.^8aThis strategy is appealing, because

a variety of macrocycles may be generated by coupling various

ω-unsaturated amino acids, followed by ring-closing metathesis

(RCM; Figure 1). Moreover, after transannular iodolactamization,

the resulting iodide has served as a handle for introducing various

side chain functional groups onto the bicyclic system.¹²

Considering that both bicycle and macrocycle constraints

serve to rigidify the peptide backbone,^5c,13eﬀorts have focused

on studying the synthesis and conformational analysis of a series

of ring systems in which the same dipeptide motif is maintained

as the ring size and oleﬁn orientation are modulated. Employing

X-ray crystallography and NMR spectroscopy, insight has now

been gained with respect to the conformational preferences of

the macrocyclic and bicyclic dipeptide motifs, as well as the

regioselective nature of the transannular lactamization. Exploring

ﬁve diﬀerent macrocycles, we have found conditions to prepare

regioselectively and stereoselectively ﬁve distinct bicyclic

dipeptide mimics, validating the eﬀectiveness of this approach

for peptidomimetic synthesis.

INTRODUCTION

■

Azabicyclo[X.Y.0]alkane structures, such as pyrrolizidines,

indolizidines, and qunolizidines, are found in numerous

biologically active alkaloid natural products.^1,2The related

azabicyclo[X.Y.0]alkanone amino acid counterparts are rigid

dipeptide surrogates that have been employed to study

conformation−activity relationships of biologically active pep-

tides.^3,4Inherent to the syntheses of both classes of heterocycles

has been the stereocontrolled construction of the bicyclic ring

system in a way that provides for eﬀective introduction of ring

functionality. Among various synthetic strategies,⁵transannular

reactions featuring amine nucleophiles reacting on macrocyclic

oleﬁn and epoxide precursors have exhibited considerable utility

for the stereoselective construction of the bicyclic amines,^6,7

albeit few examples of the related cyclizations of macrocyclic

lactams have been reported.⁸In both cases, regioselective

formation of speciﬁc bicycles has often been observed to occur

with high diastereoselectivity. Limited mechanistic understand-

ing exists however to predict the outcome of such transannular

cyclization reactions, because they have been typically performed

on a restricted number of ring sizes with substituents that have

varied greatly both in functional group and in location. Generally,

in cycloalkanes of 8−11 ring atoms, unfavorable interactions of

ring substituents can cause signiﬁcant strain, so-called “Prelog

strain”.^9,10Moreover, nitrogen lone pair electrons have been

reported to prefer an antiorientation with respect to the oleﬁn

π-bond to minimize repulsive interactions.¹¹Such steric and

electronic interactions serve likely in part as driving forces for

preferred macrocycle conformations and favored regioselective

cyclizations.

RESULTS AND DISCUSSION

■

Iodoazabicyclo[4.3.0]- and iodoazabicyclo[5.3.0]alkanones

1 and 2 were previously made by the diastereoselective

Received: February 1, 2015

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Scheme 1. Synthesis of 2-Aminopent-4-enoate 13,

2-Aminohex-5-enoate 14, and 2-Aminohept-6-enoate 15

amino acid homologues. Methyl 2-(N-Boc-amino)pent-4-enoate

(13) and methyl 2-(N-Boc-amino)hept-6-enoate (15) were thus

respectively prepared by using vinyl bromide in the Pd-catalyzed

reactions on the zincate derived from iodoalanine 12 and the

boronate derived from 13.

Starting from ^L-serine as a chiral educt, protected enantiomeri-

cally pure ω-unsaturated amino acids with chain lengths of

5−7 carbons were prepared by a common sequence. Methyl

N-Boc-iodoalanine (12; Scheme 1) was assembled in three

steps from serine and used in the synthesis of the ﬁve- and six-

carbon analogues.¹⁹On treatment with zinc, iodoalanine 12

was converted to the corresponding zincate, which was coupled

20

with vinyl bromide and Pd₂(dba)₃or allyl chloride and

CuBr·DMS,¹⁸respectively, to give pentenoate 13 and hexenoate

14 in 65% and 60% yields. Heptenoate 15 was synthesized from

pentenoate 13 in 68% yield by hydroboration of the terminal

alkene using 9-borabicyclo[3.3.1]nonane (9-BBN) and cross-

coupling to vinyl bromide using Pd₂(dba)₃.

Figure 1. General synthetic plan for making azabicyclo[X.Y.0]alkanones

and representative examples of previously prepared bicycles 1 and 2, as

well as new examples, 3−5, prepared herein.

After the syntheses of pentenoate 13 and heptenoate 15, their

enantiomeric purities were respectively evaluated by conversion

to diastereomeric dipeptides on removal of the Boc group with

HCl gas in dichloromethane and coupling to ^L- and D-N-Boc-

alanine with HATU (Supporting Information). Examination of

iodolactamization of 9- and 10-membered macrocycles (Z)-10c

and (E)-11f, respectively (Figure 1).^8a,12,14Macrocycles (Z)-10c

and (E)-11f had been made from allyl- and homoallylglycine

building blocks.¹⁴Herein, vinyl- and homohomoallylglycines

were added to provide a set of four ω-unsaturated amino acids for

RCM/electrophilic transannular cyclizations that have now given

access to the new 5,5- and 6,6-fused bicyclic ring systems 3 and 4,

as well as anti-Bredt imidate 5 (Figure 1). The latter bridgehead

imidate represents a rare substituted heterocycle example that

challenges Bredt’s rules.¹⁵From all ﬁve of these related

transannular cyclizations, only a single heterocyclic system was

typically formed diastereoselectively.

The enantiomerically pure ω-unsaturated amino acid starting

materials with lengths of 4−7 carbons were synthesized eﬃciently

by atom economical routes. Many synthetic approaches exist

for making these building blocks;^14,16,17however, they often

require long reaction sequences, especially in the cases of

2-aminopent-4-enoate (allylglycine) and 2-aminohept-6-enoate

(homohomoallylglycine).

1

the diastereotopic methyl ester singlets by H NMR spectros-

copy in CD₃CN during incremental addition of the (S,R)-

diastereomer to the (S,S)-diastereomer demonstrated in both

cases a >99:1 dr. Hence, pentenoate 13 and heptenoate 15 are

both assumed to be of >98% enantiomeric purity.

Suitably protected 2-(N-Dmb-amino) ester 16 and 2-(N-Boc-

amino) and 2-(N-Fmoc-amino) acids 17 and 18 were prepared

from 2-(N-Boc-amino) esters 13−15 using previously described

protocols (Scheme 2).¹⁴2-(N-Fmoc-amino)but-3-enoic acid

(vinylglycine 19) was synthesized as previously described.^21,22

Dipeptides 6 and 7 were synthesized by coupling ester 16 and

acids 17 and 18 using HATU and N-ethylmorpholine in 70−80%

yield (Scheme 3).¹⁴Double bond migration occurred during

coupling of but-3-enoic acid 19 to 2-(N-Dmb-amino)hex-5-oate

16b using HATU and DIEA and gave dehydropeptide 20

(Scheme 4). Double bond migration was avoided by converting

vinylglycine 19 to the corresponding acid chloride, which reacted

with 16b and 16c in the absence of base to aﬀord dipeptides 7a

and 7b in 50−60% yield.

Inspired by the relatively eﬃcient synthesis of methyl

2-(N-Boc-amino)hex-5-enoate (14),¹⁸which featured the copper-

catalyzed cross-coupling of allyl chloride and the zincate derived

from iodoalanine 12 (Scheme 1),¹⁹related transition-metal cross-

coupling methods were developed to make the higher and lower

Macrocycles 9 and 10 were prepared from dipeptides 6 and 7

in 60−90% yields in solution using RCM employing the

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Scheme 2. Protecting Group Shuﬄe To Make Boc, Fmoc, and

Dmb Building Blocks

Scheme 4. Coupling with Vinylglycine 19 and Synthesis of

Dehydroazepinone 21

Scheme 3. Syntheses of Dipeptides 6 and 7 and Macrocycles

9−11

Transannular cyclization of 8-membered macrocyclic lactam

(Z)-10a was initially studied by treatment with iodine in THF

and MeCN at room temperature to reﬂux; however, only loss

of the Dmb group was observed, and macrocycle (Z)-11a

was isolated. 8-Membered lactam (Z)-11a proved resistant to

transannular iodoamidation using I₂in THF buﬀered with

NaHCO₃, as well as using I₂in acetonitrile at reﬂux. Transannular

cyclization was achieved by treating (Z)-11a with (diacetoxyiodo)-

benzene (DIB; 1.5 equiv) and 4 equiv of iodine in acetonitrile at

reﬂux for 30 min (Scheme 5). Although DIB has been used in

oxidative cyclizations of o-hydroxystyrenes to benzofurans, to the

best of our knowledge, this is the ﬁrst use of this reagent in a

transannular iodolactamization. (3R,4R,5S,8S)-Pyrrolizidinone 3

was isolated as a single diastereomer in 62% yield after

chromatography (Scheme 5). In the mechanism for the formation

of 3, hypervalent iodine may activate the double bond as a

3-membered iodonium species, 22,²⁶which undergoes intra-

molecular reaction with the amide nitrogen to form intermediate

23. Displacement of the hypervalent iodine by the neighboring

carbamate may occur by way of an oxazole intermediate 24, which

is opened by iodide to give iodopyrrolizidinone 3 with retention of

conﬁguration. The structure of 3 was conﬁrmed by NMR

spectroscopy and X-ray diﬀractometry as described below.

Although the related double bond isomer (Z)-10c (m = 1,

n = 2) underwent iodolactamization to provide iodoindolizidi-

none 1 in 86% yield using I₂in THF at 80 °C (Figure 1),^8a

treatment of unsaturated macrocyclic lactam (Z)-10e (m = 2,

n = 1) under analogous conditions only caused removal of the

Dmb group to provide lactam (Z)-11e. Moreover, attempts to

induce transannular cyclization of 9-membered lactam (Z)-11e

using alternative conditions (I₂in MeCN;¹²DIB and I₂in

MeCN, rt to reﬂux; Lewis base-catalyzed²⁷iodolactamization

using Ph₃PS, NIS/DCM) produced a relatively less polar spot

on TLC compared to the iodobicycles. The reaction proceeded

cleanly, and the starting material was all consumed within 1 h as

indicated by TLC. After the usual aqueous workup with Na₂S₂O₃,

and puriﬁcation by silica gel chromatography in the dark, imidate

Grubbs ﬁrst-generation catalyst in dichloromethane at reﬂux

(Scheme 3).^23,24Dehydroamino acid analogue 20 failed to react

using the ﬁrst generation of the Grubbs catalyst, but could be

converted to dehydroazepinone 21 with the Grubbs second-

generation catalyst (Scheme 4).²⁵In spite of the acid sensitivity

of the Dmb group, the Boc group could be selectively removed

from macrocycle 9g using 50% TFA in DCM for 2 h to aﬀord

the corresponding amine, which was converted to its Fmoc

counterpart 10g using Fmoc-OSu and Na₂CO₃(Scheme 3).¹⁴

To remove the Dmb group, N-Fmoc-amino lactams 10 were

treated with 50% TFA/DCM for 18 h, which aﬀorded macrocycles

11 in 70−80% yields. In the case of 10-membered N-Dmb-amino

lactam 10d, starting material was however not consumed even

after treatment for 3 days, when lactam 11d was aﬀorded in

69% yield after chromatography. The oleﬁn and amide isomer

geometries of macrocycles 9−11 were established by NMR

spectroscopy and X-ray analysis (vide infra).

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Scheme 5. Proposed Mechanism for the Synthesis of

Iodoazabicyclo[3.3.0]alkanone Amino Ester 3

Scheme 7. Synthesis of Iodoazabicyclo[4.4.0]alkanone Amino

Ester 4

(3S,5R,6R,10S)-5-iodoazabicyclo[4.4.0]alkanone 4, in 53% yield

using I₂in THF at reﬂux (Scheme 7).

Stereochemical Assignment Using NMR Spectroscopy.

The assignment of the structure and stereochemistry of bicycles

3−5 was accomplished by 2D NMR spectroscopy and X-ray

crystallography (Supporting Information). Typically, a COSY

spectrum was used to assign the ring proton through-bond

connectivities starting from the downﬁeld carbamate NH proton.

The observation of magnetization transfer between the peptide

backbone protons and ring protons in the NOESY and ROESY

spectra was then used to assign the relative stereochemistry at the

ring-fusion and iodide-bearing carbons (Figure 2). For example,

Scheme 6. Synthesis of Azabicyclo[4.3.1]alkane 5

Figure 2. NOESY and ROESY correlations used to assign the relative

conﬁgurations of bicycles 3 and 4.

5 was characterized using NMR spectroscopy and X-ray

crystallography (Scheme 6). Imidate formation has been

observed commonly in halocyclizations of linear unsaturated

amides, and avoided using methods employing N,O-bis-silylation,

N-tosyl and N-alkoxycarbonyl substitution, and strong bases.²⁸

On the other hand, transannular iodolactamization has favored

azabicycloalkanone.^8b,12Albeit light-sensitive, imidate 5 is a

unique anti-Bredt heterocycle formed by attack of the lactam

oxygen on iodonium intermediate 25.^29,30

Previously, iodoazabicyclo[5.3.0]alkanone 2 (Figure 1) was

prepared diastereoselectively from 10-membered lactam (E)-11f

(m = 2, n = 2) using 4 equiv of I₂in THF at reﬂux.^8a

Iodolactamization of 10-membered N-Dmb-lactam (Z)-10d

(m = 1, n = 3) has now given diastereoselective access to

the ﬁrst example of a substituted quinolizidinone amino acid,

(4R,5S)-4-iodopyrrolizidinone N-Fmoc-amino ester 3 exhibited

a transfer of magnetization between the backbone C3α and

the ring C6α protons in C₆D₆. A second long-range NOE

between the ring C4 and C6 β-protons established the relative

stereochemistry of the iodide-bearing carbon. Long-range

transfer of magnetization was observed between the ring-fusion

C6 and backbone C3 and C10 protons in the ROESY spectrum

of (3S,5R,6R,10S)-5-iodoquinolizidinone 4. The stereochemistry

of the ring-fusion carbon of pyrrolizidinone 3 and the iodide-

bearing carbon of 4 were subsequently inferred on the basis of

mechanistic considerations that placed the protons from the cis-

double bond of the macrocycle on the same face of the bicycle.

Although through-bond couplings of azabicyclo[4,3,1]alkane

5 could be used to assign all of the ring protons, no clear long-

range NOEs were observed to assign the relative stereochemistry.

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In the infrared spectrum of 5, a CN stretching band at

1657 cm⁻¹was observed, indicative of an imidate structure.

Examination of the coupling pattern (ddd, J = 2.7, 5.4, 11.0 Hz)

for the proton on the iodide-bearing carbon, before and after

saturation of the neighboring bridgehead proton, and application

of the Karplus equation³¹gave torsion angels that were consistent

with those observed in the crystal structure.

Crystal Structures of 8-, 9-, and 10-Membered Macro-

cyclic Dipeptide Lactams. Lactams (Z)-11a, (Z)-11e, and

(Z)-10d were crystallized by a common method (Supporting

Information). In all three cases, the (Z)-double bond geometry

was observed. In 8-membered lactam (Z)-11a, the cis-(E)-amide

isomer was observed, as was previously described in the X-ray

structure of the related oleﬁn regioisomer 8-membered macro-

cycle 27 (Table 1).³²On the other hand, the trans-(Z)-amide

also been found to exhibit backbone dihedral angles similar to

those of an ideal type I β-turn (Table 1). In the case of

10-membered lactam (Z)-10d, which possesses a cis-oleﬁn at a

diﬀerent ring position, the backbone conformation was more

similar to an ideal type II β-turn, albeit the dihedral angles of the

N-terminal residue resembled an extended parallel β-pleated

sheet. In summary, lactams (Z)-11a, (Z)-11e, and (Z)-10d

appear to have potential for mimicry of three diﬀerent β-turn

conformations.

Crystal Structures of Azabicyclo[X.Y.Z]alkanes 3 and 5.

The stereochemical assignments made for iodopyrrolizidinone 3

were conﬁrmed by the X-ray structure (Figure 3). The dihedral

angle values of the peptide backbone in the 5,5-fused bicycle 3

resembled those of an extended rather than a turn structure. In

this respect, the peptide backbone geometry in azabicyclo[3.3.0]-

alkanone 3 diﬀered from those observed in X-ray analyses of

larger azabicyclo[4.3.0]alkanone and iodoazabicyclo[5.3.0]-

alkanone (2) amino ester counterparts, which were respectively

similar to ideal type II′ and type I β-turns.^34,12In addition, the

X-ray structure of 4-iodopyrrolizidinone 3 exhibited dihedral

angles diﬀerent from those of the X-ray structure of the related

6-hydroxypyrrolizidinone, which closely resembled those of a

type II′ β-turn (Table 1).^5a

Table 1. Comparison of Dihedral Angles of Macrocyclic and

Bicyclic Peptidomimetics with Ideal Secondary Structures

In the X-ray structure of cyclic imidate 5 (Figure 3), the

(Z)-anti-periplanar isomer was observed. Although related

structures of such anti-Bredt heterocycles were not found,

the bond lengths of bridging imidate 5 (C−O, 1.39 Å; CN,

1.24 Å) compared well with those from the crystal structures of

cyclic imidates (C−O, 1.36 0.2 Å; CN, 1.25 0.01 Å),^35,36

indicating that little distortion was induced by the bridgehead

geometry of 5. In addition, the dihedral angle values of 5

resembled those of an ideal type II β-turn.

type of β-turn³³

ϕ₁, deg

ψ₁, deg

ϕ₂, deg

ψ₂, deg

I

−60

60

−30

120

−90

80

0

II

II′

VIb

−120

135

−80

−75

0

−135

160

antiparallel β-sheet³⁸

parallel β-sheet³⁸

ϕ = −140

ϕ = −120

ψ = 135

ψ = 115

Peptidomimetic Dihedral Angles

Mechanistic Considerations. Transannular iodolactamiza-

tions have been studied using a series of related macrocycles of

8−10 ring atoms. In spite of the structural similarities of the

starting macrocyclic lactams, many factors may inﬂuence this

reaction, including the ring conformation and cyclization

conditions. In related iodolactamizations, regioselectivity has

previously been considered to be a consequence of the macro-

cycle conformation.³⁷In this light, the ﬂexibility of the

macrocycle ring may contribute to mixtures of bicyclic products,

yet ring substituents that orient to avoid allylic strain with the

oleﬁn substituents and diaxial interactions will signiﬁcantly

reduce the number of cyclization pathways. Typically, a relaxed

conformer may orient the lactam and oleﬁn to give regio- and

stereoselective pathways.^37,8f,dIn such cases, the iodide

substituent ends up on the lactam ring. In one case, a thermo-

dynamically less stable 9-membered lactam has been found to

give an alternative regio- and stereochemical indolizidinone

featuring a 5-membered lactam and a piperidine ring bearing the

iodide.³⁷In addition, 9-membered lactam (Z)-11e gave imidate 5

instead of a fused 7,4-bicycle with the iodide on the 7-membered

lactam or a 6,5-bicycle with the iodide on the 5-membered

pyrrolidine.

Although electrophile-induced intramolecular cyclization

reactions may proceed by formation of a dihalide that is

subsequently displaced by the lactam to form the ring,^8e

cyclizations of macrocycles (Z)-11a, (Z)-11e, and (Z)-10d are

presumed to proceed by way of iodonium-like intermediates

based on their stereochemical outcomes.⁴⁰The ambidentate

nucleophilic nature of the amide group has been observed to give

imidates in iodocyclizations of simpler oleﬁns,^41,42and such

O-selectivity has been explained on the basis of hard−soft

ϕⁱ⁺¹

,

ψⁱ⁺¹

,

ϕⁱ⁺²

,

ψⁱ⁺²

,

deg

8-membered lactam (Z)-11a

8-membered lactam 27³²

9-membered lactam (Z)-11e

10-membered lactam (Z)-10d

10-membered lactam (E)-28³⁹

chair−chair

−142

−93

−109

−161

156

177

−27

171

−158

−148

−145

63

172

90

−28

23

−107

120

−1

−64

−140

−141

−64

−1

−130

−131

−109

−40

−49

175

23

−43

173

133

136

74

chair−boat

4-iodoazabicyclo[3.3.0]alkanone 3

6-hydroxyazabicyclo[3.3.0]alkanone^5a

iodoazabicyclo[5.3.0]alkanone 2^8a

azabicyclo[4,3,1]alkane 5

−120

14

−138

−166

isomer was detected in the crystal structures of 9- and 10-

membered lactams (Z)-11e and (Z)-10d.

Examination of the backbone dihedral angles found in the

crystal structures of lactams (Z)-11a, (Z)-11e, and (Z)-10d

may provide an understanding of their potential for mimicry of

1

natural peptide structures, albeit H NMR spectroscopy of

macrocyclic lactams (Z)-11e and (Z)-10d did show doubling

of some peaks, indicative of conformational isomers in CDCl₃.

The torsion angles of lactams (Z)-11a, (Z)-11e, and (Z)-10d

were compared with those for ideal turn and sheet structures

(Table 1).³³Notably, 8-membered lactam (Z)-11a possesses a

dihedral angle geometry similar to that observed for the central

residues of an ideal type VIb β-turn, similar to its oleﬁn

regioisomer 27. The torsion angle values of 9-membered lactam

(Z)-11e are similar to those of an ideal type I β-turn. Previously,

10-membered lactam 28 possessing a trans-oleﬁn geometry had

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Figure 3. X-ray structures of macrocyclic dipeptide lactams and iodoazabicyclo[X.Y.Z]alkanes (C, gray; H, green; N, blue; O, red; I, magenta).

acid−base theory considering the iodine−oleﬁn π-complex to be

a hard electrophile.^43,44However, transannular attack of oxygen

would result in an anti-Bredt bridgehead heterocycle,⁴⁵which

may be relatively disfavored due to ring strain. Given the choices

between placing iodide on the nonlactam ring, forming a strained

N-acylazetidine or forming the anti-Bredt imidate, the latter

product 5 was favored.

Notably, the respective proximities of the amide nitrogen

and oxygen to the double bond carbons on the amine (C^N) and

carbonyl (C^CO) sides of the macrocycle did not correlate with the

mode of cyclization except in the case of the 8-membered lactam

going to the fused 5,5-bicycle (Table 2).

A working hypothesis for the selectivity of the transannular

iodolactamization begins with a favored macrocycle conforma-

tion that minimizes ring strain. Approach of iodine to the less

sterically hindered face of the oleﬁn provides the iodonium

intermediate, which is typically attacked on the carbon (C^N) on

the amide nitrogen side of the macrocycle to provide a bicycle

having the iodide on the lactam ring. Attack of the iodonium

carbon (C^CO) on the carbonyl side of the macrocycle is likely

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compounds 7e, 10e, 11e, 17a, 17b, 16a, and 16b have been previously

reported.¹⁴

(S)-Methyl 2-(N-Boc-amino)pent-4-enoate (13).

Table 2. Comparison of Transannular Distances (Å) in

Macrocyclic Lactams

8-membered

9-membered

(Z)-11e

10-membered

(Z)-10d

bond

(Z)-11a

N to C^N

N to C^CO

O to C^N

O to C^CO

3.11

3.40

3.14

4.12

3.23

3.01

3.33

3.38

3.45

3.47

3.29

3.63

disfavored due to the need to avoid allylic strain between the

carboxylate and the lactam carbonyl as well as potential diaxial

interactions between the carboxylate and the iodide. In the case

of 5, the combination of the factors mentioned above and ring

strain to make a 4-membered azetidine lead to a preferred attack

by oxygen, giving the imidate. Computational analyses are

currently being pursued to provide additional support of these

mechanistic considerations.

To a stirred solution of zinc dust (11.92 g, 182.3 mmol, 6 equiv) in

dry DMF (20 mL) was added 1,2-dibromoethane (1.57 mL, 3.42 g,

18.2 mmol, 0.6 equiv) via a syringe. The resulting mixture was heated to

60 °C, stirred for 45 min, and cooled to room temperature, and the

slurry was treated with chlorotrimethylsilane (0.77 mL, 6.0 mmol).

After being stirred for 40 min at room temperature, the activated zinc

was treated with a solution of methyl (R)-N-Boc-iodoalaninate (12;

10 g, 30.39 mmol) in dry DMF (20 mL), heated to 35 °C, and stirred

for 60 min, when insertion was judged complete by TLC analysis

[2:1 hexanes/ethyl acetate, using 254 nm UV light to visualize the

starting material 12 (R_f= 0.7) and organozinc reagent (R_f= 0.1)].

After complete zinc insertion, the reaction mixture was cooled to

room temperature, charged with Pd₂(dba)₃(779 mg, 0.85 mmol,

0.028 equiv) and tri-o-tolylphosphine (925 mg, 3.03 mmol, 0.1 equiv),

cooled to −78 °C, and treated dropwise via a cannula with a solution of

vinyl bromide in THF (1 M, 42.5 mL, 42.5 mmol, 1.4 equiv). After

complete addition of the vinyl bromide solution, the cold bath was

removed, and the reaction mixture was allowed to warm to room

temperature with stirring for 12 h. The reaction mixture was diluted

with ethyl acetate (200 mL) and water (200 mL), and ﬁltered through a

pad of Celite. The pad was washed with ethyl acetate (300 mL). The

ﬁltrate and washings were combined and transferred to a separating

funnel. The organic layer was separated. The aqueous layer was

extracted with ethyl acetate (2 × 200 mL). The combined organic layers

were washed with brine (400 mL), dried over anhydrous sodium

sulfate, ﬁltered, and concentrated under reduced pressure to give 8.2 g

of brown oil, which was puriﬁed by column chromatography on silica

gel (8−10% EtOAc in hexane) to give oleﬁn 13 (4.50 g, 19.64 mmol,

65%) as a brown oil: R_f= 0.29 (9:1 hexanes/ethyl acetate, visualized as a

UV inactive and KMnO₄active spot on heating); [α]²_D⁰+20.2 (c 1.5,

CHCl₃); FT-IR (neat) ν_max2978, 1744, 1712, 1499, 1437, 1365, 1159,

CONCLUSIONS

■

A variety of azabicyclo[X.Y.0]alkanone amino acids have been

prepared using a common approach featuring eﬀective assembly

of macrocyclic lactams of 8−10-membered ring sizes by the

synthesis and coupling of ω-unsaturated amino acids and RCM

of their dipeptide derivatives, followed by regio- and stereo-

selective electrophilic transannular cyclization. Employing X-ray

crystallographic and NMR spectroscopic analyses, we have

demonstrated that the macrocyclic and bicyclic structures oﬀer

ample potential to mimic peptide secondary structures, in

particular types I, II′, and VI β-turn geometries contingent on

ring size. Moreover, such conformational analyses have also

provided insight into the mechanism of transannular iodolactam-

ization. Considering the potential of this method for eﬀectively

making a series of related dipeptide mimics to explore peptide

conformation−activity relationships, as well as the opportunity

for replacing the iodide with other side chains to examine

functional group inﬂuences on activity, this method should have

a signiﬁcant impact on peptidomimetic approaches for studying

biologically active peptides, particularly for the discovery of

therapeutic agents.

EXPERIMENTAL SECTION

■

General Methods. Unless otherwise noted, all reactions were

performed under an argon atmosphere and distilled solvents were

transferred by syringe. Anhydrous CH₂Cl₂(DCM), THF, and diethyl

ether were obtained by passage through a solvent ﬁltration system.

Final reaction mixture solutions were dried over anhydrous MgSO₄or

Na₂SO₄, ﬁltered, and rotary-evaporated under reduced pressure.

Flash chromatography⁴⁶was on 230−400 mesh silica gel, and thin-

layer chromatography was performed on silica gel 60 F254 plates.

Speciﬁc rotations, [α]_Dvalues, were calculated from optical rotations

measured at 20 °C in CHCl₃or MeOD at the speciﬁed concentrations

(c, g/100 mL) using a 1 dm cell (l) on a polarimeter, using the general

formula [α]²_D⁰= 100α/lc. Accurate mass measurements were performed

on an LC-MSD instrument in electrospray ionization (ESI-TOF)

mode. Sodium adducts [M + Na]⁺were used for empirical formula

1

1021, 868, 779 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 5.63−5.71 (m,

1H), 5.09−5.12 (m, 2H), 5.03−5.04 (br d, 1H), 4.34−4.37 (m, 1H),

3.71 (s, 3H), 2.50−2.55 (m, 1H), 2.42−2.47 (m, 1H), 1.41 (s, 9H); ¹³

C

NMR (125 MHz, CDCl₃) δ 172.7, 155.3, 132.4, 119.1, 79.9, 53.0, 52.3,

36.9, 28.4; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₁H₁₉NO₄Na

252.1215, found 252.1217. Anal. Calcd for C₁₁H₁₉NO₄: C, 57.62; H,

8.35; N, 6.11. Found: C, 57.13; H, 8.51; N, 5.93. Attempts to ascertain

the enantiomeric purity of oleﬁn 13, as well as the hydrochloride 30

obtained on treating 13 with HCl gas in dichloromethane, were both

unsuccessful using supercritical ﬂuid chromatography on a chiral

column. To assess enantiomeric purity, diastereomeric amides were

synthesized as described below. The crude residue was examined

by ¹H NMR spectroscopy in CD₃CN at 700 MHz. Incremental

addition of (S,R)-31 to (S,S)-31 and observation of the methyl ester

singlets at 3.697 and 3.691 ppm demonstrated the diastereomers were

of >99:1 dr. Hence, oleﬁn 13 is assumed to be of >98% enantiomeric

purity.

1

conﬁrmation. H NMR spectra were measured in CDCl₃(7.26 ppm),

CD₃OD (3.31 ppm), or DMSO-d₆(2.50 ppm). ¹³C NMR spectra were

measured in CDCl₃(77.16 ppm) or DMSO-d₆(39.52 ppm). ¹H NMR

spectra for the dipeptides 7a, 7b, 6d, 7d, 6g, 11g, 11d, and 20 were

recorded at 100 °C to coalesce signals due to conformational isomers.

Coupling constant J values were measured in hertz and chemical shift

values in parts per million. Infrared spectra were recorded for neat

samples on an FT-IR apparatus. Syntheses and characterization of

G

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0.43 mmol) and tri-o-tolylphosphine (663 mg, 2.18 mmol) in THF at

−78 °C was added a 1 M solution of vinyl bromide in THF (87 mL,

87 mmol), followed by a degassed solution of boronate. The resulting

mixture was stirred at room temperature overnight, quenched with

water (100 mL), and extracted using ethyl acetate (150 mL × 2). The

combined organic extracts were washed with brine (100 mL), dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated under reduced pressure

to give 7.8 g of brown oil, which was twice puriﬁed by column

chromatography on silica gel using 4−6% EtOAc in hexane. Evaporation

of the collected fractions gave oleﬁn 15 (3.81 g, 14.81 mmol, 68%) as a

light brown oil: R_f= 0.29 (9:1 hexanes/ethyl acetate, visualized as a UV

inactive and KMnO₄active spot on heating); [α]²_D²+14.6 (c 1, CHCl₃);

FT-IR (neat) ν_max2977, 1742, 1712, 1501, 1365, 1160. 1050, 909 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 5.70−5.80 (m, 1H), 4.93−5.01 (m, 3H),

4.27−4.28 (m, 1H), 3.71 (s, 3H), 2.00−2.09 (m, 2H), 1.74−1.82 (m,

1H), 1.56−1.65 (m, 1H), 1.37−1.48 (m, 11H); ¹³C NMR (100 MHz,

CDCl₃) δ 173.5, 155.5, 138.1, 115.2, 79.9, 53.4, 52.3, 33.2, 32.3, 28.3,

24.7; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₃H₂₃NO₄Na

280.1519, found 280.1533.

Attempts to ascertain the enantiomeric purity of oleﬁn 15, as well as

the hydrochloride 32 that was obtained on treating 15 with HCl gas in

dichloromethane, were both unsuccessful using SFC on a chiral column.

To assess enantiomeric purity, diastereomeric amides were synthesized

as described below. Crude residue was examined by ¹H NMR

spectroscopy in CD₃CN at 700 MHz. Incremental addition of (S,R)-

33 to (S,S)-33 and observation of the methyl ester singlets at 3.6578

and 3.6622 ppm demonstrated the diastereomers were of >99:1 dr.

Hence, oleﬁn 15 is assumed to be of >98% enantiomeric purity.

(S)-Methyl 2-Aminopent-4-enoate Hydrochloride (30). Dry

HCl gas was bubbled into a stirred solution of (S)-13 (70 mg,

0.30 mmol) in dichloromethane at room temperature. Consumption of

(S)-13 was observed by TLC after 3 h. The resulting solution was

concentrated under reduced pressure to give (S)-30 as a brown solid:

¹H NMR (400 MHz, CD₃OD) δ 2.68−2.75 (m, 2H), 3.86 (s, 3H),

4.16−4.19 (m, 1H), 5.27−5.33 (m, 2H), 5.77−5.81 (m, 1H). (R)-30

was made from (R)-13 by a method analogous to that used to prepare

(S)-30.

(S,S)-Methyl 2-[(N-Boc-alaninyl)aminopent-4-enoate [(S,S)-31].

A stirred solution of Boc-^L-Ala (34; 86 mg, 0.45 mmol, 1.5 equiv) in

DCM (5 mL) was treated with amine hydrochloride (S)-30 (50 mg,

0.30 mmol, 1 equiv), DIEA (78 mg, 0.6 mmol, 2 equiv), and HATU

(173 mg, 0.45 mmol, 1.5 equiv), stirred at room temperature for 16 h,

diluted with DCM (∼10 mL), and washed with saturated aqueous

NaHCO₃. The layers were separated. The aqueous layer was extracted

with DCM (∼10 mL). The combined organic layers were washed with

brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated

under reduced pressure to give (S,S)-31 as a brown oil, which was

analyzed without further puriﬁcation: ¹H NMR (400 MHz, CD₃CN) δ

1.27−1.28 (d, J = 7.2, 3H), 1.44 (s, 9H), 2.43−2.51 (m, 1H), 2.53−2.60

(m, 1H), 3.71 (s, 3H), 4.06−4.10 (m, 1H), 4.44−4.49 (m, 1H), 5.10−

5.19 (m, 2H), 5.63 (br s, 1H), 5.72−5.82 (m, 1H), 6.91 (br s, 1H).

(S,R)-31 was made using (R)-30 by a method analogous to that used to

prepare (S,S)-31: ¹H NMR (400 MHz, CD₃CN) δ 1.26−1.28 (d, J = 7.2,

3H), 1.44 (s, 9H), 2.42−2.50 (m, 1H), 2.53−2.60 (m, 1H), 3.70 (s, 3H),

4.05−4.09 (m, 1H), 4.44−4.49 (m, 1H), 5.10−5.18 (m, 2H), 5.62 (br s,

1H), 5.68−5.81 (m, 1H), 6.90 (br s, 1H).

(S)-Methyl 2-(N-Boc-amino)hept-6-enoate (15).

(S)-Methyl 2-Aminohept-6-enoate Hydrochloride [(S)-32].

Dry HCl gas was bubbled into a stirred solution of (S)-15 (100 mg,

0.38 mmol) in dry dichloromethane at room temperature. Consump-

tion of (S)-15 was observed by TLC after 3 h. The resulting solution was

concentrated under reduced pressure to give (S)-32 as a white solid:

¹H NMR (500 MHz, CDCl₃) δ 5.78−5.86 (m, 1H), 4.99−5.09 (m, 2H),

4.06−4.09 (t, 1H, J = 6.4 Hz), 3.85 (s, 3H), 2.11−2.16 (m, 2H), 1.86−

1.99 (m, 2H), 1.45−1.63 (m, 2H). (R)-32 was made from (R)-15 by a

method analogous to that used to prepare (S)-32.

A solution of 9-BBN in THF (0.5 M, 109 mL) was added to a 0 °C

solution of methyl pent-4-enoate 13 (5 g, 21.8 mmol) in anhydrous

THF (40 mL). The mixture was warmed to room temperature, stirred

for 3 h, and quenched with 1 M aqueous Na₂CO₃in H₂O (76.3 mL)

with agitation using argon bubbles for 20 min. To a second round-

bottomed ﬂask containing a stirred suspension of Pd₂(dba)₃(393 mg,

(S,S)-Methyl 2-[(N-Boc-alaninyl)amino]hept-6-enoate [(S,S)-

33]. A stirred solution of 34 (87 mg, 0.46 mmol, 1.5 equiv) in DCM

(5 mL) was treated with amine hydrochloride (S)-32 (60 mg, 0.31 mmol,

H

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1 equiv), DIEA (80 mg, 0.62 mmol, 2 equiv), and HATU (180 mg,

0.45 mmol, 1.5 equiv), stirred at room temperature for 16 h, diluted

with DCM (∼10 mL), and washed with saturated aqueous NaHCO₃.

The layers were separated. The aqueous layer was extracted with DCM

(∼10 mL). The combined organic layers were washed with brine, dried

over anhydrous sodium sulfate, ﬁltered, and concentrated under reduced

pressure to give (S,S)-33 as a brown oil, which was analyzed without

4.91−4.99 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.68−3.71 (d, 1H,

J = 13.2 Hz), 3.64 (s, 3H), 3.61−3.64 (d, 1H, J = 13.2 Hz), 3.22−3.25

(t, 1H, J = 6.65 Hz), 1.99−2.01 (m, 2H), 1.59−1.65 (m, 2H), 1.39−1.46

(m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 175.9, 160.1, 158.6, 138.3,

130.3, 120.5, 114.7, 103.7, 98.5, 60.7, 55.4, 55.3, 51.5, 47.1, 33.5, 33.0,

25.0; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₇H₂₅NO₄Na

330.1675, found 330.1691.

1

further puriﬁcation: H NMR (700 MHz, CD₃CN) δ 6.86 (br s, 1H),

(S)-2-(N-Boc-amino)pent-4-enoic Acid (18a).

5.77−5.83 (m, 1H), 5.57 (br s, 1H), 4.99−5.03 (m, 1H), 4.94−4.96 (m,

1H), 4.34−4.37 (m, 1H), 4.03−4.05 (m, 1H), 3.65 (s, 3H), 2.03−2.06

(m, 2H), 1.75−1.80 (m, 1H), 1.61−1.68 (m, 1H), 1.38−1.42 (m, 11H),

1.24−1.25 (d, J = 7.1 Hz, 3H). Amide (S,R)-33 was made using (R)-32

1

by a method analogous to that used to prepare (S,S)-33: H NMR

(700 MHz, CD₃CN) δ 6.86 (br s, 1H), 5.76−5.82 (m, 1H), 5.57 (br s,

1H), 5.01−5.02 (m, 1H), 4.99−5.00 (m, 1H), 4.33−4.36 (m, 1H), 4.01−

4.03 (m, 1H), 3.66 (s, 3H), 2.01−2.08 (m, 2H), 1.75−1.80 (m, 1H),

1.60−1.66 (m, 1H), 1.39−1.40 (m, 11H), 1.24−1.25 (d, J = 7.1 Hz, 3H).

(S)-2-Aminopent-4-enoic Acid Hydrochloride (29).

A solution of (S)-13 (1.2 g, 5.23 mmol) in 1:1 H₂O/dioxane (48 mL)

was treated with LiOH·H₂O (219 mg, 5.23 mmol), stirred for 3 h, and

evaporated to a residue that was partitioned between H₂O (20 mL)

and EtOAc (20 mL). The aqueous phase was acidiﬁed with 1 M HCl to

pH 4 and extracted twice with EtOAc (20 mL). The combined organic

extracts were washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated to aﬀord acid 18a (1.09 g, 5.06 mmol, 97%) as a colorless

oil: [α]²_D²+12.3 (c 1, CHCl₃); FT-IR (neat) ν_max2978, 1698, 1699, 1507,

1

1393, 1367, 1248, 1158, 1050, 869, 754 cm⁻¹; H NMR (500 MHz,

CD₃OD) δ 5.74−5.83 (m, 1H,), 5.07−5.15 (m, 2H), 4.13−4.16 (m,

1H), 2.52−2.53 (m, 1H), 2.38−2.42 (m, 1H), 1.44 (s, 9H); ¹³C NMR

(125 MHz, CD₃OD) δ 175.4, 157.9, 134.7, 118.5, 80.5, 54.6, 37.1, 28.7;

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₁₀H₁₇NO₄Na 238.1049,

found 238.1050.

A stirred solution of (S)-13 (4 g, 17.4 mmol) in 1,4-dioxane at 0 °C was

treated with 6 N HCl (80 mL), heated to 80 °C overnight, cooled, and

evaporated to a reside that was dissolved in water and washed with

dichloromethane. The aqueous layer was concentrated to oﬀ-white solid

29 (2.51 g, 16.61 mmol, 95%): mp 206−208 °C, [α]²_D⁰+7.6 (c 1,

CH₃OH); FT-IR (neat) ν_max2914, 1730, 1490, 1427, 1215, 1174, 1124,

993, 933, 873 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.76−5.87 (m, 1H),

5.26−5.34 (m, 2H), 4.06−4.09 (m, 1H), 2.63−2.79 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃) δ 171.1, 131.8, 121.4, 53.4, 35.7 ; HRMS (ESI-

TOF) m/z [M − H]⁻calcd for C₅H₉ClNO₂150.0327, found 150.0330.

(S)-Methyl 2-[(2,4-Dimethoxybenzyl)amino]hept-6-enoate

(16c).

(S)-2-(N-Boc-amino)hept-6-enoic Acid (18c).

Employing the procedure described for acid 8a, methyl hept-6-enoate

15 (500 mg, 1.94 mmol) was converted to acid 18c (445 mg, 1.83 mmol,

94%) as a colorless oil: [α]²_D⁰+11.5 (c 1, CHCl₃); FT-IR (neat) ν_max

1

2977, 2929, 1711, 1508, 1393, 1367, 1245, 1160, 910 cm⁻¹; H NMR

(500 MHz, CD₃OD) δ 5.76−5.84 (m, 1H,), 4.94−5.04 (m, 2H), 4.05−

4.08 (m, 1H), 2.03−2.12 (m, 2H), 1.77−1.84 (m, 1H), 1.59−1.67 (m,

1H), 1.51−1.46 (m, 2H), 1.44 (s, 9H); ¹³C NMR (125 MHz, CD₃OD) δ

176.3, 158.1, 139.4, 115.3, 80.4, 54.7, 34.3, 32.3, 28.7, 26.2; HRMS (ESI-

TOF) m/z [M − H]⁻calcd for C₁₂H₂₀NO₄242.1397, found 242.1409.

(S,S)-Methyl 2-[N-[2-(N-Fmoc-amino)but-3-enoyl]-N-(2,4-

dimethoxybenzyl)amino]hex-5-enoate (7a).

A stirred solution of (S)-15 (3 g, 11.7 mmol) in dichloromethane

(60 mL) was treated with HCl gas bubbles for 3 h. The volatiles were

removed by rotary evaporation to give (S)-32 (2.19 g, 11.34 mmol,

97%) as a white solid: mp 112−114 °C; [α]²_D⁴+24.6 (c 1, CHCl₃); FT-IR

1

(neat) ν_max2922, 2134, 1745, 1438, 1234, 912 cm⁻¹; H NMR (500

MHz, CD₃OD) δ 5.78−5.86 (m, 1H), 4.99−5.09 (m, 2H), 4.06−4.09 (t,

1H, J = 6.4 Hz), 3.85 (s, 3H), 2.11−2.16 (m, 2H), 1.86−1.99 (m, 2H),

1.45−1.63 (m, 2H); ¹³C NMR (125 MHz, CD₃OD) δ 170.9, 138.6,

116.0, 53.9, 53.6, 34.0, 30.9, 25.1; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₈H₁₆NO₂158.1175, found 158.1179.

Amino ester hydrochloride 32 (2 g, 10.35 mmol) was partitioned

between a saturated NaHCO₃solution (50 mL) and CH₂Cl₂(50 mL).

The aqueous phase was extracted with CH₂Cl₂(2 × 50 mL), and

the combined organic layers were washed with 30 mL of brine, dried

over Na₂SO₄, ﬁltered, and concentrated to a volume of ∼30 mL.

The solution of free base was treated with 2,4-dimethoxybenzaldehyde

(2.23 g, 13.45 mmol) and NaBH(OAc)₃(3.28 g, 15.5 mmol), stirred for

18 h at room temperature, treated with 40 mL of saturated NaHCO₃,

and stirred for 30 min. The aqueous layer was separated and washed with

20 mL of CH₂Cl₂. The combined organic layers were washed with brine,

dried over MgSO₄, ﬁltered, and concentrated to a residue that was

puriﬁed by chromatography on silica gel (20−25% EtOAc in hexane) to

give N-Dmb-amino ester 16c (2.09 g, 6.80 mmol, 65%) as a colorless oil:

R_f= 0.35 (7:3 hexanes/ethyl acetate, visualized by UV), [α]²_D⁰−3.1 (c 1,

CHCl₃); FT-IR (neat) ν_max2943, 1732, 1612, 1587, 1505, 1457, 1437,

1287, 1260, 1206, 1154, 1035, 913 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ

7.11−7.12 (d, 1H, J = 8.25 Hz), 6.40−6.42 (m, 2H), 5.71−5.78 (m, 1H),

(S)-N-Fmoc-vinylglycine (19; 2.47 g, 7.64 mmol) was treated with

thionyl chloride (1.1 mL, 15.32 mmol) in DCM at 0 °C. The resulting

solution was then heated to reﬂux for 3 h and cooled, and the volatiles

were evaporated. The residue was dissolved and evaporated three

times from DCM. Without further puriﬁcation, acid chloride 35 was

dissolved in DCM (20 mL), cooled to 0 °C, and treated with N-Dmb-

homoallylglycine (16b; 1.5 g, 5.12 mmol). The resulting mixture was

stirred at room temperature for 3 h. The volatiles were evaporated, and

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the residue was taken up in a minimum volume of DCM, applied onto a

silica gel column, and eluted with 30−40% EtOAc/hexanes to give 7a

(1.42 g, 2.37 mmol, 46%) as a colorless oil that solidiﬁed on standing: R_f=

0.52 (4:6 EtOAc/hexanes, visualized by UV); [α]²_D⁴−40.1 (c 1, CHCl₃);

FT-IR (neat) ν_max2947, 1719, 1647, 1612, 1588, 1506, 1207, 1156, 1032,

759, 738 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 100 °C) δ 7.84−7.85 (d,

2H, J = 7.5 Hz), 7.67−7.70 (t, 2H, J = 6.7 Hz), 7.38−7.42 (m, 2H), 7.29−

7.32 (m, 2H), 7.18 (br s, 1H), 7.04 (br s, 1H), 6.55 (d, 1H, J = 2.0 Hz),

6.46−6.48 (dd, 1H, J = 2.2 Hz), 5.87−5.95 (m, 1H), 5.63−5.71 (m, 1H),

5.23−5.29 (m, 2H), 5.18−5.20 (br t, 1H), 4.92−4.93 (m, 1H), 4.90−4.91

(m, 1H), 4.55−4.58 (d, 1H, J = 16.4 Hz), 4.39−4.43 (m, 1H), 4.28−4.35

(m, 2H), 4.20−4.23 (m, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.50 (s, 3H),

1.91−2.04 (m, 3H), 1.65−1.71 (m, 1H); ¹³C NMR (125 MHz, DMSO-d₆,

100 °C) δ 170.1, 169.8, 160.1, 157.9, 154.6, 143.4, 143.3, 140.2, 137.1,

133.5, 129.5, 127.2, 126.4, 124.6, 124.5, 119.3, 117.0, 114.5, 104.5, 98.2,

78.6, 65.6, 57,.5 54.9, 54.8, 53.7, 50.9, 46.4, 29.4, 27.6; HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₃₅H₃₈N₂O₇Na 621.2571, found 621.2562.

(S,S)-Methyl 2-[N-[2-(N-Fmoc-amino)but-3-enoyl]-N-(2,4-

dimethoxybenzyl)amino]hept-6-enoate (7b).

N-Fmoc-vinylglycine (19; 274 mg, 0.85 mmol) and methyl 2-(N-Dmb-

amino)hex-5-enoate (16b; 170 mg, 0.57 mmol) were dissolved in DCM

(10 mL), treated with DIEA (147 mg, 1.14 mmol) and HATU (323.1

mg, 0.85 mmol), stirred for 24 h, and diluted with water. The aqueous

layer was extracted with DCM (3 × 50 mL). The combined organic

layers were washed with brine (50 mL), dried over anhydrous sodium

sulfate, ﬁltered, and concentrated under reduced pressure. The residue

was puriﬁed by column chromatography on silica gel (30−40% EtOAc

in hexane) to give dipeptide 20 (302 mg, 0.50 mmol, 87%) as a colorless

gummy oil: R_f= 0.27 (4.5:5.5 EtOAc/hexanes, visualized by UV); [α]_D²⁰

−63.2 (c 1, CHCl₃); FT-IR (neat) ν_max2945, 1716, 1611, 1506, 1448,

1206, 1108, 1032, 757, 738 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 100

°C) δ 8.68 (br, s, 1H), 7.85−7.86 (d, 2H, J = 7.6 Hz), 7.71−7.72 (m,

2H), 7.40−7.43 (t, 2H, J = 7.4 Hz), 7.31−7.34 (m, 2H), 7.25−7.27 (d,

1H, J = 8.5 Hz), 6.52−6.53 (d, 1H, J = 2.4 Hz), 6.44−6.46 (dd, 1H, J =

2.4 Hz), 5.60−5.68 (m, 1H), 5.45−5.49 (m, 1H), 4.84−4.89 (m, 2H),

4.56−4.59 (d, 1H, J = 16 Hz), 4.47−4.50 (d, 1H, J = 15.9 Hz), 4.355−

4.356 (d, 1H, J = 0.8 Hz), 4.34 (s, 1H), 4.23−4.26 (t, 1H, J = 13.9 Hz),

4.16 (br s, 1H), 3.77 (s, 3H), 3.7 (s, 3H), 3.51 (s, 3H), 1.88−2.07

(m, 3H), 1.71−1.81 (m, 1H), 1.64−1.66 (d, 3H, J = 7 Hz); ¹³C NMR

(125 MHz, DMSO-d₆, 100 °C) δ 170.5, 168.1, 159.6, 157.5, 153.3,

143.3, 143.3, 140.3, 137.3, 130.6, 129.3, 127.0, 126.4, 124.6, 119.4, 118.4,

117.2, 114.2, 104.6, 98.0, 78.6, 65.7, 58.2, 54.9, 54.8, 50.8, 46.4, 29.6,

27.9, 11.2; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₃₅H₃₈N₂NaO₇

621.2571, found 621.2573.

(S,S)-Methyl 2-[N-[2-(N-Boc-amino)pent-4-enoyl]-N-(2,4-

dimethoxybenzyl)amino]hept-6-enoate (6d).

As described for the synthesis of dipeptide 7a, (S)-2-(N-Fmoc-amino)but-

3-enoic acid (19; 785 mg, 2.43 mmol) was coupled with 16c (500 mg, 1.62

mmol). The residue was puriﬁed by chromatography on silica gel (30−40%

EtOAc in hexane) to give dipeptide 7b (540 mg, 0.88 mmol, 54%) as a

colorless oil: R_f= 0.55 (4:6 EtOAc/hexanes, visualized by UV); [α]²_D⁰−30.6

(c 1, CHCl₃); FT-IR (neat) ν_max2947, 1719, 1647, 1612, 1588, 1506, 1207,

1156, 1032, 916, 758, 738 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 100 °C)

δ 7.84−7.85 (d, 2H, J = 7.5 Hz), 7.67−7.70 (t, 2H, J = 6.6 Hz), 7.38−7.42

(m, 2H), 7.29−7.32 (m, 2H), 7.18−7.19 (m, 1H), 7.03 (br s, 1H) 6.55−

6.56 (m, 1H), 6.45−6.47 (m, 1H), 5.84−5.96 (m, 1H), 5.62−5.71 (m,

1H), 5.24−5.29 (m, 2H), 5.17−5.20 (m, 1H), 4.88−4.94 (m, 2H), 4.53−

4.57 (d, 1H, J = 16.4), 4.41−4.44 (m, 1H), 4.20−4.35 (m, 4H), 3.75 (s,

3H), 3.78 (s, 3H), 3.51 (s, 3H), 1.81−1.97 (m, 3H), 1.55−1.67 (m, 1H),

1.17−1.37 (m, 2H); ¹³C NMR (125 MHz, DMSO-d₆, 100 °C) δ 170.2,

160.1, 157.7, 154.6, 143.4, 143.3, 140.3, 137.6, 133.6, 129.4, 127.0, 126.4,

124.6, 124.5, 119.3, 117.0, 114.0, 104.5, 98.2, 78.6, 65.6, 57.9, 54.9, 54.8,

53.7, 50.9, 46.4, 45.3, 32.1, 27.7, 24.7; HRMS (ESI-TOF) m/z [M + Na]⁺

calcd for C₃₆H₄₀N₂O₇Na 635.2727, found 635.2738.

N-Boc-allylglycine (18a; 522 mg, 2.43 mmol) and N-Dmb-amino ester

16c (500 mg, 1.62 mmol) were dissolved in DCM (10 mL), treated

with N-ethylmorpholine (373 mg, 3.24 mmol) and HATU (923 mg,

2.43 mmol), stirred for 24 h, and diluted with water. The aqueous layer

was extracted with DCM (3 × 50 mL). The combined organic layers

were washed with brine (50 mL), dried over anhydrous sodium sulfate,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by chromatography on silica gel (30−35% EtOAc in hexane) to

give dipeptide 6d (610 mg, 1.21 mmol, 74%) as a colorless gummy oil:

R_f= 0.67 (4:6 EtOAc/hexanes, visualized by UV); [α]²_D⁰−33.1 (c 1,

CHCl₃); FT-IR (neat) ν_max2975, 2932, 1739, 1708, 1639, 1613, 1507,

1437, 1208, 1158, 1033, 753 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆, 100 °C)

δ 7.16 (br s, 1H), 6.56 (s, 1H), 6.47−6.49 (d, 1H, J = 7.7 Hz), 6.20 (brs,

1H), 5.63−5.77 (m, 2H), 5.01−5.09 (m, 2H), 4.88−4.95 (m, 2H),

4.61−4.62 (m, 2H), 4.43−4.48 (m, 1H), 4.23 (br s, 1H), 3.80 (s, 3H),

3.77 (s, 3H), 3.51 (s, 3H), 2.30−2.39 (m, 2H), 1.86−1.95 (m, 3H),

1.58−1.70 (m, 1H), 1.39 (s, 9H), 1.20−1.26 (m, 2H); ¹³C NMR

(125 MHz, DMSO-d₆, 100 °C) δ 171.6, 170.3, 160.1, 157.9, 154.2,

137.6, 133.5, 129.6, 116.8, 116.6, 114.0, 104.5, 98.2, 78.6, 77.9, 58.5,

54.9, 54.8, 50.8, 50.1, 36.1, 32.2, 28.1, 27.6, 24.6; HRMS (ESI-TOF) m/z

[M + Na]⁺calcd for C₂₇H₄₀N₂NaO₇527.2727, found 527.2732.

(Z,S)-Methyl 2-[N-[2-(N-Fmoc-amino)but-2-enoyl]-N-(2,4-

dimethoxybenzyl)amino]hex-5-enoate (20).

J

DOI: 10.1021/acs.joc.5b00237

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(S,S)-Methyl 2-[N-[2-(N-Fmoc-amino)pent-4-enoyl]-N-(2,4-

dimethoxybenzyl)amino]hept-6-enoate (7d).

1.95−2.04 (m, 2H) 1.59−1.65 (m, 1H), 1.49−1.57 (m, 1H), 1.44−1.35

(m, 11H); ¹³C NMR (125 MHz, DMSO-d₆, 100 °C) δ 172.1, 169.8,

160.1,154.3, 137.8, 134.5, 129.3, 116.3, 114.0, 104.4, 98.2, 78.6, 77.8,

57.8, 54.9, 54.8, 50.9, 50.3, 32.8, 32.7, 32.1, 31.5, 27.6, 23.8, 23.7. HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₂₇H₄₁N₂O₇505.2908, found

505.2920.

(S)-Methyl 3-(N-Fmoc-amino)-1-(2,4-dimethoxybenzyl)-2-

oxo-5,6,7-tetrahydro-1H-azepine-7-carboxylate (21).

Dipeptide 20 (150 mg, 0.25 mmol) was dissolved in DCM (300 mL),

treated with the Grubbs second-generation catalyst (42 mg, 0.050 mmol),

heated, and stirred at reﬂux for 2 days. The volatiles were removed under

reduced pressure, and the residue was taken up in a minimum volume of

DCM, applied onto a silica gel column, and eluted with 35−40% EtOAc

in hexanes. Evaporation of the collected fractions gave macrocycle 21

(95 mg, 68%) as a white foam: R_f= 0.55 (4:6 EtOAc/hexanes); [α]_D²⁰

+31.8 (c 0.5, CHCl₃); FT-IR (neat) ν_max2947, 1718, 1654, 1612, 1505,

1206, 1154, 1123, 1032, 758, 738 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ

7.75−7.77 (m, 2H); 7.59−7.63 (m, 2H), 7.37−7.43 (m, 2H), 7.27−7.34

(m, 3H), 7.05 (br s, 1H), 6.66 (br s, 1H), 6.45−6.49 (m, 2H), 5.16−5.20

(d, 1H, J = 14), 4.39−4.41 (m, 2H), 4.18−4.24 (m, 3H) 3.81 (s, 3H), 3.80

(s, 3H), 3.58 (s, 3H), 2.55−2.60 (m, 1H), 2.13−2.18 (m, 2H), 1.84−1.91

(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 171.8, 167.9, 161.0, 158.8, 153.6,

143.9, 143.9, 141.4, 141.4, 132.2, 131.5, 127.8, 127.8, 127.2, 125.2, 120.1,

120.0, 117.2, 116.2, 104.3, 98.5, 66.8, 59.5, 55.5, 55.3, 52.7, 47.2, 47.1,

32.8, 21.7; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₃₂H₃₂N₂NaO₇

579.2107, found 579.2101.

Employing the protocol described for the synthesis of dipeptide 6d,

(S)-2-(N-Fmoc-amino)pent-4-enoic acid (17a; 1.147 g, 3.40 mmol)

was coupled with 16c (700 mg, 2.27 mmol). The residue was puriﬁed

by chromatography on silica gel (30−40% EtOAc in hexane) to give

dipeptide 7d (1.080 g, 1.72 mmol, 76%) as a colorless gummy oil: R_f=

0.57 (4:7 EtOAc/hexanes, visualized by UV); [α]²_D⁰−39.7 (c 1, CHCl₃);

FT-IR (neat) ν_max2923, 1718, 1638, 1612, 1588, 1506, 1437, 1207,

1

1156, 758, 739538 cm⁻¹; H NMR (500 MHz, DMSO-d₆, 100 °C) δ

7.82−7.85 (d, 2H, J = 7.5 Hz), 7.67−7.68 (m, 2H), 7.38−7.42 (m, 2H),

7.29−7.32 (t, 2H, J = 7.4 Hz), 7.15 (br s, 1H), 6.96 (br s, 1H), 6.54−6.55

(m, 1H), 6.44−6.46 (m, 1H), 5.62−5.75 (m, 2H), 5.02−5.10 (m, 2H),

4.87−4.93 (m, 2H), 4.67 (br s, 2H), 4.41 (br s, 1H), 4.28−4.34 (m, 2H),

4.19−4.22 (t, 2H, J = 13.9), 3.77 (s, 3H), 3.74 (s, 3H), 3.49 (s, 3H),

2.36−2.41 (m, 2H), 1.81−1.93 (m, 3H), 1.56−1.67 (m, 1H), 1.16−1.27

(m, 2H); ¹³C NMR (125 MHz, DMSO-d₆, 100 °C) δ 171.5, 170.3,

160.1, 158.0, 154.9, 143.4, 140.2, 137.7, 133.4, 129.5, 127.0, 126.4, 124.6,

119.4, 116.9, 114.0, 104.5, 98.2, 78.6, 66.2, 65.4, 57.8, 54.9, 54.8,

50.8, 50.5, 46.4, 45.1, 36.0, 32.1, 27.8, 24.6. HRMS (ESI-TOF) m/z

[M + Na]⁺calcd for C₃₇H₄₂N₂O₇Na 649.2884, found 649.2873.

(S,S)-Methyl 2-[N-[2-(N-Boc-amino)hept-6-enoyl]-N-(2,4-

dimethoxybenzyl)amino]pent-4-enoate (6g).

(3S,8S,Z)-Methyl 3-(N-Fmoc-amino)-1-(2,4-dimethoxybenzyl)-

2-oxo-1,2,3,6,7,8-hexahydroazocine-8-carboxylate (10a).

Dipeptide 7a (1 g, 1.67 mmol) was dissolved in DCM (2 L), treated with

the Grubbs ﬁrst-generation catalyst (412 mg, 0.50 mmol), heated, and

stirred at reﬂux for 2 days. After 2 days, TLC showed remaining 7a,

and more catalyst (274 mg, 0.33 mmol) was added to the reaction

mixture, which was heated at reﬂux and stirred for 2 days. The volatiles

were removed under reduced pressure. The residue was taken up in a

minimum volume of DCM, applied onto a silica gel column, and eluted

with 35−40% EtOAc in hexanes. Evaporation of the collected fractions

aﬀorded macrocycle 10a (605 mg, 1.06 mmol, 63%) as a colorless

gummy oil: R_f= 0.45 (4:6 EtOAc/hexanes); [α]²_D⁴+8.7 (c 1, CHCl₃);

FT-IR (neat) ν_max2947, 1718, 1654, 1612, 1505, 1447, 1206, 1154,

1123, 738 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.75−7.77 (d, 2H, J =

7.5 Hz), 7.61−7.63 (d, 2H, J = 7.4 Hz), 7.37−7.42 (t, 2H, J = 7.5 Hz),

7.28−7.33 (m, 2H), 7.16−7.19 (d, 1H, J = 8.3 Hz), 6.40−6.45 (m, 2H),

6.17−6.19 (d, 1H, J = 7 Hz), 5.67−5.79 (m, 2H), 5.28−5.31 (d, 1H, J = 7

Hz), 4.71−4.81 (m, 2H), 4.33−4.43 (m, 2H), 4.12−4.26 (m, 2H), 3.79

(s, 3H), 3.77 (s, 3H), 3.45 (s, 3H), 1.97−2.44 (m, 2H), 1.82−1.91 (m,

2H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 169.9, 160.0, 157.7, 155.9,

144.1, 143.9, 141.4, 131.3, 129.2, 128.1, 127.8, 127.2, 125.7, 120.0, 116.8,

104.1, 98.2, 67.3, 57.6, 55.5, 55.4, 53.7, 52.2, 47.2, 41.0, 28.3, 21.4.

HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₃₃H₃₄N₂O₇Na 593.2258,

found 593.2255.

Employing the protocol described for the synthesis of dipeptide 6d, 18c

(521 mg, 2.14 mmol) was coupled with 16b (400 mg, 1.43 mmol). The

residue was puriﬁed by chromatography on silica gel (30−40% EtOAc in

hexane) to give dipeptide 6g (561 mg, 1.11 mmol, 78%) as a colorless

gummy oil: R_f= 0.72 (4:6 EtOAc/hexanes, visualized by UV); [α]_D²²

−52.5 (c 1, CHCl₃); FT-IR (neat) ν_max2975, 2932, 1739, 1708, 1639,

1

1613, 1507, 1437, 1208, 1158, 1033, 753 cm⁻¹; H NMR (500 MHz,

DMSO-d₆, 100 °C) δ 7.19 (br s, 1H), 6.56 (s, 1H), 6.47−6.49 (m, 1H),

6.16 (br s, 1H), 5.73−5.81 (m, 1H), 5.60−5.70 (m, 1H), 4.91−5.02 (m,

4H), 4.42−4.55 (m, 3H), 4.19−4.21 (m, 1H), 3.80 (s, 3H), 3.77

(s, 3H), 3.50 (s, 3H), 2.60−2.68 (m, 1H), 2.40−2.46 (m, 1H),

K

DOI: 10.1021/acs.joc.5b00237

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(3S,9S,Z)-Methyl 3-(N-Fmoc-amino)-1-(2,4-dimethoxyben-

zyl)-2-oxo-1,2,3,6,7,8,9-heptahydro-1H-azonine-9-carboxylate

(10b).

(3S,10S,Z)-Methyl 3-(N-Fmoc-amino)-1-(2,4-dimethoxyben-

zyl)-2-oxo-1,2,3,4,7,8,9,10-octahydroazecine-10-carboxylate

(10d).

Dipeptide 7b (200 mg, 0.32 mmol) was dissolved in DCM (400 mL),

treated with the Grubbs ﬁrst-generation catalyst (79 mg, 0.096 mmol),

heated, and stirred at reﬂux for 2 days, when TLC indicated remaining

7b, and another portion of catalyst (53 mg, 0.065 mmol) was added to

the mixture, which was heated at reﬂux and stirred for 1 day. The

volatiles were removed under reduced pressure. The residue was taken

up in a minimum volume of DCM, applied onto a silica gel column, and

eluted with 35−40% EtOAc in hexanes. Evaporation of the collected

fractions aﬀorded macrocycle 10b (131 mg, 0.22 mmol, 69%) as a

colorless gummy oil: R_f= 0.37 (4:6 EtOAc/hexanes); [α]²_D⁰+7.1 (c 0.22,

CHCl₃); FT-IR (neat) ν_max2946, 1718, 1637, 1612, 1587, 1505, 1447,

1288, 1206, 1034, 739 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.75−7.77

(d, 2H, J = 7.4 Hz), 7.60−7.63 (m, 2H), 7.38−7.42 (t, 2H, J = 7.4 Hz),

7.30−7.33 (t, 2H, J = 7.4), 7.08−7.10 (d, 1H, J = 8.3 Hz), 6.35−6.42 (m,

3H), 5.69−5.73 (t, 1H, J = 7.8 Hz), 5.56−5.63 (m, 1H), 5.34−5.39 (t,

1H, J = 10 Hz), 4.87−4.91 (d, 1H, J = 15.1 Hz), 4.69−4.71 (d, 1H, J = 7.6

Hz), 4.36−4.38 (m, 2H), 4.22−4.31 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H),

3.59 (s, 3H), 2.62−2.73 (m, 1H), 2.23−2.2 6 (m, 1H), 2.06−2.11 (m,

Dipeptide 7d (1 g, 1.60 mmol) was dissolved in DCM (2000 mL),

treated with the Grubbs ﬁrst-generation catalyst (263.34 mg, 0.32 mmol),

heated, and stirred at reﬂux for 2 days. The volatiles were removed under

reduced pressure, and the residue was taken up in a minimum volume of

DCM, applied onto a silica gel column, and eluted with 35−40% EtOAc

in hexanes to aﬀord macrocycle 10d (872 mg, 1.45 mmol, 91%) as a

white solid: R_f= 0.40 (4:6 EtOAc/hexanes); mp 89−92 °C; [α]²_D⁰−5.8

(c 1, CHCl₃); FT-IR (neat) ν_max3005, 1717, 1640, 1611, 1588, 1505,

1207, 1156, 1034, 758, 739, 542 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.76−7.78 (d, 2H, J = 7.5 Hz), 7.62−7.65 (m, 2H), 7.38−7.42 (t, 2H, J =

7.4), 7.30−7.33 (m, 2H), 7.06−7.08 (d, 1H, J = 8.2 Hz), 6.38−6.43 (m,

2H), 6.17−6.19 (d, 1H, J = 6.5 Hz), 5.49−5.60 (m, 2H), 5.26−5.28 (m,

1H), 4.97−5.01 (d, 1H, J = 14.4), 4.34−4.47 (m, 2H), 4.22−4.26 (m,

1H), 3.99−4.02 (m, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.39−3.44 (m, 1H),

3.33 (s, 3H), 2.80−2.90 (m, 1H), 2.40−2.52 (m, 2H), 2.27−2.36

(m, 1H), 1.84−2.09 (m, 3H), 1.67−1.74 (m, 1H); ¹³C NMR

(100 MHz, CDCl₃) δ 171.1, 170.5, 161.5, 159.9, 155.5, 144.1, 144.0,

141.4, 131.5, 127.8, 127.2, 127.1, 125.4, 125.3, 123.8, 120.1, 116.0, 103.5,

98.4, 66.8, 62.3, 55.5, 55.4, 55.4, 55.3, 52.0, 51.7, 47.4, 47.3, 26.0; HRMS

(ESI-TOF) m/z [M + Na]⁺calcd for C₃₅H₃₈N₂O₇Na 621.2571, found

621.2588.

1H), 1.63−1.69 (m, 1H), 1.47−1.57 (m, 1H), 1.31−1.39 (m, 1H); ¹³

C

NMR (100 MHz, CDCl₃) δ 170.3, 170.0, 160.5, 158.3, 155.8, 144.0,

144.0, 141.4, 130.8, 130.7, 129.1, 127.7, 127.1, 125.3, 125.3, 120.1, 120.0,

117.5, 104.1, 98.1, 67.1, 55.4, 55.3, 55.2, 52.4, 50.4, 47.2, 41.6, 28.3, 24.5,

23.7; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₃₄H₃₆N₂O₇Na

607.2414, found 607.2425.

(3S,10S,Z)-Methyl 3-(N-Boc-amino)-1-(2,4-dimethoxyben-

zyl)-2-oxo-1,2,3,4,7,8,9,10-octahydroazecine-10-carboxylate

(9d).

(3S,10S,Z)-Methyl 3-(N-Boc-amino)-1-(2,4-dimethoxyben-

zyl)-2-oxo-1,2,3,4,5,6,9,10-octahydroazecine-10-carboxylate

(9g).

Dipeptide 6g (550 mg, 1.09 mmol) was dissolved in DCM (1000 mL),

treated with the Grubbs ﬁrst-generation catalyst (173 mg, 0.21 mmol),

heated, and stirred at reﬂux for 2 days. The volatiles were removed under

reduced pressure, and the residue was taken up in a minimum volume of

DCM, applied onto a silica gel column, and eluted with 30−35% EtOAc

in hexanes to aﬀord macrocycle 9g (460 mg, 0.96 mmol, 79%) as a white

solid: R_f= 0.62 (4:6 EtOAc/hexanes); mp 79−82 °C; [α]²_D²−40.5 (c 1,

CHCl₃); FT-IR (neat) ν_max2943, 1735, 1706, 1637, 1612, 1589, 1506,

Dipeptide 6d (600 mg, 1.18 mmol) was dissolved in DCM (1300 mL),

treated with the Grubbs ﬁrst-generation catalyst (189 mg, 0.23 mmol),

heated, and stirred at reﬂux for 2 days. The volatiles were removed under

reduced pressure, and the residue was taken up in a minimum volume of

DCM, applied onto a silica gel column, and eluted with 30−35% EtOAc

in hexanes to aﬀord macrocycle 9d (490 mg, 1.02 mmol, 86%) as a white

solid: R_f= 0.55 (4:6 EtOAc/hexanes); mp 81−83 °C; [α]²_D⁰+15.1 (c 1,

CHCl₃); FT-IR (neat) ν_max2944, 1706, 1644, 1612, 1490, 1433, 1363,

1

1209, 1157, 1130, 1030, 833 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

1

1438, 1363, 1208, 1156, 1034, 750, 533 cm⁻¹; H NMR (400 MHz,

7.04−7.06 (d, 1H, J = 8.2 Hz), 6.42−6.43 (d, 1H, J = 2.2 Hz), 6.34−6.39

(m, 1H), 5.85−5.86 (d, 1H, J = 7.1 Hz), 5.53−5.58 (m, 1H), 5.44−5.46

(m, 1H), 5.23 (br s, 1H), 4.97−4.99 (d, 1H, J = 14.2), 3.93−3.98

(m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.37−3.39 (d, 1H, J = 10.5 Hz),

3.30 (s, 3H), 2.79−2.81 (m, 1H), 2.44−2.45 (m, 1H), 2.25−2.37 (m,

2H), 2.02−2.05 (m, 1H), 1.93−1.96 (m, 1H), 1.65−1.66 (m, 1H),

1.46−1.41(m, 10H); ¹³C NMR (125 MHz, CDCl₃) δ 170.2, 169.9,

160.5, 159.0, 154.2, 132.1, 130.5, 123.1, 115.2, 102.3, 97.4, 78.3,

76.3, 61.2, 54.5, 54.1, 50.7, 50.4, 49.8, 28.5, 27.5, 25.0, 22.3; HRMS

(ESI-TOF) m/z [M + Na]⁺calcd for C₂₅H₃₆N₂O₇Na 499.2414, found

499.2409.

CDCl₃) δ 7.03−7.05 (d, 1H, J = 8.16 Hz), 6.37−6.42 (m, 2H), 5.87−

5.88 (d, 1H, J = 6.76 Hz), 5.48−5.60 (m, 2H), 5.02−5.05 (t, 1H, J = 6.36

Hz), 4.81−4.85 (d, 1H, J = 14.2 Hz), 3.78 (s, 3H), 3.75 (s, 3H), 3.44−

3.49 (m, 1H), 3.42 (m, 3H), 3.26−3.35 (m, 1H), 2.46−2.55 (m, 1H),

2.25−2.31 (m, 1H), 1.98−2.04 (m, 1H), 1.84−1.93 (m, 2H), 1.74−1.78

(m, 1H), 1.39−1.53 (m, 11H); ¹³C NMR (100 MHz, CDCl₃) δ 172.5,

170.8, 161.3, 159.9, 155.2, 135.3, 131.4, 125.0, 115.9, 103.4, 98.5,

79.2, 57.9, 55.4, 55.2, 51.8, 50.7, 50.1, 28.5, 27.7, 25.0, 24.1, 21.5; HRMS

(ESI-TOF) m/z [M + Na]⁺calcd for C₂₅H₃₆N₂O₇Na 499.2414, found

499.2409.

L

DOI: 10.1021/acs.joc.5b00237

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(3S,10S,Z)-Methyl 3-(N-Fmoc-amino)-1-(2,4-dimethoxyben-

zyl)-2-oxo-1,2,3,4,5,6,,9,10-octahydroazecine-10-carboxylate

(10g).

(3S,9S,Z)-Methyl 3-(N-Fmoc-amino)-2-oxo-1,2,3,6,7,8,9-hep-

tahydro-1H-azonine-9-carboxylate (11b).

Lactam 10b (53 mg, 0.09 mmol) was treated as described for the

synthesis of 11a above with TFA (1 mL) in DCM overnight.

Chromatography (30−40% EtOAc in hexane) gave 11b (34 mg,

0.08 mmol, 87%) as a white solid: R_f= 0.2 (1:1 EtOAc/hexanes,

visualized by UV); mp 202−204 °C; [α]²_D⁰+21.1 (c 1, CHCl₃); FT-IR

(neat) ν_max3325, 2922, 1736, 1660, 1521, 1434, 1318, 1240, 1204, 1032,

985, 882, 758 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.75−7.76 (d, 2H,

J = 7.5 Hz), 7.58−7.60 (m, 2H), 7.37−7.41 (t, 2H, J = 7.4 Hz), 7.29−

7.32 (t, 2H, J = 7.4 Hz), 6.37−6.39 (d, 1H, J = 9.0 Hz), 6.13−6.14 (d,

1H, J = 5.9 Hz), 5.68−5.75 (m, 1H), 5.39−5.43 (m, 2H), 4.31−4.39 (m,

3H), 4.20−4.23 (t, 1H, J = 7.2 Hz), 3.80 (s, 3H), 2.80−2.91 (m, 1H),

2.29−2.40 (m, 1H), 1.93−2.01 (m, 2H), 1.76−1.82 (m, 1H), 162−1.71

(m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 169.8, 155.6, 144.0,

143.9, 141.4, 131.5, 128.1, 127.8, 127.2, 125.2, 120.0, 67.2, 53.1, 50.2,

50.2, 47.2, 34.1, 29.8, 25.6, 23.4; HRMS (ESI-TOF) m/z [M + Na]⁺

calcd for C₂₅H₂₆N₂O₅Na 457.1733, found 457.1745.

A stirred solution of Boc-protected dipeptide lactam 9g (200 mg,

0.42 mmol) in 10 mL of DCM was treated with TFA (4 mL) at 0 °C and

stirred for 2 h, and the volatiles were removed under reduced pressure

to provide the triﬂuoroacetate salt, which was dissolved in 15 mL of a

1:1 water/acetone solution and treated with Fmoc-OSu (138 mg,

0.42 mmol) and Na₂CO₃(90 mg, 0.84 mmol). After being stirred for

18 h at room temperature, the mixture was diluted with water and

acidiﬁed to pH 3−4 with 10% KHSO₄solution. This aqueous solution

was extracted with ethyl acetate (3 × 20 mL). The combined organic

layers were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated to a residue that was puriﬁed by chromatography on silica

gel using 25−30% EtOAc in hexane as the eluent. Evaporation of the

collected fractions gave Fmoc-protected dipeptide lactam 10g (151 mg,

0.25 mmol, 60%) as a colorless oil: R_f= 0.50 (4:6 EtOAc/hexanes,

visualized by UV); [α]_D²⁰−45.2 (c 0.5, CHCl₃); FT-IR (neat) ν_max2944,

1715, 1636, 1612, 1588, 1506, 1440, 1207, 1156, 1130, 1035, 758, 739,

535 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.76−7.78 (d, 2H, J = 7.5 Hz),

7.63−7.66 (t, 2H, J = 6.0 Hz), 7.39−7.42 (t, 2H, J = 7.4 Hz), 7.30−7.34

(m, 2H), 7.05−7.07 (d, 1H, J = 8.1 Hz), 6.39−6.43 (m, 2H), 6.21−6.23

(d, 1H, J = 6.7), 5.52−5.64 (m, 2H), 5.08−5.12 (m, 1H), 4.83−4.87 (d,

1H, J = 14.3 Hz), 4.41−4.46 (m, 1H), 4.33−4.39 (m, 1H), 4.22−4.26 (t,

1H, J = 7.2 Hz), 3.79 (s, 3H), 3.75 (s, 3H), 3.48−3.54 (m, 1H), 3.45 (s,

3H), 3.30−3.40 (m, 1H), 2.50−2.62 (m, 1H), 2.30−2.35 (m, 1H),

2.05−211 (m, 1H), 1.80−1.98 (m, 3H), 1.75−1.49 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃) δ 172.1, 170.7, 161.4, 159.8, 155.5, 144.1, 144.1,

141.5, 135.3, 131.4, 127.8, 127.1, 125.4, 125.3, 125.1, 120.1, 120.0, 115.7,

103.5, 98.5, 66.9, 58.0, 55.4, 55.4, 51.9, 50.7, 50.6, 47.4, 27.5, 25.0, 24.2,

21.5; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₃₅H₃₈N₂O₇Na

621.2571, found 621.2576

(3S,10S,Z)-Methyl 3-(N-Fmoc-amino)-2-oxo-1,2,3,4,7,8,9,10-

octahydroazecine-10-carboxylate (11d).

Lactam 10d (100 mg, 0.17 mmol) was treated with TFA (2 mL) in

DCM (5 mL) for 3 days. The volatiles were removed under vacuum, and

the residue was puriﬁed by chromatography on silica gel (40−50%

EtOAc in hexane) to give lactam 11d (52 mg, 0.11 mmol, 69%)

as a white solid: R_f= 0.2 (1:1 EtOAc/hexanes, visualized by UV);

[α]²_D⁰+48.1 (c 0.16, CHCl₃); FT-IR (neat) ν_max3327, 2920, 1723, 1649,

1505, 1437, 1349, 1221, 1022, 756 cm⁻¹; ¹H NMR (500 MHz, 100 °C

DMSO-d₆) δ 7.86−7.87 (d, 2H, J = 7.5 Hz), 7.81−7.82 (m, 1H), 7.86−

7.89 (d, 2H, J = 7.5 Hz), 7.40−7.43 (t, 2H, J = 7.4), 7.32−7.35 (m, 2H),

6.86 (br s, 1H), 5.35−5.46 (m, 2H), 4.34−4.40 (m, 2H), 4.23−4.26 (m,

1H), 4.08−4.18 (m, 2H) 3.65 (s, 3H), 2.36−2.39 (m, 1H), 2.27−2.28

(m, 1H), 1.97−2.15 (m, 2H), 1.66−1.91 (m, 3H), 1.55−1.57 (m, 1H);

¹³C NMR (125 MHz, 100 °C DMSO-d₆) δ 172.0, 169.8, 144.4, 141.3,

(3S,8S,Z)-Methyl 3-(N-Fmoc-amino)-2-oxo-1,2,3,6,7,8-hexa-

hydroazocine-8-carboxylate (11a).

134.3, 128.0, 127.5, 125.5, 123.8, 121.7, 120.6, 120.4, 120.3, 79.6, 66.4,

55.4, 54.3, 52.1, 47.5, 30.0, 26.1, 25.9, 25.6; HRMS (ESI-TOF) m/z

[M + Na]⁺calcd for C₂₆H₂₈N₂O₅Na 471.1890, found 471.1898.

(3S,10S,Z)-Methyl 3-(N-Fmoc-amino)-2-oxo-1,2,3,4,5,6,9,10-

octahydroazecine-10-carboxylate (11g).

Lactam 10a (155 mg, 0.27 mmol) was treated with TFA (2 mL) in DCM

(5 mL) overnight. The volatiles were removed under vacuum, and the

residue was puriﬁed by chromatography on silica gel (40−50% EtOAc in

hexane) to give macrocycle 11a (97 mg, 0.23 mmol, 85%) as a white

solid: R_f= 0.2 (1:1 EtOAc/hexanes, visualized by UV); mp 183−185 °C,

[α]²_D⁴+29.5 (c 1, CHCl₃); FT-IR (neat) ν_max3377, 2955, 1728, 1696,

1663, 1528, 1432, 1255, 1050, 984, 721, 549 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.74−7.76 (d, 2H, J = 7.5 Hz), 7.59−7.61 (m, 2H), 7.37−7.41

(t, 2H, J = 7.4 Hz), 7.29−7.32 (m, 2H), 6.17−6.19 (d, 1H, J = 7.7 Hz),

6.06−6.08 (d, 1H, J = 7.3 Hz), 5.77−5.84 (m, 1H), 5.63−5.68 (m, 1H),

5.15−5.19 (t, 1H, J = 6.5 Hz), 4.44−4.49 (m, 1H), 4.33−4.41 (m, 2H),

4.21−4.24 (t, 1H, J = 7.23 Hz), 3.79 (s, 3H), 2.46−2.51 (m, 2H), 2.16−

2.21 (m, 1H), 1.56−1.65 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ

172.0, 171.8, 155.9, 144.0, 143.9, 141.4, 132.7, 129.2, 127.8, 127.2, 125.3,

125.2, 120.0, 67.3, 55.9, 53.2, 52.2, 47.2, 33.0, 25.5; HRMS (ESI-TOF)

m/z [M + Na]⁺calcd for C₂₄H₂₄N₂O₅Na 443.1577, found 443.1581.

Lactam 10g (40 mg, 0.07 mmol) was treated as described for the

synthesis of 11a above with TFA (0.5 mL) in DCM overnight.

Chromatography (40−50% EtOAc in hexane) gave lactam 11g (24 mg,

0.05 mmol, 80%) as a white solid: R_f= 0.2 (1:1 EtOAc/hexanes,

visualized by UV); mp 210−215 °C; [α]²_D²+2.4 (c 0.16, CHCl₃); FT-IR

(neat) ν_max3296, 2926, 1726, 1685, 1643, 1527, 1438, 1247, 1105, 1031,

755, 736 cm⁻¹; ¹H NMR (500 MHz, 100 °C, DMSO-d₆) δ 7.92 (br, s,

1H), 7.84−7.86 (d, 2H, J = 7.6 Hz), 7.67−7.69 (m, 2H), 7.39−7.42 (t,

2H, J = 7.4 Hz), 7.30−7.33 (t, 2H, J = 7. 5), 6.74 (br s, 1H), 5.48−5.53

(m, 1H), 5.34−5.41 (m, 1H), 4.32−4.33 (m, 2H), 4.21−4.24 (t, 1H, J =

6.9), 4.06−4.09 (m, 1H), 3.90 (br s, 1H), 3.65 (s, 3H), 2.75−2.82 (m,

1H), 2.42−2.43 (m, 1H), 2.12−2.20 (m, 1H), 1.83−1.89 (m, 2H),

1.74−1.78 (m, 2H), 1.44−1.48 (m, 1H); ¹³C NMR (125 MHz, 100 °C,

DMSO-d₆) δ 171.3, 170.4, 154.5, 143.4, 140.3, 134.4, 127.0, 126.5,

124.6, 124.2, 119.4, 65.4, 53.2, 51.7, 51.2, 46.5, 35.8, 29.4, 24.7, 23.7,

M

DOI: 10.1021/acs.joc.5b00237

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

21.7, 16.5; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₂₆H₂₈N₂O₅Na

471.1890, found 471.1903.

(3R,4R,5S,8S)-Methyl 3-(N-Fmoc-amino)-4-iodo-2-oxohexa-

hydro-5H-pyrrolizine-8-carboxylate (3).

In the dark, a solution of macrocycle 10d (300 mg, 0.50 mmol) in THF

(10 mL) was treated with iodine (508 mg, 2 mmol), heated to 80 °C for

8 h, and cooled to room temperature, and the volatiles were removed

under reduced pressure to a residue that was chromatographed on silica

gel (40−50% EtOAc in hexane) to give quinolizidinone 4 (151 mg, 0.26

mmol, 53%) as a white solid: R_f= 0.45 (3:2 EtOAc/hexanes); mp 98−

101 °C; [α]²_D⁰+16.2 (c 1, CHCl₃); FT-IR (neat) ν_max2947, 1717, 1655,

1508, 1446, 1324, 1226, 738, 538 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ

7.75−7.76 (d, 2H, J = 7.1 Hz), 7.57−7.58 (d, 2H, J = 7.3 Hz), 7.38−7.40

(t, 2H, J = 7.4 Hz), 7.30−7.32 (t, 2H, J = 7.3 Hz), 5.75 (br s, 1H), 4.69−

4.70 (m, 1H), 4.31−4.42 (m, 2H), 4.17−4.20 (m, 2H), 3.73 (s, 3H),

3.65−3.68 (m, 1H), 3.44−3.45 (m, 1H), 3.06−3.08 (m, 1H), 2.45−2.51

(m, 1H), 2.24−2.25 (m, 1H), 2.06−2.09 (m, 1H), 1.94−1.98 (m, 1H),

1.83−1.89 (m, 1H), 1.59−1.60 (m, 2H) ¹³C NMR (175 MHz, CDCl₃) δ

169.6, 168.6, 156.2, 143.9, 143.8, 141.4, 141.4, 127.8, 127.2, 125.3, 120.1,

67.2, 62.9, 60.2, 52.6, 52.4,. 47.2, 37.7, 30.1, 24.8, 22.9, 20.3; HRMS

(ESI-TOF) m/z [M + Na]⁺calcd for C₂₆H₂₇IN₂O₅Na 597.0856, found

597.0861.

In the dark, a solution of macrocycle 11a (100 mg, 0.24 mmol) in

acetonitrile (4 mL) was treated with iodine (243 mg, 0.96 mmol) followed

by (diacetoxyiodo)benzene (116 mg, 0.36 mmol). The resulting mixture

was heated to 80 °C for 30 min and cooled to room temperature, and

the volatiles were evaporated under reduced pressure. The residue was

chromatographed on silica gel (40−50% EtOAc in hexane) to give

pyrrolizidinone 3 (81 mg, 0.15 mmol, 62%) as a light-sensitive white

solid: R_f= 0.45 (3:2 EtOAc/hexanes, visualized by UV); mp 94−96 °C;

[α]²_D⁰−70.8 (c 1, CHCl₃); FT-IR (neat) ν_max3374,1754, 1739, 1692,

1522, 1444, 1380, 1254, 1220, 1166, 1076, 1049, 818, 755, 741, 532 cm⁻¹;

¹H NMR (700 MHz, C₆D₆) δ 7.57−7.58 (d, 2H, J = 7.7 Hz), 7.43−7.44

(m, 2H), 7.17−7.24 (m, 4H), 4.92−4.93 (d, 1H, J = 7.6 Hz), 4.49−4.51 (t,

1H, J = 7.4), 4.40−4.43 (t, 1H, J = 7.6 Hz), 4.34−4.35 (d, 2H, J = 6.5 Hz),

3.96−3.98 (t, 1H, J = 6.5 Hz), 3.90−3.92 (t, 1H, J = 6.6 Hz), 3.26−3.29

(m, 1H), 3.22 (s, 3H), 1.70−1.78 (m, 1H), 1.43−1.48 (m, 1H), 1.32−1.34

(m, 1H), 0.80−0.83 (m, 1H); ¹³C NMR (175 MHz, C₆D₆) δ 172.0, 171.0,

156.2, 144.5, 144.4, 141.8, 127.4, 127.4, 125.5, 120.2, 67.0, 63.9, 62.6, 57.6,

51.8, 47.5, 33.5, 30.3, 30.0, 22.5; HRMS (ESI-TOF) m/z [M + Na]⁺calcd

for C₂₄H₂₃IN₂O₅Na 569.0543, found 569.0559.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra for all new compounds and X-ray data

for compounds 10d, 11a, 11e, 3, and 5 (PDF and CIF). This

material is available free of charge via the Internet at http://pubs.

acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: william.lubell@umontreal.ca.

■

Imidate 5.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by the Natural Sciences and

Engineering Research Council of Canada (NSERC), the

Canadian Institutes of Health Research (CIHR; Grants TGC-

114046 and CIP-79848), the Global Alliance to Prevent

Prematurity and Stillbirth, an initiative of Seattle Children’s,

the Bill & Melinda Gates Foundation, the March of Dimes, and

the Canadian Foundation for Innovation. We thank Dr. A.

In the dark, a solution of macrocycle 11e (50 mg, 0.11 mmol) in

acetonitrile (4 mL) was treated with NaHCO₃(27 mg, 0.33 mmol)

followed by iodine (83.7 mg, 0.33 mmol) in three portions, stirred for

1 h at rt, and treated with 1 M Na₂S₂O₃until the purple solution became

clear. The mixture was extracted quickly with ethyl acetate (3 × 10 mL).

The organic extractions were washed with brine, dried, and

concentrated under reduced pressure to a residue that was chromato-

graphed on silica gel (20−30% EtOAc in hexane). Evaporation of the

collected fractions gave imidate 5 (33 mg, 0.06 mmol, 51%) as a white

solid: R_f= 0.45 (4.5:6.5 EtOAc/hexanes, visualized by UV); mp 152−

154 °C; [α]²_D⁰+48.4 (c 1, CHCl₃); FT-IR (neat) ν_max3410, 2923, 1738,

1715, 1657, 1490, 1449, 1352, 1277, 1208, 1162, 1020, 958, 903, 739,

541 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 7.76−7.77 (d, 2H, J = 7.4 Hz),

7.60−7.63 (m, 2H), 7.39−7.41 (m, 2H), 7.31−7.33 (m, 2H), 6.17−6.18

(d, 1H, J = 5.9 Hz), 4.89−4.93 (m, 1H), 4.67−4.69 (m, 1H), 4.38−4.39

(d, 2H, J = 7 Hz), 4.26−4.29 (m, 1H), 4.21−4.23 (t, 1H, J = 6.9), 3.95−

3.97 (m, 1H), 3.85 (s, 3H), 2.69−2.73 (m, 1H), 2.12−2.17 (m, 2H),

2.03−2.10 (m, 1H), 1.94−1.98 (m, 2H); ¹³C NMR (175 MHz, CDCl₃)

δ 172.0, 164.8, 155.7, 144.1, 143.9, 141.4, 141.4, 127.8, 127.2, 125.3,

125.2, 120.1, 120.1, 67.1, 55.3, 52.7, 51.3, 47.3, 36.7, 33.2, 30.3, 30.1,

14.1; HRMS (ESI-TOF) m/z [M + Na]⁺calcd for C₂₅H₂₅IN₂O₅Na

583.0700, found 583.0705.

Furtos, K. Venne, and M-C. Tang from the Regional Laboratory

̈

for Mass Spectrometry, Sylvie Bilodeau, Antoine Hamel, and

Cedric Malveau from the Regional Laboratory for NMR

Spectroscopy, and Francine Belanger-Gariepy from the Regional

́ ́

Laboratory for X-ray Analysis, at the Universite de Montreal, for

their assistance in compound analyses. Shastri Indo-Canadian

Institute is thanked for a Quebec Tuition Fee Exemption grant to

N.D.P.A.

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O

DOI: 10.1021/acs.joc.5b00237

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Insight into Transannular Cyclization Reactions to Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams

DOI: 10.1021/acs.joc.5b00237

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Full text of DOI:10.1021/acs.joc.5b00237

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